WO2011015219A1

WO2011015219A1 - Process for the purification of azithromycin by separation from its thermal degradation products and/or isomers

Info

Publication number: WO2011015219A1
Application number: PCT/EP2009/005710
Authority: WO
Inventors: Hossein Reza Darabi; Amir Esmail Saghafinia; Ali Aghaiee; Ehsan Khatamifar
Original assignee: Shifa Pharmed Industrial Group Co.; Terramark Markencreation Gmbh
Priority date: 2009-08-06
Filing date: 2009-08-06
Publication date: 2011-02-10

Abstract

The present invention relates to methods for improving the purity of azithromycin, preferably by purifying azithromycin from degradation products and/or isomers. The invention describes a degradation product of azithromycin which may be produced during drying and/or storage of azithromycin and relates to methods of removing the degradation product(s). The invention further relates to a method for preparing azithromycin dihydrate from crude azithromycin containing the isomer azithromycin B. The invention furthermore relates to a combined process for making azithromycin dihydrate which combines the method for the purification of azithromycin from degradation products with the method for making azithromycin dihydrate which removes the isomer azithromycin B.

Description

Processes for the purification of azithromycin by separation from its thermal degradation products and/or isomers

BACKGROUND OF THE INVENTION

The purity of the pharmaceutical compounds has always been considered as an essential factor in ensuring drug safety and quality. As it is well known in the art, the result of the many different complex steps in the production of a pharmaceutical active substance is not only the desired product but also impurities which are structurally closely related compounds. Even a very low percent of impurities or degradation products present in the active substance may significantly impair drug safety.

Azithromycin (formula 1, see Figure 1) is an azalide antibiotic derived from erythromycin A with improved biological and pharmacodynamic properties over the parent compound. Both antibiotics have a common mode of action starting by binding to bacterial ribosomes. US 4,474,768 and US 4,517,359 describe methods for the preparation of azithromycin. The structural modification consists of the insertion of an N-methyl group in the lactone ring of erythromycin A, affording a 15-membered aza macrolide. The transformation of erythromycin A into azithromycin involves: Conversion of erythromycin A into its oxime; Beckmann rearrangement of the oxime to yield the imino ether of erythromycin A; reduction of the imino ether to 9-deoxo-9a-aza-9ahomoerythromycin A, and, finally, reductive N-methylation to obtain azithromycin.

US 2004/0266997 and US 2007/0043214 Al describe methods for the preparation and identification of the degradation products, such as 3'-keto-azithromycin (formula 2, see Figure 1), which may be produced during storage and/or synthesis of azithromycin. US 2004/0266997 describes the isolation of 3'-keto-azithromycin 2 using chromatography. US 2007/0043214 Al reports the process for the manufacture of 3'-keto-azithromycin 2 by oxidation of 3'- aminoazithromycin.

US 6,764,997 reports that the addition of antioxidants to azithromycin protects azithromycin from degradation at elevated temperature.

The preparation of hygroscopic and non-hygroscopic crystalline azithromycin from crude azithromycin has been summarized in US 6,451,990 Bl. The crystalline azithromycin obtained by the methods of US 4,474,768 and US 4,517,359 is a hygroscopic monohydrate azithromycin. Table 1 summarizes the different procedures for the preparation of non-hygroscopic dihydrate azithromycin from a solvent system of acetone and water. Among them, only US 6,586,576 B2 describes gradual crystallization procedures which result in azithromycin monohydrate or azithromycin dihydrate, due to temperature effect. The method of US 6,586,576 shows a moderate efficiency for removing isomers of azithromycin in about 0.5-1% from crude azithromycin. Interestingly, in all prior art methods for the preparation of azithromycin dihydrate the optimal temperature for addition of water is 20 to 25°C.

Thus, the need for and commercial utility of methods of reducing the level of impurities is self- evident. There exists a need for improved azithromycin and methods of manufacturing in which the amounts of degradation products and/or other impurities, such as isomers, of azithromycin is reduced, resulting in azithromycin with a higher degree of purity. SUMMARY OF THE INVENTION

According to the present invention this object is solved by providing methods for improving the purity of azithromycin, preferably by purifying azithromycin from degradation products and/or isomers.

According to the present invention this object is, thus, solved by a method for the purification of azithromycin by separating said azithromycin from one or more of its degradation products.

