Title of Invention

A PROCESS FOR PREPARATION OF CRYSTALLINE FORM OF AZAITHROMYCIN

Abstract

Novel crystalline form of azithromycin, namely azithromycin monohydrate acetonitrile solvate, which has improved properties over amorphous azithromycin, azithromycin monohydrate, azithromycin dihydrate and other solvates like azithromycin ethanolate and azithromycin isopropanol clathrate. Azithromycin monohydrate acetonitrile solvate has a formula II wherein n = 0.5 to 1.5 moles. The present invention also provides processes for the manufacture of azithromycin monohydrate acetonitrile solvate and simple, safe and cost effective processes for the manufacture of highly pure azithromycin monohydrate, azithromycin dihydrate and azithromycin monohydrate isopropanol clathrate from the azithromycin monohydrate acetonitrile solvate. The present invention also provides pharmaceutical compositions comprising the azithromycin monohydrate acetonitrile solvate.

Full Text

FORM - 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See Section 10) 1. TITLE OF INVENTION A PROCESS FOR PREPARATION OF CRYSTALLINE FORM OF AZITHROMYCIN 2. ALEMBIC LIMITED, Alembic Road, Vadodara-390 003, Gujarat, India, an Indian Company. The following specification particularly describes the nature of the invention and the manner in which it is to be performed. 18-3-2005 Field of the invention The present invention relates to a novel crystalline form of azithromycin, namely azithromycin monohydrate acetonitrile solvate, which has improved properties over amorphous azithromycin, azithromycin monohydrate, azithromycin dihydrate and other solvates like azithromycin ethanolate and azithromycin isopropanol clathrate. The present invention also relates to processes for the manufacture of azithromycin monohydrate acetonitrile solvate. The invention further relates to a simple, safe and cost effective process for the manufacture of highly pure azithromycin monohydrate, azithromycin dihydrate and azithromycin monohydrate isopropanol clathrate from azithromycin monohydrate acetonitrile solvate of the present invention. The present invention also related to pharmaceutical compositions comprising the azithromycin monohydrate acetonitrile solvate. Background of the invention Azithromycin, 9-Deoxo-9a-aza-9a-methyl-9a-homo-erythromycin A, is a 15 member ring macrolide belonging to a new class of antibiotics termed "Azalides", due to the incorporation of a nitrogen atom in the macrocyclic ring. Azithromycin (Formula I) is derived from the 14-membered macrolide antibiotic erythromycin A and shows significant improvement in its activity against gram - Ve organisms compared to erythromycin A (C. J. Dunn and L. B. Barradell Azithromycin: A Review of its Pharmacological properties and use as a 3-day therapy in respiratory tract infections, Drug, 1996, March, 51(3)483-505). Formula I Azithromycin was first discovered by G. Kobrehel and S. Djokic (US Patent No. 4,517,359; S. Djokic et al.). U.S. Patent No. 4,517,359 describes methylation of 11-aza-10-deoxo-10-dihydro erythromycin A (presently called 9-Deoxo-9a-aza-9a-homoerythromycin A) in an excess of formaldehyde and formic acid in a halogenated hydrocarbon, e.g., chloroform or carbon tetrachloride. In the procedure described in U.S. Patent No. 4,517,359 the isolation of azithromycin comprises extraction of the aqueous layer with a halogenated hydrocarbon solvent followed by evaporation of the solvent. The disadvantages of this process are that (i) a halogenated hydrocarbon is used which is environmentally unsafe and (ii) the isolation of azithromycin involves several cumbersome and/or inefficient extraction and solvent evaporation steps. According to European Patent Application EP 298650, the azithromycin obtained by the process taught in US 4517359 is a hygroscopic monohydrate. Because of its hygroscopic nature, this monohydrate is difficult to prepare and maintain in a form having a constant, reproducible water-content, and is particularly difficult to handle during formulation. Two other synthesis routes, affording azithromycin as a form that should differ from the crystalline ones previously mentioned, have also been described in WO 94/26758 and US 4517359. According to such processes azithromycin is obtained by single evaporation to dryness. However, in these prior art documents there is no reference to the crystalline state of the azithromycin thus obtained. Different prior art teach methods of manufacture of the two crystalline forms of azithromycin. US 4474768 teaches methods of manufacturing hygroscopic monohydrate by recrystallization of