Role of an intramolecular H-bond in lidocaine conformer distribution and polymorph stability

Abstract

• Solubility of lidocaine in scCO 2 in wide range of phase diagram was measured. • Analysis of the conformations of lidocaine in scCO 2 was performed. • Stability of intramolecular hydrogen bond in lidocaine molecule was found. In this work, we study conformational equilibria of lidocaine molecules in a saturated lidocaine solution in scCO 2 under heating conditions in the temperature range of 35–80 °C along three isochores corresponding to the scCO 2 density of 1.1, 1.3, and 1.5 of its critical value. It is established that among of 68 conformers obtained by quantum chemical calculations, it is only conformers with an intramolecular hydrogen bond that are realized within the studied range of parameters of state. The IR spectroscopy data show that the lidocaine solubility in scCO 2 increases significantly with the fluid phase temperature and density growth, reaching the concentration about 10 −1 mol·L −1 . However, this does not lead to the formation of intermolecular hydrogen bonds between the lidocaine molecules in the solution. Moreover, the heating changes the conformational equilibrium of lidocaine molecules in the scCO 2 phase, but this change is not related to the destruction of the intramolecular hydrogen bond. Higher scCO 2 phase density is found to reduce the temperature effect on the conformational equilibrium. Finally, we establish that the temperature-induced conformational changes in the lidocaine molecules in the scCO 2 phase are completely reversible. It allows us to assume that, regardless of the SCF solution parameters of state in the considered phase diagram region, lidocaine crystallization from this solution will lead to the formation of the same stable polymorph.