Said purification method comprises the stepwise crystallization of azithromycin from a mixture of a lower alcohol with water.

Said purification method preferably comprises the following steps:

(a) providing azithromycin as starting material;

(b) dissolving the starting material azithromycin in a lower alcohol at a temperature of about 28°C to about 32° C, preferably about 30°C;

(c) maintaining the temperature;

(d) adding water, preferably in two separate sequential additions;

(e) stirring the mixture for about one hour while maintaining the temperature of about 28°C to about 32° C, preferably about 30⁰C;

(f) obtaining azithromycin, which contains a reduced amount of degradation products compared to the starting material. According to the present invention this object is furthermore solved by a method for making azithromycin dihydrate, which reduces the amount of and/or removes the isomers of azithromycin, in particular azithromycin B.

Said method for making azithromycin dihydrate comprises the steps of:

(a) dissolving azithromycin in acetone;

(b) maintaining the solution of azithromycin and acetone at a temperature of about 33°C to about 37° C;

(c) adding water in three separate sequential additions; and

(d) obtaining azithromycin dihydrate, preferably by isolating the crystals of azithromycin dihydrate.

According to the present invention this object is furthermore solved by a combined process for making azithromycin dihydrate which combines the method for the purification of azithromycin from degradation products with the method for making azithromycin dihydrate which reduces the amount of and/or removes the isomers, in particular azithromycin B.

DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Before the present invention is described in more detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. For the purpose of the present invention, all references cited herein are incorporated by reference in their entireties. Ab st r act

A wet cake of crude azithromycin thermally decomposes to form 3'-keto-azithromycin. Continued high temperature storage would continue the oxidation process.

A method for the purification of azithromycin containing up to 4% 3'-keto-azithromycin as impurity with high yield is disclosed herein. Separation of azithromycin and impurities, whereby the level of impurities in the macrolide is reduced, is effected by a stepwise crystallization of a mixture of a lower alcohol (preferably methanol or ethanol) in the presence of water.

Moreover, a method for preparing azithromycin dihydrate from crude azithromycin containing 1 - 4% of the isomer azithromycin B by the gradual crystallization of azithromycin from acetone by the addition of water is disclosed.

A combination of these two methods, therefore, is applied for removing both the degradation products and the isomers of azithromycin, in particular azithromycin B, and for making a purified azithromycin dihydrate.

Azithromycin

As used herein, unless otherwise indicated, the term "azithromycin" includes, but is not limited to, azithromycin salts, including hydrochloride salts; solvates, including hydrates, alcoholates, and esters; and physiologically functional derivatives thereof. The term "azithromycin" also includes all polymorphous forms. (Formula 1, Figure 1).

As used herein, unless otherwise indicated, the term "3'-keto-azithromycin" (formula 2, see Figure 1), includes, but is not limited to, 3'-keto-azithromycin salts, including hydrochloride salts; solvates, including hydrates, alcoholates, and esters.

Azithromycin according to the present invention may be defined by its low to high content of azithromycin degradation product 2, 3'-keto-azithromycin (formula 2, see Table 2 and Figure 1). During the drying time of a wet cake of crude azithromycin, it has been found that crude azithromycin degrades to form the oxidative degradation products. For example, when a wet cake of crude azithromycin was dried at room temperature and at 40°C, 50°C and 6O⁰C for various times, practically from about 1 to about 4% degradation occurs to form 3'-keto- azithromycin 2. For example, at 50°C the amounts of impurity 2 is 0.72%, 0.92%, 1.53%, 2.51% and 2.92% after 1 hour, 2 hours, 4 hours, 8 hours and 14 hours, respectively. Thus, drying at room temperature and/or higher temperatures in the presence of oxygen can result in the presence of unacceptable levels of impurities in azithromycin.

Table 2. The formation azithromycin degradation product 2 in various drying temperatures along different drying times.

Time (h) Impurity 2 (°/ -ό) at different temperatures

45⁰C 55⁰C 65⁰C

1 1.21 0.72 2.91

2 1 0.92 3.17

4 2 1.53 3.6

8 2.67 2.51 4.34

It has been found that by lowering the temperature in the surrounding atmosphere of azithromycin the formation of the oxidative degradation product 2 may be significantly reduced (see US 2004/0266997). It has also been found that at room temperature in a package of azithromycin (without oxygen, e.g. a sealed bag), the formation of the oxidative degradation product 2 may be significantly reduced, (see Experiment 2). Therefore, the crude azithromycin samples are vacuum-dried at room temperature with no degradation product 2.

