WO2005003144A1 - Methode de preparation d'un dihydrate d'azithromycine non-hygroscopique - Google Patents

Methode de preparation d'un dihydrate d'azithromycine non-hygroscopique Download PDF

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Publication number
WO2005003144A1
WO2005003144A1 PCT/IN2004/000187 IN2004000187W WO2005003144A1 WO 2005003144 A1 WO2005003144 A1 WO 2005003144A1 IN 2004000187 W IN2004000187 W IN 2004000187W WO 2005003144 A1 WO2005003144 A1 WO 2005003144A1
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Prior art keywords
acetone
organic phase
process according
aqueous
mixture
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PCT/IN2004/000187
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English (en)
Inventor
Ravikumar Bhadravathi
Ashok Kumar Kulkarni
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Jubilant Organosys Limited
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Publication of WO2005003144A1 publication Critical patent/WO2005003144A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • This invention relates to a direct single step preparation of the semi-synthetic antibiotic azithromycin dihydrate (non-hygroscopic).
  • Description of the Prior Art 9a-Aza-9a-methyl-9-deoxo-9a-homoerythromycin A, better known by its generic name azithromycin, is a broad spectrum semi- synthetic macrolide antibiotic compound belonging to the erythromycin A family, and processes for its preparation in the monohydrate form are disclosed in the US Patent 4,517,359 and US Patent 4,474,768.
  • the azithromycin monohydrate form thus prepared also referred to as hygroscopic azithromycin monohydrate or azithromycin crude, is difficult to handle during formulation, due to its hygroscopic properties.
  • hygroscopic azithromycin monohydrate is shown by formula (II) in the Scheme below.
  • EP-A-0 298 650 describes the preparation of a new form of azithromycin, viz azithromycin dihydrate, which is essentially non-hygroscopic under the conditions of relative humidity conducive to the formulation of azithromycin.
  • the molecular structure of non-hygroscopic azithromycin dihydrate is shown by formula (III) in the Scheme below.
  • azithromycin dihydrate is prepared from hygroscopic azithromycin monohydrate which, in turn, is prepared from 9-deoxo-9a-aza-9a- homoerythromycin A, also known as azaerythromycin A, having the molecular structure shown by formula (I) in the Scheme below.
  • Azaerythromycin A is subjected to a reductive
  • N-methylation reaction using a solution of formic acid and formaldehyde in chloroform medium followed by stripping off of the solvent and precipitation from a mixture of ethanol and water, to fornish hygroscopic azithromycin monohydrate in a yield of 85% w/w from azaerythromycin A.
  • the hygroscopic azithromycin monohydrate is then crystallized from a mixture of tetrahydroforan, hexane and 2-4 molar equivalents of water at a temperature varying from 17°C to 40°C to furnish azithromycin dihydrate in about 90% w/w yield from hygroscopic azithromycin monohydrate.
  • the overall yield of azithromycin dihydrate is 76% w/w (71% of theoretical) from azaerythromycin A, in two steps.
  • drawbacks of the above process are that high volumes (20 times on azaerythromycin A input) of solvent mixtures are required for the crystallization, and that it is necessary to isolate the hygroscopic azithromycin monohydrate.
  • Several other prior art methods are known for preparing azithromycin dihydrate from azithromycin monohydrate or azithromycin crude.
  • Azithromycin dihydrate may also be made by dissolving azithromycin monohydrate in water at acidic pH and raising the pH by adding aqueous NaOH to precipitate the dihydrate (WO-A-02/15842) or by using a mixture of acetone/water (EP-A-0 941 999).
  • WO-A-01/87912 discloses a process for preparing a new polymorph of azithromycin dihydrate, by crystallizing from azithromycin monohydrate in a mixture of acetone/water at 35-40°C. The melting point of this polymorph of azithromycin dihydrate is reported to be 139°C (DSC), whereas for azithromycin dihydrate the melting point reported previously according to EP-A-0 298 650 is 126°C-127°C (DSC).
  • a more recent publication WO-A-02/094843 discloses various new crystal forms of azithromycin that are essentially hydrates or hydrate-solvates of azithromycin free base, designated as C,D,E,F,G,H,I,J,K,L,M,N,O,P,Q,R.
