US20030181469A1 - Crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound - Google Patents

Crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound Download PDF

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US20030181469A1
US20030181469A1 US10/296,990 US29699002A US2003181469A1 US 20030181469 A1 US20030181469 A1 US 20030181469A1 US 29699002 A US29699002 A US 29699002A US 2003181469 A1 US2003181469 A1 US 2003181469A1
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compound
formula
mixture
solvent
diffraction pattern
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Martin Bohlin
Steve Cosgrove
Bo Lassen
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AstraZeneca AB
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to forms of a chemical compound, in particular to crystalline and amorphous forms, more particularly four crystalline forms and an amorphous form.
  • the invention further relates to processes for the preparation of such forms, to pharmaceutical compositions comprising the compound in crystalline and/or amorphous form and to the therapeutic use of such forms.
  • the drug substance In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of subsequent manufacture of pharmaceutical formulations comprising the active compound. Chemical stability, solid state stability, and shelf life of the active ingredients are also very important factors.
  • the drug substance, and compositions containing it should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility). Moreover, it is also important to be able to provide drug in a form which is as pure as possible.
  • Amorphous materials may present significant problems in this regard. For example, such materials are typically more difficult to handle and to formulate than crystalline material, provide for unreliable solubility, and are often found to be unstable and chemically impure.
  • the skilled person will appreciate that, if a drug can be readily obtained in a stable crystalline form, the above problems may be solved.
  • drug compositions it is desirable, wherever possible, to provide drug in a substantially crystalline, and stable. form. It is to be noted, however, that this goal is not always achievable. Indeed, typically, it is not possible to predict, from molecular structure alone, what the crystallisation behaviour of a compound will be, and this can usually only be determined empirically.
  • the process of platelet adhesion to the sub-endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates can precipitate acute thrombotic occlusion of vital vascular beds, leading to events with high morbidity such as myocardial infarction and unstable angina.
  • the success of interventions used to prevent or alleviate these conditions, such as thrombolysis and angioplasty are also compromised by platelet-mediated occlusion or re-occlusion.
  • ADP adenosine 5′-diphosphate
  • P 2T receptor subtype located on the platelet membrane.
  • the P 2T receptor also known as P2Y ADP or P2T AC
  • P2Y ADP or P2T AC is to primarily involved in mediating platelet aggregation/activation and is a G-protein coupled receptor which is as yet uncloned.
  • the pharmacological characteristics of this receptor have been described, for example, in the references by Humphries et al., Br. J. Pharmacology ( 1994), 113, 1057-1063, and Fagura et al., Br. J.
  • the compound of formula (I) is conventionally named: ⁇ 1S-[1 ⁇ , 2 ⁇ , 3 ⁇ (1S*,2R*),5 ⁇ ] ⁇ -3-(7- ⁇ [2-(3,4difluorophenyl)cyclopropyl[amino ⁇ -5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol.
  • the compound of formula (I) may exist in four different substantially crystalline forms referred to hereafter as Polymorph I, Polymorph II, Polymorph III and Polymorph IV.
  • a polymorph is a particular crystalline form of a compound.
  • the preferred crystalline form of the compound of formula (I) is in the form of Polymorph I, Polymorph II, Polymorph m and/or Polymorph IV.
  • a preferred crystalline form of the compound of formula (I) is Polymorph I.
  • a preferred crystalline form of the compound of formula (I) is Polymorph II.
  • a preferred crystalline form of the compound of formula (I) is Polymorph III.
  • the compound of formula (I) is in a substantially amorphous form.
  • an amorphous form the three dimensional long range order that normally exists in a crystalline form (for example in a polymorph) does not exist, and the positions of the molecules relative to one another in the amorphous form are essentially random (see B. C. Hancock and G. Zografi, J. Pharm. Sci. (1997) 86 1).
  • the amorphous form of the compound of formula (I) is referred to as Form ⁇ .
  • anhydrous form of the compound of formula (I) in a crystalline form or an amorphous form is provided.
  • anhydrous form of the compound of formula (I) in a crystalline form or an amorphous form By the use of the term “substantially pure and essentially in the anhydrous form”, we do not exclude the presence of some solvent, including water, within the crystal lattice structure or outside the crystal lattice structure.
  • An anhydrous form has less than 0.4 water molecules per compound molecule (less than 40% hydrated).
  • the anhydrous form contains less than 0.1 water molecules per compound molecule.