HPLC has been used for the analysis of azithromycin in bulk samples (such as disclosed in US 2004/0266997), for the separation of related compounds produced during degradation. The most marked spectral differences between the samples occurred in the relative retention time (RRT) = 0.8 region, which corresponds to the 3'-keto-azithromycin 2 (such as disclosed in US 2004/0266997, see also Figure 2). The decomposition amounts of crude azithromycin at various temperatures and times are listed in Table 2.

It has been observed that the degradation rate of azithromycin in oven was strongly affected by change in temperature. For this purpose, a wet cake of crude azithromycin was dried at room temperature and at 45, 55 and 65°C within 0.5 to 14 hours.

During the drying at 45°C to upper temperatures, azithromycin is rapidly degraded via oxidation to form 3'-keto-azithromycin 2. It has been observed that initially there was an increase in 2 with increasing temperature at a defined time. At a defined temperature, an increase in 2 was observed along the time.

We have found that the crude azithromycin having a water content of 7 to 10% shows a degradation of 1.5% within 3 hours, which degradation is increasing within 14 hours to be almost 3% under 65°C storage in tray drier.

Method for purification from degradation products

As described above, a need exists to remove azithromycin degradation product 2.

As outlined above, the present invention provides a method for the purification of azithromycin by separating said azithromycin from one or more of its degradation products.

A "lower alcohol", as used herein, refers to an alcohol or alcoholic compound with at least one hydroxyl group and a linear or branched chain of one to three C atoms. Preferably, a lower alcohol as used in the methods of the present invention is selected from methanol, ethanol, propanol and isopropanol or mixtures thereof. More preferably, the lower alcohol is methanol or ethanol; most preferably methanol.

The separation of azithromycin and impurities, whereby the level of impurities in the macrolide is reduced, is effected by a stepwise crystallization of a mixture of a lower alcohol (preferably methanol) in the presence of water.

The purification method according to the present invention comprises the following steps:

(a) providing azithromycin as starting material;

(b) dissolving the starting material azithromycin in a lower alcohol at a temperature of about 28°C to about 32° C, preferably about 3O⁰C;

(c) maintaining the temperature;

(d) adding water, preferably in two separate sequential additions;

(e) stirring the mixture for about one hour at a temperature of about 28°C to about 32° C, preferably about 30°C;

(f) obtaining azithromycin, which contains a reduced amount of degradation products compared to the starting material.

Preferably, the degradation product is 3'-keto-azithromycin of formula 2 (see Figure 1).

The purification method according to the present invention allows reducing in an efficient way the impurity 2.

As described above, 3'-keto-azithromycin 2 can be characterized and identified using HPLC, where it has a relative retention time (RRT) in the 0.8 region (see also Figure 3). Preferably, the azithromycin provided as the starting material (the crude azithromycin) is azithromycin that contains degradation products as impurity, preferably up to 4 %, preferably about 1 % to about 4 % 3'-keto-azithromycin of formula 2 as impurity.

Preferably, the azithromycin provided as the starting material was obtained from drying azithromycin in a drier or an oven, drying at room temperature and/or higher temperatures, preferably in the presence of oxygen and at least at about 4O⁰C.

In step (b), the solution of azithromycin and the lower alcohol (preferably methanol) is maintained at a temperature of about 28⁰C to about 32° C, preferably at about 30⁰C.

During the sequential additions of water in step (c) the temperature of the solution is preferably maintained at a temperature of about 28°C to about 32° C, preferably at about 30⁰C.

In step (c), the addition of water is preferably carried out in two separate sequential additions, more preferably with defined addition rates:

It is preferred that in the first addition step (cl) water is added at a rate of 0.05 to 0.10 volumes of water per volume of lower alcohol (preferably methanol) per hour. A tine suspension is formed. The suspension is preferably stirred for about 1 hour at the same temperature. It is preferred that in the first addition step (cl), 12-15% volume of water is added. Preferably, the first addition of the water (cl) occurs over about 1 to about 2 hours.

