COMPOSITION COMPRISING AN AMORPHOUS NON-CRYSTALLINE GLASS FORM OF AZITHROMYCIN

Abstract

The invention relates to an amorphous non-crystalline glass form (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-11-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy}-1-oxa-6-azacyclopentadec-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside or azithromycin having an infra-red pattern displaying characteristic relatively broad peaks at approximately 3500 and 1727 cm−1 and characteristic peaks at approximately 2970 and 2938 cm−1. The invention further relates to a preparation method of increasing the solubility of azithromycin including the steps of selecting anhydrous, monohydrated or dihydrated azithromycin; elevating the temperature of the azithromycin to above the melting point thereof; and reducing the temperature of the melt sufficiently to allow it to set into an amorphous non-crystalline glass form (Form-II) of azithromycin having relatively increased solubility without decreasing the structural stability thereof.

Description

INTRODUCTION AND BACKGROUND TO THE INVENTION

This invention relates to a macrolide composition. More particularly this invention relates to a novel amorphous form, of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-11-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy}-1-oxa-6-azacyclopentadec-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside or azithromycin. This invention further relates to a preparation method of a medicament. More particularly this invention relates to a method of increasing the solubility of azithromycin.

Azithromycin is an azalide and a member of the macrolide family of antibiotics. This 15-membered-ring, macrolide antibiotic, is very similar in composition, chemical structure (semi-synthetic) and mechanism of action to erythromycin. Polymorphs of azithromycin commonly present as anhydrous (MM=749.00 g/mol), monohydrate (MM=767.02 g/mol) or dihydrate (MM=785.02 g/mol) azithromycin. It should however be noted that azithromycin is acid-stable in 0.1 N HCl and that the dihydrate is currently the most stable polymorphic form.

The chemical formula for azithromycin dihydrate is C₃₈H₇₂N₂O₁₂.2H₂O and the chemical structure of anhydrous azithromycin differs from erythromycin through methyl-substitution of a nitrogen atom in the lactone ring.

The preparation of some amorphous forms of azithromycin has previously been described in U.S. Pat. Nos. 6,245,903 and 6,451,990.

U.S. Pat. No. 6,245,903 describes an anhydrous form of azithromycin and further provides a method to purify an amorphous anhydrous azithromycin form using a chromatographic procedure or by using a solvent evaporation method.

U.S. Pat. No. 6,451,990 describes a non-crystalline form of azithromycin which includes the preparation method of forming a solution of azithromycin and an aliphatic alcohol or cyclic ethers and lyophilising said solution.

All non-crystalline forms of azithromycin referred to above are manufactured using solvents and/or lyophilisation. Although the aforesaid methods are well-known in the pharmaceutical industry for the preparation of different forms of a drug there are several disadvantages with these known methods. Some of the disadvantages are that the methods are time-consuming and require reagents for manufacturing. Yet a further disadvantage associated with these methods is that the solvents in the structure of the non-crystalline azithromycin can influence the physico-chemical properties of azithromycin.

Azithromycin has an anti-bacterial spectrum parallel to erythromycin's spectrum. It is however more effective against Haemophilus influenzae and other gram-negative bacteria, including Staphylococcus aureus; Streptococcus agalactiae; Streptococcus pneumoniae; Streptococcus pyogenes; Haemophilus ducreyi; Moraxella catarrhalis; Neisseria gonorrhoeae; Chlamydia pneumoniae; Chlamydia trachomatis; Mycoplasma pneumoniae; Helicobacter pylori; Salmonella typhi; and Mycobacterium avium intracellulare.

A disadvantage associated with known commercially available azithromycin dihydrate (raw material) is that it is poorly soluble in water.

A further disadvantage associated with azithromycin is that its poor water-solubility influences other pharmacokinetic properties resulting in the poor bioavailability (only 38% of an orally administered dose reaches systemic circulation) of the active drug.

Yet another disadvantage of azithromycin is that said poor bioavailability necessitates the administration of relatively large quantities of azithromycin in order to achieve the desired therapeutic effect.

