WO2014092589A1 - Procédé de préparation d'une forme polymorphe b de chlorhydrate de prasugrel de pureté pharmaceutique - Google Patents

Procédé de préparation d'une forme polymorphe b de chlorhydrate de prasugrel de pureté pharmaceutique Download PDF

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Publication number
WO2014092589A1
WO2014092589A1 PCT/PL2013/000164 PL2013000164W WO2014092589A1 WO 2014092589 A1 WO2014092589 A1 WO 2014092589A1 PL 2013000164 W PL2013000164 W PL 2013000164W WO 2014092589 A1 WO2014092589 A1 WO 2014092589A1
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WIPO (PCT)
Prior art keywords
prasugrel
process according
polymorphic form
group
organic solvent
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PCT/PL2013/000164
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English (en)
Inventor
Marcin Cybulski
Wioleta Maruszak
Adam Formela
Kinga TRZCIŃSKA
Anna WITKOWSKA
Magdalena BODZIACHOWSKA-PANFIL
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Instytut Farmaceutyczny
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Publication of WO2014092589A1 publication Critical patent/WO2014092589A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to the process for preparation of prasugrel hydrochloride polymorphic form B of pharmaceutical purity.
  • Prasugrel 5-[2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate, is a P2Y12 inhibitor of ADP-induced platelet aggregation. It is indicated for the reduction of thrombotic cardiovascular events in patients with acute coronary syndromes managed with percutaneous coronary intervention (PCI), when managed with primary or delayed PCI.
  • PCI percutaneous coronary intervention
  • Hydrochloric acid addition salt of 5-[2-Cyclopropyl-l-(2-fluorophenyl)-2- oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate is the active ingredient of Effient® tablets.
  • Prasugrel hydrochloride has been claimed in EP 1 298 132 Bl as the substance exhibiting excellent oral absorption, activity in inhibition of platelet aggregation after being metabolized into the active substance, low cytotoxicity, and excellent handling and storage stability.
  • Crystalline form Gl was obtained by dissolving prasugrel hydrochloride in a solvent or in the solvents mixture selected from a group comprising methyl alcohol, dichloromethane, ethyl acetate, isobutyl acetate, acetonitrile, THF, 1,4-dioxane or the mixture thereof with water, followed by the solid precipitation induced by non-polar anti-solvent addition, wherein anti-solvent was selected from a group including, inter alia, n-hexane, n-heptane, cyclohexane, toluene or the mixtures thereof.
  • Crystalline form G2 was obtained under similar conditions, i.e. by dissolving prasugrel hydrochloride in a solvent or in a mixture of solvents selected from a group comprising methyl alcohol, ethanol, isopropanol, dichloromethane, ethyl acetate, isobutyl acetate, acetonitrile, THF, 1,4-dioxane or the mixture thereof with water and adding anti-solvent selected from the group comprising n-hexane, n-heptane, cyclohexane, toluene or the mixture thereof.
  • crystalline form G2 was obtained by the addition of hexane as anti-solvent to the solution of prasugrel hydrochloride in isopropyl alcohol under reflux.
  • polymorphic form Bl and B2 The differences of diffraction angle 20 values of polymorphic form Bl and B2 (recalculated from interplanar distance d values), and polymorphic form D and E are at the error range ( ⁇ 0,2°), acceptable by the European Pharmacopoeia and prove the identity of those four crystalline forms, which will be denominated under the common name as polymorphic form B through the following description.
  • prasugrel hydrochloride can exist in two polymorphic forms: A and B, amorphous form and as the solvate with acetonitrile, which was disclosed in EP 2 145 890 B.
  • form B shows the highest stability under thermal and photolytical degradation conditions as well as the lowest hygroscopicity. Considering these physicochemical properties, form B only meets the requirements for active substance to be used in an output of solid oral dosage forms of the pharmaceutical products.
  • crystalline prasugrel hydrochloride may be obtained following standard methodology, comprising the addition of equimolar or small molar excess of concentrated aqueous solution (c.a. 36%) of hydrochloric acid, or gaseous hydrochloride or its solution in organic solvent to prasugrel base or its salt dissolved in organic solvent. Addition of anti-solvent, like for example ether, may be necessary to induce precipitation of the product.