It is furthermore preferred that in the second addition step (c2) water is added at a rate of 0.20 to 0.25 volumes of water per volume of lower alcohol (preferably methanol) per hour. It is preferred that in the second addition step (c2), 85-88% volume of water is added. Preferably, the second addition of the water (c2) occurs over about 1 to about 2 hours.

In a preferred embodiment step (f) comprises vacuum-drying at room temperature. Preferably, the azithromycin obtained in step (f) contains about 0.2 % to about 1.4 % 3'-keto- azithromycin of formula 2 as impurity.

It is preferred that the ratio of lower alcohol (e.g. methanol or ethanol) to water is from about 0.8 to about 1.2, preferably about 1 :1.

Azithromycin used as the starting material for the purification may contain 3'-keto-azithromycin 2 about 1 to about 4%. The present invention provides a process for making pure azithromycin: the azithromycin may be dissolved at a temperature of approximately 30° C and maintaining this temperature, water is added slowly in two steps. Thereafter, the mixture is stirred at approximately 30° C for one hour. For more details, see also Experiments 3 to 5.

Method for making azithromycin dihydrate

As outlined above, the present invention further provides a method for making azithromycin dihydrate.

This method preferably reduces the amount of isomers in the azithromycin, such as azithromycin B (of formula 3, see Figure 1).

This method comprises the gradual crystallization of azithromycin from acetone by the addition of water.

Said method for making azithromycin dihydrate comprises the steps of:

(a) dissolving azithromycin in acetone;

(c) adding water in three separate sequential additions; and (d) obtaining azithromycin dihydrate, preferably by isolating the crystals of azithromycin dihydrate.

In step (b), the solution of azithromycin and acetone is maintained at a temperature of about 33°C to about 37° C, preferably at about 35°C.

During the sequential additions of water (c) the temperature of the solution is preferably maintained at a temperature of about 33°C to about 37° C, preferably at about 35°C.

In step (c), the addition of water in three separate sequential additions is carried out with defined addition rates: in the first addition step (cl) water is preferably added at a rate of about 0.10 to about 0.12 volumes of water per volume of acetone per hour; in the second addition step (c2) water is preferably added at a rate of about 0.20 to about 0.25 volumes of water per volume of acetone per hour;

- in the third addition step (cl) water is preferably added at a rate of about 0.50 to about 0.70 volumes of water per volume of acetone per hour.

It is preferred that in the first addition step (cl) water is added at a rate of about 0.10 to about 0.12 volumes of water per volume of acetone per hour.

Preferably, the first addition of the water occurs over about 3 to about 5 hours.

Preferably, the solution formed after the first addition step of water (cl) is stirred for about 4 hours prior to the second addition step of water (c2). The clear solution is stirred for about 4 hours at same temperature such that crystallization is started and a tine suspension is formed. It is preferred that in the first addition step (cl), 25-30% volume of water is added.

In the second addition step (c2), preferably between about 0.20 to about 0.25 volumes of water per volume of acetone per hour are added.

Preferably, the second addition of the water occurs over about 1 to about 2 hours.

Preferably, the suspension formed after the second addition step (c2) is stirred for about 1 to about 2 hours, to make/form a crystalline suspension, prior to the third addition step of water (c3).

In the second addition step (c2), the addition rate of water is twice of the first addition rate. It is preferred that in the second addition step (c2), water is added at a same volume of the first addition step (25-30% volume of water).

In the third addition step (c3), preferably between about 0.50 to about 0.70 volumes of water per volume of acetone per hour are added.

Preferably, the third addition of the water occurs over about 1 hour, preferably between about 40% to about 50% volumes of water are added.

Preferably, the suspension formed after the third addition step (c3) is stirred for about 1 to about 2 hours.

Further, the method of the present invention provides for a final ratio of acetone to water of not less than 1 :1 which provides for high yields of azithromycin dihydrate crystals. Preferably, the final ratio of acetone to water is not less than 1 : 1, preferably about 1.15 to about 1.4.

In a preferred embodiment step (d) comprises drying at about 5O⁰C without vacuum.

The addition profile of water of the present invention provides for the formation of pure azithromycin dihydrate substantially free of azithromycin monohydrate.

Thus, the azithromycin dihydrate obtained in step (d) is preferably substantially free of azithromycin monohydrate.