A disadvantage associated with the use of relatively large quantities of azithromycin is that there is a potential increase in the side-effects associated with this active ingredient, in turn leading to poor patient compliance and potentially resulting in bacterial drug-resistance.

An even further disadvantage associated with the use of relative large quantities of azithromycin is that there is an increase in the production and manufacturing cost of the product, thereby increasing the cost of treatment.

OBJECTS OF THE INVENTION

An object of the present invention is to provide a stable novel form of azithromycin. Another object of the invention is to provide a method for increasing the solubility of azithromycin. Yet another object of the invention is to provide a medicament prepared in accordance with such a method with which the aforesaid disadvantages may be overcome or at least minimised.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided a composition comprising a stable amorphous non-crystalline glass form (Form-II) of azithromycin.

The amorphous non-crystalline glass form (Form-II) of azithromycin may display an infra-red pattern having a relatively broad peak at approximately 3500 and 1727 cm⁻¹ and at least one characteristic peak at approximately 2970 and 2938 cm⁻¹. The infra-red pattern may be substantially depicted as in FIG. 2.

The amorphous non-crystalline glass form (Form-II) of azithromycin may display a differential scanning calorimetry thermogram substantially as depicted in FIG. 12 and exhibits a glass transition between 100 and 115 degrees Celsius.

The amorphous non-crystalline glass form (Form-II) of azithromycin may have at least 50%, preferably at least 150%, increased solubility relative to anhydrous, monohydrated or dihydrated azithromycin in water.

The amorphous non-crystalline glass form (Form-II) of azithromycin may have at least 5%, preferably at least 10%, increased solubility relative to anhydrous, monohydrated or dihydrated azithromycin in 0.1 N hydrochloric acid (pH 1).

The amorphous non-crystalline glass form (Form-II) of azithromycin may have at least 10%, preferably at least 20%, increased solubility relative to anhydrous, monohydrated or dihydrated azithromycin in phosphate buffer (pH 6.8).

According to a second aspect of the invention there is provided a method of increasing the solubility of azithromycin including the steps of:

• • providing azithromycin selected from the group consisting of anhydrous, monohydrated or dihydrated azithromycin;
  • elevating the temperature of the azithromycin to above the melting point thereof; and
  • reducing the temperature of the melt sufficiently to allow it to set into an amorphous non-crystalline glass form (Form-II) of azithromycin having relatively increased solubility without decreasing the structural stability thereof.

The step of elevating the temperature of the azithromycin to above its melting point includes the step of elevating the temperature thereof to between 100 and 140 degrees Celsius, preferably 130 degrees Celsius, in the absence of a solvent.

The temperature of the selected azithromycin is elevated to above its melting point in the absence of a solvent.

According to a third aspect of the invention there is provided a medicament prepared from anhydrous, monohydrated or dihydrated azithromycin in accordance with the method of the second aspect of the invention.

According to a fourth aspect of the invention there is provided use of a pharmaceutically effective amount of an amorphous non-crystalline glass form (Form-II) of azithromycin in accordance with the first aspect of the invention and prepared in accordance with the method of the second aspect of the invention in a method of treating a patient suffering from bacterial infections.

According to a fifth aspect of the invention there is provided use of a pharmaceutically effective amount of an amorphous non-crystalline glass form in accordance with the first aspect of the invention and prepared in accordance with the method of the second aspect of the invention in a method of preparing a medicament for use in treating a patient suffering from bacterial infections.

According to a sixth aspect of the invention there is provided a method of treating a patient suffering from bacterial infections including the step of administering to such a patient a pharmaceutically effective amount of an amorphous non-crystalline glass form (Form-II) of azithromycin in accordance with the first aspect of the invention and prepared in accordance with the method of the second aspect of the invention.

