WO2013144971A1 - Nouvelles formes solides de bisulfate et de mésylate d'étéxilate de dabigatran, et leurs procédés de préparation - Google Patents

Nouvelles formes solides de bisulfate et de mésylate d'étéxilate de dabigatran, et leurs procédés de préparation Download PDF

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WO2013144971A1
WO2013144971A1 PCT/IN2012/000399 IN2012000399W WO2013144971A1 WO 2013144971 A1 WO2013144971 A1 WO 2013144971A1 IN 2012000399 W IN2012000399 W IN 2012000399W WO 2013144971 A1 WO2013144971 A1 WO 2013144971A1
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methyl
imino
pyridin
benzimidazole
hexyloxycarbonylamino
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PCT/IN2012/000399
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English (en)
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Parind Narendrabhai DHOLAKIA
Mayank Ghanshyambhai Dave
Bipin Pandey
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Cadila Healthcare Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is related to preparation of new crystalline and amorphous forms of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate and use thereof.
  • the present invention is also related to a new crystalline form III of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mesylate and processes for the preparation thereof; use thereof and pharmaceutical composition comprising the same.
  • the invention is related to new crystalline and amorphous forms 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methy 1 ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate.
  • WO 2006/114415 discloses hydrochloride, maleate, tartrate, salicylate, citrate and malonate salt of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate.
  • WO 2008/043759 discloses 2,5-dihydroxybenzoate, besylate cyclamate, edisylate, esylate, fumarate, D-glucuronate, glycolte, isethionate, L-malate, D-malate, mandelate, naphthalene- 1,5-disulfonate, naphthalene-2-sulfonate, oxalate, phosphate, propionate, saccharinate, salicylate, succinate, D-tartarate and tosylate salts of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate as well as their hydrates.
  • WO20111180876 disclosed different crystalline form of hydrochloric acid salt, phosphoric acid salt, fumaric acid salt, sulfuric acid salt, maleic acid salt, oxalic acid salt, p-toluenesulphonic acid salt and mesylate salt.
  • the crystalline forms of sulfuric acid salt disclosed are form I, monohydrate form and dihydrate form of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -l-methyl-lH- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate.
  • the present invention satisfies this need by providing novel crystalline and amorphous forms bisulphate salt 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate.
  • This salt shows certain superior pharmaceutical properties as well as efficacious properties compared to 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate (Dabigatran etexilate).
  • the present invention provides new crystalline and amorphous forms of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate which can be used as an intermediate to prepare pure 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate and/or pure 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -l-methyl-lH- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate and/
  • This compound also shows superior efficacy over the 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate from which it is derived.
  • pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline forms that have different arrangements and/or conformations of the molecules in the crystalline lattice. Amorphous solids consist of disordered arrangements of molecules, and do not possess a distinguishable crystal lattice.
  • polymorphs differ in internal solid state structure, and, therefore, possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial, and mechanical properties. These properties can have a direct impact on drug product quality/performance, including stability, dissolution, therapeutic efficacy and bioavailability.
  • the most stable polymorphic form of a drug substance is often used in a formulation because it has the lowest potential for conversion from one polymorphic form to another.
  • metastable and even amorphous forms may be chosen to enhance the bioavailability of the drug product.
  • An amorphous form being a disorganized solid mass, does not need to lose crystal structure before dissolution in the gastric juices, and, thus, often has greater bioavailability than a crystalline form. Further, such forms can be used for obtaining the stable form/marketed form.
  • the aim of the present invention is to provides a new crystalline form III of mesylate salt of compound (I) having advantageous properties for pharmaceutical use.
  • the pharmaceutical substance should also meet up the necessities of using it for the preparation of a pharmaceutical composition and so the compound should consist good physicochemical character to incorporate it in a pharmaceutical composition.
  • the preparation of new crystalline form of active pharmaceutical ingredients provides opportunities to improve the performance characteristics of a pharmaceutical product.
