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

[Display omitted] •Solubility of lidocaine in scCO2 in wide range of phase diagram was measured.•Analysis of the conformations of lidocaine in scCO2 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 scCO2 under heating conditions in the temperature range of 35–80 °C along three isochores corresponding to the scCO2 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 scCO2 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 scCO2 phase, but this change is not related to the destruction of the intramolecular hydrogen bond. Higher scCO2 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 scCO2 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.