Development of mechanistic reduced order models (ROMs)for glidant and lubricant effects in continuous manufacturing of pharmaceutical solid-dosage forms.

Abstract

As the pharmaceutical industry transitions from batch to continuous manufacturing, real-time monitoring, and mechanistic model-based control are essential to conform to FDA quality standards. Glidants and lubricants are known to affect the Critical Quality Attributes (CQAs) of a tablet such as tensile strength, tablet porosity, and dissolution profile (Razavi et al., 2018; Apeji and Olowosulu, 2020). Quantitative models for predicting these effects are essential for enabling centralized control strategies of lubricant and glidant feeding and blending in direct compression tableting lines. This work presents the development of mechanistic reduced order models to capture the effects of lubricant (magnesium stearate) and glidant (silica) on CQAs and Critical Process Parameters (CPPs). A Latin Hypercube experimental campaign with thirty different mixing conditions of silica with MCC (Avicel PH200) and APAP (Acetaminophen) was carried out using a Natoli NP400 tablet press and a SOTAX AT4 tablet tester. Experiments show that the tensile strength and blend bulk density are significantly affected by the mixing conditions of silica. Similarly, adding magnesium stearate (MgSt) changes the bulk density of the blend, compaction force required to form a tablet, and tensile strength of the tablet, depending on the lubrication conditions (Mehrotra et al., 2007; Razavi et al., 2018).