Hepatoprotective Cocrystals and Salts of Riluzole: Prediction, Synthesis, Solid State Characterization, and Evaluation

Riluzole is a drug, used to slow the course of amyotrophic lateral sclerosis. Due to its unique structure and functionalities, it is able to form both salts and cocrystals. This is a BCS class II drug with poor solubility and causes hepatotoxicity which limits its application. The present study aims toward development of novel solid forms of riluzole to address the said limitations. Apart from this, an attempt has been made to develop a prediction model using software tools to identify the appropriate synthons for formation of cocrystals. It was observed that out of 33 coformers selected, prediction results were in agreement with the experimental outcome for 25 coformers, which demonstrated the potential of the model developed. Seven new solid forms of riluzole, five cocrystals with ferulic acid, syringic acid, vanillic acid, cinnamic acid, and proline, and two salts with 2,4 dihydroxybenzoic acid and fumaric acid were successfully developed. All the solid forms were characterized by DSC, powder XRD, FTIR, and single crystal XRD. Single crystal X-ray analysis of the all solid form shows R22(8) motif between riluzole and coformers through N–H···O and O–H···N bond except riluzole-proline zwitterionic cocrystal. In riluzole-fumaric acid, partial proton transfer of O to N due to acidic H atom disorder has been observed. Dissolution profiles of all the solid forms were comparable to that of plain riluzole, and complete drug release was observed within 60 min for all systems. In vivo hepatotoxicity study with riluzole-ferulic acid and riluzole-syringic acid in mice model revealed its potential hepatoprotective effect to counterattack the hepatotoxic adverse effects of riluzole.