MXPA99011753A - Crystalline roxifiban - Google Patents

Abstract

Se produce un potente antagonista de la glucoproteina IIb/IIIa plaquetaria, el roxifibán, en forma cristalina. El roxifibán cristalino existe en dos formas polimórficas, designadas como Forma 1 y Forma 2. Estás formas polimórficas están caracterizada por difracción de rayos X en polvo y por RMN de carbono en estado sólido. Se describen composiciones farmacéuticas y métodos para el tratamiento o prevención de enfermedades mediadas por la agregación plaquetaria.

Description

ROXIFIBAN CRISTALINO FIELD OF THE INVENTION The potent antagonist of the platelet glycoprotein Ilb / IIIa, roxifiban, is produced in crystalline form. Crystal roxifiban exists in two polymorphic forms, designated as Form 1 and Form 2. These polymorphic forms are characterized by powder X-ray diffraction and solid state carbon NMR. Pharmaceutical compositions and methods for the treatment or prevention of diseases mediated by platelet aggregation are described. BACKGROUND OF THE INVENTION The present invention relates to crystalline forms of a potent glycoprotein antagonist.

Platelet IIb / IIIa, known as roxifiban. Roxifiban is a prodrug form of acetate salt methylester of a potent glycoprotein antagonist Ilb / IIIa platelet. It is a non-peptidic compound of isoxazoline represented by the following structural Formula: REF .: 31685 Roxifiban is known by the chemical name methyl-N- [2-. { 3- (4-for amidinophenyl) -isoxazolin-5- (R) -yl} -acetyl] -N - (n-butyloxycarbonyl) -2, 3- (S) -diaminopropionate. Roxifiban is covered by the description and claims of the Patent Cooperation Treaty Application No. PCT / US94 / 13155 (International Publication Number WO 95/14683) filed on November 14, 1994, the disclosure of which is incorporated herein by reference. This International Patent Application claims priority by the US Patent Application Serial No. 08 / 157,598 filed on November 24, 1993; North American Application Serial No. 08 / 232,961, filed on April 22, 1994 and North American Application Serial No. 08 / 337,920, filed on November 10, 1994, the description of each of which is incorporated herein by reference . The synthesis of the trifluoroacetic acid salt of the roxifiban base prodrug is described in Example 314B of the North American Patent. The active component of roxifiban has been found to inhibit the binding of soluble adhesive proteins, such as fibrinogen, von Willebrand factor, fibronectin and vitronectin, to the glycoprotein Ilb / IIIa platelet complex. As a consequence, the compound is capable of inhibiting platelet activation and aggregation induced by all known endogenous platelet agonists. Therefore, roxifiban is useful for the treatment or prevention of thromboembolic disorders, including thrombosis or embolism formation, pernicious platelet aggregation, thrombolysis after reocclusion, reperfusion injury, restenosis, atherosclerosis, heart attack, myocardial infarction and unstable angina. Other diseases that involve cell adhesion processes can also be treated by the administration of roxifiban. Such diseases include, for example, rheumatoid arthritis, asthma, allergies, adult respiratory syndrome, rejection of organ transplants, septic shock, psoriasis, contact dermatitis, osteoporosis, osteoarthritis, tumor metastasis, diabetic retinopathy, inflammatory disorders and inflammatory bowel disease. . The treatment or prevention of the above disorders is achieved by administering a therapeutically effective amount of roxifiban to a human or animal in need of such treatment or prevention. The compound can be administered enterally or parenterally in solid or liquid dosage forms. In general, doses of from about 0.001 to about 10 mg / kg of body weight per day, preferably from about 0.005 to about 1 mg / kg of body weight per day, are employed. The synthesis of roxifiban and its recovery as a substantially pure crystalline product are described by Zhang et al. , Tetrahedron Letters, 37 (26), 4455-58 (199_6); Zhang et al. , J. Org. Chem., 62 (8), 2469 (1997). Previously, roxifiban had not been known to exist in stable crystalline polymorphic forms. For manufacturing, purification and formulation of roxifiban, the drug is advantageously produced in a crystalline form. Accordingly, there is a need for stable crystalline forms of the drug and reliable and reproducible procedures for its manufacture. BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention relates to crystalline roxifiban. A related aspect resides in new roxifiban crystalline polymorphs, designated as Form 1 and Form 2. The polymorph Form 1 has been characterized and distinguished from the polymorph Form 2 by solid state carbon NMR analysis and powder X-ray diffraction. Other aspects of the present invention include pharmaceutical compositions of crystalline roxifiban and its polymorphs Form 1 and Form 2. The products of the crystalline prodrug of the present invention can be formulated in conventional solid pharmaceutical forms or can be used for the preparation of liquid dosage forms. combining a therapeutically effective amount of the crystalline prodrug with a pharmaceutically acceptable carrier In another aspect, the present invention includes a method for inhibiting the binding of a soluble adhesion protein to the glycoprotein Ilb / IIIa platelet complex, which comprises administering an amount of roxifiban sufficient crystalline to give or result that the platelet glycoprotein IIb / IIla comes into contact with an effective inhibitory amount of the active drug In particular aspects, the present invention includes methods for the treatment or prevention of various thrombus disorders embolic and other disorders involving cell adhesion, which comprise the administration of a therapeutically effective amount of a pharmaceutical composition comprising the novel crystalline forms of roxifiban of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention is illustrated by reference to the accompanying drawings, which are described below. Figure 1 is a spectrum of 13C CP / MAS solid state NMR of the crystalline polymorph Form 1 of roxifiban. Figure 2 is a spectrum of 13C CP / MAS solid state NMR of the crystalline polymorph Form 2 of roxifiban. Figure 3 shows powder X-ray diffractograms of the crystalline polymorphs Form 1 and Form 2 of roxifiban. Figure 4 is a standard curve that graphs the peak area ratios of the 13C CP / MAS NMR spectra of the mixtures of the polymorphs Form 1 and Form 2 of the roxifiban, versus the molar ratio of the polymorph Form 1 in such a mixture. DETAILED DESCRIPTION OF THE INVENTION In a first embodiment, the present invention provides crystalline roxifiban in substantially pure form. ~ In a more preferred embodiment, the crystalline roxifiban has a purity greater than 90 percent. In a second embodiment, the present invention provides the polymorph Form 1 of crystalline roxifiban in substantially pure form In a more preferred embodiment, crystalline roxifiban Form 1 has a purity of greater than 90 percent In another preferred embodiment, the polymorph Form 13 is characterized by a spectrum of C CP / MAS NMR having a doublet of peaks at 63 and 66 ppm.In a more preferred embodiment, the spectrum 13C CP / MAS solid state NMR of the polymorph Form 1, has a doublet of peaks at 19 and 21 ppm. In another preferred embodiment, the polymorph Form 1 of the crystalline roxifiban has a solid state 13C CP / MAS NMR spectrum substantially in accordance with that shown in Figure 1. In another preferred embodiment, the polymorph Form 1 is characterized by a diffraction pattern X-ray powder comprising values 2? 6.4 ± 0.2, 9.6 ± 0.2, 12. 5 ± 0.2, 14.7 ± 0.2, 19.3 ± 0.2, 21.5 ± 0.2, 22.5 ± 0.2, 23.2 ± 0.2, 25.2 ± 0.2, 27.5 ± 0.2 and 32.2 ± 0.2. In a more preferred embodiment, the powder X-ray diffraction pattern of the polymorph Form 1 is substantially devoid of a peak at a value of 2? from 13. 6 ± 0.2. In another preferred embodiment, the polymorph Form 1 is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in Figure 3. In a second embodiment, the present invention describes a pharmaceutical composition prepared by combining a therapeutically effective amount of the polymorph Form 1 with a pharmaceutically acceptable carrier. In a preferred embodiment, the pharmaceutical composition is in solid or liquid form. In an even more preferred embodiment, the pharmaceutical composition contains from about 0.1 to about 25 mg of the compound per unit dose. In a third embodiment, the present invention describes a pharmaceutical composition in solid pharmaceutical form, comprising a therapeutically effective amount of the polymorph Form 1 and a pharmaceutically acceptable carrier. In a preferred embodiment, the pharmaceutical composition is in the form of capsules, tablets, powders or granules and contains from about 0.1 to about 25 mg of the compound. In a fourth embodiment, the present invention describes a method for inhibiting the binding of a soluble adhesive protein to the platelet glycoprotein Ilb / IIIa complex comprising providing the polymorph Form 1 in an amount sufficient to cause the glycoprotein Ilb / IIIa platelet complex to enter contact with an effective inhibitory amount of the active substance. In a preferred embodiment, the soluble adhesive protein is fibrinogen, von Willebrand factor, fibronectin or vitronectin. In another preferred embodiment, the compound is administered to a human or an animal, to inhibit the binding of a soluble adhesive protein to the platelet glycoprotein Ilb / IIIa complex in vivo. In another preferred embodiment, the compound is provided to an extracorporeal device containing blood, to inhibit the binding of a soluble adhesive protein to the glycoprotein Ilb / IIIa platelet in vi tro complex. In a fifth embodiment, the present invention describes a method for the treatment or prevention of thromboembolic disorders that is selected from the group consisting of thrombus or embolus formation, pernicious platelet aggregation, reocclusion after thrombolysis, reperfusion injury, restenosis, atherosclerosis, heart attack, myocardial infarction and unstable angina, which comprises administering to a host in need of such treatment or prevention, a therapeutically effective amount of the polymorph Form 1. In a preferred embodiment, the compound is administered at a dose of about 0.001 to approximately 10 mg / kg of body weight per day. In another preferred embodiment, the compound is administered at a dose of about 0.005 to about 1 mg / kg of body weight per day. In a more preferred embodiment, the compound is administered for the treatment or prevention of myocardial infarction or heart attack. In the sixth embodiment, the present invention describes a method for the treatment or prevention of rheumatoid arthritis, asthma, allergies, adult respiratory syndrome, rejection of organ transplants, septic shock, psoriasis, contact dermatitis, osteoporosis, osteoarthritis, tumor metastasis. , diabetic retinopathy, inflammatory disorders and inflammatory bowel disease, which comprises administering to a host in need of such treatment or prevention, a therapeutically or prophylactically effective amount of the polymorph Form 1 _ In a seventh embodiment, the present invention describes the polymorph Form 1 of the crystalline roxifiban prepared by recrystallization of roxifiban from a mixed solvent system.