Azithromycin used as the starting material for the present invention may contain isomers of azithromycin, preferably azithromycin B, in the amount of about 1.5% to 4 %.

Preferably, the azithromycin used in step (a) contains about 1.5 % to about 4 % of azithromycin B.

An important difference between the present invention and the prior art methods listed in Table 1, such as US 6,586,576 B2, is the crystallization temperature. The crystallization in higher temperature, such as 33-37°C, according to the present invention allows making a more pure crystal with lower amount of azithromycin B. Therefore, the crystallization of azithromycin with higher amount of impurity of azithromycin B (more than 1%) resulted in pure azithromycin dihydrate. Interestingly, a gradual addition of water at 40⁰C, based on US 6,586,576 B2, results in the formation of hygroscopic azithromycin monohydrate which is due to the addition profile of water. This proves that the addition profile of water plays an important role, which can be even more important than the role of the temperature to make azithromycin dihydrate.

The method of the present invention for making azithromycin dihydrate further purifies the azithromycin by reducing the presence of isomers of azithromycin in the isolated azithromycin dihydrate. Preferably, the isomers of azithromycin in the isolated azithromycin dihydrate are present less than about 0.1% to about 0.3%. It is preferred that the azithromycin dihydrate obtained in step (d) contains less than about 0.3 % to about 1.4 % isomers, such as azithromycin B.

Preferably, about 1% to 2% of azithromycin B is removed to form the isolated azithromycin dihydrate. For example, azithromycin containing 2.88% of azithromycin B is converted to azithromycin dihydrate with 0.85% of azithromycin B.

See also Experiment 6.

Combined process for the purification of azithromycin and production of azithromycin dihydrate

As outlined above, the present invention further provides a combined process for making azithromycin dihydrate, which combines the method for the purification of azithromycin from degradation products as described herein with the method for making azithromycin dihydrate which reduces the amount of and/or removes the isomer azithromycin B as described herein.

Preferably, the method for the purification of azithromycin from degradation products (as described herein) is carried out first and is followed by the method for making azithromycin dihydrate (as described herein).

See Experiment 7.

The following examples and drawings illustrate the different aspects of the present invention without, however, limiting the same thereto.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. shows azithromycin (formula 1) 3'-ketoazithromycin (formula 2) and azithromycin B (formula 3). Figure 2. shows a diagram for the degradation of azithromycin and the formation azithromycin degradation product 2 in various drying temperatures along different drying times.

Figures 3 A and B. show HPLC chromatograms of a sample of azithromycin containing degradation product 2, before and after purification.

Figures 4 A and B. show HPLC chromatograms of a sample of azithromycin containing degradation product 2, before and after purification.

Figure 5 A and B. show HPLC chromatograms of a sample of azithromycin containing azithromycin B 3, before and after purification.

Figure 6 A and B. show HPLC chromatograms of a sample of azithromycin containing degradation product 2 and azithromycin B 3, before and after a combined purification method.

EXAMPLES

Experiment 1. Preparation of azithromycin from Aza-azithromycin

In a 100 L reactor, 10 Kg of aza-azithromycin was dissolved in 30 L of acetone. Formaldehyde 37% (2.22 Kg), formic acid 85% (2.65 Kg) and triethyl amine (50 mL) were added and the clear solution was heated at 46-48⁰C. The mixture was stirred at 46-48°C for 8 hours then cooled to less than 35°C and 30 L of water was added. The clear solution was transferred via a Buchner filter to a 200 L reactor. The pH was adjusted with ammonia solution of 7% (20 L) to 9.5-9.7. Water (60 L) was added over 2 hours. After stirring the suspension for 1 hour, the crude azithromycin (9.5 Kg, 93%) was obtained.

Experiment 2. The formation of 2 from crude azithromycin

100 g of crude azithromycin (impurity 2 = 0.21%, H₂O =10%) was dried in tray drier without vaccum at 55°C. After 8 hours, the amount of impurity 2 was arised to 2.5%. 100 g of crude azithromycin (impurity 2 = 0.21%, H₂O =10%) was kept in sealed bag for 10 days at room temperature. The amount of impurity 2 was increased to 0.32%

Experiment 3. Removing of 2 from crude azithromycin

100 g of azithromycin with 94.6% purity by HPLC and 3.20% of impurity 2 was dissolved in 300 ml of methanol at 30° C. Water (40 ml) was added at 30° C for 1 hour and it appeared a cloudy solution. The solution was stirred for 1 hour. Water (260 ml) was added at 30° C for 1 hour and stirred for 1 hour. After drying under vacuum at room temperature, 92.5 g of azithromycin with 97.2% purity and 1.15% of impurity 2 was obtained with a yield of 92.7% based on weight.

