Polymorphic forms of ziprasidone HCl and processes for their preparation
Provided are various polymorphic forms of ziprasidone HCl and processes for their preparation.
Latest Patents:
- TOSS GAME PROJECTILES
- BICISTRONIC CHIMERIC ANTIGEN RECEPTORS DESIGNED TO REDUCE RETROVIRAL RECOMBINATION AND USES THEREOF
- CONTROL CHANNEL SIGNALING FOR INDICATING THE SCHEDULING MODE
- TERMINAL, RADIO COMMUNICATION METHOD, AND BASE STATION
- METHOD AND APPARATUS FOR TRANSMITTING SCHEDULING INTERVAL INFORMATION, AND READABLE STORAGE MEDIUM
This application is a divisional of U.S. patent application Ser. No. 10/860,926, filed Jun. 3, 2004, claims the benefit of U.S. provisional application Ser. No. 60/475,806, filed Jun. 3, 2003; U.S. provisional application Ser. No. 60/487,913, filed Jul. 16, 2003; U.S. provisional application Ser. No. 60/494,970, filed Aug. 13, 2003; U.S. provisional application Ser. No. 60/528,346, filed Dec. 9, 2003, and U.S. provisional application Ser. No. 60/571,997; filed May 17, 2004, the contents of all of which are incorporated herein.
FIELD OF THE INVENTIONThe present invention relates to the solid state chemistry of ziprasidone HCl.
BACKGROUND OF THE INVENTION Ziprasidone is an antipsychotic agent that is chemically unrelated to phenothiazine or butyrophenone antipsychotic agents. Ziprasidone has the following structure:
The preparation of ziprasidone base is disclosed in U.S. Pat. No. 4,831,031 (example 16). Preparation of ziprasidone base is also disclosed in U.S. Pat. No. 5,312,925. A process for preparation of ziprasidone HCl monohydrate having a mean particle size equal to or less than about 85 microns is also disclosed in U.S. Pat. No. 6,150,366 and EP 0 965 343 A2.
Ziprasidone has been marketed under the name GEODON as an oral capsule and as an injectable drug. GEODON capsules contain the monohydrate hydrochloride salt of ziprasidone, and come in 20, 40, 60 and 80 mg dosage forms. GEODON for injection contains a lyophilized form of ziprasidone mesylate trihydrate, and contains 20 mg base equivalent of ziprasidone. The mesylate salts of ziprasidone, including monohydrate and trihydrate, are disclosed in U.S. Pat. Nos. 6,110,918 and 5,245,765.
The present invention relates to the solid state physical properties of ziprasidone HCl.
These properties can be influenced by controlling the conditions under which ziprasidone HCl is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. These conformational and orientational factors in turn result in particular intramolecular interactions and intermolecular interactions with adjacent molecules that influence the macroscopic properties of the bulk compound. A particular polymorphic form may give rise to distinct spectroscopic properties that may be detectable by powder X-Ray diffraction, solid state 13C NMR spectrometry and infrared spectrometry. The polymorphic form may also give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others.
Ziprasidone HCl hemihydrate is disclosed in U.S. Pat. No. 4,831,031, Example 16 (column 13, line 13). A ziprasidone HCl monohydrate (herein designated Form M) is disclosed in U.S. Pat. No. 5,312,925 and EP 0 586 181 A1. Form M is characterized by XRD, IR and water content. It is reported that the water content of Form M ranges from 3.8 to 4.5% by weight. Ziprasidone HCl Form M is prepared from ziprasidone base anhydrous.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. There is a need in the art for additional polymorphic forms of ziprasidone HCl.
SUMMARY OF THE INVENTIONIn one aspect, the present invention provides a crystalline form of ziprasidone HCl (Form E), wherein the crystalline form is characterized by a powder XRD pattern with peaks at 7.4, 13.0, 20.7, 23.4, 25.9±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for preparing ziprasidone HCl Form E, comprising:
a) combining aqueous HCl with ziprasidone base in the presence of ethyl acetate or acetonitrile to obtain a slurry;
b) maintaining the slurry to obtain ziprasidone HCl; and
c) recovering the ziprasidone HCl.
In another aspect, the present invention provides a crystalline form of ziprasidone HCl, wherein the crystalline form is a trihydrate.
In another aspect, the present invention provides a process for preparing ziprasidone HCl Form E in a mixture with a crystalline ziprasidone HCl having an X-Ray diffraction pattern having peaks at about 10.9, 17.4 and 19.1±0.2 degrees 2 theta, comprising:
a) combining aqueous HCl with ziprasidone base in the presence of tetrahydrofuran to obtain a slurry;
b) maintaining the slurry to obtain ziprasidone HCl; and
c) recovering the ziprasidone HCl mixture.
In another aspect, the present invention provides a crystalline form of ziprasidone HCl (Form F), wherein the crystalline form is characterized by a powder XRD pattern with peaks at 11.0, 18.1, 19.5, 21.9±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for preparing the ziprasidone HCl Form F, comprising:
a) combining aqueous HCl with ziprasidone base in a solvent selected from the group consisting of methylethylketone, tetrahydrofuran and dimethylacetamide to obtain a slurry;
b) maintaining the slurry to obtain ziprasidone HCl; and
c) recovering the ziprasidone HCl.
