Screening For Solid Forms By Ultrasound Crystallization And Cocrystallization Using Ultrasound

Abstract

The present disclosure relates to crystallizing a chemical substance(s) using ultrasound. Methods are provided for screening a chemical substance according to its solid forms by using ultrasound to generate new or unusual solid forms. Methods are also provided for crystallizing a chemical substance by novel techniques that include sonication. The present disclosure also relates to cocrystallization using ultrasound. Methods are provided for preparing cocrystals of an active agent and a guest by sonicating and crystallizing. Methods are also provided for screening a sample according to solid state phases (such as cocrystals and salts) and include generating a cocrystal from the sample using ultrasound.

Description

FIELD OF THE INVENTION

The present disclosure relates to crystallizing a chemical substance using ultrasound. Methods are provided for screening a chemical substance according to its solid forms by using ultrasound to generate new or unusual solid forms. Methods are also provided for crystallizing a chemical substance by novel techniques that include sonication. The present disclosure also relates to cocrystallization using ultrasound. Methods are provided for preparing cocrystals of an active agent and a guest by sonicating and crystallizing. Methods are also provided for screening a sample according to solid state phases (such as cocrystals and salts) and include generating a cocrystal from the sample using ultrasound.

BACKGROUND OF THE INVENTION

Chemical substances (compounds, elements, and mixtures) have properties which tend to be unpredictable and variable. Certain chemical substances may have utility for numerous different applications, including vital biological applications, yet a slight change may reduce or eliminate the utility or beneficial purpose. Similarly, certain chemical processes may have better or worse performance based upon minor differences.

An active agent may be provided in a variety of solid state phases. For example, it may be provided as a crystal of the pure compound. Alternatively, the active agent may be provided as a salt. Alternatively, the active agent may be provided as a cocrystal with another compound.

Cocrystals are crystals that contain two or more non-identical components (for example, two non-identical molecules). The properties of cocrystals may be the same or different than the properties of the individual components or mixtures of crystals of the individual components. Examples of cocrystals may be found in the Cambridge Structural Database. Examples of cocrystals may also be found at Etter et al., “The use of cocrystallization as a method of studying hydrogen bond preferences of 2-aminopyridine” J. Chem. Soc., Chem. Commun. 589-591 (1990); Etter, et al., “Graph-set analysis of hydrogen-bond patterns in organic crystals” Acta Crystallogr., Sect. B, Struct. Sci. B46 256-262 (1990); Etter, et al., “Hydrogen bond directed cocrystallization and molecular recognition properties of diarylureas” J. Am. Chem. Soc 112 8415-8426 (1990); which are incorporated herein by reference in their entireties. The following articles are also incorporated herein by reference in their entireties: Görbotz, et al., “On the inclusion of solvent molecules in the crystal structures of organic compounds” Acta Cryst. B56 625-534 (2000); and Kumar, et al., “Molecular Complexes of Some Mono- and Dicarboxylic Acids with trans-1,4,-Dithiane-1,4-dioxide” American Chemical Society, Crystal Growth & Design, Vol. 2, No. 4 (2002). Additional information and details regarding cocrystallization may be found in U.S. application Ser. No. 10/763,987, “Novel Cocrystallization,” filed Jan. 21, 2004, which is incorporated by reference herein.

A salt is a compound formed when the hydrogen of an acid is replaced by a metal or its equivalent (e.g., an NH₄⁺ radical). Hawley's Condensed Chemical Dictionary, p. 977 (14^th Ed. 2001). In a salt one or more ionic bonds are formed. In a cocrystal, two or more compounds retain their own chemical identities, and no new ionic or covalent bonds are formed, although hydrogen bonds or other interactions may hold different compounds to each other.

The identification of a desirable solid state phase for an active agent is important in the pharmaceutical field, as well as in other fields including nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials.

In particular, the pharmaceutical industry spends a great deal of time, effort and expense on the identification of particular compounds, mixtures and formulations that will have beneficial effect. Research is done as to whether such compounds, mixtures and formulations will be safe and effective. Slight differences in chemical composition or structure may yield significant differences in biological activity. Thus, researchers frequently test many different compounds, mixtures and formulations for biological activity and other effects as well as testing different processes and conditions for the preparation of such chemical compounds and mixtures.

The process of thorough analysis of different chemical compounds, mixtures, formulations, processes, or structures is commonly referred to as screening. Screening is partially a function of time and effort, with the quality or results of screening being related to the number of samples prepared and/or analyzed as well as the quality of preparation and/or analysis underlying those samples. To that end, it is frequently an objective with screening processes to increase the number of samples and decrease the amount of each sample used for analysis. Screening plays a vital role in the pharmaceutical field, as the most advantageous compound, mixture or formulation is frequently found through successful screening processes.

In some screening processes, variations are introduced in order to see the result(s), if any, of such variations, or to confirm that variations do not lead to substantially different results. Generally, at least two samples of a screened chemical substance (in other words, a compound, element, or mixture that is the subject of the screening process) are subjected to differing parameters, and one or more properties of the samples are determined to see whether the differing parameters caused different results.

Processes have been used for screening chemical compounds according to their solid form. When a compound has different solid forms, the different forms are frequently referred to as polymorphs of that compound. A polymorphic compound as used herein means a compound having more than one solid form. For example, a polymorphic compound may have different forms of its crystalline structure, or it may exist as different hydrates or solvates.

The solid form of a chemical substance may have an impact on biological activity. The same chemical compound may exhibit different properties depending upon whether it is in an amorphous, crystalline or semisolid state. A semisolid as used herein indicates materials like waxes, gels, creams, and ointments. Furthermore, a chemical compound may exist in different solid forms within the different states, and those different solid forms may also exhibit different properties. For example, there may be several different crystalline solid forms of a substance, the different crystalline solid forms having different properties. As another example, a substance may have different amorphous forms, the amorphous forms having different properties. As a result, different solid forms, including different crystalline forms, of a chemical compound may have greater or lesser efficacy for a particular application. The identification of an optimal solid form, or other possible solid forms, is important in the pharmaceutical field, as well as in other fields including nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials.

It is desirable in the pharmaceutical field as well as other fields to find the solid form of a chemical substance that exhibits desired physical and chemical properties. One form may be more stable or have other properties that make it preferable over other forms. One form of a chemical composition may have better bioavailabilty, solubility, or absorption characteristics or in other ways be more suitable for delivery of therapeutic doses than other forms. It is frequently desirable within a screening process to generate, or at least search for, all or most of the possible solid forms of a compound. Past attempts to generate a variety of solid forms included flash evaporations, cooling under different conditions and/or the addition of seeds of solid material. However, some materials strongly resist the generation of some of their possible solid forms.

It is desirable in many fields to find a solid state phase of an active agent that exhibits desired physical and chemical properties. One solid state phase may be more stable or have other properties that make it preferable over other solid state phases. One solid state phase may have better bioavailabilty, solubility, or absorption characteristics or in other ways be more suitable for delivery of therapeutic doses than other forms. It is frequently desirable within a screening process to generate, or at least search for, all or most of the possible solid state phases of a compound.

One or more solid forms may be generated by crystallization of a sample. One or more solid state phases may be generated by cocrystallization of a chemical substance with different guest molecule(s).

Among the phenomena in crystallization are nucleation and growth. Crystal nucleation is the formation of an ordered solid phase from liquids, supersaturated solutions, saturated vapors, or amorphous phases. Growth is the enlargement of crystals caused by deposition of molecules on an existing surface.

Nucleation may be induced by the presence of “seed” crystals. Some solid particle is present to provide a catalytic effect and reduce the energy barrier to formation of a new phase. Crystals may originate on a minute trace of a foreign substance (either impurities or container walls) acting as a nucleation site. Nucleation may also be promoted by external or nonchemical means, such as stirring the crystallization environment, or by applying ultrasound to the crystallization environment.

As mentioned above, ultrasound has been applied to promote nucleation. For example, U.S. Pat. No. 6,630,185 discusses a process for the crystallization of a solid phase from a liquid, characterized in that the liquid during crystallization is subjected to ultrasound in the absence of transient cavitation. According to this patent, it has been known since 1927 that exposing supercooled melts or supersaturated solutions of various substances to ultrasound has an influence on the nucleation and/or the growth of crystals. The effect is referred to as sonocrystallisation. A particular aspect of sonocrystallisation is sononucleation. It deals with the initiation of crystal formation, has been studied extensively with sugar and is applied since the late 1950's. Sonocrystallisation of supercooled water, supercooled metal melts and supersaturated solutions of various inorganic materials are said to have received a lot of attention.

U.S. Patent Application Publication No. 20030051659 A1 discusses a process for crystallizing small particles with a narrow particle size distribution. The crystals are obtained by introducing ultrasound into a solution or suspension of the substance to be crystallized while simultaneously adjusting a specific stirring power. U.S. Patent Application Publication No. 20030166726 A1 discusses a method for reducing the particle size of amino acid crystals using ultrasound.

U.S. Patent Application Publication No. 20020054892 A1 discusses a method of inducing solidification in a fluid composition comprising a cosmetic active, a crystalline organic structurant and a carrier. The method comprises exposing the fluid composition to ultrasound or converting the composition to a soft solid.

U.S. Pat. No. 5,830,418 discusses a method of using ultrasound to promote crystallization of solid substances contained in a flowable material. A flowable material, such as a supercooled melt or supersaturated solution, is dispensed onto a take-up member such as a belt or drum. Either prior to, or after being dispensed onto the take-up member, the material is exposed to ultrasound to promote the crystallization of solid substances in the material.

None of the foregoing references discloses the use of ultrasound as a variable parameter in a screening method to identify the various solid forms of a chemical substance.

There is a continued need to improve screening methods that identify all or a high percentage of possible forms of a chemical substance. There is also a need for improved methods of selectively generating the desired form of a chemical substance.

There is a continued need to improve screening methods that identify all or a high percentage of possible solid state phases of a chemical substance. There is also a need for improved methods of selectively generating solid state phases, including cocrystals, of a chemical substance.

SUMMARY OF THE INVENTION

As one aspect, a method is provided for screening a chemical substance for possible solid forms. The method comprises the steps of providing a chemical substance in a plurality of samples, sonicating at least one of the samples, and solidifying the chemical substance from the samples. The samples will usually be provided as a solution, suspension, melt, or other mixture of the chemical substance in one or more solvents. The screening method may comprise providing a first sample of the chemical substance in a first solvent, and a second sample of the chemical substance in a second solvent. The method may also comprise determining whether one or more solid forms of the chemical substance were generated.

As another aspect, a method is provided for crystallizing a chemical substance. This method is beneficial for searching for and/or generating new or unusual solid forms of a chemical substance. The method comprises forming an emulsion comprising two or more substantially immiscible solvents and the chemical substance by applying ultrasound to a mixture of said solvents and the chemical substance. The chemical substance is in solution in one or both of the solvents. The method also comprises crystallizing the chemical substance from the emulsion.

As yet another aspect, a method of crystallizing a chemical substance is provided. The method comprising the steps of providing a sample of the chemical substance in a solvent, sonicating the solution or suspension at a predetermined supersaturation level, and crystallizing the chemical substance from the sample.

As another aspect, a method is provided for generating the most stable form of a chemical substance. The method comprises the steps of providing a sample of the chemical substance in a solvent, sonicating the sample at a predetermined supersaturation level, and crystallizing the chemical substance from the sample, and the crystallized chemical substance is the most stable solid form of the chemical substance relative to known solid forms of the chemical substance.

As a further aspect, a method is provided for generating a solid form of a chemical substance from a metastable solution (a solution in which the chemical substance remains in solution indefinitely or for relatively long periods). The method comprises forming a metastable solution of the chemical substance in a solvent, sonicating the metastable solution, and crystallizing the chemical substance from the solution.

As yet another aspect, a method is provided for obtaining a substantially pure solid form of a chemical substance. A substantially pure solid form of a chemical substance is a solid that is exclusively or almost exclusively of one solid form or has little or no other solid forms present. The method comprises the steps of providing a sample of the chemical substance in a solvent, sonicating the sample at a predetermined supersaturation level, and crystallizing the chemical substance from the sample, wherein a substantially pure solid form of the chemical substance is crystallized.

As another aspect, a method is provided for preparing a solvate of a chemical substance. The method comprises the steps of providing a sample comprising the chemical substance and a solvent, sonicating the sample, and generating a solid from the sample, wherein the solid comprises a solvate of the chemical substance and the solvent.

In the present methods, the solidifying step and the sonicating step may at least partially overlap. In some embodiments, the solidifying step and the sonicating step may overlap completely or almost completely. For example, where the solidifying step comprises evaporating a solvent from the samples, the method can comprise sonicating at least one of the samples until the solvent is substantially completely evaporated. Alternatively, the solidifying step can comprise at least partially evaporating the solvent from at least one of the samples before sonicating the sample.

In the present methods, a solvent can be evaporated (to a greater or lesser extent) from at least one of the samples before, during, or after the sonicating step. The present methods may comprise the step of cooling at least one of the samples before, during or after the sonicating step. The present methods may comprise the step of crash-cooling at least one of the samples before, during or after the sonicating step. The present methods may comprise a mixture of those actions, for example, the samples may be cooled followed by sonication and evaporation of the solvent.

The sample(s) can be sonicated by sonicating at least once or more than once. In some embodiments, the samples will be sonicated by ultrasound pulses. For example, one or more samples can be sonicated by at least one ultrasound pulse, or by at least 5 ultrasound pulses, or by any number of periodic ultrasound pulses. In some embodiments, the samples will be sonicated for a period of time. For example, one or more samples may be sonicated for about 5 to about 40 seconds, for at least about 5 minutes, or for another suitable time period.

In the present methods, one or more samples may be sonicated at least once during the solidification step. In some embodiments, sonication will be substantially continuous during the solidification step; in other embodiments, sonication will be periodic during the solidification step.

The present methods may also be employed to generate solid solvates and solid hydrates of the chemical substance.

In the present methods, a predetermined supersaturation level of the chemical substance in a solvent may be selected at which to begin sonication. For example, the predetermined supersaturation level may be selected to generate a relatively stable form of the chemical substance, or the most stable form of the chemical substance, as determined by comparison of the known solid forms of the chemical substance. The predetermined supersaturation level can be selected to generate a solvate of the chemical substance.

The present methods may comprise adding an antisolvent to a solution, suspension, emulsion, slurry or other composition of matter.

The present methods increase the likelihood of generating all or a high percentage of possible solid forms of a chemical substance.

As another aspect of the present invention, a method is provided for screening for possible cocrystals comprising an active agent. The method comprises the steps of providing a plurality of samples that contain the active agent. Each sample also contains at least one guest. It is contemplated that the samples may contain the same guest or a different guest. In a screening method, the samples will usually contain several different guests being used to evaluate different cocrystals (different solid state phases). The samples are sonicated, and the active agent and the guest are crystallized from the samples. The method comprises determining whether a cocrystal was generated in one or more of the samples. The method can also comprise analyzing the crystallized samples to determine one or more properties.

As another aspect, a method is provided for preparing a cocrystal comprising an active agent and a guest. The method comprises providing a sample of an active agent and a guest. The sample is sonicated, and a cocrystal of the active agent and the guest is crystallized from the sample.

As yet another aspect, a method is provided for screening for possible solid state phases, including salts, of an ionizable active agent and a counterion and optionally a guest. The method comprises providing an ionizable active agent and a counterion in a plurality of samples. An ionizable agent is an agent that can be ionized or has already been ionized; an ionizable agent is one that can be used to forming an ionic bond with a counterion. The samples are sonicated, and the ionizable active agent and the counterion form a salt and crystallize from the samples. The method further comprises determining whether a salt was generated in one or more of the samples.

As yet another aspect, a method is provided for screening for possible salts comprising an ionizable active agent. The method comprises providing a plurality of samples comprising an ionizable active agent and one or more counterions. The samples are sonicated, and one or more crystallized salt compounds are formed from the samples. The crystallized salt compounds comprise the ionizable active agent and the counterions. The plurality of samples may contain the same or different counterions. For example, at least one sample may contain a different counterion than at least one other sample. As another example, the plurality of samples can comprise a plurality of sets, where the sets differ in having different counterions, and the samples within each set have the same counterion.

The present techniques may be utilized in methods for screening an ionizable active agent according to its possible solid state phases, including cocrystals and/or salts. Such methods can comprise providing an ionizable active agent and one or more counterions in a plurality of samples, sonicating the sample(s), and forming a crystallized salt compound comprising the active agent and counterion. Suitable counterions include but are not limited to the cations or anions set forth in the present disclosure. Using the present techniques provides a greater likelihood of generating possible salts of the ionizable active agent. Moreover, a salt developed by such a method may be employed in connection with the methods described herein which relate to cocrystals comprising a salt and a guest.

As yet another aspect, a method is provided for cocrystallizing two or more components, such as an active agent and a guest. The method comprises determining a concentration for two or more components in a sample effective for cocrystallization of the components. A sample is prepared which comprise the components, in an effective volume and an effective concentration. The sample is sonicated and a cocrystal is generated from the sample. The cocrystal comprises the components.

The present methods may be used to form at least one new solid state phase of an active agent, including new solid state phases of active pharmaceutical ingredients. This can provide substantial benefits to the pharmaceutical industry and the public at large.

In the foregoing methods, the sonicating step and the crystallizing step will usually overlap at least partially. The samples may become supersaturated with respect to at least one of the active agent and the guest before, during or after the sonicating step. In the present methods, each of the samples may comprise more than one solvent, more than one active agent, and/or more than one guest.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an x-ray powder diffraction (XRPD) pattern of sulfathiazole solidified from an acetonitrile solution which was sonicated.

FIG. 2 is an XRPD pattern of sulfathiazole solidified from an acetonitrile solution which was not sonicated.

FIG. 3 is an XRPD pattern of sulfathiazole solidified from an acetone solution which was sonicated.

FIG. 4 is an XRPD pattern of sulfathiazole solidified from an acetone solution which was not sonicated.

FIG. 5 is an XRPD pattern of carbamazepine solidified from a DMSO solution which was sonicated.

FIG. 6 is an XRPD pattern of sulfathiazole solidified from a methylethylketone solution which was sonicated.

FIG. 7 is an XRPD pattern of sulfathiazole solidified from an ethanol/p-cymene emulsion.

FIGS. 8(a) and (b) illustrate a crystal structure of an active agent and a cocrystal structure containing the same active agent with a guest.

FIGS. 9 (a) and (b) are drawings of two-dimensional and three-dimensional models of a cocrystal of fluoxetine HCl and benzoic acid (1:1).

FIG. 10 shows examples of general classes of guests.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Ultrasound generally refers to sound vibrations beyond the limit of audible frequencies. Ultrasound is often used to refer to sound vibrations having a frequency of about 20 kHz or more. In many applications where ultrasound is used, the frequencies are in the range of 20 kHz to 5 MHz. However, the definition of ultrasound as having a frequency greater than 20 kHz is related to the average perception limit of the human ear rather than to industrial applications. The benefits of the present methods may be obtained with frequencies below 20 kHz. In the context of the present specification, ultrasound refers to sound vibrations having a frequency in the range of from about 10 kHz to about 10 MHz. However, for certain applications, ultrasound having frequencies in narrower ranges (such as, for example, from about 20 kHz to about 5 MHz or from about 40 kHz to about 2.5 MHz) may be desired.

The terms sonicate and sonication are frequently used to refer to the application of ultrasound. A sample (for example, a solution or suspension) may be sonicated in a variety of ways, and may be sonicated continuously or by one or more pulses. For example, a sample may be sonicated by a series of ultrasound pulses, each pulse having a duration of from about 0.1 second to about 10 seconds. As another example, the sample may be sonicated at least once for at least about 5 minutes. In the present methods, where a method requires sonication or sonicating, it requires at least one pulse of ultrasonic energy which is generally on the order of seconds (for example, applying ultrasonic energy for 1 second or less, 5 seconds, 10 seconds or more). When a solution, suspension, solvent or other composition is sonicated “while” or “during” some other step or time period, it means at least one pulse is applied—it does not necessarily mean there is sonication over the entire step or period, although in some circumstances, it can be desirable to sonicate periodically or continuously throughout substantially an entire step or over substantially all of a time period, or for some portion of the step or period. For example, in some of the present techniques, it is stated that a solution is sonicated while a solvent is evaporated. Sonication in this situation may be a single pulse (for example, 5 seconds) to a solution, as well as multiple pulses or continuous sonication of a solution over substantially the entire time period of evaporation, or any application of ultrasound in between.

Ultrasound can be applied to a chemical substance or a sample by conventional techniques such as by immersing a receptacle containing the chemical substance or the sample in an ultrasonic bath, or by placing the tip of an ultrasonic probe directly into the sample. Sonication may be performed using commercially available equipment. For example, a quarter-inch diameter (6 mm) ultrasonic probe operating at 20 kHz and a power input of 130 watts has been found convenient, but there will be many other commercially available devices which are suitable. Lower power ultrasound apparatus may also be suitable for crystallization. Suitable ultrasound devices are advertised by Cole-Palmer Instrument Co., of Vernon Hills, Ill., or Misonix Corporation, of Farmingdale, N.Y. For larger scale operations, a sonoreactor is advertised by AEA Technologies of the United Kingdom. Techniques and equipment include the use of ultrasonic probes or transducers, which techniques will be familiar to those skilled in the art.

Where the samples are provided in a well plate, a well-plate sonicator may be used to sonicate the samples. Sonication of the sample may be performed using commercially available equipment. For example, a quarter-inch diameter (6 mm) ultrasonic probe operating at 20 kHz and a power input of 130 watts has been found convenient, but there will be many other commercially available devices which are suitable. As another example, a probe sonicator may be used for 2-5 seconds at 40 mW of power using a ⅛-inch probe. Lower power ultrasound apparatus may also be suitable for crystallization. The amount of time and power of the sonication are variable. In the example described below, sonication times of about 10 to 15 seconds applied every 5 minutes or so were used with a Misonix well-plate sonicator at medium power.

The application of ultrasound to a sample containing a chemical substance to be crystallized can reduce the Metastable Zone Width for the sample (for example, a solution containing the chemical substance and solvent). For example, the sample may have a metastable zone, and the metastable zone has a width of at least about 1° C., alternatively at least about 2° C., alternatively at least about 5° C., alternatively at least about 10° C. The application of ultrasound to the sample may narrow the metastable zone, for example from a width of greater than about 10° C. to a width of at most about 5° C., or by reducing it by at least about 1° C. A reduction of the Metastable Zone Width offers a way to limit the level of supersaturation at which nucleation occurs. For a chemical substance that has two unsolvated polymorphic forms, where one is stable and one is metastable at a given temperature, the polymorph of higher free energy (that is, lower stability) has a higher solubility in any solvent compared to the polymorph of lower energy. If there is sufficient reduction of the Metastable Zone Width by application of ultrasound, such that the system becomes supersaturated with respect to the most stable form while being undersaturated with respect to the other form, then polymorphic selection favoring the most stable form will occur. This “zone of action” may be used in order to increase the chances to generate the most stable form of a chemical substance. In practice, as ultrasound does not typically reduce the Metastable Zone Width to zero, cases may occur where two polymorphs of similar of energy can be formed. Ultrasound can therefore be used as a tool to increase the probability of generating the most stable form, when working under low levels of supersaturation, or selectively crystallizing the more stable of two solid forms.

Sometimes the most stable solid form is more difficult to generate than a less stable form. For example, with the compound WAY, the yellow form is frequently the first and most common form generated in screening method using small-scale crystallization and a variety of solvent mixtures. This may be explained by a faster nucleation and/or growth rate of the less stable form, compared to the more stable form.

The application of ultrasound to a chemical substance to be crystallized from a solution can induce nucleation of supersaturated solutions in cases where the substance otherwise remains indefinitely or for relatively long periods in solution (in other words, in metastable solution). In this respect, the application of ultrasound is of considerable interest to find new solid forms difficult to find due to difficult conditions of crystallization. For example, the present techniques are beneficial for crystallization and finding new solid forms from viscous solutions, or from systems having a large Metastable Zone Width.

Sonication generally increases the rate of nucleation in samples that are sufficiently supersaturated relative to the desired multi-component phase (the active agent(s) and the guest(s)). For example, sonication may increase the rate of cocrystallization by at least about 25%, alternatively at least about 100%, alternatively at least about 200%. Sonication generally reduces the activation barrier to nucleation and increases the number of successfully nucleated samples. The precise nature of the physical perturbations that cause nucleation when a sample is sonicated are not known with certainty. While the inventor does not intend to be bound by theory, it is presently theorized that entropic contributions may be more significant in multi-component samples because the independent components must be organized not only on a molecular level via aggregation through hydrogen bonding, but also in terms of mass transport. The growth of a cocrystal requires a consistent addition of a 1:1 mixture (or other fixed ratio) of the components to the cocrystal structure. Accordingly, local concentration gradients within the sample are undesirable. Sonication has a homogenizing effect and may assist in generating a more homogeneous distribution of the components in the sample. Thus, sonication is especially well-suited for methods of screening cocrystals where multiple compounds are to be brought together in a crystal. Sonication is also well-suited for methods of screening salts where an ionizable active agent and a counterion are to be brought together in a crystal.

Ultrasound may be particularly beneficial where multi-component crystal growth is nucleation-limited. A system is nucleation-limited where crystals are generally not observed if nucleation does not occur during evaporation, and an amorphous solid results instead. In a nucleation-limited system, if nucleation occurs, then subsequent growth occurs efficiently and substantially completely. For example, a combination of fluoxetine HCl and benzoic acid in a 1:1 molar ratio is nucleation-limited in solutions of acetonitrile. This is a difficult system to nucleate and a minimum desired supersaturation level has been identified for cocrystallization. The minimum desired supersaturation level for fluoxetine HCl and benzoic acid in a 1:1 ratio in acetonitrite is about 35 mg/ml. Using the technique disclosed herein, minimum desired supersaturation levels for other systems can also be found.

It has also been discovered that, even with ultrasound, it is desirable to maintain certain levels of supersaturation in the sample. In experiments using fluoxetine hydrochloride and benzoic acid in samples that included acetonitrile as a solvent, it was observed that sonication had a positive effect on cocrystallization. When concentrations of above 200 mg/ml of the mixture of active agent and guest in acetonitrile were used, sonication consistently nucleated the cocrystal. Between 35 and 100 mg/ml, nucleation could be caused by sonication, but nucleation was not observed spontaneously in unsonicated samples with concentrations below 100 mg/ml. Sonication provides a clear advantage in this case with respect to intermediate concentrations.

Experiments at a concentration of about 200 mg/ml nucleated with sonication using either a probe or a well-plate sonicator. About 50% of wells nucleated and about 98% of the solids were cocrystals. In a control experiment without sonication, only about 15% of the wells nucleated, and the solid was benzoic acid rather than a cocrystal of fluoxetine HCl and benzoic acid.

The application of ultrasound to the solution or suspension may narrow the metastable zone, for example, reducing it to less than 1° C. or from a width of greater than about 10° C. to a width of at most about 5° C. It appears that sonication reduces the metastable zone width, causing nucleation at lower supersaturation levels compared to slow evaporation (SE) results.

Sonication can increase the rate of nucleation in systems where nucleation is slow. Among the advantages of sonication are that nucleation can occur faster, more completely, and can be initiated at lower concentrations. In addition, the rapid nature of the growth is more likely to produce a consistent form (the first form that nucleates) because of the massive secondary nucleation that occurs during sonication—one seed becomes many very quickly due to sonication. Ultrasound can therefore be used as a tool to increase the probability of generating a cocrystal, to generate cocrystals more rapidly, and/or to generate cocrystals at relatively low levels of supersaturation.

Ultrasound may also be useful as a tool to increase the probability of generating a crystallized salt, to generate salts more rapidly, and/or to generate crystallized salts at relatively low levels of supersaturation.

The present methods are useful for the generation of new solid forms as well as for screening a chemical substance according to its solid forms. The chemical substance may be a compound, element, or mixture. Chemical substances include organic and inorganic substances. Examples of chemical substances for use in the present techniques include, but are not limited to, pharmaceuticals, dietary supplements, alternative medicines, nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials. Preferably, the chemical substance is a pharmaceutical agent. Pharmaceutical agents suitable for use in the present technique include known pharmaceutical agents as well as those which may be developed. A pharmaceutical agent can be a large molecule (in other words, a molecule having a molecular weight of greater than about 1000 g/mol), such as oligonucleotides, polynucleotides, oligonucleotide conjugates, polynucleotide conjugates, proteins, peptides, peptidomimetics, or polysaccharides. A pharmaceutical agent can be a small molecule (in other words, a molecule having a molecular weight of about 1000 g/mol or less), such as hormones, steroids, nucleotides, nucleosides, or aminoacids. Examples of suitable small molecule pharmaceuticals include, but are not limited to, cardiovascular pharmaceuticals; anti-infective components; psychotherapeutic components; gastrointestinal products; respiratory therapies; cholesterol reducers; cancer and cancer-related therapies; blood modifiers; antiarthritic components; AIDS and AIDS-related pharmaceuticals; diabetes and diabetes-related therapies; biologicals; hormones; analgesics; dermatological products; anesthetics; migraine therapies; sedatives and hypnotics; imaging components; and diagnostic and contrast components.

The chemical substances can have any utility, including utility as a pharmaceutical agent or other active agent. The present methods increase the likelihood of determining whether a chemical substance is polymorphic. A polymorphic chemical substance is a compound, element, or mixture having more than one solid form. The form of a compound, element, or mixture refers to the arrangement of molecules in the solid. The term solid form herein includes semisolids. Semisolids are materials like waxes, suspensions, gels, creams, and ointments. The forms which may be sought or generated may include amorphous forms, mixtures of amorphous forms, eutectic mixtures, mixed crystal forms, solid solutions, co-crystals, and other forms.

A chemical compound, element, or mixture may be amorphous, meaning that it is not characterized by a long-range order of the molecules. Alternatively (or even to a limited extent within a mostly amorphous form), a compound, element, or mixture may be arranged in a crystalline state, where the molecules exist in fixed conformations and are arranged in a regular way. The same compound, element, or mixture may exhibit different properties depending upon which solid form that compound, element or mixture is in.

Examples of compounds having more than one solid form include 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile and 4-methyl-2-nitroacetanilide, each of which has different colors in connection with different forms. Carbon, novobiocin, and furosemide are also examples of substances having more than one solid form.

The present disclosure provides techniques for preparing cocrystals and for screening a chemical substance according to its possible solid state phases, in which one or more active agents are cocrystallized with one or more guests. It has been found that ultrasound may be used to facilitate cocrystallization and screening.

Cocrystals are crystals that contain two or more non-identical molecules (two or more components) such as an active agent and a guest. FIGS. 8(a) and (b) illustrate a crystal structure of an active agent (a one-component crystal) and a cocrystal structure containing the same active agent with a guest (a two-component crystal), respectively.

Generating a variety of solid forms is an object of screening. A sufficient number of diverse processes and parameters should be employed to maximize the likelihood that a high percentage of possible solid forms of a chemical substance is generated. Samples should be generated under various thermodynamic and kinetic conditions. In the present methods, sonication is another parameter that is varied as part of the screening process.

A compound is a substance composed of atoms or ions in chemical combination. A compound usually is composed of two or more elements, though as used in accordance with the present methods, a compound may be composed of one element.