  • a dihydrate form A and a non- stoichiometric hydrate form B have been disclosed previously in EP-A-0 298 650 and US-A-4,517,359 & US-A-4,474,768, respectively. Therefore, it is evident from the above that prior art methods of preparing azithromycin dihydrate have, invariably, required at least two steps . starting from azaerythromycin A.
  • azaerythromycin A is converted into either azithromycin crude or azithromycin monohydrate (hygroscopic), and in the second step the latter is crystallized into azithromycin dihydrate e.g. from solvent/solvent/water or solvent/water combinations or through acid/base treatment in water or in acetone/water mixtures.
  • azithromycin dihydrate of a pharmaceutically acceptable quality can be prepared directly, in a single step, from azaerythromycin A, and in improved yields, without the need to isolate either the hygroscopic azithromycin monohydrate or the crude azithromycin.
  • the present invention provides a process for the preparation of non-hygroscopic azithromycin dihydrate directly from a reductive N-methylation reaction mass, comprising: a) reacting azaerythromycin A with formic acid and formaldehyde in an organic solvent medium, to form a reaction mass comprising N-methylated azaerythromycin A (i.e.
  • Figure 1 shows the differential scanning calorimetry (DSC) pattern of non- hygroscopic azithromycin dihydrate of formula (III) obtained in accordance with an embodiment of the invention
  • Figure 2 shows the infrared (IR) absorption spectrum of the non-hygroscopic azithromycin dihydrate of formula (III)
  • Figure 3 shows the X-ray diffraction (XRD) pattern of the non-hygroscopic azithromycin dihydrate of formula (III).
  • DSC differential scanning calorimetry
  • IR infrared
  • XRD X-ray diffraction
  • the azaerythromycin A may be made by prior art procedures, for example as disclosed in J. Chem. Soc. (Perkin Trans) 1986, 1, pi 881-1890.
  • the formic acid and formaldehyde are preferably added to the organic solvent medium as solutions, preferably as aqueous solutions, e.g. 80-90% aqueous formic acid solution and 30-37% aqueous formaldehyde solution, and may be added separately or together.
  • the organic solvent medium preferably is an organic solvent selected from chloroform, dichloromethane (methylene dichloride) and acetone, and more preferably is acetone.
  • the organic solvent is suitably present in a volume ratio of from 1 : 1 to 10 : 1, more preferably 2 : 1 to 5 : 1, with respective to the azaerythromycin A. If acetone is used as the organic solvent medium, the acetone should be present in a volume ratio of at least 2.5 : 1, and preferably is present in a volume ratio of from 2.5 : 1 to 4: 1, more preferably 3 : 1, with respective to the azaerythromycin A.
  • the ratio of 3 : 1 is comfortable enough to facilitate smooth filtrations through polishing filters or activated carbon treatment, if necessary.
  • the reductive N-methylation reaction is carried out preferably at a temperature in the range from 25 to 60°C, more preferably at a temperature in the range from 38 to 55°C, for example 50 to 55°C.
  • the reaction mass is cooled or allowed to cool, preferably to room temperature or below.
  • aqueous alkali solution is added to the reaction mass, which then forms an aqueous phase and an organic phase.
  • aqueous sodium hydroxide or aqueous potassium hydroxide, or a mixture thereof is used.
  • the aqueous alkali solution is sodium hydroxide solution, more preferably 20-50% sodium hydroxide solution, and in particular 30% sodium hydroxide solution.
  • the aqueous layer is separated, and may be removed from the organic layer.
  • the organic layer is preferably filtered, e.g. through a polishing filter, and is then heated to a temperature in the range from 25 to 40°C, preferably in the range from 38 to 40°C.
  • water is then added gradually to the separated organic phase at a temperature in the range from 25 to 40°C, more preferably at a temperature in the range from 38 to 40°C.
  • a base may be added, as described in more detail forther below. If the organic solvent medium is acetone, the water is added preferably in a volume ratio of from 1 : 1 to 2 : 1, more preferably in a volume ratio of 3 : 2, with respective to the acetone.
  • the water is added gradually as two or three portions, preferably as two portions.
  • the first portion of water may be added, preferably at 38-40°C, over a period of for example 30 minutes to 2 hrs, and preferably over a period of about 1 hour.