azithromycin from ethanol/water. EP 0298650 also teaches preparation of non-hygroscopic azithromycin dihydrate by recrystallization from THF/petroleum ether/water. CN 1093371 teaches preparation of non-hygroscopic azithromycin dihydrate by recrystallization from acetone/water as well as using other solvents such as methanol, DMF, acetonitrile, dioxane and water. EP 0941999 teaches preparation of non-hygroscopic azithromycin dihydrate by precipitation from base neutralized acid solution of azithromycin in acetone/water. WO 00/32203 teaches preparation of ethanolate of azithromycin by granual crystallization of azithromycin from ethanol by addition of a minimum amount of water. US 6245903 teaches preparation of azithromycin monohydrate by dissolving azithromycin in isopropanol, followed by the slow addition of water. Various journals also teach methods of manufacturing crystalline forms of azithromycin similar to the above-mentioned prior art methods. From the teachings of aforesaid prior art it is clear that three forms of Azithromycin are known. Anhydrous azithromycin is reported as an amorphous crude product in US 4517359 (Example 1). It is obtained by evaporating the final solvent (e.g. chloroform) used in the process of preparation of azithromycin. It is not a crystalline in nature and therefore cannot be made in pure form per se in commercial scale. US 4474768 teaches the process of making azithromycin monohydrate but do not claim the resulting product. Furthermore, the prior art does not provide a description of the drying process (temperature or pressure). Azithromycin monohydrate is known to be hygroscopic. This is an undesirable property since it complicates formulation of azithromycin drug product and can adversely affect its stability on long term storage. US 6268489 teaches azithromycin dihydrate and, in contrast to azithromycin monohydrate, a full description of the drying process used for obtaining the product is provided. Low boiling solvents (tetrahydrofuran and hexane) are used with 3-4 equivalent moles of water to obtain the crystalline product, which is dried under vacuum at lower temperatures (20°C-40°C). The use of low boiling solvents for crystallisation and low temperature for vacuum drying of the product are prescribed presumably to control the desirable amount of water that must be evaporated to afford the azithromycin dihydrate. The processes taught in US 6268489 for the preparation of azithromycin dihydrate, while producing a non-hygroscopic form of azithromycin, have a number of disadvantages: 1. Water immiscibility of the organic solvent mixture (tetrahydrofuran plus hexane) can cause problems in obtaining pure material since crystallization processes are known to afford pure material when the anti-solvent is miscible with the solvent used to dissolve the crude product. 2. The drying process must be very carefully controlled since an increase in temperature will cause the transformation of the non-hygroscopicdihydrate to the hygroscopic monohydrate. 3. The use of low boiling point solvents is complicated by their toxicity and possibility of formation of explosive peroxide during solvent recovery. Therefore, there is a need of a crystalline form of azithromycin having improved physical properties and which can be used for easy and improved methods of preparation of azithromycin crystalline forms. Objects of the invention The object of the present invention is to provide a novel form of azithromycin which is crystalline and, in contrast to anhydrous azithromycin, is obtained in pure form. A further object of the present invention is to provide a novel form of azithromycin which is not hygroscopic. Another object of the present invention is to provide a novel form of azithromycin which in contrast to azithromycin dihydrate, is obtained conveniently and reproducibly having very low impurity profile specially Azithromycin B impurity. Yet another object of the present invention is to provide a novel form of azithromycin from which azithromycin dihydrate, azithromycin monohydrate acetonitrile solvate may be obtained by very simple methods and in pure form. It has been found that methylation of 9-deoxo-9a-aza-9a-homoerythromycin A (also known as azaerythromycin A) in acetonitrile in presence of methylating agent results in the formation of a new solvate of azithromycin, namely azithromycin monohydrate acetonitrile solvate. The physical properties of this product and the processes used for its preparation and that of other azithromycin crystalline forms from the product have a number of major advantages over the existing azithromycin