Virtual hydrate screening and coformer selection for improved relative humidity stability

Drug formulations of anhydrous solid forms are generally preferred over hydrated forms. This is due to the risks of low exposure and unacceptable physical and chemical stability in comparison with anhydrous formulations. The purpose of the current study was to determine which descriptors can be most efficiently applied to virtual screening in order to provide answers to the following questions: 1) what is the propensity to form a solid state hydrate of a pharmaceutical compound, and 2) in regards to cocrystalline formulation, which coformer would provide for the highest stability with respect to relative humidity (RH) conditions? A number of properties of different complexity were tested to provide answers to these questions, including COSMO-RS excess free energy G(ex) and enthalpy H-ex of hydration of the compound in amorphous state; octanol-water partition coefficient clogP; polar surface area TPSA; different combinations of molecular H-bond donor and acceptor counts; an excess enthalpy of API (active pharmaceutical ingredient)-coformer mixing; and coformer solubilities. It was demonstrated that the G(ex) property provides the most efficient way of virtual screening of hydration propensity of solid pharmaceutical compounds. It was also demonstrated that a virtual coformer screening based on the API coformer miscibility, as measured by the COSMO-RS H-ex property, may be efficiently used to guide the experimental selection of coformers which have an increased probability of cocrystallization and provide the highest RH stability.