In an eighth embodiment, the present invention provides the polymorph Form 2 of crystalline roxifiban in substantially pure form. In a preferred embodiment, Form 2 of crystalline roxifiban has a purity greater than 90 percent. In another preferred embodiment, the polymorph Form 2 is characterized by a spectrum of 13C CP / MAS NMR in solid state having a single peak at 66 ppm and no significant peak at 63 ppm. In a more preferred embodiment, the spectrum of 1 C CP / MAS NMR in the solid state of the polymorph Form 2, has a single peak at 19 ppm and no significant peak at 21 ppm. In another preferred embodiment, the polymorph Form 2 has a spectrum of C CP / MAS NMR in the solid state substantially in accordance with that shown in Figure 2. In another preferred embodiment, the polymorph Form 2 is characterized by a diffraction pattern of lightning X powder comprising values 2? 6.4 ± 0.2, 9.6 ± 0.2, 12.4 ± 0.2, 13.6 ± 0.2, 18.8 ± 0.2, 20.7 ± 0.2, 22.6 ± 0.2, 23.T. ± 0.2, 25.1 ± 0.2, 26.1 ± 0.2, 27.3 ± 0.2 and 28.5 ± 0.2. In another preferred embodiment, the polymorph Form 2 is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in Figure 3. In a ninth embodiment, the present invention describes a pharmaceutical composition prepared by the combination of a Therapeutically effective amount of the polymorph Form 2, with a pharmaceutically acceptable vehicle. In a preferred embodiment, the pharmaceutical composition is in liquid or solid form. In an even more preferred embodiment, the pharmaceutical composition contains from about 0.1 to about 25 mg of the compound per unit dose. In a tenth embodiment, the present invention describes a pharmaceutical composition in the form of a solid dose unit, comprising a therapeutically effective amount of the polymorph Form 2 and a pharmaceutically acceptable carrier. In a preferred embodiment, the pharmaceutical composition is in the form of capsules, tablets, powders or granules and contains from about 0.1 to about 25 mg of the compound. In a eleventh embodiment, the present invention describes a method for inhibiting the binding of a soluble adhesive protein to the platelet glycoprotein Ilb / IIIa complex, which comprises providing the polymorph Form 2 in an amount sufficient to render the platelet glycoprotein Ilb / IIIa complex comes in contact with an effective inhibitory amount of the active substance. In a preferred embodiment, the soluble adhesive protein is fibrinogen, von Willebrand factor, fibronectoin or vitronectin. In another preferred embodiment, the compound is administered to a human or animal to inhibit the binding of a soluble adhesive protein to the platelet glycoprotein Ilb / IIIa complex in vivo. In another preferred embodiment, the compound is applied to an extracorporeal device containing blood to inhibit the binding of a soluble adhesive protein to the platelet glycoprotein Ilb / IIIa in vi tro complex. In a twelfth embodiment, the present invention describes a method for the treatment or prevention of thromboembolic disorders that are selected from the group consisting of thrombus or embolus formation, pernicious platelet aggregation, reocclusion after thrombolysis, reperfusion injury, restenosis, atherosclerosis, heart attack, myocardial infarction and unstable angina, which comprises administering to the host in need of such treatment or prevention, a therapeutically effective amount of the polymorph Form 2.