product forms and the procedure used for their preparation. Summary of the invention According to the main aspect of the invention, there is provided a compound of formula II: Formula II wherein n = 0.5 to 1.5 mole. According to another aspect of the present invention there is provided a process for the preparation of azithromycin monohydrate acetonitrile solvate, which comprises the steps of: a) at least partially dissolving and/or suspending 9-deoxo-9a-aza-9a-homoerythromycin A in acetonitrile to form a mixture ; b) adding a methylating solution to said mixture; c) refluxing or heating said mixture; d) adding an alkaline solution after substantial completion of reaction; (a) recovering azithromycin monohydrate acetonitrile solvate from said mixture. According to another aspect of the invention there is provided pharmaceutical compositions for treating microbial infection, comprising the azithromycin monohydrate acetonitrile solvate of formula II and a pharmaceutically acceptable carrier. According to another aspect of the present invention there is provided a process for the preparation of azithromycin monohydrate acetonitrile solvate comprising: a) at least partially dissolving and/or suspending azithromycin in acetonitrile to form a mixture; b) refluxing or heating said mixture; c) cooling the organic layer to precipitate azithromycin monohydrate acetonitrile solvate; d) filtering out said azithromycin monohydrate acetonitrile solvate; and optionally e) vacuum drying the said azithromycin monohydrate acetonitrile solvate. According to yet another aspect of the present invention there is provided a process for preparation of pure azithromycin monohydrate from azithromycin monohydrate acetonitrile solvate, the process comprising: a) at least partially dissolving azithromycin monohydrate acetonitrile solvate of formula II in polar organic solvent to form a mixture ; b) refluxing or heating said mixture; c) filtering said mixture to obtain clear solution; d) adding water to said clear solution to precipitate said azithromycin monohydrate; e) separating said azithromycin monohydrate from said solution by filtration; and optionally f) washing said azithromycin monohydrate with water; and g) vacuum drying said azithromycin monohydrate. According to yet another aspect of the present invention there is provided a process for the preparation of pure azithromycin dihydrate from azithromycin monohydrate acetonitrile solvate, the process comprising: a) at least partially dissolving of azithromycin monohydrate acetonitrile solvate in polar organic solvent to form a mixture; b) refluxing or heating said mixture; c) filtering said mixture to obtain clear solution; d) adding water to said clear solution and stirring the reaction mixture for 24-30 hrs to precipitate said azithromycin dihydrate; e) filtering out said azithromycin dihydrate ; and optionally f) washing said azithromycin dihydrate with water and vacuum drying. According to a further aspect of the present invention there is provided process for the preparation of pure azithromycin isopropanol clathrate from azithromycin monohydrate acetonitrile solvate, the process comprising: a) dissolving azithromycin monohydrate acetonitrile solvate in isopropanol b) heating the mixture; c) filtering said mixture to obtain clear solution; d) adding water to said said clear solution to precipitate said azithromycin isopropanol clathrate; e) filtering out said azithromycin isopropanol clathrate; and optionally f) vacuum drying said azithromycin isopropanol clathrate. According to yet another aspect of the present invention there is provided a process for the preparation of pure azithromycin ethanolate form azithromycin monohydrate acetonitrile solvate, the process comprising: a) dissolving azithromycin monohydrate acetonitrile solvate in ethanol; b) heating the mixture; c) filtering said mixture to obtain clear solution; d) adding water to said clear solution to precipitate said azithromycin ethanolate; e) filtering out said azithromycin ethanolate. Description of accompanying drawings: 1. Figure 1 is a XRD graph of Azithromycin Monohydrate acetonitrile solvate. 