A mixture is a heterogeneous association of compounds or elements. The components of a mixture may or may not be uniformly dispersed.

The present methods include providing samples comprising the chemical substance(s). In some embodiments, the samples may contain the chemical substance(s) alone, for example, in a melt or a physical mixture. More commonly, the sample will also contain a solvent(s) in which the active agent(s) and the guest(s) are dissolved, dispersed or otherwise disposed. The active agent(s) and the guest(s) may be completely or partially soluble in the solvent(s) or one or more of them may be substantially insoluble in the solvents. Accordingly, the sample may be in a solution, suspension, dispersion, mixture, slurry or emulsion, or other physical state. The sample's physical state going into the present methods is not critical to the broader applicability of the present methods, though in some embodiments, use of particular physical states for samples can be beneficial, as described in more detail herein. For example, the present methods may have additional benefits when the samples are metastable solutions, viscous solutions, emulsions or slurries.

In the present methods, the chemical substance is solidified from the sample using a suitable solidification technique. As used herein, solidification includes any suitable technique for preparing a solid from the sample including but not limited to crystallization.

The solidification technique(s) employed will depend in part on the sample(s). The samples may be provided as solutions, suspensions, melts, slurries, emulsions, or any other composition of matter which includes the chemical substance.

Suitable crystallization (solidification) techniques include cooling, heating, evaporation, addition of an antisolvent, reactive crystallization, and using supercritical fluids as solvents. A fluid is an antisolvent with respect to a given solution of a chemical substance when the chemical substance is less soluble in that fluid than in the solvent used to form the solution; preferably, an antisolvent is a fluid in which the chemical substance is essentially insoluble or has a low solubility. Reactive crystallization refers to processes where means a chemical substance is formed from reactants and crystallized substantially simultaneously, for example, where the reaction is a driving force toward crystallization. A supercritical fluid is a fluid above its critical temperature and critical pressure which combines properties of gases and liquids. Examples of compounds employed as supercritical fluids include xenon, ethane and carbon dioxide.

Alternatively, the mechanism by which crystallization is accomplished may include gel diffusion methods, thin-layer deposition methods, or other suitable methods. Other thermodynamic and kinetic conditions may be employed to solidify the compound or mixture. Slow cooling of a saturated solution is a typical thermodynamic condition. An addition of a solution of the compound or mixture to an excess of cold anti-solvent is a typical kinetic condition.

Additionally, melt crystallization techniques may be used to generate a solid form. Through such techniques, the use of a solvent can be avoided. In such techniques, formation of crystalline material is from a melt of the crystallizing species rather than a solution. Additionally, the crystallization process may be done through sublimation techniques.

In many embodiments, the samples will comprise the chemical substance in a solvent. Any suitable solvent can be used. Suitable solvents include acetone, acetonitrile, chloroform, dioxane, ethanol, ethyl acetate, heptane, butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, isopropyl acetate, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, propanol, butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, methyl-tert-butyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide. It is also contemplated that the samples may be provided as the chemical substance in two or more solvents, either as a homogeneous solution or as an emulsion.

In the solidifying step, the chemical substance is generally separated from the solvent though solids such as hydrates or solvates may be formed which include some solvent molecules. For example, the solvent may be evaporated either slowly (for example, evaporating to dryness over a time period of four days, alternatively two days or more) or quickly (for example, evaporating to dryness over a time period of 24 hours, alternatively under two days). By varying the rate of evaporation, one can introduce desired variability into a screening method. For example, in a screening method, a first portion of samples can be subjected to relatively slow evaporation, and a second portion of the samples can be subjected to relatively fast evaporation.

In the present methods, ultrasound may be applied at different stages of a screening process or a crystallization process (or other solidification process). For example, a solution which comprises a solute to be crystallized can be sonicated at some point during the screening process. One may sonicate such a solution before, during, or after the initiation of cooling of the solution from an undersaturated, saturated, or supersaturated state. As other examples, one may sonicate a solution before, during, or after the beginning of evaporation of solvent, or before, during, or after the addition of an immiscible antisolvent to the solution.

In the present methods, the solidifying step and the sonicating step can overlap. For example, where the samples are provided as a solution of the chemical substance in a solvent, the solidifying step may be performed by evaporating the solvent, and the sample may be sonicated during that evaporation. Furthermore, the sonication can be periodic during the evaporation. For example, the sample can be periodically sonicated for about 20 seconds, and the periods can be about 30 minutes (in other words, the sample is sonicated for about 20 seconds every 30 minutes). Furthermore, the sonication can be a single pulse. For example, the sonication could be carried out one time for 5 to 40 seconds or multiple times for a like period, or for other suitable period(s).

In the present methods, the samples can comprise a solution, suspension, or melt of the chemical substance. Such a solution, suspension, or melt will typically be prepared by heating above room temperature to achieve supersaturation. It may be desirable to begin cooling the samples (for example, to room temperature) before the sonicating step. Alternatively, the samples may be cooled and sonicated at the same time. Alternatively, the method can include crash-cooling the samples (rapidly lowering the temperature, for example, by immersing in an ice bath) before the sonicating step. Alternatively, the samples may be crash-cooled and sonicated at the same time.

The present methods can include the step of adding a second solvent to a solution containing the chemical substance. For example, the second solvent may be added to facilitate solidification.

The solidification step can be initiated by sonication, and/or it may be initiated by seed materials or other techniques. In the various embodiments of the present methods, solidification may start before, during, or after the application of ultrasound. Frequently solidification will start during sonication and continue after sonication ceases. In many cases, the solidification and sonication steps will overlap. For example, sonication may begin before solidification but continue even after solidification begins. As another example, solidification may begin before sonication. As yet another example, the chemical substance may be sonicated in a pulsing manner throughout the solidification process. Alternatively, sonication may be employed to initiate solidification and be discontinued when solidification (such as nucleation) begins.

As a broad example, solidification may be performed as follows: A solution containing a solvent and a chemical substance (such as a compound, element, or mixture) to be solidified is disposed in a receptacle, such as a vial, well-plate (such a 96 well plate) or capillary tube. The solution may be formed in the receptacle or formed outside the receptacle and then placed in it. The chemical substance can be present in a solution below, at or above its saturation point at a given temperature at the time it is placed in the receptacle. Through evaporation, the use of an antisolvent, temperature variation, and/or other suitable means, the solution reaches a point of supersaturation. The solution is sonicated, and further evaporation, the use of an antisolvent, temperature variation, and/or other suitable solidification technique may be employed. After a suitable amount of time, solidification progresses until a sufficient amount of solid or semisolid appears, and is ready for analysis to determine the solid form.

The most preferred solidification techniques foster crystallization of the chemical substance. Suitable crystallization techniques may be employed with and without ultrasound in the present methods. Indeed, in a screening method, it may be desirable that some samples are sonicated and other samples are unsonicated.

Crystallization may be performed as a seeded operation or an unseeded operation. In a seeded operation, a selected quantity of seed crystals is included in the system. The characteristics of the seed crystals typically influence the characteristics of the crystals generated from the system. Crystallization may be performed by heterogeneous or homogeneous mechanisms. However, it is noted that ultrasound may be applied as a way of omitting the presence of seed crystals.

In other embodiments of the present methods, solids are generated other than by crystallization. The sample may be provided as a melt that is then added to the receptacle or may be provided within the receptacle and melted therein and allowed to solidify in an amorphous form.

Another technique for crystallizing a chemical substance employs an emulsion. An emulsion is a mixture of two or more immiscible liquids where one liquid is in a discontinuous phase within the other liquid. Emulsions are frequently formed and/or stabilized by the use of agents called emulsifiers. However, sonication of an immiscible mixture of solvents also allows the generation of emulsions.

The present methods may also include the step of forming an emulsion comprising two or more substantially immiscible solvents and the chemical substance. The emulsion can be formed during the sonicating step, wherein an immiscible mixture of said solvents is sonicated to form the emulsion. Alternatively, the emulsion can be formed before the sonicating step. Where an emulsion is employed, the chemical substance can be substantially soluble in one of the immiscible solvents and substantially insoluble in another of the immiscible solvents. The chemical substance is in solution in one or both of the solvents.

Emulsions can be employed as part of a screening method and/or solidification method to generate additional solid forms of a chemical substance. Emulsions can allow interface between the two solvents over a high surface area. At such interfaces, nucleation and/or growth of some polymorphs may be favored, based on the influence of each solvent on the growth of each polymorph.

An emulsion may be prepared by combining a solution of a chemical substance in a first solvent with a second solvent, wherein the first solvent and the second solvent are substantially immiscible with each other. The combined solvents may then be sonicated while evaporating, cooling, adding antisolvent, or using other solidification techniques until a precipitate containing the chemical substance appears.

Another technique for crystallizing a chemical substance employs a slurry. A slurry is a dispersion of solid particles in a liquid phase. The liquid phase comprises one or more solvents in which the chemical substance is not completely soluble. The process of slurrying a metastable form of a chemical substance, aiming at finding a form of lower solubility in the solvent used, in other words, a form of lower energy (in the case of the transition between two unsolvated polymorphs) or a solvated form (in the case of a transition between an unsolvated form or solvated form from a different solvent to a solvated form), is foreseen to be accelerated by the use of ultrasound during the slurrying process.

The present methods may also include the step of forming a slurry comprising a solvent and the chemical substance. The slurry can be formed during the sonicating step, wherein a mixture of the chemical substance and the solvent are sonicated to form the slurry. Alternatively, the slurry can be formed before the sonicating step.

It is preferable in a screening method that the generation of solid forms is carried out under a wide variety of conditions. For example, solids should be generated in the presence and absence of various solvents, as the solvent may play a role in the formation of certain forms, and with and without sonication. As another example it is also preferable to prepare solid forms under different conditions of temperature and pressure, as different solid forms may be favored by different conditions. In some embodiments of the screening method, at least one sample is unsonicated so that the effect of ultrasound on solid form for that chemical substance can be determined.

It is also contemplated that the present methods are advantageous for generating solid forms from viscous solutions. For example, the present methods may be used with samples that are solutions having a viscosity greater than about 5 cPoise, alternatively greater than 10 cPoise, alternatively greater than 20 cPoise, before the solution is sonicated.

It is also contemplated that the present methods are advantageous for generating solid forms from amorphous forms of the chemical substance. Samples can be formed or provided by preparing a solution from an amorphous solid comprising the chemical substance and a solvent. The solvent may be sonicated while the amorphous solid is added to the solvent.

It is contemplated that, in the context of a comprehensive screening method, the samples can be divided into subsamples or sets of subsamples. A multiplicity of subsamples and sets are useful so that more than one parameter may be varied and the cumulative effect of multiple varied parameters may be assessed. For example, a first sample (and/or a second sample) may be divided into subsamples, such as a first set of subsamples, a second set, a third set, and a fourth set. The first set and the second set can comprise a solution of the chemical substance in a first solvent, such as acetone, while the third set and the fourth set comprise a solution of the chemical substance in a second solvent, such as tetrahydrofuran. The first set and the third set can be sonicated, and the second set and the fourth set can be unsonicated. The benefit of this method is that the effects of ultrasonic crystallization on acetone and tetrahydrofuran solutions can be analyzed and compared.

Solid forms generated after the solidification and sonication steps may be identified by any suitable method, including but not limited to visual analysis (such as when different forms exhibit different colors), microscopic analysis including electron microscopy (such as when different forms happen to have different morphologies), thermal analysis (such as determining the melting points), conducting diffraction analysis (such as x-ray diffraction analysis, electron diffraction analysis, neutron diffraction analysis, as well as others), conducting Raman or infrared spectroscopic analysis, or conducting other spectroscopic analysis. Any appropriate analytical technique that is used to differentiate structural, energetic, or performance characteristics may be used in connection with the present methods.

In a preferred embodiment, the samples are placed in a well plate and then sonicated. The chemical substances solidify in the wells of the well plate. The solidified chemical substances are then analyzed in the well plate or a portion of the well plate. The solidified chemical substances can be analyzed by any one of the foregoing analysis techniques, preferably by x-ray diffraction (such as transmission x-ray diffraction or reflection x-ray diffraction) and/or by Raman spectroscopy. Well plates may be used which have a detachable portion, such as a detachable bottom portion. For example, well plates may be used which have polymer films, glass plates, or other substrates that are detachable from another portion of the well plates. Solidified chemical substances can be analyzed in the well plate or the detachable portion of the well plate. In particular, x-ray diffraction techniques such as transmission or reflection x-ray diffraction may be used to analyze the solidified chemical substances in well plates or the detachable portion of well plates (for example, the polymer film, glass plate, or other substrate).

A synchrotron may be used as the source of radiation for conducting diffraction analyses. A synchrotron is a type of particle accelerator, which emits high energy, focused radiation. Synchrotron radiation is the byproduct of circulating electrons or positrons at speeds very close to the speed of light. Synchrotron radiation contains all the wavelengths of the electromagnetic spectrum and comprises the most intense source of wavelengths available in the x-ray and ultraviolet region. Synchrotron radiation allows analysis of smaller quantities of sample that would be difficult to analyze using other sources of x-ray radiation.

One location for research using synchrotron radiation is the Stanford Synchrotron Radiation Laboratory (SSRL), which is funded by the Department of Energy as a national user facility. Another location is Argonne National Laboratory, which is available to outside users on a fee basis.

Synchrotron radiation may be used to study structural details of solid samples with a resolution not practically attainable using traditional x-ray instrumentation. This may enable differentiation between different polymorphic forms or compounds that is not attainable with other x-ray radiation sources.

The present methods can significantly assist in the identification of the solid form of a chemical substance that is most stable or has other properties that make it preferable over other forms. For example, the present methods can be used as part of a screening method and can improve the likelihood of identifying a form having biological activity such as better stability, bioavailability, solubility, or absorption characteristics. In some cases, an identified form may have better activity as an active agent.

After a chemical substance (including a solution, melt, emulsion, slurry, suspension, or mixture containing the chemical substance) is placed in a receptacle, the receptacle may be centrifuged. Centrifugation may be employed for a variety of reasons. First, use of a centrifugal evaporator may assist evaporation while concentrating solid or semisolid material at one end of a capillary space. This has advantages in connection with in-situ analysis, in that the generated form will be located at a consistent place in the receptacle. Also or alternatively, centrifuging may be used to provide additional environmental variation, which is desirable in a screening method.

The application of ultrasound to solutions containing multiple components to be crystallized can induce nucleation in cases where the components otherwise remain indefinitely or for relatively long periods in solution (in other words, in metastable solution). In this respect, the application of ultrasound is of considerable interest to find new cocrystals and salts which are otherwise difficult to find. For example, the present techniques are beneficial for cocrystallization from viscous solutions, or from systems having a large Metastable Zone Width.

The present techniques are applicable to cocrystallize two or more active agents. (It is contemplated that more than one active agent may be employed in a cocrystal.) An active agent is a molecule whose activity is desirable or the object of interest. For example, where the active agent is an active pharmaceutical ingredient, the pharmaceutical activity of the active agent is desired or the object of interest. Active agents include organic and inorganic substances. Examples of active agents for use in the present techniques include, but are not limited to, pharmaceuticals, dietary supplements, alternative medicines, nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials. Preferably, the active agent is an active pharmaceutical ingredient (API). Pharmaceutical agents suitable for use in the present technique include known pharmaceutical agents as well as those which may be developed. A pharmaceutical agent can be a large molecule (in other words, a molecule having a molecular weight of greater than about 1000 g/mol), such as oligonucleotides, polynucleotides, oligonucleotide conjugates, polynucleotide conjugates, proteins, peptides, peptidomimetics, or polysaccharides. A pharmaceutical agent can be a small molecule (in other words, a molecule having a molecular weight of about 1000 g/mol or less), such as hormones, steroids, nucleotides, nucleosides, aminoacids, acetaminophen, nonsteroidal anti-inflammatory drugs, and others. Examples of suitable small molecule pharmaceuticals include, but are not limited to, cardiovascular pharmaceuticals; anti-infective components; psychotherapeutic components; gastrointestinal products; respiratory therapies; cholesterol reducers; cancer and cancer-related therapies; blood modifiers; antiarthritic components; AIDS and AIDS-related pharmaceuticals; diabetes and diabetes-related therapies; biologicals; hormones; analgesics; dermatological products; anesthetics; migraine therapies; sedatives and hypnotics; imaging components; and diagnostic and contrast components.

The active agent may be provided as a salt. It is contemplated that one or more salts may be employed in a cocrystal, according to any of the present techniques. The salt may be prepared from an ionizable active agent or obtained from a commercial source. Hydrochloride salts of active pharmaceutical ingredients, especially of amine APIs, are especially preferred in the pharmaceutical industry.

In general, it is contemplated that the present techniques will have particularly good results as applied to amine HCl salts as well as other ammonium salts as described in more detail herein. In ammonium acid salts, the active agent has at least one amine moiety which is relatively basic (at least one relatively basic nitrogen), and a salt is formed with an acid that reacts with the amine moiety. Cocrystals may be then formed between the ammonium salts and guests which act as hydrogen-bond donors to the salts. Cocrystals may be formed of chloride salts of APIs, for example buspirone hydrochloride and fluoxetine hydrochloride.

While the inventors do not wish to be bound to theory, it is believed that excellent cocrystals may be formed using hydrochloride salts and similar salts which are strong hydrogen bond acceptors yet contain relatively undercoordinated ions. “Undercoordinated” in this case refers to ions, for example a chloride ion, that are able to form a number of strong hydrogen bonds. An undercoordinated counterion may have hydrogen bonds within a crystal of that salt, but it could form additional hydrogen bonds in a cocrystal and/or form relatively stronger hydrogen bonds in a cocrystal with a guest. An ion is “undercoordinated” when the system is limited in the number of hydrogen bond donors that are available and bonded to the ion. In these cases, the extra hydrogen bond acceptor sites are typically filled by weakly interacting donors such as C—H groups Chloride ions are strong hydrogen bond acceptors in a crystal structure. In a crystal structure such as fluoxetine hydrochloride, the chloride ion coordinates to the two strong hydrogen bond donors available in the system, and the chloride ion also has three weaker CH—Cl interactions resulting in a pseudo-octahedral coordination environment. There is an opportunity for bonding with these coordination sites, by displacing the weak CH donors that the chloride has recruited to fill its coordination sphere with somewhat stronger hydrogen bond donors from a guest such as benzoic acid, succinic acid, fumaric acid, or another carboxylic acid.

It is useful in forming cocrystals to recognize that relatively weak interactions may be replaced by stronger interactions, even though those stronger interactions may be relatively weak themselves, compared to other interactions. For example, an undercoordinated chloride may have one strong hydrogen bond donor and several weak hydrogen bond donors or two strong hydrogen bond donors and several weak hydrogen bond donors. In a cocrystal, weaker interactions may be replaced by stronger interactions, although those stronger interactions may still be weaker than the strong interactions (charge-assisted hydrogen bonds) present in fluoxetine HCl crystals. The strongest interactions involving chloride ions in crystal structures of organic salts are the charge assisted hydrogen bonds that invariably form between the protonated nitrogen base and the chloride ion. The strongest interactions between neutral molecular groups and the chloride ion involve acids and the chloride ion. Carboxylic acids, for instance, have strong interactions with chloride ions. It can be seen that a combination of carboxylic acids and hydrochloride salts of nitrogen containing bases are especially well suited to cocrystal formation (as demonstrated by the examples included). Furthermore, it can be anticipated that different combinations of these elements could lead to other cocrystals. For example, the active molecule of interest may contain either the neutral carboxylic acid moiety or the protonated nitrogen. The potential exists to cocrystallize an API having a neutral carboxylic acid moiety with a guest that is a hydrochloride salt of a nitrogen-containing organic base.

It is further contemplated that the nature of the protonated nitrogen base will affect the potential for cocrystallization. Numerous strong hydrogen bond donor groups will compete with the carboxylic acid guest for the open acceptor sites on the chloride ion. In order to favor cocrystal formation, the nitrogen base is preferably a tertiary amine because this presents a situation where only one strong charged hydrogen bond donor exists and thus will only occupy one site on the chloride acceptor. Additionally, systems that have only this one tertiary amine and no other strong donors present an especially favorable system for potential cocrystallization. Protonated secondary amines with two N—H donor groups are also favored, although protonated primary amines may also be used. Special consideration must be taken for systems with additional strong hydrogen bond donor and acceptor sites in order to determine the potential for cocrystallization and the optimal guest molecule type for cocrystallization. The potential for cocrystallization involving a carboxylic acid and a hydrochloride salt may be reduced as the number of available strong donors in the system is increased. Additional guidance as to evaluating undercoordination particularly in its discussion of nonbonded motifs may be found in: Scott L. Childs, “Nonbonded Interactions In Molecular Crystal Structures”, Emory Univ., USA, available from UMI, Order No. DA3009424 (288 pp.), Dissertation Abstract Int. Ref. B2001, 62(3), 1394 (which is incorporated by reference herein). In some circumstances, the undercoordination can be determined by measuring distances, comparing profiles in the Cambridge Structural Database, measuring the pKa of the donors and acceptors, or evaluating the ratio of strong hydrogen bond donors to available acceptors. Other crystal engineering theories may also be used.

By cocrystallizing an active agent with a guest, one can create new solid state phases which may have improved properties over existing solid state phases of that active agent. For example, new drug formulations comprising salt of active pharmaceutical ingredients may have superior properties over existing drug formulations. The active agent and guest will vary depending on the industry. For example, in the pharmaceutical field, the active agent or guest may be an API, and the other component of the salt must be a pharmaceutically acceptable compound. The present techniques are also applicable to active agents from other fields including nutraceuticals, agricultural chemicals, pigments, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials.

The present techniques may be employed to generate a wide variety of cocrystals of active agents and guests. For example, the present techniques may be used to generate cocrystals of a salt of an active agent, such as a salt of an active pharmaceutical ingredient, with a neutral guest. Alternatively, a cocrystal of a neutral or zwitterionic active agent (or a salt of an active agent) may be generated with a guest salt, which includes a positive ion and a negative ion of its own. Where the active agent is provided in a salt, it may be positively or negatively charged and have a negative or positive counterion. As an example, for fluoxetine HCl, the active agent fluoxetine is positively charged by virtue of accepting a proton from HCl to form a protonated amine, and chloride is present as a negative counterion. Furthermore, some of the present methods may be employed with a neutral or zwitterionic active agent to form a cocrystal with a neutral guest or ionic guest.

The present techniques provide an opportunity to create a stable solid state phase of a hydrochloride salt of an API (or other active agents) that was previously found to have properties that were unsuitable for development. Opportunities for continued development in such a situation have often relied on the fortuitous formation of a stable hydrate or solvate, but the present techniques present the ability to systematically examine alternative formulations of the hydrochloride salt by cocrystallizing the hydrochloride salt of the API with appropriate guest molecules.

Cocrystallization may be an attractive technique for salts of APIs that have been rejected due to problems relating to physical properties. Since cocrystals may have different physical properties than the individual components, APIs with unfavorable physical properties can be cocrystallized with suitable guest molecules and the physical properties of the resulting crystalline solids can be evaluated.

Cocrystals of fluoxetine HCl provide examples of the modification of a physical property (solubility) of an API salt. Cocrystals of fluoxetine HCl:benzoic acid are less soluble and have a lower dissolution rate than crystals of fluoxetine HCl, while cocrystals of fluoxetine HCl:succinic acid are more soluble and have a faster dissolution rate than crystals of fluoxetine HCl.

Other physical properties of APIs or their salts that may be modified by forming a cocrystal include: melting point, density, hygroscopicity, crystal morphology, loading volume, compressibility, and shelf life. Furthermore, other properties such as bioavailability, toxicity, taste, phy sical stability, chemical stability, production costs, and manufacturing method may be modified by the use of the present cocrystallization techniques.

An active agent can be screened for possible cocrystals where polymorphic forms, hydrates or solvates are especially problematic. A ne-utral compound that can only be isolated as amorphous material could be cocrystallized. Forming a cocrystal may improve the performance of a drug formulation of an active pharmaceutical ingredient by changing physical properties. Some APIs are problematic during wet granulation and compression stages. A bioequivalent cocrystal could rectify this problem.

An active agent can also be screened for possible salts. Forming a salt may improve the performance of a drug formulation by changing physical properties. A salt screen refers to a screening method in which one attempts to make one or more salts comprising an active agent under a variety of conditions and/or parameters, preferably including a variety of different counterions.

A cocrystal or salt can be used to isolate or purify an active agent during manufacturing. If it is desirable to identify the solid state phases of an active pharmaceutical ingredient, then cocrystallization and/or salt formation may be particularly desirable.

The present techniques provide new methods of developing and screening active pharmaceutical ingredients or other active agents. Non-toxic cocrystalline forms of neutral active pharmaceutical ingredients may be prepared, screened, tested, and commercialized. Furthermore, new types of HCl salt structures may be prepared. The properties of hydrochloride salts can be tuned and perfected. New, unique, stable, and marketable phases of hydrochloride salts may be prepared. One can choose whether to make the formulation more soluble or less soluble.

As another aspect, the present techniques may also be used to remove or reduce the water of hydration, and/or to prepare a cocrystal substantially free of water of hydration. Water and guest acids perform a similar role in the stabilization of the crystal structure. In fact, about 28% of the hydrochloride salts of API in the Cambridge Structure Database are hydrates, compared to about 8% of all other organic structures. This indicates an affinity for hydration. The present techniques both capitalize and rectify this affinity, in that an affinity for cocrystallization (as evidence by hydration) is likely indicated, and this affinity for cocrystallization may be employed for the formation of cocrystals with a suitable guest, such as an acid, for example a carboxylic acid. Indeed, in many cocrystals, an acid may have stronger interactions than water molecules and may displace the water of hydration during the formation of the cocrystal. Accordingly, the present techniques provide a method of preparing a cocrystal from a hydrate. A hydrate of a salt is provided, and the hydrate comprises water of hydration. A guest is selected to coordinate with the counterion. Preferably, the guest coordinates more strongly with the counterion than the water of hydration does. A solution, melt or physical mixture is prepared which comprises the hydrate and the guest. The solution or melt is subjected to a crystallization process, or the physical mixture is subjected to grinding, and a cocrystal comprising the salt of the active agent and the guest is formed, and the salt comprises the active agent and a counterion. Similarly, the present techniques provide a method of preparing a cocrystal from a solvate. A solvate of a salt is provided, and the solvate comprises solvent molecules coordinated with the salt. A guest is selected to coordinate with the counterion. Preferably, the guest coordinates more strongly with the counterion than the solvent does. A solution, melt or physical mixture is prepared comprising the solvate and the guest. The solution or melt is subjected to a crystallization process, or the physical mixture is subjected to grinding, and a cocrystal comprising the salt of the active agent and the guest is formed. The salt comprises the active agent and a counterion.

FIGS. 9(a) and (b) are drawings of two-dimensional and three-dimensional models of a cocrystal of fluoxetine HCl and benzoic acid (1:1). FIG. 9(a) shows a two-dimensional model in which the chloride ion interacts with the hydrogens of the amine group of fluoxetine and of the hydroxyl group of benzoic acid. Through these interactions, which may be characterized as hydrogen bonding, fluoxetine hydrochloride and benzoic acid form a supramolecular structure that may be the basis of a cocrystal. FIG. 9(b) shows a three-dimensional model of the supramolecular organization of fluoxetine hydrochloride and benzoic acid.

The present cocrystals may comprise salts other than chloride salts—the hydrochloride API salts that are listed above are only a sampling of the relevant compounds because the starting material need not be a known hydrochloride. Indeed, many relevant APIs are salts that are not HCl salts because the HCl salt was not believed to be an appropriate material and a different salt was commercialized instead. The present techniques may enable one to employ an HCl salt of an API that is marketed as another type of salt. Alternatively, it may be desirable to employ a salt other than an HCl salt, by replacing the HCl or by forming a salt comprising an active agent that acts as a base with an acid other than HCl. The following acids provide anionic counterions that would be used to replace chlorine. These are relatively strong acids, and include but are not limited to mineral acids, and the carboxylic acid guest is expected to form one or more hydrogen bonds with a hydrogen bond acceptor on the anionic counterion. The list is the conjugate acid that would react with a basic active agent to form a salt:

sulfuric acid

phosphoric acid

hydrobromic acid

nitric acid

pyrophosphoric acid

methanesulfonic acid

thiocyanic acid

naphthalene-2-sulfonic acid

1,5-naphthalenedisulfonic acid

cyclamic acid

p-toluenesulfonic acid

maleic acid

L-aspartic acid

2-hydroxy-ethanesulfonic acid

glycerophosphoric acid

ethanesulfonic acid

hydroiodic acid

The present techniques also extend beyond salts as starting materials and also include many weak bases that may have been marketed as neutral forms because the known salts did not have appropriate properties. These salts could be revisited and attempts could be made to cocrystallize the HCl salt. For example, a drug formulation marketed as a tartrate salt of an API could be reformulated by cocrystallizing the HCl salt of the active molecule with an appropriate guest molecule. Thus, cocrystallization could make a useful HCl cocrystal out of the API that is currently marketed as a tartrate, sulfate, or other salt formulation. For this reason the present disclosure includes APIs that are not HCl salts as starting materials.

Furthermore, the present techniques relate to salts other than chloride salts. It is contemplated that hydrobromide salts and sodium salts of APIs may especially benefit from the present techniques, since they form relatively strong nonbonded interactions. For example, the hydrobromide salts citalopram hydrobromide and galantamine hydrobromide are contemplated for cocrystallization with benzoic acid, succinic acid, and other guests compatible with hydrochloride salts.

The present techniques may be employed to form cocrystals of sodium salts of APIs such as, for example, naproxen sodium, tolmetin sodium, and warfarin sodium. When a sodium salt (or other salt of an API having a positive counterion) is employed, different guests are expected to be suitable for cocrystallization than when a hydrochloride salt (or other anionic salt) of an API is employed.

Anions and Cations

As one aspect, the active agent is provided as a salt. The salt of the active agent may be formed as part of sample preparation or separately. Alternatively or additionally, the guest is provided as a salt or a salt of the guest is formed. The salt may comprise the active agent and a counterion that is either a cation or an anion. Among the preferred cations (including cations as well as compounds that can form cations) are aluminum, ammonium, benzathine, calcium, diethanolamine, diethylamine, dimeglumine, disodium, lithium, lysine, magnesium, meglumine, potassium, sodium, and zinc. Among the preferred anions are acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate, DL-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, acefyllinate, aceturate, aminosalicylate, ascorbate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate.

When a metal cation is employed as a counterion of the active agent, the interaction between guest and cation is not a hydrogen bond but rather is an intermolecular interaction between an electron rich group such as a carbonyl and the metal cation. This interaction is often not as strong as a hydrogen bond, but is still a favorable interaction and thus can contribute to the stabilization of a cocrystal.

The HCl salt of an active pharmaceutical ingredient is especially preferred to create a new type of cocrystal. In this type of solid state phase, one can cocrystallize the HCl salt with a neutral guest molecule. By doing this one can create solid state phases with specific properties. For instance one can make a solid comprising an active pharmaceutical ingredient having greater or lesser intrinsic solubility and/or a faster or slower dissolution rate, depending on the guest compound that is chosen.

