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  Cristalline and amorphous form of a triazolo (4,5-d) pyridimine compoundRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The Cyclos, Polycyclo Ring System Having 1,3-diazine As One Of The Cyclos, A Ring Nitrogen Is Shared By The Two Cyclos Of The Bicyclo Ring System (e.g., Pyrrolo [1,2-a]pyrimidine, Imidazo[1,2-a]pyrimidine, Etc.),The Patent Description & Claims data below is from USPTO Patent Application 20070293513. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] 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. [0002] 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. Thus, in the manufacture of commercially viable and pharmaceutically acceptable, 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. [0003] Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although 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. [0004] It has been found that adenosine 5'-diphosphate (ADP) acts as a key mediator of thrombosis. ADP-induced platelet aggregation is mediated by the P.sub.2T receptor subtype located on the platelet membrane. The P.sub.2T receptor (also known as P2Y.sub.ADP or P2T.sub.AC) is 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. Pharmacology (1998) 124, 157-164. Recently it has been shown that antagonists at this receptor offer significant improvements over other anti-thrombotic agents (see J. Med. Chem. (1999) 42, 213). International Patent Application WO 9905143 discloses generically a series of triazolo[4,5-d]pyrimidine compounds having activity as P.sub.2T (P2Y.sub.ADP or P2T.sub.AC) antagonists. The compound of formula (I) (as depicted below) is embraced by the generic scope of International Patent Application WO 9905143 but is not specifically disclosed therein. This compound exhibits high potency as a P.sub.2T (P2Y.sub.ADP or P2T.sub.AC) antagonist. It also has a surprisingly high metabolic stability and bioavailibility. [0005] Accordingly the present invention relates to the compound of formula (I): in a substantially crystalline form. [0006] The compound of formula (I) is conventionally named: {1S-[1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.]}-3-(7- {[2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazo- lo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. [0007] 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. [0008] The different physical properties of polymorphic forms with respect to each other and with respect to the amorphous state may influence markedly the chemical and pharmaceutical processing of a compound, particularly when the compound is prepared or used on an industrial scale. [0009] In one aspect of the invention, the preferred crystalline form of the compound of formula (I) is in the form of Polymorph I, Polymorph II, Polymorph III and/or Polymorph IV. [0010] In an alternative aspect of the invention, a preferred crystalline form of the compound of formula (I) is Polymorph I. [0011] In another aspect of the invention, a preferred crystalline form of the compound of formula (I) is Polymorph II. [0012] In a further aspect of the invention, a preferred crystalline form of the compound of formula (I) is Polymorph III. [0013] In an additional aspect of the invention, a preferred crystalline form of the compound of formula (I) is Polymorph IV. [0014] In a further aspect of the invention, the compound of formula (I) is in a substantially amorphous form. In 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 .alpha.. [0015] We have isolated the compound of formula (I) in crystalline and amorphous forms. These forms may exist substantially or essentially free of water ("anhydrous" forms). Therefore in one aspect of the invention there is provided an 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 is molecule (less than 40% hydrated). Preferably, the anhydrous form contains less than 0.1 water molecules per compound molecule. [0016] 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. [0017] Polymorph I has an onset of melting which is in the range 146-152.degree. C., for example about 151.degree. C., when it is substantially pure and essentially in the anhydrous form. [0018] Polymorph II has an onset of melting that is in the range 136-139.degree. C., for example about 137.5.degree. C., when it is substantially pure and essentially in the anhydrous form. [0019] Polymorph III has an onset of melting that is in the range 127-132.degree. C., for example about 132.degree. C., when it is substantially pure and essentially in the anhydrous form. [0020] Polymorph IV has an onset of melting which is typically about 139.degree. C., when it is substantially pure and essentially in the anhydrous form. [0021] Form .alpha. typically undergoes a glass transition followed by crystallisation into one of the above Polymorph forms, for example Polymorph II, prior to melting. [0022] The melting points were determined using differential scanning calorimetry (DSC) using Perkin Elmer DSC7 instrumentation. 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. [0023] 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.degree. (.+-.0.1.degree.), 20.1.degree. (.+-.0.1.degree.), 20.7.degree. (.+-.0.1.degree.), 21.0.degree.(.+-.0.1.degree.) and 21.3.degree. (.+-.0.1.degree.) 2.theta.. More preferably, substantially pure and essentially anhydrous Polymorph I has an X-ray powder diffraction pattern containing specific peaks at 5.3.degree. (.+-.0.1.degree.), 8.0.degree. (.+-.0.1.degree.), 9.6.degree. (.+-.0.1.degree.), 13.9.degree. (.+-.0.1.degree.), 15.3.degree. (.+-.0.1.degree.), 20.1.degree. (.+-.0.1.degree.), 20.7.degree. (.+-.0.1.degree.), 21.0.degree. (.+-.0.1.degree.), 21.3.degree. (.+-.0.1.degree.), 26.2.degree. (.+-.0.1.degree.) and 27.5.degree. (.+-.0.1.degree.) 2.theta.. [0024] 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.degree. (.+-.0.1.degree.), 13.5.degree. (.+-.0.1.degree.), 18.3.degree. (.+-.0.1.degree.), 22.7.degree. (.+-.0.1.degree.) and 24.3.degree. (.+-.0.1.degree.) 2.theta.. More preferably, substantially pure and essentially anhydrous Polymorph II has an X-ray powder diffraction pattern containing specific peaks at 5.5.degree. (.+-.0.1.degree.), 6.8.degree. (.+-.0.1.degree.), 10.6.degree. (.+-.0.1.degree.), 13.5.degree. (.+-.0.1.degree.), 14.9.degree. (.+-.0.1.degree.), 18.3.degree. (.+-.0.1.degree.), 19.2.degree. (.+-.0.1.degree.), 22.7.degree. (.+-.0.1.degree.), 24.3.degree. (.+-.0.1.degree.), and 27.1.degree. (.+-.0.1.degree.), 2.theta.. Continue reading... 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