WO2011125069A1 - Procédé de préparation de la forme cristalline i du bisulfate de clopidogrel - Google Patents

Procédé de préparation de la forme cristalline i du bisulfate de clopidogrel Download PDF

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Publication number
WO2011125069A1
WO2011125069A1 PCT/IN2011/000179 IN2011000179W WO2011125069A1 WO 2011125069 A1 WO2011125069 A1 WO 2011125069A1 IN 2011000179 W IN2011000179 W IN 2011000179W WO 2011125069 A1 WO2011125069 A1 WO 2011125069A1
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Prior art keywords
clopidogrel
bisulfate
crystalline form
temperature
free base
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PCT/IN2011/000179
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English (en)
Inventor
Anita Ranjan Srivastava
Yuvraj Suresh Sonar
Ranjan Prasad Srivastava
Krishna Anand Poojari
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Rpg Life Sciences Limited
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Publication of WO2011125069A1 publication Critical patent/WO2011125069A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for preparation of crystalline Form I of clopidogrel bisulfate also known as clopidogrel hydrogen sulfate or hydrogen sulfate of methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate and crystalline Form I of clopidogrel bisulfate produced thereby.
  • the present invention relates to a process for preparation of highly0 pure crystalline Form I of clopidogrel bisulfate having melting point of 180 to 185°C, chiral purity of >99% by HPLC, preferably 99.5% by HPLC with optical rotation ([ ] D 20 ) of +55° to 56°, preferably +55.4° (1.89 g/100 ml; Methanol) and crystalline Form I of clopidogrel bisulfate produced thereby.
  • the clopidogrel bisulfate also known as bisulfate of methyl (+)-(S)- a-(2- chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate in crystalline Form I is known to be platelet aggregation inhibitor.
  • clopidogrel bisulfate was prepared by precipitation by action of corresponding acid on the base either in a solution of a solvent from which it could be precipitated spontaneously or by addition of non-solvent (anti-solvent), and the ideal solvent suggested was acetone.
  • the US'210 discloses process to prepare clopidogrel hydrogen sulfate Form II, but simultaneously clopidogrel hydrogen sulfate Form I is also formed.
  • the US'210 confirms that Form II is thermodynamically more stable as compared to Form I of clopidogrel hydrogen sulfate, which means that over a period of time, Form I is more likely to be converted to Form II of clopidogrel hydrogen sulfate, and/or at least the process to prepare Form I is less likely to be reproducible and/or at least the process to prepare Form I is likely to result in Form I, but to be contaminated with Form II.
  • the US'210 also confirms that any attempt of crystallization of clopidogrel hydrogen sulfate from a solvent may result in formation of Form I as per US'265 or in formation of Form II. Therefore, from teachings of US'210, it may be concluded that if crystalline form of Form I of clopidogrel hydrogen sulfate is not formed "directly" during the process of its preparation, then any attempt to crystallize these is more likely to result in formation of Form II as well, meaning thereby, Form I prepared by process of preparation of clopidogrel hydrogen sulfate involving crystallization step is more likely to be contaminated by its Form II, because of its greater thermodynamic stability, and hence, resulting in rejection thereof.
  • Form I prepared in accordance with methods of US'210 was found to have a melting point varying from 181°C to 187°C (184 ⁇ 3°C), which itself indicates that Form I formed even by methods of US'210 is not pure.
  • Form I of clopidogrel hydrogen sulfate as per method of US'210 they found that Form I is contaminated with Form II as the compound prepared was found to have melting point varying from 176-177°C for product prepared as per Experiment I B, and varying from 177-178°C for product prepared as per Experiment 1C.
  • WO2004/020443 [PCT'49]
  • This application proposes crystallization of Form I from solvents selected from C 1 -C5 alcohols, particularly iso-propanol, or their esters, particularly n-butyl acetate, optionally combination thereof, particularly combination of iso-propanol and n-butyl acetate.
  • Form I of clopidogrel hydrogen sulfate without detectable impurity of Form II by dissolving clopidogrel base in iso- propanol then cooling to 0 to -5°C or only upto 0°C followed by addition of concentrated sulphuric acid while stirring for about 2.5 hours.