The present techniques may be utilized in methods for screening an ionizable active agent according to its possible salts or for preparing a salt comprising an ionizable active agent and a guest. Such methods can comprise providing a plurality of samples comprising the active agent and one or more counterions; sonicating the sample(s); and forming crystallized salt compounds comprising the active agent and counterions. The counterions may be any of the cations or anions set forth above or elsewhere in the present disclosure. Using the present techniques provides a greater likelihood of generating possible salts of the ionizable active agent. Moreover, a salt developed by such a method may be employed in connection with the methods described herein which relating to cocrystals comprising a salt and a guest.

Guests

The guest is present in order to form the cocrystal with the active agent. It is contemplated that one or more guests may be employed in a cocrystal, according to any of the present techniques. Accordingly, the guest is not required to have an activity of its own, although it may have some activity that does not overly derogate from the desired activity of the active agent. In some situations, the guest may have the same activity as or an activity complementary to that of the active agent. The guest may be another API. For example, some guests may facilitate the therapeutic effect of an active pharmaceutical ingredient. For pharmaceutical formulations, the guest may be any pharmaceutically acceptable molecule(s) that forms a cocrystal with the API or its salt. The RTECS database is a useful source for toxicology information, and the GRAS list contains about 2500 relevant compounds.

The guest may be neutral (such as benzoic acid and succinic acid in the examples below) or ionic (such as sodium benzoate or sodium succinate). Neutral guests are nonionic guests. Ionic guests are compounds or complexes having ionic bonds. FIG. 10 shows several general classes of guests (organic bases, organic salts, alcohols & aldehydes, amino acids, sugars, ionic inorganics, aliphatic esters & ketones, organic acids, and aromatic esters & ketones).

The guest may be an acid that forms hydrogen bonds with the chloride (or other anion). For example, suitable guests which are acids include (but not are not limited to):

ascorbic acid

glucoheptonic acid

sebacic acid

alginic acid

cyclamic acid

ethane-1,2-disulfonic acid

2-hydroxyethanesulfonic acid

2-oxo-glutaric acid

naphthalene-1,5-disulfonic acid

nicotinic acid

pyroglutamic acid

4-acetamidobenzoic acid

Table 8 sets forth a group of presently preferred guests. It is contemplated that the guests set forth in the Table may be arranged in subgroups based upon molecular structure and/or physiological effect. Furthermore, the foregoing list is intended to provide a written description of any sublist that omits one or more guests.

Table 9 sets forth another group of preferred guests. It is contemplated that the guests set forth in the Table may be arranged in subgroups based upon molecular structure and/or physiological effect. Furthermore, the foregoing list is intended to provide a written description of any sublist that omits one or more guests.

Table 10 sets forth the group comprising molecules believed at present to be suitable guests. It is contemplated that the guests set forth in the Table may be arranged in subgroups based upon molecular structure and/or physiological effect. Furthermore, the foregoing list is intended to provide a written description of any sublist that omits one or more guests.

Ionic guests are salts themselves, and may be formed from bases and acids prior to being used to form cocrystals. For example, the following bases and acids may be reacted to form ionic guests:

Bases

Ammonia

L-Arginine

Benethamine

Benzathine

Betaine

Calcium Hydroxide

Choline

Deanol

Diethanolamine

Diethylamine

2-(Diethylamino) ethanol

2-Aminoethanol

Ethylenediamine

N-Methylglucamine

Hydrabamine

1H-Imidazole

Lysine

Magnesium Hydroxide

Morpholine

4-(2-Hydroxyethyl)Morpholine

Piperazine

Potassium Hydroxide

Pyrrolidine

1-(2-Hydroxyethyl)Pyrrolidine

Sodium Hydroxide

Triethanolamine

Tromethamine

Zinc Hydroxide

Acids

(+)-L-Tartaric Acid

1,2, 2-Trimethyl-1,3-cyclopentanedicarboxylic Acid

10-Undecylenic Acid

1-Hydroxy-2-naphthoic Acid

(+)-Camphor-10-sulfonic Acid

2,5-Dihydroxybenzoic Acid

2-Furancarboxylic Acid

2-Mercaptobenzoic Acid

3-Cyclopentylpropionic Acid

3-Phenylpropionic Acid

4-Aminosalicylic Acid

4-Hydroxybenzoic Acid

Acetic Acid

Adipic Acid

alpha-Hydroxypropionic Acid

Benzenesulfanic Acid

Benzoic Acid

Carbonic Acid

Cholic Acid

Citric Acid

(−)-D-Tartaric Acid

(+)-D-Camphoric Acid

(+)-D-Malic Acid

(+)-L-Malic Acid

2,2-Dichloroacetic Acid

DL-10-Camphorsulfonic Acid

DL-Glutamic Acid

DL-Malic Acid

DL-Tartaric Acid

Dodecylsulfuric Acid

Ethanesulfonic Acid

Ethylenediaminetetraacetic Acid

Ethylsulfonic Acid

Fumaric Acid

Galactaric Acid

Gallic Acid

Gluconic Acid

Glutaric Acid

Glycolic Acid

Hippuric Acid

Hydriodic Acid

Hydrobromic Acid

Hydrochloric Acid

(−)-L-Apple Acid

(+)-L-Lactic Acid

(+)-L-Tartaric Acid

D,L-Lactic Acid

Lactobionic Acid

L-Aspartic Acid

Lauric Acid

L-Glutamic Acid

Maleic Acid

(−)-L-Malic Acid

Malonic Acid

D,L-Mandelic Acid

Methanesulfonic Acid

Naphthalene-2-sulfonic acid

n-Butyric Acid

n-Decanoic Acid

n-Hexanoic Acid

Nitric acid

n-Tetradecanoic Acid

Octanoic Acid

Oleic Acid

Orotic Acid

Orthoboric Acid

Oxalic Acid

4-Acetamidobenzoic Acid

Palmitic Acid

Pamoic Acid

Phosphoric Acid

Picric Acid

Pivalic Acid

Propionic Acid

p-Toluenesulfonic Acid

Pyrophosphoric Acid

Salicylic Acid

Stearic Acid

Succinic Acid

Sulfosalicylic Acid

Sulfuric Acid

Terephthalic Acid

Thiocyanic Acid

Valeric Acid

Valproic Acid

Typically, suitable guests will have complementary ability to noncovalently bond to the active agent or its salt, for example the ability to form hydrogen bonds with the active agent or its salt. Suitable guests for active agents having negative counterions include, but are not limited to, compounds having alcohol, ketone, ester, and/or carboxylic acid functionalities. Suitable guests may include organic acids, organic bases, organic salts, alcohols, aldehydes, amino acids, sugars, ionic inorganic compounds, aliphatic esters and ketones, and aromatic esters and ketones.

Among the presently preferred neutral guests are those which are not liquids at room temperature. Also among the presently preferred neutral guests are carboxylic acids having at least three carbon atoms, alternatively at least four carbon atoms, and which do not form solvates. For example, if the following acids were combined with active agents, the combination would more properly be considered a solvate than a cocrystal: acetic acid, propionic acid, and butyric acid. However, in certain embodiments of the present invention (for example, in certain cocrystals, cocrystallization methods, and screening methods), the use of solvents and solvates may still be desirable, and the use of solvents and solvates is not excluded from the scope of any cocrystal or method except where explicitly stated.

In the present methods, the active agent(s) and guest(s) to be cocrystallized are provided as one or more samples to be used within the present techniques. The samples may be provided by being formed, created or prepared as an initial step in the present methods, or they may be obtained ready-to-use from another source.

In some embodiments, the samples may contain the active agent(s) and the guest(s) alone, for example, in a melt or a physical mixture. Alternatively, the sample will also contain a solvent(s) in which the active agent(s) and the guest(s) are dissolved, dispersed or otherwise disposed. The active agent(s) and the guest(s) may be completely or partially soluble in the solvent(s) or one or more of them may be substantially insoluble in the solvents. Accordingly, the sample may be in a solution, dispersion, suspension, mixture, slurry or emulsion, or other physical state. The sample's physical state going into the present methods is not critical to the broader applicability of the present methods, though in some embodiments, use of particular physical states for samples can be beneficial, as described in more detail herein. For example, the present methods may have additional benefits when the samples are metastable solutions, viscous solutions, emulsions or slurries.

Cocrystallization

In the present methods, the active agent and the guest are cocrystallized from the sample using a suitable crystallization technique. As used herein, crystallization includes any suitable technique for preparing a crystal from the sample.

The crystallization technique(s) employed will depend in part on the sample(s). Suitable crystallization techniques include cooling, heating, evaporation, addition of an antisolvent, reactive crystallization, and using supercritical fluids as solvents. A fluid is an antisolvent with respect to a given solution of components to be cocrystallized when at least one component is less soluble in that fluid than in the solvent used to form the solution; preferably, an antisolvent is a fluid in which both components are essentially insoluble or have a low solubility. Reactive crystallization refers to processes where a chemical compound is formed from reactants and crystallized substantially simultaneously, for example, where the reaction is a driving force toward crystallization. A supercritical fluid is a fluid above its critical temperature and critical pressure which combines properties of gases and liquids. Examples of compounds employed as supercritical fluids include xenon, ethane and carbon dioxide.

Alternatively, the mechanism by which crystallization is accomplished may include gel diffusion methods, thin-layer deposition methods, or other suitable methods. Other thermodynamic and kinetic conditions may be employed for cocrystallization. Slow cooling of a saturated solution is a typical thermodynamic condition. An addition of a solution of the components to be cocrystallized to an excess of cold anti-solvent is a typical kinetic condition.

Additionally, melt crystallization techniques may be used to generate a cocrystal. Through such techniques, the use of a solvent can be avoided. In such techniques, formation of crystalline material is from a melt of the crystallizing components rather than a solution. Additionally, the crystallization process may be done through sublimation techniques.

In many embodiments, the samples will comprise a solvent. Any suitable solvent can be used. Suitable solvents include acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide. It is also contemplated that the samples may comprise the components to be cocrystallized in two or more solvents, either as a homogeneous solution, as an emulsion, or in another physical state.

The crystallization may be accomplished in a variety of ways, and preferably includes evaporation of the solvent(s). For example, the solvent may be evaporated either slowly (for example, evaporating to dryness over a time period of four days, alternatively two days or more) or quickly (for example, evaporating to dryness over a time period of 24 hours, alternatively under two days). By varying the rate of evaporation among separate samples, one can introduce desired variability into a screening method. For example, in a screening method, a first portion of samples can be subjected to relatively slow evaporation, and a second portion of the samples can be subjected to relatively fast evaporation.

In the present methods, ultrasound may be applied at different stages of a screening process or a crystallization process. For example, a solution which comprises the components to be cocrystallized can be sonicated at some point during the screening process. One may sonicate such a solution before, during, or after the initiation of cooling of the solution from an undersaturated, saturated, or supersaturated state. As other examples, one may sonicate a solution before, during, or after the beginning of evaporation of solvent, or before, during, or after the addition of an immiscible antisolvent to the solution.

In the present methods, the crystallizing step and the sonicating step can overlap. For example, where the samples are provided as a solution of the components to be cocrystallized in a solvent, the crystallizing step may be performed by evaporating the solvent, and the sample may be sonicated during that evaporation. Furthermore, the sonication can be periodic during the evaporation. For example, the sample can be periodically sonicated for about 20 seconds, and the periods can be about 30 minutes (in other words, the sample is sonicated for about 20 seconds every 30 minutes). Furthermore, the sonication can be a single pulse. For example, the sonication could be carried out one time for 5 to 40 seconds or multiple times for a liked period, or for other suitable period(s).

In the present methods, the samples can comprise a solution, suspension (such as a melt), or other mixture of the components to be cocrystallized. The sample will typically be prepared by heating above room temperature to achieve supersaturation of the components. It may be desirable to begin cooling the samples (for example, to room temperature) before the sonicating step. Alternatively, the samples may be cooled and sonicated at the same time. Alternatively, the method can include crash-cooling the samples (rapidly lowering the temperature, for example, by immersing in an ice bath) before the sonicating step. Alternatively, the samples may be crash-cooled and sonicated at the same time.

The present methods can include the step of adding a second solvent to a solution containing the components to be cocrystallized. For example, the second solvent may be added to facilitate crystallization.

The crystallization step can be initiated by sonication, and it may additionally be initiated by seed materials or other techniques. In the various embodiments of the present methods, crystallization may start before, during, or after the application of ultrasound. In many cases, the crystallization and sonication steps will overlap. For example, sonication may begin before crystallization but continue even after crystallization begins. As another example, crystallization may begin before sonication. As yet another example, the samples may be sonicated in a pulsing manner throughout the crystallization process. Alternatively, sonication may be employed to initiate crystallization and be discontinued when crystallization (such as nucleation) begins.

The sample containing two or more components to be cocrystallized is provided in a receptacle suitable for crystallization, such as a vial, well-plate or capillary tube. The sample may be formed in the receptacle or formed outside the receptacle and then placed in it. The components can initially be present in the sample below, at or above the point of saturation at a given temperature at the time of placement in the receptacle. Through evaporation, the use of an antisolvent, temperature variation, and/or other suitable means, the sample will reach a point where crystallization begins. After a suitable amount of time, when a solid or semisolid appears, the resulting sample (more particularly, the solid formed from the sample) is ready for analysis.

Crystallization may be performed as a seeded operation or an unseeded operation. In a seeded operation, a selected quantity of seed crystals is included in the system. The characteristics of the seed crystals typically influence the characteristics of the crystals generated from the system. Crystallization may be performed by heterogeneous or homogeneous mechanisms. However, it is noted that ultrasound may be applied as a way of omitting the presence of seed crystals.

Another technique for cocrystallizing chemical substances employs an emulsion. An emulsion is a mixture of two or more immiscible liquids where one liquid is in a discontinuous phase within the other liquid. Emulsions are frequently formed and/or stabilized by the use of agents called emulsifiers. However, sonication of an immiscible mixture of solvents also allows the generation of emulsions.

The present methods may also include the step of forming an emulsion comprising two or more substantially immiscible solvents and the components to be cocrystallized. The emulsion can be formed during the sonicating step, wherein an immiscible mixture of said solvents is sonicated to form the emulsion. Alternatively, the emulsion can be formed before the sonicating step.

Emulsions can be employed as part of a screening method and/or solidification method to generate additional solid state phases of an active agent. Emulsions can allow interface between the two solvents over a high surface area. At such interfaces, nucleation and/or growth of some solid state phases may be favored, based on the influence of each solvent on the growth of each solid state phase.

An emulsion may be prepared by combining a solution of an active agent and a guest in a first solvent with a second solvent, wherein the first solvent and the second solvent are substantially immiscible with each other. The combined solvents may then be sonicated while evaporating cooling, adding and antisolvent, or using other solidification techniques until a precipitate containing the active agent and the guest appears.

Another technique for cocrystallizing employs a slurry. A slurry is a dispersion of solid particles in a liquid phase. The liquid phase comprises one or more solvents in which at least one of the active agent and a guest is not completely soluble. The process of slurrying a metastable form of an active agent and/or guest, aiming at finding a cocrystal or a solvated form, is foreseen to be accelerated by the use of ultrasound during the slurrying process.

The present methods may also include the step of forming a slurry comprising a solvent and the active agent and the guest. The slurry can be formed during the sonicating step, wherein a mixture of the active agent and the guest and the solvent are sonicated to form the slurry. Alternatively, the slurry can be formed before the sonicating step.

Generating a variety of solid state phases is an important object of screening. A sufficient number of diverse processes and parameters should be employed to maximize the likelihood that a high percentage of possible solid state phases is generated. Samples should be generated under various thermodynamic and kinetic conditions.

It is preferable that the generation of solid state phases is carried out under a wide variety of conditions. For example, solids should be generated in the presence and absence of various solvents, as the solvent may play a role in the formation of certain forms, and with and without sonication. As another example it is also preferable to prepare solid forms under different conditions of temperature and pressure, as different solid forms may be favored by different conditions.

It is also contemplated that the present methods are advantageous for generating solid state phases from viscous solutions. For example, the present methods may be used with samples that are solutions having a viscosity greater than about 0.9 poise before the solution is sonicated.

It is also contemplated that the present methods are advantageous for generating solid state phases from amorphous forms of the active agent. Samples can be formed or provided by preparing a solution from a solvent and an amorphous solid comprising the active agent. The solvent may be sonicated while the amorphous solid is added to the solvent.

It is contemplated that, in the context of a comprehensive screening method, a plurality of samples can be divided into a large number of sets and subsets. A multiplicity of sets and subsets are useful so that more than one parameter may be varied and the cumulative effect of multiple varied parameters may be assessed. For example, a plurality of samples may be divided into a first set, a second set, a third set, and a fourth set. The first set and the second set can comprise a solution of the active agent in a first solvent or with a first guest, while the third set and the fourth set comprise a solution of the active agent in a second solvent or with a second guest. The first set and the third set can be sonicated, and the second set and the fourth set can be unsonicated. The benefit of this method is that the effects of ultrasonic crystallization with different solvents and/or different guests can be analyzed and compared.

Detection of Cocrystals and Crystals

Cocrystals (as well as other crystals) may be detected by x-ray diffraction analysis, Raman analysis, or other suitable techniques. The observation of physical properties of a solid (particularly its melting point) which differ from the physical properties of the starting materials and the polymorphs and/or solvates and/or hydrates of the starting materials, is an indicator that a cocrystal has been formed.

Cocrystals and other crystals generated after crystallization and sonication steps may be identified by any suitable method, including but not limited to visual analysis (such as when different forms exhibit different colors), microscopic analysis including electron microscopy (such as when different forms happen to have different morphologies), thermal analysis (such as determining the melting points), conducting diffraction analysis (such as x-ray diffraction analysis, electron diffraction analysis, neutron diffraction analysis, as well as others), conducting Raman or infrared spectroscopic analysis, or conducting other spectroscopic analysis. Any appropriate analytical technique that is used to differentiate structural, energetic, or performance characteristics may be used in connection with the present methods.

In a preferred embodiment, the samples are placed in a well plate and then sonicated. The chemical substances solidify in the wells of the well plate (for example, a 96-well plate or 384-well plate). The solidified chemical substances are then analyzed in the well plate by one of the foregoing analysis techniques, preferably by x-ray diffraction (such as transmission x-ray diffraction) and/or by Raman spectroscopy. A synchrotron may be used as the source of radiation for conducting diffraction analyses.

Synchrotron radiation may be used to study structural details of solid samples with a resolution not practically attainable using traditional x-ray instrumentation. This may enable differentiation between different solid state phases that is not attainable with other x-ray radiation sources.

The present methods can significantly assist in the identification of the possible cocrystals of a chemical substance(s). For example, the present methods can be used as part of a screening method and can improve the likelihood of identifying a solid state phase having properties such as better stability, bioavailability, solubility, or absorption characteristics. In some cases, an identified cocrystal of an active agent and a guest may have better biological activity than a crystal of the active agent.

After samples (including a solution, emulsion, slurry, or mixture containing the active agent and guest) are placed in a receptacle, the receptacle may be centrifuged. Centrifugation may be employed for a variety of reasons. First, use of a centrifugal evaporator may assist evaporation while concentrating solid or semisolid material at one end of a capillary space. This has advantages in connection with in-situ analysis, in that the generated form will be located at a consistent place in the receptacle. Also or alternatively, centrifuging may be used to provide additional environmental variation, which is desirable in a screening method.

EXAMPLE 1

In this Example, a new solid form of sulfathiazole was prepared from solution in acetonitrile using sonication. This form was not seen without sonication under the same conditions. Form II of sulfathiazole was generated without sonication.

A saturated solution of sulfathiazole in acetonitrile at 45° C. was prepared, filtered hot and split between two pre-heated 1-dram vials (about 1 ml each). The samples were left to slowly cool to room temperature. One sample was then nucleated by ultrasound treatment using 5 pulses of one second each at 20 kHz, amplitude control set at 40, using a Cole Palmer ultrasonic processor CP130 fitted with a 6 mm tip stainless steel probe, while the other sample was left undisturbed (unsonicated). Both samples were then left to evaporate slowly to dryness. XRPD patterns of the sonicated and unsonicated samples showed that the sonicated sample gave an unknown pattern (FIG. 1) whereas the unsonicated sample yielded the known Form II of sulfathiazole (FIG. 2). The sonicated sample is believed to be a novel solid form of sulfathiazole.

EXAMPLE 2

In this Example, an unusual solid form of an acetone solvate of sulfathiazole was prepared. Without sonication, this form was only seen in a mixture with the known form of an acetone solvate of sulfathiazole.

A saturated solution of sulfathiazole in acetone at 45° C. was prepared, filtered hot and split between two pre-heated 1-dram vials (about 1 ml each). The samples were left to slowly cool to room temperature. One sample was then nucleated by ultrasound treatment using 5 pulses of one second each at 20 kHz, amplitude control set at 40, using a Cole Palmer ultrasonic processor CP130 fitted with a 6 mm tip stainless steel probe, while the other sample was left undisturbed (unsonicated). Both samples were then left to evaporate slowly to dryness. XRPD patterns of the sonicated and unsonicated patterns showed that the sonicated sample gave an unknown pattern (FIG. 3) whereas the unsonicated sample yielded a mixture of this same form with the known acetone solvate of sulfathiazole (FIG. 4). The sonicated sample is believed to contain an unusual solid form which is novel in its purity.

EXAMPLE 3

In this Example, a new DMSO solvate of carbamazepine was prepared.

Three 100 μl samples of a saturated solution of carbamazepine in DMSO at 50° C. were placed in 3 pre-heated HPLC vials. The samples were allowed to cool to ambient temperature. One sample was nucleated by ultrasound treatment (5 one-second pulses, 20 kHz, amplitude control set at 40, using the Cole Palmer ultrasonic processor with a 3 mm tip stainless steel probe), while another was stirred using a stir bar and the other was left undisturbed (unsonicated). While the sonicated sample yielded a new DMSO solvate, the other samples remained as solutions indefinitely. The XRPD pattern of the new DMSO solvate is shown in FIG. 5.

EXAMPLE 4

In this Example, a new form of sulfathiazole was made from a sonicated supersaturated solution in methylethylketone.

A saturated solution of sulfathiazole in methylethylketone at 55° C. was split in 3 pre-heated vials (about 0.5-1 ml each). The samples were crash-cooled by placing them in an ice/water bath. One sample was then sonicated for five minutes (amplitude 20 kHz, amplitude control set at 40, using the Cole Palmer ultrasonic processor with a 6 mm probe), while another was stirred using a magnetic stir bar. The last sample was left undisturbed. The three samples were then placed in the refrigerator (5-6° C.). While the sonicated sample was found to have crystallized, the unsonicated samples remained indefinitely as solutions (still solutions after three weeks). The solids in the sonicated sample were filtered and an XRPD pattern taken (FIG. 6), indicative of an unknown form, and it was determined that this solid was unsolvated according to TGA and DSC scans.

EXAMPLE 5

In this Example, crystallization of the most stable form of 4-methyl-2-nitroacetanilide was performed on a small scale. The compound 4-methyl-2-nitroacetanilide is known to crystallize in three polymorphic forms, White, Amber, or Yellow. The compound is known as “WAY” due to the colors of its forms. The relative stability of the three forms has been studied and it was demonstrated that the white form was the most stable form, and the yellow form was more stable than the amber form. (See, for example, Yeadon, PhD thesis, Burnel University, West Yorkshire, UK (1985), and Xiaorong He, “Thermodynamic and kinetic control of the crystallization of polymorphs”, PhD thesis, Purdue University, West Lafayette, Ind. USA (2000)). The least stable amber form has rarely been seen. All three crystal structures have been solved and published. (See, for example, Moore et al., “Yellow and white forms”, J. Cryst. Spect. Res., 13, 279 (1983), and Moore et al., “Amber form”, J. Cryst. Spect. Res., 14, 283 (1984).

Sixty-four evaporative experiments in various solvents and combinations of solvents (32 sonicated samples and 32 unsonicated samples) were carried out on the compound WAY.

A weighed amount of the compound WAY was placed in a vial and a measured volume (V) of solvent added (solvent 1), so as to dissolve the solids. In some samples, an additional volume of a second solvent (solvent 2) was added to the solution. All solutions were filtered using a 0.2 μm nylon filter and split 4-ways into 4 1-dram vials. The vials were then covered individually with aluminum foil. The aluminum foil was pierced with one hole for slow evaporations (SE) and 5 holes for fast evaporations (FE). Half of the vials were then sonicated twice a day, every day, until complete evaporation of the solvents. The other half of the vials were left to evaporate undisturbed. Table 1 summarizes the solvent conditions used for these evaporations, each set of solvent conditions being used for four vials (two for samples to be sonicated while evaporating (SE and FE), two for control experiments without sonication (SE and FE)).

TABLE 1
Solutions used for crystallization of
4-methyl-2-nitroacetanilide
WAY (mg)	Solvent 1	V (S1)	Solvent 2	V (S2)
146.3	1,4-dioxane	3 ml	—	—
149.8	acetone	3 ml	—	—
155.2	tetrahydrofuran	3 ml	—	—
149.9	ethanol	10 ml	—	—
147.7	2-butanone	3 ml	—	—
155.6	dichoromethane	1 ml	—	—
146.2	chloroform	1 ml	—	—
155.0	trifluroethanol	1 ml	—	—
151.0	ethyl acetate	3 ml	—	—
148.9	dichloroethane	1 ml	—	—
149.1	pyridine	1 ml	—	—
156.5	methanol	5 ml	—	—
150.2	acetonitrile	2 ml	—	—
144.9	dichloromethane	2 ml	nitromethane	2 ml
155.5	dichloromethane	2 ml	heptane	2 ml
146.7	trifluoroethanol	2 ml	water	2 ml
154.3	acetone	3 ml	toluene	1 ml
146.4	acetone	3 ml	water	1 ml

The results are presented in Table 2, showing the occurrences of mixtures of the white and yellow solid forms and of the most stable solid form of the compound, the white form of WAY. All other solids were the faster growing, less stable yellow form. These results show that using ultrasound as part of a screening process can increase the likelihood of obtaining the possible solid forms of a chemical substance. These results also show that using ultrasound in a crystallization process can facilitate the generation of the most stable form of the chemical substance.

TABLE 2
	Sonicated	Sonicated	Unsonicated	Unsonicated
Evaporative	SE	FE	SE	FE
conditions
# of	16	16	16	16
samples
Solids	16	16	14	16
White +	5	3	1	1
yellow
mixture
Pure White	4	2	0	1
Form

EXAMPLE 6

In this Example, a micro-scale crystallization study was performed to yield the most stable form of 4-methyl-2-nitroacetanilide (WAY).

Solutions of WAY were prepared in various solvents by dissolution of a weighed amount of the solid compound in a measured volume of solvent (solvent 1). These solutions were then filtered using a 0.2 μm nylon filter. The weights and volumes used to prepare each solutions are summarized in Table 3.

TABLE 3
Summary Table Of Experimental Conditions For
The Preparation Of Solutions Of Way
WAY (mg)	Solvent	V (ml)
103.2	chloroform	5.16
107.7	1,4-dioxane	5.37
101.9	acetone	5.1
100.8	tetrahydrofuran	5.04
112.7	ethanol	11.3
105.7	2-butanone	5.27
108.6	acetonitrile	5.43
94.0	methanol	4.7

Each solution was then used directly or was diluted with a second solvent in a 3:1 ratio of the first solvent to the second solvent. Aliquots of 200 μl of the solutions were placed in wells of a flat bottom polypropylene 96-well plate and covered by a polypropylene mat. The mat was pierced to provide one hole per well. Two identical plates were prepared. The solvent(s) used in each of the wells are shown in Table 4. One plate was sonicated for 20 seconds every 30 minutes until evaporation to dryness of all or the majority of the samples in each well. Sonication was performed using a Misonix 3000 sonicator with microplate horn. The second plate was kept undisturbed (unsonicated) during the time of the evaporation.

TABLE 4

Solvent Conditions Used For Individual Wells

Of The 96-Well Plate Evaporation Experiment

1

2

3

4

5

6

7

8

9

10

11

12

A

CH

CH

CH:WA

CH:WA

CH:NM

CH:NM

CH:TO

CH:TO

CH:EA

CH:EA

CH:HE

CH:HE

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:

B

DX

DX

DX:WA

DX:WA

DX:NM

DX:NM

DX:TO

DX:TO

DX:EA

DX:EA

DX:HE

DX:HE

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:

C

AC

AC

AC:WA

AC:WA

AC:NM

AC:NM

AC:TO

AC:TO

AC:EA

AC:EA

AC:HE

AC:HE

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

D

TH

TH

TH:WA

TH:WA

TH:NM

TH:NM

TH:TO

TH:TO

TH:EA

TH:EA

TH:HE

TH:HE

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

E

EO

EO

EO:WA

EO:WA

EO:NM

EO:NM

EO:TO

EO:TO

EO:EA

EO:EA

EO:HE

EO:HE

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

F

MK

MK

MK:WA

MK:WA

MK:NM

MK:NM

MK:TO

MK:TO

MK:EA

MK:EA

MK:HE

MK:HE

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

G

AN

AN

AN:WA

AN:WA

AN:NM

AN:NM

AN:TO

AN:TO

AN:EA

AN:EA

AN:HE

AN:HE

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

H

MO

MO

MO:WA

MO:WA

MO:NM

MO:NM

MO:TO

MO:TO

MO:EA

MO:EA

MO:HE

MO:HE

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

3:1

In Table 4, the solvent mixtures are described as X:Y volume:volume ratio of solvents. In Table 4, the following abbreviations are used: AC=acetone; AN=acetonitrile; CH=chloroform; DX=1,4-dioxane; EO=ethanol; EA=ethyl acetate; HE=heptane; MK=2-butanone; MO=methanol, NI=nitromethane; TH=tetrahydrofuran; TO=toluene; WA=water.

TABLE 5

Summary Table Of Results Obtained For The Sonicated

Plate

1

2

3

4

5

6

7

8

9

10

11

12

A

Y

W

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

B

NC

NC

N

N

NC

NC

NC

NC

NC

NC

NC

NC

C

W

W

Y

Y

NC

W

W

W

Y

Y

W

W

D

W

W

W

W

Y

Y

W

W

W

W

W

Y

E

NC

NC

NC

NC

NC

Y

NC

Y

NC

NC

NC

NC

F

W

NC

W

NC

NC

W

W

Y

W

Y

W

W

G

Y

W

W

NC

NC

W

W

NC

W

NC

Y

Y

H

W

W

W

W

W

Y

W

W

NC

W

Y

Y

In Table 5, the following abbreviations are used:

Y = Yellow form;

W = White form;

N = Nucleated = mostly liquid with a small fraction of indeterminate solids;

NC = Not Crystallized).

Table 5 shows which solid form of WAY was generated in each of the wells of the 96-well plate that was sonicated.

TABLE 6

Summary Table Of Results Obtained For The Unsonicated

Plate

1

2

3

4

5

6

7

8

9

10

11

12

A

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

W

Y

B

NC

NC

N

N

NC

NC

NC

NC

NC

NC

NC

NC

C

Y

Y

Y

Y

Y

NC

Y

Y

Y

Y

Y

Y

D

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

E

NC

NC

NC

NC

NC

NC

Y

Y

NC

Y

NC

NC

F

Y

Y

Y

Y

NC

NC

NC

NC

Y

Y

Y

NC

G

Y

Y

Y

Y

NC

Y

Y

Y

Y

Y

Y

Y

H

Y

Y

Y

Y

Y

Y

Y

Y

Y

NC

Y

Y

In Table 6, the following abbreviations are used:

Y = Yellow form;

W = White form;

N = Nucleated = mostly liquid with a small fraction of indeterminate solids;

NC = Not Crystallized).

