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

• Published in: Journal of Chromatography A Vol. 1619; p. 460971
• Main Authors: Maljurić, Nevena, Otašević, Biljana, Malenović, Anđelija, Zečević, Mira, Protić, Ana
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 24.05.2020
• Subjects: acetonitrile; beta-cyclodextrin; chemical species; computer simulation; Cyclodextrin; enthalpy; entropy; Gibbs free energy; high performance liquid chromatography; HPLC; Inclusion complexes; ionization; ligands; prediction; QSRR; quantitative structure-activity relationships; Stability constants; Thermodynamic parameters; Thermodynamic parameters; Cyclodextrin; Inclusion complexes; Stability constants; QSRR; HPLC
• ISSN: 0021-9673; 1873-3778
• DOI: 10.1016/j.chroma.2020.460971

•Chromatographic approach in complex stability constant assessment is time-consuming.•QSRR model was used to predict change in analyte retention time upon complexation.•Predicted change in retention time was used to calculate stability constants.•HPLC and QSRR approach were not applicable under all experimental conditions.•β-CD concentration and acetonitrile content affected stability constant calculation. When cyclodextrins (CDs) are used in chromatography analytes’ retention time is decreased with an increase 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 approach implies extensive and time-consuming HPLC experiments, the goal of this research was to investigate the possibility of using in silico prediction tools instead. Quantitative structure–retention relationship (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 factor 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 predicted 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.