  • Such preparation enlarge the repertoire of materials that formulation scientist have available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic and so the present invention provides new crystalline form III of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate mesylate.
  • WO 1998/37075 discloses l-methyl-2-[N-[4-(N-n- hexyloxycarbonylamidino)phenyl]-aminomethyl]benzimidazol-5-ylcarboxylic acid-N- (2-pyridyl)-N-(2-ethoxy-carbonylethyl)-amide and 3-[(2- ⁇ [4-(hexyloxycarbonylamino- imino-methyl)-pheny lamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)- pyridin-2-yl-amino]-propionate.
  • WO 2003/074056 discloses mesylate salt of 3- [(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -l-methyl-lH- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate.
  • WO 2005/28468 discloses two crystalline form of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -l-methyl-lH- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mesylate namely 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -l-methyl-lH- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mesylate form I and 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5.-carbonyl)-pyridin-2-yl-amino]-propionate mesylate
  • crystalline 3-[(2- ⁇ [4-(hexyloxycarbonylamino- imino-methyl)-phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)- pyridin-2-yl-amino]-propionate mesylate form I has a powder XRD (PXRD) pattern with peaks at 4.4, 8.94, 9.23, 9.55, 10.55, 10.95, 12.73, 13.46, 13.95, 14.26, 15.17, 15.93, 16.46, 17.66, 18.07, 18.60, 19.89, 20.28, 20.54, 21.12, 22.06, 22.85, 24.12, 25.10, 25.99,26.52, 26.83, 27.16, 27.64, 28.09, 29.08, 29.26, 29.94, 31.88, 34.37, 36.21, 38.26, 39.47 and 39.98 ⁇ 0.2 degree theta.
  • crystalline 3-[(2- ⁇ [4-(hexyloxycarbonylamino- imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)- pyridin-2-yl-amino]-propionate mesylate form II has a powder XRD pattern with peaks at 4.3, 8.72, 9.68, 11.15, 12.42, 13.59, 13.95, 15.11, 15.97, 16.52, 17.45, 17.86, 18.45, 19.22, 19.89, 21.46, 21.98, 22.48, 23.75, 25.29, 28.17 and 28.59 degree two theta.
  • WO 2005/28468 which is hereby incorporated by reference in its entirely, also discloses hemihydrate form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate mesylate.
  • the present invention provides a pharmaceutically active substance which not only is characterized by high pharmacological potency and therapeutic efficacy but also satisfies the above-mentioned physicochemical requirements as far as possible.
  • the present invention provides crystalline form of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate.
  • the present invention provides a process for the preparation of crystalline form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate bisulphate.
  • the present invention provides amorphous form of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate.
  • the present invention provides a process for the preparation of amorphous form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-y 1-amino]- propionate bisulphate.
  • the present invention provides a crystalline 3-[(2- ⁇ [4-
  • the present invention provides a pharmaceutical composition comprising crystalline form III of 3-[(2- ⁇ [4-(hexyloxycarbonylamino- imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)- pyridin-2-yl-amino]-propionate mesylate of the present invention.
  • Figure 1 (fig. 1) - PXRD of crystalline 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino- methyl)-phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin- ⁇ amino] -propionate bisulphate.
  • Figure 2 is PXRD of crystalline form III of 3-[(2- ⁇ [4-(hexyloxycarbonylamino- imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)- pyridin-2-yl-amino]-propionate mesylate.
  • Figure 3 is DSC of crystalline form III of 3-[(2- ⁇ [4-(hexyloxycarbonylamino- imino-methyl)-phenylamino]-methyl ⁇ -l-methyl-lFf-benzimidazole-5-carbonyl)- pyridin-2-yl-amino]-propionate mesylate.
  • Figure 4 (fig. 4) - PXRD of amorphous form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino- imino-methy l)-phenylamino] -methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5 -carbony 1)- pyridin-2-yl-amino]-propionate bisulphate.
  • the present invention provides new crystalline form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate.
