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WO2018178997A1 - Nouvelle forme cristalline du ticagrelor - Google Patents

Nouvelle forme cristalline du ticagrelor Download PDF

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Publication number
WO2018178997A1
WO2018178997A1 PCT/IN2017/050244 IN2017050244W WO2018178997A1 WO 2018178997 A1 WO2018178997 A1 WO 2018178997A1 IN 2017050244 W IN2017050244 W IN 2017050244W WO 2018178997 A1 WO2018178997 A1 WO 2018178997A1
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WO
WIPO (PCT)
Prior art keywords
ticagrelor
crystalline form
mixture
novel crystalline
polar solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2017/050244
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English (en)
Inventor
Pulla Reddy Muddasani
Shankar Reddy BUDIDETI
Srinivasa Krishna murthhy KONDURI
Satya Srinivas HANUMARA
Santhosh Kumar KOKKU
Venkateswarlu BANDLA
Govinda Raju POTHABATHULA
Kali Satya Bhujanga Rao Adibhatla
Venkaiah Chowdary Nannapaneni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Natco Pharma Ltd
Original Assignee
Natco Pharma Ltd
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Filing date
Publication date
Application filed by Natco Pharma Ltd filed Critical Natco Pharma Ltd
Publication of WO2018178997A1 publication Critical patent/WO2018178997A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel crystalline form Form N of Ticagrelor and process for preparation of the same.
  • Ticagrelor which is (15,25,3i?,55)-3-[7- ⁇ [(li?,25)-2-(3,4-Difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol, having the structure
  • Ticagrelor is approved under the trademark "BRILINTA" by US Food and Drug Administration for indicated for the prevention of thrombotic events.
  • the U.S. patent Nos. 7265124 discloses four crystalline forms (I, II, III and IV) and amorphous (Form a) of Ticagrelor, process for their preparation, and characterizes the polymorphs by powder X-ray diffraction (XRPD) pattern and melting points which were determined using differential scanning calorimetry (DSC).
  • XRPD powder X-ray diffraction
  • DSC differential scanning calorimetry
  • the Ticagrelor crystalline Form-I can be prepared by two methods.
  • Ticagrelor Form-I was prepared by heating and cooling of Ticagrelor Form II using DSC at temperatures 35 to 143 to 35 to 148 to 35 to 148 to 35° C.
  • Ticagrelor Form-I was prepared by dissolving Ticagrelor in methanol and water mixture (5:7.3 ratio ml/g) followed by added seed of Ticagrelor Form-I.
  • the Ticagrelor Form-Ill prepared by seed crystals of mixture of polymorphs of Form-II&III and was prepared by crystallization of Ticagrelor from ethanol overnight.
  • the resulted seed crystals of mixture polymorph was added to the slurry of Ticagrelor Form-II suspended in 50% aqueous isopropanol and this slurry was stir for 2 days to afford Ticagrelor polymorphic Form-Ill.
  • a novel crystalline Form- N of Ticagrelor wherein the ratio of intensities of the significant 2 ⁇ angles (XRPD, Fig.l) peaks of 5.5 ⁇ 0.2 (I) and 13.9 ⁇ 0.2 (I 0 ) is about 3.5 (I/ I 0 ).
  • a novel crystalline Form-N of Ticagrelor further characterized by differential scanning calorimetry curve to have an onset of melting which is in the range 133-134° C.
  • a novel crystalline Form- N of Ticagrelor further characterized by Raman spectra having the following characteristic absorption bands, expressed in wave number (cm-1): 2920, 1583, 1451, 1331, 1241, 1222, 815, 771.
  • a novel crystalline Form-N of Ticagrelor further characterized by IR spectrum comprising absorbances at the following wavenumbers (cm-1): 3292. 1624, 1590, 1521, 1451, 1328, 1091, 1052, 881, & 771 ⁇ 1.
  • novel crystalline Form-N of Ticagrelor characterized by insignificant weight loss by thermogravimetric analysis.
  • a crystal morphology that, the crystal morphology of novel crystalline Form-N of Ticagrelor indicates the product exists as monoclinic micro needles.
  • a process for the preparation of novel crystalline Form-N of Ticagrelor comprising:
  • Fig, 1 XRPD diffractogram of novel crystalline Form-N of Ticagrelor.
  • Fig, 2 DSC thermogram of novel crystalline Form-N of Ticagrelor
  • Fig. 3 Raman spectrum of novel crystalline Form-N of Ticagrelor.
  • Fig, 4 infrared spectrum of novel crystalline Form-N of Ticagrelor.
  • Fig. 5 Thermograviraetric analysis of novel crystalline Forrn-N of Ticagrelor.
  • Fig, 6 Crystal morphology of novel crystalline Form-N of Ticagrelor.
  • a novel crystalline Form-N of Ticagrelor having XPRD 20-reflections (°) at about 6.9 ⁇ 0.2.
