Thermodynamic and spectroscopic evaluation of the eutectic mixture of myristic acid and the local anaesthetics, bupivacaine and ropivacaine

Local anaesthetics provide an opioid-sparing alternative for pain management; however, their short-lived analgesic effect necessitates repeat or sustained drug delivery to the target site. Improving drug loading and enhancing physical stability is a challenge when formulating sustained release devices. Here, myristic acid's interaction with bupivacaine and ropivacaine was studied to evaluate whether eutectic formation between these drugs and myristic acid can similarly influence drug crystallization and increase drug loading in poly ethylene-co-vinyl acetate (EVA). Binary mixtures of ropivacaine and bupivacaine with myristic acid were thermodynamically evaluated by differential scanning calorimetry. Fourier transfer infrared (FTIR) spectra of bupivacaine or ropivacaine and myristic acid binary mixtures at different ratios were obtained and synchronous and asynchronous two-dimensional correlation spectroscopy (2DCOS) maps analysed. Stabilizing effects were observed visually by preparing EVA films containing each drug with and without myristic acid. Thermodynamic and spectroscopic studies suggested that both bupivacaine and ropivacaine form a eutectic with myristic acid at the molar ratio of 2 : 3 and 1 : 3, respectively. 2DCOS FTIR analysis revealed hydrogen bonding between the carbonyl and hydroxyl groups of myristic acid and amide carbonyl group of bupivacaine and ropivacaine, respectively, when myristic acid was present in excess. Furthermore, myristic acid transiently stabilized both bupivacaine and ropivacaine in EVA matrices, but crystallization was evident by the 6-month timepoint. Myristic acid forms a eutectic with both bupivacaine and ropivacaine due to hydrogen bonding interaction. Eutectic formation inhibits crystallization and stabilizes bupivacaine and ropivacaine in EVA matrices, for 1 month, however crystallization of both local anaesthetics was evident after 6-months.