Green Synthesis of Lidocaine Ionic Liquids and Salts: Mechanisms of Formation and Interactions in the Crystalline and Supercooled States

Abstract

Mechanochemistry has been recognized as an optimal route for the synthesis of ionic liquids incorporating active pharmaceutical ingredients (API-ILs) as it eliminates the need for large volumes of solvents and purification steps, thus making it a sustainable alternative to conventional solution synthesis. In this work, a range of API-ILs incorporating lidocaine and medium-chain dicarboxylic acids as the counterions were synthesized by neat grinding, and the effect of an alkyl chain length on the phase formation was investigated. The evaluation of thermal and dynamic behaviors as well as crystallographic analysis of API-ILs was carried out in an attempt to devise a prediction tool for the structure–property relationship. Alternating trends in morphology, melting points, glass transition temperatures, and crystallographic properties of the new phases were observed across the dicarboxylic acid series. This study enhanced our understanding of the mechanisms of API-ILs formation and contributed to the current aim of the IL community to devise a systematic approach for API-IL discovery and development for pharmaceutical applications.