Chemometric evaluation of the retention behavior of risperidone and its related compounds

Abstract

Chemometric evaluation of the Quantitative Structure-Retention Relationship (QSRR) of antipsychotic drug risperidone and its impurities A, B, C, D, E, K, L, and M, has been performed, together with correlation analysis. The aim of the study was to develop a model capable of predicting the retention behavior of structurally related compounds not included in the European Pharmacopoeia monograph (EP12.2-01/2011:1559), thereby facilitating rapid evaluation of new impurities/metabolites of potential toxicological concern. QSRR modeling and molecular descriptor calculations were performed using ChemMaster Software 1.3 Basic and the Partial Least Squares (PLS) method. The developed model established a relationship between the calculated molecular descriptors and relative retention time (RRT) obtained under the chromatographic conditions prescribed by the official Ph. Eur. method. Among the evaluated models, the PLS-QSRR model with two significant components showed the best predictive performance and was selected for further analysis. The model achieved R² values of 0.969 and 0.807 and RMSE values of 0.034 and 0.100 for the training and test sets, respectively. Correlation analysis revealed strong positive relationships between RRT and most physi cochemical descriptors (r>0.76), including molecular weight, exact molecular weight, heavy atom molecular weight, and Hydrogen bond acceptors (HBA). LogP exhibited the strongest positive correlation with RRT (r=0.852). The QSRR model successfully predicted retention behavior of additional impurities H, I, F, J and risperidone-N-oxide under the chromatographic conditions specified for related substances (EP12.2-01/2011:1559). Since these compounds were not used for model development, the results confirmed its applicability for retention behavior prediction of structurally related compounds.