Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts
Inventors
Song, Jiangao • McWherter, Charles A. • Ma, Fang • Andres, Mark • Ivanisevic, Igor • Albert, Ekaterina • Andres, Patricia
Assignees
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Publication Number
US-9150567-B2
Publication Date
2015-10-06
Expiration Date
Abstract
Crystalline salts of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine, compositions thereof, methods for their preparation, and methods for their use are disclosed.
Core Innovation
The crystalline hydrochloride salt of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine is provided as polymorph Form I and polymorph Form II. Form I has an XRPD pattern comprising peaks at about 2-theta diffraction angles of 8.8, 10.8, 16.1, 17.4, 20.4, 20.9, 21.5, 21.7, 26.6, and 28.1, while Form II has peaks at about 7.8, 10.1, 12.5, 18.4, 19.0, 20.8, 23.0, and 23.5.
Form I is prepared by crystallizing the hydrochloride from a solution comprising one or more specified solvents selected from acetone, acetonitrile, dichloromethane, diethyl ether, ethyl acetate, ethanol, heptane, hexane, hexafluoroisopropanol, isopropyl alcohol, isopropyl ether, methyl ethyl ketone, methanol, methyl-tert-butyl ether, 2,2,2-trifluoroethanol, or tetrahydrofuran, and a dependent narrowing specifies an acetone solution. Form II is prepared by crystallizing the hydrochloride from a solution comprising one or more of the same specified solvents, with dependent claims further specifying a methanol solution and optionally including ethyl acetate or acetone.
Crystallinity and solid-state characterization are described for the crystalline salts of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine, including HCl polymorphs and other pharmaceutically acceptable counterion salts. The characterization is supported using XRPD, DSC, and TGA, with reported DSC endotherms and XRPD peak positions or arrays.
Claims Coverage
The claims content provides two independent claims, each focused on a specific crystalline hydrochloride polymorph, Form I or Form II, characterized by a defined XRPD peak pattern and prepared by crystallization from a solution containing one or more of a specified set of solvents.
Preparing a form I polymorph with defined XRPD peaks from a specified solvent set
Crystallizing 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine hydrochloride to obtain polymorph Form I having an XRPD pattern with peaks at about 2-theta diffraction angles of 8.8, 10.8, 16.1, 17.4, 20.4, 20.9, 21.5, 21.7, 26.6, and 28.1.
Preparing a form II polymorph with defined XRPD peaks from a specified solvent set
Crystallizing 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine hydrochloride to obtain polymorph Form II having an XRPD pattern with peaks at about 2-theta diffraction angles of 7.8, 10.1, 12.5, 18.4, 19.0, 20.8, 23.0, and 23.5.
The inventive coverage centers on obtaining specific crystalline hydrochloride polymorphs of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine via crystallization from defined solvent sets, with each polymorph identified by a characteristic XRPD peak pattern.
Stated Advantages
Higher systemic exposure (AUC and plasma levels) for the salt forms versus micronized free base after a single oral dose.
Documented Applications
Use in therapy/therapeutic framing for diabetes/metabolic disorders, including Type I diabetes, Type II diabetes, and metabolic syndrome.
Combination therapy with DPP IV inhibitors, including sitagliptin and vildagliptin.
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