Table 6 shows which solid form of WAY was generated in each of the wells of the 96-well plate that was not sonicated.

This shows that a screening process in which samples are sonicated yielded more occurrences of the most stable (but less-frequently generated) white form.

EXAMPLE 7

In this Example, a micro-scale crystallization study of sulfamerazine was performed. The study showed that sonication facilitated the generation of a difficult-to-make more stable form.

Sulfamerazine is known to crystallize in two polymorphic forms, Form I and Form II, with Form I being the most commonly encountered form. Despite the elusive character of Form II, it has been demonstrated that Form II was the most stable form at room temperature. Zhang et al., J. Pharm. Sci., 91(4), 1089-1100 (2002).

Solutions of sulfamerazine at a concentration of 10 mg/ml were prepared in acetone and in tetrahydrofuran by dissolution of a weighed amount of sulfamerazine in a measured volume of solvent. The solutions were then filtered using a 0.2 μm nylon filter. Aliquots of 150 μl of solution (acetone or tetrahydrofuran) were added to 50 μl of a second solvent in the wells of a flat bottom polypropylene 96-well plate. The plate was covered by a polypropylene mat, and the mat was pierced with one hole per well. Two identical plates were prepared. One of the plates was sonicated for 20 seconds every 30 minutes until evaporation to dryness of all samples in each well. Sonication was performed using a Misonix 3000 sonicator with microplate horn. The second plate was kept undisturbed (unsonicated), during the time of the evaporation. Table 7 summarizes the results obtained for the sonicated and unsonicated plates for each condition of evaporation. The difficult-to-make but more stable Form II was found in the sonicated plate but not in the unsonicated plate.

TABLE 7
Conditions Of Evaporations From Mixture Of Solvents
				Non-
			Sonicated	sonicated
	Solvent 1	Solvent 2	Form	Form
	acetone	Acetonitrile	IIa	Ia
	acetone	Chloroform	I	I
	acetone	1,4-dioxane	I	Ac
	acetone	Ethanol	I	I
	acetone	ethyl acetate	I	I
	acetone	Heptane	I	I
	acetone	2-butanone	I	I
	acetone	Methanol	I	I
	acetone	Nitromethane	IIb	Ia
	acetone	Tetrahydrofuran	I	I
	acetone	Toluene	I	I
	acetone	Water	I	I
	tetrahydrofuran	Acetone	I	I
	tetrahydrofuran	Acetonitrile	I	I
	tetrahydrofuran	Chloroform	I	I
	tetrahydrofuran	1,4-dioxane	I	Ac
	tetrahydrofuran	Ethanol	I	I
	tetrahydrofuran	ethyl acetate	I	I
	tetrahydrofuran	heptane	I	I
	tetrahydrofuran	2-butanone	I	I
	tetrahydrofuran	methanol	I	I
	tetrahydrofuran	nitromethane	I	I
	tetrahydrofuran	toluene	I	I
	tetrahydrofuran	Water	I	I
	aduplicate experiment gave the same result
	bduplicate experiment gave form I
	cnew form

In this example, the elusive, more stable Form II of sulfamerazine was generated by a crystallization process that included ultrasound application, but was not generated without ultrasound application. This example shows that a screening process that includes sonication is more likely to generate the more stable solid forms of the chemical substance. This example also demonstrates that it may be desirable to include some unsonicated samples in a screening process, as this can increase the likelihood of obtaining the possible solid forms of the chemical substance.

EXAMPLE 8

In this Example, the difficult-to-make Form I of sulfathiazole was generated by crystallization from a solvent mixture with sonication used to form an emulsion.

Sulfathiazole Form I is a disappearing polymorph, today rarely seen crystallized directly from solution. This result is of interest for polymorph screening purposes. Blagden et al., “Crystal structure and solvent effects in polymorphic systems: sulfathiazole,” J. Chem. Soc. Faraday, 94, 1035-1045 (1998)

A 500 μl aliquot of a saturated solution of sulfathiazole in ethanol at 50° C. was filtered hot and added to 500 μl of warm p-cymene in a pre-heated 1-dram vial on a hotplate at 55° C. The biphasic sample was then sonicated while evaporating until a precipitate appeared (40 minutes sonication, using a Cole-Palmer ultrasonic processor fitted with a 6 mm tip stainless steel probe, amplitude control set at 60). The solids obtained were filtered and analyzed by XRPD. The XRPD pattern was characteristic of sulfathiazole Form I (FIG. 7)

EXAMPLE 9

In this example a polymorph screen is carried out. Solutions of chemical substance A in the following solvents or solvent mixtures (with volume:volume ratio indicated) are prepared by robotic weighing of chemical substance and solvent delivery and mixing: acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, trimethylpentane, n-octane, tri-chloroethane, trifluoroethanol, pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, dimethylformamide, 2:1 methanol:acetonitrile, 2:1 methanol:dichloromethane, 3:1 methanol:ethyl acetate, 4:1 methanol:methyl-tert-butyl ether, 1:1 methanol:2-butanone, 3:1 trifluoroethanol:isopropyl acetate, 2:1 trifluoroethanol:isopropyl ether, 1:1 trifluoroethanol:nitromethane, 1:5 water:acetone, 1:4 water:acetonitrile, 1:5 water:dioxane, 1:9 water:2-propanol, and 1:5 water:tetrahydrofuran.

Aliquots of 200 μL of each solution are delivered in duplicate using a liquid handler to the wells of a 96 well plate. Concentrations of the solutions are selected such that the final amount of chemical substance in each well is between 0.1 mg and 1.0 mg. The well plate body is made of polypropylene. The well plate is a thin bottom well plate suitable for x-ray diffraction analysis of crystals in the well plate. Two wells contain samples of an x-ray powder diffraction standard. The well plate solutions are left uncovered and are allowed to evaporate to dryness while being sonicated for 20 seconds every hour using a Misonix 3000 sonicator with microplate horn. Nitrogen flow into wells is used when evaporation needs to be facilitated. The well plate is mounted on edge on the stage of a Bruker D8 microdiffractometer with the well openings facing the x-ray source. The solids at the bottom of each well are analyzed by automated stage movement. It is expected that a useful variety of different solid forms of the chemical substance will be produced in the wells.

EXAMPLE 10

Cocrystals of fluoxetine HCl:benzoic acid were formed using the following procedures. A solution of fluoxetine HCl and benzoic acid in acetonitrile was prepared. A physical mixture of fluoxetine HCl and benzoic acid in a 1:1 molar ratio was used to make a solution having a concentration of about 200 mg/mL. The solution was placed in four 96-well plates. The only difference among well plates was the amount of solution put into each well. Two well plates were charged with 15 μL per well, and two plates were charged with 50 μL per well. One of the well plates containing 15 μL samples and one of the well plates containing 50 μL samples were sealed and left standing at room temp. The other well plate containing 15 μL samples and the other well plate containing 50 μL samples were sealed and sonicated with a Misonix 96-well plate sonicator.

None of the wells in the 15 μL plates (either standing or sonicated) nucleated (even after very strong sonication with the Misonix plate sonicator or the probe). The plate left standing at room temp with 50 μL volumes nucleated in about 15% of the wells nucleated on standing (but the majority of the wells had benzoic acid growth, not cocrystal nucleation). For the 50 μL plate that was sonicated, almost half of the wells nucleated (with only one well of benzoic acid and the rest as cocrystal).

In a system comprising a 1:1 molar ratio of fluoxetine HCl and benzoic acid in acetonitrile, concentrations of about 200 mg/ml of the API:guest mixture in CH₃CN (acetonitrile) were used. Nucleation could be caused by sonication in a concentration range of from about 35 to about 100 mg/ml. Sonication indicates a clear advantage in this case of intermediate concentrations. Almost all of the samples having a concentration of 200 mg/ml nucleated with sonication using either a probe or the well-plate sonicator. In contrast, about 15% of the wells in a plate at 200 mg/ml nucleated the cocrystal without sonication.

EXAMPLE 11

Cocrystal screening of chlorzoxazone is carried out using the following procedures. Solutions of chlorzoxazone and various guests are prepared in acetonitrile, methanol, aqueous ethanol, and acetone in 1:1 molar ratios having a concentrations of about 10 mg/mL. The guests used include benzoic acid, gallic acid, and 2,5-dihydroxybenzoic acid. Aliquots of 20 microliters of the solutions are placed in different capillary tubes. The samples are sonicated for 1 minute by placement of the capillary tubes in a sonication bath after the volume of the solutions are reduced to the point where both components are supersaturated. This concentration is calculated based on the solubility of the individual components. The sonication is repeated every hour for 24 hours as the solutions evaporate. A duplicate set of capillary tubes is allowed to evaporate at room temperature without sonication.

Solids are present in most of the capillary tubes and are analyzed by Raman spectroscopy and by x-ray powder diffraction. It is expected that a number of cocrystals are present in the sonicated capillary tubes and that different polymorphs, hydrates, or solvates of the cocrystals may also be present. It is expected that solids in the unsonicated capillary tubes will have a different variety of solid forms present compared to the sonicated samples and that there will not be as many cocrystals formed.

This example demonstrates the use of capillary tubes for cocrystallization. This example also demonstrations that samples having low concentrations and/or low volumes may be employed in a cocrystallization process.

EXAMPLE 12

Cocrystal and salt screening of imipramine hydrochloride is carried out using the following procedures. Solutions of imiprimine hydrochloride and various guests are prepared in acetonitrile, methanol, aqueous ethanol, and acetone in 1:1 molar ratios having a concentrations of about 10 mg/mL. The guests include benzoic acid, gallic acid, and 2,5-dihydroxybenzoic acid. Aliquots of 100 microliters of the solutions are placed in different wells of 96-well polypropylene plates that have thin walls. The plates are sonicated for 1 minute in a sonication bath after the volume of the solutions are reduced to the point where both components are supersaturated. This concentration is calculated based on the solubility of the individual components. The sonication is repeated every hour for 24 hours as the solutions continue to evaporate. A duplicate set of well plates is allowed to evaporate at room temperature without sonication.

Solids are present in most of the wells and are analyzed in situ, automatically by transmission x-ray powder diffraction through the well plates. It is expected that a number of cocrystals and/or salts are present in the sonicated plates and that different polymorphs, hydrates, solvates, desolvates, and dehydrates of the cocrystals and/or salts may also be present. It is expected that solids in the unsonicated plates will have a different variety of solid forms present compared to the sonicated samples and that there will not be as many cocrystals and/or salts formed.

All patents, test procedures, and other documents cited herein, including priority documents, are fully incorporated by reference to the extent such disclosure is not inconsistent with this invention and for all jurisdictions in which such incorporation is permitted.

While the present invention has been described and illustrated by reference to particular-embodiments, it will be appreciated by those off ordinary skill in the art that the invention lends itself to many different variations not illustrated herein. For these reasons, then, reference should be made solely to the appended claims for purposes of determining the true scope of the present invention.

Although the appendant claims have single appendencies in accordance with U.S. patent practice, each of the features in any of the appendant claim can be combined with each of the features of other appendant claims or the main claim.

TABLE 8
10-camphorsulfonic acid
10-undecylenic acid
1-hydroxy-2-naphthoic acid
2,4-dihydroxybenzoic acid
2,5-dihydroxybenzoic acid
2-aminopropionic acid
2-ethylbutyrinc acid
2-furancarboxylic acid
2-mercaptobenzoic acid
3-methylbutanoic acid
3-phenylpropionic acid
4-aminobenzoic acid
4-aminosalicylic acid
4-hydroxybenzoic acid
adipic acid
alginic acid
anisic acid
arginine
ascorbic acid
asparagine
aspartic acid
aspirin
benzenesulfonic acid
benzoic acid
4-acetamidobenzoic acid
beta-alanine
camphoric acid
camphorsulfonic acid
carbonic acid
cholic acid
cinnamic acid
citric acid
cyclamic acid
cyclohexanecarboxylic acid
cyclohexylacetic acid
cysteine
diphenylacetic acid
dodecylsulfonic acid
ethane-1,2-disulfonic acid
ethanesulfonic acid
ethanesulfonic acid, 2-hydroxy
ethylenediaminetetraacetic acid
ethylsulfuric acid
fumaric acid
galactaric acid
gallic acid
gentisic acid
glucoheptonic acid
gluconic acid
glutamic Acid
glutamine
glutaric acid
glutaric acid, 2-oxo-
glycine
glycolic acid
hippuric acid
histidine
hydroxyproline
isoleucine
lactobionic acid
lauric acid
leucine
levulinic acid
lysine
maleic acid
malic acid
malonic acid
mandelic acid
m-methoxybenzoic acid
naphthalene-1,5-disulfonic acid
naphthalene-2-sulfonic acid
n-decanoic acid
niacin
nicotinic acid
n-tetradecanoic acid
oleic acid
o-methylbenzoic acid
orotic acid
orthoboric acid
o-toluic acid
p-acetamidobenzoic acid
palmitic acid
pamoic acid
phenoxyacetic acid
phenylacetic acid
phenylalanine
picric acid
pivalic acid
proline
p-toluenesulfonic acid
pyroglutamic acid
pyruvic acid
salicylic acid
sebacic acid
serine
sorbic acid
stearic acid
succinic acid
sulfosalicylic acid
tartaric acid
terephthalic acid
thiocyanic acid
threonine
tiglic acid
tryptophan
tyrosine
valeric acid
valine

