Factors that influence the spontaneous formation of pharmaceutical cocrystals by simply mixing solid reactants

Abstract

The purpose of this study was to investigate whether cocrystals form by simply mixing pure solid components without the need to comill. The effects of moisture and temperature during storage were studied in binary mixtures where pure components were exposed to different levels of mechanical stress: (a) two components unmilled, (b) one component milled, or (3) two components individually milled. Equimolar mixtures of anhydrous monoclinic form III carbamazepine (CBZ) with form I nicotinamide (NCT) or saccharin (SAC) were stored at 25 °C-75%RH, 45 °C-0%RH and 45 °C-75%RH. Transformation to cocrystal was monitored by FTIR and XRPD. Results show that conversion to cocrystal occurs even when components are not mechanically stressed at all storage conditions within 3 months except for unmilled CBZ/SAC at 25 °C-75%RH. Free energy calculations from solubilities and equilibrium constants confirm that transformation from reactants to cocrystal is thermodynamically favorable. Increasing temperature and relative humidity as well as mechanical activation by individually milling reactants enhances cocrystal formation. CBZ-NCT cocrystal forms faster than CBZ-SAC at all storage conditions. A metastable CBZ-SAC polymorph was detected in mixtures of individually milled CBZ and SAC.