  • Polymorphs I, II, III and IV can be distinguished by reference to their onset of melting, powder X-ray diffraction patterns and/or single crystal X-ray data,
  • Polymorph I has an onset of melting which is in the range 146-152° C., for example about 151° C., when it is substantially pure and essentially in the anhydrous form.
  • Polymorph II has an onset of melting that is in the range 136-139° C., for example about 137.5° C., when it is substantially pure and essentially in the anhydrous form.
  • Polymorph III has an onset of melting that is in the range 127-132° C., for example about 132° C., when it is substantially pure and essentially in the anhydrous form.
  • Polymorph IV has an onset of melting which is typically about 139° C., when it is substantially pure and essentially in the anhydrous form.
  • Form ⁇ typically undergoes a glass transition followed by crystallisation into one of the above Polymorph forms, for example Polymorph II, prior to melting.
  • the melting points were determined using differential scanning calorimetry (DSC) using Perkin Elmer DSC7 instrumentation.
  • DSC differential scanning calorimetry
  • the onset of melting is defined as the point at which a significant change from the baseline occurs and was measured by Perkin Elmer Pyris software. It will be appreciated that alternative readings of melting point may be given by other types of equipment or by using conditions different to those described here. Hence the figures quoted are not to be taken as absolute values. The skilled person will realise that the precise value of the melting point will be influenced by the purity of the compound, the sample weight, the heating rate and the particle size.
  • Polymorph I when it is substantially pure and essentially in the anhydrous form, has an X-ray powder diffraction pattern containing specific peaks of high intensity at 5.3° ( ⁇ 0.1°), 20.1° ( ⁇ 0.1), 20.7° ( ⁇ 0.1°), 21.0° ( ⁇ 0.1°) and 21.3° ( ⁇ 0.1°) 2 ⁇ .
  • substantially pure and essentially anhydrous Polymorph I has an X-ray powder diffraction pattern containing specific peaks at 5.3° ( ⁇ 0.1°), 8.0° ( ⁇ 0.1°), 9.6° ( ⁇ 0.1°), 13.9° ( ⁇ 0.1°), 15.3° ( ⁇ 0.1°), 20.1° ( ⁇ 0.1° ), 20.7° ( ⁇ 0.1°), 21.0° ( ⁇ 0.1°), 21.3° ( ⁇ 0.1°), 26.2° ( ⁇ 0.1°) and 27.5° ( ⁇ 0.1°) 2 ⁇ .
  • Polymorph II when it is substantially pure and essentially in the anhydrous form, has an X-ray powder diffraction pattern containing specific peaks of high intensity at 5.5° ( ⁇ 0.1°), 13.5° ( ⁇ 0.1°), 18.3° ( ⁇ 0.1°), 22.7° ( ⁇ 0.1°) and 24.3° ( ⁇ 0.1°) 2 ⁇ .
  • substantially pure and essentially anhydrous Polymorph II has an X-ray powder diffraction pattern containing specific peaks at 5.5° ( ⁇ 0.1°), 6.8° ( ⁇ 0.1°), 10.6° ( ⁇ 0.1°), 13.5° ( ⁇ 0.1°), 14.9° ( ⁇ 0.1°), 18.3° ( ⁇ 0.1°), 19.2° ( ⁇ 0.1°), 22.7° ( ⁇ 0.1°), 24.3° ( ⁇ 0.1°) and 27.1° ( ⁇ 0.1°) 2 ⁇ .
  • Polymorph III when it is substantially pure and essentially in the anhydrous form, has an X-ray powder diffraction pattern containing specific peaks of high intensity at 14.0° ( ⁇ 0.1°), 17.4° ( ⁇ 0.1°), 18.4° ( ⁇ 0.1°), 21.4° ( ⁇ 0.1°) and 24.1° ( ⁇ 0.1°) 2 ⁇ .
  • substantially pure and essentially anhydrous Polymorph m has an X-ray powder diffraction pattern containing specific peaks at 5.6° ( ⁇ 0.1°), 12.5° ( ⁇ 0.1°), 14.0° ( ⁇ 0.1°), 17.4° ( ⁇ 0.1°), 18.4° ( ⁇ 0.1°), 21.4° ( ⁇ 0.1°), 22.2° ( ⁇ 0.1°), 22.9° ( ⁇ 0.1°), 24.1° ( ⁇ 0.1°) and 24.5° ( ⁇ 0.1°) 2 ⁇ .
