Abstract
Drugs with poor biopharmaceutical performance are the main obstacle to the development and design of medicinal preparations. The anisotropic surface chemistry of different surfaces on the crystal influences its physical and chemical properties, such as solubility, tableting, etc. In this study, the antisolvent crystallization and rapid-cooling crystallization were carried out to tune the crystal habits of ticagrelor (TICA) form II. Different crystal habits of ticagrelor (TICA) form II (TICA-A, TICA-B, TICA-C, TICA-D, and TICA-E) were prepared and evaluated for solubility. The single-crystal diffraction (SXRD) indicated that TICA form II belongs to the triclinic P1 space group with four TICA molecules in the asymmetric unit. The TICA molecules are generated through intermolecular hydrogen bonds along the (010) direction, forming an infinite molecular chain, which are further stacked by hydrogen bonds between hydroxyethoxy side chains, forming molecular circles composed of six TICA molecules along bc directions. Thus, in the case of TICA form II, hydrogen bonds drive growth along one axis (b-axis), which results in the formation of mostly needle-shape crystals. Morphology and face indexation reveals that (001), (010) and (01-1) are the main crystal planes. Powder diffractions showed that five habits have the same crystal structure and different relative intensity of diffraction peak. The solubility of the obtained crystals showed the crystal habits affect their solubility. This work is helpful for studying the mechanism of crystal habit modification and its effect on solubility.
Highlights
Ticagrelor (TICA) is an oral antiplatelet drug that can be used in combination with a small amount of aspirin to reduce the danger of stroke and myocardial infarction in patients with acute coronary syndrome [1,2,3]
This compound crystallizes in the P1 space group, with the asymmetric unit consisting of four ticagrelor molecules, which is similar to that of TICA form I [13]
Investigations on the single-crystal structure of the TICA form II (TICA-II) suggest that faces determine the crystal habit
Summary
Ticagrelor (TICA) is an oral antiplatelet drug that can be used in combination with a small amount of aspirin to reduce the danger of stroke and myocardial infarction in patients with acute coronary syndrome [1,2,3]. Ticagrelor inhibits the pro-thrombotic effect of ADP by blocking the platelet P2Y12 receptor. TICA has been used in clinical trials to reduce the incidence of recurrent myocardial infarction and stent thrombosis and was approved for use in the USA in 2011 [5,6,7,8,9,10]. Only two crystal structures of them (form I and DMSO solvate) have been reported [11,12,13]. Ticagrelor belongs to biopharmaceutics classification system(BCS) class IV drug, with limited bioavailability (30–42%) [14]
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