Conformational equilibria of pharmaceuticals in supercritical CO2, IR spectroscopy and quantum chemical calculations

In this work we demonstrate a self-consistent effective technique of analyzing the conformational equilibria of active pharmaceutical ingredient (API) molecules dissolved in supercritical carbon dioxide in a wide range of thermodynamic parameters of state. This approach can be useful for pharmaceutics when the crystalline forms of pharmaceuticals with a high purity degree and desirable polymorphism are produced using CO2-based supercritical fluids technologies. Within this approach we use a combination of quantum chemical calculations and in situ IR spectroscopy. Quantum chemical calculations allow us to perform the initial conformational search and to determine the energy characteristics of the most stable conformers of API and the energy barriers of transitions between them. IR spectroscopy gives the information on the equilibrium of the most stable conformers of pharmaceuticals dissolved in scCO2 in the thermodynamic parameter range of interest. Finally we validate our approach by applying it to the study of carbamazepine dissolved in scCO2 being in permanent contact with an excess of crystalline carbamazepine as an example. The conformational search for carbamazepine molecules in scCO2 was also performed using molecular dynamics simulation for comparison with the results obtained by the technique presented in this paper. [Display omitted] •Approach for analysis of the conformations of drugs molecules in scCO2 is shown.•It can be used when drugs production by CO2-based supercritical fluid technologies.•Method was applied for conformational analysis of carbamazepine dissolved in scCO2.•Conformational crossover was found under isochoric heating conditions.