In another aspect, the present invention provides a process for preparing the ziprasidone HCl form M, comprising:
a) heating a slurry of ziprasidone HCl in n-butanol or THF, optionally in mixture with water; and
b) recovering the ziprasidone HCl form M.
In another aspect, the present invention provides a process for preparing the ziprasidone HCl form M comprising:
a) combining aqueous HCl with ziprasidone base at a temperature of at least about 40° C. in a solvent selected from the group consisting of ethanol, methanol, n-butanol, acetone, ethyl acetate, ethyl lactate, dimethyl-carbonate, optionally in a mixtures with water to obtain a slurry,
b) maintaining the slurry to obtain the ziprasidone HCl form M; and
c) recovering the ziprasidone HCl form M.
In another aspect, the present invention provides a process for preparing the ziprasidone HCl form M comprising:
a) contacting gaseous hydrogen chloride with ziprasidone base in methanol to obtain a slurry of ziprasidone hydrochloride in methanol;
b) maintaining the slurry to obtain the ziprasidone HCl form M; and
c) recovering the ziprasidone HCl form M.
In another aspect, the present invention provides a process for preparing the ziprasidone HCl form M substantially free of the crystalline ziprasidone HCl characterized by a powder XRD pattern with peaks at 10.9, 17.4, 19.1, 25.0, 26.0±0.2 degrees 2 theta comprising:
a) combining a solution or slurry of ziprasidone base in a solvent with less than one equivalent HCl to obtain a reaction mixture containing ziprasidone HCl;
b) stirring or agitating the reaction mixture;
c) adding additional HCl to obtain additional ziprasidone HCl; and
d) recovering the ziprasidone HCl form M.
In another aspect, the present invention provides for amorphous form of ziprasidone HCl.
In another aspect, the present invention provides a process for preparing amorphous form comprising slurrying ziprasidone base with methyl ethyl ketone or mono-chloro benzene with gaseous hydrochloride.
In another aspect, the present invention provides a crystalline form of ziprasidone HCl (Form G), wherein the crystalline form is characterized by a powder XRD pattern with peaks at 9.0, 20.6, 22.7, 25.0, 27.0±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for preparing ziprasidone HCl Form G comprising:
a) combining gaseous HCl with a mixture of ziprasidone base in a solvent selected from the group consisting of carbon tetrachloride, di-isopropyl-ether, ethyl acetate, ethyl lactate and mixtures thereof to obtain a slurry of ziprasidone HCl;
b) maintaining the slurry to obtain ziprasidone HCl Form G; and
c) recovering the ziprasidone HCl.
In another aspect, the present invention provides a process for preparing a mixture of the ziprasidone HCl of Form F and ziprasidone HCl Form G comprising:
a) combining gaseous HCl with a mixture of ziprasidone base in ethyl acetate to obtain a slurry of ziprasidone HCl;
b) maintaining the slurry to obtain ziprasidone HCl; and
c) recovering the mixture.
In another aspect, the present invention provides a crystalline form of ziprasidone HCl (Form I), wherein the crystalline form has an XRD pattern with peaks at 15.8, 16.2, 18.9, 23.8, 27.0±0.2 degrees 2 theta,
In another aspect, the present invention provides a crystalline form of ziprasidone HCl (Form J), wherein the crystalline form is characterized by a powder XRD pattern with peaks at 9.1, 19.1, 25.7, 26.3, 26.9±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for preparing ziprasidone HCl Form J comprising:
a) combining ziprasidone base with HCl to obtain a slurry of ziprasidone HCl in a C5 to C12 hydrocarbon;
b) maintaining the slurry to obtain the crystalline ziprasidone HCl; and
c) recovering the ziprasidone HCl.
In another aspect; the present invention provides a crystalline form of ziprasidone HCl, wherein the crystalline form has a water content of about 24% by LOD.
In another aspect, the present invention provides a crystalline from of ziprasidone HCl (Form E1), wherein the crystalline form is characterized a powder XRD pattern with peaks at 7.5, 13.0, 21.2, 23.4 and 26.0±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for preparing ziprasidone HCl Form E1 comprising drying the ziprasidone HCl Form J.
In another aspect, the present invention provides a crystalline form of ziprasidone, wherein the crystalline form has a water content of about 6% to about 8%.
In another aspect, the present invention provides a pharmaceutical composition and method of treating a patient suffering from schizophrenia.
FIGURES
As used herein, the term slurry refers to a heterogeneous mixture.
As used herein, the term reduced pressure refers to a pressure below about 1 atm, more preferably below about 100 mmHg.