  • WO 2011/069473 discloses synthesis of prasugrel hydrochloride containing low level of impurities.
  • Prasugrel base dissolved or suspended in organic solvent is treated with hydrochloric acid dissolved in organic solvent or water, and resulting product crystallizes, optionally due to addition of co-solvent, such as acetic acid ester, preferably ethyl or isopropyl acetate.
  • co-solvent such as acetic acid ester, preferably ethyl or isopropyl acetate.
  • prasugrel hydrochloride polymorphic form B thus obtained is higher than 99.6% and the content of deacetylation product, (5-[2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]- 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-on), is below 0.1%.
  • prasugrel hydrochloride polymorphic form B is obtained without addition of seed crystals.
  • Protic solvents allowing generation of hydrochloride from trialkylsilyl chloride are aliphatic and aromatic alcohols, silanoles, ketones undergoing enolization or carbonic acids.
  • Aprotic solvents such as for example, esters, nitriles, ethers, chlorinated and aromatic solvents and alkanes are not susceptible to silylation and are used to dissolve or suspend amine and enable crystallization of favorable crystalline form.
  • the preferred aprotic solvent is acetone and acetic acid is used as protic solvent.
  • the authors of the present invention have solved this problem, running the addition reaction of hydrogen chloride to prasugrel base under non-hydrolytic conditions, in presence of some amount of polar solvent, such as methyl alcohol, and seed crystals of prasugrel hydrochloride polymorphic form B to induce nucleation of expected crystalline form B.
  • polar solvent such as methyl alcohol
  • prasugrel hydrochloride crystallization depends not only on addition of methyl alcohol and seed crystals of form B, but it is also strongly influenced by the mixture of solvents used in addition reaction and crystallization.
  • the selective crystallization of prasugrel hydrochloride of expected and pharmaceutically accepted polymorphic form B is favored in the mixtures of solvents at particular compositions. Exemplary solvents mixtures are collected in Table 1.
  • IPA propan-2-ol
  • polymorphic form A is obtained.
  • polymorphic form A containing some amount of expected form B is formed. It has been observed, that concomitant addition of methyl alcohol and form B seed crystals results in crystallization of pure polymorphic form B, free of detectable impurities (including polymorphic form A co-crystals) and amorphous inclusions.
  • Pure polymorphic form B is obtained in the mixture of acetone / methyl tert-butyl ether and ethyl acetate / methyl tert-butyl ether, among others. Using the same mixtures of solvents but altering reaction conditions, obtained prasugrel hydrochloride crystals do not meet demands of polymorphic purity.
  • the term 'pure prasugrel hydrochloride polymorphic form B' relates to the substance in polymorphic form B free of other polymorphic or pseudo-polymorphic impurities at amounts detected by routinely used analytical methods, such as X-ray powder diffraction and infrared absorption, ie. including less than 2%, preferably less then 1% of other polymorphic forms contaminations.
  • 'pure prasugrel hydrochloride polymorphic form B' refers to the substance of chemical purity, evaluated, for example, by high performance liquid chromatography (HPLC), that is higher than 99%, preferably higher than 99.5%.
  • HPLC high performance liquid chromatography
  • Process for preparation of prasugrel hydrochloride polymorphic form B of pharmaceutical purity comprises the steps of:
  • organic solvent selected from group I is acetone.
  • the other organic solvent selected from the group I is ethyl acetate.
  • organic solvent selected from group I of ketones or aliphatic esters is used as the first solvent, preferably, to the reaction mixture anti-solvent, selected from group II of aliphatic or cyclic ethers is added to facilitate precipitation of the product.
  • organic solvent selected from group II of aliphatic or cyclic ethers is methyl tert-butyl ether.
  • Seed crystals of polymorphic form B are added at amount of 1-5% by weight in relation to prasugrel base.
