Micronization and crystal form of ticagrelor and preparation method and pharmaceutical application of crystal form of ticagrelor

Abstract

The invention relates to a micronized substance and a micronized crystal form of a water-insoluble compound ticagrelor and further relates to a preparation method and pharmaceutical application of the crystal form of ticagrelor. The preparation method comprises the steps of completely dissolving ticagrelor with a proper organic solvent, adding the solution to a water-containing solvent, stirring to immediately separate ticagrelor out and disperse ticagrelor into the water-containing solvent, filtering, separating solids, and drying. The micronized ticagrelor has excellent water wettability and water dispersibility, the powder stacking density and the powder fluidity of the ticagrelor are well improved, and a pharmaceutical preparation utilizing ticagrelor as a active ingredient has important significance in the aspects of improving the dissolution rate of the pharmaceutical preparation, improving the uniformity of pharmaceutical preparation and improving the quality standard, absorption and utilization.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a micronized substance of ticagrelor, an insoluble water-soluble compound, and its crystal form in a micronized state, as well as its preparation method and application in medicine. Background technique [0002] Ticagrelor (Ticagrelor, also known as ticagrelor), belongs to the cyclopentyl triazolopyrimidine compound, the chemical name is (1S, 2S, 3R, 5s)-3-[7-[(1R, 2S) -2-(3,4-difluorophenyl)cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3]-triazol[4,5-d]pyrimidin-3-yl ]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol, molecular formula: C 23 h 28 f 2 N 6 o 4 S, molecular weight 522.57, CAS number: 274693-27-5, structure as follows: [0003] . [0004] [0005] International Publication WO00 / 34283 of PCT patent application and Chinese Patent No. 99815926.3 disclose ticagrelor compounds and preparation methods and pharmaceutical uses; International Publication WO2001 / 092262 of PCT pa...

AI Technical Summary

Problems solved by technology

[0007] However, there are problems that, on the one hand, ticagrelor has poor water solubility, and the water solubility at room temperature is about 10 μg / ml, which is not conducive to the preparation of pharmaceutical preparations and the application of drugs, and the dissolution effect of its preparations is poor, which seriously affects its pharmaceutical quality. and controllability; on the other hand, according to the multiple compound crystalline forms and amorphous forms of ticagrelor disclosed in International Publication WO2001 / 092262 and Chinese Patent No. 01810582.3, according to the crystal forms and methods provided in its specification, the obtained Ticagrelor is a flaky or flocculent crystalline solid, lacks brittleness, is difficult to crush mechanically, has a small bulk density, and has poor fluidity. It is difficult to mix evenly with pharmaceutical excipients in the preparation of preparations. The preparation of ticagrelor and the improvement of quality brings great difficulties, and is not conducive to the needs of large-scale industrial production

The mechanical pulverization method is a pulverization process of a solid drug, using mechanical methods to increase the surface area, that is, the process of converting mechanical energy into surface energy, such as jet pulverization technology, ball mill pulverization in a ball mill, etc., but these mechanical pulverization methods consume energy High, low yield, easy to generate static electricity, poor uniformity of powder particle size, poor micronization effect

Images