Quantitative structure retention relationship modeling as potential tool in chromatographic determination of stability constants and thermodynamic parameters of β-cyclodextrin complexation process

Abstract

When cyclodextrins (CDs) are used in chromatography analytes’ retention time is decreased with an in- crease in concentration of CD in the mobile phase. Thus complex stability constants can be determined from the change in retention time of the ligand molecule upon complexation. Since the preceding ap- proach implies extensive and time-consuming HPLC experiments, the goal of this research was to inves- tigate the possibility of using in silico prediction tools instead. Quantitative structure–retention relation- ship (QSRR) model previously developed to explain the retention behavior of risperidone, olanzapine and their structurally related impurities in β-CD modified HPLC system was applied to predict retention fac- tor under different chromatographic conditions within the examined domains. Predicted retention factors were further used for calculation of stability constants and important thermodynamic parameters, namely standard Gibbs free energy, standard molar enthalpy and entropy, contributing to inclusion phenomenon. Unexpected prolonged retention with an increase in β-CD concentration was observed, in contrast to the employed chromatographic theory used for the calculation of the stability constants. Consequently, it led to failure in stability constants and thermodynamic parameters calculation for almost all analytes when acetonitrile content was 20% (v/v) across the investigated pH range. Moreover, ionization of investigated analytes and free stationary phase silanol groups are pH dependent, leading to minimization of secondary interactions if free silanol groups are non-ionized at pH lower than 3. In order to prove accuracy of pre- dicted retention factors, HPLC verification experiments were performed and good agreement between predicted and experimental values was obtained, confirming the applicability of proposed in-silico tool. However, the obtained results opened some novel questions and revealed that chromatographic method is not overall applicable in calculation of stability constants and thermodynamic parameters indicating the complexity of β-CD modified systems.