  • present invention provides new crystalline form of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5 -carbony l)-pyridin-2-yl-amino] -propionate bisulphate which can be characterized by its powder X-ray diffraction pattern.
  • the invention provides a process for the synthesis of new crystalline form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate bisulphate which comprises
  • the 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylaminoj-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate is soluble or partially soluble in suitable solvents.
  • suitable solvents are selected from alcohols, esters, ketones, nitriles, THF, 1,4 dioxane, nitrobenzene or suitable mixture thereof.
  • the suitable solvents are Q-C6 alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 2-methyl- 1-propanol, 2-methyl-2-propanol and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile and the like; alkyl halides such as dichloromethane, dichloroethane, chloroform, 1,1,1-trichloro ethene, 1,1,1-trichloro ethane and the like; THF; 1,4-dioxane; nitrobenzene and the like or their suitable mixture
  • 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate is dissolved in suitable solvent at 15-25°C, more preferably at 20°C, and thereafter sulfuric acid is added with stirring at 15-30°C, more preferably at 20-25°C, to obtain 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 - methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate.
  • the new crystalline form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate bisulphate of the present invention is characterized by its powder X-ray diffraction pattern having peaks expressed as 2 ⁇ at about 6.39(100), 7.82(8), 1033(11), 12.83(12), 14.06(5), 15.29(11), 15.79(9), 16.80(26), 17.28(11), 18.29(19), 19.25(23), 20.28(26), 21.46(15), 22.16(13), 24.21(28), 25.21(19), 25.79(15), 26.78(8), 27.78(8), 28.61(8), 29.89(7), 30.94(6), 31.64(6), 32.80(5), 33.17(6) and 33.85(6) ⁇ 0.2 degree 20.
  • the new crystalline form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate bisulphate is useful as an intermediate for the preparation of pure 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate and/or pure 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methy 1 ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mesylate.
  • the new crystalline form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenyJamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propioriate bisulphate may also be useful as a therapeutic agent for treatment of certain disorders.
  • the new crystalline form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate bisulphate prepared according to the present invention has chemical and polymorphic stability on storage at 25 °C ⁇ 2 °C / 60% ⁇ 5% RH.
  • WO9837075 does not provide any biological activity data of the 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-rnethyl)-phenylamino]-methyl ⁇ - 1 - methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate but provide the inhibitory effect on thrombocyte aggregation of the l-methyl-2-[N-(4-amidinophenyl)- aminomethyl]-benzimidazole-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2- hydroxycarbonylethyl)-amide.
  • the new crystalline form of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate of the present invention is derived from 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino] -methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbony l)-pyridin-2-y 1-am ino]- propionate, & therefore, we are providing comparison of the crystalline form of bisulfate salt with 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-
  • Body wt. range: 300 to 400 gms
  • APTT Activated Partial Thromboplastin Time
  • the new crystalline form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- pheriylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate bisulfate [DB-HS] shows 2.6 fold more BC-AUC for APTT as compared to 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate [DB (base)].
  • This increase in BC-AUC for in APTT for bisulfate was significantly higher than the corresponding base.
  • the present invention provides amorphous form 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -l-methyl-lH- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate which can be characterized by its powder X-ray diffraction pattern substantially as depicted in Fig.4.
  • the invention provides a process for the synthesis of amorphous form of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate which comprises
  • the suitable solvents are selected from poplar or non polar organic solvent.
  • the suitable solvent can be esters, alkyl halides, alcohols or ketones or suitable mixtures thereof.
  • the esters can be ethyl acetate, isopropyl acetate and the like;
  • alkyl halides can be dichloromethane, trichloromethane, tetrachloromethatne and the like;
  • alcohols can be Ci-C 6 alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2- butanol, 2-methyl- 1-propanol, 2-methyl-2-propanol and the like; ketones can be acetone, methyl ethyl ketone, methyl isobutyl ketone and the like or mixtures thereof.
