EP2867235A1 - Novel pharmaceutical solid forms of (1s,2s,3r,5s)-3-[7-[(1r,2s)-2-(3,4difluorophenyl)cyclopropylamino]-5-(propylthio)-3h-[1,2,3]triazolo[4,5-d]pyrimidin-3yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol - Google Patents

Novel pharmaceutical solid forms of (1s,2s,3r,5s)-3-[7-[(1r,2s)-2-(3,4difluorophenyl)cyclopropylamino]-5-(propylthio)-3h-[1,2,3]triazolo[4,5-d]pyrimidin-3yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol

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Publication number
EP2867235A1
EP2867235A1 EP12740458.0A EP12740458A EP2867235A1 EP 2867235 A1 EP2867235 A1 EP 2867235A1 EP 12740458 A EP12740458 A EP 12740458A EP 2867235 A1 EP2867235 A1 EP 2867235A1
Authority
EP
European Patent Office
Prior art keywords
ticagrelor
cocrystal
solvate
preparation
dioxane
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.)
Withdrawn
Application number
EP12740458.0A
Other languages
German (de)
English (en)
French (fr)
Inventor
Sharmarke MOHAMED
Ludmila Hejtmankova
Ludek Ridvan
Marcela Tkadlecova
Ondrej Dammer
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.)
Zentiva KS
Original Assignee
Zentiva KS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP2867235A1 publication Critical patent/EP2867235A1/en
Withdrawn legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to novel solid forms of ticagrelor (I) as well as to methods of preparation.
  • the specific solid forms claimed are a dioxane solvate and a cocrystal of ticagrelor derived from 3-hydroxy-2-naphthoic acid.
  • (I) is known to be a platelet aggregation inhibitor that is indicated for the prevention of thrombotic events in patients with myocardial infarction. Details of the synthetic method for isolating ticagrelor can be found in WO 00/34283. At least four anhydrous polymorphs of ticagrelor are known in the prior art and further details about these can be found in EP1289992. In addition, a number of cocrystals of ticagrelor are described in the prior art, specifically in WO2011067571.
  • ticagrelor represents a new class of platelet inhibitor. Unlike clopidogrel, ticagrelor is a not a thienopyridine but best described as a cyclopentyl-triazolo-pyrimidine.
  • Ticagrelor is a low solubility, low permeability active pharmaceutical ingredient (API) and categorised as a class IV compound under the Biopharmaceutical Classification System (BCS).
  • APIs are typically subjected to salt formation so as to improve their solubility and hence bioavailability.
  • Another option, and an increasingly popular one, is to form a co-crystal of the API.
  • a co-crystal is defined herein as a distinct solid form of the API that consists of a stoichiometric ratio of the API and a guest molecule (also known as a coformer) to give a periodically repeating crystal form.
  • Co-crystals typically provide distinct physicochemical properties with respect to the reference API.
  • Co-crystals offer great utility as they modify the physicochemical properties of the API without affecting the chemical structure of the API. Moreover co-crystallisation does not depend on the presence of ionisable functional groups, and this contrasts with the requirements for salt formation. Co-crystals are known to dissociate in solution at a rate faster than the time it takes for the API to reach the active site. Thus the therapeutic effect is delivered by the API alone with the cocrystal having rapidly dissociated by the time it is placed in water.
  • the present invention relates to the solid state structures of (lS,2S,3R,5S)-3-[7-[(l ?,2S)-2-(3,4- Difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2- hydroxyethoxy)cyclopentane-l,2-diol (hereafter referred to as Ticagrelor) in the form of a stable co- crystal solid form as well as a 1,4-dioxane solvate.
  • ticagrelor has four polymorphs of which Form I is the most stable with a melting point of 146-152 °C.
  • Form II is used in the drug product and this polymorph is known to have a melting point in the range 136- 139°C.
  • Forms I and II interconvert upon heating/cooling and this is illustrated in Figure 2.
  • the present invention relates to a 1,4-dioxane solvate of ticagrelor. More specifically the invention relates to the crystalline form of the 1,4-dioxane solvate of ticagrelor which has the characteristic X-ray powder diffraction (XRPD) peaks listed in Table 1 and the XRPD diffraction pattern shown in Figure 3.
  • XRPD characteristic X-ray powder diffraction
  • Table 1 characteristic X-ray powder diffraction
  • Figure 3 The 1,4-dioxane solvate of ticagrelor was characterised by gas chromatographic residual solvent analysis, which showed that there was approximately 24.37% of 1,4-dioxane by mass, suggesting a 2:1 molar stoichiometric ratio of l,4-dioxane:ticagrelor.
  • the characteristic X-ray powder diffraction peaks for 1,4-dioxane solvate of ticagrelor are 5,1; 15,3; 17,2; 19,3; 20,4; 25,6 a 30,8 ⁇ 0,2° 2 ⁇ .
  • the HPLC-determined purity of the solvate (98.4%) is comparable to that of ticagrelor Form II (98.8%).
  • the 1,4-dioxane solvate of ticagrelor has a greater stability than ticagrelor Form II as illustrated by a melting point approximately 14°C higher.
  • a process for preparation of 1,4-dioxane solvate which comprises a crystallization of ticagrelor solution or suspension in 1,4-dioxane in the temperature in the range of 20-101 °C for sufficient time to convert to the crystalline solvate.
  • Temperature is optimally in the range of 30-101°C and the most optimally by heating to 50 °C followed by precipitation by cooling to room temperature. It means the temperature in the range of 18-25°C.
