Virtual Screening, Polymorphism, and Formation Thermodynamics Study of Riluzole Multicomponent Crystals with Dihydroxybenzoic Acids

The sublimation thermodynamics of the neuroprotective and potential anticancer drug riluzole was studied by the transpiration method, and the obtained data were used in a virtual screening based on cocrystallization Gibbs free energy estimation. The method was successfully validated against 19 reported riluzole crystal forms and correctly predicted the salt formation with dihydroxybenzoic acid isomers. Variation of experimental conditions led to the isolation of the novel polymorphic modification of riluzolium 2,6-dihydroxybenzoate and the new salt cocrystal of riluzole with 2,3-dihydroxybenzoic acid with an unexpected (3:4) stoichiometry. The hydrogen bond topology was found to be identical in polymorphic forms of riluzolium 2,6-dihydroxybenzoate, and the packing difference is caused by the variable mutual orientation of hydrogen-bonded ribbons. The metastable Form 1 was found to undergo an irreversible exothermic phase transition upon heating, indicating a monotropic relationship between the polymorphs. In serial batch crystallization experiments, Form 1 was found to nucleate at a lower supersaturation level with subsequent transformation to Form 2. Thermodynamic functions of salt formation for riluzolium 2,6-dihydroxybenzoate Form 2 from parent compounds have confirmed that the process is enthalpy-driven. At pH > 4.4, the solubility of Form 2 is found to be higher than that of pure riluzole.