According to yet another aspect of the invention there is provided a medicament prepared from amorphous non-crystalline glass form (Form-II) of azithromycin in accordance with the method of the second aspect of the invention, together with at least one inert pharmaceutically acceptable carrier or diluents in the dosage form selected from the group consisting of tablets; capsules; powders; solutions; syrups; suspensions; bolus injection; continuous infusion; powder for reconstitution; enemas; douche; pessary; transdermal patch; dermal patch; ointments; creams; gels; lotions; sprays and lozenges.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described further, by way of example only, with reference to the accompanying drawings wherein:

FIG. 1: is an infra-red (IR) pattern of prior art azithromycin dihydrate (Vertical axis: transmittance (percentage); Horizontal axis: wavenumbers (cm⁻¹)); (The infra-red pattern was obtained on a Shimadzu IRPrestige-21 (Japan), using a Pike Multi-Reflectance ATR accessory, with Shimadzu IRsolution version 1.40 software. Pattern was recorded over a range of 400-4000 cm⁻¹. KBr was used as background. The sample was dispersed in a matrix of powdered potassium bromide and, through diffuse reflectance infra-red Fourier transform spectroscopy (DRIFTS), the IR-spectrum was measured in a reflectance cell.);

FIG. 2: is an IR pattern of amorphous non-crystalline glass form (Form-II) of azithromycin according to the invention (Vertical axis: transmittance (percentage); Horizontal axis: wavenumbers (cm⁻¹));

FIG. 3: is a characteristic XRPD (x-ray powder diffraction pattern) of prior art azithromycin dihydrate raw material (Vertical axis: intensity (Lin (counts)); Horizontal axis: 2 Theta (degrees)); (Obtained on a PANalytical Xpert-Pro, Goniometer=PW3050/60 (Theta/Theta); Minimum step size 2Theta: 0.001; Measurement Temperature [° C.]: 25.00, Anode Material: Cu, K-Alpha1 [Å]: 1.54060, K-Alpha2 [Å]: 1.54443, K-Beta [Å]: 1.39225, K-A2/K-A1 Ratio: 0.50000, Generator Settings: 45 mA, 40 kV, Diffractometer Type: 0000000011018023, Goniometer Radius [mm]: 240.00, Dist. Focus-Diverg. Slit [mm]: 91.00, Incident Beam Monochromator: No, Spinning: Yes);

FIG. 4: is a characteristic XRPD (x-ray powder diffraction pattern) of amorphous non-crystalline glass form (Form-II) of azithromycin (Vertical axis: intensity (Lin (counts)); Horizontal axis: 2 Theta (degrees));

FIG. 5: is a characteristic XRPD (x-ray powder diffraction pattern) of amorphous non-crystalline glass form (Form-II) of azithromycin taken over a period of time wherein 0 is at time of preparation, 1 is week 1, 2 is week 2, 3 is week 3 and 4 is week 4 (Vertical axis: intensity (Lin (counts)); Horizontal axis: 2 Theta (degrees));

FIG. 6: is a solubility profile comparing the solubility of prior art azithromycin dihydrate raw material and amorphous non-crystalline glass form (Form-II) of azithromycin in water (Vertical axis: concentration (mg/mL); Horizontal axis: azithromycin form);

FIG. 7: is a solubility profile comparing the solubility of prior art azithromycin dihydrate raw material and amorphous non-crystalline glass form (Form-II) of azithromycin in 0.1 N HCl (Vertical axis: concentration (mg/mL); Horizontal axis: azithromycin form);

FIG. 8: is a solubility profile comparing the solubility of prior art azithromycin dihydrate raw material and amorphous non-crystalline glass form (Form-II) of azithromycin in Phosphate buffer (Vertical axis: concentration (mg/mL); Horizontal axis: azithromycin form);

FIG. 9: is a solubility profile comparing the solubility of prior art azithromycin dihydrate raw material in different mediums (Vertical axis: concentration (mg/mL); Horizontal axis: medium);

FIG. 10: is a solubility profile comparing the solubility of amorphous non-crystalline glass form (Form-II) of azithromycin in different mediums (Vertical axis: concentration (mg/mL); Horizontal axis: medium);

FIG. 11: is a DSC (differential scanning calorimetry) trace of prior art azithromycin dihydrate raw material taken over a period of time wherein 1 is week 0, 2 is week 2 and 3 is week 4 (Vertical axis: Heat flow (mW); Horizontal axis: temperature (degrees Celsius)); (DSC trace obtained on a Shimadzu DSC-60A (Japan) with TA60 version 2.11 software. Approximately 2 to 4 mg of each sample was weighed and heated in open aluminium crucibles. Samples were heated at 2° C./min in an inert nitrogen atmosphere.)