Experiment 4. Removing of 2 from crude azithromycin

100 g of azithromycin with 92.5% purity by HPLC and 2.29% of impurity 2 and 1.53% of isomer 3 was dissolved in 300 ml of methanol at 30° C. Water (40 ml) was added at 30° C for 1 hour and it appeared a cloudy solution. The solution was stirred for 1 hour. Water (260 ml) was added at 30° C for 1 hour and stirred for 1 hour. After drying under vacuum at room temperature, 91.8 g of azithromycin with 97.3% purity and 0.93% of impurity 2 and 1.49% of isomer 3 was obtained with a yield of 91.8% based on weight.

Experiment 5. Removing of 2 from crude azithromycin

100 g of azithromycin with 92.17% purity by HPLC and 4.18% of impurity 2 and 1.52% of isomer 3 was dissolved in 300 ml of methanol at 30° C. Water (40 ml) was added at 30° C for 1 hour and it appeared a cloudy solution. The solution was stirred for 1 hour. Water (260 ml) was added at 30° C for 1 hour and stirred for 1 hour. After drying under vacuum at room temperature, 91.8 g of azithromycin with 96.16% purity and 1.68% of impurity 2 and 1.53% of isomer 3 was obtained with a yield of 91.8% based on weight. Experiment 6. Preparation of azithromycin dihydrate

85 Kg of azithromycin with 96.72% purity and 2.44% of impurity azithromycin B and 0.84% of impurity 2 was dissolved in 255 L of acetone at 35° C. Water (60 L) was added at 35°C for 2 hours. The addition of water was stopped and the solution was stirred for 4 hours. Water (60 L) was added at 35° C for 2 hours and stirred for 2 hours. Water (85 L) was added at 35° C for 1 hour and stirred for 1 hour. After drying, 78 Kg of azithromycin dihydrate with 98.7% purity and 0.93% impurity azithromycin B was obtained with a yield of 91.8% based on weight.

Experiment 7. Removing of the impurities 2 and 3 to make azithromycin dihydrate

100 g of azithromycin with 96.16% purity by HPLC and 1.68% of impurity 2 and 1.53% of azithromycin B was dissolved in 300 ml of methanol at 30° C. Water (300 ml) was added at 30° C for 1 hour and stirred for 1 hour. After drying, 88.8 g of azithromycin with 96.0% purity and 0.48% of impurity 2 and 1.47% of azithromycin B was obtained with a yield of 94% based on weight.

The cake of azithromycin, 100 g, was dissolved in 250 mL of acetone at 35° C. Water (57 mL) was added at 35°C for 2 hours. The addition of water was stopped and the solution was stirred for 4 hours. Water (57 mL) was added at 35° C for 2 hours and stirred for 2 hours. Water (75 mL) was added at 35° C for 1 hour and stirred for 1 hour. After drying, 94 g of azithromycin dihydrate containing 0.39% azithromycin B was obtained with a yield of 98.78% based on weight.

The features disclosed in the foregoing description, in the claims and/or in the accompanying drawings may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof. REFERENCES

J. Chem. Res. 1988, 132.

J. Org. Chem., 1997, 7479.

Table 1. The crystallization of azithromycin from a solvent system of acetone and water.

Crystalline form Reference Solvent Addition profile for water Yield dihydrate hygroscopic J. Chem. Res., Aceton/H₂O pH control 80 %

1988, 132

dihydrate hygroscopic EC 95-1389 Aceton/H₂O Non-hygroscopic - dihydrate hygroscopic J. Org. Chem., Aceton/H₂O One-step water addition, 25°C 88 %

1997, 7479

dihydrate hygroscopic EP O 941 999 Aceton/H₂O pH control - dihydrate hygroscopic Us 5,869,629 Aceton/H₂O One-step water addition, 25°C 88 %

(1.3: 1)

dihydrate hygroscopic US 6,586,576 Aceton/H₂O Two-step water addition, 25 °C 91 %

(1 :1)

monohydrate non-hygroscopic US 6,586,576 Aceton/ H₂O (l :l) Three step water addition, 4O⁰C 93.8 %

Claims

1. A method for the purification of azithromycin by separating said azithromycin from one or more of its degradation products, comprising the stepwise crystallization of azithromycin from a mixture of a lower alcohol with water.

