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

The\nsublimation thermodynamics of the neuroprotective and potential\nanticancer drug riluzole was studied by the transpiration method,\nand the obtained data were used in a virtual screening based on cocrystallization\nGibbs free energy estimation. The method was successfully validated\nagainst 19 reported riluzole crystal forms and correctly predicted\nthe salt formation with dihydroxybenzoic acid isomers. Variation of\nexperimental conditions led to the isolation of the novel polymorphic\nmodification of riluzolium 2,6-dihydroxybenzoate and the new salt\ncocrystal of riluzole with 2,3-dihydroxybenzoic acid with an unexpected\n(3:4) stoichiometry. The hydrogen bond topology was found to be identical\nin polymorphic forms of riluzolium 2,6-dihydroxybenzoate, and the\npacking difference is caused by the variable mutual orientation of\nhydrogen-bonded ribbons. The metastable Form 1 was found to undergo\nan irreversible exothermic phase transition upon heating, indicating\na monotropic relationship between the polymorphs. In serial batch\ncrystallization experiments, Form 1 was found to nucleate at a lower\nsupersaturation level with subsequent transformation to Form 2. Thermodynamic\nfunctions of salt formation for riluzolium 2,6-dihydroxybenzoate Form\n2 from parent compounds have confirmed that the process is enthalpy-driven.\nAt pH > 4.4, the solubility of Form 2 is found to be higher than\nthat\nof pure riluzole.