FIG. 12: is a DSC (differential scanning calorimetry) trace of amorphous non-crystalline glass form (Form-II) of azithromycin, taken over a period of time, according to one embodiment of the invention wherein 0 is at time of preparation, 1 is week 1, 2 is week 2, 3 is week 3 and 4 is week 4 (Vertical axis: Heat flow (mW); Horizontal axis: temperature (degrees Celsius));

FIG. 13: is a thermal microscopy image (at 25 degrees Celsius) of amorphous non-crystalline glass form (Form-II) of azithromycin taken in the fourth week after preparation according to one embodiment of the invention; and

FIG. 14: is a thermogravimetric analysis (TGA) trace overlay of amorphous non-crystalline glass form (Form-II) of azithromycin during stability study (Vertical axis: Weight (mg); Horizontal axis: temperature (degrees Celsius)); (Obtained on a Shimadzu DTG-60 (Japan) with TA60 version 2.11 software. Samples were heated from 25 degrees Celsius to 150 degrees Celsius at 2° C./min, in open aluminium crucibles. Nitrogen gas was used as inert atmosphere.).

DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION

According to a preferred embodiment of the invention there is provided a method for increasing the solubility of azithromycin, by providing a stable amorphous non-crystalline glass form (Form-II) of azithromycin.

The method includes the steps of selecting azithromycin from the group consisting of anhydrous, monohydrated or dihydrated azithromycin; elevating the temperature of the azithromycin to above the melting point thereof; and reducing the temperature of the melt sufficiently to allow it to set into an amorphous non-crystalline glass form (Form-II) of azithromycin having relatively increased solubility.

Further Details of Respective Steps in the Method According to the Invention:

The first step of the method, according to a preferred embodiment of the invention is to select azithromycin raw material from known commercially available anhydrous, monohydrate or dihydrated form.

The following step of the method is to place the azithromycin raw material in a suitable container, in the absence of any solvents, and heat it to approximately 130 degrees Celsius in a dry heat oven and afterwards cooling the melt to room temperature (25 degrees Celsius).

Alternatively, the azithromycin raw material can be placed in a suitable container and heated in any suitable environment to approximately 130 degrees Celsius. The melt is then cooled to room temperature (25 degrees Celsius).

Further Analysis and Findings

It has surprisingly been found that the amorphous non-crystalline glass form (Form-II) of azithromycin is structurally stable and significantly more soluble in water, phosphate buffer and 0.1 N hydrochloric acid compared to conventional anhydrous, monohydrate or dihydrated azithromycin prepared according to prior art methods.

In further analysis of the amorphous non-crystalline glass form (Form-II) of azithromycin, each of five replicate test tubes were filled with an excess of amorphous non-crystalline glass form (Form-II) of azithromycin and 10 ml of solubility medium. The process was performed with each of the following mediums: 0.1 N hydrochloric acid (pH 1), acetate buffer (pH 4.5), phosphate buffer (pH 6.8) and distilled water. This method was also used for testing the prior art azithromycin dihydrate.

The test tubes were then fixed to a rotating axis (54 rpm) and submerged in a water bath at 37 degrees Celsius±2 degrees Celsius for twenty-four hours. The contents of the test tubes were filtered through a 0.45 μm filter and the respective filtrates were subsequently diluted.

The concentrations of the filtrates were determined by HPLC (high performance liquid chromatography) assay. The HPLC assay was performed utilising a mobile phase (600:400) consisting of 8.7 g/L potassium dihydrogen phosphate buffer (pH 4.5) and acetonitrile. A Luna C18 250 mm×4.6 mm column was used with a flow rate of 0.5 mL/min and a wavelength of 210 nm. Validation of this method provided a linear regression r² of 0.9999.