In a preferred embodiment, the compound is administered at a dose of about 0.001 to about 10 mg / kg of body weight per day. In another preferred embodiment, the compound is administered at a dose of about 0.005 to about 1 mg / kg of body weight per day. In a more preferred embodiment, the compound is administered for the treatment or prevention of myocardial infarction or heart attack. In a thirteenth modality, the present invention describes a method for the treatment or prevention of rheumatoid arthritis, asthma, allergies, adult respiratory syndrome, rejection of organ transplantation, septic shock, psoriasis, contact dermatitis, osteoporosis, osteoarthritis, tumor metastasis, diabetic retinopathy, inflammatory disorders and inflammatory bowel disease, which comprises administering to the host in need of such treatment or prevention, a therapeutically or prophylactically effective amount of the polymorph Form 1. In a fourteenth embodiment, the present invention describes the polymorph Form 2 of crystalline roxifiban, prepared by recrystallization of roxifiban from a mixed solvent system.SYNTHESIS Roxifiban is the acetate salt of the methyl ester of the prodrug of an optically pure enantiomer of a therapeutically active isoxazoline compound, which has the following structure: The synthesis of the trifluoroacetic acid salt of the methyl ester of the active drug substance (II) is described in Example 314B of the North American Patent PCT / US94 / 13155. As will be observed by the technicians in organic chemical synthesis, the process described herein can be adapted for the production of roxifiban by the substitution of acetic acid by trifluoroacetic acid in the final stage of the process. An alternative method for the production of crystalline roxifiban is described in the aforementioned publications of Zhang et al. This synthesis begins with the reaction of 4-cyanobenzaldehyde with hydroxyamine sulfate, to obtain 4-cyanobenzaldoxime, essentially using the method described by Kawase and Kakugawa, J. Chem. Soc., Perkin Trans I, 1979, p. 643. The reaction is illustrated with the following equation: The "reaction of 4-cyanobenzaldoxime with N-chlorosuccinymy in the presence of triethylamine generates the intermediate active nitrile oxide, which is further condensed with isobutyl vinylacetate to obtain a racemic mixture of a compound represented by the Formula: Enzymatic hydrolysis of the racemic mixture of the compound of Formula III with a lipase produces an isoxazoline acid in the optically pure R configuration. This isoxazoline acid is represented by the Formula: The enzymatic reaction can be carried out using a commercially available lipase preparation, such as PS30 lipase, available from Amano Enzyme.

The reaction can be carried out in a phosphate buffer solution, pH 7.5. The non-hydrolyzed isobutyl ester of Formula III having the S configuration can be racemised with a catalytic amount of potassium t-butoxide. By repeating this enzymatic epimerization process based on hydrolysis, the optically pure isoxazoline acid can be recovered in good yield. The optically pure isoxazoline acid of the Formula IV is coupled with the N-α-butoxycarbonyl-1,2-diaminopropionic acid methyl ester to obtain an optically pure intermediate of the Formula: (V) The optically pure N-α-butoxycarbonyl-1,2-diaminopropionic amino acid is commercially available (for example, in Bachem) and can be transformed into its methyl ester by reaction with methanol in the presence of thionyl chloride. Compound V is transformed into the imidate intermediate by the Pinner reaction (Alien et al., J. Am. Chem. Soc. (1958) 80, 591; Zhang et al., Tetrahedron Letters, (1996) 37 (26) , 4455-58). The imidate intermediate can be reacted with ammonium acetate to obtain the desired acetate salt, roxifiban (I) with a good yield. The crystalline roxifiban can be recovered from the reaction medium and dried, to obtain crystalline roxifiban with a good yield. "This procedure has been found to produce a mixture of two crystalline polymorphs of roxifiban, designated as Form 1 and Form 2. The recrystallization of roxifiban from solutions diluted in methanol, produces the polymorph Form 1. The recrystallization solution, advantageously, contains more than about 20 ml methanol per gram of roxifiban, preferably more than about 25 ml of methanol per gram of roxifiban. • higher concentrations of roxifiban, recrystallization from methanol often produces mixtures of the polymorphs Form 1 and Form 2. The production of the polymorph Form 1 is favored by the relatively rapid cooling of the methanol solution. Advantageously, a solution in dilute methanol of roxifiban is heated to a temperature of about 50 about 65 ° C, to effect complete dilution of the compound. Subsequently, this solution is cooled to < 35 ° C, to cause the crystallization of a product that is predominantly Form 1.

The polymorph Form 1 can also be produced by the addition of antisolvents, such as methyl acetate, to the solutions diluted in methanol of the compound. Alternatively, the addition of hot xylene to heated roxifiban-methanol solutions, followed by rapid distillation of the methanol from the solution, produces a crystalline product that is predominantly the polymorph Form 1. A process has been found that produces the crystalline polymorph. 1 of roxifiban in a substantially pure form, which is described in Example 2 below. The production of the polymorph Form 2 is favored by the relatively slow cooling of the recrystallization solution. Advantageously, a solution containing less than about 20 ml of solvent per gram of roxifiban, preferably less than about 10 ml of solvent per gram of roxifiban, is heated to a temperature of about 50 to about 65 ° C to carry out the Complete dissolution of the compound. Then, this solution is cooled to < 35 ° C to cause the recrystallization of a product that is predominantly Form 2. The polymorph Form 2 can be recovered with a good yield and high purity by slow cooling of the concentrated solutions of roxifiban in a solvent mixture methanol-acetic acid -acetonitrile. A preferred solvent mixture contains methanol-acetic acid-acetonitrile in a volume ratio of about 10: 1.5: 10. The polymorphs Form 1 and Form 2 of crystalline roxifiban can be easily distinguished by powder X-ray diffraction and carbon NMR in the solid state. The X-ray diffractograms of the polymorphs Form 1 and Form 2 are shown in Figure 3. The main peaks of the diffractogram for the polymorph Form 1 occur at values of 2? of approximately 6.4, 9.6, 12.5, 14.7, 19.3, 21.5, 22.5, 23.2, 25.2, 27.5 and 32.2. The relative intensities of the peaks may vary, depending on the technique of sample preparation, the method of assembling the sample and the particular instrument used. Also, variations of the instrument and other factors can affect the values 2 ?; therefore, peak assignments can vary by a value of plus or minus 0.2. The region of the diffractogram that is most useful for distinguishing the polymorphs, Form 1 and Form 2, occurs in the region of approximately 13.6 °. The polymorph Form 2 exhibits a strong peak at this angle, while the diffractogram of the polymorph Form 1 is substantially flat in this region.

