FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
An Improved Process for Preparation of Azithromycin monohydrate
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Azithromycin monohydrate. More particularly, the present invention is directed to a more simplified process for the commercial preparation of stable Azithromycin monohydrate having residual solvent content between 0 to 200 ppm.
BACKGROUND OF THE INVENTION
Azithromycin (Formula I), 9-Dexo-9a-aza-9a-methyI-9a-homoerytrrromycin A; is a semisynthetic macrolide antibiotic which is classified as a member of second generation erythromycin antibacterial agent. Azithromycin is often used to treat respiratory infections and is marketed under the tradename ZITHROMAX ® (Pfizer Inc.; New York).


Azithromycin was first discovered by G. Kobrehel and S. Djokic (Belgium Patent No 892357; related U.S. Pat. No. 4,517,359; S. Djokic et al. J. Chem. Research (S), 1988,132 and idem miniprint,1988, 1239).
Azithromycin is obtained in three forms namely amorphous anhydrous form, monohydrate and dihydrate form. There are various processes disclosed in the prior art for the preparation of Azithromycin in different forms.
US 4474768 and US 6268489 teach the process of making Azithromycin monohydrate but do not claim the resulting product. The product obtained was hygroscopic and unstable in nature. The theoretical percentage of water in Azithromycin monohydrate is 2.3% whereas the water content of Azithromycin monohydrate obtained in US 6268489 was 3.92%. Further, the patents do not provide the detail description of the drying process (temperature and pressure).
Canadian patent CA 1191843 claims the process for preparation of anhydrous amphorus form of Azithromycin. However, the product can not be made in pure form at commercial scale.
EP 298650 discloses crystalline dihydrate form of Azithromycin and the process for preparing it. The patent further describes the process for preparing hygroscopic monohydrate form of Azithromycin from Azaerythromycin. Azaerythromyin is converted to Azithromycin by Eschweiler-Clarke methylation reaction with formaldehyde and formic acid in presence of solvent chloroform and the resulting Azithromycin is crystallized from ethanol and water to obtain monohydrate form of Azithromycin. The monohydrate form obtained by this process is highly hygroscopic and can be used only with difficulty, since the monohydrate absorbs variable amount of water, which further makes it difficult to use for medicinal formulations.

US 6949519 discloses an Azithromycin monohydrate form having 4.0 to 6.5 % w/w of water that is stable and non-hygroscopic. Azithromycin monohydrate is prepared by the addition of an alkali solution to a hydrochloric acid solution of Azithromycin. However, as discussed in US 6586576 it should be noted that Azithromycin is unstable under acidic condition and results into formation of potential undesirable impurities during precipitation.
US 6703372 discloses the stable form of Azithromycin monohydrate and process for preparing it by dissolving Azithromycin as its free base or salt or dihydrate in an organic solvent such as ethanol, acetone, isopropanol or methylacetate followed by distilling off organic solvent and, if desired, excess of water and thus isolating Azithromycin in the form of a stable monohydrate. The patent further states that Azithromycin thus obtained in the form of stable crystalline monohydrate contains content of organic solvent as low as an analytical detectable amount up to 0.5% w/w.
CN 101177441 describes the preparation of monohydrate form of Azithromycin by dissolving Azithromycin into organic solvent, wherein the organic solvent is polar solvent mixed with water, adding this obtained solution into water and simultaneously distilling out the organic solvent followed by separating and drying the Azithromycin monohydrate crystals wherein the water content is less than 6.5% and the solvent residue is no more than 5000 ppm.
US 7683162 describes the process of preparing a crystalline Azithromycin monohydrate by i) dissolving Azithromycin in a first solution comprising at least 50% (v/v) of a alcohol ii) adding the dissolved Azithromycin to a second solution comprising at least about 50% (v/v) water to form a precipitate, iii) isolating the precipitate, and drying the isolated precipitate to a water content of about 5% (w/w) to about 7% (w/w). The resulting monohydrate is stable, exhibiting less than 2%