The present invention provides for obtaining ziprasidone HCl Form M from ziprasidone base, or other forms of ziprasidone hydrochloride. Ziprasidone base, such as form B, but not limited to this form, is combined with aqueous hydrochloric acid and slurried in solvents such as methanol, ethanol, n-butanol, ethyl acetate, ethyl lactate, acetone, dimethyl carbonate, optionally in mixtures with water. Gaseous hydrogen chloride may be used with methanol. The slurry is then allowed to last for a sufficient amount of time (maintained) to obtain the monohydrate, preferably for about half a day. The slurry process is preferably carried out about room temperature to about reflux temperature of the solvents. Preferred combination of starting bases and solvents include Form B and ethyl acetate/ethanol/methanol/n-butanol. In another embodiment, rather than starting with ziprasidone base, another polymorphic form of ziprasidone HCl is used for the slurry process preferred combination of solvents and starting forms include ziprasidone HCl Form F and THF and ziprasidone HCl Form E and n-butanol, preferably in mixtures with water. Preferably, the slurry is heated for a sufficient amount of time, more preferably to at least about 40° C.
The present invention also provides a process for preparation of Form M, but in a substantially pure form, by slow crystallization from slurry or solution of ziprasidone base in an organic solvent. Preferred solvents are mixtures of THF/AcOH, THF/MeOH, DMA, n-BuOH/AcOH. The temperature of crystallization is more than about 50° C., preferably of about 55 to about 70° C., more preferably about 55 to about 65° C., and most preferably 65±2° C. The mode of HCl addition is preferably portion-wise.
In one embodiment, a first portion of HCl is added until opalescence is obtained, and the mixture is stirred to induce nucleation, followed by the rest of HCl addition. Typically, opalescence resulting from formation of ziprasidone HCl is observed after adding ˜ 1/10 portion of the HCl. Seeding of ziprasidone base before the HCl addition is ideal.
In one embodiment, A process ziprasidone HCl form M substantially free of the crystalline ziprasidone HCl characterized by a powder XRD pattern with peaks at 10.9, 17.4, 19.1, 25.0 26.0±0.2 degrees 2 theta is prepared by combining a solution or slurry of ziprasidone base in a solvent with less than one equivalent HCl to obtain a reaction mixture containing ziprasidone HCl, stirring or agitating the reaction mixture, adding additional HCl to obtain additional ziprasidone HCl and recovering the ziprasidone HCl form M.
In another aspect, the present invention provides for ziprasidone HCl Form E. Ziprasidone HCl Form E is characterized by an X-Ray diffraction pattern (
This corresponds approximately to a trihydrate, which may contain solvent approximately as 1½-1⅓ solvate of acetonitrile, or ⅔-¾ solvate of ethyl acetate.
The FTIR spectrum of ziprasidone HCl form E is shown in
Ziprasidone HCl Form E when exposed to a high relative humidity, such as for about 22 days, transforms to form M. Ziprasidone HCl form E transforms to amorphous form when exposed to about 10% to about 0%, more preferably about 0% relative humidity, for such as 22 days, or after heating at elevated temperature, preferably at about 80° C. overnight. Ziprasidone HCl Form E transforms to Form A when exposed to a relative humidity of about 20% to about 60% for about 22 days (see table 1 and 2). Form A is characterized by an X-Ray diffraction pattern having peaks at about 10.9, 17.4 19.1, 25.0 and 26.0±0.2 degrees 2 theta.
Ziprasidone HCl novel form E may be prepared by combining ziprasidone base with aqueous HCl in acetonitrile or ethyl acetate to obtain a slurry, and allowing the slurry to last for a sufficient time to obtain Form E. The slurry process is preferably carried out overnight. The combining of HCl with ziprasidone base is preferably carried out at a temperature of about 40° C. to about 60° C., with about 50° C. being preferred. The slurrying after the combining is preferably carried out at a temperature of about 20° C. to about 30° C., more preferably at about room temperature. Ziprasidone Form E may also be obtained as a mixture with Form A by a slurry process that uses tetrahydrofuran as a solvent. Slurrying at room temperature results in the mixture, while slurrying at higher temperatures, such as above about 50° C. results substantially in Form A.
In another aspect, the present invention provides for ziprasidone HCl Form F. Ziprasidone HCl Form F is characterized by an XRD pattern (
The IR spectrum of ziprasidone HCl form F in
Ziprasidone HCl novel Form F may be prepared by combining ziprasidone base with aqueous HCl in tetrahydrofuran, methylethylketone or dimethylacetamide to obtain a slurry, and allowing the slurry to last for a sufficient time to obtain Form F. The slurry may be diluted by addition of water. The combining step is preferably carried out at elevated temperature, more preferably of about 50° C. to about 70° C., most preferably at about 60° C. The slurrying after the combining is preferably carried out at a temperature of about 20° C. to about 30° C., more preferably at about room temperature. Preferably, when the solvent is dimethylacetamide, a mixture of Form F and Form M is obtained.
Form F may be used for the preparation of Form M, by combining ziprasidone HCl Form F, THF and water, heating the slurry to about 50° C., cooling the slurry to room temperature, and maintaining for a sufficient time to obtain Form M.
In another aspect, the present invention provides for amorphous form of ziprasidone HCl. Amorphous ziprasidone HCl has an X-Ray diffraction pattern as substantially depicted in
Amorphous form of ziprasidone HCl may be prepared by placing Form E in a dessicator (dry chamber) having low humidity for a sufficient time to obtain amorphous form. In a preferred embodiment, ziprasidone Form E is put in a dessicator having about 0% relative humidity for about 18 days.