Referring to FIGS. 6 to 10, it was determined that the solubility of azithromycin raw material (dihydrate) is 17.966±0.113 mg/mL in acetate buffer (pH 4.5), 8.442±0.069 mg/mL in phosphate buffer (pH 6.8), 40.814±0.368 mg/mL in 0.1N HCl and 0.148±0.028 mg/mL in distilled water. The phosphate buffer consists of potassium dihydrogen phosphate, sodium hydroxide and water and the acetate buffer consists of sodium acetate trihydrate, glacial acetic acid and water. It was further determined that the solubility of amorphous non-crystalline glass form (Form-II) of azithromycin is 18.045±0.485 mg/mL in acetate buffer (pH 4.5), 10.968±0.182 mg/mL in phosphate buffer (pH 6.8), 45.703±0.917 mg/mL in 0.1 N HCl and 1.357±0.233 mg/mL in distilled water. In fact, in comparison with the raw material, amorphous non-crystalline glass form (Form-II) of azithromycin has a 9.16 fold (816%) improvement in solubility in water (FIG. 6), a 1.3 fold (30%) improvement in pH 6.8 phosphate buffer and a 1.12 fold (12%) improvement in 0.1 N HCl (FIG. 7) as medium. It was found that the amorphous non-crystalline glass form (Form-II) of azithromycin is at least 50%, more particularly at least 150% more soluble than anhydrous, monohydrated or dihydrated azithromycin in water. It was further found that the amorphous non-crystalline glass form (Form-II) of azithromycin is at least 5% more, particularly at least 10% more soluble than dihydrated azithromycin in a 0.1 N HCl medium. It was yet further found that the amorphous non-crystalline glass form (Form-II) of azithromycin is at least 10% more, particularly at least 20% more soluble than dihydrated azithromycin in a phosphate buffer medium.

FIG. 3 shows a characteristic XRPD pattern of the raw material azithromycin and confirms that the azithromycin is in a crystalline form. This is in contrast to the amorphous non-crystalline glass form (Form-II) of azithromycin (FIG. 4) which exhibits the characteristic amorphous halo generally obtained with amorphous forms.

Referring to FIGS. 1 and 2, the infra-red (IR) pattern wavenumbers associated with peaks for both the raw material (FIG. 1) and the amorphous non-crystalline glass form (Form-II) of azithromycin (FIG. 2) can be summarised as follow:

Azithromycin dihydrate           Azithromycin glass
3567 and 3496 cm−1 (Sharp peaks) 3500 cm−1 (Relatively broad peak)
3251 cm−1 (Relatively broad peak) No peak
2971 cm−1                        2970 and 2938 cm−1
1720 cm−1 (Sharp peak)           1727 cm−1 (Relatively broad peak)

The most distinguishing difference between the IR patterns of the raw material (FIG. 1) in comparison with the IR pattern obtained for the amorphous non-crystalline glass form (Form-II) of azithromycin (FIG. 2) lies between wavenumbers 3580 to 1727 cm⁻¹.

The IR pattern of azithromycin dihydrate (FIG. 1) displays peaks of interest at wavenumber 3600 to 3000 cm⁻¹. These peaks represent the hydrate (two water molecules) found in the structure of azithromycin dihydrate. In contrast, FIG. 2 displays only one broad peak at wavenumber 3500 cm⁻¹ and no peak at 3251 cm⁻¹, which indicates a lack of hydrated molecules in the amorphous non-crystalline glass form (Form-II) of azithromycin.

The IR-pattern of the raw material (FIG. 1) displays five separate, clearly distinguishable peaks at 3567, 3496, 3251, 2971 and 1720 cm⁻¹. This is in contrast to the amorphous non-crystalline glass form (Form-II) of azithromycin which display peaks at 3500 (broad peak), 2970, 2938 and 1727 (broad peak) cm⁻¹.

The applicant established that amorphous non-crystalline glass form (Form-II) of azithromycin is structurally stable (at 40° C. and 75% relative humidity) over a period of time and remained amorphous as shown in the XRPD pattern (FIG. 5). In FIG. 5 the amorphous non-crystalline glass form (Form-II) of azithromycin displayed the characteristic amorphous halo generally obtained with amorphous forms over the 4 week testing period. In FIG. 13 it was further evident from the micrograph of the amorphous non-crystalline glass form (Form-II) of azithromycin that Form-II did not transform to a crystalline solid form of azithromycin but remained non-crystalline.