  • For preparation of the solvate can be used all known forms of ticagrelor, for example form I or form II, III or IV as described in EP1289992. The amorphous form could be also used.
  • the ticagrelor 3-hydroxy-2-naphthoic acid cocrystal has the characteristic XRPD peaks listed in Table 2 and XRPD diffraction pattern is shown in Figure 5.
  • the characteristic X-ray powder diffraction peaks for the cocrystal are 3,6; 7,2; 9,3; 14,3; 16,2; 18,7 a 24,5 ⁇ 0,2° 2 ⁇ .
  • the cocrystal has an onset of melting of 136 °C, which is approximately 2 °C higher than the onset of melting for ticagrelor Form II.
  • the HPLC purity of the cocrystal is also high at 97.9%.
  • One of the advantageous of formulating ticagrelor as a cocrystal can be seen in its polymorphic behavior relative to ticagrelor API.
  • Ticagrelor This polymorphic transformation was not foreseen by the developers of Norvir and caused significant challenges.
  • Ticagrelor a similar challenge exists.
  • the polymorphic Form II used in the drug product is a metastable form, which readily transforms via a reversible temperature induced phase transition to the thermodynamically more stable Form I upon heating.
  • Ticagrelor also exhibits significant conformational flexibility, making it susceptible to polymorphic changes as a function of crystallisation conditions (principally the temperature and solvent).
  • the cocrystal of ticagrelor and 3-hydroxy-2-naphthoic acid allows for better control of the solid state properties as it is not susceptible to polymorphic changes as a function of temperature and solvent (the latter being limited by time and availability).
  • Figure 6 shows the DSC trace of the cocrystal which exhibits only one endotherm corresponding to the melting point of the cocrystal.
  • the cocrystal was shown not to be polymorphic - within the limitations of manual crystallisation techniques - as a function of the crystallisation solvent according to the results of extensive solution crystallisation experiments using different solvents.
  • Figure 7 shows identical PXRD patterns of the cocrystal when crystallized ticagrelor is crystallised with 1 equivalent of 3-hydroxy-2- naphthoic acid from suitable solvent at temperature in the range of 20-65°C.
  • suitable common solvents are used for example water, nitromethane, ethanol, propanol, diethylether, 2-butanol, cyclohexane, dichloromethane, acetone, methylethylketone, 1,2-dimethyoxyethane, ethylformate, methylacetate, propylacetate, isopropylacetate, trichloroethylene, tetrahydrofuran (THF) or acetonitrile or their mixtures.
  • THF tetrahydrofuran
  • acetonitrile or their mixtures for preparation of the cocrystal can be used all known forms of ticagrelor, for example form I or form II, III or IV as described in EP1289992. The amorph
  • the final added benefit of formulating ticagrelor as a cocrystal relates to the superior water sorption stability of the cocrystal relative to the API at elevated % relative humidity values.
  • the cocrystal has a water content of 3.2% by mass and this compares to 3.7% for Ticagrelor Form II.
  • the cocrystal was found to have a water content of approximately 13.2% by mass when compared to 16.8% for Ticagrelor Form II. Both samples are stable to water uptake up to 60% relative humidity.
  • Table 2 Table of diffraction peaks for the ticagrelor 3-hydroxy-2-naphthoic acid cocrystal.
  • the solvate and the cocrystal according to this invention could be used directly to the pharmaceutical composition or as an intermediate for preparation of a pharmaceutically accepted form.
  • Figure 1 XRPD pattern of ticagrelor Form II.
  • Figure 2 DSC trace for ticagrelor Form II.
  • Figure 3 XRPD pattern of the 1,4-dioxane solvate of ticagrelor.
  • Figure 4 DSC trace for the 1,4-dioxane solvate of ticagrelor.
  • Figure 5 XRPD pattern of the ticagrelor 3-hydroxy-2-naphthoic acid cocrystal.
  • Figure 6 DSC trace for the ticagrelor 3-hydroxy-2-naphthoic acid cocrystal.
  • Figure 7 Overlay of the PXRD patterns from crystallisations of ticagrelor 3-hydroxy-2-naphthoic acid cocrystal in different solvents. The overlay illustrates lack of polymorphism for the cocrystal.
  • Figure 8 Comparison of the sorption-desorption isotherms (25 °C) for a) Ticagrelor 3-hydroxy-2- naphthoic acid and b) Ticagrelor Form II.
  • Carrier gas N 2 20 ml/min. An amount of solvent was evaluated with Gas chromatography (GC) in a Agilent 7890 with Fl detection
  • Capillary column DB-624 (30 m, 0.53 mm ID, 3.0 ⁇ df) or equivalent
  • Carrier gas helium
  • Example 1 Method for the preparation of ticagrelor 1,4-dioxane solvate
  • Example 2 Method for the preparation of ticagrelor 3-hydroxy-2-naphthoic acid cocrystal
  • Example 3 Preparation of ticagrelor 3-hydroxy-2-naphthoic acid cocrystal from a range of solvents via slurrying
  • Ticagrelor Form II was placed inside a 1ml capacity vial. To this was added 14.34mg (lmol equiv.) of 3-hydroxy-2-naphthoic acid. To the vial was added 1ml of one of the following solvents to create a saturated suspension: Water, nitromethane, ethanol, propanol, diethylether, 2-butanol, cyclohexane, dichloromethane, acetone, methylethylketone, 1,2- dimethyoxyethane, ethylformate, methylacetate, propylacetate, isopropylacetate, trichloroethylene, THF or acetonitrile.
  • solvents Water, nitromethane, ethanol, propanol, diethylether, 2-butanol, cyclohexane, dichloromethane, acetone, methylethylketone, 1,2- dimethyoxyethane, ethy