Ziprasidone HCl amorphous may be prepared by drying ziprasidone HCl form E at an elevated temperature, preferably of about 80 to about 105° C., for a sufficient period of time, preferably of about 5 to about 30 hours, more preferably overnight (˜15 hours). Ziprasidone HCl amorphous may also be prepared by exposing ziprasidone HCl form E to low relative humidity, preferably about 0%, for a sufficient period, preferably a time of about 1-3 weeks, more preferably for about 3 weeks.
Ziprasidone hydrochloride amorphous may also be prepared by treating the slurry of ziprasidone base in MEK or mono-chlorobenzene with gaseous HCl.
In another aspect, the present invention provides for ziprasidone HCl Form G. Ziprasidone HCl Form G has an XRPD diffraction pattern with preferred peaks at 9.0, 20.6, 22.7, 25.0, 27.0±0.2 degrees 2 theta, and other peaks at 11.3, 12.5, 13.9, 15.6, 21.5, 23.5, 25.8, 28.0, 31.5±0.2 degrees two-theta.
Ziprasidone HCl Form G may have a water content of about 5% to about 12%. Ziprasidone HCl Form G may be a dihydrate (about 7.4% stoichiometric value for the dihydrate) or a trihydrate (about 10.7% stoichiometric value for the trihydrate). Ziprasidone HCl Form G is sparingly soluble in methanol, hence the water determination by Karl Fisher is carried out for more than 30 minutes in order to ensure that all the material is dissolved and all the water is analyzed.
Ziprasidone HCl Form G may be prepared by introducing HCl gas into a mixture of ziprasidone base in ethyl acetate, ethyl lactate, carbon tetrachloride, di-isopropyl-ether and mixtures thereof to obtain a slurry of ziprasidone HCl, and allowing the slurry to last for a sufficient time. The slurry is preferably stirred. When ethyl acetate is used in the absence of an ether, the result may be a mixture of Form G with Form F. The resulting wet product may be separated by techniques known in the art such as filtration, and may be dried, preferably at a temperature of about 40° C. to about 60° C. for about half a day.
In another aspect, the present invention provides for ziprasidone HCl Form I. Ziprasidone HCl Form I is characterized by an XRD pattern with peaks at 15.8, 16.2, 18.9, 23.8, 27.0±0.2 degrees 2 theta, and other peaks at 10.5, 11.3, 21.1, 24.8, 26.0±0.2 degrees two-theta. Ziprasidone HCl Form I may be prepared by heating ziprasidone HCl Form G, preferably a ziprasidone Form G obtained from a slurry in di-iso-propyl ether. The heating is preferably carried out at a temperature of about 40° C. to about 60° C. for about half a day
The polymorphic forms of the present invention are preferably used with particle size up to 100 microns in light of low solubility of ziprasidone HCl in water.
Ziprasidone HCl anhydrous may be prepared by drying ziprasidone HCl Form M, for example by exposing the material to low relative humidity, preferably about 0% relative humidity, for a sufficient period, preferably for about 1-3 weeks, more preferably for about 3 weeks.
The present invention also provides for ziprasidone HCl form J. Ziprasidone HCl Form J is characterized by XRD peaks at 9.1, 19.1, 25.7, 26.3, 26.9±0.2 degrees 2 theta, and other less characteristic peaks at 11.9, 21.4, 23.4, 30.7, 32.2±0.2 degrees two-theta. Form J has an FTIR spectrum as substantially depicted in FIGS. 18 to 20. The present invention also provides for ziprasidone HCl Form J with a water content of about 24%.
Ziprasidone HCl Form J may be obtained by slurry of ziprasidone base in a C5 to C12 hydrocarbon, preferably toluene. A few hours of slurrying is sufficient after combining of HCl with ziprasidone base to obtain the slurry. Ziprasidone HCl Form J may then be recovered for example by solvent removal.
The present invention also provides for ziprasidone HCl Form E1. Ziprasidone HCl Form E1 is characterized by XRD peaks at 7.5, 13.0, 21.2, 23.4 and 26.0±0.2 degrees 2 theta, and other less characteristic peaks at 10.9, 16.2, 20.8, 25.4, 30.3 and 34.8±0.2 degrees two-theta. Ziprasidone HCl Form E1 has an FTIR spectrum as substantially depicted in FIGS. 22 to 24. The present invention also provides for ziprasidone HCl Form E1 with a water content of about 6% to about 8%.
Ziprasidone HCl Form E1 may be prepared by removing solvent from ziprasidone HCl Form J. Such removal may be done by drying Form J at elevated temperature, and/or under ambient or reduced pressure. A dry nitrogen atmosphere is preferred with a temperature of about 30° C. to about 50° C., with about 40° C. being preferred.
A slurry is most effective when the solids of the heterogeneous mixture are in substantial contact with the solvent. When the solids settle down, the efficiency of the slurry process often decreases due to a decrease in contact. Thus, one of skill in the art would appreciate that if during the slurry process the solids settle down, a force such as stirring, agitating to disperse the solid. Even when the solids have not settled down, bringing of movement in the solvent may even further increase the efficiency of the slurry process.