degradation, and non-hygroscopic. The patent also discloses the ethanol content in obtained crystalline Azithromycin monohydrate as 601 ppm.
US 6855813 describes an improved process for the preparation of Azithromycin monohydrate from Azaerythromycin comprising reacting Azaerythromycin with formic acid and formaldehyde in non-halogenated solvent at reflux temperature followed by adjusting the pH of solution to give Azithromycin monohydrate.
Thus, the prior art processes are tedious. Also, Azithromycin monohydrate produced by prior art processes is unstable, hygroscopic and hence difficult to handle on large
scale.
Hence, there is a continuing need in the art for an industrially viable process of preparing stable Azithromycin monohydrate. Also, it is essentially important to prepare stable monohydrate form of Azithromycin that is substantially free of organic solvents.
The inventors of the present invention have developed a simple, efficient and industrially scalable process for preparation of stable Azithromycin monohydrate with lower content of .residual solvent.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of Azithromycin monohydrate. More particularly, an object of the present invention is to prepare stable monohydrate form of Azithromycin showing lower hygroscopicity.

Another object of the present invention is to provide an improved process for the preparation of stable Azithromycin monohydrate having lower content of residual solvents.
Another object of the present invention is to provide an improved process for the preparation of stable Azithromycin monohydrate using an organic solvent selected from chlorinated solvents like dichloromethane, alcohols like methanol, ethanol, ketones like acetone or non-alcoholic solvents like toluene, acetonitrile.
Another object of the present invention is to provide an improved process for the preparation of stable Azithromycin monohydrate having residual content of chlorinated solvents like dichloromethane or ketones like acetone below 50 ppm.
Another object of the present invention is to provide an improved process for the preparation of stable Azithromycin monohydrate having residual content of alcoholic solvents like methanol, ethanol or non-alcoholic solvents like toluene, acetonitrile below 200 ppm.
Yet another object of the present invention is to provide an improved process for the preparation of stable Azithromycin monohydrate with good yield and purity.
Yet another object of the present invention is to provide simple, cost-effective and industrially scalable process for the preparation of stable Azithromycin monohydrate.
Yet another object of the present invention is to provide an improved process for the preparation of stable Azithromycin monohydrate with lower content of residual solvents from Azaerythromycin.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an Infrared Spectrum of a sample of Azithromycin monohydrate crystals made according to Example 1 of the present invention.
Fig.2 is an X-ray diffraction of a sample of Azithromycin monohydrate crystals made according to Example 1 of the present invention.
SUMMARY OF THE INVENTION

from Azaerythromycin (Formula III),
According to an aspect of the present invention, there is provided an improved process for the preparation of stable Azithromycin monohydrate (Formula II)


comprising steps of,
a) converting Azaerythromycin to Azithromycin
b) dissolving obtained Azithromycin of step (a) in an organic solvent
c) optionally adding the seed of Azithromycin monohydrate to water and heating it
d) adding the solution obtained in step (b) to the solution of step (c)
e) constantly displacing the organic solvent from hot water
f) filtering and drying the wet cake to obtain Azithromycin monohydrate,
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Azithromycin monohydrate. More particularly, the present invention is related to a simple and cost-effective process for the commercial preparation of stable Azithromycin monohydrate that is substantially free of organic solvents.