  • acetone is used as the organic solvent
  • the first portion of water added is preferably in a volume ratio of 0.20 : 1 to 0.25 : 1, with respect to the acetone employed. If the first portion of water used is ⁇ 0.2 : 1 of acetone, the crystallization is not sufficiently induced.
  • the first portion of water used is >0.25 : 1
  • premature precipitation takes place and furnishes a hygroscopic product.
  • the mixture is maintained to allow the formation of crystals.
  • the mixture is stirred during this time.
  • the mixture is preferably maintained at the same temperature, for example for 1 to 5 hours, preferably for 1.5 to 4 hours, and more preferably for about 2 hours, to allow abundant formation of crystals.
  • the mixture may optionally be seeded with azithromycin dihydrate.
  • the second portion of water is then added. If acetone is used as the organic solvent, the second portion is preferably in a volume ratio of 1.25 : 1 to 1.3 : 1, with respect to the acetone.
  • the second portion of water is added, preferably at 38-40°C, over a period of for example 1 to 4 hours, in particular over a period of about 2 hours.
  • the mixture is maintained at a temperature in the range from 25 to 40°C, more preferably at a temperature in the range from 30 to 40°C, and most preferably at a temperature in the range from 38 to 40°C.
  • Higher temperatures t ' .e. more than 40°C may lead to degradation products, whereas temperatures lower than 25 °C may speed up the formation of the product, resulting in hygroscopic material.
  • the mixture After addition of the second portion of water, the mixture is maintained at the temperature over a period of for example 6 to 12 hours, preferably 8 to 12 hours, more preferably 8 to 10 hours, for completion of crystallization process. Crystallisation cycle times of longer than 12 hours do not provide any advantages whereas times less than 6 hours may give lower yields.
  • the mixture is stirred during this time.
  • a base is added to the organic phase in addition to water.
  • the base may be added separately from or together with the water, and, if the water is added in two or more portions, is preferably added only after the first water portion has been added, e.g. together with only the second water portion.
  • the base is preferably aqueous sodium hydroxide, aqueous potassium hydroxide or liquor ammonia (ammonium hydroxide), and most preferably is liquor ammonia.
  • a base such as liquor ammonia helps to improve the yield.
  • the base may be added in such amount as to provide a pH in the range from 9.5 to 11, preferably 9.7 to 10.5, for the mixture.
  • the quantity of liquor ammonia used is 0.1% w/v to 0.2% w/v with respect to azaerythromycin A input.
  • the slightly enhanced yields obtainable when a base such as liquor ammonia is added may be due to the slight increase in the pH of the crystallization medium, i.e. to ⁇ 10.0 pH, effected by the base. In the absence of added base, the pH would be in the range of- 9.0 to 9.5. Since a more basic pH of the medium decreases the solubility of azithromycin, the yields are comparatively higher. However, an excessive amount of added base such as ammonia would produce a hygroscopic product.
  • the acetone should be added in a volume ratio ofat least 2.5 : 1, and preferably is present in a volume ratio of from 2.5 : 1 to 4: 1, more preferably 3 : 1, with respective to the initial azaerythromycin A input.
  • the reaction medium is preferably washed with aqueous alkali, such as sodium hydroxide solution, before the solvent is distilled off.
  • the mixture is preferably cooled or allowed to cool, e.g. to 10 to 15°C, and may be maintained at the cooling temperature for a period, for example for 1 to 3 hours.
  • the crystals are then recovered, preferably by filtration, and are preferably washed, e.g. with water.
  • the crystals are dried, preferably under vacuum, and preferably at a temperature in the range from 40 to 60°C, more preferably in the range from 45 to 50°C.
  • the drying is preferably completed when the crystals attain a moisture content in the range from 4.5 to 5%.
  • acetone is used as the organic solvent medium
  • the reductive N-methylation reaction is carried out at 50-55°C
  • the reaction mixture is stirred with a 30% aqueous solution of sodium hydroxide.
  • the bottom aqueous layer is separated, and the top acetone layer, containing the product, is then filtered, e.g. through a polishing filter, and heated to 38-40°C.
  • azithromycin dihydrate as made above, is stable and water content (KF) value is around 4.6 - 4.7%, with a melting point of 129-130°C (129.94°C by DSC, as shown in Figure 1) with characteristic infra-red (KBr) absorption values (as shown in Figure 2) and X-ray diffraction pattern (as shown in Figure 3).