One of skill in the art would appreciate that as the slurry is allowed to last for a sufficient time to obtain a particular polymorphic form, the slurry may dry up due to for example evaporation of the solvents. As the examples illustrate, additional amounts of a solvent may be added (same or different solvent), preferably followed by stirring, to obtain a slurry.
The various forms of ziprasidone may be recovered from the slurry by conventional techniques in the art such as decanting, filtration and centrifugation.
Pharmaceutical formulations of the present invention contain crystalline ziprasidone HCl, such as one of those disclosed herein, or ziprasidone HCl amorphous, optionally in mixture with other form(s) of ziprasidone. In addition to the active ingredient(s), the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, ziprasidone and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
According to the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
The dosage of GEODON may be used as a guidance. The oral dosage form of the present invention is preferably in the form of an oral capsule having a dosage of about 10 mg to about 160 mg, more preferably of about 20 mg to about 80 mg, and most preferably capsules of 20, 40, 60 and 80 mg.
Instrumentation:
X-Ray powder diffraction data were obtained using by method known in the art using a SCINTAG powder X-Ray diffractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.5418 Å was used. A round aluminum sample holder with round zero background quartz plate, with cavity of 25(diameter)*0.5(dept) mm.
DSC analysis was done using a Mettler 821 Stare. The weight of the samples was about 5 mg; the samples were scanned at a rate of 10° C./min from 30° C. to 320° C. The oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard 40 μl aluminum crucibles covered by lids with 3 holes were used.
TGA analysis was done using a Mettler M3 meter. The weight of the samples was about 10 mg; the samples were scanned at a rate of 10° C./min from 25° C. to 200° C. The oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard 70 μl alumina crucibles covered by lids with 1 hole were used.
IR analysis was done using a Perkin Elmer SPECTRUM ONE FT-IR spectrometer in DRIFTt mode. The samples in the 4000400 cm−1 interval were scanned 16 times with 4.0 cm−1 resolution.
The water content of ziprasidone HCl was measured by the methods known in the art like Karl Fisher or thermogravimetric analysis (TGA). In the case of ziprasidone HCl F, the TGA and Karl Fisher analysis matched, while for ziprasidone HCl form E the TGA analysis exceeded by far that of Karl Fisher, as an indication that a significant quantity of solvent is present.
Ziprasidone Base
Ziprasidone free base used for preparations of the crystal forms of ziprasidone HCl is characterized by X-Ray peaks at 12.1, 15.2, 16.3, 18.4, 25.0 degrees 2 theta and is further characterized by XRD peaks at 5.2, 10.4, 11.3, 13.1, 21.1, 22.1. The ziprasidone free base has a DSC thermogram like the one shown in
Ziprasidone base for the experiments below was prepared according to the procedure “EXPERIMENT” in U.S. Pat. No. 5,312,925, column 4. The water content of the base was 1.2% (Karl Fisher).
Example 2 Preparation of Ziprasidone Base Form BZiprasidone base (50 g) and toluene (250 ml) were charged into a 0.5 L three necked flask. The obtained slurry was heated at 85° C. for 2 hours. The hot slurry was filtrated and the solid was washed with methanol. The solid was dried in air-circulated oven at 50° C. to afford the dried Ziprasidone base form B (by XRD) (45.39 g).
Example 3 Preparation of Ziprasidone HCl Form E from Ziprasidone Base Form B in Acetonitrile and Aqueous HClAqueous HCl (37%) (10 ml) was added to a slurry of ziprasidone base Form B (10 g) in acetonitrile (200 ml) at reflux. After the addition, the slurry was heated over night. A solid was filtered and washed with acetonitrile. After drying at 50° C. for ˜16 hours, ziprasidone HCl Form E was obtained (12.71 g) (The water content was 9.25% by K.F. and the loss on drying by TGA is 18.8%), as confirmed by XRD.
Example 4 Preparation of Ziprasidone HCl Form E from Ziprasidone Base Form B in Ethyl Acetate and Aqueous HClA slurry of ziprasidone base form B (10 g) in ethyl acetate (100 ml) was heated at reflux without complete dissolution. The slurry was then cooled. When the temperature was about 50° C., aqueous HCl (37%) (10 ml) was added, and the slurry was diluted by addition of ethyl acetate (100 ml). The slurry was stirred for ˜16 hours. A solid was filtered and washed with ethyl acetate. The wet solid was ziprasidone HCl Form E, as confirmed by XRD. The wet solid was dried at 50° C. The dried solid had a water content of 9.62% (by K.F.) and a loss on drying of 19% (by TGA). The dried solid was Form E, as confirmed by XRD.
Example 5 Preparation of Ziprasidone HCl Form F from Ziprasidone Base Form B in Methylethylketone and Aqueous HClAqueous HCl (37%) (10 ml) was added drop-wise to a hot slurry of ziprasidone base Form B (10 g) in methylethylketone (MEK) (200 ml). The slurry was stirred at room temperature over night. A solid was filtered and washed with MEK. The wet solid was ziprasidone HCl Form F. The wet solid was dried at 50° C. for two days. The dried product was ziprasidone HCl Form F (10.62 g) (The water content was 3.87% by K.F. and the loss on drying is 4.1% by TGA), as confirmed by XRD.