  • Polymorph IV when it is substantially pure and essentially in the anhydrous form, has an X-ray powder diffraction pattern containing specific peaks of high intensity at 4.9° ( ⁇ 0.1°), 9.2° ( ⁇ 0.1°), 11.6° ( ⁇ 0.1°), 15.6° ( ⁇ 0.1°) and 16.4° ( ⁇ 0.1°) 2 ⁇ .
  • substantially pure and essentially anhydrous Polymorph IV has an X-ray powder diffraction pattern containing specific peaks at 4.9° ( ⁇ 0.1°), 6.0° ( ⁇ 0.1°), 9.2° ( ⁇ 0.1°), 11.6° ( ⁇ 0.1°), 12.8° ( ⁇ 0.1°), 15.6° ( ⁇ 0.1°), 16.4° ( ⁇ 0.1°), 17.2° ( ⁇ 0.1°) and 18.1° ( ⁇ 0.1°) 2 ⁇ .
  • Form ⁇ when it is substantially pure and essentially in the anhydrous form, has an X-ray powder diffraction pattern containing no sharp peaks.
  • a solvated form may be formed, for example, a hydrated form (a “hydrate”). Therefore in this aspect of the invention there is provided a hydrate of the compound of formula (I) in crystalline form.
  • a hydrate has 0.8 or more water molecules per compound molecule (80% or more hydrated).
  • a hemi-hydrate has between 0.4 and 0.8 water molecules per compound molecule (40-80% hydrated).
  • the mixture is of Polymorph I, Polymorph II, Polymorph III, Polymorph IV and/or Form ⁇ . More preferably, the invention provides any mixture of Polymorph II and Polymorph III.
  • a process for the production of a crystalline form of the compound of formula (I) by crystallisation of the compound of formula (I) from a suitable solvent is selected from the group: ethanol, ethyl acetate, iso-propanol, iso-octane, acetonitrile, water, or a mixture thereof. More preferably, the solvent is selected from the group: ethanol, ethyl acetate, iso-propanol, iso-octane, water, or a mixture thereof.
  • the solvent is selected from the group: a mixture of methanol and water, ethanol, ethyl acetate, a mixture of ethanol and water, a mixture of iso-propanol and water, a mixture of ethyl acetate and iso-octane, and acetonitrile.
  • the compound of formula (I) can be prepared by methods analogous to those described in WO 9905143.
  • Crystallisation of the compound of formula (I) from an appropriate solvent system may be achieved by attaining supersaturation, for example, by cooling, by solvent evaporation and or by the addition of an anti-solvent (a solvent in which the compound of formula (I) is poorly soluble; examples of suitable anti-solvents include heptane or isooctane). Crystallisation temperatures and times will vary depending upon the concentration of the compound in solution, the solvent system used and the method of crystallisation adopted.
  • the compound of formula (I) in crystalline form may be isolated from the above reaction mix using techniques well known to those skilled in the art, for example, by decanting, filtration or centrifuging. Similarly the compound of formula (I) in crystalline form may be dried in accordance with well-known procedures.
  • the crystallisation is carried out directly from the reaction solution.
  • the crystallisation is performed from a subsequent solution.
  • a process for preparing Polymorph I which comprises obtaining a few seed crystals of Polymorph I from the slow crystal growth of Polymorph I from a melt of Polymorph II, and using this to seed a reaction mixture comprising of the compound of formula (I), and a suitable mixed solvent system such as methanol/water.
  • a process for preparing Polymorph III which comprises crystallisation in a suitable solvent such as an alcohol, for example ethanol or isopropyl alcohol (IPA), in particular seeding with crystals of Polymorph m or slurrying a compound of formula (I) in a suitable solvent such as IPA.
  • a suitable solvent such as an alcohol, for example ethanol or isopropyl alcohol (IPA)
  • IPA isopropyl alcohol
  • a process for preparing Polymorph IV which comprises crystallisation from a suitable solvent such as acetonitrile, in particular seeding with crystals of Polymorph IV or a period of slurrying a compound of formula (I) in a suitable solvent such as acetonitrile.
  • a further feature of the invention provides a process for preparing Polymorph III substantially free of Polymorph II, which comprises, for example, slurrying a compound of formula (I) in C 1-6 aliphatic alcohol/water solvent system (preferably IPA/water) at a temperature of 5-65° C. for 1-10 days.
  • C 1-6 aliphatic alcohol/water solvent system preferably IPA/water
  • a process for the production of the compound of formula (I) in substantially amorphous form which comprises freeze drying or spray drying a solution of a compound of Formula (I) using a suitable solvent system, for example ethanol/water.
  • substantially free refers to less than 10% of the other polymorph, preferably less than 5%.