2. Figure 2 is a IR graph of Azithromycin Monohydrate acetonitrile solvate (in KBr). Detailed description of the invention Azithromycin monohydrate acetonitrile solvate according to the invention is useful for the preparation of medicines for treating various microbial infections. Azithromycin monohydrate acetonitrile solvate according to the invention contains 0.5 to 1.5 moles of acetonitrile for every molecule of azithromycin monohydrate. The process for manufacture of Azithromycin monohydrate acetonitrile solvate comprises n-methylation of azaerythromycin A in acetonitirle in presence of methylating agent and the reaction is terminated by adding aqueous base to the reaction mixture. The methylating agent is selected from formaldehyde, formic acid, paraformaldehyde and mixtures thereof. The aqueous base is an alkaline solution selected from sodium hydroxide solution, potassium hydroxide solution and the like. The organic layer is separated and cooled slowly, resulting in the precipitation of crystalline azithromycin monohydrate acetonitrile solvate. The volume of solvent used is such as to sufficiently suspend or dissolve azaerythromycin A. The suspension temperature is between ambient to reflux temperature of solvent. Preferably, the refluxing and heating is carried out for 20 to 30 hours at 40 to 90°C. An amount of water, which is necessary for the formation of azithromycin solvate in the form of a monohydrate, may be present in the organic solvent. The mixture is stirred for 2 to 24 hrs and the reaction temperature is maintained from room temperature to the reflux temp of solvent. The product is filtered and washed with acetonitrile and dried under vacuum (1-10 mm Hg) at 40-90°C for 12-36 hours to obtain azithromycin monohydrate acetonitrile solvate in high yields. Extension of vacuum drying does not reduce either the water content or the acetonitrile content of azithromycin monohydrate acetonitrile solvate. According to a further aspect of the invention there is provided a process for preparation of azithromycin monohydrate acetonitrile solvate comprising taking suspension of azithromycin in acetonitirle, heating the reaction mass upto the reflux, filtering the solid and drying under vacuum (1-10 mm Hg) at 30 to 60°C, preferably 40 to 60°C for 4-10 hrs to obtain azithromycin monohydrate acetonitrile solvate. The refluxing/heating is preferably carried out for 12 to 24 hours at 40 to 90°C. The final azithromycin monohydrate acetonitrile solvate has the following d-spacing values in powder XRD as appearing in the XRD graph of figure 1: 11.15, 9.94, 9.09, 7.91, 6.91, 5.44, 5.08, 4.76, 4.26, 3.83. Detailed d-spacing values from the graph are: 14.72, 12.53, 11.15, 9.94, 9.04, 9.04, 8.27, 7.91, 7.39, 6.90, 6.62, 6.37, 6.11, 5.43, 4.76, 4.27, 3.83, 3.70. The final azithromycin monohydrate acetonitrile solvate has the following cm"1 values in IR (with KBr) as appearing in the IR graph of figure 2: 3495, 2970, 2836, 2796, 2250, 1721,1379,1270, 1109, 1122, and an extra peak at 2250 cm'1-. The compound of present invention can be used in formulating various pharmaceutical compositions for treating various microbial infections. Such a composition contains the inventive solvate together with pharmaceutically acceptable excipients and carriers, which may be administrated orally, injectably, rectally, transdermalIy, bucally or nasally. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets of powder for reconstitution, hard or soft gelatin capsules, syrups and emulsions et al. Suitable forms for parenteral administration include aqueous or non¬aqueous solution, emulsion, while for rectal administration suitable forms include suppositories with hydrophilic or hydrophobic vehicles. For topical application the invention provides ointments or aerosol formulations known in the art; for transdermal delivery, there are provided suitable delivery systems as known in the art. For nasal delivery there are provided suitable aerosol delivery systems known in the art. According to a preferred aspect of the process for preparation of azithromycin monohydrate from azithromycin monohydrate acetonitrile solvate, the polar organic solvent is selected from solvents which are appropriate to dissolve azithromycin, preferably water-miscible organic solvents. Water-miscible organic solvent includes organic solvent which may form a one-phase system with water, preferably water-miscible ketones such as acetone; lower alcohols, e.g. C1-4 alcohols, such as methanol, ethanol, isopropanol, lower alkyl acetates, such as methyl acetate, ethyl acetate; and acetic acid and formic acid amides, such as dimethyl acetamide, N-N-dimethyl formamide; or a mixture of individual organic solvents, e.g. as listed above. Water may present in organic solvent. An appropriate temperature for the production of a solution of azithromycin in organic solvent and the temperature of refluxing includes a temperature at which azithromycin is not degraded. The temperature is preferably maintained between 40 to 90°C for 2 to 4 hours. The concentration