Scalable Design and Development of Modified Release Hydrochlorothiazide Formulation Employing Quality by Design Approach

Abstract

Myocardial infarction, generally known as ‘heart attack’ occurs predominantly during the early morning hours and a cause of millions of death worldwide. Hydrochlorothiazide is the recommended drug for the prevention of heart disease, but the commercial market lacks its long action (>4 h) formulation. The endeavor of the present research was to develop a quality product profile of hydrochlorothiazide modified release tablets (~14 h release) by applying computational quality by design approach. Three independent factors were identified by qualitative and quantitative risk assessment. Selected dependent variables were cumulative percent of dissolved hydrochlorothiazide in 2, 5, 8 and 12 h. Graphical tools like half normal, normal and Pareto charts were used to manage model selection. The graphical relationship among the critical, independent variables was represented using contour plot and three-dimensional surface plot. Design space was identified by plotting overlay plot using three factors, two-level full factorial design. Outstanding correlation was observed between predicted and actual values. Similarity factor (F2) of reproducible trials was 78 and 79, and content uniformity was 100.9 % and 100.4 %. Average weight, hardness, thickness, diameter and friability were within acceptable limits. Quality by design approach, along with quality risk management tool furnished an efficient and effective paradigm to structure quality modified release tablets of hydrochlorothiazide.