  • KF water content
  • EXAMPLE 1 lOOg (0.136g moles) of azaerythromycin A was dissolved in 300mL of acetone under stirring at room temperature.
  • Formic acid 85%, 15.6g, 0.288g moles
  • formaldehyde solution 37%, 14.10g, 0.1737g moles
  • the mixture was then cooled to room temperature and stirred with 16mL of 30% aqueous NaOH solution.
  • the aqueous layer was separated and acetone layer containing material was filtered through polishing filter and the clear filtrate was heated to 38 to 40°C.
  • the first portion of water (70mL) was added to this in about 1 hr maintaining a temperature of 38 to 40°C followed by stirring for 2hrs at the same temperature to allow abundant formation of crystals.
  • the second portion of water (380mL) was then added in about 2 hrs and thereafter maintained for 8-10 hrs at 38-40°C.
  • the resulting crystals were cooled to 10 to 15°C, maintained for 2hrs and recovered by filtration.
  • the crystals were washed with 50mL X 2 of chilled water and dried under vacuum at 45 to 50°C till constant weight furnishing 80gms of azithromycin dihydrate in 80% w/w yield from azaerythromycin A (74.9% of theoretical) with a moisture content of 4.7%.
  • EXAMPLE 2 Example 1 was repeated except that the second portion of water used in the crystallization process contained lOmL of liq. ammonia (i.e. 370mL of water + lOmL of liq. ammonia). Thus, 82g of azithromycin dihydrate was obtained in 82% w/w yield from azaerythromycin A (76.7% of theoretical).
  • EXAMPLE 3 lOOg (0.136g moles) of azaerythromycin A was dissolved in 400mL of chloroform under stirring at room temperature. Formic acid (85%, 15.6g, 0.288g.
  • Example 4 The procedure described in Example 3 was repeated but using methylene dichloride as a solvent during the reaction (20 hrs / reflux conditions) to fornish 80g of azithromycin dihydrate in 80% w/w yield from azaerythromycin A (74.9% of theoretical).
  • EXAMPLE 5 lOOg (0.136g moles) of azaerythromycin A was dissolved in 400mL of chloroform under stirring at room temperature.
  • the aqueous layer cool to 25-30°C and adjust the aqueous layer pH to 9.5 -10.00 by using 30% aqueous NaOH solution.
  • the resulting solid was extracted with chloroform.
  • the chloroform layer was washed with 100 ml water. Chloroform layer dried over anhydrous magnesium sulphate and distilled off completely under reduced pressure till dryness. This was forther chased with lOOmL of acetone till dryness.
  • the residual product was cooled to room temperature and dissolved in 300mL of acetone and the resulting solution was filtered through polishing filter and crystallization was carried out as per the procedure given in Example 1 to get 78g of azithromycin dihydrate in 78% w/w from azaerythromycin A (73% of theoretical).

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Abstract

L'invention concerne une méthode directe de préparation d'un dihydrate d'azithromycine antibiotique semi-synthétique (non-hygroscopique), qui s'effectue en une seule étape par une N-méthylation réductrice d'azaerythromycine A et une cristallisation subséquente à partir d'un mélange d'acétone et d'eau, de préférence avec une quantité catalytique d'une base telle qu'une liqueur ammoniacale. La méthode consiste à: mettre en réaction l'azaerythromycine A (c.-à-d. l'azithromycine); b) ajouter à la masse de réaction une solution alcaline aqueuse pour former une phase aqueuse et une phase organique; c) i) si le milieu de solvant organique est l'acétone, séparer la phase aqueuse de la phase organique d'acétone et éliminer la phase aqueuse; ou ii) si le milieu de solvant organique est un solvant autre que l'acétone; séparer la phase aqueuse de la phase organique et éliminer la phase aqueuse, laver éventuellement la phase organique séparée avec une solution alcaline aqueuse, éliminer complètement par distillation le solvant de la phase organique pour laisser un résidu, et ajouter de l'acétone pour dissoudre le résidu et former une phase organique d'acétone; d) ajouter de l'eau, et éventuellement une base, à la phase organique d'acétone pour former un mélange; et permettre la formation de cristaux dans le mélange; e) récupérer les cristaux du mélange et les laver éventuellement; f) sécher les cristaux pour obtenir un dihydrate d'azithromycine non-hygroscopique, avec un rendement de qualité pharmaceutique acceptable peut atteindre 78 à 82 % en poids.
