Micro-feeding and mixing of pharmaceutical solid dosage forms under external vibration

Abstract

This study addresses the challenges of micro-dosing and mixing in the continuous manufacturing of solid pharmaceutical formulations by developing a novel continuous feeding-mixing system based on external vibration excitation. The innovative design of a hopper structure with adjustable outlet area distribution demonstrated the potential for achieving precise mixing control of an active pharmaceutical ingredient (API) and an excipient across varying ratios. Experiments first validated the promotion of viscous particle flow by vertical vibration, achieving stable feeding within the range of 0.6–15 mg/s. Building on this, precise control of mixing ratios was enabled by designing different outlet area ratios. In mixing performance evaluation, online X-ray fluorescence spectroscopy confirmed the system achieves high-uniformity mixing with a coefficient of variation below 10%. The study further revealed that optimal mixing stability occurs when Γ < 5, whereas excessive vibration degrades mixing quality.

Highlights

A novel vibration-driven system enables continuous micro-feeding (0.6-15 mg/s) of cohesive powders.
Precise mixing ratio control is achieved by designing hoppers with adjustable outlet area distributions.
Mixing stability is optimal at dimensionless acceleration Γ < 5; excessive vibration degrades quality.
The system provides a simple, reliable unit operation for pharmaceutical continuous manufacturing.

Introduction

Continuous manufacturing technology is driving the global pharmaceutical industry into a new stage of development (Blackshields and Crean, 2018, Burcham et al., 2018). This innovative model not only significantly reduces the cost of new drug development and production, but also improves the level of process automation and product quality consistency, and has become the core development direction of the pharmaceutical industry in the post-pandemic era-the scope of its application has been extended from solid oral preparations to Active Pharmaceutical Ingredients (APIs), injectables, vaccines, and other diversified product forms (Blackshields and Crean, 2018, Munos, 2009). As a key upstream link in continuous manufacturing (Kim et al., 2023, Ndama et al., 2011), constructing a stable, precise, and reliable powder feed stream poses a serious challenge to safeguard the production quality in scenarios such as low-dose administration of small clinical samples (CTMs) and highly active APIs (Kim et al., 2023).

Most APIs, lubricants, disintegrants and carriers in the pharmaceutical industry consist of fine particles with high cohesive particles. The dissipative dynamics between such particles (e.g., elastic rebound, viscous deformation dissipation (Kawasaki and Miyazaki, 2024), and van der Waals force-dominated cohesive effects) greatly impede continuous and precise particle flow control (Vo et al., 2020, Hou et al., 2023). Specifically, the cohesive force of fine particles dominates the inter-particle interactions through van der Waals forces, leading to abnormal macroscopic flow characteristics (e.g., agglomeration, bridging, flow dead zone, etc.) of the particulate system (Kendall, 1994, Rognon et al., 2008), which in turn triggers the flow fluctuation and inhomogeneity during the feeding process, seriously affecting the production stability.

The regulation of particle cohesion is the core of breaking through this bottleneck. Cohesion significantly reduces the powder flowability by limiting the swelling behaviour of particles in the flow, while enhancing the interparticle contact force and relaxation time under loading (Eshuis et al., 2007, BarkerMehta, 1993). Therefore, perturbing the particle bed by external excitation (e.g., vibration, airflow) to modulate the cohesion distribution has become an effective strategy to improve the flowability of highly cohesive particles (BarkerMehta, 1993). In modern continuous pharmaceutical manufacturing, achieving precise and stable delivery of fine powders is a critical technological challenge (Oka et al., 2017, Pernenkil and Cooney, 2006). Currently, the industry primarily relies on two technologies: screw powder feeders (Liu et al., 2024, Kobayashi et al., 2024) and pneumatic powder feeders (Sacher et al., 2020, Singh, 2018). Screw conveyors achieve positive displacement transport through the mechanical displacement of rotating screws. Their high precision across a wide flow range (up to ±1-2%) has established them as the industry standard, particularly for applications requiring strict metering control (Muzzio et al., 2003, Rantanen and Khinast, 2015). However, their mechanical contact characteristics may cause wear on shear-sensitive APIs, and their complex internal structures pose challenges for thorough cleaning, increasing the risk of product cross-contamination. Pneumatic powder feeding systems transport powder by conveying it through airflow via venturi tubes or fluidization devices (Ndama et al., 2011, Olaleye et al., 2019). This method avoids mechanical contact but is highly sensitive to powder properties. It is prone to pulsation or “rat-holing” due to instability in gas-solid two-phase flow and may induce static electricity buildup or particle segregation based on particle size/density. Castellanos et al (Castellanos et al., 2001). pointed out that highly cohesive powders composed of fine particles are difficult to achieve dense flow due to their susceptibility to be solidified by interstitial fluids into fragile agglomerates; while Hou et al (Hou et al., 2023). designed a novel pneumatic micro-feeding system to control the flow through powder entrainment effect, combined with air entrainment to reduce inter-particle and particle-wall contact, achieved a relative standard deviation (RSD) of ±20%-5% within the flow range of 0.7-20 g/h, which verified the feasibility of external excitation for flow regulation.

