Continuous micro feeding and mixing of solid dosage forms under vibrational excitation

Abstract

Continuous manufacturing has intrigued many researchers in the pharmaceutical industry in the post-COVID-19 world. We experimentally studied the discharge characteristics of pharmaceutical excipients under vibrational excitation. The successful accurate dosing and filling of powders at fill rates of 0.6–15 mg/s was developed. A simple particle model includes fluid-grain coupling which is relevant to Faraday tilting resulting from gas trapped in the powder bed accurately predicts the discharge rate. A novel continuous micro mixing system was designed based on the discharge model. Any specified proportions can be realized by setting appropriate vibration parameters. The low variability (<2.5 %) in the content of components has verified the reliability of the mixing system. The continuous mixing performance was determined by the discharge characteristics. Yet the particle size distribution and cohesion lead to different mixing performances when the stability of micro feeding is satisfied. Reasonable process parameters for continuous mixing are determined and optimized.

Highlights

The accurate dosing and filling of cohesive powders was achieved under vibrational excitation.

A theoretical model was developed for prediction of W considering the fluid-grain coupling.

The continuous mixing operation based on continuous feeding was designed and verified.

Introduction

Continuous manufacturing is triggering a worldwide transformation in the pharmaceutical industry (Muzzio and Oka, 2022, Singh, 2018, Blackshields and Crean, 2018, Vervaet and Remon, 2005, Munos, 2009). This emerging technology has been shown to significantly reduce the cost of developing and manufacturing new medicines, while significantly improving the consistent product quality and the automation of the manufacturing process (Burcham et al., 2018). It is expected to be a theme for the pharmaceutical industry in the post-COVID-19 world, not only for solid dose products but also for active pharmaceutical ingredients (APIs), injectable products, vaccines, and other product forms (Rantanen and Khinast, 2015). As a key upstream process step in continuous manufacture, creating a constant, accurate, and reliable powder feeding stream presents significant challenges to the manufacturing process (Sacher et al., 2020). Especially for low-dose feeding of small-scale clinical trial material (CTM), and high-potency API (HPAPI) (Kim et al., 2023). High accuracy and uniformity are required.

However, most APIs, lubricants, disintegrants, and carriers are mostly composed of fine and cohesive particles. The dissipative dynamics between cohesive particles have posed a great challenge for creating a continuous, precisely controlled particle flow (Vo et al., 2020). In principle, interactions between particles are a combination of elastic rebound, dissipation due to viscous deformations, and cohesion caused by the van der Waals forces (Kendall, 1994), which determines the unusual macroscopic properties of granular systems (Rognon et al., 2008). For fine, cohesive particles, van der Waals forces play a dominant role in dissipative particle systems, leading to special aggregation properties (Zhu et al., 2022, Royer et al., 2009). Complex inter-particle interactions and agglomeration behaviors greatly affect the flowability of powders and induce instability and inaccuracy in the feeding process (Luding et al., 2003, Klausner et al., 2000). Under extreme conditions, harsh flow behaviors such as segregation, plugging, flow dead zones, rat holes, etc. occur (Saleh et al., 2018).