of a solution of azithromycin in organic solvent is not critical; preferably a saturated or almost saturated solution may be used. The ratio of the amount of water added to the clear solution to the polar solution is substantially 1:1. The vacuum drying is preferably carried out at a temperature less than 40°C under 1 to 10mm Hg vacuum. According to a preferred aspect the process for the preparation of azithromycin dihydrate from azithromycin monohydrate acetonitrile solvate, the polar organic solvent includes solvents, which are appropriate to dissolve azithromycin, preferably water-miscible organic solvents. Water-miscible organic solvents include organic solvent which may form a one-phase system with water, preferably water-miscible ketones such as acetone; lower alcohols, e.g. C1.4 alcohols, such as methanol, ethanol, isopropanol, lower alkyl acetates, such as methyl acetate, ethyl acetate; and acetic acid and formic acid amides, such as dimethyl acetamide, N-N-dimethyl formamide; or a mixture of individual organic solvents, e.g. as listed above. The ratio of amount of water added to the clear solution to the amount of polar organic solvent is critical for obtaining dihydrate and is selected as at least 2:1. Pure azithromycin isopropanol clathrate and pure azithromycin ethanolate may be prepared from azithromycin monohydrate acetonitrile solvate by processes as discussed above. Elemental analysis, 1HNMR, 13C NMR, and IR spectroscopy, mass spectrometry, and power x-ray diffraction and IR have identified the azithromycin monohydrate acetonitrile solvate produced according to the invention. The water content of azithromycin monohydrate acetonitrile solvate was measured by Karl-Fischer method and its acetonitrile content was determined by gas chromatography. The invention will be more fully understood by the following examples, which illustrate the present invention but are not to be considered limiting to the scope of the invention. Example 1: Preparation of azithromycin monohydrate acetonitrile solvate. Azaerythromycin i(200g) is suspended in acetonitrile (500ml) and raised temperature to 40-45°C The methylation solution (prepared by mixing of 45ml formic acid {99%} and 45ml formaldehyde {35%}) is added over a period of 3 to 4 hrs. At this temperature the reaction mixture is stirred for 20 hrs. The sodium hydroxide solution (25 % w/v,140 ml) is added in the reaction mixture and stirred for 20 minutes. Aqueous layer is separated and extracted with 100ml acetonitrile. Combine organic layer is clarified by filtration and slowly cooled to 0 °C in 2 hrs. White crystalline product (180-185 gm) is filtered and dried under vacuum (1 to 10 mm Hg) at 40-80° C for 6 hrs. Raw Material HPLC Purity (Azaerythromycin): Purity (93.61 %) and Impurity B (0.63%) Final Product (Azithromycin Acetonitrile Solvate) HPLC Purity: Purity (98.53 %) and Impurity B (0.28%) Example 2: Preparation of azithromycin monohydrate acetonitrile solvate Azaerythromycin (100g) is suspended in acetonitrile (250ml). Paraformaldehyde (10.Ogms) and formic acid (13.6ml) is added and the reaction mixture is heated upto 75 -80°C temp. The mixture is stirred at this temperature for 10hrs after that the reaction mass is cooled to 45°C. The sodium hydroxide solution (25 % w/v,140 ml) is added in the reaction mixture and stirred for 20 minutes and separate layers. Aqueous layer is separated and extracted with 50ml acetonitrile. Combine organic layer is clarified by filtration and slowly cooled to 0°C in 2 hrs. White crystalline product (85-95 gm) is filtered and dried under vacuum at 50° C for 6 hrs. Raw Material HPLC Purity (Azaerythromycin): Purity (93.58 %) and Impurity B (0.64%) Final Product ( Azithromycin Acetonitrile Solvate) HPLC Purity: Purity ( 98.52 %) and Impurity B (0.27%) Example 3: Preparation of azithromycin monohydrate acetonitrile solvate Azithromycin (500g) is suspended in acetonitrile (3000ml) and the reaction mixture is heated upto 55-60 ° C. The reaction mass is slowly cooled 0°C in 3.0 hrs. and stirred the mass at 0°C for 1.0 hrs. The slurry is filtered and dried cake under vacuum (1-10mm/Hg) at 50°C for 6-8 hrs gives 450gm of azithromycin monohydrate acetonitrile solvate. Raw Material HPLC Purity (Azithromycin): Purity (98.68 %) and Impurity B (0.74%) Final Product (Azithromycin Acetonitrile Solvate) HPLC Purity. Purity (99.56 %) and Impurity B (0.26%) Example 4: Preparation of azithromycin monohydrate from azithromycin monohydrate acetonitrile solvate. Azithromycin monohydrate acetonitrile solvate (50g) prepared by following examples 1 to 3 is dissolved in