TABLE 9
Name                            CAS #
Potassium bicarbonate           298-14-6
Potassium carbonate             584-08-7
Potassium chloride              7447-40-7
Potassium hydroxide             1310-58-3
Potassium metabisulfite         16731-55-8
Potassium nitrate               7757-79-1
Potassium nitrite               7758-09-0
Potassium permanganate          7722-64-7
Potassium persulfate            7727-21-1
Potassium phosphate, dibasic    2139900
Potassium Phosphate Monobasic   7778-77-0
potassium phosphate, tribasic,  7778-53-2
n-hydrate
Potassium sulfate               7778-80-5
Sodium bicarbonate              144-55-8
Sodium bisulfite                7631-90-5
Sodium borohydride              16940-66-2
Sodium carbonate                497-19-8
Sodium Carbonate Monohydrate    1486118
Sodium chloride                 7647-14-5
Sodium dithionite               7775-14-6
Sodium fluoride                 7681-49-4
Sodium hexametaphosphate        10124-56-8
Sodium hydroxide                1310-73-2
Sodium hypochlorite             7681-52-9
Sodium Metabisulfite            7681-57-4
Disodium metasilicate           6834-92-0
sodium monophosphate            7681-53-0
Sodium nitrate                  7631-99-4
Sodium nitrite                  7632-00-0
sodium hydrogen phosphate       7558-79-4
Sodium phosphate Monobasic      7558-80-7
Sodium Pyrophosphate            7722-88-5
Sodium silicate                 1344-09-8
Sodium Sulfate Decahydrate      7727-73-3
Sodium sulfite                  7757-83-7
Sodium Thiosulfate              10102-17-7
Pentahydrate
Calcium acetate                 5743-26-0
Calcium Carbonate               471-34-1
Calcium Chloride Dihydrate      10035-04-8
Calcium gluconate               299-28-5
Calcium hydroxide               1305-62-0
Calcium oxide                   1305-78-8
Calcium phosphate, dibasic      7757-93-9
Calcium Phosphate Monobasic     7758-23-8
Calcium sulfate                 7778-18-9
Magnesium hydroxide             1309-42-8
Magnesium Sulfate Heptahydrate  10034-99-8
Aluminum                        7429-90-5
Aluminum ammonium sulfate       7784-26-1
Aluminum chloride               7446-70-0
Aluminum hydroxide              21645-51-2
Aluminum potassium sulfate,     7784-24-9
dodecahydrate
Orthoboric acid                 10043-35-3
formaldehyde                    50-00-0
DL-Isoleucine                   443-79-8
(2S,7S)-(−)-Cystine             56-89-3
DL-Alanine                      302-72-7
beta-Alanine                    107-95-9
(S)-(+)-Arginine                74-79-3
(S)-(−)-Cysteine                52-90-4
DL-Glutamic acid                617-65-2
Glycine                         56-40-6
(S)-(−)-Histidine               71-00-1
(S)-(+)-Lysine                  56-87-1
DL-Methionine                   59-51-8
DL-Phenylalanine                150-30-1
(S)-(−)-Phenylalanine           63-91-2
D-(+)-Proline                   344-25-2
(S)-(−)-Tryptophan              73-22-3
(S)-(−)-Tyrosine                60-18-4
Carvone                         99-49-0
Citral                          5392-40-5
Ethyl butyrate                  105-54-4
Isobutyl propionate             540-42-1
Methyl butyrate                 623-42-7
n-Propyl acetate                109-60-4
Isobutyl formate                542-55-2
Benzyl acetate                  140-11-4
6-Methyl-5-hepten-2-one         110-93-0
Butyl acetate                   123-86-4
Ethyl acetoacetate              141-97-9
Isopentyl Acetate               123-92-2
Cinnamaldehyde                  104-55-2
Methyl benzoate                 93-58-3
Butyl sulfide                   544-40-1
Ethyl benzoate                  93-89-0
2,4-Hexadienoic acid,           24634-61-5
potassium salt, (E,E)-
Potassium bitartrate            868-14-4
Lauric acid                     143-07-7
Benzyl benzoate                 120-51-4
Picric acid                     88-89-1
Benzoyl peroxide                94-36-0
Palmitic acid                   57-10-3
Dibutyl phthalate               84-74-2
Stearic acid                    57-11-4
Succinic anhydride              108-30-5
Diethylenetriamine              111-40-0
Diethanolamine                  111-42-2
Benzaldehyde                    100-52-7
Phenethylamine                  64-04-0
Salicylylaldehyde               90-02-8
Sodium benzoate                 532-32-1
Cinnamic acid                   621-82-9
Triethanolamine                 102-71-6
L-(+)-Tartaric Acid             87-69-4
Eugenol                         97-53-0
D-mannitol                      69-65-8
Butyl paraben                   94-26-8
Benzoin                         119-53-9
Diethyl phthalate               84-66-2
Oleic acid                      112-80-1
Sodium lactate                  72-17-3
Indole                          120-72-9
ethyl lactate                   97-64-3
quinoline                       91-22-5
Thymol                          89-83-8
Methyl anthranilate             134-20-3
Methyl salicylate               119-36-8
Diethyl malonate                105-53-3
Citric acid                     77-92-9
Sodium dodecyl sulfate          151-21-3
Morpholine                      110-91-8
Furfural                        98-01-1
Niacin                          59-67-6
Choline chloride                67-48-1
L-Menthol                       2216-51-5
Meso-inositol                   87-89-8
ethylenediaminetetraacetic      60-00-4
acid
EDTA, calcium derivative,       62-33-9
disodium salt
Calcium pantothenate            137-08-6
Riboflavin                      83-88-5
Zinc carbonate                  3486-35-9
Amyl alcohol                    71-41-0
Mineral oil                     8012-95-1
Triton(R) X-100                 9002-93-1
Acetaldehyde                    75-07-0
Acetic Acid                     64-19-7
Acetone                         67-64-1
Acetophenone                    98-86-2
4-Aminobenzoic acid             150-13-0
Anisole                         100-66-3
Vitamin C                       50-81-7
Benzoic Acid                    65-85-0
Biphenyl                        92-52-4
2-Methyl-1-propanol             78-83-1
n-Butanol                       71-36-3
n-Butylamine                    109-73-9
ethyl acetate                   141-78-6
Caffeine                        58-08-2
Chloroacetic Acid               79-11-8
Dichloroacetic Acid             79-43-6
Diethylamine                    109-89-7
Ethanol Amine                   141-43-5
n-Butyric Acid                  107-92-6
Ethylenediamine                 107-15-3
Formic acid                     64-18-6
n-Hexanol                       111-27-3
Methanol                        67-56-1
Methyl Acetate                  79-20-9
Methyl 4-hydroxybenzoate        99-76-3
m-Cresol                        108-39-4
p-Cresol                        106-44-5
Phenol                          108-95-2
n-Propanol                      71-23-8
Propionic Acid                  79-09-4
Salicylic acid                  69-72-7
Sucrose                         57-50-1
Vanillin                        121-33-5
Vitamin E                       59-02-9
Potassium citrate, monohydrate  1534146
p-toluenesulfonic acid          6192-52-5
monohydrate
D-(+)-Maltose                   69-79-4
Tetrasodium                     64-02-8
ethylenediaminetetraacetate
Saccharin sodium                128-44-9
Sodium Acetate Trihydrate       6131-90-4
Quinine sulfate, dihydrate      6119-70-6
Sulfosalicylic acid, dihydrate  5965-83-3
L-(+)-Arginine                  1119-34-2
monohydrochloride
Procaine hydrochloride          51-05-8
Pyridoxine Hydrochloride        58-56-0
Thiamine hydrochloride          67-03-8
Propionaldehyde                 123-38-6
Urea                            57-13-6
2-Propanol                      67-63-0
Pyrrole                         109-97-7
Sodium formate                  141-53-7
Pyrrolidine                     123-75-1
Methyl ethyl ketone             78-93-3
Ethyl formate                   109-94-4
Propylene glycol                57-55-6
Thiourea                        62-56-6
Ammonium acetate                631-61-8
Benzene                         71-43-2
Sodium acetate                  127-09-3
Cyclopentanone                  120-92-3
Cyclohexane                     110-82-7
piperidine                      110-89-4
2-Pentanone                     107-87-9
hexane                          110-54-3
Isoamyl Alcohol                 123-51-3
Lactic acid                     50-21-5
2-Ethoxyethanol                 110-80-5
Propionic acid, sodium salt     137-40-6
Potassium acetate               127-08-2
cyclohexyl amine                108-91-8
methyl methacrylate             80-62-6
methyl isobutyl ketone          108-10-1
Acetic anhydride                108-24-7
Isopropyl Acetate               108-21-4
2,2′-Oxybisethanol              111-46-6
Benzyl alcohol                  100-51-6
Resorcinol                      108-46-3
2-Butoxy ethanol                111-76-2
Cumene                          98-82-8
2-Amino-2-(hydroxymethyl)-1,3-  77-86-1
propanediol
Phenethyl alcohol               60-12-8
2-Ethyl-1-hexanol               104-76-7
2-Octanol                       123-96-6
2-(2-Ethoxyethoxy)ethanol       111-90-0
2,6-Dimethyl-4-heptanone        108-83-8
Benzophenone                    119-61-9
D-(−)-Fructose                  57-48-7
D-Glucose                       50-99-7
D-Ribose                        50-69-1
D-(+)-Xylose                    58-86-6
Pectin sugar                    5328-37-0
D-(+)-Lactose                   63-42-3
Camphene                        79-92-5
Isoquinoline                    119-65-3
2,4-Dimethylphenol              105-67-9
2,5-Dimethylphenol              95-87-4
2,6-Dimethylphenol              576-26-1
Methanesulfonic Acid            75-75-2
o-Methoxybenzoic Acid           579-75-9
Saccharin                       81-07-2
Thiazole                        288-47-1
Trifluoromethanesulfonic Acid   1493-13-6
Trimethylamine                  75-50-3
Coumarin                        91-64-5
Dimethylamine                   124-40-3
Ethyl Alcohol                   64-17-5
Butyl benzyl phthalate          85-68-7
2,6-dimethylpyrazine            108-50-9
taurocholic acid                81-24-3
geraniol                        106-24-1
linalool                        78-70-6
ethyl isovalerate               108-64-5
ethyl 2-methylbutyrate          7452-79-1
1-octen-3-ol                    3391-86-4
ethyl 2-trans-4-cis-            3025-30-7
decadienoate
Dihydromyrcenol                 18479-58-8
citronellal                     106-23-0
linalyl acetate                 115-95-7
8-mercapto-p-menthan-3-one      38462-22-5
Ammonium citrate                3012-65-5
Ammonium bicarbonate            1066-33-7
Ammonium chloride               12125-02-9
Ammonium hydroxide              1336-21-6
Ammonium persulfate             7727-54-0
Ammonium phosphate, dibasic     7783-28-0
Ammonium Phosphate Monobasic    7722-76-1
Ammonium sulfate                7783-20-2
Ammonium sulfide                12135-76-1
Hydrazine                       302-01-2
Nitric acid                     7697-37-2
phosphoric acid                 7664-38-2
Phosphorus oxychloride          10025-87-3
Hydriodic acid                  10034-85-2
Hydrobromic acid                10035-10-6
Hydrochloric acid               7647-01-0
hydrogen peroxide               7722-84-1
Periodic Acid                   10450-60-9
Sulfamic acid                   5329-14-6
Sulfuric acid                   7664-93-9
Sulfurous acid                  7782-99-2
Dexpanthenol                    81-13-0
4-oxoisophorone                 1125-21-9
Copper(II) sulfate              7758-98-7
ferric chloride                 7705-08-0
Ferric oxide                    1309-37-1
ferric sulfate                  10028-22-5
Iron(II)Sulfate Heptahydrate    7782-63-0
Iron                            7439-89-6
Manganese (II) Sulfate          10034-96-5
Monohydrate
Nickel                          7440-02-0
Titanium dioxide                13463-67-7
Zinc chloride                   7646-85-7
Zinc oxide                      1314-13-2
1,1′-Azobisformamide            123-77-3
1,3-Butanediol                  107-88-0
1-Methylnaphthalene             90-12-0
2,6-Di-tert-Butyl-p-Cresol      128-37-0
2,6-Dimethylpyridine            108-48-5
Disodium                        138-93-2
cyanodithioimidocarbonate
3-Methyl-2-Cyclopentene-2-ol-   80-71-7
one
6-Methylcoumarin                92-48-8
acetoin                         513-86-0
alpha-Phellandrene              99-83-2
alpha-Terpinene                 99-86-5
Benzenesulfonic Acid            98-11-3
Benzothiazole                   95-16-9
borates, tetrasodium salts      1330-43-4
Butyl butyrate                  109-21-7
Butyl Mercaptan                 109-79-5
Butyraldehyde                   123-72-8
Capsaicin                       404-86-4
Chloromethyl Methyl Ether       107-30-2
Cymene                          99-87-6
Diallyl Disulfide               2179-57-9
Diethylaminoethanol             100-37-8
dimethyldisulfide               624-92-0
Dimethyl Succinate              106-65-0
Dimethyl Sulfate                77-78-1
Dimethyl Sulfide                75-18-3
Dipropyl Disulfide              629-19-6
Dipropyl Ketone                 123-19-3
Ethyl Acrylate                  140-88-5
Ethyl Butyl Ketone              106-35-4
Ethyl Propionate                105-37-3
Furfuryl Alcohol                98-00-0
gamma-Butyrolactone             96-48-0
Glutaraldehyde                  111-30-8
glycerin                        56-81-5
Glycolic Acid                   79-14-1
Isobutyl Acetate                110-19-0
Isobutyl Isobutyrate            97-85-8
Isobutyraldehyde                78-84-2
Isoheptanol                     543-49-7
Isophorone                      78-59-1
Isopropyl Mercaptan             75-33-2
Methyl isobutenyl ketone        141-79-7
Methyl n-amyl ketone            110-43-0
methyl acrylate                 96-33-3
Methyl Isobutyrate              547-63-7
Methyl Mercaptan                74-93-1
N,N-Dimethylethanolamine        108-01-0
n-Butyl Lactate                 138-22-7
n-Hexyl Acetate                 142-92-7
n-Valeraldehyde                 110-62-3
Nitrous Oxide                   10024-97-2
p-Anisaldehyde                  123-11-5
2-Methylcyclohexanone           583-60-8
Octanoic Acid                   124-07-2
Oxalic Acid                     144-62-7
Phenyl ether                    101-84-8
Phenylmercaptan                 108-98-5
Propargyl Alcohol               107-19-7
Propyl paraben                  94-13-3
sec-Butyl Alcohol               78-92-2
Sodium Gluconate                527-07-1
Sodium Tripolyphosphate         7758-29-4
Tetrahydro-2-furanmethanol      97-99-4
Valeric Acid                    109-52-4
3,4-xylenol                     95-65-8
3-hexanol                       623-37-0
3-methyl-1-pentanol             589-35-5
1,1-diethoxyethane              105-57-7
Aluminum Sulfate                10043-01-3
ammonium sulfite                10196-04-0
amyl butyrate                   540-18-1
borneol                         507-70-0
butyl formate                   592-84-7
calcium peroxide                1305-79-9
n-Hexanoic Acid                 142-62-1
cyclohexyl acetate              622-45-7
diacetyl                        431-03-8
dimethyl carbonate              616-38-6
ethyl butyraldehyde             97-96-1
Ethyl crotonate                 623-70-1
ethyl isobutyrate               97-62-1
ethyl nitrite                   109-95-5
fumaric acid                    110-17-8
hexaldehyde                     66-25-1
isobutyric acid                 79-31-2
methyl isovalerate              556-24-1
methyl propionate               554-12-1
methyl valeraldehyde            123-15-9
nitrosyl chloride               2696-92-6
octafluorocyclobutane           115-25-3
peroxyacetic acid               79-21-0
propyl formate                  110-74-7
propyl mercaptan                107-03-9
Sodium aluminate                1302-42-7
sodium chlorite                 7758-19-2
Terephthalic Acid               100-21-0
allyl isothiocyanate            57-06-7
Vitamin B1                      59-43-8
Valproic acid                   99-66-1
Ethoxyquin                      91-53-2
n-Amyl Ethyl Ketone             106-68-3
Nabam                           142-59-6
Sodium sulfide                  1313-82-2
Thiocyanic acid                 463-56-9
2-Methyl-5-(1-methylethenyl)-   2244-16-8
2-cyclohexene-1-one
4-(2,6,6-Trimethyl-2-           127-41-3
cyclohexen-1-yl)-3-buten-2-one
4-(2,6,6-trimethyl-1-           14901-07-6
cyclohexen-1-yl)-3-buten-2-one
Isoamyl propionate              105-68-0
3-Methylbutanoic acid           503-74-2
L-Menthone                      14073-97-3
4-Ethylphenol                   123-07-9
o-cresol                        95-48-7
dimethyl-Carbamodithioic acid,  128-04-1
sodium salt
Anethole                        104-46-1
Dimethyl terephthalate          120-61-6
propyl gallate                  121-79-9
L-Ascorbic Acid Sodium Salt     134-03-2
4-Hexylresorcinol               136-77-6
Estragole                       140-67-0
L-monosodium glutamate          142-47-2
Malonaldehyde, sodium salt      24382-04-5
Butylated hydroxyanisole        25013-16-5
allyl 3-methylbutyrate          2835-39-4
DL-monosodium glutamate         32221-81-1
3-Acetyl-6-methyl-2,4-          520-45-6
pyrandione
L-Glutamic Acid                 56-86-0
DL-alpha-tocopheryl acetate     58-95-7
D-limonene                      5989-27-5
Calcium Acetate                 62-54-4
Erythorbic Acid Monosodium      6381-77-7
Salt
Ethyl methylphenylglycidate     77-83-8
2,4,6-Trinitro-1,3-dimethyl-5-  81-15-2
tert-butylbenzene
Dimethoxane                     828-00-2
3,5-Di-tert-butyl-4-            88-26-6
hydroxybenzyl alcohol
6-Methylquinoline               91-62-3
alpha-Methylbenzyl alcohol      98-85-1
Nicotinamide                    98-92-0
3,4-Dihydrocoumarin             119-84-6
Geranyl Acetate                 105-87-3
Sodium (2-Ethylhexyl)Alcohol    126-92-1
Sulfate
Cyclohexanol, 5-methyl-2-(1-    89-78-1
methylethyl)-,
(1alpha,2beta,5alpha)-
(+)-Camphor                     464-49-3
(1S)-(−)-alpha-Pinene           7785-26-4
1,3-Dihydroxy-5-methylbenzene   504-15-4
1,5-Naphthalenedisulfonic Acid  1655-29-4
Disodium Salt
1-Hydroxy-2-naphthoic Acid      86-48-6
1-Penten-3-ol                   616-25-1
1-Phenyl-1-propanol             93-54-9
10-Undecylenic Acid             112-38-9
2′-Hydroxyacetophenone          118-93-4
2,4-Dihydroxybenzoic Acid       89-86-1
2-Acetylfuran                   1192-62-7
2-Furancarboxylic Acid          88-14-2
2-Isopropylphenol               88-69-7
2-Ketoglutaric Acid             328-50-7
2-Ketovaline                    759-05-7
2-n-Propylphenol                644-35-9
2-Naphthalenethiol              91-60-1
2-Phenyl-1-propanol             1123-85-9
3,3′-Thiodipropionic Acid       111-17-1
3,5,5-Trimethylhexanal          5435-64-3
3-Phenyl-1-propanol             122-97-4
3-Phenylpropionic Acid          501-52-0
4-Aminosalicylic Acid           65-49-6
4-Ethoxyphenol                  622-62-8
4-Hydroxybenzoic Acid           99-96-7
4-Phenyl-2-butanol              2344-70-9
4-tert-Octylphenol              140-66-9
Allyl Cinnamate                 1866-31-5
Allyl Mercaptan                 870-23-5
alpha-L-Rhamnose                3615-41-6
Alpha-Terpineol                 98-55-5
Anisic Acid                     100-09-4
Benzalacetone                   122-57-6
Benzaldehyde Dimethylacetal     1125-88-8
Benzyl Ether                    103-50-4
Benzyl Formate                  104-57-4
Benzyl Mercaptan                100-53-8
Benzyl Salicylate               118-58-1
Calcium Citrate                 813-94-5
Calcium Glycerophosphate        27214-00-2
Calcium Hypophosphite           7789-79-9
Calcium Iodate                  7789-80-2
Propanoic acid, 2-hydroxy-,     814-80-2
calcium salt (2:1)
Calcium Phosphate Tribasic      7758-87-4
Calcium Propionate              4075-81-4
Calcium Pyrophosphate           7790-76-3
Cholic Acid                     81-25-4
Choline                         123-41-1
Choline Bitartrate              87-67-2
trans-Cinnamic Aldehyde         14371-10-9
Cinnamyl Alcohol                104-54-1
Citronellol                     106-22-9
Copper(I)Iodide                 7681-65-4
D-(+)-Glucono-1,5-lactone       90-80-2
D-(−)-Tartaric Acid             147-71-7
D-Isoascorbic Acid              89-65-6
D-Tyrosine                      556-02-5
Sodium dehydroacetate           4418-26-2
Deoxycholic Acid                83-44-3
Dibenzyl Ketone                 102-04-5
Diethyl L-(+)-Tartrate          87-91-2
Diethyl Succinate               123-25-1
Dimethylacetal                  534-15-6
DL-Cystine                      923-32-0
DL-Proline                      609-36-9
DL-Tartaric Acid                133-37-9
DL-Tyrosine                     556-03-6
DL-Valine                       516-06-3
Enanthoic Acid                  111-14-8
Erythorbic Acid Sodium Salt     7378-23-6
Ethyl 2-Aminobenzoate           87-25-2
Ethyl Cinnamate                 103-36-6
Ethyl n-Valerate                539-82-2
Ethyl Phenylacetate             101-97-3
Ethyl Salicylate                118-61-6
Ethyl Sulfide                   352-93-2
Ethyl Vanillin                  121-32-4
Ethylene Mercaptan              540-63-6
Farnesene                       502-61-4
Folic acid                      59-30-3
gamma-Nonanolactone             104-61-0
gamma-Valerolactone             108-29-2
Gluconic Acid                   526-95-4
Gluconic Acid Potassium Salt    299-27-4
Glutaric Acid                   110-94-1
Guanosine-5′-monophosphate,     1333479
disodium salt
Heliotropine                    120-57-0
Hippuric Acid                   495-69-2
Hydroquinone Dimethyl Ether     150-78-7
Inosine-5′-monophosphate        4691-65-0
Sodium Salt
iso-Amyl Mercaptan              541-31-1
Isoamyl Salicylate              87-20-7
iso-Butyl n-Hexanoate           105-79-3
isovaleraldehyde                590-86-3
Isoamyl Benzoate                94-46-2
Isoamyl Formate                 110-45-2
Isoamyl n-Butyrate              106-27-4
Isoamylamine                    107-85-7
Isobutyl n-Butyrate             539-90-2
Isocaproic Acid                 646-07-1
Isoeugenol                      97-54-1
Isopropyl Benzoate              939-48-0
Isopropyl Formate               625-55-8
Isopropyl N-Butyrate            638-11-9
Isopropyl Propionate            637-78-5
isobutyl Mercaptan              513-44-0
L-(+)-Isoleucine                73-32-5
L-(−)-Apple Acid                97-67-6
L-2-Aminopropionic Acid         56-41-7
L-Aspartic acid                 56-84-8
L-Carnitine                     541-15-1
L-Cysteine Hydrochloride        52-89-1
L-Glutamic Acid Hydrochloride   138-15-8
L-Glutamine                     56-85-9
L-Hydroxyproline                51-35-4
L-Proline                       147-85-3
L-Serine                        56-45-1
L-Threonine                     72-19-5
L-Valine                        72-18-4
N-Acetylglycine                 543-24-8
n-Amyl Formate                  638-49-3
n-Amyl n-Caproate               540-07-8
n-Butyl n-Caproate              626-82-4
n-Butyl Propionate              590-01-2
n-Butyl Salicylate              2052-14-4
n-Decanoic Acid                 334-48-5
n-Hexyl Mercaptan               111-31-9
n-Propyl Benzoate               2315-68-6
n-Propyl Isobutyrate            644-49-5
n-Tetradecanoic Acid            544-63-8
Nitrilotriacetic Acid           5064-31-3
Trisodium Salt
o-Toluenethiol                  137-06-4
Orotic Acid                     65-86-1
p-Acetamidobenzoic Acid         556-08-1
p-Anise Alcohol                 105-13-5
Phenoxyacetic Acid              122-59-8
Phenyl Acetate                  122-79-2
Piperine                        94-62-2
Pivalic Acid                    75-98-9
Potassium Benzoate              582-25-2
Potassium Diphosphate           7320-34-5
Potassium Hypophosphite         7782-87-8
Potassium Metaphosphate         7790-53-6
Potassium Sulfite               10117-38-1
Quinine Hydrochloride           130-89-2
sec-Amyl Alcohol                6032-29-7
Sodium D-Pantothenate           867-81-2
Di(2-ethylhexyl) sulfosuccinic  577-11-7
acid, sodium salt
Sodium Sorbate                  7757-81-5
Succinic acid, disodium salt    150-90-3
Sodium Taurocholate             145-42-6
Taurine                         107-35-7
Thiamine Nitrate                532-43-4
Thioanisole                     100-68-5
Tiglic Acid                     80-59-1
Tri-n-butyrin                   60-01-5
Triacetin                       102-76-1
Trisodium Citrate               68-04-2
Veratraldehyde                  120-14-9
Veratrole                       91-16-7
Vitamin P                       520-26-3
Vitamin U Chloride              582174
L-methionine                    63-68-3
2-Chloro-1-propanol             78-89-7
2-Ethylbutyric acid             88-09-5
2-Methylbutyraldehyde           96-17-3
2-Methyl-5-ethylpyridine        104-90-5
n-propyl butyrate               105-66-8
Ethyl caprylate                 106-32-1
Propyl propionate               106-36-5
2-Methylpyrazine                109-08-0
3,3,5-Trimethyl-1-cyclohexanol  116-02-9
Ethyl caproate                  123-66-0
o-methoxybenzaldehyde           135-02-4
2,4-Hexadienal                  142-83-6
3-Hexanone                      589-38-8
3-Methyl-2-butanol              598-75-4
Methyl isopropenyl ketone       814-78-8
3-Methyl-2-butanethiol          2084-18-6
3,5,5-Trimethylhexanol          3452-97-9
Methylglyoxal                   78-98-8
Malonaldehyde                   542-78-9
1,4-Dithiane                    505-29-3
Amylcinnamaldehyde              122-40-7
Benzyl cinnamate                103-41-3
tert-Butylhydroquinone          1948-33-0
Fusidic Acid Sodium Salt        751-94-0
Hydroxycitronellal              107-75-5
Musk ketone                     81-14-1
L-Asparagine                    70-47-3
phenethyl acetate               103-45-7
Riboflavin-5-Phosphate          146-17-8
Potassium Sodium Tartrate       304-59-6
Galactaric acid                 526-99-8
Sodium Tartrate                 868-18-8
trisodium phosphate             7601-54-9
Disodium Pytophosphate          7758-16-9
Magnesium chloride              7786-30-3
Sodium Polymethacrylate         54193-36-1
propiophenone                   93-55-0
2-ethylhexanoic acid            149-57-5
3,7,7-trimethyl bicyclohep-3-   13466-78-9
ene
2,6-dimethyl-4-heptanol         108-82-7
5-isopropyl-2-methyl-phenol     499-75-2
L-Bornyl acetate                5655-61-8
caryophyllene                   87-44-5
hydroxymethylpyrone             118-71-8
neosperidin dihydrochalcone     20702-77-6
2,2-Dibromo-3-                  10222-01-2
nitrilopropionamide
Xylitol                         87-99-0
Sulfosalicylic acid             97-05-2
Riboflavin 5′-(dihydrogen       130-40-5
phosphate), monosodium salt
Ethylenediaminetetraacetic      139-33-3
acid, disodium salt
Gallic acid                     149-91-7
Carbonic acid                   463-79-6
Potassium carbonate,            6381-79-9
sesquihydrate
Magnesium phosphate tribasic    7757-87-1
diallyl sulfide                 592-88-1
ethyl 4-oxopentanoate           539-88-8
methyl caproate                 106-70-7
isopropyl isobutyrate           617-50-5
diethyl hydroxybutanedioate     2065419
propyl isopentanoate            557-00-6
benzyl ethyl ether              539-30-0
isobutyl isopentanoate          589-59-3
propyl hexanoate                626-77-7
4-methylquinoline               491-35-0
methyl cinnamate                103-26-4
cumic alcohol                   536-60-7
thujone                         471-15-8
dihydrocarveol                  619-01-2
fenchyl alcohol                 1632-73-1
Nerol                           106-25-2
isopentyl isopentanoate         659-70-1
methyleugenol                   93-15-2
methyl 2-naphthyl ketone        93-08-3
diphenyldisulfide               882-33-7
citronellyl acetate             150-84-5
menthyl acetate                 89-48-5
menthyl isovalerate             16409-46-4
5-Ethyl-3-hydroxy-4-methyl-     698-10-2
2(5H)-furanone
malic acid                      6915-15-7
3-methylbutanoic acid butyl     109-19-3
ester
3-phenyloxiranecarboxylic acid  121-39-1
ethyl ester
1,2-Benzisothiazol-3(2H)-one    6381-61-9
1,1-dioxide, ammonium salt
1-methyl-4-(1-methylethyl)-     99-85-4
1,4-Cyclohexadiene
3-mercapto-2-Butanol            54812-86-1
(1R)-2,6,6-                     7785-70-8
trimethylbicyclo[3.1.1]hept-2-
ene
(1S)-6,6-dimethyl-2-            18172-67-3
methylenebicyclo[3.1.1]heptane
1-methyl-4-(1-                  586-62-9
methylethylidene)cyclohexene
1-(3-pyridinyl)ethanone         350-03-8
1-pyrazinylethanone             22047-25-2
1-(2-furyl)-2-propanone         6975-60-6
1-Penten-3-one                  1629-58-9
2,3-pentanedione                600-14-6
2,5-dimethylpyrazine            123-32-0
2-isobutyl-3-methoxypyrazine    24683-00-9
4-methyl-2,3-pentanedione       7493-58-5
5-methylfurfural                620-02-0
Dimethyltrisulfide              3658-80-8
furfuryl acetate                623-17-6
furfurylmethylether             13679-46-4
terpinen-4-ol                   562-74-3
Calcium sorbate                 7492-55-9
Potassium lactate               996-31-6
1-Hydroxyethylidene-1,1-        2809-21-4
diphosphonic acid
L-glutamic acid monopotassium   19473-49-5
salt
3-methyl-2-buten-1-ol           556-82-1
phenylethanal                   122-78-1
4′-Methoxyacetophenone          100-06-1
L-borneol                       464-45-9
2,4-Hexadien-1-ol               111-28-4
D-Fenchone                      4695-62-9
3-Phenylpropyl formate          104-64-3
Cinnamyl formate                104-65-4
D-galacturonate                 685-73-4
D-glucuronate                   1700908
5′ IMP                          131-99-7
1-Methoxy-4-methylbenzene       104-93-8
2-Methylbutanoic acid           116-53-0
2,4,6-Tribromophenol            118-79-6
3-Ethyl pyridine                536-78-7
Zinc acetate                    557-34-6
Methyl pentanoate               624-24-8
Methylthioethane                624-89-5
3-Penten-2-one                  625-33-2
Glycocholic acid                475-31-0
m-Methoxybenzoic acid           586-38-9
alpha-Hydroxypropionic acid     598-82-3
Methyl 2-furoate                611-13-2
2-Furancarboxylic acid, propyl  615-10-1
ester
Benzylacetoacetic acid, ethyl   620-79-1
ester
2,5-Dimethyl pyrrole            625-84-3
4-methyl-1,1′-biphenyl          644-08-6
p-Isopropylacetophenone         645-13-6
4-methyl-thiazole               693-95-8
gamma-Decalactone               706-14-9
2-acetylpyrrole                 1072-83-9
2-acetylpyridine                1122-62-9
tetramethyl-pyrazine            1124-11-4
Methyl 4-phenylbutyrate         2046-17-5
2,3,6-trimethyl-phenol          2416-94-6
2-Methoxypyrazine               3149-28-8
2-Ethylfuran                    3208-16-0
2,3-dimethyl-pyrazine           5910-89-4
Thiophenethiol                  7774-74-5
o-Tolyl isobutyrate             36438-54-7
cis-3-Hexenyl pyruvate          68133-76-6
cis-3-Hexenyl cis-3-hexenoate   61444-38-0
trans-2-Hexenyl isovalerate     68698-59-9
trans-2-Hexenyl formate         53398-78-0
trans-2-Hexenyl valerate        56922-74-8
1-Octen-3-yl butyrate           16491-54-6