To address these challenges, vibration-assisted powder feeding has been proposed and studied as an alternative principle. This method does not rely on mechanical displacement or airflow entrainment. Instead, it applies external vibration to the hopper, transferring periodic mechanical energy to the powder. This disrupts the cohesive network between particles, inducing bulk flow. Compared to conventional techniques, vibration-assisted powder feeding demonstrates unique potential in principle: its mechanical structure is exceptionally simple (no internal moving parts or complex air circuits), significantly reducing cleaning complexity and costs; energy is input as low-intensity oscillations, exerting far less shear stress on particles than screw conveyors, offering a gentler processing approach. Wang et al (Wang et al., 2018). utilized the pulsed inertial force generated by a lead zirconate titanate (PZT) stack actuator to drive the flow of highly cohesive powders, and induced self-accelerating inertial flow by reducing the particle contact friction through the small-amplitude high-frequency vibration; another study utilized acoustic radiation forces generated by an ultrasonic standing wave system to break up agglomerates, effectively suppressing the clumping phenomenon of highly viscous powders during flow (Kaliyaperumal et al., 2011a). This result further demonstrates the potential application value of vibration technology in regulating the fluidization process of highly viscous powders (Kaliyaperumal et al., 2011b). Mechanical loading to extend the relaxation time of fine particles is also noteworthy: Besenhard et al (Besenhard et al., 2017). developed a plunger-type volumetric feeding system and a “pepper shaker” type vibratory feeding device, which achieved <5% loading variability at mg/h and 1-2 mg/s flow rates, respectively, demonstrating that vibration-assisted feeding can be effective in low-dose scenarios.

It is worth noting that modern formulations are often co-mingled with multiple powders to enhance dose delivery efficiency and bioavailability (Blackshields and Crean, 2018, Rantanen and Khinast, 2015), and the APIs and excipients need to be homogeneously mixed before filling the capsule or model (Kim et al., 2023). The uniformity and effectiveness of the final product depend heavily on the quality of mixing (Singh, 2018). Although traditional batch mixing equipment (1 quart to 150 cubic feet in volume) is widely used in the pharmaceutical industry, its batch operation mode of horizontally layered loading and hundreds of revolutions of mixing has been difficult to meet the demand for real-time and process control of downstream processes in continuous manufacturing (Muzzio and Oka, 2022). In addition, the mixing energy consumption of large-scale equipment is prone to change the material properties and lacks the real-time monitoring interface of process analytical technology (PAT), which further limits its application in continuous manufacturing. Thus, developing a stable, precise, and dependable continuous feeding-mixing unit has emerged as a critical challenge in the contemporary pharmaceutical field. In this study, we designed and implemented a novel continuous micro-feeding and mixing system driven by external vibration, enabling the precise handling of pharmaceutical solids with diverse flow behaviors. By systematically examining the micro-feeding dynamics of cohesive particles across varying vibration intensities, we elucidated how amplitude and frequency modulate discharge rates. Comprehensive characterization of vibrational effects on cohesive particle flow further clarified the underlying mechanisms.

Additionally, the mixing efficiency under vibration-assisted conditions was rigorously assessed during continuous operation. Real-time quantification of component distribution via X-ray fluorescence spectroscopy confirmed exceptional homogeneity, with a mixing uniformity coefficient variation below 10%—a level fully compliant with demanding pharmaceutical formulation standards.

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Liang Zhang, Haifeng Lu, Xiaolei Guo, Haifeng Liu, Micro-feeding and mixing of pharmaceutical solid dosage forms under external vibration, Chemical Engineering Research and Design, 2026, ISSN 0263-8762, https://doi.org/10.1016/j.cherd.2026.01.048.