acetonitrile (300ml) at 50-60 °C. The suspension is stirred for 15-25 min and made it clear solution by filtration. Water (180ml) is added slowly at 40-60°C till haziness observed. Water addition is stopped for 5.0 min to grow crystal. Again water (270ml) is added over 45min. period at the same temp. The mixture is filtered and washed with water (100ml) and dried at less than 40°C. White crystalline product (40-45 gm) is obtained. Azithromycin Acetonitrile Solvate HPLC Purity: Purity (98.49 %) and Impurity B (0.25%) Azithromycin Monohydrate HPLC Purity: Purity (99.53 %) and Impurity B (0.23%) Example 5: Preparation of azithromycin monohydrate from azithromycin monohydrate acetonitrile solvate. Azithromycin monohydrate acetonitrile solvate (50g) prepared following examples 1 to 3 is dissolved in methanol (300ml) at 50-60 °C. The suspension is stirred for 15- 25 min and made it clear solution by filtration. Water (180ml) is added slowly at 40-60°C till haziness observed. Water addition is stopped for 5.0 min to grow crystal. Again water (270ml) is added over 45min. period at the same temp. The mixture is filtered and washed with water (100ml) and dried at less than 40°C. Yield 40-45 gm Azithromycin Acetonitrile Solvate HPLC Purity: Purity (98.52 %) and Impurity B (0.28%) Azithromycin Monohydrate HPLC Purity: Purity (99.53 %) and Impurity B (0.23%) Example 6: Preparation of azithromycin monohydrate from azithromycin monohydrate acetonitrile solvate Azithromycin monohydrate acetonitrile solvate (50g) prepared following examples 1 to 3 is dissolved in acetone (200ml) at 40-60 °C. The suspension is stirred for 15-25 min and made it clear solution by filtration. Water (180ml) is added slowly at 40-60°C till haziness observed. Water addition is stopped for 5.0 min to grow crystal. Again water (270ml) is added over 45min. period at the same temp. The mixture is filtered and washed with water (100ml) and dried at less than 40°C. White crystalline product (40-45 gm) is obtained. Azithromycin Acetonitrile Solvate HPLC Purity: Purity (98.50 %) and Impurity B (0.27%) Azithromycin Monohydrate HPLC Purity: Purity (99.53 %) and Impurity B (0.24%) Example 7: Preparation of Azithromycin dihydrate: Azithromycin monohydrate acetonitrile solvate (50g) prepared following examples 1 to 3 is dissolved in acetone (60ml) at 50 -60 °C. The solution is stirred for 15min. at the same temperature and then cooled the solution at room temperature. Water (200ml) is added over 15-20min. The mixture is stirred for 12 hrs. and then filtered, washed with water(2 X 20ml) and dried at 40°C. Yield 40-45 gm. Azithromycin Acetonitrile Solvate HPLC Purity: Purity (98.49 %) and Impurity B (0.25%) Azithromycin Dihydrate HPLC Purity. Purity (99.64 %) and Impurity B (0.29%) Example 8: Preparation of Azithromycin monohydrate isopropanol clathrate: Azithromycin monohydrate acetonitrile solvate (20g) prepared following examples 1 to 3 is dissolved in isopropanol (20ml) at 50-60 °C. Isopropanol is distilled out completely under vacuum (10-1mm/Hg) at 50°C. Isopropanol (20ml) is added into the solution and distilled out it again. Isopropanol(60ml) is added in the mixture and made it clear solution by filtration. The reaction mixture is cooled at room temperature and water (90.0ml) is added over 15-20min period. The solution is stirred for 6hrs. The resulting product is filtered, washed with a 40:60 mixture of isopropanol:water. The cake was dried vacuum (1-10mm/Hg) at 50°C for 12 hrs. White crystalline product (15-18gm) is obtained. Azithromycin Acetonitrile Solvate HPLC Purity: Purity (98.49 %) and Impurity B (0.25%) Azithromycin Isopropanol Clathrate HPLC Purity: Purity (99.48 %) and Impurity B (0.28%) Example 9: Preparation of Azithromycin ethanolate: Azithromycin monohydrate acetonitrile solvate (20g) prepared following examples 1 to 3 is dissolved in spirit (80ml) at 50 -60 °C. The suspension is stirred for 15min and made it clear solution by filtration. Water (60ml) is added slowly at 40-60°C till haziness observed. Water addition is stopped and allowed the mass to grow crystals for 5.0 min. Again water (60ml) is added over 45min. period at the same temp. The mixture is filtered and washed with water (2 X 60ml) and dried it at less than 40°C. White crystalline product (15-18gm) is obtained (Azithromycin Acetonitrile Solvate) HPLC Purity: Purity (98.49 %) and Impurity B (0.25%) (Azithromycin Ethanolate) HPLC Purity: Purity (99.48 %) and Impurity B (0.32%) Advantages of the invention 1. Azithromyin monohydrate acetonitrile solvate is crystalline and, in contrast to anhydrous azithromycin, may be obtained in pure form. 2. Azithromycin monohydrate acetonitrile solvate is not hygroscopic. 