Quality by Design Based Method Development for Simultaneous Estimation of Montelukast Sodium and Theophylline in Tablet Dosage Form

Background: Analytical Quality by design (AQbD) is one of the upcoming regulatory requirements in the field of pharmaceutical analysis for the development of reliable and robust analytical methods. Montelukast sodium and theophylline available in tablet dosage forms are used widely for the treatment of airway disorders. Liquid chromatographic methods for estimation of the drugs are reported but those chromatographic methods developed by the AQbD approach are not available. Methods: A systematic design of experiments has been employed to develop a liquid chromatographic method for simultaneous estimation of montelukast sodium and theophylline. Critical process parameters are defined and optimization of methanol content in mobile phase, the concentration of trifluoroacetic acid and flow rate was employed within the framework of the full factorial design. The statistical analysis of the experimental data for critical quality attributes namely tailing factor of both the drugs and resolution was performed. Results: A multi-dimensional design space for the critical process parameters was obtained. The optimal chromatographic separation of the two API was achieved using C18 (250mmx4.6mm, 5μm) column as stationary phase and mobile phase composed of acetonitrile, trifluoroacetic acid (TFA) (0.2%v/v in water) and methanol in the ratio of 25:15:60 (v/v/v) at flow rate of 1.0 ml min-1. The influence of the CPP was evaluated by various data tables for example, analysis of variance and lack of fit. Interpretation of various plots obtained from the experimental data such as predicted vs. actual, predicted vs. run, pareto chart, perturbation plot and contour plot provided the information on the manner in which each factor affects the critical quality attributes. Conclusion: A design space generated by design of experiments is an evidence for the robustness of the method. The assay results show the applicability of the method for analysis of commercially available tablets.