  • the compound of formula (I) in crystalline and/or amorphous form acts as P 2T (P2Y ADP or P2T AC ) receptor antagonists. Accordingly, the compound of formula (I) in crystalline and/or amorphous form is useful in therapy, including combination therapy.
  • the compound of formula (I) in crystalline form is indicated for use in the treatment or prophylaxis of arterial thrombotic complications in patients with coronary artery, cerebrovascular or peripheral vascular disease.
  • Arterial thrombotic complications may include unstable angina, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, transient ischaemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, including coronary angioplasty (PTCA), endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including ski and muscle flaps, conditions with a diffuse thrombotic/platelet consumption component such as disseminated intravascular coagulation, thrombotic thrombocytopaenic purpura, haemolytic uraemic syndrome, thrombotic complications of septicaemia, adult respiratory distress syndrome, anti-phospholipid syndrome, heparin-induced thrombocytopaenia and pre-eclampsia/eclampsia
  • platelet concentrates, or shunt occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ graft rejection, conditions such as migraine, Raynaud's phenomenon, conditions in which platelets can contribute to the underlying inflammatory disease process in the vascular wall such as atheromatous plaque formation/progression, stenosis/restenosis and in other inflammatory conditions such as asthma, in which platelets and platelet-derived factors are implicated in the immunological disease process. Further indications include treatment of CNS disorders and prevention of the growth and spread of tumours.
  • a compound of formula (I) in crystalline and/or amorphous form for use in a method of treatment of the human or animal body by therapy.
  • the compound of formula (I) in crystalline and/or amorphous form for use as a medicament.
  • the compound of formula (I) in crystalline and/or amorphous form is used as a medicament to antagonise the P 2T (P2Y ADP or P2T AC ) receptor in a warm-blooded animal such as a human being.
  • the compound of formula (I) in crystalline and/or amorphous form is used as a medicament for treating or preventing arterial thrombotic complications in patients with coronary artery, cerebrovascular or peripheral vascular disease in a warm-blooded animal such as a human being.
  • the use of the compound of formula (I) in crystalline and/or amorphous form in the manufacture of a medicament for use as an antagonist of the P 2T (P2Y ADP or P2T AC ) receptor in particular there is further provided the use of the compound of formula (I) in crystalline and/or amorphous form in the manufacture of a medicament for use in the treatment or prevention of arterial thrombotic complications in patients with coronary artery, cerebrovascular or peripheral vascular disease.
  • the invention also provides a method of treatment or prevention of arterial thrombotic complications in patients with coronary artery, cerebrovascular or peripheral vascular disease, which comprises administering to a person suffering from or susceptible to such a disorder a therapeutically effective amount of the compound of formula (I) in crystalline and/or amorphous form.
  • the compound of formula (I) in crystalline and/or amorphous form may be administered on its own or as a pharmaceutical composition comprising the compound of formula (I) in crystalline and/or amorphous form in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier. Therefore there is provided as a further feature of the invention a pharmaceutical composition comprising the compound of formula (I) in crystalline and/or amorphous form in association with a pharmaceutically acceptable diluent, adjuvant and/or carrier. Particularly preferred are compositions not containing material capable of causing an adverse reaction, such as an adverse allergic reaction.
  • Dry powder formulations and pressurised HFA aerosols of the compound of formula (I) in crystalline and/or amorphous form may be administered by oral or nasal inhalation.
  • the compound of formula (I) in crystalline and/or amorphous form is desirably finely divided.
  • the compound of formula (I) in crystalline and/or amorphous form may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • One possibility is to mix the finely divided compound of formula (I) in crystalline and/or amorphous form with a carrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyol. Suitable carriers include sugars and starch.
  • a carrier substance e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyol.
  • Suitable carriers include sugars and starch.
  • the finely divided compound of formula (I) in crystalline and/or amorphous form may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound of formula (I) in crystalline and/or amorphous form.
  • the compound of formula (I) in crystalline and/or amorphous form may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • a carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, par
  • the compound of formula (I) in crystalline and/or amorphous form may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol, mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound of formula (I) in crystalline and/or amorphous form, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • FIG. 1. 1 is an X-ray diffraction pattern for Polymorph I was obtained using a Philips X'Pert MPD machine in ⁇ - ⁇ configuration over the scan range 1° to 40° 2 ⁇ with 2 or 5 seconds exposure per 0.02° 2 ⁇ increment.
  • the X-rays were generated by a copper long-fine focus tube operated at 40 kV and 50 mA.