The NMR analysis of solid state carbon is also a useful procedure for the polymorphic characterization of crystalline roxifiban. The spectra of 13C NMR in solid state using the CP / MAS technique, confirm the existence of the polymorphs Form 1 and Form 2 of roxifiban. As illustrated in the spectrum of Figure 1, the polymorph Form 1 has a lower symmetry structure, which is evidenced by the occupation of the n-butyl group in one of the crystallographically non-equivalent positions. In contrast, as illustrated in the spectrum of Figure 2, the n-butyl group of the polymorph Form 2 resides in a single defined structural location. Thus, the spectrum of the polymorph Form 1 is characterized by a doublet of peaks at 63 and at 66 ppm and at 19 and 21 ppm. The spectrum of the polymorph Form 2 exhibits simple peaks at 66 and 19 ppm. The 13C NMR procedure in the solid state can be used for the quantitative analysis of mixtures of the polymorphs Form 1 and Form 2. The ratio of the area of the peaks to 63 ppm with respect to the area of the peaks at 66 ppm, correlates well with the molar ratio of the polymorphs Form 1 with respect to Form 2. In addition, the ratio of the area of the peaks to 21 ppm with respect to the area of the peaks at 19 ppm also correlates well with the molar ratio. Form 1: Form 2. A standard curve prepared by regression analysis of the relationships obtained from the mixtures of the polymorphs, it can be prepared and used for analysis. Such a calibration curve is illustrated in Figure 4 of the drawings. Since the solid state carbon NMR procedure can be used for the quantitative analysis of polymorphic mixtures, the present invention is not restricted to any particular method of analysis for the identification of the desired polymorphs. Isothermal microcalorimetry and phase solubility studies have revealed that the thermodynamic solubilities of the two forms of roxifiban are very similar. It is thought that the polymorph Form 2 is more stable at temperatures below about 132 ° C, while the polymorph Form 1 is slightly more stable at temperatures above 132 ° C. These differences are minor and the product Form 1 is polymorphically stable after storage for 19 months at room temperature. The spontaneous transformation of the polymorph Form 1 to the polymorph Form 2 has not been observed. The aqueous solubilities of the crystalline polymorphs Form 1 and Form 2 of roxifiban are very close and no biological differences of the two polymorphic forms have been observed. Parameters of cell units AND atomic coordinates of the crystalline polymorphs Form 1 and Form 2 can be determined by single-crystal X-ray diffraction techniques if sufficiently large crystals are available. If Forms 1 and 2 of roxifiban form crystals in needles or plates, they may never reach a volume large enough for simple diffraction patterns. In general, the analysis of the two forms in studies of a single crystal, shows that the crystals are paired or agglomerated. In this case, transmission electron microscopy (MET) and powder X-ray diffraction can be used to determine cell units. DEFINITIONS The term "mixed solvent system" as used herein, refers to a solvent system comprising a mixture of two or more solvents. Preferred mixed solvent systems in the present invention are mixed solvent systems comprising acetic acid, acetonitrile and acetone or acetic acid, anisole and acetone. The present invention describes polymorphs in substantially pure form. As used herein, the term "substantially pure" means a compound having a purity greater than 90 percent, including 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100 by hundred. The crystalline forms of roxifiban described in the present invention can be formulated in pharmaceutical compositions and use e? therapeutic and prophylactic methods, as described in the aforementioned International Patent Application No. PCT / US94 / 13155. For example, in addition to its use in the treatment of thromboembolic disorders and other diseases related to cell adhesion referred to above, the new products of crystalline roxifiban of the present invention can be used in surgery of peripheral arteries (arterial grafts, carotid endoarterectomy) and in cardiovascular surgery, where the manipulation of arteries and organs and / or the interaction of platelets with artificial surfaces, cause aggregation and the consumption of platelets and aggregate platelets can form thrombi and thromboembolism. The formulations containing the compounds of the present invention can be administered to surgical patients to prevent thrombus formation and thromboembolism. Such crystalline compounds can also be used in extracorporeal devices, to inhibit the interaction of glycoprotein IIb / IIla platelet found in the platelet membrane, with fibrinogen or other cell adhesion proteins absorbed at the surface of the extracorporeal circuit. The crystalline forms of roxifiban of the present invention can be administered in oral dosage forms such as tablets., capsules (each of which includes formulations of sustained release or regulated release), pills, powders, granules, elixirs, dyes, suspensions, syrups and emulsions. Similarly, they can also be given intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly.; or by transdermal iontophoretic administration; all of these forms of administration being known to technicians in the pharmaceutical field. When it dissolves, roxifiban loses its crystalline structure; however, it can be used for the preparation of liquid formulations in which the drug is dissolved or suspended. In addition, crystalline roxifiban can be incorporated into solid formulations such as tablets, capsules, suspensions and the like. A therapeutically effective amount of crystalline roxifiban is combined with a pharmaceutically acceptable carrier, to produce the pharmaceutical compositions of the present invention. The term "therapeutically effective amount" as used herein means an amount which, when administered alone or with an additional therapeutic agent, is effective to prevent or ameliorate the disease or disorder, or the progress of the disease or disorder. . Pharmaceutical forms (pharmaceutical compositions) suitable for administration will generally contain from about 0.05 to about 50 mg of crystalline roxifiban per unit dose. In these pharmaceutical compositions, the crystalline roxifiban would ordinarily be present in an amount of about 0.1 to 95% by weight, based on the total weight of the composition. For oral administration in the form of tablets or capsules, the crystalline roxifiban can be combined with a pharmaceutically acceptable, inert and non-toxic carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. For oral administration in liquid form, crystalline roxifiban can be combined with any pharmaceutically acceptable, inert, non-toxic carrier, such as ethanol, glycerol, water and the like. When desirable or necessary, suitable binders, lubricants, disintegrating agents, flavorings and colorants may be incorporated. Suitable binders include starch, gelatin, natural sugars, glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia gum, tragacanth or sodium alginate, carboxymethylcellulose, propylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The crystalline roxifiban compounds of the present invention can also be formulated into compositions for intranasal or topical application, using delivery systems already known to those skilled in the art. Alternatively, cutaneous patches of transdermal iontophoretic administration can be used for the continuous delivery of the drug. Crystal roxifiban can also be administered in liposome distribution systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine. Crystal roxifiban can also be coupled with soluble polymers as targeting drug vehicles. Such polymers include the polyvinylpyrrolidone-pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidophenol or polyethylene-polylysine oxide, substituted with palmitoyl residues. In addition, crystalline roxifiban can be coupled with a class of biodegradable polymers useful for achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals , polydihydropyrans, polycyanoacrylates and copolymers of amphipathic or crosslinked blocks of hydrogels. The crystalline roxifiban hard gelatin capsules can contain the compound and powdery vehicles such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to prepare compressed tablets. Both the tablets and the capsules can be manufactured as sustained release products to provide a continuous release of the drug for a number of hours. The tablets may be coated with sugar or a film may be applied to mask any unpleasant taste and to protect the tablet from the atmosphere, or an enteric layer may be applied for selective disintegration in the gastrointestinal tract. In general, water, a suitable oil, saline solution, aqueous dextrose solution (glucose) and solutions of related sugars and glycols, such as propylene glycol or polyethylene glycols, are suitable vehicles for parenteral solutions. Solutions for parenteral administration are prepared by dissolving the crystalline roxifiban in the vehicle and, if necessary, adding buffer substances. Antioxidant agents such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. You can also use citric acid and its salts and sodium EDTA. Parenteral solutions may contain preservatives such as benzalkonium chloride, methylparaben or propylparaben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., which is a standard text of reference in this field. Representative useful dosage forms for the administration of crystalline roxifiban of the present invention can be illustrated as follows: Capsules A large number of capsule units are prepared by filling two-piece standard hard gelatin capsules, each with 2 milligrams of crystalline roxifiban, 150 milligrams of lactose, 50 milligrams of cellulose and 6 milligrams of magnesium stearate. Soft Gelatin Capsules A mixture of crystalline roxifiban is prepared in a digestible oil such as soybean oil, cottonseed oil or olive oil and is injected by means of a positive displacement pump into the gelatine of soft gelatine capsules containing 2 milligrams of roxifiban. The capsules are washed and dried. Tablets A large number of tablets were prepared by conventional procedures, so that the unit dose had 2 milligrams of crystalline roxifiban, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings were applied to increase tastability or to delay absorption. Injectables A suitable parenteral composition is prepared for administration by injection, stirring 0.2% by weight of crystalline roxifiban in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium fluoride and sterilized.

