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

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.