Quality by Design Enabled Anti-hypertensive Floating Drug Delivery System by Risk Assessment and Design of Experiment (DoE) - In Vitro - In Vivo Correlation Studies

Abstract

Background: The present research aimed to develop and optimize extended-release floating tablets of Sacubitril and Valsartan by Quality by Design (QbD) approach. Methods: Risk analysis by formulation assessment and process parameters showed that optimizing the levels of the polymer will minimize the high risk to meet the target profile. A two (2) level three (3) full factorial experimental design along with midpoints was carefully chosen for optimization and statistical analysis. Based on the literature, the independent and dependent variables were selected. Results: HPMC K100, Carbopol 934P had a positive effect, Ethyl cellulose with the negative effect on Floating time, Drug release at 2 h, Drug release at 12 h and, t50% responses. Drug release kinetics followed the first-order release with Higuchi and fickian diffusion. Contour and overlay plots were utilized for an assortment of design space and optimized formula. ANOVA results of all the factors exhibited significance at p < 0.05. Abdominal X-ray imaging of the optimized tablets on a healthy rabbit’s stomach confirmed the floating behavior for more than 12 h. In vivo pharmacokinetic studies in rabbits have shown that the optimized formulation exhibited prolonged and extended drug release with improved Cmax, tmax, AUCo-t, and t1/2 of test product when compared to marketed product. IVIVC model was developed by using dissolution data of in vitro and pharmacokinetics data of in-vivo by deconvolution method (Wagner-Nelson method). Conclusion: The Quality by Design implementation in the formulation and optimization abridged the number of trials to produce a cost-effective formula. In vivo studies have demonstrated that the formula was successfully developed with extended floating time (12 h) and drug release by risk analysis and experimental designs. Level A correlation was observed, which confirmed a good correlation between in vitro and in vivo data.