  • Form I of clopidogrel hydrogen sulfate without detectable impurity of Form II by dissolving clopidogrel base in n-butyl acetate then cooling to 0 to +5°C in a water-and-ice bath followed by addition of concentrated sulphuric acid by allowing temperature to rise upto +5°C.
  • pre-condition of inoculation that's too twice with crystals of Form I not only elongates overall duration of process, that is makes it highly time consuming, but also adds-on additional steps, and hence, makes it more complex process.
  • the inventors of present invention have found that when an attempt to prepare Form I of clopidogrel hydrogen sulfate was made in accordance with method of US'735 and US'453 by dissolving the clopidogrel base in ethyl acetate at room temperature and seeding with crystals of Form I of clopidogrel hydrogen sulfate followed by addition of concentrated sulfuric acid at room temperature a sticky mass is formed which makes it very difficult not only to stir the reacting mixture, but also makes it difficult to crystallize and separate Form I of clopidogrel hydrogen sulfate.
  • the step of seeding with crystals of Form I of clopidogrel hydrogen sulfate is not only expected to increase process step and cost of process but is also expected to formation of Form II of clopidogrel hydrogen sulfate due to its greater thermodynamical stability.
  • the another object of present invention is to provide a process to prepare dextrorotatory crystalline Form I of clopidogrel hydrogen sulfate without contamination of Form II.
  • FIG. 1 illustrates Fourier Transform Infrared (FTIR) Spectra of crystalline
  • FIG. 2 illustrates Powder X Ray Diffractogram (PXRD) of crystalline Form I of clopidogrel bisuifate as prepared in accordance with present invention.
  • FIG. 3 illustrates Differential Scanning Calorimetry (DSC) spectra of crystalline Form I of clopidogrel bisuifate as prepared in accordance with present invention.
  • the present invention relates to process for preparation of crystalline Form I of clopidogrel bisulfate comprising steps of:- a) preparing clear solution of clopidogrel free base in ethyl acetate at room temperature;
  • step - a) cooling clear solution of step - a) to a temperature varying from about -7 to about -10°C;
  • step - b) adding concentrated sulphuric acid to cooled solution of step - b) while maintaining said temperature varying from about -7 to about -10°C while stirring it for additional about 30 min to 1 hr, and a care is taken that said temperature of reacting mass does not go beyond about -7°C;
  • step - c) slowly warming the reaction mass of step - c) to room temperature;
  • step - d) heating to reflux the reaction mass of step - d) to a temperature of about 70 to 80°C under constant stirring and maintained at this temperature for upto about 2 hr;
  • step f) cooling the reaction mass of step - e) to room temperature while stirring, which is continued upto about 1 hr, and which on filtration, washing and vacuum drying results in crystalline Form 1 of clopidogrel bisulfate.
  • step - d) of slowly warming the reaction mass of step - c) to room temperature is completed in about 1 hr.
  • step - e) of heating to reflux the reaction mass of step - d) to a temperature of about 70 to 80°C under constant stirring is completed in about 2 hrs, preferably in about 1 hr.
  • step - f) of cooling the reaction mass of step - e) to room temperature is completed in about 1 hr.
  • the crystalline Form 1 of clopidogrel bisulfate produced by method of present invention has been found to have FTIR spectrum as illustrated in accompanying Figure 1, which was recorded on a Perkin-Elmer Paragon- 1000 FTIR using a KBr pellet.
  • the crystalline Form 1 of clopidogrel bisulfate produced by method of present invention has been found to have PXRD as illustrated in accompanying Figure 2, which was recorded on SHIMADZU model XRD 6000 defractometer with Cu k alpha Radiation source.
  • the characteristic peaks with 2 Theta (2 ⁇ ), d spacing and Intensity (I/Io) values are described in following Table - 2.
  • the enclosed PXRD having above peaks confirms formation of Form I of clopidogrel bisulfate having polymorphic purity of more than 99%.
  • the absence of peaks at 2Theta 8.797 and 12.89 confirms the absence of Form II of clopidogrel bisulfate.
  • the crystalline Form 1 of clopidogrel bisulfate produced by method of present invention has been found to have DSC spectra as illustrated in accompanying Figure 3, which was recorded on Mettler Toledo, DSC 822. The onset and main peak were observed at 180.24°C and 184.62°C respectively, which confirms formation of Form I of clopidogrel bisulfate having melting point varying from 180°C to 185°C.
