NMR analysis of ion pair formation between timolol and sorbic acid in ophthalmic preparations

Ion pair formation between timolol and sorbic acid was investigated using NMR spectroscopy in order to clarify their interactions within ophthalmic preparation. 13C and 1H NMR spectra of timolol, sorbic acid, and a mixture of the two were obtained, and the signal changes induced by pairing were observed. The carbon signals of the butylaminopropanol moiety of timolol were markedly shifted in the mixture, as were the carboxyl and conjugated carbons assigned to sorbic acid. The localizations of the changes in each molecule revealed the binding sites. The profiles of butylaminopropanol carbon chemical shifts plotted against a molar ratio of sorbate were synchronized, which suggested a single type of interaction with sorbic acid. The Job plot showed a typical pattern with a single–maximum at a mole function of 0.5, indicating the presence of a 1:1 complex of timolol and sorbic acid. The stability constants (K) of the timolol–sorbate and timolol–maleate pairs were 1.9 × 101 and 2.2 × 102 M−1, respectively. The higher K value of the timolol–maleate interaction suggested that it was dominant to the timolol–sorbate interaction when maleate and sorbate coexisted within a timolol solution. Here, we demonstrated evidence of an interaction between timolol and sorbic acid using simple NMR measurements, which suggested the existence of ion pair formation derived from charge neutralization. Our analysis using NMR spectroscopy should advance the understanding and optimization of formulations that are based on ion pair.