Salts and Cocrystals of Benzocaine with Increased Dissolution Rate and Permeability Open New Avenues for Enhancing the Duration of Action

Abstract

Benzocaine, a widely used local anesthetic, has some usage limitations due to its short duration of action, resulting in inconsistent clinical outcomes. In this study, the formation of salts and cocrystals is explored as a strategy to enhance the pharmacokinetic profile of benzocaine, aiming for a higher dissolution rate and permeability in vitro as well as to potentially increase its pharmacological effect and duration of action in vivo. A new cocrystal and nine new salts with two different categories of acids (carboxylic and sulfonic) were prepared and characterized: BH oxalate, BH naphthalenesulfonate, BH camphorsulfonate, BH maleate, BH mesylate, BH tartrate, BH benzenesulfonate, BH p-toluenesulfonate, BH esylate (BH: protonated benzocaine), and benzocaine–ligustrazine (cocrystal). Dissolution rate and permeability were improved for all newly synthesized forms. Indeed, every system was completely dissolved within 1 h, while benzocaine was dissolved at 54%, and it was still present in suspension after 4 h. Furthermore, permeability was increased 2-fold for benzocaine maleate and up to seven times for benzocaine camphorsulfonate, highlighting the potential of salification and cocrystallization to increase the in vivo performances of benzocaine.