PCT/IN2004/000187 2003-07-03 2004-06-28 Methode de preparation d'un dihydrate d'azithromycine non-hygroscopique WO2005003144A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006132486A1 (fr) * 2005-06-08 2006-12-14 Hanmi Pharm. Co., Ltd. Monohydrate de l-malate d'azithromycine cristallin et composition pharmaceutique le contenant
US8106111B2 (en) 2009-05-15 2012-01-31 Eastman Chemical Company Antimicrobial effect of cycloaliphatic diol antimicrobial agents in coating compositions
CN104910222A (zh) * 2015-06-29 2015-09-16 石药集团欧意药业有限公司 阿奇霉素新晶型化合物及其制备方法
CN105030704A (zh) * 2015-06-29 2015-11-11 石药集团欧意药业有限公司 阿奇霉素片剂及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4517359A (en) * 1981-03-06 1985-05-14 Sour Pliva Farmaceutska, Kemijska Prehrambena I Kozmeticka Industrija, N.Sol.O. 11-Methyl-11-aza-4-0-cladinosyl-6-0-desosaminyl-15-ethyl-7,13,14-trihydroxy-3,5,7,9,12,14-hexamethyl-oxacyclopentadecane-2-one and derivatives thereof
EP0298650A2 (fr) * 1987-07-09 1989-01-11 Pfizer Inc. Dihydrate de l'azithromycine
EP0827965A2 (fr) * 1996-07-11 1998-03-11 Astur-Pharma, S.A. Synthèse de 9-déoxo-9a-aza 11,12-déoxy-9a-méthyl-9a-homoérythromycin A 11,12-hydrogenorthoborate dihydrate
EP0941999A2 (fr) * 1998-03-13 1999-09-15 Hovione Inter Ltd. Préparation de dihydrate d'azithromycine
US20010047089A1 (en) * 2000-01-04 2001-11-29 Judith Aronhime Preparation method of azithromycin dihydrate

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN190080B (fr) * 2001-01-29 2003-06-07 Alembic Ltd

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4517359A (en) * 1981-03-06 1985-05-14 Sour Pliva Farmaceutska, Kemijska Prehrambena I Kozmeticka Industrija, N.Sol.O. 11-Methyl-11-aza-4-0-cladinosyl-6-0-desosaminyl-15-ethyl-7,13,14-trihydroxy-3,5,7,9,12,14-hexamethyl-oxacyclopentadecane-2-one and derivatives thereof
EP0298650A2 (fr) * 1987-07-09 1989-01-11 Pfizer Inc. Dihydrate de l'azithromycine
EP0827965A2 (fr) * 1996-07-11 1998-03-11 Astur-Pharma, S.A. Synthèse de 9-déoxo-9a-aza 11,12-déoxy-9a-méthyl-9a-homoérythromycin A 11,12-hydrogenorthoborate dihydrate
EP0941999A2 (fr) * 1998-03-13 1999-09-15 Hovione Inter Ltd. Préparation de dihydrate d'azithromycine
US20010047089A1 (en) * 2000-01-04 2001-11-29 Judith Aronhime Preparation method of azithromycin dihydrate

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006132486A1 (fr) * 2005-06-08 2006-12-14 Hanmi Pharm. Co., Ltd. Monohydrate de l-malate d'azithromycine cristallin et composition pharmaceutique le contenant
AU2006255914B2 (en) * 2005-06-08 2009-09-03 Hanmi Pharm. Co., Ltd. Crystalline azithromycin L-malate monohydrate and pharmaceutical composition containing same
US8106111B2 (en) 2009-05-15 2012-01-31 Eastman Chemical Company Antimicrobial effect of cycloaliphatic diol antimicrobial agents in coating compositions
CN104910222A (zh) * 2015-06-29 2015-09-16 石药集团欧意药业有限公司 阿奇霉素新晶型化合物及其制备方法
CN105030704A (zh) * 2015-06-29 2015-11-11 石药集团欧意药业有限公司 阿奇霉素片剂及其制备方法

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