Example 6 Preparation of Ziprasidone HCl Form F from Ziprasidone Base Form B in THF and Aqueous HClAqueous hydrochloric acid (37%) (910 ml) was added to a hot slurry of ziprasidone base (10 g) in tetrahydrofuran (THF) (200 ml). The slurry was stirred at room temperature for about 16 hours. A solid was filtered, washed with THF and dried in an oven at 50° C. for two days. The wet and the dried solid samples were ziprasidone HCl Form F (The water content was 3.63%), as confirmed by XRD.
Example 7 Preparation of a Mixture of Ziprasidone HCl Form F and Form M from Dimethylacetamide/Water and Aqueous HClZiprasidone base (10 g) was dissolved in dimethylacetamide (100 ml) at ˜95° C. The solution was cooled to 70° C. and aqueous HCl (37%) (10 ml) was added, resulting in precipitation and formation of a slurry. The slurry was then cooled to room temperature, followed by addition of water (100 ml). Stirring was continued for 1 hour at room temperature, followed by filtration, and washing of a solid material obtained from filtration with water. The wet solid was dried at 50° C. for about 16 hours to a dry solid (7.1 g). The wet and the dried solid were ziprasidone HCl Form F in mixture with Form M (The water content of the dried solid is 4.17% by K.F.), as confirmed by XRD.
Example 8 Preparation of Ziprasidone HCl Amorphous from Form E by DryingZiprasidone hydrochloride Form E (4.05 g) was heated at 80-105° C. in an oven for about 16 hours. The solid after heating was ziprasidone HCl amorphous (3.33 g) (The water content was 1.21% by K.F.), as confirmed by XRD.
Example 9 Preparation of Ziprasidone HCl Form M in Dimethylcarbonate/Methanol from Ziprasidone Base Form B and Aqueous HClZiprasidone base (10 g) was taken in dimethylcarbonate (DMC) (100 ml) and the mixture was heated at ˜90° C. Aqueous HCl (37%) (10 ml) was added, resulting in a sticky material. Additional amount of DMC (100 ml), and methanol (50 ml), were added, resulting in a slurry. The slurry was stirred at room temperature over night. A solid was filtered and washed with DMC, and subsequently dried at 50° C. overnight. The wet and the dried solids were ziprasidone HCl monohydrate, as confirmed by XRD. The water content of the dried solid by K.F. is 4.78%.
In all the above examples except example 8, drying was carried out in an air-circulated oven. In example 8, the pressure was atmospheric pressure.
Example 10 Preparation of Ziprasidone HCl Form G from Ethyl-Lactate/Ether/HCl(g)Ziprasidone base Form B (10 g) was added to ethyl-lactate (50 ml) and the slurry obtained was cooled to 5° C. HCl(g) was bubbled through the above slurry and ether (150 ml) was added. The slurry was stirred over night at room temperature, filtrated and washed with ether. The wet material was dried at 50° C. in an air-circulated oven and ziprasidone HCl Form G was obtained.
Example 11 Preparation of Ziprasidone HCl Form G from Carbon-Tetrachloride/HCl(g)Ziprasidone base Form B (5 g) was added to carbon-tetrachloride (50 ml) and HCl(g) was bubbled until pH 1 was reached. The temperature rose to ˜40° C. The slurry was stirred at room temperature for 3 hours and filtrated. The solid was dried in an air-circulated oven at 50° C. for 17 hours. The wet and the dried solid both were ziprasidone HCl Form G.
Example 12 Preparation of Ziprasidone HCl Form G from Di-Isopropyl-Ether/HCl(g)Ziprasidone base Form B (10 g) was added to di-iso-propyl-ether (200 ml) and the slurry was stirred at room temperature; through the slurry HCl(g) was bubbled while the temperature rose to ˜50° C. The slurry was stirred at room temperature over-night, the solid was filtrated and washed with di-iso-propyl-ether. The wet solid gave ziprasidone HCl Form G. Drying of the wet solid in an air-circulated oven at 50° C. for ˜16 h gave ziprasidone HCl Form I.
Example 13 Preparation of Ziprasidone HCl Mixture of Form G and F from Ethyl-acetate/HCl(g)Ziprasidone base Form B (10 g) was added to ethyl-acetate (200 ml) and HCl(g) was bubbled through the slurry; the temperature rose to ˜35° C. The slurry was stirred at room temperature for 3 hours and the solid was filtrated, washed with ethyl-acetate and dried for ˜16 h in an air-circulated oven at 45° C. The wet and dried solids both gave a mixture of ziprasidone HCl Form G and F.
Example 14 Preparation of Ziprasidone HCl Form M A) Preparation of Ziprasidone HCl Form M from Ziprasidone Base in Ethyl-Lactate/aq. HClConcentrated HCl (37%) was added to the slurry of ziprasidone base (form B) (10 g) in ethyl-lactate (200 ml) at 60° C. The reaction mixture was stirred at room temperature for about 16 hours, and a solid was filtrated, washed with ethyl-lactate (20 ml) and dried at 50° C. for two days. The solid was ziprasidone HCl Form M. (K.F. 4.02%).