Referring to FIG. 11, the DSC (differential scanning calorimetry) trace of prior art azithromycin dihydrate illustrates the two desolvation peaks of the dihydrate between 80 degrees Celsius and 100 degrees Celsius and further illustrates a melting point at 119 degrees Celsius to 121 degrees Celsius. In contrast to FIG. 11, FIG. 12 shows the thermogram of amorphous non-crystalline glass form (Form-II) of azithromycin and depicts the absence of the two desolvation peaks between 80 degrees Celsius and 100 degrees Celsius and further displays a glass transition between 100 degrees Celsius and 115 degrees Celsius.

The stability tests indicate that the amorphous non-crystalline glass form (Form-II) of azithromycin remained structurally stable as an amorphous non-crystalline form.

The thermogravimetric analysis (TGA) trace of FIG. 14 illustrates the weight loss of amorphous non-crystalline glass form (Form-II) of azithromycin over a period of time. The TGA, together with the Karl Fischer titration, results (averaging 3 to 4%) indicate the presence of water in the amorphous azithromycin. It is submitted that the presence of water did however not influence the solubility or structural stability of amorphous azithromycin in any way.

Amorphous non-crystalline glass form (Form-II) of azithromycin is formulated for administration in any convenient way and the invention includes within its scope pharmaceutical compositions comprising amorphous non-crystalline glass form (Form-II) of azithromycin adapted for use in human or veterinary medicine.

The pharmaceutical compositions are presented for use in a conventional manner with the aid of a pharmaceutically acceptable carrier or excipient and may also contain, if required, other active ingredients. The amorphous non-crystalline glass form (Form-II) of azithromycin is typically formulated for oral, buccal, topical or parenteral administration.

Oral administration is the preferred dosage form, particularly in the form of tablets and capsules. The pharmaceutical composition for oral administration conveniently takes the form of tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. Buccal administration compositions take the form of tablets or lozenges formulated in conventional manner.

The amorphous non-crystalline glass form (Form-II) of azithromycin is further formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection are presented in unit dosage forms in ampoules, or in multi-dose containers, with an added preservative. The compositions further take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient is in powder form for reconstitution with a suitable vehicle.

The amorphous non-crystalline glass form (Form-II) of azithromycin is yet further formulated in topical applications, comprising ointments, creams, gels, lotions, powders; transdermal patches, dermal patches or sprays prepared in a conventional manner.

The particulate unsolvated anhydrous form of nevirapine (Form-I) is yet further formulated in rectal and vaginal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

For oral administration a convenient daily dosage regime of amorphous non-crystalline glass form (Form-II) of azithromycin is a total of 200 mg to 500 mg per day for three days, dependent upon the age and condition of the patient.

The amorphous non-crystalline glass form (Form-II) of azithromycin prepared in accordance with the method of the present invention is formulated into a medicament and used in a method of treating a patient suffering from a bacterial infection by administering to such a patient a pharmaceutically effective amount thereof of a total of 200 mg to 500 mg per day for three days, dependent upon the age and condition of the patient.

It will be appreciated that the disadvantages associated with prior art forms of azithromycin, namely anhydrous, monohydrate of dihydrate forms, could be alleviated with the method according to the invention. In particular, the bioavailability of azithromycin could be increased as a result of the increased solubility of amorphous non-crystalline glass form (Form-II) of azithromycin. Moreover, reduced quantities of amorphous non-crystalline glass form (Form-II) of azithromycin would be required in use in treating patients suffering from bacterial infections, resulting not only in reduced risk to side-effects but to a reduced cost in treatment. Yet further, the advantages associated with the preparation of Form-II is done in the absence of any solvent, this being more cost-effective and less time consuming than known prior art methods.