Cohesion is pivotal to the flow behavior of cohesive particles. It acts similarly to confined stress, preventing powder from expanding in the flow regime (Brilliantov et al., 2007). Besides cohesion enhances the contact force and probability between particles and reduces the relaxation time under loading (Richefeu et al., 2006). Thus, introducing external excitations into the particle system to expand the powder bed for manipulating the flow of the cohesive particles is the most suitable means (D’Anna et al., 2003, Kou et al., 2017). Castellanos et al. (Castellanos et al., 1999, Castellanos et al., 2001) confirmed that dense flows cannot be achieved with cohesive powders composed of fine particles, since they are directly fluidized by the interstitial fluid from a solid to a suspension of fragile clusters. We noted that this conclusion was unfolded by the work of P. Hou et al. (Hou et al., 2023) They designed a novel pneumatic micro-feeder that enables highly consistent feeding. This system utilizes the effect of powder entrainment to control the powder flow rate. The air entrainment minimizes both the agglomeration and particle–particle, particle–wall contacts. It creates a powder flow rate of 0.7 to 20 g/h, with an RSD of ± 20 to 5 %, depending on the powder properties. Besides, the potential of vibration for particle manipulation is constantly being explored (Kaliyaperumal et al., 2011, Kaliyaperumal et al., 2011). It is well known that vibration increases the free volume in the powder (Nicodemi et al., 1999). The rearrangement of individual particles induced by vibration allows particles to adopt a packing arrangement with lower gravitational potential energy and hence higher apparent density. An increase in free volume breaks agglomerations by overcoming cohesion and may provide vacancies for particle displacements (Barker, 1993). Wang et al. (Wang et al., 2018) described a method of feeding cohesive powder actuated by pulse inertia forces induced by a PZT stack actuator. Small amplitude and high-frequency waves reduced the interparticle friction at grain contacts triggering a self-accelerated inertial flow or a creep-like regime. Interestingly, they designed an ultrasonic standing wave generating system, by which the acoustic radiation force induced broke the agglomerates into small pieces, eliminating the aggregation phenomenon in the fluidization of cohesive powders. Additionally, increasing the relaxation time of fine cohesive powders by applying mechanical loads is also an important topic. Besenhard et al. (Besenhard et al., 2017) presented a volumetric micro-feeder using a cylinder piston system, which allows precise feeding of fine cohesive powders at a rate of a few grams per hour. Besenhard et al. (Besenhard et al., 2015) also described a powder dosing system based on the principle of the “pepper shaker”. Hard gelatin capsules are filled directly through a sieve combined with a vibrating chute where the powder is fully expanded for uniform dispersion. The feeding system provided effective powder feeding even in a range of 1–2 mg/s with less than 5 % fill-weight variability.

Further, pharmaceutical products are often blends of many different powders to improve dose delivery and bioavailability (Pernenkil and Cooney, 2006). APIs and excipients are mixed before being processed and filled into capsules or dies. The quality of the final product is directly affected by the homogeneity of the powder mixture entering the capsules or dies (Muzzio et al., 2003). In the past, batch blenders were commonly used in the pharmaceutical industry (Muzzio and Oka, 2022, Oka et al., 2017). A typical batch blender ranges from about 1 quart to about 150 cubic feet (Kushner and Schlack, 2014). Powder ingredients are loaded in a horizontal layered pattern into blenders (Pingali et al., 2011). Ingredients are tumbled for a few hundred revolutions during which they get progressively mixed. Once the mixing is complete, the mixed ingredients are discharged into one or more intermediate storage containers for further successive powder mixing or lubrication processing. However, as a typical batch operation, batch mixing no longer meets the demands of the downstream process steps of continuous manufacturing. It has a large equipment footprint. It is neither suitable for meaningful Process Analytical Technology (PAT) measurements nor for real-time process control of mixing operations (Kushner and Schlack, 2014). Furthermore, the energy dissipated during the mixing operation in large-scale devices generally changes the material properties of the ingredients. Therefore, creating a constant, accurate, and reliable feeding and mixing cell operation is a valuable and challenging task.

In the present work, the continuous micro feeding and mixing of pharmaceutical excipients with different flowabilities was conducted. The properties of micro feeding of cohesive particles under different vibration intensities were characterized. Condensation of powders with a particular feature of non-deforming stable voids with different heaping behaviors was observed. Further, the fluid-grain coupling was revealed from the Faraday tilting in cohesive granular materials under condensation. We developed a simple particle model to predict the discharge rate. Consequently, continuous mixing performance for continuous micro feeding was evaluated, with a low coefficient of variations. The particle size distribution and cohesion also lead to different mixing performances when the stability of discharge is satisfied.

Read also our introduction article on Binders here:

excipients formulation