B) Preparation of Ziprasidone HCl Form M from Ziprasidone Base in Ethanol/aq. HClTo the slurry of ziprasidone base (Form B) (10 g) in ethanol (200 ml) at room temperature was added concentrated hydrochloric acid 37% (˜5 g); the temperature rose to ˜30° C. during the HCl addition. The slurry was than stirred at room temperature for about 16 hours. A solid was filtrated, washed with ethanol and dried in an air-circulated oven at 50° C. The product was ziprasidone HCl form M. (K.F. 4.37%).
C) Preparation of Ziprasidone Form M from Ziprasidone Base in Methanol/HCl(g)To the slurry of ziprasidone base (Form B) (10 g) in methanol (100 ml) at 5° C. was bubbled HCl(g); the obtained slurry was then stirred over night at room temperature. A solid was filtrated, washed with methanol and dried at 50° C. for about 16 hours. The product was ziprasidone HCl Form M (KF. 4.5%).
D) Preparation of Ziprasidone HCl Form M from Ziprasidone Base in Methanol/aq. HClTo the slurry of ziprasidone base (Form B) (10 g) in methanol (200 ml) at 60° C. was added concentrated HCl (10 ml); the slurry was then stirred at room temperature for about 16 hours. A solid was filtrated, washed with methanol (2×10 ml) and dried at 50° C. in an air-circulated oven for 2 days. The product was ziprasidone HCl Form M (K.F. 4.26%).
E) Preparation of Ziprasidone HCl Form M from Ziprasidone Base in n-BuOH/aq. HClA slurry of ziprasidone base (Form B) (10 g) in n-butanol (250 ml) was heated to 60° C. While maintaining the temperature, concentrated HCl was added (10 ml). The reaction mixture was than stirred at room temperature for about 16 hours. A solid was filtrated, washed with n-butanol (2×20 ml) and dried for about 16 hours at 50° C. in an air-circulated oven. The dried solid was ziprasidone HCl Form M (K.F. 4.12%).
F) Preparation of Ziprasidone HCl Form M from Ziprasidone Base in Acetone/aq. HClTo the slurry of ziprasidone base. (Form B) (10 g) in acetone (200 ml) at room temperature was added concentrated HCl (100 ml); the temperature rose to about 30° C. The reaction mixture was stirred at room temperature for about 16 hours. A solid was filtrated, washed with acetone (2×10 ml) and dried for two days in an air-circulated oven at 50° C. The dried solid was ziprasidone HCl Form M (K.F. 4.57%).
G) Preparation of Ziprasidone HCl Form M from Form FA slurry of ziprasidone HCl Form F (5 g) in THF/water 95:5 (50 ml) was heated at 50° C. for two hours. After cooling to room temperature, a solid was filtrated, washed with mixture THF/water and dried for 18 hours in an air-circulated oven. The dried solid was ziprasidone HCl Form M (K.F. 4.50%).
H) Preparation of Ziprasidone HCl Form M from Form EZiprasidone HCl Form E (2 g) was heated in n-butanol (200 ml) and water (40 ml) at 85° C.; complete dissolution was not obtained. More water was added (20 ml) and the slurry was stirred at 90° C. for 1.5 hours. A solid was filtrated from the hot slurry, washed with n-butanol/water (4 ml 3:1) and dried. From the filtrate a solid was obtained upon cooling to 10° C. This material was filtrated, washed and dried in the same conditions. Both dried solids were ziprasidone HCl Form M.
Example 15 Preparation of Ziprasidone HCl Form JAqueous HCl was drop-wise added over 10 minutes, to a slurry of ziprasidone base (5 g) in toluene (100 ml) at room temperature. The obtained mixture was stirred at room temperature for 3 hours, and then the solvent was evaporated under vacuum. The solid obtained after the toluene evaporation was ziprasidone HCl Form J.
Example 16 Preparation of Ziprasidone HCl Form E1The above material (ZPR HCl form J form Example 20) was dried by maintaining it at 40° C. and under nitrogen atmosphere over night, followed by additional drying with a rotary evaporator. The dried material collected after the two drying stages was ziprasidone HCl Form E1 (water content by K.F. ˜6% and ˜8% respectively).
Example 17 Preparation of ZPR HCl Form M Substantially Pure of Form A A) Preparation of ZPR HCl Form M from THF:AcOHIn a 250 ml three necked flask were charged Ziprasidone base (5 g) and a mixture 9:1 THF:acetic acid. The slurry was heated at 60° C. and more solvent was added until complete dissolution was obtained. The total volume of the solvents mixture was 175 ml. To the solution 4 drops of 10% hydrochloric acid was added; upon HCl addition a precipitate is formed. The hazy solution was stirred for 1 h at 60° C. and after this 15 ml 10% HCl was added over 30 minutes. The slurry was than stirred for 2.5 h maintaining the temperature at 60° C. The solid was filtrated from the slurry after cooling to room temperature and washed with solvent. The solid obtained after drying at 50° C. is ZPR HCl Form M substantially pure of form A. (4.58 g). (Water content by K.F. 4.04%).