  • process of present invention when process of present invention is performed as per above described process steps it, surprisingly and unexpectedly, results in production of crystalline Form 1 of clopidogrel bisulfate in less than 6 hrs, preferably less than 4 hrs after completion of addition of sulphuric acid vis-a-vis of about 10 hrs or more of conventional processes rendering the process of present invention highly time saving
  • the inventors have also observed that when sulphuric acid is added in the manner as described, no sticky mass is formed, and hence, neither stirring problem is observed nor uneven dispersion of formed soft precipitates of clopidogrel bisulfate is observed.
  • the inventors have also observed that when solution after complete addition of sulphuric acid is maintained at said temperature varying from -7 to -10°C for about 30 min to 1 hr, it results in complete conversion of clopidogrel base to Form 1 of clopidogrel bisulfate and clopidogrel bisulfate formed is in the form of precipitates (not crystals).
  • the inventors have also observed that when solution after complete addition of sulphuric acid and stirring for about 30 min to 1 hr is gradually, first, warmed to room temperature, which is, then, heated to reflux to a temperature of about 70 to 80°C under constant stirring and maintained at this temperature for about 1 to 2 hr surprisingly results in separation of crystalline Form I of clopidogrei bisulfate with ease and convenience, and without step of seeding (inoculation) with crystals of Form I of clopidogrei hydrogen sulfate or additional step of crystallization.
  • the step of heating to reflux is performed immediately after warming the reaction mixture to room temperature as otherwise the clopidogrei bisulfate produced gets contaminated with its Form II.
  • the inventors have also observed that when solution after complete addition of sulphuric acid and stirring for about 30 min to 1 hr at said temperature of about -7 to about -10°C is gradually warmed to room temperature it does not disturb soft precipitates formed on addition of concentrated sulphuric acid and the precipitates were found to remain intact, which on heating to reflux results in crystal formation of Form I of clopidogrei bisulfate with ease, and without step of seeding (inoculation).
  • the inventors of present invention have found that if temperature of cooled solution of step - b) during addition of concentrated sulphuric acid is increased beyond about -7°C, not only the isolation of crystalline Form I of clopidogrei bisulfate becomes difficult due to formation of a sticky mass, but its yield also reduces substantially, and the clopidogrei bisulfate produced is also substantially contaminated with its Form II or other forms of clopidogrei bisulfate.
  • the concentrated sulphuric acid is 98% or more pure.
  • the inventors of present invention have observed that if concentrated sulphuric acid is less than 98%, the clopidogrei bisulfate produced is substantially contaminated with its Form II.
  • process of present invention in addition to above-described advantages, is not only simpler, but is also less time consuming, and suitable and economical for large scale production, and also results in formation of crystalline Form I of clopidogrei bisulfate without involving step of seeding (inoculation) with crystals of Form I of clopidogrei hydrogen sulfate or additional step of crystallization, meaning thereby it not only avoids associated drawbacks of inoculation, but is also independent of requirement of product which is yet to be produced by the process, and possibility of formation of Form II of clopidogrel bisulfate is also ruled out, and hence, probability of contamination of Form I with its Form II or other forms of clopidogrel bisulfate is ruled out or at least has been minimized to maximum possible extent.
  • the crystalline Form I of clopidogrel bisulfate as produced by present invention has also been found to be stable as it did not convert to any other form including Form II even in six months from date of its preparation.
  • the clopidogrel free base used in preparation of crystalline Form I of clopidogrel bisulfate of present invention is chemically and optically highly pure having chemical purity of more than 99.0% and optical purity of more than 99.0% and can be prepared by any method.
  • the chemically and optically pure (+)clopidogrel free base is prepared as follows:- a) preparing a clear solution of optically impure (+) clopidogrel free base in acetone;
  • step-a) treating clear solution of step-a) with L (-) camphorsulphonic acid by heating to reflux, which on cooling, filtration, washing and drying results in S(+) clopidogrel camphor- 10-sulphonate salt;
  • step-b) treating S(+) clopidogrel camphor- 10-sulphonate salt of step-b) with aqueous ammonia solution in presence of an organic solvent, preferably n-hexane till pH of 7 is achieved; and
  • L (-) camphorsulphonic acid is added at room temperature of about 25 to 30°C.