Methyl 4-(methylthio)butyrate   53053-51-3
2,4-Octadien-1-ol               18409-20-6
2,4-Nonadien-1-ol               62488-56-6
2,4-Decadien-1-ol               18409-21-7
(e,z)-2,6-Nonadienyl acetate    68555-65-7
3-Hexenal                       4440-65-7
Tetrahydro-2-furanmethanol      637-64-9
acetate
Methyl benzaldehyde             1334-78-7
Dodecylsulfonic acid            1510-16-3
Methylethyl disulfide           4253-89-8
Farnesol                        4602-84-0
Thiobenzoic acid, S-methyl      5925-68-8
ester
Hexyl benzoate                  6789-88-4
2,5-Diethyltetrahydrofuran      41239-48-9
Zinc hydrosulfite               7779-86-4
(2R,3S)-Tartaric Acid           147-73-9
Ethylsulfuric acid              540-82-9
1,2,2-Trimethyl-1,3-            5394-83-2
cyclopentanedicarboxylic acid
2-Methyl-3-buten-2-ol           115-18-4
trans-2-Hexenal                 6728-26-3
4-Hexen-3-one                   2497-21-4
1-Hexen-3-ol                    4798-44-1
2-Methyl-1-butanethiol          1878-18-8
4-Methylcyclohexanone           589-92-4
3-Heptanol                      589-82-2
o-methylanisole                 578-58-5
trans-2-octenal                 2363-89-5
2,3,4-Trimethyl-3-pentanol      3054-92-0
Acetylacetaldehyde dimethyl     5436-21-5
acetal
p-methylacetophenone            122-00-9
o-aminoacetophenone             551-93-9
4-Propylphenol                  645-56-7
2,4-Dimethylanisole             6738-23-4
Benzyl methyl sulfide           766-92-7
Methyl phenylacetate            101-41-7
4-Ethoxybenzaldehyde            10031-82-0
p-tolyl acetate                 140-39-6
2,6-Dimethoxyphenol             91-10-1
Isoborneol                      124-76-5
Methyl 2-methoxybenzoate        606-45-1
Phenylacetaldehyde dimethyl     101-48-4
acetal
3-Phenylpropyl acetate          122-72-5
Ethyl 3-phenylpropionate        2021-28-5
Benzyl butyrate                 103-37-7
Anisyl acetate                  104-21-2
Isobutyl phenylacetate          102-13-6
p-vinylphenol                   2628-17-3
o-tolyl acetate                 533-18-6
2,5-Dihydroxybenzoic acid       490-79-9
o-methoxyphenyl acetate         613-70-7
Lactobionic acid                96-82-2
Magnesium hydrogen phosphate    7782-75-4
trihydrate
Iberverin                       505-79-3
alpha-methylcinnamaldehyde      101-39-3
benzyl phenylacetate            102-16-9
1,3-dimercaptopropane           109-80-8
p-cymen-8-ol                    1197-01-9
phenethyl anthranilate          133-18-6
trihydroxybutyrophenone         1421-63-2
o-methoxycinnamaldehyde         1504-74-1
3-propylidene phthalide         17369-59-4
trans,trans-2,4-decadienal      25152-84-5
piperonyl acetate               326-61-4
2,3-hexanedione                 3848-24-6
isopropyl phenylacetate         4861-85-2
ethyl 3-hydroxybutyrate         5405-41-4
furfural acetone                623-15-4
beta-(2-furyl)acrolein          623-30-3
linalyl anthranilate            7149-26-0
citral diethyl acetal           7492-66-2
allyl anthranilate              7493-63-2
acetyl tributyl citrate         77-90-7
butyl anthranilate              7756-96-9
cyclohexyl anthranilate         7779-16-0
isoamyl cinnamate               7779-65-9
isobutyl anthranilate           7779-77-3
carvyl acetate                  97-42-7
carveol                         99-48-9
3-(Methylthio)propionaldehyde   3268-49-3
Alpha-damascone                 43052-87-5
Dimethyldicarbonate             4525-33-1
Procaine                        59-46-1
5-hydroxy-6-methyl-3,4-         65-23-6
pyridinedimethanol
2-methoxy-Naphthalene           93-04-9
Methyl nicotinate               93-60-7
Ethyl benzoylacetate            94-02-0
Phenethyl benzoate              94-47-3
2-methyl-pentanoic acid         97-61-0
Cyclohexanecarboxylic acid      98-89-5
Methyl b-phenylpropionate       103-25-3
Benzyl 3-methyl butanoate       103-38-8
Naphthalene-2-sulfonic acid     120-18-3
Methyl 4-methoxybenzoate        121-98-2
3-Phenylprop-2-enyl cinnamate   122-69-0
7-methyl-3-methylene-1,6-       123-35-3
Octadiene
Levulinic acid                  123-76-2
2-Mercaptobenzoic acid          147-93-3
m-Dimethoxybenzene              151-10-0
3-butyl-1(3H)-isobenzofuranone  6066-49-5
5-Methylquinoxaline             13708-12-8
2-Ethyl Pyrazine                13925-00-3
trimethyl-pyrazine              14667-55-1
2-ethyl-3-methyl-pyrazine       15707-23-0
2,3-diethyl-pyrazine            15707-24-1
2,3-diethyl-5-methyl-pyrazine   18138-04-0
2-Methylthiopyrazine            21948-70-9
5-Methyl-3H-furan-2-one         591-12-8
cis-3-Hexen-1-ol                928-96-1
3,7-Dimethyl-1,3,6-octatriene   13877-91-3
calcium cyclamate               139-06-0
aconitic acid                   499-12-7
2-Dehydrolinalool               29171-20-8
2-Mercaptopropionic acid        79-42-5
3-Methyl-2-butenal              107-86-8
Allylacetic acid                591-80-0
Allyl cyclohexylacetate         4728-82-9
Allyl cyclohexylpropionate      2705-87-5
Allyl phenoxyacetate            7493-74-5
Allyl phenylacetate             1797-74-6
Allyl alpha-ionone              79-78-7
Butyl butyrolactate             7492-70-8
Cinnamyl isobutyrate            103-59-3
Cinnamyl propionate             103-56-0
Dibenzyl disulfide              150-60-7
Isobornyl acetate               125-12-2
Methyl heptyne carbonate        111-12-6
Triethyl citrate                77-93-0
gamma-Undecalactone             104-67-6
alpha-Amylcinnamyl alcohol      101-85-9
1,3,4,6,7,8-Hexahydro-          1222-05-5
4,6,6,7,8,8-hexamethyl
cyclopenta[g][2]benzopyran
2-Ethylbutyl acetate            10031-87-5
Triphosphoric acid,             13845-36-8
pentapotassium salt
L-(+)-Lactic acid               79-33-4
Mannitol                        87-78-5
2-Methoxy-4-methylphenol        93-51-6
1,2,3-Propanetricarboxylic      144-33-2
acid, 2-hydroxy-, disodium
salt
Ethanesulfonic acid, 2-         1562-00-1
hydroxy-, monosodium salt
2-Methoxy-4-propylphenol        2785-87-7
3,7-Dimethyl-3-octanol          78-69-3
2-Pentyl-furan                  3777-69-3
Butanoic acid, 3-oxo-, butyl    591-60-6
ester
4-(4-Hydroxy-4-methyl pentyl)-  31906-04-4
3-cyclohexene-1-carboxaldehyde
Methyl 3-oxo-2-                 24851-98-7
pentylcyclopentaneacetate
Naphthalene, 2-(2-              2173-57-1
methylpropoxy)-
Perillol                        536-59-4
2-Acetyl-1-methylpyrrole        932-16-1
4-Allyl-2,6-dimethoxyphenol     6627-88-9
Butyl levulinate                2052-15-5
D-(+)-Camphoric acid            124-83-4
D(+)-10-Camphorsulfonic acid    3144-16-9
L-(−)-Carvone                   6485-40-1
(−)-Carvyl propionate           97-45-0
(−)-Caryophyllene oxide         1139-30-6
Cyclohexylacetic acid           5292-21-7
3-Cyclopentylpropionic acid     140-77-2
(−)-Dihydrocarvyl acetate       20777-49-5
3,3-Dimethylacrylic acid        541-47-9
2,4-Dimethylbenzaldehyde        15764-16-6
1,4-Dithiane-2,5-diol           40018-26-6
Ethanesulfonic acid             594-45-6
Ethyl butyrylacetate            3249-68-1
Ethyl (methylthio)acetate       4455-13-4
Ethyl pyruvate                  617-35-6
Ethyl sorbate                   2396-84-1
5-Formyl-2-furansulfonic acid,  31795-44-5
sodium salt
Furfuryl mercaptan              98-02-2
1,6-Hexanedithiol               1191-43-1
trans-2-Hexenoic acid           13419-69-7
trans-2-Hexen-1-ol              928-95-0
4-(4-Hydroxyphenyl)-2-butanone  5471-51-2
Isopulegol                      89-79-2
Isopulegyl acetate              89-49-6
2-Ketobutyric acid              600-18-0
(−)-Limonene                    5989-54-8
4-Methoxyphenylacetone          122-84-9
Methyl cyclohexanecarboxylate   4630-82-4
3-Methylcyclohexanone           591-24-2
3-Methyl-2-cyclohexen-1-one     1193-18-6
3-Methyl-1,2-cyclopentanedione  765-70-8
3-Methyl-2-cyclopenten-1-one    2758-18-1
N-Methyl-D-glucamine            6284-40-8
Methyl 3-                       13532-18-8
(methylthio)propionate
4-Methyl-5-thiazoleethanol      137-00-8
5-Methyl-2-                     13679-70-4
thiophenecarboxaldehyde
DL-3-Methylvaleric acid         105-43-1
(−)-Myrtenal                    564-94-3
Nopol                           128-50-7
gamma-Octanoic lactone          104-50-7
3-Octanol                       589-98-0
E-2-Octenoic acid               1871-67-6
Pamoic acid                     130-85-8
4-Phenyl-2-butyl acetate        10415-88-0
1-Phenyl-1,2-propanedione       579-07-7
2-Phenylpropyl butyrate         80866-83-7
2-Phenylpropyl isobutyrate      65813-53-8
cis-2-Hexen-1-ol                928-94-9
Bis(methylthio)methane          1618-26-4
Magnesium carbonate hydroxide,  39409-82-0
Light
N-Acetyl-L-methionine           65-82-7
4-Methyl-5-vinylthiazole        1759-28-0
2-Methyl-1-phenyl-2-propanol    100-86-7
3-Phenylpropionaldehyde         104-53-0
N-Benzyl-2-phenylethylamine     3647-71-0
1-Phenylethyl propionate        120-45-6
3-Phenylpropyl isobutyrate      103-58-2
Allyl hexanoate                 123-68-2
alpha, 4-Dimethylbenzylalcohol  536-50-5
(−)-Menthyl lactate             59259-38-0
2,6-Dimethylthiophenol          118-72-9
2,4,5-Trimethylthiazole         13623-11-5
Ethyl 3-(methylthio)propionate  13327-56-5
Phenylethyl isovalerate         140-26-1
2-Propylpyrazine                18138-03-9
2-Methyltetrahydrofuran-3-one   3188-00-9
Ethyl 2-                        23747-43-5
(methyldithio)propionate
3,4-Dimethyl-1,2-               13494-06-9
cyclopentanedione
Difurfurylsulfide               13678-67-6
Difurfuryldisulfide             4437-20-1
3-(Methylthio)propanol          505-10-2
Methyl phenyl disulfide         14173-25-2
2-(Methyldithio)-               67952-60-7
isobutyraldehyde
Methyl 2-thiofuroate            13679-61-3
2-Isobutylthiazole              18640-74-9
4-Methyl-5-thiazolylethyl       656-53-1
acetate
2-Acetylthiazole                24295-03-2
2-Ethyl-3,5(6)-                 27043-05-6
dimethylpyrazine
5-Methyl-6,7-dihydro-5H-        23747-48-0
cyclopenta(b)pyrazine
Cinnamyl acetate                103-54-8
2,5-Dihydroxy-2,5-dimethyl-     55704-78-4
1,4-dithiane
5,6,7,8-Tetrahydroquinoxaline   34413-35-9
2-Methyl-3-furanethiol          28588-74-1
Styrallyl acetate               93-92-5
2-Methylhexanoic acid           4536-23-6
2-Methylheptanoic acid          1188-02-9
2,2,6-Trimethylcyclohexanone    2408-37-9
L-Tyrosine ethyl ester          4089-07-0
hydrochloride
Ethyl 4-methoxybenzoate         94-30-4
4-Ethylbenzaldehyde             4748-78-1
N-Ethyl-p-menthane-3-           39711-79-0
carboxamide
1-(2-Furyl)-1,3-butanedione     25790-35-6
Menthofuran                     494-90-6
Methylsulfuric acid sodium      512-42-5
salt
Sucrose diacetate               126-13-6
hexaisobutyrate
N,2,3-Trimethyl-2-              51115-67-4
isopropylbutamide
Tripropionin                    139-45-7
(+/−)-Citronellic acid          502-47-6
5-Acetyl-2,4-dimethylthiazole   38205-60-6
Neryl acetate                   141-12-8
Benzyl propionate               122-63-4
1R-(−)-Camphorsulfonic acid     35963-20-3
3,4-Hexanedione                 4437-51-8
cis-3-Hexenoic acid             4219-24-3
cis-4-Heptenal                  6728-31-0
(E,Z)-2,6-nonadienal            557-48-2
trans-2,trans-6-Nonadienal      17587-33-6
4-Methyl-2-pentenal             5362-56-1
cis-6-Nonenal                   2277-19-2
Methyl propyl disulfide         2179-60-4
8-p-Menthen-1-ol                138-87-4
p-Menthan-2-one                 499-70-7
Bisabolene                      495-62-5
Ethyl cyclohexanecarboxylate    3289-28-9
Phenylpyruvate                  156-06-9
Hydroxypyruvate                 1113-60-6
4-Methyl-2-oxopentanoate        816-66-0
(+)-Neomenthol                  2216-52-6
trans-Citral                    141-27-5
Piperitenone                    491-09-8
Sabinene hydrate                546-79-2
Perillyl aldehyde               2111-75-3
2-Hydroxyethanesulfonate        107-36-8
Acetyl isovaleryl               13706-86-0
Acetyl valeryl                  96-04-8
Butylidene phthalide            551-08-6
Carvacryl ethyl ether           4732-13-2
Ethyl vanillin propylene        68527-76-4
glycol acetal
Hexyl hexanoate                 6378-65-0
2-Methyl-5-(methylthio)-furan   13678-59-6
2-Methyl-4-pentenoic acid       1575-74-2
2-Methyl-4-propyl-1,3-          67715-80-4
oxathiane
3-Methylthio-1-hexanol          51755-66-9
cis-6-Nonenol                   35854-86-5
Rose oxide                      16409-43-1
L-Linalool                      126-91-0
5,6-Dimethyl-8-                 4674-50-4
isopropenylbicyclo[4.4.0]dec-
1-en-3-one
2-Ethyl-3,5-dimethylpyrazine    13925-07-0
2-Isopropylpyrazine             29460-90-0
2-Isobutyl-3-methyl-pyrazine    13925-06-9
2-Methoxy-3-sec-butyl-pyrazine  24168-70-5
2-Methylthio-3(6)-methyl-       67952-65-2
pyrazine
Benzylcarbinyl propionate       122-70-3
Bornyl acetate                  76-49-3
furaneol                        3658-77-3
Methoxycinnamaldehyde           1963-36-6
Methylphenol, hydrogen sulfate  68127-34-4
Lactitol monohydrate            81025-04-9
2H-Pyrrole, 3,4-dihydro-        5724-81-2
2-Butenal, 2-methyl-, (E)-      497-03-0
2-Pentenal                      764-39-6
Ethanethioic acid, S-methyl     1534-08-3
ester
2-Hexenal                       505-57-7
2-Methyl-2-pentenal             623-36-9
Cyclopentanethiol               1679-07-8
Butane, 2-ethoxy-               2679-87-0
S-Ethyl thioacetate             625-60-5
ethyl methyl carbonate          623-53-0
3(2H)-Furanone, 2,5-dimethyl-   14400-67-0
Allyl propionate                2408-20-0
methyl 2-methylbutanoate        868-57-5
2-Butanone, 1-(methylthio)-     13678-58-5
Ethanethioic acid, S-propyl     2307-10-0
ester
1,2-Butanedithiol               16128-68-0
6-Methyl-3,5-heptadiene-2-one   1604-28-0
2-Octen-4-one                   4643-27-0
2,5-dimethyl-3-furanthiol       55764-23-3
2-Heptenoic acid                18999-28-5
Butanoic acid, 2-propenyl       2051-78-7
ester
6-Methyl-5-hepten-2-ol          1569-60-4
trans-2-Octen-4-ol              20125-81-9
cis-3-Octen-1-ol                20125-84-2
1-Butanol, 2-methyl-, acetate   624-41-9
4-methyl-alpha-methylstyrene    1195-32-0
trans-3-phenyl-2-propen-1-ol    4407-36-7
Benzeneacetaldehyde, alpha-     93-53-8
methyl-
Benzene, (2-methoxyethyl)-      3558-60-9
Cyclohexene, 1-methyl-4-(1-     7705-14-8
methylethenyl)-, (+−)-
Phenol, 2-(methylthio)-         1073-29-6
2-Hexen-1-yl acetate            2497-18-9
3-Hexen-1-ol, acetate, (Z)-     3681-71-8
5-Hydroxy-4-octanone            496-77-5
butyl 2-methylpropanoate        97-87-0
Benzofuran-2-carboxaldehyde     4265-16-1
DL-Lysine                       70-54-2
1-Hexanethiol, 2-ethyl-         7341-17-5
2′,4′-Dimethylacetophenone      89-74-7
2-Pentylpyridine                2294-76-0
1-Methoxy-4-propyl benzene      104-45-0
1-Hydroxy-2-methoxy-4-ethyl     2785-89-9
benzene
Nonalactone                     6008-27-1
Cyclohexyl propionate           6222-35-1
Allyl 2-ethylbutyrate           7493-69-8
Butanoic acid, 3-oxo-, 2-       7779-75-1
methylpropyl ester
n-Butyl pentanoate              591-68-4
3,7-Dimethyl-1-octanol          106-21-8
3-Buten-2-one, 3-methyl-4-      1901-26-4
phenyl-
2-Propenoic acid, 3-phenyl-,    1754-62-7
methyl ester, (E)-
Benzene, 4-ethenyl-1,2-         6380-23-0
dimethoxy-
Benzenepropanol, alpha,alpha-   103-05-9
dimethyl-
Benzene, (butoxymethyl)-        588-67-0
Dimethyl anthranilate           85-91-6
2-Hexanoylfuran                 14360-50-0
Cyclohexyl butyrate             1551-44-6
Naphthalene, 2-ethoxy-          93-18-5
Acetoacetic acid isoamyl ester  2308-18-1
Propanoic acid, 2-methyl-, 4-   103-93-5
methylphenyl ester
4-(4-Methoxyphenyl)-2-butanone  104-20-1
Isobutyl benzoate               120-50-3
Benzene, 1,2-dimethoxy-4-(1-    93-16-3
propenyl)-
beta-                           10415-87-9
Phenylethylmethylethylcarbinol
1,1-Dimethoxy-2-phenylpropane   90-87-9
Geranyl formate                 105-86-2
Bornyl formate                  7492-41-3
6-Octen-1-ol, 3,7-dimethyl-,    105-85-1
formate
Benzeneacetic acid, butyl       122-43-0
ester
3,5,9-Undecatrien-2-one, 6,10-  141-10-6
dimethyl-
Anisyl propionate               7549-33-9
Butanoic acid, 3-phenyl-2-      103-61-7
propenyl ester
2-Propenoic acid, 3-phenyl-,    122-67-8
2-methylpropyl ester
Eugenyl acetate                 93-28-7
3-Methylbutyl phenylacetate     102-19-2
Benzoic acid, 2-(methylamino)-, 65505-24-0
2-methylpropyl ester
Phenoxy ethyl isobutyrate       103-60-6
Anisyl butyrate                 6963-56-0
2,6-Octadien-1-ol, 3,7-         105-91-9
dimethyl-, propanoate, (Z)-
Isobornyl propionate            2756-56-1
1,3,5-Trithiane, 2,2,4,4,6,6-   828-26-2
hexamethyl-
Geranyl N-butyrate              106-29-6
Geranyl isobutyrate             2345-26-8
Thiophene, 2,2′-dithiobis-      6911-51-9
2-Propenoic acid, 3-phenyl-,    7779-17-1
cyclohexyl ester
Benzeneacetic acid, 3-phenyl-   7492-65-1
2-propenyl ester
Anisyl phenylacetate            102-17-0
2-Propenoic acid, 3-phenyl-,    122-68-9
3-phenylpropyl ester
Geranyl phenylacetate           102-22-7
hexyl 2-methylbutyrate          10032-15-2
4-heptanolide                   105-21-5
Neral                           106-26-3
(E)-2-octenol                   18409-17-1
Ethyl 3-hydroxyhexanoate        2305-25-1
isopropyl hexanoate             2311-46-8
hexyl butanoate                 2639-63-6
bis(2-methyl-3-furyl)disulfide  28588-75-2
3-hydroxy-4,5-dimethyl-2(5H)-   28664-35-9
furanone
2-acetyl-2-thiazoline           29926-41-8
(E,E)-2,4-octadienal            30361-28-5
geranyl acetone                 3796-70-1
1-octen-3-one                   4312-99-6
3-mercapto-2-pentanone          67633-97-0
(Z)-3-hexenal                   6789-80-6
4-hexanolide                    695-06-7
5-octanolide                    698-76-0
delta-decalactone               705-86-2
4-vinylguaiacol                 7786-61-0
Amyl salicylate                 2050-08-0
Cyclohexyl formate              4351-54-6
Dimethylbenzylcarbinyl acetate  151-05-3
Geranyl propionate              105-90-8
Terpinyl acetate                80-26-2
isopropyl 3-methylbutanoate     32665-23-9
isopropyl 2-methylbutanoate     66576-71-4
3-Hexenyl 3-methylbutanoate     10032-11-8
Isoamyl 2-methylbutyrate        27625-35-0
3-Octyl acetate                 4864-61-3
Benzyl isobutyrate              103-28-6
Cis-3-hexenyl butyrate          16491-36-4
Cis-3-hexenyl lactate           61931-81-5
Citronellyl butyrate            141-16-2
Citronellyl propionate          141-14-0
Isoamyl hexanoate               2198-61-0
1,3,5-Undecatriene              16356-11-9
1-Benzyloxy-2-methoxy-4-        120-11-6
propenyl benzene
1-Octen-3-yl acetate            198242
2-Acetyl-3-ethyl pyrazine       32974-92-8
2-Isopropyl-4-methyl thiazole   15679-13-7
2-Methyl-2-pentenoic acid       3142-72-1
2-sec-butyl thiazole            18277-27-5
4,5-Dimethyl thiazole           3581-91-7
4-(2,6,6-Trimethyl-2-           31499-72-6
cyclohexen-1-yl)butan-2-one
4-(2,6,6-Trimethyl cyclohexa-   23696-85-7
1,3-dienyl)but-2-en-4-one
Acetaldehyde phenethyl propyl   7493-57-4
acetal
Acetaldehyde ethyl cis-3-       28069-74-1
hexenyl acetal
Acetone propylene glycol        1193-11-9
acetal
Acetyl isoeugenol               93-29-8
2-Acetyl-5-methyl furan         1193-79-9
Allyl cyclohexylbutyrate        7493-65-4
Alpha,alpha-dimethylphenethyl   10094-34-5
butyrate
Alpha,alpha-dimethyl phenethyl  10058-43-2
formate
Alpha,beta-santalol             11031-45-1
Alpha-amyl cinnamaldehyde       91-87-2
dimethyl acetal
Alpha-fenchyl acetate           13851-11-1
Alpha-furfuryl pentanoate       36701-01-6
Alpha-ionol                     25312-34-9
6-Methyl-alpha-ionone           79-69-6
Alpha-methyl-p-                 103-95-7
isopropylphenylpropanaldehyde
Alpha-n-amyl-beta-phenylacryl   7493-78-9
acetate
Alpha-piperitone                6091-50-5
Alpha-n-amyl-beta-phenyl acryl  7493-80-3
isovalerate
6-Amyl-alpha-pyrone             27593-23-3
Anisyl formate                  122-91-8
Benzylcarbinyl 2-methyl         24817-51-4
butyrate
Benzylcarbinyl 3-phenyl         103-53-7
propenoate
Benzylcarbinyl alpha-toluate    102-20-5
Benzylcarbinyl butyrate         103-52-6
Benzylcarbinyl caproate         6290-37-5
Benzylcarbinyl formate          104-62-1
Benzylcarbinyl isobutyrate      103-48-0
Benzylcarbinyl salicylate       87-22-9
Benzylcarbinyl tiglate          55719-85-2
Benzyl dipropyl ketone          7492-37-7
Benzyl tiglate                  37526-88-8
Beta-homocyclocitral            472-66-2
Beta-ionol                      22029-76-1
3-Phenylpropyl propanoate       122-74-7
Bois de rose oxide              7392-19-0
Butyl 2-methyl butyrate         15706-73-7
Butyl cinnamate                 538-65-8
ortho-sec-Butyl cyclohexanone   14765-30-1
isobutyl cis-2-methyl-2-        7779-81-9
butenoate
5-n-Butyl-delta-valerolactone   3301-94-8
Campholenic aldehyde            4501-58-0
Cedran-8-yl acetate             77-54-3
Cinnamyl isovalerate            140-27-2
Cis-3-hexenyl benzoate          25152-85-6
Cis-3-hexenyl caproate          31501-11-8
Cis-3-hexenyl formate           33467-73-1
Cis-3-hexenyl isobutyrate       41519-23-7
Cis-3-hexenyl phenylacetate     42436-07-7
Cis-3-hexenyl propionate        33467-74-2
Cis-3-hexenyl tiglate           67883-79-8
Cis-3-hexenyl valerate          35852-46-1
cis-4-Hepten-1-ol               6191-71-5
Cis-5-octen-1-ol                64275-73-6
Citral dimethyl acetal          7549-37-3
Citronellyl isobutyrate         97-89-2
Citronellyl isovalerate         68922-10-1
Citronellyl valerate            7540-53-6
Citroxide                       7416-35-5
Cocal                           21834-92-4
p-Cresyl alpha-toluate          101-94-0
p-Cresyl isovalerate            55066-56-3
Dehydro-beta-cyclocitral        116-26-7
8,8-Diethoxy-2,6-dimethyl-2-    7779-94-4
octanol
5,7-Dihydro-2-methyl            36267-71-7
thieno(3,4-d)pyrimidine
2,5-Dihydro-4,5-dimethyl-2-(2-  65894-83-9
methyl propyl)thiazole
Dihydrojasmone                  1128-08-1
Dihydroxyacetophenone           28631-86-9
1,1-Dimethoxy-3,7-dimethyl-7-   141-92-4
octanol
3,7-Dimethyl-1,6-octadien-3-yl  126-64-7
benzoate
3,7-Dimethyl-1,6-octadien-3-yl  78-36-4
butyrate
3,7-Dimethyl-1,6-octadien-3-yl  78-35-3
isobutyrate
3,7-Dimethyl-1,6-octadien-3-yl  144-39-8
propanoate
cis-3,7-Dimethyl-2,6-octadien-  2345-24-6
1-yl 2-methyl propanoate
2,4-Dimethyl-3-cyclohexene-1-   68039-49-6
carboxaldehyde
2,6-Dimethyl-5-hepten-1-al      106-72-9
trans,cis-2,6-Dodecadien-1-al   21662-13-5
Eglantal                        26643-91-4
Ethyl E-2-hexenoate             27829-72-7
Ethyl tiglate                   5837-78-5
Ethyl trans-4-decenoate         76649-16-6
5-Ethyl-4-hydroxy-2-methyl-     27538-09-6
3[2H]furanone
2-Ethyl-4-methyl thiazole       15679-12-6
2,6,10-Trimethyl-2,6,10-        762-29-8
pentadecatrien-14-one
Guaiacyl phenyl acetate         4112-89-4
3-Hepten-2-one                  1119-44-4
trans-2-Hexen-1-ol              2305-21-7
Trans-2-hexenyl butyrate        53398-83-7
Hexyl phenylacetate             5421-17-0
Hexyl propionate                2445-76-3
Hydroxycitronellol              107-74-4
Isobutyl 2-butenoate            589-66-2
Isobutyl salicylate             87-19-4
Isodihydro lavandulal           35158-25-9
Isoeugenyl phenyl acetate       120-24-1
Isopropyl alpha-                1733-25-1
methylcrotonate
p-Menth-1-en-8-yl propionate    80-27-3
Menthalactone                   13341-72-5
3-Methoxy-p-cymene              1076-56-8
Methyl 4-methyl pentanoate      2412-80-8
alpha-Methyl benzyl formate     7775-38-4
2-Methylbutyl 2-                2445-78-5
methylbutanoate
Methyl e-2-octenoate            2396-85-2
p-Methyl hydratropaldehyde      99-72-9
3-(5-Methyl-2-furyl)butanal     31704-80-0
Nerol oxide                     1786-08-9
trans,cis-2,6-Nonadien-1-ol     7786-44-9
trans-2-Octen-1-yl acetate      3913-80-2
3-Octen-2-one                   1669-44-9
2-Phenyl-2-butenal              4411-89-6
2-Propionylthiazole             43039-98-1
1-Hydroxy-2-butanone            5077-67-8
2-Butanone, 3-hydroxy-, (+−)-   52217-02-4
Thiazole, 2,5-dimethyl-         4175-66-0
Butanethioic acid, S-methyl     2432-51-1
ester
2,4-Hexadienoic acid, methyl    689-89-4
ester, (E,E)-
Benzeneacetaldehyde, 4-methyl-  104-09-6
Bicyclo[4.1.0]hept-3-ene,       498-15-7
3,7,7-trimethyl-, (1S)-
Ethyl 3-hexenoate               2396-83-0
1H-Pyrrole, 1-(2-               1438-94-4
furanylmethyl)-
6-Octenal, 3,7-dimethyl-, (R)-  2385-77-5
Ethanethioic acid, S-(2-        13678-68-7
furanylmethyl) ester
6-Octen-1-ol, 3,7-dimethyl-,    1117-61-9
(R)-
6-Octen-1-ol, 3,7-dimethyl-,    7540-51-4
(S)-
DL-Tetrohydrofurfuryl           637-65-0
propionate
Benzenepentanol                 10521-91-2
Cyclohexaneethanol, acetate     21722-83-8
Benzyl isobutyl ketone          5349-62-2
Butanoic acid, 3-oxo-,          5396-89-4
phenylmethyl ester
1,2-Ethanediamine, N,N′-        140-28-3
bis(phenylmethyl)-
2-Ethyl-3-hydroxy-4-pyrone      1110651
Dicyclohexyl disulfide          2550-40-5
Tetrahydrofurfuryl butyrate     2217-33-6
Thujone                         546-80-5
Benzyl alcohol, alpha-methyl-,  3460-44-4
butyrate
Citronellyl tiglate             24717-85-9
Lactitol                        585-86-4
Nonivamide                      2444-46-4
2-Acetoxy-3-butanone            4906-24-5
3-Acetyl-2,5-dimethylthiophene  230378
3-Acetyl-2-5dimethylfuran       10599-70-9
4-Acetyl-6-t-butyl-1,1-         13171-00-1
dimethylindan
Allyl 2-furoate                 4208-49-5
Allyl sorbate                   7493-75-6
Allyl thiopropionate            41820-22-8
Allyl tiglate                   7493-71-2
Amylcyclohexyl acetate          67874-72-0
Benzaldehyde glyceryl acetal    1319-88-6
Benzaldehyde propylene glycol   2568-25-4
acetal
Bornyl isovalerate              76-50-6
1,3-Butanedithiol               24330-52-7
2,3-Butanedithiol               4532-64-3
Butyl cinnamic aldehyde         7492-44-6
Cinnamyl benzoate               5320-75-2
Citral ethylene glycol acetal   66408-78-4
Citronellyloxyacetaldehyde      7492-67-3
Citronellyl phenylacetate       139-70-8
Cyclohexyl isovalerate          7774-44-9
Decalactone                     5579-78-2
2,5-Dimethyl-4-methoxy-3(2H)-   4077-47-8
furanone
6,10-Dimethyl-9-undecen-2-one   4433-36-7
2-Ethoxythiazole                15679-19-3
Ethyl 2-mercaptopropionate      19788-49-9
Ethyl 2-methyl-4-pentenoate     53399-81-8
Ethyl 3-(2-furyl)propanoate     94278-27-0
Ethyl cyclohexanepropionate     10094-36-7
Ethyl (p-tolyloxy)acetate       67028-40-4
3-Ethyl-2-hydroxy-2-            21835-01-8
cyclopenten-1-one
Ethylene brassylate             105-95-3
2-Ethylfenchol                  18368-91-7
Furfuryl 3-methylbutanoate      13678-60-9
Furfuryl butyrate               623-21-2
Furfuryl isopropyl sulfide      1883-78-9
Furfuryl methyl sulfide         1438-91-1
Furfuryl propionate             623-19-8
Furfuryl thiopropionate         59020-85-8
Geranyl acetoacetate            10032-00-5
Geranyl benzoate                94-48-4
Geranyl isovalerate             109-20-6
delta-Hexalactone               823-22-3
trans-3-Hexenal                 69112-21-6
cis-3-Hexenyl anthranilate      65405-76-7
trans-2-Hexenyl propionate      53398-80-4
5-(cis-3-Hexenyl) dihydro-5-    70851-61-5
methyl-2(3H)furanone
Hexyl 2-formate                 39251-86-0
Hexyl crotonate                 19089-92-0
Hexyl formate                   629-33-4
Isoamyl 3-(2-furyl)propionate   7779-67-1
Isoamyl pyruvate                7779-72-8
Isobutyl furylpropionate        105-01-1
Isohexenyl cyclohexenyl         37677-14-8
carboxaldehyde
p-Isopropyl phenylacetaldehyde  4395-92-0
Linalyl cinnamate               78-37-5
Linalyl formate                 115-99-1
Linalyl isovalerate             1118-27-0
Linalyl phenylacetate           7143-69-3
Maltol isobutyrate              65416-14-0
Methyl 2-methylpentanoate       2177-77-7
Methyl 3-hydroxyhexanoate       21188-58-9
Methyl 3-nonenoate              13481-87-3
Methyl furfuryl disulfide       57500-00-2
Methyl p-tert-                  3549-23-3
butylphenylacetate
3-Methyl-1,2-cyclohexanedione   3008-43-3
alpha-Methylanisalacetone       104-27-8
2-Methylbutyl isovalerate       2445-77-4
4-Methylnonanoic acid           45019-28-1
4-Methyloctanoic acid           54947-74-9
2-Methyltetrahydrothiophen-3-   13679-85-1
one
3-(Methylthio)butanal           16630-52-7
4-(Methylthio)butanol           20582-85-8
4-Methylthio-2-butanone         34047-39-7
4-Methylthio-4-methyl-2-        23550-40-5
pentanone
Neryl butyrate                  999-40-6
Neryl formate                   2142-94-1
Neryl isovalerate               3915-83-1
Octahydrocoumarin               4430-31-3
Phenethyl 2-furoate             7149-32-8
1-Phenyl-2-pentanol             705-73-7
Phenylacetaldehyde              68345-22-2
diisobutylacetal
Phenylacetaldehyde glyceryl     29895-73-6
acetal
2-(3-Phenylpropyl)pyridine      2110-18-1
Propyl phenylacetate            4606-15-9
Pyrazineethanethiol             35250-53-4
Ethyl 2-methyl pentanoate       39255-32-8
Methyl 2,4-decadienoate         4493-42-9
alpha-Isomethyl ionone          127-51-5
5-Methyl hexanoic acid          628-46-6
Ethyl 3-methyl pentanoate       5870-68-8
Ethyl 2-methyl-3,4-             60523-21-9
pentadienoate
3-Nonen-2-one                   14309-57-0
5-Methyl-3-hexen-2-one          5166-53-0
Maltol propionate               68555-63-5
2-Methyl-3-(2-furyl) acrolein   874-66-8
Ethyl 3(2-furyl)propanoate      10031-90-0
2-Phenyl-3-(2-furyl)-propenal   57568-60-2
4-Methyl-2-pentyl-1,3-          1599-49-1
dioxolane
2-Ethyl-4,5-dimethyl oxazole    53833-30-0
Isobornyl isovalerate           7779-73-9
Theophylline-7-acetic acid      652-37-9
Ethyl trans-2-octenoate         7367-82-0
DL-Arginine                     7200-25-1
Allyl Crotonate                 20474-93-5
2-Methoxystyrene                612-15-7
Magnesium Fumarate              7704-71-4
2-Propionylpyrrole              1073-26-3
2-methyl-1,3-dithiolane         5616-51-3
2-ethyl-5-methyl pyrazine       13360-64-0
2-methyl-3-(dimercaptomethyl)-  65505-17-1
furan
Magnesium gluconate             3632-91-5
Manganese gluconate             6485-39-8
Erythritol                      149-32-6
D-Arabinose                     28697-53-2
D-Galactose                     59-23-4
D-(+)-Mannose                   3458-28-4
Sorbitol                        50-70-4
Aspartame                       22839-47-0
Cyclamic Acid                   100-88-9
Dulcin                          150-69-6
Glucose-1-phosphate             29732-59-0
Dipotassium Salt
L-(+)-Arabinose                 87-72-9
Fructose-6-Phosphate            643-13-0
D-Maltose Monohydrate           6363-53-7
Ribose                          24259-59-4
Fructose 1,6-Diphosphate        26177-85-5
Disodium Salt
Saccharin sodium, dihydrate     6155-57-3
1,2-Benzisothiazol-3(2H)-one    6485-34-3
1,1-dioxide, calcium salt
1,2-Benzisothiazolin-3-one      10332-51-1
1,1-dioxide, potassium salt
zeranol                         26538-44-3
beta-D-fructopyranose           7660-25-5
D-fructose 1,6-bisphosphate     488-69-7
Ribose 5-phosphate              4300-28-1
Arabinose                       147-81-9
Saccharin, sodium salt hydrate  82385-42-0
Maltitol                        585-88-6
D-Fructose 1-phosphate          15978-08-2
D-Sorbitol 6-phosphate          108392-12-
alpha-D-Xylose                  31178-70-8
Inositol 1-phosphate            573-35-3

