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) (Snick et al., 2017; Karttunen et al., 2019). However, as the majority of the newly developed APIs are cohesive materials with a mean particle size of ¡ 100 um, a wide particle size distribution (PSD) and a high tendency to agglomerate, making them difficult to handle on CM lines (Yang et al. 2005; Jallo et al. 2012; Chen et al. 2019). 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 coeffient (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, overall the RSD BU values obtained with the continuous blender were relatively low.

Introduction

Continuous manufacturing (CM) of solid dosage forms in the pharmaceutical industry offers many advantages over batch processing. The benefits of CM include lower labor costs due to minimized manual interventions, reduced footprint, smaller inventory, enhanced in-line quality control facilitated by process analytical technology (PAT) tools, and more scale-up flexibility (Vanhoorne and Vervaet, 2020, Ervasti et al., 2015). Moreover, regulatory agencies such as the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) are encouraging pharmaceutical companies to shift from batch manufacturing to CM by providing guidelines and instructions for its successful implementation (Lee et al., 2015, Allison et al., 2015, EMA, 2021).

The most straightforward and studied CM manufacturing pathway within the pharmaceutical industries is continuous direct compression (CDC). The CDC process consists of three main consecutive steps, including loss-in-weight feeding, continuous blending and tableting (die-filling and compaction) (Van Snick et al., 2017, Karttunen et al., 2019).

Currently, as the majority of the newly developed active pharmaceutical ingredients (APIs) are cohesive materials with a mean particle size of <100 um, a wide particle size distribution (PSD) and a high tendency to agglomerate, they are difficult to handle on CM lines (Yang et al., 2005, Jallo et al., 2012, Chen et al., 2019). Many research papers have explored the ability of fumed silica glidants (e.g. Aerosil® and CAB-O-SIL®) to enhance the flowability of cohesive powders. These nano-sized glidants can adhere to the surface of the API, thereby reducing the Van-der-Waals (VdW), frictional and attractive forces between particles (Kunnath et al., 2023, Capece et al., 2021, Jallo et al., 2012, Ruzaidi et al., 2017). Other excipients such as mesoporous silica grades and tricalcium phosphate (TCP) also allowed to improve powder flow. Whereas mesoporous glidants (e.g. Syloid® 244FP) improve the flowability by creating as a porous structure thereby lowering the attractive forces, TCP (e.g. TRI-CAFOS® 200–7) de-agglomerates during dry-coating into nano-sized particles which have the same working mechanism as fumed silica glidants (Heß et al., 2016, Lumay et al., 2019).

Despite the numerous research papers studying the effects of glidants on the bulk properties of cohesive APIs, only limited research addressed their effect on dry powder blending processes. Huang et al. (2017) studied the effect of different fumed silica grades on the blend uniformity (BU) of low-dosed drug formulations. The study showed less agglomeration of the cohesive APIs after dry-coating, thereby improving BU. Similar findings were reported by Kim et al. (2023) attributing the improved BU to a lower cohesion of the APIs after the addition of fumed silica glidants. Moreover, this study also showed positive effects of fumed silica grades on the dissolution rate of the drug product due to the reduced agglomeration of the cohesive API. However, all these papers studied the effects of glidants on batch blending. As the mechanism of batch blending substantially differs from continuous blending, the obtained conclusions can not directly be transferred to a continuous blending process (Karttunen et al., 2019, Jaspers et al., 2022).

Up till now, no research has been done to assess the impact of glidant addition on continuous blending. Therefore, the current work aims to establish a quantitative relationship between various glidant concentrations, blend characteristics, process settings, and blending responses. Multiple linear regression (MLR) models were calibrated to statistically assess the impact of each factor on the bulk residence time (BRT) and RSD of the blend uniformity (RSD BU). Using a partial least squares (PLS) model, important blend characteristics affecting hold-up mass (HM), BRT, and blender fill fraction % (BFF %) were identified. The impact of glidants on HM, BRT, and BFF % was studied in-depth. Secondly, current research addresses the impact of glidant addition on RSD BU, investigating the advantages and disadvantages of glidant use in CDC. Previous research articles by our group showed the effect of various glidants on the blend properties (Verbeek et al., 2025b) and loss-in-weight feeding (Verbeek et al., 2025a) of different APIs. Current research aims to assist CDC formulation development by inclusion of glidants to improve the processability of cohesive APIs.

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Materials

Two challenging APIs were selected for this study (acetaminophen micronized (APAP) and metoprolol tartrate (MPT)) based on their small particle size, irregular shape and tendency to agglomerate. Furthermore, three excipients for flow improvement were selected: a hydrophilic (Aerosil® 200) and hydrophobic (Aerosil® R972) fumed silica grade and a mesoporous silica grade (Syloid® 244FP). The fumed silica grades on the one hand adhere to the surface of the host particles during the dry-coating

Tom Verbeek, Alexander De Man, Bernd Van Snick, Martin Otava, Thomas De Beer, Ashish Kumar, Chris Vervaet, Valérie Vanhoorne, The impact of glidant addition on continuous blending of active pharmaceutical ingredients,
International Journal of Pharmaceutics, 2025, 125927, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125927.

Read also our introduction article on Mesoporous Silica here: