Patent polymorphs

United States polymorph and solvatomorph patents issued during 2005 276... 

UNITED STATES POLYMORPH AND SOLVATOMORPH PATENTS ISSUED DURING 2005... 

The listing of patents published by the United States Patent Office was searched for polymorph and solvatomorph patents using the keywords polymorph(s), polymorphic, solvate(s), hydrate(s), crystal form(s), and crystal modification, and the following patents issued during 2005 were returned using these keywords. 

US patent 6,677,373, Polymorphic B form of 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one [96]. This invention concerns Form B of the title compound, crystallizing in the hexagonal R-3 space group, and which was characterized by its unit cell parameters. For this form, a = 18.183 A, b = 18.183 A, c = 26.950 A, a = jS = 90°, and y = 120°. The unit-cell volume was found to be 7716.5 A3, and there were 18 molecules per unit cell. 

US patent 6,677,453, Production of polymorphic forms I and II of finasteride by complexation with group I or II metal salts [97]. Finasteride Form I of was prepared by first forming a substantially insoluble complex of the compound and a Group I or Group II metal salt (such as lithium bromide), and then dissociating the complex by dissolving away the salt component with water to obtain substantially pure crystalline finasteride Form I. 

US patent 6,683,085, Salt form and polymorphs [98]. This invention encompasses... 

US patent 6,689,802, Polymorphs of an epothilone analog [100]. This invention describes two crystalline polymorphs, as well as mixtures of these, of an epothilone analog. Also provided are methods of forming the novel polymorphs, therapeutic methods utilizing them, and pharmaceutical dosage forms containing them. 

US patent 6,696,458, Compositions and formulations of 9-nitrocamptothecin polymorphs and methods of use thereof [101]. Amorphous forms of 9-nitrocamptothecin are obtained by grinding or pulverizing different polymorphic forms of 9-nitrocamptothecin, and the polymorphic forms are characterized by having an X-ray powder diffraction pattern with discernable diffraction lines at different scattering angles for Cu Ka radiation. 

US patent 6,713,481, Crystalline antifungal polymorph [104]. This patent discloses the crystalline polymorph Form I of ( )-4-[4-[4-[4-[[(2R-cA)-5-(2,4-difluoro-phenyl)tetrahydro-5-( 1H-1,2,4-triazol- l-ylmethyl)furan-3-yl]methoxy]phenyl]-1 -piper azinyl]phenyl-2,4-dihydro-2-[(S)-l-ethyl-2(S)-hydroxylpropyl]-3H-l,2,4-triazol-3-one,... 

US patent 6,720,453, Formoterol tartrate polymorph [105], A method of preparation of a highly pure salt of R,R-formoterol L-tartrate is disclosed. The process provides the most thermodynamically stable polymorph by recrystallization of a novel polymorph. 

US patent 6,723,728, Polymorphic and other crystalline forms cis-FTC [106], The present invention relates to polymorphic and other crystalline forms of (—)-and ( )-cA-(4-amino-5-fluoro-l-(2-(hydroxymethyl)-l,3-oxathiolan-5-yl)-2(lH)-pyrimidinone, or FTC) [106]. Solid phases of (—)-cz>FTC that were designated as amorphous (—)-FTC, and Forms II and III were found to be distinguishable from Form I by X-ray powder diffraction, thermal analysis properties, and their methods of manufacture. A hydrated crystalline form of ( )-cA-FTC and a dehydrated form of the hydrate, were also disclosed, and can similarly be distinguished from other forms of FTC by X-ray powder diffraction, thermal properties, and their methods of manufacture. These FTC forms can be used in the manufacture of other forms of FTC, or as active ingredients in pharmaceutical compositions. Particularly preferred uses of these forms are in the treatment of HIV or hepatitis B. 

US patent 6,753,426, Polymorph and process for preparing same [111], In this patent are disclosed are processes, a new polymorph, and intermediate compounds for preparing various aryl- and heteroaryl-substituted urea compounds. The product compounds are useful in pharmaceutical compositions for treating diseases... 

US patent 6,759,521, Polarization switching to control crystal form [113]. This patent describes a method to select and prepare polymorphs of materials by switching the polarization state of light and employing non-photochemical laser-induced nucleation. 

US patent 6,767,921, Polymorphic forms of fasidotril, their methods of preparation and pharmaceutical compositions comprising them [115]. The subject of this invention are polymorphic Forms I, II, III, IV of benzyl (S,S)-2-(2-acetylsul-phanylmethyl-3-benzo[l,3]dioxol-5-ylpropionyl-amino)propionate (i.e., fasidotril), their methods of preparation, and novel pharmaceutical compositions containing them. 