TABLE 10
Name                           CAS #
Sodium Metabisulfite           7681-57-4
sodium hydrogen phosphate      7558-79-4
Sodium Phosphate Monobasic     7558-80-7
Sodium thiosulfate             7772-98-71
Orthoboric acid                10043-35-3
Diethanolamine                 111-42-2
Benzaldehyde                   100-52-7
Sorbic acid                    110-44-1
L-(+)-Tartaric Acid            87-69-4
D-mannitol                     69-65-8
Butyl paraben                  94-26-8
Thymol                         89-83-8
Methyl salicylate              119-36-8
Citric acid                    77-92-9
Creatinine                     60-27-5
Vitamin C                      50-81-7
Benzoic Acid                   65-85-0
Methyl 4-hydroxybenzoate       99-76-3
m-Cresol                       108-39-4
p-Cresol                       106-44-5
Aspirin                        50-78-2
Phenol                         108-95-2
Sucrose                        57-50-1
Potassium citrate, monohydrate 1534146
Sodium acetate                 127-09-3
Lactic acid                    50-21-5
Propionic acid, sodium salt    65-85
Benzyl alcohol                 100-51-6
Phenethyl alcohol              60-12-8
Cholesterol                    57-88-5
D-Glucose                      50-99-7
Sorbitol                       50-70-4
Aspartame                      22839-47-0
Saccharin                      81-07-2
2,6-Di-tert-Butyl-p-Cresol     128-37-0
4-Chloro-3-methylphenol        59-50-7
glycerin                       56-81-5
Propyl paraben                 94-13-3
fumaric acid                   110-17-8
dabco                          280-57-9
p-Phenylenediamine             106-50-3
Anethole                       4180-23-8
propyl gallate                 121-79-9
L-monosodium glutamate         142-47-2
Butylated hydroxyanisole       25013-16-5
Cyclohexanol, 5-methyl-2-(1-   89-78-1
methylethyl)-,
(1alpha,2beta,5alpha)-
alpha-Thioglycerol             96-27-5
Sodium dehydroacetate          4418-26-2
Ethyl 4-hydroxybenzoate        120-47-8
Ethyl Vanillin                 121-32-4
Triacetin                      102-76-1
Potassium sorbate              590-00-1
Triethyl citrate               77-93-0
(S)-(+)-Arginine               74-79-3
Glycine                        56-40-6
(S)-(−)-Histidine              71-00-1
(S)-(+)-Lysine                 56-87-1
Quinone                        106-51-4
Naphthalene, 2-ethoxy-         93-18-5
Methanesulfonic Acid           75-75-2
DL-Tartaric Acid               133-37-9
Cyclamic acid                  100-88-9
(S)-(−)-Phenylalanine          63-91-2
(S)-(−)-Tyrosine               60-18-4
Carvone                        99-49-0
Ethyl butyrate                 105-54-4
6-Methyl-5-hepten-2-one        110-93-0
Ethyl acetoacetate             141-97-9
Methyl benzoate                93-58-3
Phenylacetic Acid              103-82-2
Adipic acid                    124-04-9
Ethyl benzoate                 93-89-0
Benzyl benzoate                120-51-4
Pyruvic acid                   127-17-3
Succinic acid                  110-15-6
Indole                         120-72-9
Methyl anthranilate            134-20-3
Diethyl malonate               105-53-3
Niacin                         59-67-6
Meso-inositol                  87-89-8
4-Aminobenzoic acid            150-13-0
Anisole                        100-66-3
Urea                           57-13-6
Pyrrolidine                    123-75-1
Cyclopentanone                 120-92-3
Acetic anhydride               108-24-7
Benzophenone                   119-61-9
D-(−)-Fructose                 57-48-7
D-(+)-Xylose                   58-86-6
o-Methoxybenzoic Acid          579-75-9
linalool                       78-70-6
ethyl isovalerate              108-64-5
1,1′-Azobisformamide           123-77-3
6-Methylcoumarin               92-48-8
acetoin                        513-86-0
alpha-Phellandrene             99-83-2
Cymene                         99-87-6
Dimethyl Succinate             106-65-0
p-Anisaldehyde                 123-11-5
Phenyl ether                   101-84-8
Tetrahydro-2-furanmethanol     97-99-4
Valeric Acid                   109-52-4
3,4-xylenol                    95-65-8
1,1-diethoxyethane             105-57-7
ethyl butyraldehyde            97-96-1
Ethyl crotonate                623-70-1
ethyl isobutyrate              97-62-1
methyl isovalerate             556-24-1
methyl propionate              554-12-1
methyl valeraldehyde           123-15-9
4-(2,6,6-Trimethyl-2-          127-41-3
cyclohexen-1-yl)-3-buten-2-one
4-(2,6,6-trimethyl-1-          14901-07-6
cyclohexen-1-yl)-3-buten-2-one
Maleic acid                    110-16-7
3-Methylbutanoic acid          503-74-2
L-Glutamic Acid                56-86-0
D-limonene                     5989-27-5
1-Phenyl-1-propanol            93-54-9
2′-Hydroxyacetophenone         118-93-4
2,4-Dihydroxybenzoic Acid      89-86-1
2-Phenyl-1-propanol            1123-85-9
3-Phenylpropionic Acid         501-52-0
4-Ethoxyphenol                 622-62-8
Alpha-Terpineol                98-55-5
Benzaldehyde Dimethylacetal    1125-88-8
Benzyl Ether                   103-50-4
Benzyl Formate                 104-57-4
Benzyl Salicylate              118-58-1
Cinnamyl Alcohol               104-54-1
D-(+)-Glucono-1,5-lactone      4253-68-3
D-Isoascorbic Acid             89-65-6
2,3-Naphthalenediol            92-44-4
Diethyl Succinate              123-25-1
Ethyl 2-Aminobenzoate          87-25-2
Ethyl Cinnamate                103-36-6
Ethyl Phenylacetate            101-97-3
Ethyl Salicylate               118-61-5
gamma-Valerolactone            108-29-2
Hydroquinone Dimethyl Ether    150-78-7
Isocaproic Acid                645-07-1
Isoeugenol                     97-54-1
Isopropyl Benzoate             939-48-0
L-(+)-Isoleucine               73-32-5
L-Malic acid                   97-67-6
L-2-Aminopropionic Acid        56-41-7
L-Carnitine                    541-15-1
L-Glutamine                    56-85-9
L-Hydroxyproline               51-35-4
L-Proline                      147-85-3
L-Serine                       56-45-1
L-Threonine                    72-19-5
L-Valine                       72-18-4
Phenoxyacetic Acid             122-59-8
Veratrole                      91-16-7
2-Ethylbutyric acid            88-09-5
2-Methylpyrazine               109-08-0
o-methoxybenzaldehyde          135-02-4
L-Leucine                      61-90-5
L-Asparagine                   70-47-3
propiophenone                  93-55-0
5-isopropyl-2-methyl-phenol    499-75-2
Xylitol                        87-99-0
ethyl 4-oxopentanoate          539-88-8
methyl cinnamate               103-26-4
cumic alcohol                  536-60-7
methyl 2-naphthyl ketone       93-08-3
1-methyl-4-(1-methylethyl)-    99-85-4
1,4-Cyclohexadiene
en-ethylene diamine
Caffeine                       58-08-2
5-methylfurfural               620-02-0
furfuryl acetate               623-17-6
terpinen-4-ol                  10482-56-1
phenylethanal                  122-78-1
4′-Methoxyacetophenone         100-06-1
D-Fenchone                     4695-62-9
1-Methoxy-4-methylbenzene      104-93-8
o-methylanisole                578-58-5
Acetylacetaldehyde dimethyl    5436-21-5
acetal
p-methylacetophenone           122-00-9
Methyl phenylacetate           101-41-7
4-Ethoxybenzaldehyde           10031-82-0
p-tolyl acetate                140-39-6
2,6-Dimethoxyphenol            91-10-1
Methyl 2-methoxybenzoate       606-45-1
alpha-methylcinnamaldehyde     101-39-3
2-methoxycinnamaldehyde        60125-24-8
Potassium bicarbonate          298-14-6
piperonyl acetate              326-61-4
2,3-hexanedione                3848-24-6
furfural acetone               623-15-4
trans beta-(2-furyl)acrolein   623-30-3
carveol                        99-48-9
Methyl nicotinate              93-60-7
Ethyl benzoylacetate           94-02-0
Methyl 4-methoxybenzoate       121-98-2
Levulinic acid                 123-76-2
m-Dimethoxybenzene             151-10-0
2-acetylpyridine               1122-62-9
tetramethyl-pyrazine           1124-11-4
2,3-dimethyl-pyrazine          5910-89-4
trimethyl-pyrazine             14667-55-1
2-ethyl-3-methyl-pyrazine      15707-23-0
5-Methyl-3H-furan-2-one        591-12-8
2-Methoxy-4-methylphenol       93-51-6
piperazine                     110-85-0
2-Methoxy-4-propylphenol       2785-87-7
Naphthalene, 2-(2-             2173-57-1
methylpropoxy)-
2-Acetyl-1-methylpyrrole       932-16-1
3,3-Dimethylacrylic acid       541-47-9
Ethyl sorbate                  2396-84-1
4-(4-Hydroxyphenyl)-2-butanone 5471-51-2
4-Methoxyphenylacetone         122-84-9
(−)-Myrtenal                   564-94-3
3-Phenylpropionaldehyde        104-53-0
1-Phenylethyl propionate       120-45-6
2-Methyltetrahydrofuran-3-one  3188-00-9
Cinnamyl acetate               103-54-8
Styrallyl acetate              93-92-5
Ethyl 4-methoxybenzoate        94-30-4
Benzyl propionate              122-63-4
Phenylpyruvate                 156-06-9
furaneol                       3658-77-3
methyl 2-methylbutanoate       868-57-5
Benzeneacetaldehyde, alpha-    93-53-8
methyl-
Dimethyl anthranilate          85-91-6
1,1-Dimethoxy-2-phenylpropane  90-87-9
4-hexanolide                   695-06-7
Dimethylbenzylcarbinyl acetate 151-05-3
Benzyl isobutyrate             103-28-6
Acetyl isoeugenol              93-29-8
2-Acetyl-5-methyl furan        1193-79-9
Alpha-methyl-p-                103-95-7
isopropylphenylpropanaldehyde
Benzylcarbinyl formate         104-62-1
p-Cresyl alpha-toluate         101-94-0
Potassium bisulfate            7646-93-7
Potassium carbonate            584-08-7
Potassium chloride             7447-40-7
Potassium hydroxide            1310-58-3
Ethyl tiglate                  5837-78-5
Nerol oxide                    1786-08-9
DL-Tetrohydrofurfuryl          637-65-0
propionate
Benzaldehyde propylene glycol  2568-25-4
acetal
2-Methyl-3-(2-furyl) acrolein  874-66-8
vanillin                       121-33-5
Cholic acid                    81-25-4
R-Carvone                      6485-40-1
Potassium nitrate              7757-79-1
Potassium permanganate         7722-64-7
Potassium persulfate           7727-21-1
Potassium phosphate, dibasic   2139900
Potassium Phosphate Monobasic  7778-77-0
Potassium sulfate              7778-80-5
Sodium bicarbonate             144-55-8
Sodium bisulfite               7631-90-5
Sodium carbonate               497-19-8
Sodium chloride                7647-14-5
Sodium dithionite              7775-14-6
Sodium hydroxide               1310-73-2
Sodium nitrite                 7632-00-0
Sodium Pyrophosphate           7722-88-5
Sodium sulfate                 7757-82-6
Sodium sulfite                 7757-83-7
Sodium thiocyanate             540-72-7
Calcium Carbonate              471-34-1
Calcium chloride               10043-52-4
Calcium gluconate              299-28-5
Calcium hydroxide              1305-62-0
Calcium phosphate, dibasic     7757-93-9
Calcium sulfate                7778-18-9
N-Methyl-D-glucamine           6284-40-8
Calcium oxide                  1305-78-8
Calcium Phosphate Monobasic    7758-23-8
Magnesium chloride hexahydrate 7791-18-6
Magnesium sulfate              7487-88-9
Magnesium Sulfate Heptahydrate 10034-99-8
Aluminum chloride hexahydrate  7784-13-6
aluminum nitrate nonahydrate   7784-27-2
Aluminum potassium sulfate,    7784-24-9
dodecahydrate
Aluminum sulfate,              7784-31-8
octadecahydrate
(S)-(−)-Cysteine               52-90-4
p-Toluenesulfonic Acid         104-15-4
Potassium bitartrate           868-14-4
DL-aspartic acid               617-45-8
p-Dimethylaminobenzaldehyde    100-10-7
Sodium salicylate              54-21-7
Benzoin                        119-53-9
Sodium dodecyl sulfate         151-21-3
L-Menthol                      2216-51-5
Tiron                          149-45-1
Riboflavin                     83-88-5
Sodium Acetate Trihydrate      6131-90-4
Disodium Succinate Hexahydrate 6106-21-4
Disodium                       6381-92-6
ethylenediaminetetraacetate
dihydrate
sodium citrate, dihydrate      1545801
Sodium potassium tartrate,     6381-59-5
tetrahydrate
L-(+)-Arginine                 1119-34-2
monohydrochloride
Ethylenediamine                333-18-6
dihydrochloride
Sodium formate                 141-53-7
Sodium acetate                 127-09-3
Potassium acetate              127-08-2
Ammonium citrate               3012-65-5
Ammonium bicarbonate           1066-33-7
Ammonium chloride              12125-02-9
Ammonium nitrate               6484-52-2
Ammonium persulfate            7727-54-0
Ammonium sulfate               7783-20-2
Zinc chloride                  7646-85-7
Sulfuric acid, zinc salt       7446-20-0
(1:1), heptahydrate
Sodium Tripolyphosphate        7758-29-4
ammonium benzoate              1863-63-4
ammonium bisulfite             10192-30-0
1,5-Naphthalenedisulfonic Acid 1655-29-4
Disodium Salt
4-Hydroxybenzoic Acid          99-96-7
Diphenylacetic Acid            117-34-0
Glutaric Acid                  110-94-1
L-(−)-Fucose                   2438-80-4
L-Cysteine Hydrochloride       52-89-1
L-Histidine Hydrochloride      1880304
Monohydrate
o-Toluic Acid                  118-90-1
Pivalic Acid                   75-98-9
Pyruvic Acid Sodium Salt       113-24-6
Potassium bromide              2139626
Sodium Dithionate Dihydrate    7631-94-9
Sodium Malonate                141-95-7
Trisodium Citrate              68-04-2
Potassium Sodium Tartrate      304-59-6
Potassium Citrate              866-84-2
D-Maltose Monohydrate          6363-53-7
Cyclohexaamylose               10016-20-3
Dodecyl sulfate, lithium salt  2044-56-6
Manganese chloride             2145076
methyl-urea                    598-50-5
beta-Cyclodextrin              7585-39-9
Triphosphoric acid,            13845-36-8
pentapotassium salt
Glycine ethyl ester            623-33-6
hydrochloride
L-Histidine methyl ester       7389-87-9
dihydrochloride
L-Leucine methyl ester         7517-19-3
hydrochloride
D-Lysine hydrochloride         7274-88-6
2-Naphthalenesulfonic acid     532-02-5
sodium salt
calcium nitrate tetrahydrate   13477-34-4
Vitamin B1                     59-43-8
Zinc Acetate Dihydrate         5970-45-6
Potassium fluoride             7789-23-3
Potassium iodate               2139718
Potassium iodide               7681-11-0
Potassium thiocyanate          333-20-0
Sodium bromide                 7647-15-6
Sodium fluoride                7681-49-4
Sodium iodide                  7681-82-5
Sodium nitrate                 7631-99-4
Calcium acetate                5743-26-0
Trichloroacetic acid           76-03-9
Ammonium acetate               631-61-8
Ammonium fluoride              12125-01-8
DL-malic acid                  617-48-1
t-Butyl Alcohol                75-65-0
beta-Alanine                   107-95-9
(S)-(−)-Tryptophan             73-22-3
Malonic acid                   141-82-2
Phenethylamine                 64-04-0
Salicylylaldehyde              90-02-8
Sodium benzoate                532-32-1
Mandelic acid                  90-64-2
Calcium pantothenate           137-08-6
Chloroacetic Acid              79-11-8
Ethanol Amine                  141-43-5
Salicylic acid                 69-72-7
Saccharin sodium               128-44-9
Thiamine hydrochloride         67-03-8
2,2′-Oxybisethanol             111-46-6
Resorcinol                     108-46-3
2-Amino-2-(hydroxymethyl)-1,3- 77-86-1
propanediol
2,5-Dimethylphenol             95-87-4
Ammonium Phosphate Monobasic   7722-76-1
1,3-Butanediol                 107-88-0
Glycolic Acid                  79-14-1
Sodium Gluconate               527-07-1
Terephthalic Acid              100-21-0
L-Ascorbic Acid Sodium Salt    134-03-2
3-Acetyl-6-methyl-2,4-         520-45-6
pyrandione
Calcium Acetate                62-54-4
Nicotinamide                   98-92-0
1-Hydroxy-2-naphthoic Acid     86-48-6
2-Isopropylphenol              88-69-7
4-Aminosalicylic Acid          65-49-6
Calcium Glycerophosphate       27214-00-2
Erythorbic Acid Sodium Salt    7378-23-6
Gluconic Acid Potassium Salt   299-27-4
Orotic Acid                    65-86-1
p-Anise Alcohol                105-13-5
Potassium Benzoate             582-25-2
Taurine                        107-35-7
Thiamine Nitrate               532-43-4
3,3,5-Trimethyl-1-cyclohexanol 116-02-9
tert-Butylhydroquinone         1948-33-0
Sulfosalicylic acid            97-05-2
Gallic acid                    149-91-7
L-borneol                      464-45-9
Isoborneol                     124-76-5
2,5-Dihydroxybenzoic acid,     490-79-9
Gentisic acid
5-hydroxy-6-methyl-3,4-        65-23-6
pyridinedimethanol
Naphthalene-2-sulfonic acid    120-18-3
Ethanesulfonic acid, 2-        1562-00-1
hydroxy-, monosodium salt
Pamoic acid                    130-85-8
2,4-Dimethylphenol             105-67-9
3,5-Dihydroxyacetophenone      51863-60-6
Eugenol                        97-53-0
n-Butyric Acid                 107-92-6
Hydroquinone                   123-31-9
Propionic Acid                 79-09-4
meta-Phenylenediamine          108-45-2
Oxalic Acid                    144-62-7
n-Hexanoic Acid                142-62-1
2-Furancarboxylic Acid         88-14-2
4′-Nitroacetanilide            104-04-1
D-(−)-Tartaric Acid            147-71-7
p-Acetamidobenzoic Acid        556-08-1
Galactaric acid                526-99-8
D-glucuronate                  1700908
Lactobionic acid               96-82-2
p-Formylacetanilide            122-85-0
2-Mercaptobenzoic acid         147-93-3
Propanoic acid, 2-hydroxy-,    28305-25-1
calcium salt (2:1), (S)-
D(+)-10-Camphorsulfonic acid   3144-16-9
3-Cyclopentylpropionic acid    140-77-2
1R-(−)-Camphorsulfonic acid    35963-20-3
DL-Lysine                      70-54-2
Cinnamic acid                  621-82-9
Triethanolamine                102-71-6
Acetic Acid                    64-19-7
Dichloroacetic Acid            79-43-6
Diethylamine                   109-89-7
Diethylaminoethanol            100-37-8
N-(2-Hydroxyethyl)Morpholine   622-40-2
Octanoic Acid                  124-07-2
isobutyric acid                79-31-2
Anisic Acid                    100-09-4
Betaine                        107-43-7
Enanthoic Acid                 111-14-8
Hippuric Acid                  495-69-2
Tiglic Acid                    80-59-1
Cyclohexanecarboxylic acid     98-89-5
m-Methoxybenzoic acid          586-38-9
D-(+)-Camphoric acid           124-83-4
N-(2-Hydroxyethyl)pyrrolidine  2955-88-6
Sodium Metabisulfite           7681-57-4
sodium hydrogen phosphate      7558-79-4
Sodium Phosphate Monobasic     7558-80-7
Sodium thiosulfate             7772-98-71
Orthoboric acid                10043-35-3
Diethanolamine                 111-42-2
Benzaldehyde                   100-52-7
Sorbic acid                    110-44-1
L-(+)-Tartaric Acid            87-69-4
D-mannitol                     69-65-8
Butyl paraben                  94-26-8
Thymol                         89-83-8
Methyl salicylate              119-36-8
Citric acid                    77-92-9
Creatinine                     60-27-5
Vitamin C                      50-81-7
Benzoic Acid                   65-85-0
Methyl 4-hydroxybenzoate       99-76-3
m-Cresol                       108-39-4
p-Cresol                       106-44-5
Aspirin                        50-78-2
Phenol                         108-95-2
Sucrose                        57-50-1
Potassium citrate, monohydrate 1534146
Sodium acetate                 127-09-3
Lactic acid                    50-21-5
Propionic acid, sodium salt    65-85
Benzyl alcohol                 100-51-6
Phenethyl alcohol              60-12-8
Cholesterol                    57-88-5
D-Glucose                      50-99-7
Sorbitol                       50-70-4
Aspartame                      22839-47-0
Saccharin                      81-07-2
2,6-Di-tert-Butyl-p-Cresol     128-37-0
4-Chloro-3-methylphenol        59-50-7
glycerin                       56-81-5
Propyl paraben                 94-13-3
fumaric acid                   110-17-8
dabco                          280-57-9
p-Phenylenediamine             106-50-3
Anethole                       4180-23-8
propyl gallate                 121-79-9
L-monosodium glutamate         142-47-2
Butylated hydroxyanisole       25013-16-5
Cyclohexanol, 5-methyl-2-(1-   89-78-1
methylethyl)-,
(1alpha,2beta,5alpha)-
alpha-Thioglycerol             96-27-5
Sodium dehydroacetate          4418-26-2
Ethyl 4-hydroxybenzoate        120-47-8
Ethyl Vanillin                 121-32-4
Triacetin                      102-76-1
Potassium sorbate              590-00-1
Triethyl citrate               77-93-0
(S)-(+)-Arginine               74-79-3
Glycine                        56-40-6
(S)-(−)-Histidine              71-00-1
(S)-(+)-Lysine                 56-87-1
Quinone                        106-51-4
Naphthalene, 2-ethoxy-         93-18-5
Methanesulfonic Acid           75-75-2
DL-Tartaric Acid               133-37-9
Cyclamic acid                  100-88-9
(S)-(−)-Phenylalanine          63-91-2
(S)-(−)-Tyrosine               60-18-4
Carvone                        99-49-0
Ethyl butyrate                 105-54-4
6-Methyl-5-hepten-2-one        110-93-0
Ethyl acetoacetate             141-97-9
Methyl benzoate                93-58-3
Phenylacetic Acid              103-82-2
Adipic acid                    124-04-9
Ethyl benzoate                 93-89-0
Benzyl benzoate                120-51-4
Pyruvic acid                   127-17-3
Succinic acid                  110-15-6
Indole                         120-72-9
Methyl anthranilate            134-20-3
Diethyl malonate               105-53-3
Niacin                         59-67-6
Meso-inositol                  87-89-8
4-Aminobenzoic acid            150-13-0
Anisole                        100-66-3
Urea                           57-13-6
Pyrrolidine                    123-75-1
Cyclopentanone                 120-92-3
Acetic anhydride               108-24-7
Benzophenone                   119-61-9
D-(−)-Fructose                 57-48-7
D-(+)-Xylose                   58-86-6
o-Methoxybenzoic Acid          579-75-9
linalool                       78-70-6
ethyl isovalerate              108-64-5
1,1′-Azobisformamide           123-77-3
6-Methylcoumarin               92-48-8
acetoin                        513-86-0
alpha-Phellandrene             99-83-2
Cymene                         99-87-6
Dimethyl Succinate             106-65-0
p-Anisaldehyde                 123-11-5
Phenyl ether                   101-84-8
Tetrahydro-2-furanmethanol     97-99-4
Valeric Acid                   109-52-4
3,4-xylenol                    95-65-8
1,1-diethoxyethane             105-57-7
ethyl butyraldehyde            97-96-1
Ethyl crotonate                623-70-1
ethyl isobutyrate              97-62-1
methyl isovalerate             556-24-1
methyl propionate              554-12-1
methyl valeraldehyde           123-15-9
4-(2,6,6-Trimethyl-2-          127-41-3
cyclohexen-1-yl)-3-buten-2-one
4-(2,6,6-trimethyl-1-          14901-07-6
cyclohexen-1-yl)-3-buten-2-one
Maleic acid                    110-16-7
3-Methylbutanoic acid          503-74-2
L-Glutamic Acid                56-86-0
D-limonene                     5989-27-5
1-Phenyl-1-propanol            93-54-9
2′-Hydroxyacetophenone         118-93-4
2,4-Dihydroxybenzoic Acid      89-86-1
2-Phenyl-1-propanol            1123-85-9
3-Phenylpropionic Acid         501-52-0
4-Ethoxyphenol                 622-62-8
Alpha-Terpineol                98-55-5
Benzaldehyde Dimethylacetal    1125-88-8
Benzyl Ether                   103-50-4
Benzyl Formate                 104-57-4
Benzyl Salicylate              118-58-1
Cinnamyl Alcohol               104-54-1
D-(+)-Glucono-1,5-lactone      4253-68-3
D-Isoascorbic Acid             89-65-6
2,3-Naphthalenediol            92-44-4
Diethyl Succinate              123-25-1
Ethyl 2-Aminobenzoate          87-25-2
Ethyl Cinnamate                103-36-6
Ethyl Phenylacetate            101-97-3
Ethyl Salicylate               118-61-6
gamma-Valerolactone            108-29-2
Hydroquinone Dimethyl Ether    150-78-7
Isocaproic Acid                646-07-1
Isoeugenol                     97-54-1
Isopropyl Benzoate             939-48-0
L-(+)-Isoleucine               73-32-5
L-Malic acid                   97-67-6
L-2-Aminopropionic Acid        56-41-7
L-Carnitine                    541-15-1
L-Glutamine                    56-85-9
L-Hydroxyproline               51-35-4
L-Proline                      147-85-3
L-Serine                       56-45-1
L-Threonine                    72-19-5
L-Valine                       72-18-4
Phenoxyacetic Acid             122-59-8
Veratrole                      91-16-7
2-Ethylbutyric acid            88-09-5
2-Methylpyrazine               109-08-0
o-methoxybenzaldehyde          135-02-4
L-Leucine                      61-90-5
L-Asparagine                   70-47-3
propiophenone                  93-55-0
5-isopropyl-2-methyl-phenol    499-75-2
Xylitol                        87-99-0
ethyl 4-oxopentanoate          539-88-8
methyl cinnamate               103-26-4
cumic alcohol                  536-60-7
methyl 2-naphthyl ketone       93-08-3
1-methyl-4-(1-methylethyl)-    99-85-4
1,4-Cyclohexadiene
en-ethylene diamine
Caffeine                       58-08-2
5-methylfurfural               620-02-0
furfuryl acetate               623-17-6
terpinen-4-ol                  10482-56-1
phenylethanal                  122-78-1
4′-Methoxyacetophenone         100-06-1
D-Fenchone                     4695-62-9
1-Methoxy-4-methylbenzene      104-93-8
o-methylanisole                578-58-5
Acetylacetaldehyde dimethyl    5436-21-5
acetal
p-methylacetophenone           122-00-9
Methyl phenylacetate           101-41-7
4-Ethoxybenzaldehyde           10031-82-0
p-tolyl acetate                140-39-6
2,6-Dimethoxyphenol            91-10-1
Methyl 2-methoxybenzoate       606-45-1
alpha-methylcinnamaldehyde     101-39-3
2-methoxycinnamaldehyde        60125-24-8
Potassium bicarbonate          298-14-6
piperonyl acetate              326-61-4
2,3-hexanedione                3848-24-6
furfural acetone               623-15-4
trans beta-(2-furyl)acrolein   623-30-3
carveol                        99-48-9
Methyl nicotinate              93-60-7
Ethyl benzoylacetate           94-02-0
Methyl 4-methoxybenzoate       121-98-2
Levulinic acid                 123-76-2
m-Dimethoxybenzene             151-10-0
2-acetylpyridine               1122-62-9
tetramethyl-pyrazine           1124-11-4
2,3-dimethyl-pyrazine          5910-89-4
trimethyl-pyrazine             14667-55-1
2-ethyl-3-methyl-pyrazine      15707-23-0
5-Methyl-3H-furan-2-one        591-12-8
2-Methoxy-4-methylphenol       93-51-6
piperazine                     110-85-0
2-Methoxy-4-propylphenol       2785-87-7
Naphthalene, 2-(2-             2173-57-1
methylpropoxy)-
2-Acetyl-1-methylpyrrole       932-16-1
3,3-Dimethylacrylic acid       541-47-9
Ethyl sorbate                  2396-84-1
4-(4-Hydroxyphenyl)-2-butanone 5471-51-2
4-Methoxyphenylacetone         122-84-9
(−)-Myrtenal                   564-94-3
3-Phenylpropionaldehyde        104-53-0
1-Phenylethyl propionate       120-45-6
2-Methyltetrahydrofuran-3-one  3188-00-9
Cinnamyl acetate               103-54-8
Styrallyl acetate              93-92-5
Ethyl 4-methoxybenzoate        94-30-4
Benzyl propionate              122-63-4
Phenylpyruvate                 156-06-9
furaneol                       3658-77-3
methyl 2-methylbutanoate       868-57-5
Benzeneacetaldehyde, alpha-    93-53-8
methyl-
Dimethyl anthranilate          85-91-6
1,1-Dimethoxy-2-phenylpropane  90-87-9
4-hexanolide                   695-06-7
Dimethylbenzylcarbinyl acetate 151-05-3
Benzyl isobutyrate             103-28-6
Acetyl isoeugenol              93-29-8
2-Acetyl-5-methyl furan        1193-79-9
Alpha-methyl-p-                103-95-7
isopropylphenylpropanaldehyde
Benzylcarbinyl formate         104-62-1
p-Cresyl alpha-toluate         101-94-0
Potassium bisulfate            7646-93-7
Potassium carbonate            584-08-7
Potassium chloride             7447-40-7
Potassium hydroxide            1310-58-3
Ethyl tiglate                  5837-78-5
Nerol oxide                    1786-08-9
DL-Tetrohydrofurfuryl          637-65-0
propionate
Benzaldehyde propylene glycol  2568-25-4
acetal
2-Methyl-3-(2-furyl) acrolein  874-66-8
vanillin                       121-33-5
Cholic acid                    81-25-4
R-Carvone                      6485-40-1
Potassium nitrate              7757-79-1
Potassium permanganate         7722-64-7
Potassium persulfate           7727-21-1
Potassium phosphate, dibasic   2139900
Potassium Phosphate Monobasic  7778-77-0
Potassium sulfate              7778-80-5
Sodium bicarbonate             144-55-8
Sodium bisulfite               7631-90-5
Sodium carbonate               497-19-8
Sodium chloride                7647-14-5
Sodium dithionite              7775-14-6
Sodium hydroxide               1310-73-2
Sodium nitrite                 7632-00-0
Sodium Pyrophosphate           7722-88-5
Sodium sulfate                 7757-82-6
Sodium sulfite                 7757-83-7
Sodium thiocyanate             540-72-7
Calcium Carbonate              471-34-1
Calcium chloride               10043-52-4
Calcium gluconate              299-28-5
Calcium hydroxide              1305-62-0
Calcium phosphate, dibasic     7757-93-9
Calcium sulfate                7778-18-9
N-Methyl-D-glucamine           6284-40-8
Calcium oxide                  1305-78-8
Calcium Phosphate Monobasic    7758-23-8
Magnesium chloride hexahydrate 7791-18-6
Magnesium sulfate              7487-88-9
Magnesium Sulfate Heptahydrate 10034-99-8
Aluminum chloride hexahydrate  7784-13-6
aluminum nitrate nonahydrate   7784-27-2
Aluminum potassium sulfate,    7784-24-9
dodecahydrate
Aluminum sulfate,              7784-31-8
octadecahydrate
(S)-(−)-Cysteine               52-90-4
p-Toluenesulfonic Acid         104-15-4
Potassium bitartrate           868-14-4
DL-aspartic acid               617-45-8
p-Dimethylaminobenzaldehyde    100-10-7
Sodium salicylate              54-21-7
Benzoin                        119-53-9
Sodium dodecyl sulfate         151-21-3
L-Menthol                      2216-51-5
Tiron                          149-45-1
Riboflavin                     83-88-5
Sodium Acetate Trihydrate      6131-90-4
Disodium Succinate Hexahydrate 6106-21-4
Disodium                       6381-92-6
ethylenediaminetetraacetate
dihydrate
sodium citrate, dihydrate      1545801
Sodium potassium tartrate,     6381-59-5
tetrahydrate
L-(+)-Arginine                 1119-34-2
monohydrochloride
Ethylenediamine                333-18-6
dihydrochloride
Sodium formate                 141-53-7
Sodium acetate                 127-09-3
Potassium acetate              127-08-2
Ammonium citrate               3012-65-5
Ammonium bicarbonate           1066-33-7
Ammonium chloride              12125-02-9
Ammonium nitrate               6484-52-2
Ammonium persulfate            7727-54-0
Ammonium sulfate               7783-20-2
Zinc chloride                  7646-85-7
Sulfuric acid, zinc salt       7446-20-0
(1:1), heptahydrate
Sodium Tripolyphosphate        7758-29-4
ammonium benzoate              1863-63-4
ammonium bisulfite             10192-30-0
1,5-Naphthalenedisulfonic Acid 1655-29-4
Disodium Salt
4-Hydroxybenzoic Acid          99-96-7
Diphenylacetic Acid            117-34-0
Glutaric Acid                  110-94-1
L-(−)-Fucose                   2438-80-4
L-Cysteine Hydrochloride       52-89-1
L-Histidine Hydrochloride      1880304
Monohydrate
o-Toluic Acid                  118-90-1
Pivalic Acid                   75-98-9
Pyruvic Acid Sodium Salt       113-24-6
Potassium bromide              2139626
Sodium Dithionate Dihydrate    7631-94-9
Sodium Malonate                141-95-7
Trisodium Citrate              68-04-2
Potassium Sodium Tartrate      304-59-6
Potassium Citrate              866-84-2
D-Maltose Monohydrate          6363-53-7
Cyclohexaamylose               10016-20-3
Dodecyl sulfate, lithium salt  2044-56-6
Manganese chloride             2145076
methyl-urea                    598-50-5
beta-Cyclodextrin              7585-39-9
Triphosphoric acid,            13845-36-8
pentapotassium salt
Glycine ethyl ester            623-33-6
hydrochloride
L-Histidine methyl ester       7389-87-9
dihydrochloride
L-Leucine methyl ester         7517-19-3
hydrochloride
D-Lysine hydrochloride         7274-88-6
2-Naphthalenesulfonic acid     532-02-5
sodium salt
calcium nitrate tetrahydrate   13477-34-4
Vitamin B1                     59-43-8
Zinc Acetate Dihydrate         5970-45-6
Potassium fluoride             7789-23-3
Potassium iodate               2139718
Potassium iodide               7681-11-0
Potassium thiocyanate          333-20-0
Sodium bromide                 7647-15-6
Sodium fluoride                7681-49-4
Sodium iodide                  7681-82-5
Sodium nitrate                 7631-99-4
Calcium acetate                5743-26-0
Trichloroacetic acid           76-03-9
Ammonium acetate               631-61-8
Ammonium fluoride              12125-01-8
DL-malic acid                  617-48-1
t-Butyl Alcohol                75-65-0
beta-Alanine                   107-95-9
(S)-(−)-Tryptophan             73-22-3
Malonic acid                   141-82-2
Phenethylamine                 64-04-0
Salicylylaldehyde              90-02-8
Sodium benzoate                532-32-1
Mandelic acid                  90-64-2
Calcium pantothenate           137-08-6
Chloroacetic Acid              79-11-8
Ethanol Amine                  141-43-5
Salicylic acid                 69-72-7
Saccharin sodium               128-44-9
Thiamine hydrochloride         67-03-8
2,2′-Oxybisethanol             111-46-6
Resorcinol                     108-46-3
2-Amino-2-(hydroxymethyl)-1,3- 77-86-1
propanediol
2,5-Dimethylphenol             95-87-4
Ammonium Phosphate Monobasic   7722-76-1
1,3-Butanediol                 107-88-0
Glycolic Acid                  79-14-1
Sodium Gluconate               527-07-1
Terephthalic Acid              100-21-0
L-Ascorbic Acid Sodium Salt    134-03-2
3-Acetyl-6-methyl-2,4-         520-45-6
pyrandione
Calcium Acetate                62-54-4
Nicotinamide                   98-92-0
1-Hydroxy-2-naphthoic Acid     86-48-6
2-Isopropylphenol              88-69-7
4-Aminosalicylic Acid          65-49-6
Calcium Glycerophosphate       27214-00-2
Erythorbic Acid Sodium Salt    7378-23-6
Gluconic Acid Potassium Salt   299-27-4
Orotic Acid                    65-86-1
p-Anise Alcohol                105-13-5
Potassium Benzoate             582-25-2
Taurine                        107-35-7
Thiamine Nitrate               532-43-4
3,3,5-Trimethyl-1-cyclohexanol 116-02-9
tert-Butylhydroquinone         1948-33-0
Sulfosalicylic acid            97-05-2
Gallic acid                    149-91-7
L-borneol                      464-45-9
Isoborneol                     124-76-5
2,5-Dihydroxybenzoic acid,     490-79-9
Gentisic acid
5-hydroxy-6-methyl-3,4-        65-23-6
pyridinedimethanol
Naphthalene-2-sulfonic acid    120-18-3
Ethanesulfonic acid, 2-        1562-00-1
hydroxy-, monosodium salt
Pamoic acid                    130-85-8
2,4-Dimethylphenol             105-67-9
3,5-Dihydroxyacetophenone      51863-60-6
Eugenol                        97-53-0
n-Butyric Acid                 107-92-6
Hydroquinone                   123-31-9
Propionic Acid                 79-09-4
meta-Phenylenediamine          108-45-2
Oxalic Acid                    144-62-7
n-Hexanoic Acid                142-62-1
2-Furancarboxylic Acid         88-14-2
4′-Nitroacetanilide            104-04-1
D-(−)-Tartaric Acid            147-71-7
p-Acetamidobenzoic Acid        556-08-1
Galactaric acid                526-99-8
D-glucuronate                  1700908
Lactobionic acid               96-82-2
p-Formylacetanilide            122-85-0
2-Mercaptobenzoic acid         147-93-3
Propanoic acid, 2-hydroxy-,    28305-25-1
calcium salt (2:1), (S)-
D(+)-10-Camphorsulfonic acid   3144-16-9
3-Cyclopentylpropionic acid    140-77-2
1R-(−)-Camphorsulfonic acid    35963-20-3
DL-Lysine                      70-54-2
Cinnamic acid                  621-82-9
Triethanolamine                102-71-6
Acetic Acid                    64-19-7
Dichloroacetic Acid            79-43-6
Diethylamine                   109-89-7
Diethylaminoethanol            100-37-8
N-(2-Hydroxyethyl)Morpholine   622-40-2
Octanoic Acid                  124-07-2
isobutyric acid                79-31-2
Anisic Acid                    100-09-4
Betaine                        107-43-7
Enanthoic Acid                 111-14-8
Hippuric Acid                  495-69-2
Tiglic Acid                    80-59-1
Cyclohexanecarboxylic acid     98-89-5
m-Methoxybenzoic acid          586-38-9
D-(+)-Camphoric acid           124-83-4
N-(2-Hydroxyethyl)pyrrolidine  2955-88-6
Sodium Metabisulfite           7681-57-4
sodium hydrogen phosphate      7558-79-4
Sodium Phosphate Monobasic     7558-80-7
Sodium thiosulfate             7772-98-71
Orthoboric acid                10043-35-3
Diethanolamine                 111-42-2
Benzaldehyde                   100-52-7
Sorbic acid                    110-44-1
L-(+)-Tartaric Acid            87-69-4
D-mannitol                     69-65-8
Butyl paraben                  94-26-8
Thymol                         89-83-8
Methyl salicylate              119-36-8
Citric acid                    77-92-9
Creatinine                     60-27-5
Vitamin C                      50-81-7
Benzoic Acid                   65-85-0
Methyl 4-hydroxybenzoate       99-76-3
m-Cresol                       108-39-4
p-Cresol                       106-44-5
Aspirin                        50-78-2
Phenol                         108-95-2
Sucrose                        57-50-1
Potassium citrate, monohydrate 1534146
Sodium acetate                 127-09-3
Lactic acid                    50-21-5
Propionic acid, sodium salt    65-85
Benzyl alcohol                 100-51-6
Phenethyl alcohol              60-12-8
Cholesterol                    57-88-5
D-Glucose                      50-99-7
Sorbitol                       50-70-4
Aspartame                      22839-47-0
Saccharin                      81-07-2
2,6-Di-tert-Butyl-p-Cresol     128-37-0
4-Chloro-3-methylphenol        59-50-7
glycerin                       56-81-5
Propyl paraben                 94-13-3
fumaric acid                   110-17-8
dabco                          280-57-9
p-Phenylenediamine             106-50-3
Anethole                       4180-23-8
propyl gallate                 121-79-9
L-monosodium glutamate         142-47-2
Butylated hydroxyanisole       25013-16-5
Cyclohexanol, 5-methyl-2-(1-   89-78-1
methylethyl)-,
(1alpha,2beta,5alpha)-
alpha-Thioglycerol             96-27-5
Sodium dehydroacetate          4418-26-2
Ethyl 4-hydroxybenzoate        120-47-8
Ethyl Vanillin                 121-32-4
Triacetin                      102-76-1
Potassium sorbate              590-00-1
Triethyl citrate               77-93-0
(S)-(+)-Arginine               74-79-3
Glycine                        56-40-6
(S)-(−)-Histidine              71-00-1
(S)-(+)-Lysine                 56-87-1
Quinone                        106-51-4
Naphthalene, 2-ethoxy-         93-18-5
Methanesulfonic Acid           75-75-2
DL-Tartaric Acid               133-37-9
Cyclamic acid                  100-88-9
(S)-(−)-Phenylalanine          63-91-2
(S)-(−)-Tyrosine               60-18-4
Carvone                        99-49-0
Ethyl butyrate                 105-54-4
6-Methyl-5-hepten-2-one        110-93-0
Ethyl acetoacetate             141-97-9
Methyl benzoate                93-58-3
Phenylacetic Acid              103-82-2
Adipic acid                    124-04-9
Ethyl benzoate                 93-89-0
Benzyl benzoate                120-51-4
Pyruvic acid                   127-17-3
Succinic acid                  110-15-6
Indole                         120-72-9
Methyl anthranilate            134-20-3
Diethyl malonate               105-53-3
Niacin                         59-67-6
Meso-inositol                  87-89-8
4-Aminobenzoic acid            150-13-0
Anisole                        100-66-3
Urea                           57-13-6
Pyrrolidine                    123-75-1
Cyclopentanone                 120-92-3
Acetic anhydride               108-24-7
Benzophenone                   119-61-9
D-(−)-Fructose                 57-48-7
D-(+)-Xylose                   58-86-6
o-Methoxybenzoic Acid          579-75-9
linalool                       78-70-6
ethyl isovalerate              108-64-5
1,1′-Azobisformamide           123-77-3
6-Methylcoumarin               92-48-8
acetoin                        513-86-0
alpha-Phellandrene             99-83-2
Cymene                         99-87-6
Dimethyl Succinate             106-65-0
p-Anisaldehyde                 123-11-5
Phenyl ether                   101-84-8
Tetrahydro-2-furanmethanol     97-99-4
Valeric Acid                   109-52-4
3,4-xylenol                    95-65-8
1,1-diethoxyethane             105-57-7
ethyl butyraldehyde            97-96-1
Ethyl crotonate                623-70-1
ethyl isobutyrate              97-62-1
methyl isovalerate             556-24-1
methyl propionate              554-12-1
methyl valeraldehyde           123-15-9
4-(2,6,6-Trimethyl-2-          127-41-3
cyclohexen-1-yl)-3-buten-2-one
4-(2,6,6-trimethyl-1-          14901-07-6
cyclohexen-1-yl)-3-buten-2-one
Maleic acid                    110-16-7
3-Methylbutanoic acid          503-74-2
L-Glutamic Acid                56-86-0
D-limonene                     5989-27-5
1-Phenyl-1-propanol            93-54-9
2′-Hydroxyacetophenone         118-93-4
2,4-Dihydroxybenzoic Acid      89-86-1
2-Phenyl-1-propanol            1123-85-9
3-Phenylpropionic Acid         501-52-0
4-Ethoxyphenol                 622-62-8
Alpha-Terpineol                98-55-5
Benzaldehyde Dimethylacetal    1125-88-8
Benzyl Ether                   103-50-4
Benzyl Formate                 104-57-4
Benzyl Salicylate              118-58-1
Cinnamyl Alcohol               104-54-1
D-(+)-Glucono-1,5-lactone      4253-68-3
D-Isoascorbic Acid             89-65-6
2,3-Naphthalenediol            92-44-4
Diethyl Succinate              123-25-1
Ethyl 2-Aminobenzoate          87-25-2
Ethyl Cinnamate                103-36-6
Ethyl Phenylacetate            101-97-3
Ethyl Salicylate               118-61-6
gamma-Valerolactone            108-29-2
Hydroquinone Dimethyl Ether    150-78-7
Isocaproic Acid                646-07-1
Isoeugenol                     97-54-1
Isopropyl Benzoate             939-48-0
L-(+)-Isoleucine               73-32-5
L-Malic acid                   97-67-6
L-2-Aminopropionic Acid        56-41-7
L-Carnitine                    541-15-1
L-Glutamine                    56-85-9
L-Hydroxyproline               51-35-4
L-Proline                      147-85-3
L-Serine                       56-45-1
L-Threonine                    72-19-5
L-Valine                       72-18-4
Phenoxyacetic Acid             122-59-8
Veratrole                      91-16-7
2-Ethylbutyric acid            88-09-5
2-Methylpyrazine               109-08-0
o-methoxybenzaldehyde          135-02-4
L-Leucine                      61-90-5
L-Asparagine                   70-47-3
propiophenone                  93-55-0
5-isopropyl-2-methyl-phenol    499-75-2
Xylitol                        87-99-0
ethyl 4-oxopentanoate          539-88-8
methyl cinnamate               103-26-4
cumic alcohol                  536-60-7
methyl 2-naphthyl ketone       93-08-3
1-methyl-4-(1-methylethyl)-    99-85-4
1,4-Cyclohexadiene
en-ethylene diamine
Caffeine                       58-08-2
5-methylfurfural               620-02-0
furfuryl acetate               623-17-6
terpinen-4-ol                  10482-56-1
phenylethanal                  122-78-1
4′-Methoxyacetophenone         100-06-1
D-Fenchone                     4695-62-9
1-Methoxy-4-methylbenzene      104-93-8
o-methylanisole                578-58-5
Acetylacetaldehyde dimethyl    5436-21-5
acetal
p-methylacetophenone           122-00-9
Methyl phenylacetate           101-41-7
4-Ethoxybenzaldehyde           10031-82-0
p-tolyl acetate                140-39-6
2,6-Dimethoxyphenol            91-10-1
Methyl 2-methoxybenzoate       606-45-1
alpha-methylcinnamaldehyde     101-39-3
2-methoxycinnamaldehyde        60125-24-8
Potassium bicarbonate          298-14-6
piperonyl acetate              326-61-4
2,3-hexanedione                3848-24-6
furfural acetone               623-15-4
trans beta-(2-furyl)acrolein   623-30-3
carveol                        99-48-9
Methyl nicotinate              93-60-7
Ethyl benzoylacetate           94-02-0
Methyl 4-methoxybenzoate       121-98-2
Levulinic acid                 123-76-2
m-Dimethoxybenzene             151-10-0
2-acetylpyridine               1122-62-9
tetramethyl-pyrazine           1124-11-4
2,3-dimethyl-pyrazine          5910-89-4
trimethyl-pyrazine             14667-55-1
2-ethyl-3-methyl-pyrazine      15707-23-0
5-Methyl-3H-furan-2-one        591-12-8
2-Methoxy-4-methylphenol       93-51-6
piperazine                     110-85-0
2-Methoxy-4-propylphenol       2785-87-7
Naphthalene, 2-(2-             2173-57-1
methylpropoxy)-
2-Acetyl-1-methylpyrrole       932-16-1
3,3-Dimethylacrylic acid       541-47-9
Ethyl sorbate                  2396-84-1
4-(4-Hydroxyphenyl)-2-butanone 5471-51-2
4-Methoxyphenylacetone         122-84-9
(−)-Myrtenal                   564-94-3
3-Phenylpropionaldehyde        104-53-0
1-Phenylethyl propionate       120-45-6
2-Methyltetrahydrofuran-3-one  3188-00-9
Cinnamyl acetate               103-54-8
Styrallyl acetate              93-92-5
Ethyl 4-methoxybenzoate        94-30-4
Benzyl propionate              122-63-4
Phenylpyruvate                 156-06-9
furaneol                       3658-77-3
methyl 2-methylbutanoate       868-57-5
Benzeneacetaldehyde, alpha-    93-53-8
methyl-
Dimethyl anthranilate          85-91-6
1,1-Dimethoxy-2-phenylpropane  90-87-9
4-hexanolide                   695-06-7
Dimethylbenzylcarbinyl acetate 151-05-3
Benzyl isobutyrate             103-28-6
Acetyl isoeugenol              93-29-8
2-Acetyl-5-methyl furan        1193-79-9
Alpha-methyl-p-                103-95-7
isopropylphenylpropanaldehyde
Benzylcarbinyl formate         104-62-1
p-Cresyl alpha-toluate         101-94-0
Potassium bisulfate            7646-93-7
Potassium carbonate            584-08-7
Potassium chloride             7447-40-7
Potassium hydroxide            1310-58-3
Ethyl tiglate                  5837-78-5
Nerol oxide                    1786-08-9
DL-Tetrohydrofurfuryl          637-65-0
propionate
Benzaldehyde propylene glycol  2568-25-4
acetal
2-Methyl-3-(2-furyl) acrolein  874-66-8
vanillin                       121-33-5
Cholic acid                    81-25-4
R-Carvone                      6485-40-1
Potassium nitrate              7757-79-1
Potassium permanganate         7722-64-7
Potassium persulfate           7727-21-1
Potassium phosphate, dibasic   2139900
Potassium Phosphate Monobasic  7778-77-0
Potassium sulfate              7778-80-5
Sodium bicarbonate             144-55-8
Sodium bisulfite               7631-90-5
Sodium carbonate               497-19-8
Sodium chloride                7647-14-5
Sodium dithionite              7775-14-6
Sodium hydroxide               1310-73-2
Sodium nitrite                 7632-00-0
Sodium Pyrophosphate           7722-88-5
Sodium sulfate                 7757-82-6
Sodium sulfite                 7757-83-7
Sodium thiocyanate             540-72-7
Calcium Carbonate              471-34-1
Calcium chloride               10043-52-4
Calcium gluconate              299-28-5
Calcium hydroxide              1305-62-0
Calcium phosphate, dibasic     7757-93-9
Calcium sulfate                7778-18-9
N-Methyl-D-glucamine           6284-40-8
Calcium oxide                  1305-78-8
Calcium Phosphate Monobasic    7758-23-8
Magnesium chloride hexahydrate 7791-18-6
Magnesium sulfate              7487-88-9
Magnesium Sulfate Heptahydrate 10034-99-8
Aluminum chloride hexahydrate  7784-13-6
aluminum nitrate nonahydrate   7784-27-2
Aluminum potassium sulfate,    7784-24-9
dodecahydrate
Aluminum sulfate,              7784-31-8
octadecahydrate
(S)-(−)-Cysteine               52-90-4
p-Toluenesulfonic Acid         104-15-4
Potassium bitartrate           868-14-4
DL-aspartic acid               617-45-8
p-Dimethylaminobenzaldehyde    100-10-7
Sodium salicylate              54-21-7
Benzoin                        119-53-9
Sodium dodecyl sulfate         151-21-3
L-Menthol                      2216-51-5
Tiron                          149-45-1
Riboflavin                     83-88-5
Sodium Acetate Trihydrate      6131-90-4
Disodium Succinate Hexahydrate 6106-21-4
Disodium                       6381-92-6
ethylenediaminetetraacetate
dihydrate
sodium citrate, dihydrate      1545801
Sodium potassium tartrate,     6381-59-5
tetrahydrate
L-(+)-Arginine                 1119-34-2
monohydrochloride
Ethylenediamine                333-18-6
dihydrochloride
Sodium formate                 141-53-7
Sodium acetate                 127-09-3
Potassium acetate              127-08-2
Ammonium citrate               3012-65-5
Ammonium bicarbonate           1066-33-7
Ammonium chloride              12125-02-9
Ammonium nitrate               6484-52-2
Ammonium persulfate            7727-54-0
Ammonium sulfate               7783-20-2
Zinc chloride                  7646-85-7
Sulfuric acid, zinc salt       7446-20-0
(1:1), heptahydrate
Sodium Tripolyphosphate        7758-29-4
ammonium benzoate              1863-63-4
ammonium bisulfite             10192-30-0
1,5-Naphthalenedisulfonic Acid 1655-29-4
Disodium Salt
4-Hydroxybenzoic Acid          99-96-7
Diphenylacetic Acid            117-34-0
Glutaric Acid                  110-94-1
L-(−)-Fucose                   2438-80-4
L-Cysteine Hydrochloride       52-89-1
L-Histidine Hydrochloride      1880304
Monohydrate
o-Toluic Acid                  118-90-1
Pivalic Acid                   75-98-9
Pyruvic Acid Sodium Salt       113-24-6
Potassium bromide              2139626
Sodium Dithionate Dihydrate    7631-94-9
Sodium Malonate                141-95-7
Trisodium Citrate              68-04-2
Potassium Sodium Tartrate      304-59-6
Potassium Citrate              866-84-2
D-Maltose Monohydrate          6363-53-7
Cyclohexaamylose               10016-20-3
Dodecyl sulfate, lithium salt  2044-56-6
Manganese chloride             2145076
methyl-urea                    598-50-5
beta-Cyclodextrin              7585-39-9
Triphosphoric acid,            13845-36-8
pentapotassium salt
Glycine ethyl ester            623-33-6
hydrochloride
L-Histidine methyl ester       7389-87-9
dihydrochloride
L-Leucine methyl ester         7517-19-3
hydrochloride
D-Lysine hydrochloride         7274-88-6
2-Naphthalenesulfonic acid     532-02-5
sodium salt
calcium nitrate tetrahydrate   13477-34-4
Vitamin B1                     59-43-8
Zinc Acetate Dihydrate         5970-45-6
Potassium fluoride             7789-23-3
Potassium iodate               2139718
Potassium iodide               7681-11-0
Potassium thiocyanate          333-20-0
Sodium bromide                 7647-15-6
Sodium fluoride                7681-49-4
Sodium iodide                  7681-82-5
Sodium nitrate                 7631-99-4
Calcium acetate                5743-26-0
Trichloroacetic acid           76-03-9
Ammonium acetate               631-61-8
Ammonium fluoride              12125-01-8
DL-malic acid                  617-48-1
t-Butyl Alcohol                75-65-0
beta-Alanine                   107-95-9
(S)-(−)-Tryptophan             73-22-3
Malonic acid                   141-82-2
Phenethylamine                 64-04-0
Salicylylaldehyde              90-02-8
Sodium benzoate                532-32-1
Mandelic acid                  90-64-2
Calcium pantothenate           137-08-6
Chloroacetic Acid              79-11-8
Ethanol Amine                  141-43-5
Salicylic acid                 69-72-7
Saccharin sodium               128-44-9
Thiamine hydrochloride         67-03-8
2,2′-Oxybisethanol             111-46-6
Resorcinol                     108-46-3
2-Amino-2-(hydroxymethyl)-1,3- 77-86-1
propanediol
2,5-Dimethylphenol             95-87-4
Ammonium Phosphate Monobasic   7722-76-1
1,3-Butanediol                 107-88-0
Glycolic Acid                  79-14-1
Sodium Gluconate               527-07-1
Terephthalic Acid              100-21-0
L-Ascorbic Acid Sodium Salt    134-03-2
3-Acetyl-6-methyl-2,4-         520-45-6
pyrandione
Calcium Acetate                62-54-4
Nicotinamide                   98-92-0
1-Hydroxy-2-naphthoic Acid     86-48-6
2-Isopropylphenol              88-69-7
4-Aminosalicylic Acid          65-49-6
Calcium Glycerophosphate       27214-00-2
Erythorbic Acid Sodium Salt    7378-23-6
Gluconic Acid Potassium Salt   299-27-4
Orotic Acid                    65-86-1
p-Anise Alcohol                105-13-5
Potassium Benzoate             582-25-2
Taurine                        107-35-7
Thiamine Nitrate               532-43-4
3,3,5-Trimethyl-1-cyclohexanol 116-02-9
tert-Butylhydroquinone         1948-33-0
Sulfosalicylic acid            97-05-2
Gallic acid                    149-91-7
L-borneol                      464-45-9
Isoborneol                     124-76-5
2,5-Dihydroxybenzoic acid,     490-79-9
Gentisic acid
5-hydroxy-6-methyl-3,4-        65-23-6
pyridinedimethanol
Naphthalene-2-sulfonic acid    120-18-3
Ethanesulfonic acid, 2-        1562-00-1
hydroxy-, monosodium salt
Pamoic acid                    130-85-8
2,4-Dimethylphenol             105-67-9
3,5-Dihydroxyacetophenone      51863-60-6
Eugenol                        97-53-0
n-Butyric Acid                 107-92-6
Hydroquinone                   123-31-9
Propionic Acid                 79-09-4
meta-Phenylenediamine          108-45-2
Oxalic Acid                    144-62-7
n-Hexanoic Acid                142-62-1
2-Furancarboxylic Acid         88-14-2
4′-Nitroacetanilide            104-04-1
D-(−)-Tartaric Acid            147-71-7
p-Acetamidobenzoic Acid        556-08-1
Galactaric acid                526-99-8
D-glucuronate                  1700908
Lactobionic acid               96-82-2
p-Formylacetanilide            122-85-0
2-Mercaptobenzoic acid         147-93-3
Propanoic acid, 2-hydroxy-,    28305-25-1
calcium salt (2:1), (S)-
D(+)-10-Camphorsulfonic acid   3144-16-9
3-Cyclopentylpropionic acid    140-77-2
1R-(−)-Camphorsulfonic acid    35963-20-3
DL-Lysine                      70-54-2
Cinnamic acid                  621-82-9
Triethanolamine                102-71-6
Acetic Acid                    64-19-7
Dichloroacetic Acid            79-43-6
Diethylamine                   109-89-7
Diethylaminoethanol            100-37-8
N-(2-Hydroxyethyl)Morpholine   622-40-2
Octanoic Acid                  124-07-2
isobutyric acid                79-31-2
Anisic Acid                    100-09-4
Betaine                        107-43-7
Enanthoic Acid                 111-14-8
Hippuric Acid                  495-69-2
Tiglic Acid                    80-59-1
Cyclohexanecarboxylic acid     98-89-5
m-Methoxybenzoic acid          586-38-9
D-(+)-Camphoric acid           124-83-4
N-(2-Hydroxyethyl)pyrrolidine  2955-88-6