Suspension An aqueous suspension is prepared for oral administration, so that every 5 ml contains 2 mg of finely divided crystalline roxifiban, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanilla.

ANALYTICAL METHODS Powdered X-ray Diffraction X-ray powder diffraction data was obtained with a Philips 3720 automated powder diffractometer. The samples were batch processed with a multi-position sample changer model PW 1775. The diffractometer was equipped with a variable slot (? compensating slot), a scintillation counter and a graphite monochromator. The radiation was CuKa (40kV, 30mA). We collected data at room temperature from 2 to 60 degrees 2 ?; the step length was 0.02 degrees; the count time was 0.5 seconds per step. Samples were prepared in glass sample containers as a thin layer of solvent-free powder material. Solid State Carbon NMR The solid state NMR C spectra were acquired in a VRN-200S Varian NMR operating at 50.3 MHz for 13C using the CP / MAS technique. Approximately 200 mg of the sample was used in the acquisition of the spectra. All measurements were made at room temperature. Chemical changes were reported on the TMS scale using hexamethylbenzene as a secondary reference. The solid state resonance assignments were made using the interrupted decoupling pulse sequence in combination with the solution state of C experiments performed on a Varn 400 model NMR unit operating at 100 MHz. A positive assignment of the origin of. the signal multiplicities in the spectra, required additional experiments of C CM / MAS NMR at lower static field strengths. This was done on a 100 MHz spectrometer with a resonance frequency of 13C of 25.2 MHz. Diffraction of X-Rays in Synchrotron Powder The parameters of the cell unit and the two polymorphs of Roxifiban were determined by a combination of transmission electron microscopy (MET) and powder X-ray diffraction in synchrotron. The MET used a JEM-2000EX model microscope (at 200 kV accelerated voltage), equipped with a Gatan 1024 x 1024 CCD camera, to characterize the materials. X-ray powder diffraction patterns in synchrotron were collected in a Huber diffractometer with a linear beam DND-5BMB. A Si (111) analyzer and slots of the order of 1 x 8 mm were used in conjunction with a scintillation counter, to achieve the highest possible resolution and the best signal-to-noise ratio. EXAMPLES The present invention will be illustrated by the following Examples, which are not intended to limit it. EXAMPLE 1 Synthesis of Roxifiban Crystalline 4-Cyanobenzaldoxime. A solution of methanol (272.1 1), 4-cyanobenzaldehyde (50 kg, 381.3 mol) and hydroxylamine sulfate (36.1 kg, 219.7 mol) were stirred at 55-60 ° C for 3 hours and then water (272 1) was added. . The mixture was cooled to a temperature of 0 to 5 ° C and kept so for 30 minutes. The crude product was collected by filtration. The filtered pellet was washed with a mixed solvent consisting of cold methanol and water (ratio 2: 3, 735.0 1) and water (750.0 1) and dried under vacuum (60-70 ° C), at constant weight: 54.1 kg, 97% yield; p.f. 174-176 ° C; aH NMR 6 7.82 (2H), 7.88 (2H), 88.26 (ÍH), 12.00 (ÍH). / Analysis calculated for C8H6N20: C, 65.75; H, 4.14; N, 19.17. Found: C, 65.73; H, 4.26; N, 19.14. (-) 2- [3- (4-Cyanophenyl) -4,5-dihydro-5-isoxazolyl] -isobutyl (III) -acetate. To a solution of dimethylformamide (DMF) (262.0 1), 4-cyanobenzaldoxime (46 kg, 342.1 mol) and N-chlorosuccinimide (54 kg, 389.4 mol) was added isobutyl vinyl acetate (95 kg, 665.7 mol). The solution was collected at a temperature of 2 to 6 ° C and triethylamine (40 kg, 388.6 mol) was added slowly over a period of 4 hours. The reaction was stirred at the same temperature for an additional hour. Water was added (330.0 1) and hydrochloric acid (1 N, 49 1). The crude product was collected by filtration, washed with water (555.0 1) and redissolved in toluene (500.0 1, 40 ° C). The organic phase was washed with water (291.0 1) and dried by azeotropic distillation (stirring approximately 250 1 of toluene). Heptane (300.0 1) was added and the reaction mixture was cooled to a temperature of 0 to 5 ° C for 3 hours. The product was collected by filtration and washed with a toluene / heptane mixture (150.0 1, ratio 1: 2). The product was dried under vacuum at 55-60 ° C, at constant weight: 81.8 kg, 90% yield, m.p. 98-100 ° C; "" "H NMR (CDC13) d 0.96 (6H), 1.96 (ÍH), 2.70 (1H), 2.92 (ÍH), 3.15 (HH), 3.56 (HH), 3.90 (2H), 5.20 (HH), 7.70 (2H), 7.80 (2H). Analysis calculated for C 16 H 18 N 2 O 3: C, 67.12; H, 6.34; N, 9.78. Found: C, 67.06; H, 6.20; N, 9.76.

(R) -2- [3- (4-Cyanophenyl) -4,5-dihydro-5-isoxazolyl] -acetic acid. A suspension of H20 (597.0 1) NaH2P04-H20 (60.0 kg), aqueous NaOH (33%, 36.0 1), Triton X-100 (3.2 kg), compound III (40.0 kg, 139.7 mol) and lipase PS30 (4.0 kg, enzyme content of 8% ), was slowly heated to 40 ° C and maintained in a temperature range of 40 to 43 ° C until the resolution was complete (~ 16 hours). The pH of the reaction mixture was maintained between 7.4 and 8.0 and adjusted by the addition of an aqueous solution of 33% NaOH. The batch was cooled to a temperature of 20 to 25 ° C when the reaction was complete and the pH of the reaction mixture was adjusted to a value between 8.0 and 8.2 by the addition of an aqueous solution of NaOH (33%, 11.0 1). ). The crude s-ester that did not react was collected by filtration through a celite layer (20 kg) and washed with water (70 1). The crude ester was recycled through a racemization stage: XH NMR (CDC13) d 0.95 (6H), 1.8 (HH), 2.69 (ÍH), 2.91 (ÍH), 3.14 (ÍH), 3.54 (HH), 3.91 (2H), 5.13-5.23 (HH), 7.68- 7.78 (4H). The pH of the solution of the filtrate (-800 1) and isopropyl acetate (20 1) was adjusted to a value of 2.8 to 3.2 with concentrated hydrochloric acid (~ 57 kg). The crude acid product of Formula IV was precipitated, collected by filtration and washed with water (70 l). This crude product was crystallized from hot ethanol (525.0 1) to obtain the optically pure Formula IV compound. The isoxazoline of Formula IV was collected by filtration, washed with ethanol (76.0 1) and dried to constant weight: 12.3 kg, 77% yield based on the amount of a compound of Formula IV in the compound were obtained of Formula III; p.f. 198-200 ° C; XH NMR d 2.70 (2H), 3.20 (ÍH), 3.59 (ÍH), 5.00-5.10 (ÍH), 7.78-7.91 (4H), 12.44 (HH). 7 Calculated analysis for: C12H3.0N2O3: C, 62.61; H, 4.38; N, 12.17. Found: C, 62.39; H, 4.49; N, 11.98. Racemization of the S-ester to the compound of formula III. A solution of toluene (414.0 1) and crude s-ester (~ 120 kg wet weight) was heated to 50 ° C and filtered to remove celite (~ 40 kg). The filtered tablet was washed with toluene (72.0 1). The organic phases were combined and the combined was washed with brine (108.0 1). After removing the aqueous phase, the organic phase was dried by azeotropic distillation at a constant boiling point. (111 ° C). The batch was cooled to 40 ° C and potassium tert-butoxide in tert-butyl alcohol (1 N, 1.6 1) was added.