from Azaerythromycin (Formula III),

According to an aspect of the present invention, there is provided an improved process for preparation of stable Azithromycin monohydrate (Formula II)

comprising steps of,
a) converting Azaerythromycin to Azithromycin
b) dissolving obtained Azithromycin of step (a) in an organic solvent

c) optionally adding the seed of Azithromycin monohydrate to water and heating it
d) adding the solution obtained in step (b) to the solution of step(c)
e) constantly displacing the organic solvent from hot water
f) filtering and drying the wet cake to obtain Azithromycin monohydrate.
According to an embodiment of the present invention, Azaerythromycin is converted to Azithromycin in step a) by following the process as described in US 4517359 using formaldehyde and formic acid in presence of acetone.
According to an embodiment of the present invention, the organic solvent used to dissolve Azithromycin in step b) is selected from chlorinated solvents such as dichloromethane, alcohols such as methanol, ethanol or ketones such as acetone or non-alcoholic solvents such as toluene, acetonitrile.
According to an embodiment of the present invention, the water that optionally containing seed of Azithromycin monohydrate is heated in step c) at a temperature range of 60-100° C, preferably at 70-90°C.
According to another embodiment of the present invention, the Azithromycin solution in organic solvent of step b) is added to the solution of step c) at a temperature ranging from 60-100° C, preferably at 70-90°C. The said addition is carried out in 1-6 hr, preferably in 2 hours.
According to yet another embodiment of the present invention, the reaction of step b), step c). step d) and step e) is carried out optionally under inert condition.

According to yet another embodiment of the present invention, in step e) the organic solvent is constantly displaced using high vacuum.
According to yet another embodiment of the present invention, the wet cake obtained in step f) is dried under vacuum or air dried at 35-50°C, preferably at 40°C to obtain desired Azithromycin monohydrate of formula II.
In an embodiment of the present invention, the Azithromycin monohydrate obtained by the above-mentioned process is stable, lower hygroscopic and has residual solvent content between 0 to 200 ppm.
It has been found that, residual solvent content in Azithromycin monohydrate in presence of chlorinated solvent such as dichloromethane or ketones such as acetone is below 50 ppm and with alcohols such as methanol, ethanol or non-alcoholic solvent such as toluene, acetonitrile residual solvent content is below 200 ppm.
Thus, Azithromycin monohydrate obtained by the process of present invent ion is substantially free of any organic solvent.
The following examples illustrate the process of the present invention, but they arc not intended to limit the scope of invention.
Examples
Example 1
To a solution of Azaerythromycin (25g. 0.034moles) in acetone (75mL) was added a •• mixture of 4.3mL Formaldehyde and 4.3mL Formic acid. The reaction mixture was

refluxed for 3 hours. After completion of reaction, the reaction mixture was cooled to room temperature and further basified with NaOH solution up to pH 12. Water (162mL) was added to the reaction mass to precipitate the product. The Azithromycin obtained was filtered. The wet cake was dissolved in dichloromethane (MDC) (125mL). Water (240mL). seed of Azithromycin monohydrate (0.7g) was heated up to 90°C under argon bubbling. To this solution was added dropwise the MDC solution of Azithromycin in about 2 hours with simultaneous removal of solvent. Further, reaction mass was degassed at 90°C to remove residual MDC. Solution was cooled to room temperature and filtered. The wet cake was dried under vacuum at 40°C to obtain 24 gm of Azithromycin monohydrate with 92% yield (IR spectrum incorporated: FIG.l, PXRD pattern incorporated: FIG 2).
Residual solvent content: Acetone content: 5ppm, MDC content: 15ppm.
Example 2
To a solution of Azaerythromycin (25g, 0.034moles) in acetone (75mL) was added a mixture of 4.3mL Formaldehyde and 4.3mL Formic acid. The reaction mixture was refluxed for 3 hours. After completion of reaction, the reaction mixture was cooled to room temperature and further basified with NaOH solution up to pH 12. Water (162mL) was added to the reaction mass to precipitate the product. The Azithromycin obtained was filtered. The wet cake was dissolved in MDC (125mL). Water (240mL), seed of Azithromycin monohydrate (0.7g) was heated up to 70°C under argon bubbling. To this solution was added dropwise the MDC solution of Azithromycin in about 2 hours with simultaneous removal of MDC. Further, reaction mass was degassed at 70°C to remove residual MDC. Solution was cooled to room temperature and filtered. The wet cake was dried under vacuum at 40°C to obtain 24 gm of