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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)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP12740458.0A 2012-06-29 2012-06-29 Novel pharmaceutical solid forms of (1s,2s,3r,5s)-3-[7-[(1r,2s)-2-(3,4difluorophenyl)cyclopropylamino]-5-(propylthio)-3h-[1,2,3]triazolo[4,5-d]pyrimidin-3yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol Withdrawn EP2867235A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CZ2012/000059 WO2014000719A1 (en) 2012-06-29 2012-06-29 Novel pharmaceutical solid forms of (1s,2s,3r,5s)-3-[7-[(1r,2s)-2-(3,4difluorophenyl)cyclopropylamino]-5-(propylthio)-3h-[1,2,3]triazolo[4,5-d]pyrimidin-3yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol

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EP2867235A1 true EP2867235A1 (en) 2015-05-06

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EP12740458.0A Withdrawn EP2867235A1 (en) 2012-06-29 2012-06-29 Novel pharmaceutical solid forms of (1s,2s,3r,5s)-3-[7-[(1r,2s)-2-(3,4difluorophenyl)cyclopropylamino]-5-(propylthio)-3h-[1,2,3]triazolo[4,5-d]pyrimidin-3yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol

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EP (1) EP2867235A1 (ru)
BR (1) BR112014032085A2 (ru)
EA (1) EA024825B8 (ru)
WO (1) WO2014000719A1 (ru)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015162630A1 (en) 2014-04-25 2015-10-29 Anlon Chemical Research Organization Novel processes for preparing triazolo [4,5-d]- pyrimidines, including ticagrelor, vianew intermediates and new route of synthesis.
WO2016116942A1 (en) 2015-01-20 2016-07-28 Anlon Chemical Research Organization Novel pharmaceutical compounds comprising ticagrelor with salts of aspirin
US10905691B2 (en) 2016-09-09 2021-02-02 Université de Liège Use of triazolo(4,5-d)pyrimidine derivatives for prevention and treatment of bacterial infection
DK3292867T3 (da) * 2016-09-09 2019-07-22 Univ Liege Ny brug af triazol(4,5-d)pyrimidinderivater til brug i forebyggelsen og behandlingen af bakteriel infektion
WO2018178997A1 (en) * 2017-03-31 2018-10-04 Natco Pharma Limited Novel crystalline form of ticagrelor

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TWI229674B (en) * 1998-12-04 2005-03-21 Astra Pharma Prod Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses
GB0013407D0 (en) 2000-06-02 2000-07-26 Astrazeneca Ab Forms of a chemical compound
MX2012006375A (es) * 2009-12-03 2013-03-21 Astrazeneca Ab Co-cristales de un inhibidor de agregacion de plaquetas de triazolo [4, 5-d] pirimidina.

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EA024825B8 (ru) 2016-12-30
WO2014000719A1 (en) 2014-01-03
EA024825B1 (ru) 2016-10-31
BR112014032085A2 (pt) 2017-06-27
EA201590112A1 (ru) 2015-05-29

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