Polymeric precipitation inhibitor differently affects cocrystal surface and bulk solution phase transformations

Abstract

During the dissolution of cocrystal particles, solution-mediated phase transformation (SMPT) can occur either on the particle surface (PS-SMPT) or in the bulk phase solution (BP-SMPT). In this study, we compared the effect of various polymers on PS-SMPT and BP-SMPT for the first time using carbamazepine saccharine cocrystal (CBZ-SAC) as a model drug. Polyethylene glycol 6000 (PEG), polyvinylpyrrolidone K-30 (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), amino methacrylate copolymer (EPO), and methacrylic acid copolymers (L100-55) were used as polymeric precipitation inhibitors. In the non-sink dissolution test, CBZ-SAC rapidly transforms to CBZ dihydrate (CBZ DH) via PS-SMPT in the absence of polymers. The polymers enhanced the dissolution rate and subsequent supersaturated CBZ concentration in the order of HPMC-AS > HPMC > EPO ≫ PVP ≈ L100-55 ≈ PEG. On the other hand, in the solvent-shift precipitation test, these polymers inhibited the precipitation of CBZ DH in a different order (EPO > HPMC > HPMC-AS ≫ L100-55 ≈ PVP ≫ PEG). The polymers affected the crystal habit of CBZ DH differently between PS-SMPT and BP-SMPT. Direct PS-SMPT observation by real-time polarized light microscopy (RT-PLM) showed that PS-SMPT was significantly inhibited by HPMC-AS, HPMC, and EPO, but less by PVP, L100-55, and PEG. Differences in solid surface pH and heterogeneous nucleation were discussed as the reason for the difference in the inhibitory effect between polymers in PS-SMPT and BP-SMPT. In conclusion, the inhibitory effect of polymers can differ between PS-SMPT and BP-SMPT. For the successful development of a cocrystal formulation, it is important to select a potent inhibitor of PS-SMPT.