2. The method according to claim 1, comprising the following steps

(a) providing azithromycin as starting material;

(c) maintaining the temperature;

(d) adding water;

3. The method according to claim 1 or claim 2, wherein the degradation product is 3'-keto- azithromycin of formula 2

4. The method according to claim 3, wherein the azithromycin provided as the starting material is azithromycin that contains up to 4 %, preferably about 1 % to about 4 % 3'- keto-azithromycin of formula 2 as impurity, and wherein, preferably, the azithromycin provided as the starting material was obtained from drying azithromycin in a drier or an oven, drying at room temperature and/or higher temperatures, preferably in the presence of oxygen and at least at about 40°C.

5. The method according to any of claims 1 to 4, wherein the lower alcohol is selected from methanol, ethanol, propanol and isopropanol, preferably methanol, and wherein, preferably, the ratio of the lower alcohol to water is from about 0.8 to about 1.2, preferably about 1 :1.

6. The method according to any of claims 1 to 5, wherein in step (d) water is added in two separate sequential additions, wherein in the first addition step (cl) water is added at a rate of 0.05 to 0.10 volumes of water per volume of lower alcohol per hour, preferably over about 1 to about 2 hours, wherein preferably the solution or suspension formed after the first addition step of water (cl) is stirred for about 1 hour prior to the second addition step of water (c2), and wherein in the second addition step (c2) water is added at a rate of 0.20 to 0.25 volumes of water per volume of lower alcohol per hour, preferably over about 1 to about 2 hours.

7. The method according to any of claims 2 to 6, wherein step (f) comprises vacuum-drying at room temperature, and wherein preferably the azithromycin obtained in step (f) contains about 0.2 % to about 1.4 % 3'-keto-azithromycin of formula 2 as impurity.

8. A method for making azithromycin dihydrate comprising the steps of:

(a) dissolving azithromycin in acetone;

(c) adding water in three separate sequential additions; and

(d) obtaining azithromycin dihydrate, preferably by isolating the crystals of azithromycin dihydrate, wherein preferably during the sequential additions of water (c) the temperature of the solution is maintained at a temperature of about 33°C to about 37° C, preferably at about 35°C.

9. The method according to claim 8, wherein in the first addition step (cl) between about 0.10 to about 0.12 volumes of water per volume of acetone per hour are added, preferably over about 3 to about 5 hours, and wherein preferably the solution formed after the first addition step of water (cl) is stirred for about 4 hours prior to the second addition step of water (c2).

10. The method according to claim 8 or 9, wherein in the second addition step (c2) between about 0.20 to about 0.25 volumes of water per volume of acetone per hour are added, preferably over about 1 to about 2 hours, and wherein preferably the suspension formed after the second addition step (c2) is stirred for about 1 to about 2 hours prior to the third addition step of water (c3).

11. The method according to any of claims 8 to 10, wherein in the third addition step (c3) between about 0.50 to about 0.70 volumes of water per volume of acetone per hour are added, preferably over about 1 hour, and wherein preferably the suspension formed after the third addition step (c3) is stirred for about 1 to about 2 hours.

12. The method according to any of claims 8 to 11, wherein the final ratio of acetone to water is not less than 1 : 1 , preferably about 1.15 to about 1.4.

13. The method according to any of claims 8 to 12, wherein step (d) comprises drying at about 50°C without vacuum.

14. The method according to any of claims 8 to 13, wherein azithromycin dihydrate obtained in step (d) is substantially free of azithromycin monohydrate, and wherein preferably the azithromycin dihydrate obtained in step (d) contains less than about 0.3 % to about 1.4 % isomers, such as azithromycin B, and wherein preferably the azithromycin used in step (a) contains about 1.5 % to about 4 % isomers, such as azithromycin B.

15. A combined process for making azithromycin dihydrate comprising the method according to any of claims 1 to 7 and subsequently the method according to any of claims 8 to 14.