  • the wavelength of the X-rays was 1.5406 ⁇ .
  • FIG. 1.2 is an X-ray diffraction pattern for Polymorph II obtained using a Siemens D5000 machine in ⁇ - ⁇ configuration over the scan range 2° to 30° 2 ⁇ with 4 seconds exposure per 0.02° 2 ⁇ increment.
  • the X-rays were generated by a copper long-fine focus tube operated at 45 kV and 40 mA.
  • the wavelength of the X-rays was 1.5406 ⁇ .
  • Data were collected using a zero background on which ⁇ 10 mg of the compound was placed.
  • the holder was made from a single crystal of silicon, which had been cut along a non-diffracting plane and then polished to an optically flat finish The X-rays incident upon this surface were negated by Bragg extinction.
  • FIG. 1. 4 is an X-ray diffraction pattern for Polymorphs IV obtained using a Siemens D5000 machine as described above.
  • FIG. 1. 5 is an X-ray diffraction pattern for Form a obtained using a Siemens D5000 machine as described above.
  • a solution comprising of the compound of formula (I), 5 ml/g methanol and 7.3 ml/g water and a small quantity of seeds of Polymorph I, was crystallised at 30° C. XRPD and DSC confirmed that substantially pure Polymorph I had been formed.
  • Ethanol 200 ⁇ l was added to 10 mg of the compound of formula (I) and the mixture warmed to dissolution over a steam bath. The resulting solution was left to crystallise over night.
  • XRPD and DSC confirmed that a mixture of Polymorphs II and III had been formed. This material was used to seed a larger scale preparation: 191 mg of Polymorph II were slurried in 1 ml of a 50% aqueous solution of isopropanol. To this slurry, 15 mg of seeds of mixed Polymorph II/III were added. After 2 days complete conversion into Polymorph III had occurred as shown by XRPD.
  • the starting materials are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations of the preparation of some of the starting materials used in the above reactions.
  • DIBAL-H® (1.0M solution in hexanes, 5.15 ml) was added to an ice-cooled solution of ⁇ 3aR-[3a ⁇ ,4 ⁇ ,6 ⁇ (1R*,2S*),6a ⁇ ] ⁇ - ⁇ [6-(7- ⁇ [2-(3,4-Difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy ⁇ acetic acid, methyl ester (Method B, 0.76 g) in THF (1 ml) and the solution was stirred at this temperature for 2 hours.
  • the title compound may be prepared according to the procedure described in WO 9905143.
  • Mass Spectra were measured as follows: EI spectra were obtained on a VG70-250S or Finnigan Mat Incos-XL spectrometer, FAB spectra were obtained on a VG70-250SEQ spectrometer, ESI and APCI spectra were obtained on Finnigan Mat SSQ7000 or a Micromass Platform spectrometer.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060041132A1 (en) * 2000-06-02 2006-02-23 Astrazeneca Ab Novel triazolo pyrimidine compounds
US20080108635A1 (en) * 2006-10-31 2008-05-08 Han-Cheng Zhang Triazolopyrimidine derivatives as ADP P2Y12 receptor antagonists
WO2009064249A1 (en) * 2007-11-15 2009-05-22 Astrazeneca Ab A process for the preparation of (3ar,4s, 6r, 6as)-6-amino-2, 2- dimethyltetrahydro-3ah-cyclopenta[d] [1,3] dioxol-4-ol dibenzoyl-l-tartrate and to products of said process

Families Citing this family (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
JP4298212B2 (ja) * 2002-03-29 2009-07-15 大日本印刷株式会社 塩酸エピナスチン高融点型結晶の製造法
TWI482772B (zh) * 2006-08-21 2015-05-01 Astrazeneca Ab 適合口服且包含三唑并[4,5-d]嘧啶衍生物之組合物
WO2008024044A1 (en) * 2006-08-21 2008-02-28 Astrazeneca Ab Compositions, suitable for oral administration, comprising a triazolo [4, 5] pyrimidin derivate
BRPI0809655B8 (pt) * 2007-04-13 2021-05-25 Millennium Pharm Inc uso de um composto e um agente terapêutico,composição farmacêutica,e,kit
UA100864C2 (uk) 2007-12-03 2013-02-11 Астразенека Аб Спосіб лікування або запобігання аневризмі черевної аорти
US8563755B2 (en) 2008-09-09 2013-10-22 Astrazeneca Ab Process for preparing [1S-[1-α, 2-α, 3-β(1S*,2R*) 5-β]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1,2-diol and to its intermediates
WO2011017108A2 (en) 2009-07-27 2011-02-10 Auspex Pharmaceuticals, Inc. Cyclopropyl modulators of p2y12 receptor
WO2011067571A1 (en) * 2009-12-03 2011-06-09 Astrazeneca Ab Co - crystals of a triazolo [4,5 - d] pyrimidine platelet aggregation inhibitor
ES2550033T3 (es) 2009-12-23 2015-11-04 Ratiopharm Gmbh Forma de dosificación farmacéutica sólida de ticagrelor
CZ2011229A3 (cs) * 2011-04-19 2012-08-15 Zentiva, K.S. Opticky aktivní soli (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyklopenta-[d][1,3]dioxol-4-olu a zpusob jejich prípravy
CA2836394A1 (en) * 2011-06-01 2012-12-06 Astrazeneca Ab Novel ticagrelor co - crystal
MX2014006190A (es) * 2011-11-30 2014-07-10 Actavis Group Ptc Ehf Nueva forma cristalina de ticagrelor y proceso para la preparacion de la misma.
