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

Abstract

Mechanochemistry has been recognised 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 synthesised by neat grinding and the effect of an alkyl chain length on the phase formation was investigated.The evaluation of thermal and dynamic behaviours as well as crystallographic analysis of API-ILs was performed in an attempt to devise a prediction tool for 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 ILs community to devise a systematic approach for API-IL discovery and development for pharmaceutical applications.

Submerged Eutectic-Assisted, Solvent-Free Mechanochemical Formation of a Propranolol Salt and Its Other Multicomponent Solids

“…Chadwick and co-workers proposed that the liquid phase was a submerged eutectic, which facilitated the formation of a cocrystal [16]. A similar phenomenon was seen but with lidocaine ionic liquids, and not a cocrystal, based on dicarboxylic acids [24]. Therefore, the hypothesis of a submerged eutectic being a precursor of PRC was tested using optical microscopy.…”

“…The solvent was then removed under vacuum, and samples were left at −20 • C until analysed. In contrast to Stott et al, we concentrated on a solvent-free approach [24,41]. The melting temperatures of pure PRO and CAP were observed at 91.8 • C and 31.9 • C, respectively.…”

“…The polarised light microscopy experiment was performed using an Olympus BX53 polarising optical microscope (Tokyo, Japan) equipped with a U-POT cross polarizer [24]. The microscope was equipped with Q IMAGING Fast 1394 camera (Olympus, Tokyo, Japan).…”

“…An idea of the submerged eutectic forming between the reactants and acting as a reaction intermediate to form a co-crystal has previously been described by Chadwick et al [16]. Recently, a similar concept of a submerged eutectic (also referred to as 'deep eutectic') facilitating salt/ionic liquid formation was proposed by Zotova et al [24].…”

Impact of the Dicarboxylic Acid Chain Length on Intermolecular Interactions with Lidocaine

“… 21 , 11 , 22 , 23 In previous work on the LID:DA systems, we have observed alternating trends in morphology, melting points, glass transition temperatures, and crystallographic properties of the new phases across the dicarboxylic acid series. 20 In addition, we have investigated the influence of a changing counterion ratio on the nature of intermolecular interactions and the identity of new phase formation. 24 Upon addition of excess LID base component to azelaic acid, a neutral cocrystal multicomponent phase was obtained.…”