3. Azithromycin monohydrate acetonitrile solvate is, in contrast to azithromycin dihydrate, obtained conveniently and reproducibly by crystallization from acetonitrile water which has very low impurity profile specially Azithromyin B impurity. 4. In contrast to azithromycin dihydrate, azithromycin monohydrate acetonitrile solvate is obtained by very simple method. 5. It is very easy to make azithromycin monohydrate acetonitrile solvate and it is really advantageous to reduce the impurity level in azithromycin monohydrate and azithromycin dihydrate which are prepared from the solvate of the present invention. 6. The basic advantage in preparing azithromycin monohydrate acetonitrile solvate is to reduce Impurity B i.e. azithromycin B from 2.0% to 0.5%, which cannot be controlled by any other crystallization. 7. It is really advantageous to prepare pure azithromycin monohydrate, azithromycin dihydrate and azithromycin isopropanol clathrate from azithromycin monohydrate acetonitrile solvate. The impurity level is in the control specially Impurity B (azithromycin B) and N-De-methyl azithromycin. This solvate is really helpful in the reduction of Impurity B (i.e. azithromycin B) from azithromycin dihydrate and monohydrate. 8. The experimental conditions are simple and applicable to large-scale production. 9. The present processes are reproducible in a wide spectrum of physical conditions and consistently afford azithromycin monohydrate acetonitrile solvate with a constant ratio of azithromycin, water and acetonitrile. 10. The product generated by the processes of the present invention is highly pure. 11. The processes taught in this invention afford high yield of the product within the range of impurity profile. WE CLAIM : 1. A process for the preparation of azithromycin monohydrate acetonitrile solvate comprising: a) at least partially dissolving and/or suspending 9-deoxo-9a-aza-9a-homoerythromycin A in acetonitrile to form a mixture ; b) adding a methylating solution to said mixture; c) refluxing or heating said mixture; d) adding an alkaline solution after substantial completion of reaction; and e) recovering azithromycin monohydrate acetonitrile solvate from said mixture. 2. A process as claimed in claim 1, wherein said step of recovering azithromycin monohydrate acetonitrile solvate comprises: a) combining and cooling the organic layer obtained from said mixture to precipitate azithromycin monohydrate acetonitrile solvate b) filtering out said azithromycin monohydrate acetonitrile solvate; and optionally c) washing the product with acetonitrile; and d) vacuum drying said azithromycin monohydrate acetonitrile solvate. 3. The process as claimed in claim 1, wherein the said methylating solution is selected from formaldehyde, formic acid, paraformaldehyde and mixtures thereof. 4. The process as claimed in claim 1, wherein the said alkaline solution is selected from group consisting of sodium hydroxide solution, potassium hydroxide solution. 5. The process as claimed in claim 1, wherein the alkaline solution is preferably sodium hydroxide solution. 6. The process as claimed in claim 1, wherein the said refluxing or heating is carried out for 20 to 30 hrs. 7. The process as claimed in claim 1, wherein the said refluxing or heating is carried out at 40 to 90°C. 8. The process as claimed in claim 2, wherein said vacuum drying comprises drying said azithromycin monohydrate acetonitrile solvate at 40 to 60°C under 1 to 10 mm Hg vacuum. 9. A process for the preparation of azithromycin monohydrate acetonitrile solvate comprising: a) at least partially dissolving and/or suspending azithromycin in acetonitrile to form a mixture; b) refluxing or heating said mixture; c) cooling the organic layer to precipitate azithromycin monohydrate acetonitrile solvate; d) filtering out said azithromycin monohydrate acetonitrile solvate; and optionally e) vacuum drying the said azithromycin monohydrate acetonitrile solvate. 10. The process as claimed in claim 9, wherein the said refluxing or heating is carried out for 12 to 24 hrs, 11. The process as claimed in claim 9, wherein the said refluxing or heating is carried out at 40 to 90°C. 12. The process as claimed in claim 9, wherein said vacuum drying is carried out at a temperature of 40 to 60°C under 1 to 10 mm Hg vacuum. 