Risk based approach for design and optimization of stomach specific delivery of rifampicin

Abstract

The research envisaged focuses on risk management approach for better recognizing the risks, ways to mitigate them and propose a control strategy for the development of rifampicin gastroretentive tablets. Risk assessment using failure mode and effects analysis (FMEA) was done to depict the effects of specific failure modes related to respective formulation/process variable. A Box-Behnken design was used to investigate the effect of amount of sodium bicarbonate (X1), pore former HPMC (X2) and glyceryl behenate (X3) on percent drug release at 1st hour (Q1), 4th hour (Q4), 8th hour (Q8) and floating lag time (min). Main effects and interaction plots were generated to study effects of variables. Selection of the optimized formulation was done using desirability function and overlay contour plots. The optimized formulation exhibited Q1 of 20.9%, Q4 of 59.1%, Q8 of 94.8% and floating lag time of 4.0 min. Akaike information criteria and Model selection criteria revealed that the model was best described by Korsmeyer-Peppas power law. The residual plots demonstrated no existence of non-normality, skewness or outliers. The composite desirability for optimized formulation computed using equations and software were 0.84 and 0.86 respectively. FTIR, DSC and PXRD studies ruled out drug polymer interaction due to thermal treatment.

Keywords: AIC; Akaike Information Criterion; BBD; Box–Behnken design; Box–Behnken designs; CQA; CR; Controlled Release; Critical Quality Attributes; DDS; DOE; DSC; Design of Experiments; Desirability function; Differential Scanning Calorimetry; Drug Delivery System; ES; Experimental Sequence; FMEA; FT-IR; Failure Mode and Effects Analysis; Failure mode and effects analysis; Fourier Transform Infra Red; Gastroretention; HDPE; HPMC; High Density Polyethylene; Hydroxy Propyl Methyl Cellulose; ICH; International Conference on Harmonization; MIC; MSC; Minimum Inhibitory Concentration; Model Selection Criteria; Overlay contour plots; PXRD; Powder X-Ray Diffraction; QTPP; QbD; Quality Target Product Profile; Quality by Design; RIF; RPN; Rifampicin; Risk Priority Number; Risk management; SD; SEM; SSR; Scanning Electron Microscopy; Standard Deviation; Sum of the Squared Residuals; TB; Tuberculosis; USP; United States Pharmacopoeia; WHO; World Health Organization.