  • the clear solution is heated to reflux at a temperature of about 54 to 56°C for about 2 to about 3 hours under constant stirring.
  • the organic (n-hexane) layers of mixture of step-3) are collected after repeated treatments of aqueous layer with organic solvent (n-hexane), which on concentration, drying result in chemically and optically pure (+) clopdigrel base as a colourless oil in substantially higher yield of about 90% or more, preferably of about 94% or more, and purity as accessed by Gas Chromatography (GC) of 99% or more.
  • organic solvent n-hexane
  • the chemically and optically pure (+)clopidogrel free base is prepared by a process comprising steps of:- a) treating chemically and optically pure pharmaceutically acceptable acid addition salt of (+) Clopidogrel with water and n-hexane at about 25 - 30°C under constant stirring;
  • the pharmaceutically acceptable acid addition salt of (+) Clopidogrel is bisulfate salt.
  • the water and n-hexane are taken in equal amounts by volume.
  • the aqueous ammonia solution is about 20 to 30% aqueous ammonia solution. It has been found that this method produces about 97.86 % Molar yield of chemically and optically pure (+) clopidogrel free base with purity of about 99.0% by Gas Chromatography.
  • Clopidogrel free base (800 gm) is taken with 9.6 L of ethyl acetate at room temperature (25 - 30°C) in a cylindrical glass vessel under nitrogen atmosphere and stirred to obtain a clear solution.
  • the clear solution is gradually cooled to a temperature of -8 to -9°C and 248.8 gm of concentrated sulphuric acid (98%) is added slowly at said temperature of -8 to -9°C with agitation at preferred rate.
  • the reaction mixture is continuously stirred at said temperature of -8 to -9°C for 45 minutes, and then warmed to room temperature (25 to 30°C), and then heated to reflux at about 75°C under constant stirring and maintained at this temperature for 1 hr, and the reaction mixture is then cooled to 25 to 30°C with continuous stirring for one hour.
  • Example-2 Preparation of chemically and optically pure (+) clopidogrel base to be used for preparation of crystalline Form I of clopidogrel bisulfate: A] Preparing S(+) clopidogrel camphor-10-sulphonate salt:-
  • Example-3 Preparation of chemically and optically pure (+) clopidogrel free base to be used for preparation of crystalline Form I of clopidogrel bisulfate (Alternate route):

Abstract

La présente invention concerne un procédé de préparation de la forme cristalline I du bisulfate de clopidogrel, comprenant les étapes consistant à préparer une solution claire de la base libre du clopidogrel dans de l'acétate d'éthyle, à la faire refroidir jusqu'à une température variant d'environ -7 à environ -10 °C, puis à la faire réagir avec de l'acide sulfurique concentré à la même température. Le tout est ensuite lentement réchauffé jusqu'à température ambiante, puis chauffé à reflux, avant d'être à nouveau refroidi jusqu'à température ambiante, filtré, lavé et séché sous vide pour donner la forme cristalline I du bisulfate de clopidogrel.
PCT/IN2011/000179 2010-03-22 2011-03-18 Procédé de préparation de la forme cristalline i du bisulfate de clopidogrel WO2011125069A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102432625A (zh) * 2011-11-05 2012-05-02 江南大学 一种制备高纯度i型氯吡格雷硫酸氢盐的结晶方法
CN102875568A (zh) * 2012-09-06 2013-01-16 苏州晶云药物科技有限公司 制备(+)-(s)-氯吡格雷硫酸氢盐纯晶型i的方法
CN104610274A (zh) * 2013-11-05 2015-05-13 亚宝药业集团股份有限公司 一种i型氯吡格雷硫酸氢盐的制备方法
KR20160142578A (ko) 2015-06-03 2016-12-13 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102432625A (zh) * 2011-11-05 2012-05-02 江南大学 一种制备高纯度i型氯吡格雷硫酸氢盐的结晶方法
CN102875568A (zh) * 2012-09-06 2013-01-16 苏州晶云药物科技有限公司 制备(+)-(s)-氯吡格雷硫酸氢盐纯晶型i的方法
CN104610274A (zh) * 2013-11-05 2015-05-13 亚宝药业集团股份有限公司 一种i型氯吡格雷硫酸氢盐的制备方法
KR20160142578A (ko) 2015-06-03 2016-12-13 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법

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