13. A process for the preparation of pure azithromycin monohydrate as claimed in any preceding claim comprising: a) at least partially dissolving azithromycin monohydrate acetonitrile solvate of formula II in polar organic solvent to form a mixture ; b) refluxing or heating said mixture; c) filtering said mixture to obtain clear solution; d) adding water to said clear solution to precipitate said azithromycin monohydrate; e) separating said azithromycin monohydrate from said solution by filtration; and optionally f) washing said azithromycin monohydrate with water; and g) vacuum drying said azithromycin monohydrate. 14. The process as claimed in claim 13, wherein the ratio of water added in step (d) to said polar organic solvent in step (a) is substantially 1:1. 15. The process as claimed in any of claims 13 or 14, wherein said polar organic solvent is water-miscible organic solvent selected from organic solvent, preferably water-miscible ketones such as acetone, lower alcohols, preferably C=1-4 alcohols, such as methanol, ethanol, isopropanol, lower alkyl acetates, such as methyl acetate, ethyl acetate; and acetic acid and formic acid amides, such as dimethyl acetamide, N-N-dimethyl formamide; or mixtures thereof. 16. The process as claimed in claim 13, wherein said refluxing or heating is carried out for 2 to 4 hrs. 17. The process as claimed in claim 13, wherein said refluxing or heating is carried out at 40 to 90°C. 18. The process as claimed in claim 13, wherein said vacuum drying is carried out at a temperature less than 40°C under 1 to 10 mm Hg vacuum. 19. A process for the preparation of pure azithromycin dihydrate as claimed in claims 1 to 12 comprising: a) at least partially dissolving azithromycin monohydrate acetonitrile solvate of formula II in polar organic solvent to form a mixture; b) refluxing or heating said mixture; c) filtering said mixture to obtain clear solution; d) adding water to said clear solution and stirring the reaction mixture for 24 to 30 hrs to precipitate said azithromycin dihydrate; e) filtering out said azithromycin dihydrate ; and optionally f) washing said azithromycin dihydrate with water and vacuum drying. 20. A process as claimed in claim 19, wherein the ratio of amount of water added in step (d) to that of polar organic solvent of step (a) is at least 2:1. 21. A process for the preparation of pure azithromycin isopropanol clathrate as claimed in claims 1 to 12 comprising: a) dissolving azithromycin monohydrate acetonitrile solvate of formula II in isopropano b) heating the mixture; c) filtering said mixture to obtain clear solution; d) adding water to said clear solution to precipitate said azithromycin isopropanol clathrate e) filtering out said azithromycin isopropanol clathrate; and optionally f) vacuum drying said azithromycin isopropanol clathrate. 22. A process for the preparation of pure azithromycin ethanolate as claimed in claims 1 to 12 comprising: a) dissolving azithromycin monohydrate acetonitrile solvate of formula II in ethanol; b) heating the mixture; c) filtering said mixture to obtain clear solution; d) adding water to said clear solution to precipitate said azithromycin ethanolate; e) filtering out said azithromycin ethanolate. 23. A process as claimed in anyone of claims 1 to 12 wherein the final azithromycin monohydrate acetonitrile solvate has the following d-spacing values in powder XRD: 11.15, 9.94, 9.09, 7.91, 6.91, 5.44, 5.08, 4.76, 4.26, 3.83. 24. A process as claimed in anyone of claims 1 to 12 wherein the final azithromycin monohydrate acetonitrile solvate has the following d-spacing values in powder XRD: 14.72, 12.53, 11.15, 9.94, 9.04, 9.04, 8.27, 7.91, 7.39, 6.90, 6.62, 6.37, 6.11, 5.43, 4.76, 4.27, 3.83, 3.70. 25. A process as claimed in any one of claims 1 to 9, wherein the final azithromycin monohydrate acetonitrile solvate has the following cm"1 values in IR (with KBr): 3495, 2970, 2836, 2796, 2250, 1721, 1379, 1270, 1109, 1122, and an extra peak at 2250 cm"1. Dated this 10th day of December, 2003. Dr. .SANCHITA GANGULI OF S. MAJUMDAR & CO. Applicant's agent

Documents:

1265-mum-2003-abstract(18-03-2005).doc

1265-mum-2003-abstract(18-03-2005).pdf

1265-mum-2003-cancelled page(18-03-2005).pdf

1265-mum-2003-claims(granted)-(18-03-2005).doc

1265-mum-2003-claims(granted)-(18-03-2005).pdf

1265-mum-2003-correspondence(28-03-2007).pdf

1265-mum-2003-correspondence(ipo)-(16-05-2007).pdf

1265-mum-2003-drawing(18-03-2005).pdf

1265-mum-2003-form 1(12-12-2003).pdf

1265-mum-2003-form 1(26-02-2004).pdf

1265-mum-2003-form 19(09-01-2004).pdf

1265-mum-2003-form 2(granted)-(18-03-2005).pdf

1265-mum-2003-form 3(12-12-2003).pdf

1265-mum-2003-form-2-(granted)-(18-03-2005).doc

1265-mum-2003-power of attorney(08-02-2004).pdf

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