The development of retention time prediction model using multilinear gradient profiles of seven pharmaceuticals.

The ICH guidance on pharmaceutical development recommends a systematic development approach including robustness studies which assure performance of manufacturing and analytical method development of drug product. The retention model by T. Kawabe et al have an excellent correlation between observed and predicted retention time in various kinds of pharmaceutical compounds during isocratic elution by the multiple regression modeling of solvent strength parameters. However, it cannot be successfully applied to the predictability of the retention time during multilinear gradient elution and also it does not consider the instrument dependent parameters such as dwell volume. The current study demonstrated that the solution of the fundamental gradient elution equation was applied to T. Kawabe's retention time prediction model to predict the retention time using a multilinear gradient profile with taking the delay volume of HPLC system into account. Seven pharmaceutical compounds were used for evaluation of prediction models for retention time. The predicted retention time was compared with the measured retention time obtained by several multilinear gradient using two HPLC systems with different dwell volume. The evaluated prediction error (%) was 1.10 % and 1.54 % with H-Class and Nexera XR HPLC systems, respectively. In order to evaluate the robustness of the analytical method and to set the system suitability test (SST) for proper method performance, the design space for the ACN/MeOH mixture ratio in the total organic solvent and the full width at half maximum (FWHM) relationship to the minimum resolution was simulated by the developed retention time prediction. The optimized condition of the ACN/MeOH mixture ratio, the acceptance criterion of the SST for achieving the robust separation was estimated based on the simulated design space. As a conclusion, the developed retention time prediction will be useful during analytical method transfer among different manufacturing/analytical sites of the pharmaceuticals with different HPLC systems.