Solution-mediated phase transformation of cocrystals at the solid-liquid interface: Relationships between the supersaturation generation rate and transformation pathway.

Abstract

Cocrystals easily undergo solution-mediated phase transformation at the surface of dissolving cocrystals during dissolution, which significantly deteriorates the solubility advantage of cocrystals. Here, a new scenario for the phase transformation of liquiritigenin (LQ) cocrystals in which the boundary of phase transformation diffuses along the surface to the bulk of the cocrystal was identified. Additionally, depending on the rate of supersaturation generation, phase transformation processes to the anhydrate and hydrate of LQ compete during cocrystal dissolution. The liquiritigenin - nicotinamide (LQ - NIC) cocrystal yielded a higher supersaturation rate, causing the nucleation kinetics to dominate the recrystallization process and the formation of a metastable form of LQ. However, in the liquiritigenin - isoniazid (LQ - INZ) cocrystal, the low supersaturation rate leading to recrystallization was controlled by thermodynamics and the subsequent formation of monohydrates of LQ (less soluble). As a result, in plain buffer, a multistep pathway for phase transformation of the LQ - NIC cocrystal was observed, in which the cocrystal was first converted into the anhydrate LQ (metastable form) and subsequently transformed into LQ·H₂O. A one-step phase transformation was observed for the LQ - INZ cocrystal, where the cocrystal was directly converted to LQ·H₂O. In a buffer containing the Eudragit E100 additive, for the LQ - NIC cocrystal, the dissolution performance improved, which can presumably be attributed to the solubilization effect of E100 on the anhydrate and the inhibitory effect on the transformation of the anhydrate to the monohydrate. However, for the LQ - INZ cocrystal, a negligible improvement in drug concentration was observed in the presence of E100 because of the slight effects of E100 on the solubility of LQ·H₂O. These findings provide valuable insights into the phase transformation pathways of cocrystals at the liquid-solid interface and the effects of additives on the dissolution behavior of cocrystals.