Diflunisal salts of bupivacaine, lidocaine and morphine: Use of the common ion effect for prolonging the release of bupivacaine from mixed salt suspensions in an in vitro dialysis model

The present work describes the characterization of diflunisal salts of the analgesic agents bupivacaine, lidocaine, and morphine including their solubility behaviour and release characteristics from solutions and selected salt suspensions in vitro using the rotating dialysis cell model. The solubility of the 1:1 salts at pH 7.4 differed by a factor of 9 with the bupivacaine and lidocaine salts representing the poorest and most soluble salt (0.73 and 6.6 mM, respectively). Common ion effects were observed for the diflunisal salts of bupivacaine and morphine when various concentrations of the lidocaine-diflunisal salt were present in aqueous buffer (pH 7.4). The most pronounced salting-out effect was observed for the poorest soluble salt. From Setschenow type plots apparent salting-out constants of 265 M−1 (bupivacaine) and 54.7 M−1 (morphine) were calculated. After instillation of mixed salt suspensions comprising the diflunisal salts of bupivacaine and lidocaine into the donor cell of the release model, lidocaine appeared rapidly in the acceptor phase. After clearance of lidocaine from the donor cell, equal and constant fluxes of bupivacaine and diflunisal were observed. The residence times of bupivacaine within the donor compartment was prolonged with increasing lidocaine-diflunisal salt load in the mixed suspensions whereas the slopes of the linear part of the bupivacaine release profiles were affected to a minor extent only. The obtained data indicate that local multimodal analgesia, characterized by rapid onset and extended duration of action, can be achieved upon injection of mixed suspensions of salts differing with respect to aqueous solubility comprising a common ion into a small body compartment (such as the joint cavity).