Applicant thus foresees that amorphous non-crystalline glass form (Form-II) of azithromycin would not only present a relatively cheaper alternative to conventional production and manufacturing methods, but would also present a product that is superior in solubility to conventional anhydrous, monohydrate or dihydrate forms of azithromycin.

It will be appreciated further that variations in detail are possible with a method for preparing a medicament and a medicament prepared with such a method, according to the invention without departing from the scope of this disclosure.

Claims

1. A composition comprising an amorphous non-crystalline glass form (Form-II) of azithromycin.

2. A composition according to claim 1 wherein the amorphous noncrystalline glass form (Form-II) of azithromycin displays an infra-red pattern having a characteristic relatively broad peak at approximately 3500 and 1727 cm″1 and characteristic peaks 2970 and 2938 cm″1.

3. A composition according to claim 1 wherein the amorphous non-crystalline glass form (Form-II) of azithromycin displays an infra-red pattern substantially as depicted in FIG. 2.

4. A composition according to claim 1 displaying a differential scanning calorimetry thermogram substantially as depicted in FIG. 12 and exhibiting a glass transition between 00 and 115 degrees Celsius.

5. A composition according to claim 1 having at least 50% increased solubility over anhydrous, monohydrated or dihydrated azithromycin in water.

6. A composition according to claim 5 having at least 150% increased solubility over anhydrous, monohydrated or dihydrated azithromycin in water.

7. A composition according to claim 1 having at least 5% increased solubility over anhydrous, monohydrated or dihydrated azithromycin in 0.1 N HCl.

8. A composition according to claim 7 having at least 10% increased solubility over anhydrous, monohydrated or dihydrated azithromycin in 0.1 N HCl.

9. A composition according to claim 1 having at least 10% increased solubility over anhydrous, monohydrated or dihydrated azithromycin in a phosphate medium.

10. A composition according to claim 9 having at least 20% increased solubility over anhydrous, monohydrated or dihydrated azithromycin in a phosphate medium.

11. A method of increasing the solubility of azithromycin including the steps of providing azithromycin selected from the group consisting of anhydrous, monohydrated or dihydrated azithromycin; elevating the temperature of the azithromycin to above the melting point thereof; and reducing the temperature of the melt sufficiently to allow it to set into an amorphous non-crystalline glass form (Form-II) of azithromycin having relatively increased solubility without decreasing the structural stability thereof.

12. A method according to claim 11 wherein the step of elevating the temperature of the azithromycin to above its melting point includes the further step of elevating the temperature thereof to between 100 and 140 degrees Celsius, preferably 130 degrees Celsius.

13. A method according to claim 11 wherein the temperature of the selected azithromycin is elevated to above its melting point in the absence of a solvent.

14. A medicament prepared from anhydrous, monohydrated or dihydrated azithromycin in accordance with the method of claim 11.

15. A medicament prepared from amorphous non-crystalline glass form (Form-II) of azithromycin in accordance with the method of claim 11 together with at least one inert pharmaceutically acceptable carrier or diluents in a dosage form selected from the group consisting of tablets; capsules; powders; solutions; syrups; suspensions; bolus injection; continuous infusion; powder for reconstitution; ointments; creams; gels; lotions; sprays enemas, douche, pessary, transdermal patches, dermal patches and lozenges.

16. Use of a pharmaceutically effective amount of an amorphous noncrystalline glass form (Form-II) of azithromycin according to claim 1 and prepared in accordance with the method of claim 11 in a method of treating a patient suffering from a bacterial infection.

17. Use of a pharmaceutically effective amount of an amorphous noncrystalline glass form according to claim 1 and prepared in accordance with the method of claim 11 in a method of preparing a medicament for use in treating a patient suffering from a bacterial infection.

18. A method of treating a patient suffering from bacterial infections including the step of administering to such a patient a pharmaceutically effective amount of an amorphous non-crystalline glass form (Form-II) of azithromycin prepared in accordance with the method of claim 11.

19. A composition comprising an amorphous non-crystalline glass form (Form-II) of azithromycin substantially as herein described and exemplified with reference to the accompanying figures.

20. A method of increasing the solubility of azithromycin substantially as herein described and exemplified, with reference to the accompanying figures.