The reaction mixture was stirred (200 rpm) at 40 ° C until the racemisation was complete. The batch was cooled to a temperature of 20 to 25 ° C and water was added (108.0 1) The reaction mixture was neutralized by the addition of aqueous hydrochloric acid (1 N, 1.6 1) .The aqueous phase of the bottom was removed and the organic phase was concentrated by distillation, the reaction mixture was cooled to 60 ° C when ~ 380.0 1 of toluene were removed, heptane (115 1) was added to this solution and the reaction mixture was kept at 50 ° C for 15 minutes. 1 hour The mixture was cooled to a temperature of 0 to 5 ° C and maintained at that temperature for 2 hours The product of Formula IV was collected by filtration and washed with a solvent mixture of toluene and heptane (ratio 1: 2, 70 1) The product of Formula III was dried under vacuum (50-55 ° C) at constant weight: 17.3 kg, 87% yield was obtained. (R) -methyl-3- [[[ -3- (4-cyanophenyl) -4,5-dihydro-5-isoxazolyl] -acetyl] -amino] -N- (butoxycarbonyl) -L-alanine (V) A solution of acetonitrile (402.0 1), acid of Formula IV (12.0 kg, 52.10 mol), amine (22.4 kg, 57.30 mol) and thionyl chloride (6.8 kg, 57.30 mol) was stirred at a temperature of 0 to 5. ° C for 1 hour. To this solution was added diisopropylethylamine (22.2 kg, 172.00 mol) at 20 ° C over a period of 90 minutes. Water (612.0 1) was added after the reaction. The crude product of Formula V was precipitated. This crude product of Formula V was collected by filtration and washed with water (96.0 1). The precipitated wet pellet was dissolved with hot methanol (50-60 ° C, 311.0 1) and any insoluble particle was removed by filtration. The solution was cooled to a temperature of 0 to 5 ° C for 3 hours and the product was collected by filtration and washed with methanol (75.0 1). The product was dried under vacuum (55-60 ° C) at constant weight: 18.3 kg, 82% yield, m.p. 154-156 ° C; H NMR 0.92 (3H), 1.37 (2H), 1.59 (2H), 1.67 (ÍH), 2.58 (ÍH), 2.71 (ÍH), 3.22 (ÍH), 3.51 (ÍH), 3.67 (2H), 3.77 (3H) ), 4.06 (2H), 4.44 (HH), 5.14 (HH), 5.70 (HH), 6.38 (1H), 7.70 (2H), 7.77 (2H). / Analysis calculated for: C? 2H? Or N2? 6; C, 62 61; H, 4 38; N, 12 .17. Found: C, 62. 3 $; H, 44 49; N, 11. 98.

(R) -methyl-3- [[[3- [4- (aminoiminomethyl) -phenyl] -4,5-dihydro-5-isoxazolyl] -acetyl] -amino] -N- (butoxycarbonyl) -L- monoacetate Alanine (I). A solution of methyl acetate (55.8 1), methanol (4.8 1), HCl (9.6 kg) and the compound of Formula IV (12.0 kg, 27.88 mol) was cooled to -20 ° C and stirred at 3-5 ° C. psi (HCl) at 10 ° C for 27 hours. After the reaction, the HCl was removed in vacuo and methyl acetate (21.5 1) and methanol were added. (63.2 1). The residual HCl was neutralized with ammonia (2.5 kg) at a temperature below 10 ° C. The resulting ammonium chloride was removed by filtration. The filtered pellet was washed with methyl acetate and methanol (20.0 1).