EP2834247A4 (en) 2012-04-05 2016-03-30 Reddys Lab Ltd Dr PREPARATION OF TICAGRELOR
WO2014000719A1 (en) * 2012-06-29 2014-01-03 Zentiva, K.S. 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
CN104640864B (zh) 2012-07-04 2016-11-16 力奇制药公司 替格瑞洛与二价金属盐的加合物
CZ2012705A3 (cs) 2012-10-16 2014-04-23 Zentiva, K.S. Pevná orální farmaceutická formulace obsahující ticagrelor
CN103772393B (zh) * 2012-10-18 2017-08-04 博瑞生物医药（苏州）股份有限公司 替卡格雷的晶型及其制备方法
WO2014083139A1 (en) * 2012-11-29 2014-06-05 Actavis Group Ptc Ehf Novel amorphous form of ticagrelor
CN103848836B (zh) * 2012-12-07 2016-08-03 天津市汉康医药生物技术有限公司 替卡格雷倍半水合物及其制备方法
WO2014118808A2 (en) * 2013-02-04 2014-08-07 Hetero Research Foundation Ticagrelor solid dispersion
CZ307217B6 (cs) 2013-03-14 2018-04-04 Zentiva, K.S. Zlepšený způsob výroby a nové intermediáty syntézy ticagreloru
IN2013MU01111A (no) * 2013-03-25 2015-05-01 Glenmark Generics Ltd
CN104098570A (zh) * 2013-04-07 2014-10-15 杭州领业医药科技有限公司 替卡格雷晶型及其制备方法和用途
CN104098572A (zh) * 2013-04-08 2014-10-15 博瑞生物医药技术(苏州)有限公司 替卡格雷共晶型
CN107573333B (zh) * 2013-04-10 2019-10-18 江苏恒瑞医药股份有限公司 替格瑞洛的中间体及其制备方法和替格瑞洛的制备方法
WO2014170026A1 (en) 2013-04-18 2014-10-23 Zentiva, K.S. Stabilized amorphous ticagrelor
EP2813216A1 (en) 2013-06-10 2014-12-17 Zentiva, a.s. Stabilized amorphous ticagrelor
US20160120869A1 (en) 2013-05-29 2016-05-05 Ratiopharm Gmbh Solid pharmaceutical dosage form
CN106496235A (zh) * 2013-06-03 2017-03-15 杭州领业医药科技有限公司 结晶形态的三唑[4,5‑d]嘧啶化合物及其制备方法和用途
WO2014195861A2 (en) * 2013-06-04 2014-12-11 Dr. Reddy’S Laboratories Limited Preparation of ticagrelor
EP2816043A1 (en) 2013-06-21 2014-12-24 LEK Pharmaceuticals d.d. Spherical ticagrelor particles
WO2015001489A1 (en) * 2013-07-01 2015-01-08 Ranbaxy Laboratories Limited Pharmaceutical compositions of ticagrelor
CN104341423B (zh) * 2013-08-02 2017-03-01 上海京新生物医药有限公司 替格瑞洛的一水合物及其制备方法与在制药中的应用
CN104370912A (zh) * 2013-08-13 2015-02-25 开原亨泰制药股份有限公司 替卡格雷多晶型体及其制备方法
WO2015037016A2 (en) * 2013-09-10 2015-03-19 Laurus Labs Private Limited An improved process for the preparation of ticagrelor and intermediates thereof
CZ2013866A3 (cs) 2013-11-08 2015-05-20 Zentiva, K.S. Způsob výroby a nová krystalická forma intermediátu syntézy ticagreloru
CN104650085A (zh) * 2013-11-22 2015-05-27 天津市汉康医药生物技术有限公司 替卡格雷倍半水合物化合物
CN103601726B (zh) * 2013-12-02 2016-09-28 浙江大学 两种替格瑞洛药物共晶及其制备方法
CN104710425B (zh) * 2013-12-16 2019-06-14 石药集团中奇制药技术（石家庄）有限公司 一种替格瑞洛新结晶及其制备方法
CN104650091B (zh) * 2014-01-24 2016-10-05 福州乾正药业有限公司 替格瑞洛的微粉化及其晶型，以及制备方法和药物应用
CN104940204A (zh) * 2014-03-27 2015-09-30 广东东阳光药业有限公司 一种替格瑞洛固体制剂及其制备方法
WO2015162537A1 (en) * 2014-04-23 2015-10-29 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of ticagrelor
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.