  • the novel crystalline Form-N of Ticagrelor is characterized by XRPD, wherein the ratio of intensities of the significant 2 ⁇ angles peaks of 5.5 ⁇ 0.2 (I) and 13.9 ⁇ 0.2 (Io) is about 3.5 (1/ 1 0 ).
  • the novel crystalline Form-N of Ticagrelor is further characterized by a differential scanning calorimetry curve to have an onset of melting which is in the range 133-134° C.
  • the novel crystalline Form-N of Ticagrelor is further characterized by Raman spectra having the following characteristic absorption bands, expressed in wave number (cm-1): 2920, 1583, 1451, 1331, 1241, 1222, 815, 771.
  • the novel crystalline Form-N of Ticagrelor is further characterised by having an infrared spectrum comprising absorbances at the following wavenumbers (cm-1): 3292. 1624, 1590, 1521 , 1451 , 1328, 1091 , 1052, 881, & 771 ⁇ 1.
  • the novel crystalline Form-N of Ticagrelor is confirmed by thermogravimetric analysis as it is substantially anhydrous in nature.
  • the crystal morphology of novel crystalline Form-N of Ticagrelor is shown to be monoclinic micro needles.
  • Ticagrelor or Ticagrelor solvate is selected from Ticagrelor Form-I, Form-II, amorphous form or Ticagrelor DMF solvate preferably Ticagrelor DMF solvate.
  • the polar solvent or mixture is selected from acetonitrile, propionitrile, methanol, isopropyl alcohol, ethanol, 1-propanol, butanol or its mixture, preferably mixture of acetonitrile-isopropyl alcohol.
  • the ratio of acetonitrile and isopropyl alcohol is 7:3, 8:2 or 9: 1, preferably 9: 1.
  • the dissolution temperature at which Ticagrelor or Ticagrelor solvate is dissolved in the range of 50-70°C preferably 65-70°C.
  • the solution is optionally clarified over activated carbon, and filtrate is gradually cooled to 0-20°C preferably cooled to 0-5°C.
  • the wet Ticagrelor Form-N thus obtained is dried at 40-60°C, preferably at 50-60°C
  • the process of the present invention is feasible to produce novel crystalline polymorph, Form-N of Ticagrelor on commercial scale.
  • Novel crystalline polymorph, Form-N of Ticagrelor is stable during standard pharmaceutical operations such as drying, milling, compression, granulation and blending with excipients.
  • the process of the present invention is suitable to convert Ticagrelor (technical grade) Ticagrelor Form-I, Form-II, amorphous form and Ticagrelor DMF solvate to novel crystalline Ticagrelor polymorph, Form-N.
  • Novel crystalline polymorph, Form-N is stable at ambient temperature and also at elevated temperatures (60°C).
  • Form-N of Ticagrelor is non-hygroscopic and is compatible for further pharmaceutical processing operations.
  • Example 1 Process for the preparation of novel crystalline polymorph, Form-N of Ticagrelor.
  • the Ticagrelor DMF solvate (150 g) was dissolved in 1200 ml of acetonitrile (1080 mL)-isopropyl alcohol (120 mL) (9: 1) mixture. The reaction mixture was heated to 65- 70°C to dissolve completely. After complete dissolution, the solution was treated with activated carbon (15g) and filtered. The filtrate was again heated to 65-70°C and maintained for ⁇ 2h and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form -N dried under vacuum at 55-60°C.
  • Crystal morphology Crystal morphology of Form-N of ticagrelor exhibits monoclinic microneedles
  • Example 2 Process for the preparation of crystalline polymorph, Form-N of Ticagrelor from Form-I
  • the Ticagrelor Form-I (lOg) was dissolved in 80 ml of acetonitrile (72 mL)-isopropyl alcohol (8 mL) (9: 1) mixture. The reaction mixture was heated to 65-70°C to dissolve completely. After complete dissolution maintained for 2h at 65-70° and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form -N dried under vacuum at 55-60°C.
  • Example 3 Process for the preparation of crystalline polymorph, Form-N of Ticagrelor from Form-II
  • the Ticagrelor Form-II (150g) was dissolved in 1200 mL of acetonitrile (1080 mL)- isopropyl alcohol (120 mL) (9: 1) mixture. The reaction mixture was heated to 65-70°C to dissolve completely. After complete dissolution maintained for 2h at 65-70°C and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form-N dried under vacuum at 55-60°C.
  • Example 4 Process for the preparation of crystalline polymorph, Form-N of Ticagrelor from Amorphous form
  • the Ticagrelor amorphous form (25g) was dissolved in 200 ml of acetonitrile (180 mL)-isopropyl alcohol (20 mL) (9: 1) mixture. The reaction mixture was heated to 65- 70°C to dissolve completely. After complete dissolution maintained for 2h at 65-70° and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form -N dried under vacuum at 55-60°C. Yield: 21.5g; 86% by theory; HPLC Purity: >99.8%