  • the present invention provides crystalline 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mesylate form III which can be characterized by its powder X-ray diffraction pattern having peaks expressed as 2 ⁇ at about 9.30, 9.74, 11.09, 18.85, 21.30, 21.74, 22.43, 23.03, 23.96, 24.67,26.88, 31.25, 31.86, 32.56, 33.97 ⁇ 0.2 degree two theta.
  • the crystalline 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino- methyl)-phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl- aminoj-propionate mesylate form HI is characterized by its DSC endothermic peak at about 82°C to 100°C.
  • the DSC was recorded, within the scope of the present invention, using a Pyris 1 DSC made by Perkin Elmer.
  • the present invention also provides a process for the preparation of 3-
  • the present invention provides a process for the preparation of crystalline form III of 3-[(2- ⁇ [4-(hexyloxycarbonyla ' mino-imino- methyl)-pheny lamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5 -carbony l)-pyridin-2-yl- amino]-propionate mesylate which comprises:
  • 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate mesylate is dissolved in suitable solvent at 20-30°C, preferably at 25°C, reacted with water and stirred to form precipitate.
  • the obtained precipitate is filtered, washed with water, vacuum dried and further dried, in an oven to get crystalline form III of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate mesylate.
  • the 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate mesylate used as a starting material is soluble or partially soluble in suitable solvents.
  • suitable solvents are alcohols.
  • alcohols can be Ci-C 6 alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 2-methyl- 1-propanol, 2-methyl-2-propanol and the like.
  • the alcohol is methanol.
  • pharmaceutical formulation of the present invention may comprise crystalline form III of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ -l-methyl-lH-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate mesylate or the amorphous/crystalline form of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulphate of the present invention.
  • the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes. Excipients are added to the composition for preparing various dosage forms using the techniques and processes known. Further, the pharmaceutical formulation of the present invention may also comprise second active pharmaceutical substance other than 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino- methyl)-phenylamino]-methyl ⁇ - 1 -meto ⁇
  • the crystalline form III of 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl ⁇ - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]- propionate mesylate and the novel crystalline form of bisulfate salt of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate may be useful in prevention and treatment of venous and arterial thrombotic diseases, such as for example the treatment of deep leg vein thrombosis, for preventing reciusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular
  • the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with rt-PA or streptokinase, for preventing long-term restenosis after PT(C)A, for preventing metastasis and the growth of clot dependent tumours and fibrin-dependent inflammatory processes.
  • each of the new forms may be suitable as starting materials for obtaining the therapeutically beneficial forms/salts.
  • the XRD pattern is substantially as provided in Figure 4.
  • the XRD pattern is substantially as provided in Figure 1.
  • the characterization data showed to be crystalline form III of 3-[(2- ⁇ [4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ - 1 -methyl- 1 H- benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mesylate. (Melting point 82-92°C, yield 40%):
  • the XRD pattern is substantially as provided in Figure 2 (XRD) &
  • the DSC pattern is substantially as provided in Figure 3.

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Abstract

La présente invention concerne une préparation de nouvelles formes cristallines et amorphes de 3-[(2-{[4-(hexyloxycarbonylamino-imino-méthyl)-phénylamino]-méthyl}-1 -méthyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate bisulfaté et leur utilisation. La présente invention concerne également une nouvelle forme cristalline III de 3-[(2-{[4-(hexyloxycarbonylamino-imino-méthyl)-phénylamino]-méthyl}- 1-méthyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mésylaté et des procédés pour sa préparation ; son utilisation et une composition pharmaceutique la comprenant. Formule (I)
PCT/IN2012/000399 2012-03-27 2012-06-06 Nouvelles formes solides de bisulfate et de mésylate d'étéxilate de dabigatran, et leurs procédés de préparation WO2013144971A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016009405A1 (fr) * 2014-07-18 2016-01-21 Sifavitor S.R.L. Composés cristallins du dabigatran étexilate

Citations (8)

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