CN105315282B (zh) * 2014-07-15 2018-09-21 博瑞生物医药（苏州）股份有限公司 一种制备替卡格雷无定型的方法
WO2016016907A1 (en) * 2014-08-01 2016-02-04 Msn Laboratories Private Limited Novel polymorphs of (1s,2s,3r,5s)-3-[7-{[(1r,2s)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3h-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yi]-5-(2-hydroxvethoxy) cyclopentane-1,2-diol
US10017515B2 (en) 2014-08-11 2018-07-10 Sun Pharmaceutical Industries Limited Stable amorphous ticagrelor and a process for its preparation
CN104193747B (zh) * 2014-08-12 2016-05-11 许彩霞 替卡格雷无定形的制备
WO2016116942A1 (en) 2015-01-20 2016-07-28 Anlon Chemical Research Organization Novel pharmaceutical compounds comprising ticagrelor with salts of aspirin
CN105968113B (zh) * 2015-03-12 2019-06-07 四川海思科制药有限公司 一种三唑并嘧啶衍生物及其应用
WO2017072790A1 (en) * 2015-10-26 2017-05-04 Avra Laboratories Pvt. Ltd. An improved process for synthesis of ticagrelor
WO2017118633A1 (en) * 2016-01-05 2017-07-13 Amneal Pharmaceuticals Company Gmbh Crystalline form of ticagrelor
CN107595789B (zh) 2016-04-21 2021-01-15 阿斯利康(瑞典)有限公司 口腔崩解片
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
EP3292867B1 (en) * 2016-09-09 2019-05-15 Université de Liège Triazolo(4,5-d)pyrimidine derivatives for use in the prevention and treatment of bacterial infection
KR101916956B1 (ko) 2016-12-13 2018-11-08 보령제약 주식회사 티카그렐러의 신규한 고체 형태 및 이의 제조방법
WO2018178997A1 (en) 2017-03-31 2018-10-04 Natco Pharma Limited Novel crystalline form of ticagrelor
WO2019127294A1 (zh) * 2017-12-29 2019-07-04 浙江天宇药业股份有限公司 一种纯化替格瑞洛的方法
WO2019170244A1 (en) 2018-03-08 2019-09-12 Pharmaceutical Oriented Services Ltd. Ticagrelor—containing tablet formulation
EP3829547A1 (en) 2018-07-27 2021-06-09 KRKA, d.d., Novo mesto Pharmaceutical composition of ticagrelor
CN110194771A (zh) * 2019-05-08 2019-09-03 北京济美堂医药研究有限公司 一种替格瑞洛药用ii晶型的制备方法
CN114634489B (zh) * 2022-04-19 2023-07-04 奎马特里克斯有限公司 结晶形式

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6525060B1 (en) * 1998-12-04 2003-02-25 Astrazeneca Uk Limited Triazolo(4,5-d)pyrimidine compounds
US20030148888A1 (en) * 2000-06-02 2003-08-07 Ulf Larsson Novel triazolo pyrimidine compounds
US6713483B1 (en) * 1999-11-15 2004-03-30 Astrazeneca Ab [1,2,3]-triazolo[4,5-d] pyrimidine compounds

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5561134A (en) * 1990-09-25 1996-10-01 Rhone-Poulenc Rorer Pharmaceuticals Inc. Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties
JP4084415B2 (ja) * 1995-07-11 2008-04-30 アストラゼネカ・アクチエボラーグ 新しい血小板凝集抑制剤
ATE213245T1 (de) * 1996-12-20 2002-02-15 Triazolo(4,5-d)pyrimidinyl-derivate und ihre verwendung als medikamente
AR017014A1 (es) 1997-07-22 2001-08-22 Astrazeneca Ab Compuestos de triazolo [4,5-d]pirimidina, composiciones farmaceuticas, uso de los mismos para preparar medicamentos y procesos para la preparacionde dichos compuestos