US patent 6,806,280, Polymorph of 5-[4-[2-( -methyl- (2-pyridyl)amino)ethoxy] benzyl]-thiazolidine-2,4-dione, maleic acid salt [117]. This invention discloses a polymorphic form of 5-[4-[2-(A-methyl-jV-(2-pyridyl)amino)cthoxy]benzyl]-thia-zolidine-2,4-dione, maleic acid salt. The polymorphic form is characterized by (i) an infrared spectrum containing peaks at 1763, 912, 856, and 709 cm-1 and/or... 

Polymorphism is critically important in the design of new drug API [9] and affects a number of areas. The main impact is to the bioavailability and release profile of a drug substance into the body. This is due to differences in solubility and dissolution rate, between the polymorphs. The chemical and physical stability of the formulated drug substance is also dependent on the polymorphic form. Patented registration of all discovered forms and their manufacturing conditions is an important element in protecting a pharmaceutical companies intellectual property. 

It is clear that kinetic effects must be utilized in the design of a process to make the commercially available Form A, because it is never the most thermodynamically stable form. Information from the literature and patents in reference [14] indicates that Form A can be successfully isolated from Acetonitrile, Acetone, Methyl isobutyl ketone, Toluene, the C2 to C4 alkenols, Ethanol, Methanol and Propan-2-ol. In these solvents it is likely that solvation is favourable to the nucleation rate of Form A or detrimental to crystal growth of the other forms, or both. For a new development compound there should be similar solvent interaction data available from polymorph screening experiments. 

The past nearly six decades have seen a chronological progression in molecular sieve materials from the aluminosilicate zeolites to microporous silica polymorphs, microporous aluminophosphate-based polymorphs, metallosilicate and metaHo-phosphate compositions, octahedral-tetrahedral frameworks, mesoporous molecular sieves and most recently hybrid metal organic frameworks (MOFs). A brief discussion of the historical progression is reviewed here. For a more detailed description prior to 2001 the reader is referred to [1]. The robustness of the field is evident from the fact that publications and patents are steadily increasing each year. 

The second and third patents on which GSK sued Apotex were anhydrate patents. The second was Patent No. 5,872,132 (the 132 patent), which claims paroxetine hydrochloride anhydrate (having no associated water molecules) and so differs from the hemihydrate form sold by GSK. In fact, the hemihydrate form is prior art to this patent and, thus, GSK represented to the Patent Office that the anhydrate is patentably distinct from the hemihydrate. GSK also sued on Patent No. 6,080,759 (the 759 patent), which claims the anhydrate made according to a specified process. The 132 and 759 patents raise the issue of whether polymorph patents should be listed in the Orange Book, discussed in Appendix H. 

Brand-name companies also have listed patents that claim a drug substance differing from the approved drug substance in some way. These patents generally fall into three subcategories metabolites, polymorphs, and intermediates. Each subcategory raises its own specific issues, as elaborated below. 

Whether a brand-name company may appropriately list polymorph patents, or those claiming a use or formulation containing a polymorph, could be clarified through FDA regulation or guidance. This is the subjeet of the FTC Staff s Citizen Petition. 

Several patents have recently published that claim the preparation of several different hydrates and polymorphic crystal forms of olanzapine. Dr. Reddy s Laboratories has recently disclosed the preparation of the monohydrate and the dihydrate of olanzapine. A mixture of 24 and A-methylpiperazine was refluxed in DMSO and toluene and then cooled (Scheme 8). Water was added and the precipitate was filtered and washed with water. The resulting solid was placed under vacuum at 30 to 50 °C to give the monohydrate or at ambient temperature to give the dihydrate. Recrystallization of crude olanzapine or one of its hydrates from CH2CI2 provided crystal form 1, whereas recrystallization from EtOAc provides crystal form 2. 

Besides regulatory importance, salts, polymorphs, and hydrates/solvates have clear novelty and patentability considering their different chemical compositions or distinguishable solid state ( fon Raumer et al., 2006). Those new forms can affect not only their processibilities, such as crystallization,Lltration, and compression, but also their biological properties, such as solubility and bioavailability. Besides, the manufacturing processes for those forms are often innovative, and thus patentable. 

Cabri, W., Ghetti, P., Pozzi, G, and Alpegiani, M. (2007). Polymorphisms and patent, market, and legal battles cefdinir case studyQrg. Process Res. Dev., 11 64-72. 

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