  • prasugrel base in acetone 1-2% (by volume in relation to acetone amount) of methyl alcohol, 1-5% (by weight in relation to prasugrel base used) of seed crystals of prasugrel hydrochloride form B, 1 - 1.1 molar equivalent of hydrogen chloride in methyl tert-butyl ether and finally methyl tert-butyl ether as anti-solvent, are added.
  • the reaction mixture is stirred at room temperature until crystallization process is completed.
  • the crystalline product is separated by means of one of routinely used methods, for example, filtration, decantation or solvent evaporation. Then, obtained crystals are washed with inert solvent, preferably aliphatic or cyclic ether.
  • the crystalline product thus obtained is dried to the constant weight under reduced pressure at 30-50°C, preferable at 40°C.
  • Acid addition reaction yields prasugrel hydrochloride polymorphic B, crystals of which are of irregular shape and tend to agglomerate. Crystals obtained in different batches are characterized by volume moment mean (De Broucker mean) D[4,3] at 45-50 ⁇ ⁇ ⁇ range and d(0.9) of about 90 ⁇ . On account of the product properties, usually during the attempts to reduce, by simple drying, content of the residual solvents to the level accepted by ICH guidelines, some difficulties are met.
  • process for preparation of prasugrel hydrochloride of pharmaceutical purity can be achieved, preferably, due to obtaining crystals of uniform particle size, reducing volume moment mean D[4,3] to less than 10 ⁇ , more preferably less than 5 ⁇ .
  • the substance of demanded pharmaceutical purity can be obtained due to drying prasugrel hydrochloride to the constant weight under reduced pressure, at 30-50°C, preferable at 40°C, followed by micronization to obtain volume moment mean D[4,3] less than 10 ⁇ , more preferably less than 5 ⁇ , and additional drying.
  • Fig. 4A - before pre-drying Characteristic microscopic images of prasugrel hydrochloride crystals obtained according to the present invention are depicted on Fig. 4A - before pre-drying, Fig. 4B - before micronization, and Fig. 4C - after micronization.
  • prasugrel hydrochloride obtained according to the present invention after micronization has volume moment mean D[4,3] at 2.00 - 3.50 ⁇ range and d(0.5) at 0.18-0.20 ⁇ range, 10% of particles have size below 0.10 ⁇ (d(0.1) ⁇ 0.10 ⁇ ⁇ ⁇ ), and 90% below 5.00 ⁇ (d(0.9) ⁇ 5.00 ⁇ ).
  • Fig. 6 Exemplary X-ray powder XRPD pattern of prasugrel hydrochloride obtained according to the present invention is depicted on Fig. 6.
  • the present invention provides the preparation method of prasugrel hydrochloride polymorphic form B, which is stable and contains impurities and residual solvents at the level meeting the demands for active pharmaceutical ingredients.
  • X-ray powder XRPD patterns were recorded on X-ray powder diffractometer type MiniFlex by Rigaku, with the following parameters:
  • TGA curve represents the changes of a sample mass as a function of temperature or time.
  • the effects of solvent evaporation and a substance melting are shown.
  • Feeder 240° C, carrier gas - nitrogen (100 kPa), split 5 : 1, sensitivity -5
  • Particle size distribution was measured by laser diffraction method with particle size distribution analyzer Mastersizer 2000, Malvern and dispersion adapter Hydro 2000S, Malvern. Microscopic visualization was performed with automated microscopic analyzer Morphologi G3s Malvern in diascopic light.
  • the crystalline solid was micronized in a jet mill and dried at 40°C under reduced pressure for 5 h.
  • Prasugrel hydrochloride form B was obtained as white crystals (yield 0,83 g, 76%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne un procédé de préparation d'une forme polymorphe B de chlorhydrate de prasugrel de pureté pharmaceutique, ledit procédé étant caractérisé en ce qu'une réaction d'addition d'une base de prasugrel et de chlorhydrate est mise en œuvre dans un solvant organique choisi dans le groupe constitué par des cétones, un ester aliphatique et des éthers aliphatiques ou cycliques, conjointement avec l'addition d'alcool méthylique à hauteur de 0,1 à 10 % en volume par rapport au volume de solvant utilisé dans la réaction, et de germes cristallins de la forme polymorphe B du chlorhydrate de prasugrel.
