Insight into the Formation of Heteromolecular Hydrogen Bonds between Dasatinib and GRAS Molecules

Abstract

Purpose: To obtain multicomponent crystals and salts of dasatinib, a weakly basic oral anticancer agent, to improve its solubility and dissolution rate. Methods: Liquid-assisted grinding using a mortar and pestle and ball milling were used for multicomponent crystallization screening. Differential scanning calorimetry, infrared spectroscopy, dynamic vapor sorption, powder X-ray diffraction, and single-crystal X-ray diffraction studies were conducted for the solid-state characterization. Results: Binary phase diagrams through thermal analysis were developed for various multicomponent crystals. Crystal structure analysis showed that dasatinib gained a proton from succinic acid and turned into a salt. The dissolution profile and equilibrium solubility at pH 3.6 buffer showed that dasatinib release was significantly faster than dasatinib–succinic acid–water salt. Similarly, during the first 120 min, the dissolution profile at pH 3.6 buffer showed that the dasatinib release was significantly faster, but the latter multicomponent crystal disintegrated into a free hydrated dasatinib and l-glutamic acid, and consequently, the solubility was decreased. Conclusions: Solubility and dissolution measurements conducted at pH 3.6 and 7.2 aqueous buffer media revealed that the salt with succinic acid and the multicomponent crystal with l-glutamic acid improved the apparent solubility and dissolution rate of the resulting multicomponent crystals compared to the free dasatinib.

Cocrystals by Design: A Rational Coformer Selection Approach for Tackling the API Problems

“…Drugs which do not exhibit pH-dependent solubility are classified into the class Iic category (neutral drugs such as danazol, fenofibrate, etc.) [18,42,43]. The formation of cocrystals and salt can be predicted by a study of the transfer of protons and is determined by the ∆pKa = [pKa (base) − pKa (acid)].…”

“…By introducing a more soluble coformer into the crystal lattice, which results in a lower solvation barrier, significant attempts have been undertaken in recent decades to increase the solubility, permeability, or bioavailability of poorly water-soluble medicines. The ultimate aim of using the coformer is to improve the solubility and dissolution rate of a poorly aqueous soluble drug by introducing the coformers into the BCS class-II drugs [18,92,142].…”

“…Pharmaceutics 2023, 15, x FOR PEER REVIEW 30 of 45 solubility, permeability, or bioavailability of poorly water-soluble medicines. The ultimate aim of using the coformer is to improve the solubility and dissolution rate of a poorly aqueous soluble drug by introducing the coformers into the BCS class-II drugs [18,92,142].…”

“…There have been a few studies that have reported deterioration of API properties after cocrystallization [3]. A variety of (GRAS) coformers generally regarded as safe are used to prepare pharmaceutically acceptable cocrystals [1,[17][18][19]. The nature of the coformer used (acidic/basic/neutral) is known to influence the stability of the final cocrystal [1].…”