Smith, David J.; Shah, Jindal K.; Maginn, Edward J.
Molecular Dynamics Simulation Study of the Association of Lidocainium Docusate and Its Derivatives in Aqueous Solution

Ionic liquid active pharmaceutical ingredients (IL APIs) are novel materials in which the ions themselves are APIs, but the pure salt is a liquid under ambient conditions. It has been found that IL APIs can have superior performance relative to their conventional salt analogues, but the mechanism for this is unclear. We have used molecular simulations to estimate the aqueous phase association constants of the IL API lidocainium docusate and their sodium and chloride counterparts. Lidocainium is the cationic form of lidocaine, a local anesthetic, while the docusate anion is an emollient. From strongest to weakest, the calculated association constants are 10.1 M-1 (lidocainium docusate); 0.77 M-1 (sodium chloride); 0.086 M-1 (sodium docusate); and 0.065 M-1 (lidocainium chloride). These results suggest that the experimentally observed enhanced efficacy of lidocainium docusate relative to the traditional drug formulation as a lidocaine hydrochloride salt could result from association of the ions in aqueous solution and at the cell membrane, leading to a synergistic activity effect.


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