Azithromycin monohydrate with 92% yield (IR spectrum is identical to FIG.l; PXRD pattern is identical to FIG 2).
Residual solvent content: Acetone content: 4ppm. MDC content: 23ppm.
Example 3
To a solution of Azaerythromycin (25g, 0.034moles) in acetone (75mL) was added a mixture of 4.3mL Formaldehyde and 4.3mL Formic acid. The reaction mixture was refluxed for 3 hours. After completion of reaction, the reaction mixture was cooled to room temperature and further basified with NaOH solution up to pH 12. Water (162mL) was added to the reaction mass to precipitate the product. The Azithromycin obtained was filtered. The wet cake was dissolved in Acetone (150mL). Water (250inL), seed of Azithromycin monohydrate (0.7g) was heated up to 90°C under argon bubbling. To this solution was added dropwise the Acetone solution of Azithromycin in about 2 hours with simultaneous removal of acetone. Further, reaction mass was degassed at 90°C to remove residual Acetone. The slurry was cooled to room temperature and filtered. The wet cake was dried under vacuum at 40°C to obtain 24 gm of Azithromycin monohydrate with 92% yield (IR spectrum incorporated: FIG.l. PXRD pattern incorporated: FIG 2).
Residual solvent content: Acetone content: 14.4ppm
Example 4
To a solution of Azaerytliromycin (25g, 0.034moles) in acetone (75mL) was added a mixture of 4.3mL Formaldehyde and 4.3mL Formic acid. The reaction mixture was refluxed for 3 hours. After completion of reaction, the reaction mixture was cooled to

room temperature and further basified with NaOH solution up to pH 12. Water (162mL) was added to the reaction mass to precipitate the product. The Azithromycin obtained was filtered. The wet cake was dissolved in Methanol (150mL). Water (250mL), seed of Azithromycin monohydrate (0.7g) was heated up to 90°C under argon bubbling. To this solution was added dropwise the Methanol solution of Azithromycin in about 2 hours with simultaneous removal of Methanol . Further, reaction mass was degassed at 90°C to remove residual Methanol. The slurry was cooled to room temperature and filtered. The wet cake was dried under vacuum at 40°C to obtain 24 gm of Azithromycin monohydrate with 92% yield (IR spectrum is identical to FIG.l; PXRD pattern is identical to FIG 2).
Residual solvent content: Methanol content: 17.31ppm, Acetone content: 6.17ppm
Example 5
To a solution of Azaerythromycin (25g, 0.034moles) in acetone (75mL) was added a mixture of 4.3mL Formaldehyde and 4.3mL Formic acid. The reaction mixture was refluxed for 3 hours. After completion of reaction, the reaction mixture was cooled to room temperature and further basified with NaOH solution up to pH 12. Water (162mL) was added to the reaction mass to precipitate the product. The Azithromycin obtained was filtered. The wet cake was dissolved in Ethanol (150mL). Water (250mL), seed of Azithromycin monohydrate (0.7g) was heated up to 90°C under argon bubbling. To this solution was added dropwise the Ethanol solution of Azithromycin in about 2 hours with simultaneous removal of Ethanol . Further, reaction mass was degassed at 90°C to remove residual Ethanol. The slurry was cooled to room temperature and filtered. The wet cake was dried under vacuum at 40°C to obtain 24 gm of Azithromycin monohydrate with 92% yield (IR spectrum is identical to FIG.l; PXRD pattern is identical to FIG 2).