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle forme cristalline (forme N) du ticagrelor et son procédé de préparation.
PCT/IN2017/050244 2017-03-31 2017-06-19 Nouvelle forme cristalline du ticagrelor Ceased WO2018178997A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201741011565 2017-03-31
IN201741011565 2017-03-31

Publications (1)

Publication Number Publication Date
WO2018178997A1 true WO2018178997A1 (fr) 2018-10-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7265124B2 (en) 2000-06-02 2007-09-04 Astrazeneca Ab Cristalline and amorphous form of a triazolo (4,5-D) pyridimine compound
WO2014000719A1 (fr) * 2012-06-29 2014-01-03 Zentiva, K.S. Nouvelles formes pharmaceutiques solides de (1s,2s,3r,5s)-3-[7-[(1r,2s)-2-(3,4difluorophényl)cyclopropylamino]-5-(propylthio)-3h-[1,2,3]triazolo[4,5-d]pyrimidin-3yl]-5-(2-hydroxyéthoxy)cyclopentane-l,2-diol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7265124B2 (en) 2000-06-02 2007-09-04 Astrazeneca Ab Cristalline and amorphous form of a triazolo (4,5-D) pyridimine compound
WO2014000719A1 (fr) * 2012-06-29 2014-01-03 Zentiva, K.S. Nouvelles formes pharmaceutiques solides de (1s,2s,3r,5s)-3-[7-[(1r,2s)-2-(3,4difluorophényl)cyclopropylamino]-5-(propylthio)-3h-[1,2,3]triazolo[4,5-d]pyrimidin-3yl]-5-(2-hydroxyéthoxy)cyclopentane-l,2-diol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA ED - MONTCHAMP JEAN-LUC: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY; [TOPICS IN CURRENT CHEMISTRY], SPRINGER, BERLIN, DE, vol. 198, 1998, pages 163 - 208, XP008166276, ISSN: 0340-1022 *

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