The impact of glidant addition on continuous blending of active pharmaceutical ingredients

Abstract

Continuous manufacturing (CM) of solid dosage forms in the pharmaceutical industry offers several advantages over batch processing. The most straightforward CM pathway within the pharmaceutical industry is continuous direct compression (CDC), which consists of three main consecutive steps: loss-in-weight feeding, continuous blending and tableting (die-filling and compaction). However, as the majority of the newly developed APIs are cohesive materials with a mean particle size of < 100 μm, a wide particle size distribution (PSD) and a high tendency to agglomerate, they are difficult to handle on CM lines. In this research paper, the impact of a diverse selection of glidants on the continuous blending unit was assessed. Two cohesive APIs (acetaminophen micronized and metoprolol tartrate) and three different glidants (Aerosil^{\protect \relax \special {t4ht=®}} 200, Aerosil^{\protect \relax \special {t4ht=®}} R972 and Syloid^{\protect \relax \special {t4ht=®}} 244 FP) were included. Via multivariate data analysis, quantitative relationships were established between glidant concentration, blending responses (hold-up mass (HM), bulk residence time (BRT), blender fill fraction (BFF %) and relative standard deviation of the blend uniformity (RSD_BU)), blend properties and process settings. The dry-coating of APIs with small quantities of glidants efficiently improved the flowability of cohesive powders, thereby optimizing the gravimetric feeding performance. Dry powder coating of the API altered its bulk properties which affected the bulk properties of the final blend as well as the blending responses (HM, BRT, BFF %). This was mainly attributed to the changes in basic flow energy (BFE), conditioned bulk density (CBD), flowability rate index (FRI) and flow function coefficient (ffc), which are all correlated to HM, BRT and BFF %. It was also observed that glidants did not improve RSD_BU during continuous blending within the investigated experimental space. Moreover, adding higher concentrations of glidants can even increase RSD_BU due to fluidization segregation and less paddle interactions. However, the overal RSD_BU values obtained with the continuous blender were relatively low.

Keywords: Continuous blending; Continuous direct compression; Flow enhancers; Formulation development; Glidants; Particle engineering.