ID24701A (id) * 1997-07-25 2000-08-03 Gilead Sciences Inc Komposisi dan metode sintesis analog nukleotida
GB0013407D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Forms of a chemical compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6525060B1 (en) * 1998-12-04 2003-02-25 Astrazeneca Uk Limited Triazolo(4,5-d)pyrimidine compounds
US6713483B1 (en) * 1999-11-15 2004-03-30 Astrazeneca Ab [1,2,3]-triazolo[4,5-d] pyrimidine compounds
US20030148888A1 (en) * 2000-06-02 2003-08-07 Ulf Larsson Novel triazolo pyrimidine compounds

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100004444A1 (en) * 2000-06-02 2010-01-07 Astrazeneca Ab Novel Triazolo pyrimidine compounds
US20080234481A1 (en) * 2000-06-02 2008-09-25 Astrazeneca Ab Novel triazolo pyrimidine compounds
US20060041132A1 (en) * 2000-06-02 2006-02-23 Astrazeneca Ab Novel triazolo pyrimidine compounds
US7381828B2 (en) 2000-06-02 2008-06-03 AstraZēneca AB Triazolo pyrimidine compounds
US8273879B2 (en) 2000-06-02 2012-09-25 Astrazeneca Ab Triazolo pyrimidine compounds
US20070049755A1 (en) * 2000-06-02 2007-03-01 Astrazeneca Ab Novel triazolo pyrimidine compounds
US20110218330A1 (en) * 2000-06-02 2011-09-08 Astrazeneca Ab Novel triazolo pyrimidine compounds
US7566722B2 (en) 2006-10-31 2009-07-28 Janssen Pharmaceutica, N.V. Triazolopyrimidine derivatives as ADP P2Y12 receptor antagonists
US20080108635A1 (en) * 2006-10-31 2008-05-08 Han-Cheng Zhang Triazolopyrimidine derivatives as ADP P2Y12 receptor antagonists
WO2009064249A1 (en) * 2007-11-15 2009-05-22 Astrazeneca Ab A process for the preparation of (3ar,4s, 6r, 6as)-6-amino-2, 2- dimethyltetrahydro-3ah-cyclopenta[d] [1,3] dioxol-4-ol dibenzoyl-l-tartrate and to products of said process
US7816545B2 (en) 2007-11-15 2010-10-19 Astrazeneca Ab Process 054
US20110009647A1 (en) * 2007-11-15 2011-01-13 Astrazeneca Ab Process 054
US20090182157A1 (en) * 2007-11-15 2009-07-16 Rhony Aufdenblatten New Process 054
AU2008321575B2 (en) * 2007-11-15 2012-07-05 Astrazeneca Ab A process for the preparation of (3aR,4S, 6R, 6aS)-6-amino-2, 2- dimethyltetrahydro-3aH-cyclopenta[d] [1,3] dioxol-4-ol dibenzoyl-L-tartrate and to products of said process
CN101861310A (zh) * 2007-11-15 2010-10-13 阿斯利康(瑞典)有限公司 一种制备(3aR,4S,6R,6aS)-6-氨基-2,2-二甲基四氢-3aH-环戊二烯并[d][1,3]间二氧杂环戊烯-4-醇二苯甲酰基-L-酒石酸盐的方法及所述方法的产物
RU2477277C2 (ru) * 2007-11-15 2013-03-10 Астразенека Аб СПОСОБ ПОЛУЧЕНИЯ (3aR,4S,6R,6aS)-6-АМИНО-2,2-ДИМЕТИЛТЕТРАГИДРО-3aН-ЦИКЛОПЕНТА[d][1,3]ДИОКСОЛ-4-ОЛ-ДИБЕНЗОИЛ-L-ТАРТРАТА И ПРОДУКТЫ УКАЗАННОГО СПОСОБА
TWI496776B (zh) * 2007-11-15 2015-08-21 Astrazeneca Ab 製備(3aR,4S,6R,6aS)-6-胺基-2,2-二甲基四氫-3aH-環戊并[d][1,3]二氧雜環戊烯-4-醇之純非對映異構性之二苯甲醯-L-酒石酸鹽之方法

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