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Patent
Zentiva and Sanofi S.A. | Date: 2012-07-18

New solid salts of ambrisentan, including the phosphate salt, ambrisentan sodium salt and ambrisentan tert-butylammonium salt, in crystalline, amorphous, anhydrous or hydrated form.


The present invention relates to novel solid forms of agomelatine (I), specifically novel pharmaceutically acceptable cocrystals thereof, as well as to methods of preparing them. Three pharmaceutically acceptable cocrystals of (I) that have physicochemical properties acceptable for pharmaceutical development were obtained.


New crystalline forms of 5-Chloro-3-(4-methanesulfonylphenyl)-6-methyl-[2,3]bipyridinyl in the form of stable salts and cocrystals with pharmaceutically acceptable inorganic and/or organic acids. Organic acid is selected from succinic, adipic, fumaric, benzoic, salicylic, 1-hydroxy-2-naphthoic, 3-hydroxy-2-naphthoic acid and saccharin and inorganic acid is selected from hydrochloric, hydrobromic, nitric and sulfuric acid. By the appropriate use of the salts and cocrystals described herein it is possible to modulate and ensure the consistency of the physicochemical properties of the active pharmaceutical ingredient and enable its administration in different dosage forms including for oral delivery.


Patent
Zentiva and Institute Of Organic Chemistry And Biochemistry As CR | Date: 2015-04-15

An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof, comprising following steps:a) alkylation of adenine with (R)-4-methyl-1,3-dioxolan-2-one and isolation of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol;b) alkylation of (R)-1-(6-amino-9H-purin-9-yl) propan-2-ol with a dialkyl p-toluenesulphonyloxymethylphosphonate or dialkyl halomethylphosphonate to give dialkylester of (R)-9-[2-(phosphonomethoxy)propyl]adenine;c) preparation of (R)-9-[2-(phosphonomethoxy)propyl]adenine ((R)-PMPA; Tenofovir) by dealkylation of the phosphonate moiety with a mineral acid under microwave irradiation;d) preparation of Tenofovir disoproxil;e) preparation of the fumarate salt or other pharmaceutically acceptable salt of Tenofovir disoproxil.


Patent
Zentiva | Date: 2010-05-05

Method of manufacturing ruboxistaurin, comprising the steps of preparation of L-2-deoxyribose 1-cyano-3,4-dibenzoate, followed by deprotection to 1-cyano L-2-deoxyribose, oxidative cleaving to (S)-4-hydroxy-2-(2-hydroxy-ethoxy)-butyronitrile and transformation to the methanesulfonic acid (S)-3-cyano-3-(2-methanesulfonyloxyethoxy)-propyl ester, then coupling with 1-substituted-3,4-bis(3-indolyl)maleimide leading to 9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13] oxadiazacyclohexadecine-18,20(19H)-dione, 6,7,10,11-tetrahydro-19-substituted-9(S)-cyano, followed by methylation of the amino group and deprotection forming 5,21:12,17-dimetheno-9H-dibenzo[e,k]furo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20-dione, 6,7,10,11-tetrahydro-9-[(dimethylamino)methyl]-, (S)- (9CI), and the final step consisting of imido preparation to form ruboxistaurin.


Patent
Zentiva | Date: 2011-04-20

New acetate salt of bazedoxifene, which is preferably characterized by the following reflections in the X-Ray diffraction pattern: 13.17; 15.97; 17.95; 19.62; 20.54; 22.08; 25.27.


A method for the preparation of the hydrochloride salt from the duloxetine base by reaction of the duloxetine base with concentrated hydrochloric acid in ethylemthylketone, wherein the duloxetine base of formula I is prepared by the procedure comprisinga) reaction of (RS)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula III with optically active D-tartaric acid or an acid salt derived from D-tartaric acid in the presence of water, forming a mixture of diastereoisomeric salts of N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine and D-tartaric acid (2:1),b) isolation of the salt (S)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate (2:1) from the mixture of diastereoisomeric salts in an organic solvent, water or a mixture thereof and release of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula (S)-(III) by action of an inorganic or organic base,c) demethylation of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine by action of an alkylchloroformate of formula ClCOOR (R = C_(1) - C_(5) alkyl, or C_(6) - C_(12) aryl or alkylaryl), especially phenyl, ethyl or methyl chloroformate, andd) hydrolytic release of the duloxetine base of formula I and optionally conversion of the base to a salt with the respective acid, or salt of a weak base,wherein one uses, as the optically active substance in step (a), D-tartaric acid in the molar ratio 1:2 relative to the substance of formula III, or an alkali metal acid D-tartrate or ammonium tartrate, or alternatively alkylammonium tartrate of formula IV in the molar ratio 1:1 relative to the substance of formula III.


A pharmaceutical formulation of agomelatine for oral use, comprising- agomelatine in the form of agomelatine co-crystals with organic acids and- pharmaceutically acceptable excipients,in which- the agomelatine co-crystals are used in the form of pre-blend of the agomelatine co-crystals with a glidant,- the ratio of the agomelatine co-crystals to the glidant in the pre-blend is lower than or equal to 30 : 1, and- the free-water content in the used pharmaceutically acceptable excipients is lower than or equal to 7% w/w.


Patent
Zentiva | Date: 2010-04-28

The trisodium salt of ibandronate of formula (I): A process of preparing said salt comprises:a) mixing 3-(methylpentylamino)propionic acid hydrochloride, phosphorous acid (in a 2.5-3.5 molar excess with respect to 3-(methylpentylamino)propionic acid hydrochloride), sunflower oil (in an amount of 6-9 volume parts for 1 weight part of 3-(methylpentylamino)propionic acid hydrochloride) and phosphorus trichloride (in a 3-4 molar excess with respect to 3-(methylpentylamino)propionic acid hydrochloride);b) adding water (in an amount of 6-9 volume parts for 1 weight part of 3-(methylpentylamino)propionic acid hydrochloride) and after separation of the phases;c) adjusting pH of the water phase to pH 12.5;d) adding a water-miscible co-solvent and cooling down to precipitate the product or evaporate to dryness. Another process for preparing the trisodium salt of ibandronate comprises admixing the monosodium salt of ibandronate or ibandronic acid or their solvates with water or a mixture water/sodium hydroxide and adjustment of pH to 12.5. Various crystalline, semicrystalline and amorphous forms of trisodium ibandronate are disclosed.


Patent
Zentiva | Date: 2015-04-15

Tenofovir disoproxil dihydrogenphosphate, showing the following characteristic reflections in the XRPD measured by CuK emission 5,6; 7,7; 12,4; 13,6; 16,4; 22,4 a 25,4 0,2 2, and methods for the preparation thereof.

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