Ammonium acetate (6 kg) was added to the filtrate and the reaction mixture was stirred at room temperature overnight. The crude product was collected by filtration to obtain DMP 754: 10.4 kg, 74% yield. EXAMPLE 2 Polymorph Form 1 of Crystalline Roxifiban A slurry of roxifiban (1.38 kg, 2.73 mol) in acetonitrile (5.5 1) was added to glacial acetic acid (2.77 1, 48.4 mol). This slurry was heated to 80 ° C and all the solids dissolved. Subsequently, the solution was cooled to a temperature of 40 to 45 ° C and acetone (12.5 1) was added over a period of 30 minutes. The resulting slurry was stirred at a temperature of 20 to 25 ° C for one hour, then cooled to a temperature of 0-5 ° C for one hour. The solids were filtered, rinsed with a solution of 10% methanol-acetone (11 1) and dried under vacuum at 65 ° C. This procedure produced 1.26 kg (91%) of the polymorph Form 1 of crystalline roxifiban. The powder X-ray diffraction analysis of this material was carried out in the manner described above. The diffractogram is shown in Figure 3. The diffractogram exhibits 2? 6.4 ± 0.2, 9.6 ± 0.2, 12.5 ± 0.2, 14.7 ± 0.2, 19.3 ± 0.2, 21.5 ± 0.2, 22.5 ± 0.2, 23.2 ± 0.2, 25.2 ± 0.2, 27.5 ± 0.2 and 32.2 ± 0.2. A C CP / MAS NMR in the solid state was also performed in the manner described above. The resulting spectrum is shown in Figure 1. The spectrum exhibits doubled peaks at 19/21 ppm and at 63/66 ppm, which are characteristic of the polymorph Form 1. It was determined that this material was the polymorph Form 1 of the substantially pure roxifiban, without any detectable amount of the polymorph Form 2. EXAMPLE 3 To a solution of roxifiban (2.0 g, 3.9 mmol) was precipitated by dissolving in methanol (15 ml) and acetic acid (3 ml) at reflux. Any insolubles were removed by filtration through celite; any amount of roxifiban that crystallized in the filter paper particles was well washed with 5 ml of hot methanol. The filtrate was reheated to reflux and once all the solids had dissolved, acetonitrile (20 ml) was added in a period of 10 minutes. The solution was heated for another 10 minutes to redissolve any solids that might have appeared during the addition of the acetonitrile and cooled slowly to room temperature over a period of 2 hours. Once cooling was initiated, the solution was seeded with traces of Form 2 crystals until a persistent opacity in suspension was observed. After 2 hours, the suspension was reheated to reflux and 30 ml of the distillate was removed while the volume was maintained with acetonitrile. The volume was further diluted with another 8 ml of acetonitrile and the slurry was cooled to 15 ° C in a period of 100 minutes. The crystals were filtered, washed with 15 ml of acetonitrile and dried under vacuum to obtain roxifiban (1.82 g, 91% recovery) as a white solid. Using a powder X-ray diffraction analysis, it was determined that this compound was Form 2 and no traces of Form 1 were found. EXAMPLE 4 Recrystallization was performed in a manner similar to that of Example 3, except that once that the exchange of solvents was complete, the reflux was maintained overnight. Processing continued subsequently in the same manner as in Example 3, to obtain roxifiban (1.83 g, 91% recovery) in the form of a white solid. Using a powder X-ray diffraction analysis, it was determined that this compound was Form 2 and no traces of Form 1 were detected. EXAMPLE 5 To a 100 ml flask was added Form 1 of roxifiban (3.6 g). , 6.1 mmol), 30 ml of methanol and ammonium acetate (0.47 g, 6.1 mmol). The mixture was heated to reflux gently with vigorous stirring and the suspension was stirred at reflux for 6 hours. Subsequently, the mixture was cooled slowly to room temperature over a period of 4 hours. The solids were filtered and washed with 20 ml of a solvent mixture of methanol and acetonitrile (1: 1, v / v). The solids were dried under vacuum to obtain roxifiban (3.1 g, 86% recovery) in the form of white needles. Using a powder X-ray diffraction analysis, it was determined that this compound was Form 2 and no traces of Form 1 were detected. EXAMPLE 6 To a 3 1 flask was added roxifiban (108.0 g, 0.182 mmol, mixture of Forms 1 and 2), ammonium acetate (15.2 g, 0.182 mmol) and 1100 ml of methanol. The mixture was heated to reflux and the resulting suspension was stirred for 4 hours. Subsequently, the mixture was cooled to 10 ° C in a period of 5 hours. The solids were collected and washed with 400 ml of a solvent mixture of methanol and acetonitrile (1: 1, v / v). The solids were dried under vacuum to obtain roxifiban (101.0 g, 93.5% recovery) of white needles, with 99.9% area and 100.6% by weight purity, determined by HPLC. Using powder X-ray diffraction analysis, it was determined that this product was Form 2 of roxifiban and no traces of Form 1 were found. EXAMPLE 7 Powder difractions were taken in synchrotron from Roxifiban samples of Forms 1 and 2, in order to determine the cell unit parameters of the two Shapes. Nine repetitions of the test were performed using an identical optic: crystal monochromator Si (111), a Si (111) glass analyzer and a slot Soller Two wavelengths were used: 0.49617 Á and 1.00006 Á. Samples were prepared as follows: Sample preparation wavelength Form 1 in a 1.0 mm capillary 0.49617 Á Form 1 in a capillary of 1.5 mm F? -_ ma 2 in a capillary of 1.0 mm Form 2 in a capillary of 1.5 mm E pta 1 mentada sc ± re anger plaque without reaching ptafi? R_ic__d 1.00006? Efcrpa 1 pcptada sc ± re a flat plate l__ag_r_5b to px__u_d_____d -Tcpra 2 -irritada scfcre a flat flat without reaching pc fin_______d Rune 2 mentioned sc ± re ina plate plaia "got to p_Ofir_______d rrra 1 and 2 nuil ptl_ scire a flat plate to arrive to pxf_p_t__ _d Determination of the Unit of 'Cell of Form 1: The transmission electron microscopy (TEM) suggested that the cell of Form 1 was of low symmetry, either monoclinic or triclinic, where two of the three axes of the cell were of approximately 5 and 9-10 Á and an angle of 81 °. The synchrotron patterns showed that the third axis was much longer (approximately 27-28 Á). The volume per molecule is approximately 648 A, which is compatible with two molecules per cell. The cell parameters were refined with CELLREF and the numbers were used in a routine adjustment test of LeBail in GSAS. The refined triclinic cell unit parameters, being the separation group Pl and Z = 2, provided the final cell unit determined for the polymorph Form 1. FORM 1 _ to ß Value: 5.02349 28.07480 9.29536 98.533 98.498 Sigma: 0.00047 0.00228 0.00092 0.006 0.009 and V Value: 92,244 1279,712 Sigma: 0.008 0.208 Determination of the Cell Unit of Form 2: The results of transmission electron microscopy (MET) indicated that the values a, c and ß of Forms 1 and 2 are similar. The peaks in the pattern of Form 2 could not be indexed unless one of the edges of the cell was duplicated. "This requires that four molecules reside in the cell and as such the cell is likely to be monoclinic, with a group of separation P21. The prolonged axis was assumed to be, because the diffraction pattern of MET suggested that the projection from 5 to 9 Á had an angle of 81 °. Adjusting the angles a. Y ? at 90 °, while adjusting the angles a, c and β, a cell consistent with the pattern of Form 2 was obtained. The cell parameters were refined by CELLREF and the numbers were used in a routine LeBail adjustment test in GSAS to determine the final cell unit for the polymorph Form 2. FORM 2 to ß Value: 4.99190 54.77106 9.37211 90.000 99.154 Sigma: 0.00175 0.02405 0.00325 0.000 0.037 Y V Value: 90.000 2529.806 Sigma: 0.000 1.461 It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (50)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. Crystal Roxifiban.
2. 2. The crystalline compound according to claim 1, characterized in that it is in substantially pure form.
3. 3. The compound according to claim 2, characterized in that substantially pure means more than 90 percent purity.
4. 4. The polymorph Form 1 of crystalline roxifiban.
5. 5. The compound according to claim 4, characterized in that it is in substantially pure form.
6. 6. The compound according to claim 5, characterized in that substantially pure means greater than 90 percent purity.
7. 7. The polymorph Form 1 according to claim 4, characterized by a spectrum of 13C CP / MAS NMR in solid state that has a doublet of peaks at 63 and at 66 ppm.
8. 8. The polymorph Form 1 according to claim 7, characterized in that the spectrum of C CP / MAS NMR in solid state has a peak double at 19 and at 21 ppm.
9. 9. The polymorph Form 1 according to claim 4, characterized in that the spectrum of C CP / MAS NMR in solid state is substantially concordant with that shown in Figure 1.
