| 摘要 |
FIELD: medicine, pharmaceutics.SUBSTANCE: invention relates to novel crystalline form of 2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]-benzonitrile(aloglyptine in form of free base). Said compound possesses properties of DPP-IV inhibitor and can be used in treatment of pathological conditions, mediated by DPP-IV activity, such as diabetes. Crystalline form of 2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]-benzonitrile has values of powder pattern peaks at 2-theta 10.9° ± 0.2°, 12.5° ± 0.2°, 18.0° ± 0.2°, 19.0° ± 0.2°, 21.8° ± 0.2°, contains in infrared spectrum peaks at 3358.7 +/- 2 cm, 2223.7 +/- 2 cm, 1642.2 +/- 2 cm, 1433.4 +/- 2 cm, 818.4 +/- 2 cmand 771.2 +/- 2 cm. in fact crystalline form is water-free form, which contains less than 1.6% of water, when stored at 25°C and relative humidity 90%, and contains less than 1% of area of the total quantity of admixtures by HPLC data. In particular, crystalline form contains less than 0.5% of area of dimer admixture of compound of general formulaInvention also relates to method of obtaining said crystalline form, which includes: a) preparation of solution of 2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]-benzonitrile in appropriate chlorinated hydrocarbon, in which concentration of said compound is high enough to provide crystallisation of 2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]-benzonitrile; b) addition of ether, aliphatic or aromatic hydrocarbon as antisolvent at appropriate rate and in quantity, sufficient to provide crystallisation from solution, obtained at stage a); and c) separation of crystalline form of 2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]-benzonitrile. Ether is preferably selected from the group, including symmetric or non-symmetric C-C-alkyl ether, and aliphatic hydrocarbon represents pentane or hexane. Invention also relates to application of crystalline form in form of free base for preparation of addition salt with acid, for instance, 2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]-benzonitrile benzoate, which contains less than 0.1% of area of dimer admixture of general formula (B), and for application for preparation of pharmaceutical composition.EFFECT: obtained product possesses high purity, claimed crystalline form possesses flowability, low hygroscopicity and stability, with said properties being favourable in application, transportation and storage of product.9 cl, 2 dwg, 4 ex |
