Optimization of a liquid chromatography method for the analysis of related substances in daclatasvir tablets using design of experiments integrated with the steepest ascent method and Monte Carlo simulation

Publication date: Available online 22 October 2019Source: Journal of Pharmaceutical and Biomedical AnalysisAuthor(s): Trupti Tol, Harshad Tawde, Savita Gorad, Avinash Jagdale, Amol Kulkarni, Avinash Kasbale, Anita Desai, Gautam SamantaAbstractAnalytical method for the determination of related substances (RS) in Daclatasvir tablets was optimised using quality by design (QbD) approach. Seven degradants (each more than 1.0%) generated during oxidation study, adversely affected the selectivity of the method. Coelution of the degradant peaks with API and known impurities, suggested failure in developing a stability indicating method. To overcome the shortcomings and develop a robust method, QbD principles were incorporated. Resolution was the critical quality attribute (CQA) and buffer pH, column oven temperature, gradient slope and flow rate were the critical method variables (CMVs) studied through design of experiments (DoE). Discovery of an unknown impurity (named as impurity D, about1.0%) was a key finding from this DoE study. The most crucial responses viz. Resolution between impurity D and the main peak and resolution between the main peak and impurity E demanded contradictory pH requirements. To select the right pH, responses were prioritised and eventually to attain the desired resolution between Daclatasvir and impurity E the value for pH was fixed to 3.0. Next, to improve resolution between impurity D and Daclatasvir, method of steepest ascent was applied to locate an ap...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research