10. 10. The polymorph Form 1 according to claim 4, characterized by a powder X-ray diffraction pattern comprising 2? 6.4 ± 0.2, 9.6 ± 0.2, 12.5 ± 0.2, 14.7 ± 0.2, 19.3 ± 0.2, 21.5 ± 0.2, 22.5 ± 0.2, 23.2 ± 0.2, 25.2 ± 0.2, 27.5 ± 0.2 and 32.2 ± 0.2.
11. 11. The polymorph Form 1 according to claim 10, characterized in that the X-ray diffraction pattern is substantially devoid of a peak at a value of 2? of 13.6 ± 0.2.
12. 12. The polymorph Form 1 according to claim 4, characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in Figure 3.
13. 13. A pharmaceutical composition characterized in that it is prepared by combining a therapeutically effective amount of the compound according to claim 4, with a pharmaceutically acceptable carrier.
14. 14. The pharmaceutical composition according to claim 13, characterized in that it is in solid or liquid form.
15. 15. The pharmaceutical composition according to claim 14, characterized in that it contains from about 0.1 to about 25 mg of the compound per unit dose.
16. 16. A pharmaceutical composition in the form of a solid dose unit, characterized in that it comprises a therapeutically effective amount of the compound according to claim 4 and a pharmaceutically acceptable carrier.
17. 17. The pharmaceutical composition according to claim 16, characterized in that it is in the form of capsules, tablets, powders or granules and contains from about 0.1 to about 25 mg of the compound.
18. 18. A method for inhibiting the binding of a soluble adhesive protein to the platelet glycoprotein Ilb / IIIa complex, characterized in that it comprises providing the compound according to claim 4 in an amount sufficient to cause the glycoprotein Ilb / IIIa platelet complex to come in contact with an effective inhibitory amount of the active drug substance.
19. 19. The method according to claim 18, characterized in that the soluble adhesive protein is fibrinogen, von Willebrand factor, fibronectin or vitronectin.
20. The method according to claim 18, characterized in that the compound is administered to a human or an animal, to inhibit the binding of a soluble adhesive protein to the platelet glycoprotein Ilb / IIIa complex in vivo.
21. 21. The method according to claim 18, characterized in that the compound is applied to an extracorporeal device containing blood, to inhibit the binding of a soluble adhesive protein to the platelet glycoprotein Ilb / IIIa in vi tro complex.
22. 22. A method for the treatment or prevention of thromboembolic disorders that are selected from the group consisting of thrombus formation or emboli, pernicious platelet aggregation, reocclusion after thrombolysis, reperfusion injury, restenosis, atherosclerosis, heart attack, myocardial infarction and unstable angina, characterized in that it comprises administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound according to claim 4.
23. 23. The method according to claim 22, characterized in that the compound is administered at a dose of from about 0.001 to about 10 mg / kg of body weight per day.
24. 24. The method according to claim 22, characterized in that the compound is administered at a dose of from about 0.005 to about 1 mg / kg of body weight per day.
25. 25. The method according to claim 24, characterized in that the compound is administered for the treatment or prevention of myocardial infarction or heart attack
26. 26. A method for the treatment or prevention of rheumatoid arthritis, asthma, allergies, syndrome adult respiratory, rejection of organ transplants, septic shock, psoriasis, contact dermatitis, osteoporosis, osteoarthritis, tumor metastasis, diabetic retinopathy, inflammatory disorders or inflammatory bowel disease, characterized in that it comprises administering to a host in need of such treatment or prevention, a therapeutically or prophylactically effective amount of a compound according to claim 4.
27. 27. The polymorph Form 1 of crystalline roxifiban, characterized in that it is prepared by recrystallization of roxifiban from a mixed system of solvents.
28. 28. The polymorph Form 2 of crystalline roxifiban.
29. 29. The compound according to claim 28, characterized in that it is in substantially pure form.
30. 30. The compound according to claim 29, characterized in that substantially pure means greater than 90 percent purity.
31. 31. The polymorph Form 2 according to claim 28, characterized by a spectrum of 13C CP / MAS solid state NMR having a single peak at 66 ppm and no significant peaks at 63 ppm.
32. 32. The polymorph Form 2 according to claim 31, characterized in that the spectrum of 13C CP / MAS NMR in solid state has a single peak at 19 ppm and no significant peak at 21 ppm.
33. 33. The polymorph Form 2 according to claim 28, characterized by a spectrum of C CP / MAS NMR in the solid state substantially in accordance with that shown in Figure 2.
34. 34. The polymorph Form 2 according to claim 28, characterized by a powder X-ray diffraction pattern comprising 2? 6.4 ± 0.2, 9.6 ± 0.2, 12.5 ± 0.2, 13.6 ± 0.2, 18.8 ± 0.2, 20.7 ± 0.2, 22. 6 ± 0.2, 23.1 ± 0.2, 25.1 ± 0.2, 27.3 ± 0.2 and 28.5 ± 0.2.
35. 35. The polymorph Form 2 according to claim 28, characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in Figure 3.
36. 36. A pharmaceutical composition characterized in that it is prepared by combining an amount Therapeutically effective compound according to claim 28, with a pharmaceutically acceptable carrier.
37. 37. The pharmaceutical composition according to claim 36, characterized in that it is in solid or liquid form.
38. 38. The pharmaceutical composition according to claim 37, characterized in that it contains from about 0.1 to about 25 mg of the compound per unit dose.
39. 39. A pharmaceutical composition in the form of a solid dose unit, characterized in that it comprises a therapeutically effective amount of the compound according to claim 28 and a pharmaceutically acceptable carrier.
40. 40. The pharmaceutical composition according to claim 39, characterized in that it is in the form of capsules, tablets, powders or granules and contains from about 0.1 to about 25 mg of the compound.
41. 41. A method to inhibit the binding of a soluble adhesive protein to the glycoprotein complex Platelet IIb / IIIa, characterized in that it comprises providing the compound according to claim 28 in an amount sufficient to cause the glycoprotein Ilb / IIIa platelet complex to come into contact with an effective inhibitory amount of the active drug substance.
42. 42. The method according to claim 41, characterized in that the soluble adhesive protein is fibrinogen, von Willebrand factor, fibronectin or vitronectin.
43. 43. The method according to claim 41, characterized in that the compound is administered to a human or animal to inhibit the binding of a soluble adhesive protein to the glycoprotein Ilb / IIIa platelet complex in vivo.
44. 44. The method according to claim 41, characterized in that the compound is applied to an extracorporeal device containing blood, to inhibit the binding of a soluble adhesive protein to the glycoprotein IIb / IIla platelet complex in vi tro.
45. 45. A method for the treatment or prevention of thromboembolic disorders that are selected from the group consisting of thrombus or embolus formation, pernicious platelet aggregation, post-reocclusion thrombolysis, reperfusion injury, restenosis, atherosclerosis, heart attack, myocardial infarction, and unstable angina , characterized in that it comprises administering to a host in need of such treatment or prevention, a therapeutically effective amount of a compound according to claim 28.
46. 46. The method according to claim 45, characterized in that the compound is administered at a dose of about 0.001 to about 10 mg / kg of body weight per day.
47. 47. The method according to claim 45, characterized in that the compound is administered at a dose of about 0.005 to about 1 mg / kg of body weight per day.
48. 48. The method according to claim 47, characterized in that the compound is administered for the treatment or prevention of myocardial infarction or heart attack.
49. 49. A method for the treatment or prevention of rheumatoid arthritis, asthma, allergies, adult respiratory syndrome, rejection of organ transplants, septic shock, psoriasis, contact dermatitis, osteoporosis, osteoarthritis, tumor metastasis, diabetic retinopathy, inflammatory disorders and inflammatory bowel disease, characterized in that it comprises administering to a host in need of such treatment or prevention, a therapeutically or prophylactically effective amount of a compound according to claim 28.
50. 50. The polymorph Form 2 of crystalline roxifiban, characterized in that it is prepared by the recrystallization of roxifiban from a mixed system of solvents.