Application of Quality Risk Management and DoE ...

Application of Quality Risk Management and DoE Tools for Development and Optimization of Carbamazepine Orally Disintegrating Tablet Formulation S. M. Mishra, B. D. Rohera St. John's University Purpose The objective of the present investigations was to design and develop an orally disintegrating tablet (ODT) formulation of carbamazepine using QbD principles. Methods In this study, highly porous, orally disintegrating tablets of carbamazepine with sufficient mechanical strength were prepared by incorporating a volatile material and subsequent sublimation of it. The ODT formulations included mannitol as tablet diluent, a tablet disintegrant from one of the three main classes of superdisintegrants represented by Ac-Di-Sol® (Croscarmellose Sodium), Kollidon® CL-SF (Crospovidone) and Explotab® (Sodium starch glycolate) and a sublimating agent. Selection of the sublimating material was done by comparative evaluation of commonly used volatile materials, such as menthol, camphor and ammonium bicarbonate. Box Behnken response surface methodology was used to study the effect of formulation and process variables on quality attributes of ODTs. The independent variables selected were compression pressure (X1), type and concentration of sublimating agent (X2), type and concentration of disintegrating agent (X3), and the response variables were tablet crushing strength, tablet porosity, disintegration time, water absorption time, % friability and dissolution time. A commercial software (Minitab®) was used to study the extent of influence of each sublimating material and superdisintegrant on disintegration time and friability index of ODTs. Target product profile (TPP) and target product quality profile (TPQP) of ODTs were also identified. Risk assessment was carried out by leveraging prior knowledge and experience to define the criticality of independent variables based on their impact by Ishikawa fish bone diagram and potential hazard analysis tool. Results A systematic link was established between critical process parameters (CPP) and material attributes (CMA) with the critical quality attributes of ODTs. Risk assessment and screening helped to identify and select the material attributes (CMA) and critical process parameters (CPP) for the development of ODT formulation. ANOVA and lack-of-fit test illustrated that selected independent variables had significant effect on the selected response variables, and excellent correlation was observed between actual and predicted values. Significant Pearson correlation coefficient (0.753) between water absorption time with disintegration time of tablet suggested water absorption as the most crucial step for disintegration of tablets. Optimization by desirability function indicated optimum levels of compression pressure, X1 (1533 psi), ammonium bicarbonate, X2 (7.68%) and Kollidon CL-SF, X3 (6%) for ODT formulation of specified attributes complying with target product quality profile. Conclusion An excellent fit was observed between actual and predicted values of responses indicating that selected DoE tool is an excellent tool for multivariate approach to build sequential design and estimation of the linear, quadratic model parameters. The carbamazepine ODT formulation was successfully developed with a high level of quality assurance and performance by application of QbD principles.