Dependence of cocrystal formation and thermodynamic stability on moisture sorption by amorphous polymer

Abstract

The purpose of this study was to determine the influence of water vapor sorbed by and dissolved in an amorphous polymer on the formation and thermodynamic stability of cocrystals that are incongruently saturating in water. The conversion of crystalline phases of a hydrophobic drug (carbamazepine) and a hydrophilic coformer (nicotinamide) to cocrystal as a function of moisture sorption (43%, 62% and 75% RH) by an amorphous polymer (polyvinylpyrrolidone, PVP), molecular weight (K12 and K90) and fraction of polymer in ternary mixtures (25 and 50 wt%) was investigated. Moisture uptake and crystallization behavior were studied by gravimetric and dynamic vapor sorption, X-ray powder diffraction, FT-IR, Raman microscopy, and polarized optical microscopy. Results indicate that moisture uptake by PVP can generate cocrystals at moisture contents as low as 3.3% in a ternary mixture corresponding to 13.1% moisture sorbed by PVP. Cocrystal formation rate increased with moisture uptake. The same level of moisture sorption by PVP resulted in higher cocrystal formation rates with lower PVP molecular weight and higher PVP fraction in mixture. This behavior is explained by the increased mobility of water and PVP leading to more effective dissolution of components and higher supersaturation with respect to cocrystal. PVP was also found to change the eutectic point associated with the cocrystal/drug hydrate/solution equilibrium such that the ratio of cocrystal to drug solubility decreases with increasing PVP. Thus, PVP increases the thermodynamic stability of this cocrystal relative to drug.