Residual solvent content: Ethanol content: 130 ppm, Acetone content: 18 ppm
Example 6
To a solution of Azaerythromycin (25g, 0.034moles) in acetone (75mL) was added a mixture of 4.3mL Formaldehyde and 4.3mL Formic acid. The reaction mixture was refluxed for 3 hours. After completion of reaction, the reaction mixture was cooled to room temperature and further basified with NaOH solution up to pH 12. Water (162mL) was added to the reaction mass to precipitate the product. The Azithromycin obtained was filtered. The wet cake was dissolved in Toluene (150mL). Water (250mL), seed of Azithromycin monohydrate (0.7g) was heated up to 90°C under argon bubbling. To this solution was added dropwise the toluene solution of Azithromycin in about 2 hours. Further, reaction mass was degassed at 90°C to remove residual toluene. The slurry was cooled to room temperature and filtered. The wet cake was dried under vacuum at 40°C to obtain 24 gm of Azithromycin monohydrate with 92% yield (IR spectrum is identical to FIG.l; PXRD pattern is identical to FIG 2).
Residual solvent content: Toluene content: 182 ppm
Example 7
To a solution of Azaerythromycin (25g, 0.034moles) in acetone (75mL) was added a mixture of 4.3mL Formaldehyde and 4.3mL Formic acid. The reaction mixture was refluxed for 3 hours. After completion of reaction, the reaction mixture was cooled to room temperature and further basified with NaOH solution up to pH 12. Water (162mL) was added to the reaction mass to precipitate the product. The Azithromycin

obtained was filtered. The wet cake was dissolved in Acetonitrile (150mL). Water (250mL). seed of Azithromycin monohydrate (0.7g) was heated up to 90°C under argon bubbling. To this solution was added dropwise the acetonitrile solution of Azithromycin in about 2 hours. Further, reaction mass was degassed at 90°C to remove residual acetonitrile with simultaneous removal of acetonitrile. The slurry was cooled to room temperature and filtered. The wet cake was dried under vacuum at 40°C to obtain 24 gm of Azithromycin monohydrate with 92% yield (IR spectrum is identical to FIG.l; PXRD pattern is identical to FIG 2).
Residual solvent content: Acetonitrile content: 106 ppm

We claim,
from Azaerythromycin (Formula III),

1) An improved process for the preparation of stable Azithromycin monohydrate (Formula II)

comprising steps of,
a) converting Azaerythromycin to Azithromycin

b) dissolving obtained Azithromycin of step (a) in an organic solvent
c) optionally adding the seed of Azithromycin monohydrate to water and heating it
d) adding the solution obtained in step (b) to the solution of step (c)
e) constantly displacing the organic solvent from hot water
f) filtering and drying the wet cake to obtain Azithromycin monohydrate

2) The process as claimed in claim 1, wherein the organic solvent used is selected from chlorinated solvents such as dichloromethane, alcohols such as methanol, ethanol, ketones such as acetone or non-alcoholic solvents such as toluene. acetonitrile
3) The process as claimed in claim 1, wherein the water that optionally containing seed of Azithromycin monohydrate is heated at temperature 60-100°C, preferably at 70-90°C
4) The process as claimed in claim 1, wherein the addition of solution in step d) is carried out at temperature ranging from 60-100°C, preferably at 70-90°C
5) The process as claimed in claim 1, wherein the addition of solution in step d) is carried out drop wisely in 1-6 hr, preferably in 2 hours
6) The process as claimed in claim 1, wherein Azithromycin monohydrate is dried under vacuum or air dried at 35-50°C, preferably at 40°C
7) The process as claimed in claim 1, wherein the content of residual solvent in obtained Azithromycin monohydrate is between 0 to 200 ppm
8) The process as claimed in claim 7 or 2, wherein the content of residual solvent in obtained Azithromycin monohydrate is below 50 ppm when the organic solvent used is chlorinated solvent such as dichloromethane or ketones such as acetone
9) The process as claimed in claim 7 or 2, wherein the content of residual solvent in obtained Azithromycin monohydrate is below 200 ppm when the organic solvent

used is alcoholic solvents such as methanol, ethanol or non-alcoholic solvent such as toluene, acetonitrile 10) The process as claimed in claim 1, wherein the step b), step c), step d) and step e) is carried out optionally under inert condition.