PCT/PL2013/000164 2012-12-12 2013-12-12 Procédé de préparation d'une forme polymorphe b de chlorhydrate de prasugrel de pureté pharmaceutique WO2014092589A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL402028A PL402028A1 (pl) 2012-12-12 2012-12-12 Sposób wytwarzania postaci polimorficznej B chlorowodorku prasugrelu o czystości farmaceutycznej
PLP.402028 2012-12-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105669696A (zh) * 2014-11-21 2016-06-15 四川海思科制药有限公司 一种盐酸普拉格雷化合物
CN112898359A (zh) * 2019-12-03 2021-06-04 晨光生物科技集团股份有限公司 一种低溶残晶体的制备方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1298132B1 (fr) 2000-07-06 2006-11-22 Sankyo Company, Limited Sels d'addition acides de d riv s hydropyridine
EP2003136A1 (fr) 2006-04-06 2008-12-17 Daiichi Sankyo Company, Limited Procede de production de prasugrel de grande purete et sel d'addition d'acide de celui-ci
WO2009062044A2 (fr) 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Procédés de préparation de prasugrel et ses sels et polymorphes
EP2145890A2 (fr) 2006-06-27 2010-01-20 Sandoz AG Cristallisation d'hydrohalogénures de composés pharmaceutiques
WO2010070677A2 (fr) 2008-12-15 2010-06-24 Glenmark Generics Limited Procédé de préparation de prasugrel et de ses sels pharmaceutiquement acceptables
WO2011069473A1 (fr) 2009-12-09 2011-06-16 Zentiva, K.S. Méthode de préparation de chlorhydrate de prasugrel sous sa forme polymorphe b
WO2011117782A1 (fr) 2010-03-23 2011-09-29 Alembic Pharmaceuticals Limited Procédé de préparation du sel hcl de prasugrel
WO2012018791A2 (fr) * 2010-08-06 2012-02-09 Dr. Reddy's Laboratories Ltd. Préparation de chlorhydrate de prasugrel

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1298132B1 (fr) 2000-07-06 2006-11-22 Sankyo Company, Limited Sels d'addition acides de d riv s hydropyridine
EP2003136A1 (fr) 2006-04-06 2008-12-17 Daiichi Sankyo Company, Limited Procede de production de prasugrel de grande purete et sel d'addition d'acide de celui-ci
EP2145890A2 (fr) 2006-06-27 2010-01-20 Sandoz AG Cristallisation d'hydrohalogénures de composés pharmaceutiques
EP2145890B1 (fr) 2006-06-27 2012-08-01 Sandoz AG Cristallisation d'hydrohalogénures de composés pharmaceutiques
WO2009062044A2 (fr) 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Procédés de préparation de prasugrel et ses sels et polymorphes
WO2010070677A2 (fr) 2008-12-15 2010-06-24 Glenmark Generics Limited Procédé de préparation de prasugrel et de ses sels pharmaceutiquement acceptables
WO2011069473A1 (fr) 2009-12-09 2011-06-16 Zentiva, K.S. Méthode de préparation de chlorhydrate de prasugrel sous sa forme polymorphe b
WO2011117782A1 (fr) 2010-03-23 2011-09-29 Alembic Pharmaceuticals Limited Procédé de préparation du sel hcl de prasugrel
WO2012018791A2 (fr) * 2010-08-06 2012-02-09 Dr. Reddy's Laboratories Ltd. Préparation de chlorhydrate de prasugrel

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105669696A (zh) * 2014-11-21 2016-06-15 四川海思科制药有限公司 一种盐酸普拉格雷化合物
CN105669696B (zh) * 2014-11-21 2019-03-26 四川海思科制药有限公司 一种盐酸普拉格雷化合物
CN112898359A (zh) * 2019-12-03 2021-06-04 晨光生物科技集团股份有限公司 一种低溶残晶体的制备方法

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