Impact of Crystal Habit on Solubility of Ticagrelor

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.Crystals 2019, 9, 556 2 of 15 such as crystal habit, polymorphism and reduction of the particle size [15][16][17][18][19][20]. There have been many studies demonstrating the effect of polymorphism on oral bioavailability and/or dissolution rate [21]. However, the dissolution rate not only differs for different polymorphisms, but also, for different crystal habits [22], which has received scant attention. Meanwhile, crystal habits also influence stability, flowability, suspension, packing, density, compaction, etc. [23][24][25][26][27]. Thus, optimizing crystal properties by modification of the crystal habit of a drug seems to offer an alternative approach to changing the bioavailability of drugs. The relative growth rate of each surface determines the overall shape of the crystal. The growth rate of the crystal surface will be controlled by a combination of structure-related factors, such as dislocations and intermolecular bonds, and by exterior factors such as solvents, rate of agitation, additives, temperature, etc. [28][29][30][31][32][33][34][35].This study aims to systematically investigate how crystal behavior affects the ticagrelor's solubility. TICA form II (TICA-II) with different crystal habits were prepared by controlling the crystallization process. To systematically investigate the relationship between crystal habit and orientation of the molecules of TICA form II in the crystal lattice, single crystals were obtained, and the cr...

Impact of Crystal Habit on the Dissolution Rate and In Vivo Pharmacokinetics of Sorafenib Tosylate

“…The preferred crystal growth directions that impact the crystal sizes and habits could be determined by some higher peaks [ 21 ]. In these crystals, their relative peak intensities were varied ( Table S1 ).…”

“…The PXRD patterns exhibited diffraction peaks at 2θ values of 4.4, 11.0, 13.2, 14.7, 16.6, 17.8, 20.4, 20.8, 21.5, and 22.9 • (Figure 3), which were identical to the calculated patterns of Sor-Tos, indicating that the structure of the two Sor-Tos crystal habits was not changed (such as polymorphic change or solvate [26]). The preferred crystal growth directions that impact the crystal sizes and habits could be determined by some higher peaks [21]. In these crystals, their relative peak intensities were varied (Table S1).…”

“…For example, the higher dissolution rate and oral bioavailability of celecoxib crystals in plate-shaped crystals than that in acicular crystals was attributed to their different hydrophilic surfaces [ 20 ]. The plate-shaped crystals of ticagrelor showed a higher hydrophilic nature than the needle-like crystals, resulting in a faster dissolution rate [ 21 ]. Moreover, crystal habit also influences industrial crystallization processes, such as filtration, washing, drying, packaging, etc.…”

Preface of the Special Issue “Pharmaceutical Crystals”

“…Solubility of a pharmaceutical crystal is one of the most exciting topics, and two groups contributed to this aspect. Ren et al [1] studied the relationship between the solubility and crystal faces and crystal habits, providing a new idea on the mechanism of crystal habit modification and its impact on solubility. Co-crystal formation is known as one of the effective methods to improve solubility.…”

Understanding Crystal Cleavability and Physical Properties of Crystal Surfaces Using <i>in Silico</i> Simulation

“…For example, a study of polymorphs using tibolone reported that the elution rate differs among polymorphs. 13) In addition, a study of crystal habit using ticagrelor reported that the dissolution rate differs with the crystal habit. 14) These findings suggest that the difference in molecular arrangement on the crystal surface affects the dissolution characteristics of APIs.…”