Solution-mediated phase transformation at particle surface during cocrystal dissolution

Abstract

In this study, we investigated solution-mediated phase transformation (SMPT) during cocrystal particle dissolution. When the solubility of a cocrystal is higher than that of the free form, the concentration of the free form can be supersaturated at the dissolving cocrystal surface, as well as in the bulk phase. Therefore, SMPT may occur either in the bulk phase or at the particle surface (PS-SMPT). Carbamazepine - glutaric acid cocrystal (CBZ-GLA) was used as a model cocrystal. Dissolution tests were performed under a non-sink condition. The residual particles were analyzed by polarized light microscopy (PLM), scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry. Solvent-shift bulk phase precipitation tests and real-time PLM observation of PS-SMPT were also performed. In the dissolution test, little or no supersaturation was observed. CBZ-GLA particles rapidly and completely transformed to aggregates of CBZ dihydrate (CBZ DH) (>95% within 3 min). The outer shape of the aggregates preserved that of initial CBZ-GLA particles, but distinctly differed from CBZ DH precipitated from the bulk phase. Real-time PLM observation revealed that PS-SMPT started within several seconds after contact with the medium. These results suggested that CBZ-GLA particles transformed to the aggregates of CBZ DH via PS-SMPT.