Claims

1. A method of screening a chemical substance for possible solid forms, said method comprising the steps of:

preparing a first sample comprising a chemical substance in a first solvent;

preparing a second sample comprising the chemical substance in a second solvent;

sonicating the first and second samples; and

solidifying the chemical substance from the first and second samples.

2. The method of claim 1, wherein the solidifying step and the sonicating step at least partially overlap.

3. The method of claim 1, wherein at least one of said solvents is selected from the group consisting of acetone, acetonitrile, chloroform, dioxane, ethanol, ethyl acetate, heptane, butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, isopropyl acetate, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, propanol, butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, methyl-tert-butyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide.

4. The method of claim 1, wherein the first solvent comprises a mixture of solvents.

5. The method of claim 4, wherein the second solvent comprises a mixture of solvents.

6. The method of claim 1, wherein at least one of the samples is a solution having a viscosity greater than about 10 cPoise before the solution is sonicated.

7. The method of claim 1, wherein the samples are provided by preparing a solution from an amorphous solid comprising the chemical substance.

8. The method of claim 7, wherein the solvent is sonicated while the amorphous solid is added to the solvent.

9. The method of claim 1, wherein at least one of the samples is an emulsion comprising two or more substantially immiscible solvents and the chemical substance.

10. The method of claim 1, wherein at least one of the samples is a slurry comprising a solvent and the chemical substance.

11. The method of claim 1, comprising providing a plurality of subsamples of said first sample, and wherein a first portion of the subsamples are subjected to relatively slow evaporation, and a second portion of the subsamples are subjected to relatively fast evaporation.

12. The method of claim 1, wherein the solidifying step comprises evaporating a solvent from the samples, and the method comprises sonicating at least one of the samples until the solvent is substantially completely evaporated.

13. The method of claim 1, comprising the step of evaporating a solvent from at least one of the samples during the sonicating step.

14. The method of claim 1, comprising the step of evaporating a solvent from at least one of the samples after the sonicating step.

15. The method of claim 1, comprising the step of cooling at least one of the samples before the sonicating step.

16. The method of claim 1, comprising the step of cooling at least one of the samples during the sonicating step.

17. The method of claim 1, comprising the step of cooling at least one of the samples after the sonicating step.

18. The method of claim 1, comprising the step of crash-cooling at least one of the samples before the sonicating step.

19. The method of claim 1, wherein at least one of the samples is sonicated by at least one ultrasound pulse.

20. The method of claim 1, wherein at least one of the samples is sonicated by a series of at least 5 ultrasound pulses.

21. The method of claim 1, wherein at least one of the samples is sonicated by sonicating at least once for about 5 minutes.

22. The method of claim 1, wherein the sonication is substantially continuous during the solidification step.

23. The method of claim 1, wherein the solidification comprises generating at least one solid solvate of the chemical substance.

24. The method of claim 1, wherein the solidification comprises generating at least one solid hydrate of the chemical substance.

25. The method of claim 1, wherein the first sample and the second sample are placed in a well plate.

26. The method of claim 25, wherein the solidified chemical substances are analyzed in the well plate by x-ray diffraction.

27. The method of claim 1, wherein the solidified chemical substances are analyzed by transmission x-ray diffraction.

28. The method of claim 1, wherein the solidified chemical substances are analyzed by Raman spectroscopy.

29. The method of claim 1, wherein the first sample and the second sample are sonicated in a well plate.

30. The method of claim 1, further comprising the step of determining whether one or more solid forms were generated using an analytical method selected from the group consisting of visual analysis, microscopic analysis, thermal analysis, diffraction analysis, and spectroscopic analysis.

31. The method of claim 1, further comprising the step of determining whether one or more solid forms were generated using x-ray diffraction analysis

32. The method of claim 1, further comprising the step of determining whether one or more solid forms were generated using Raman spectroscopic analysis.

33. A method of crystallizing a chemical substance, said method comprising the steps of:

forming an emulsion comprising two or more substantially immiscible solvents and the chemical substance by applying ultrasound to a mixture of said solvents and the chemical substance; and

crystallizing the chemical substance from the emulsion.

34. The method of claim 33, further comprising the steps of adding an antisolvent to the emulsion, and thereafter further sonicating the emulsion.

35. The method of claim 33, wherein the chemical substance is substantially soluble in one of said immiscible solvents and substantially insoluble in another of said immiscible solvents.

36. A method of crystallizing a chemical substance, said method comprising the steps of:

providing a sample of the chemical substance in a solvent;

sonicating the sample at a predetermined supersaturation level; and

crystallizing the chemical substance from the sample.

37. The method of claim 36, wherein the sonicating and crystallizing steps at least partially overlap.

38. The method of claim 36, wherein the sample is cooled before sonicating.

39. The method of claim 36, wherein the solvent is evaporated after sonicating.

40. The method of claim 36, wherein the predetermined supersaturation level is selected to generate a relatively stable form of the chemical substance.

41. The method of claim 36, wherein the predetermined supersaturation level is selected to generate a solvate of the chemical substance.

42. The method of claim 36, further comprising adding an additional solvent to the sample.

43. The method of claim 36, wherein the sample is a solution having a viscosity greater than about 10 cPoise before the solution is sonicated.

44. The method of claim 36, wherein the sample has a metastable zone, and the metastable zone has a width of at least about 1° C.

45. The method of claim 36, wherein the sample has a metastable zone, and the metastable zone has a width that is reduced by at least about 1° C. through sonicating the sample.

46. The method of claim 36, wherein the forming step comprises forming a solution or suspension from a solvent and an amorphous solid comprising the chemical substance.

47. A method of screening a chemical substance for possible solid forms, said method comprising the steps of:

providing a chemical substance in a plurality of samples;

sonicating at least one of the samples, wherein at least one other sample is unsonicated;

solidifying the samples of the chemical substance; and

determining whether one or more solid forms of the chemical substance were generated.

48. A method of generating the most stable form of a chemical substance, said method comprising the steps of:

providing a sample of the chemical substance in a solvent;

sonicating the sample at a predetermined supersaturation level; and

crystallizing the chemical substance from the sample;

wherein the crystallized chemical substance is the most stable solid form of the chemical substance relative to known solid forms of the chemical substance.

49. A method of generating a solid form of a chemical substance from a meta stable solution, said method comprising the steps of:

forming a metastable solution of the chemical substance in a solvent;

sonicating the metastable solution; and

crystallizing the chemical substance from the solution.

50. A method of obtaining a substantially pure solid form of a chemical substance, said method comprising the steps of:

providing a sample of the chemical substance in a solvent;

sonicating the sample at a predetermined supersaturation level; and

crystallizing the chemical substance from the sample;

wherein a substantially pure solid form of the chemical substance is crystallized.

51. A method of preparing a solvate of a chemical substance, said method comprising the steps of:

providing a sample comprising the chemical substance and a solvent;

sonicating the sample; and

generating a solid from the sample, wherein the solid comprises a solvate of the chemical substance and the solvent.

52. A method of screening for possible cocrystals comprising an active agent, said method comprising the steps of:

providing a plurality of samples, each sample comprising the active agent and one or more guests, wherein the plurality of samples contains the same or different guests;

sonicating the samples;

crystallizing the active agent and the guest from the samples; and

determining whether a cocrystal was generated in one or more of the samples.

53. The screening method of claim 52, wherein at least one sample contains a different guest than at least one other sample.

54. The screening method of claim 52, wherein each sample contains a different guest.

55. The screening method of claim 52, wherein the sonicating step and the crystallizing step at least partially overlap.

56. The screening method of claim 52, wherein the samples are placed in a well plate and sonicated in the well plate.

57. The screening method of claim 52, wherein the samples are supersaturated with respect to at least one of the active agent and the guest before the sonicating step.

58. The method of claim 52, wherein at least some of the samples comprise more than one solvent.

59. The method of claim 52, wherein the samples are sonicated by at least one ultrasound pulse.

60. The method of claim 52, wherein at least one of the samples is sonicated by a series of ultrasound pulses, each pulse having a duration of from about 0.1 second to about 10 seconds.

61. The method of claim 52, wherein at least one of the samples is sonicated at least once for at least about 1 minute.

62. The method of claim 52, wherein at least one of the samples is sonicated at least once for at least about 5 minutes.

63. The method of claim 52, further comprising the step of determining whether a cocrystal was generated using an analytical method selected from the group consisting of visual analysis, microscopic analysis, thermal analysis, diffraction analysis, and spectroscopic analysis.

64. The method of claim 52, further comprising the step of determining whether a cocrystal was generated using x-ray diffraction analysis.

65. The method of claim 52, further comprising the step of determining whether a cocrystal was generated using Raman spectroscopic analysis.

66. The method of claim 52, wherein at Least one new solid state phase is formed by the crystallizing step.

67. The method of claim 52, further comprising crystallizing at least one unsonicated sample that is substantially the same as at least one sonicated sample.

68. A method of preparing a cocrystal comprising an active agent and a guest, said method comprising the steps of:

providing a sample of an active agent and a guest;

sonicating the sample; and

crystallizing a cocrystal from the sample, the cocrystal comprising the active agent and the guest.

69. The method of claim 68 wherein the active agent is an active pharmaceutical ingredient.

70. The method of claim 68, wherein the active agent is provided as a salt in the sample.

71. The method of claim 70, wherein the salt comprises chloride.

72. The method of claim 68, wherein the guest is a salt.

73. The method of claim 68, wherein the guest is an organic acid.

74. The method of claim 68, wherein the active agent is not a salt.

75. The method of claim 68, wherein the active agent is neutral or zwitterionic.

76. The method of claim 68, wherein the sample comprises a solvent selected from the group consisting of acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide.

77. The method of claim 68, wherein the sample comprises more than one solvent.

78. The method of claim 68, wherein the sample comprises more than one guest.

79. The method of claim 68, wherein at least one of the samples is sonicated by at least one ultrasound pulse.

80. The method of claim 68, wherein at least one of the samples is sonicated by a series of ultrasound pulses, each pulse having a duration of from about 0.1 second to about 10 seconds.

81. The method of claim 68, wherein at least one of the samples is sonicated at least once for at least about 1 minute.

82. The method of claim 68, wherein at least one of the samples is sonicated at least once for at least about 5 minutes.

83. The method of claim 68, wherein the sonication is substantially continuous during the crystallization step.

84. A method of cocrystallizing two or more components, said method comprising the steps of:

(a) determining a concentration for two or more components in a sample effective for cocrystallization of the components;

(b) preparing the sample comprising the components, said sample having an effective concentration of the components;

(c) sonicating the sample; and

(d) generating a cocrystal from the sample, the cocrystal comprising the components.

85. The method of claim 84, wherein the components comprise an active agent and a guest.

86. A method for speeding the cocrystallization of an active agent and a guest comprising:

providing a sample in an effective volume;

sonicating the sample;

cocrystallizing said active agent and said guest from the sample;

wherein the rate of cocrystallization is increased by at least 25%.

87. The method of claim 84, wherein the sample is a metastable solution.

88. A method for screening for possible salts comprising an ionizable active agent, said method comprises:

providing a plurality of samples comprising an ionizable active agent and one or more counterions, wherein the plurality of samples contains the same or different counterions;

sonicating the samples;

forming one or more crystallized salt compounds from the samples, said crystallized salt compounds comprising the ionizable active agent and the counterions.

89. The method of claim 88, wherein at least one sample contains a different counterion than at least one other sample.

90. The method of claim 88, wherein the plurality of samples comprises a plurality of sets, and the sets differ in having different counterions, and the samples within each set have the same counterion.