B) Preparation of ZPR HCl Form M from THF:MeOHIn a 250 ml three necked flask were charged Ziprasidone base (5 g) and mixture of THF:MeOH 10:3. The mixture was heated at 60° C. and diluted with the solvents until the complete dissolution was observed. (the total volume is 240 ml.). Hydrochloric acid 10% (2 ml) was added and the reaction mixture was stirred for 30 minutes. After this period of time more hydrochloric acid was added to complete the reaction. The stirring was continued for 1 h at 60° C.; the mixture was than cooled to room temperature and the solid filtrated and washed with solvent. After drying at 50° C. the ZPR HCl Form M substantially pure of form A was obtained. (Water content by K.F. 4.08%).
C) Preparation of ZPR HCl Form M from n-Butanol:Acetic AcidIn a 250 ml three necked flask were charged Ziprasidone base (5 g) and n-BuOH (100 ml) and the slurry was heated at 60° C. Acetic acid was added (10 ml) and more n-BuOH (100 ml). To the slurry 10% hydrochloric acid (2 ml) was added and the mixture was stirred for 1 h. After this more HCl was added drop-wise over 30′. The reaction mixture was stirred for 1 h at 60° C. to complete the reaction. After cooling to the room temperature the solid was filtrated, washed with solvent and dried at 50° C. to give ZPR HCl Form M substantially pure of form A (4.25 g). (Water content by K.F. 4.33%).
D) Preparation of ZPR HCl Form M from N,N-dimethyl-acetamideIn a 250 ml three necked flask were charged Ziprasidone base (5 g) and N,N-dimethyl-acetamide (DMA) (100 ml) and the mixture has been heated at 60° C. To the obtained solution 32% HCl (3 ml) was added and the stirring was continued for 4 h. After cooling, the solid was filtrated and then dried to afford ziprasidone HCl Form M substantially pure of form A.
(Water content by K.F. 4.15%).
Example 20 Preparation of Ziprasidone Form J and Form E1To the slurry of ziprasidone base (5 g) in toluene (100 ml) at room temperature was drop-wise added aqueous HCl over 10 minutes. The obtained mixture was stirred at room temperature for 3 hours, then the solvent was distilled under vacuum. The solid obtained after the toluene distillation was ziprasidone HCl Form J.
The above material (ZPR HCl form J) was dried by maintaining it at 40° C. and under nitrogen over night, followed by an additional drying operation on a rotary evaporator. The dried material collected in the two drying stages was ziprasidone HCl Form E1 (water content by K.F. 6% and 7.8% respectively).
Example 21 Preparation of ZPR.HCl Amorphous from ZPR Base and HCl in methyl-ethyl-ketoneTo the chilled slurry of ZPR base (5 g) in methylethyl-ketone (MEK) (100 ml) (˜2° C.) Was bubbled hydrogen chloride until the pH 1 was reached. The temperature was in the range 2 to 10° C. The slurry was than stirred at the above temperature for 5 hours, the solid was filtrated and washed with MEK (2×10 ml). After drying at 60° C. was obtained a solid which is ZPR.HCl amorphous by XRD.
Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. Polymorphism in Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences, Volume 95 may be used for guidance. All references mentioned herein are incorporated in their entirety.
Claims
1. A crystalline form of ziprasidone HCl (Form F), wherein the crystalline form is characterized by a powder XRD pattern with peaks at 111.0, 18.1, 19.5, 21.9±0.2 degrees 2 theta.
2. The crystalline form of claim 1, wherein the crystalline form is further characterized by peaks at 14.9, 24.9, 26.1±0.2 degrees two-theta.
3. The crystalline form of claim 2, wherein the crystalline form is further characterized by an XRD pattern as substantially depicted in FIG. 7.
4. A process for preparing the ziprasidone HCl of claim 1, comprising:
- a) combining aqueous HCl with ziprasidone base in a solvent selected from the group consisting of methylethylketone, tetrahydrofuran and dimethylacetamide to obtain a slurry;
- b) maintaining the slurry to obtain ziprasidone HCl; and
- c) recovering the ziprasidone HCl.
5. The process of claim 4, wherein the slurry is diluted by addition of water.
6. The process of claim 4, wherein the ziprasidone base is ziprasidone Form B.
7. The process of claim 4, wherein the slurry is carried out at a temperature of at least about 40 EC.
8. Crystalline form of ziprasidone HCl prepared by the process of claim 4.
9. A pharmaceutical composition comprising crystalline ziprasidone HCL of claim 1 and at least one pharmaceutically acceptable excipient.
10. A method of treating a patient suffering from schizophrenia comprising administering to the patient the pharmaceutical composition of claim 9.
Type: Application
Filed: Dec 3, 2007
Publication Date: Apr 17, 2008
Applicant:
Inventors: Tamas Koltai (Natanja), Lilach Hedvati (Doar Na Hefer), Marioara Mendelovici (Rehovot), Tamar Nidam (Yehud)
Application Number: 11/999,337
International Classification: A61K 31/501 (20060101); A61P 25/18 (20060101); C07D 417/02 (20060101);
