Setting up multivariate specifications on critical raw material attributes to ensure consistent drug dissolution from high drug-load sustained-release matrix tablet

The purpose of this study was to describe the raw material variability that influenced the in-vitro dissolution behavior of high drug-load sustained-release matrix tablet and to ensure the consistent quality of the final product. The Panax notoginseng saponins (PNS) – hydroxypropyl methylcellulose – anhydrous lactose – magnesium stearate (57:20:23:0.5%, w/w) was used as the model formulation. PNS extract powders with lot-to-lot and source-to-source differences were collected to cover the common cause variations and their physicochemical properties were characterized by the chromatographic fingerprints and the SeDeM expert system. It was found that the release behavior of active pharmaceutical ingredients (APIs) in PNS from different batches exhibited considerable variations. Latent variable modeling results demonstrated that the physical properties of raw materials played major roles in predicting the drug dissolution. PNS extracts with high specific surface area, the width of particle size distribution and hygroscopicity or low moisture content led to an increase in drug release. In order to perform efficient pass/fail judgments for incoming new materials, multivariate specifications of critical material attributes (CMAs) were established and the multivariate design space in line with the quality by design (QbD) principles was explored to achieve the release target.