A continuous micro-feeder for cohesive pharmaceutical materials

Over the past decade, continuous manufacturing has garnered significant attention in the pharmaceutical industry. Still, numerous continuous unit operations need developments, such as powder blending and feeding at low and high throughputs. Especially the continuous and consistent feeding of solid drug substances and excipients at low feed rates remains challenging. This study demonstrates a micro-feeder capable of feeding poorly-flowing pharmaceutical powders at low feed rates. The system performance was investigated using three grades of pharmaceutical powder: croscarmellose sodium (cohesive), magnesium stearate (very cohesive), and an active ingredient, paracetamol (non-flowing). The results show that the micro-feeder can continuously and consistently feed powders at low flow rates (<20 g/h) with low variability (<10 % for non-flowing materials and < 5 % for cohesive materials). Notably, the micro-feeder achieves these results without any feedback control and remains unaffected by refilling, making it a truly versatile and industry-relevant solution. The study’s results demonstrate that this micro-feeder system effectively tackles the challenge of consistent and accurate powder feeding at low rates.

1. Introduction

Consistent feeding of powder materials is a critical aspect of the manufacturing process for oral medicines (Besenhard et al., 2017, Besenhard et al., 2016, Besenhard et al., 2015, Chen et al., 2012, Fathollahi et al., 2021, Sacher et al., 2021, Sacher et al., 2020). Any variations in the feed stream can directly influence the quality of the final drug product (Janssen et al., 2022). This factor becomes even more significant in light of current industry trends, such as smaller batch sizes for clinical trials or smaller patient populations, and the use of high-potency active pharmaceutical ingredients (APIs). For instance, delivering high-potency APIs in doses of milligrams or lower per tablet demands a feeding rate of less than 10 g/h with minimal fluctuation over time (Chamberlain et al., 2022). Achieving consistent and precise powder flow rates in micro-feeding is still challenging in the pharmaceutical and biopharmaceutical industries. To tackle this challenge, innovative manufacturing technologies are needed to ensure the delivery of high-quality products in a sustainable and affordable manner (Nagy et al., 2020, Oladeji et al., 2022).

The primary challenges in achieving consistent powder feeding is the strong dependence of flow rate performance on material properties. Particle size distribution, cohesion force between particles, and adhesion force between particles and the equipment contact surface are critical factors that influence powder feeding. Additionally, equipment design and environmental conditions can also play a role. This challenge is particularly significant given that many new APIs are classified as cohesive or poorly flowing materials (Burcham et al., 2018). Consequently, continuously and consistently feeding micrograms of powder remains challenging (Huang et al., 2022, Janssen et al., 2022, Sacher et al., 2021).

The most common feeders in the pharmaceutical sector are loss-in-weight (LIW) screw feeders. LIW feeders are built on a load cell and rely on gravitational control to attain the preferred powder flow rate and reduce fluctuations through adjusting the screw speed. LIW feeders have been improved through the refinement of the screws (Barati Dalenjan et al., 2015, Engisch and Muzzio, 2014, Santos et al., 2018) and the optimisation of the feedback control system (Blackshields and Crean, 2018). Despite these advancements, conventional LIW feeders cannot achieve consistent feeding at low flow rates, particularly for cohesive materials (Blackshields and Crean, 2018, Burcham et al., 2018, Peterwitz et al., 2022). In addition, refilling LIW feeders remains a challenge due to their dependence on the load cell and the feedback control, resulting in additional variations in the mass flow rate during the refilling process. Other difficulties for LIW feeders that affect the consistency and precision of powder feeding include issues such as bridging, adhesion, cohesion, and vibrations (Janssen et al., 2022, Minglani et al., 2020, Peterwitz et al., 2022).

Several other technologies have been developed for feeding at low rates. Besenhard et al. (2017) created a powder pump that utilised a piston in a cartridge to push the powder into a chamber where a rotating scraper would scrub the powder from the cartridge and transfer it to the process. Fathollahi et al. (2021) improved the powder pump by adding a LIW function to enhance its feeding consistency. In contrast, we developed a pneumatic micro-feeder that uses adjustable cross-sectional areas to maintain the entrainment energy, which controls the powder feed (P Hou et al., 2023). While both the powder pump and pneumatic micro-feeder show promise in feeding small quantities of cohesive powders, they still have weaknesses, such as the inability to perform long-term continuous feeding operation. This limitation arises because powder cannot be filled or recharged during operation, and the operation time is restricted by the reservoir size.

Only a few commercial feeders have been deployed for dosing or feeding small amounts of pharmaceutical material. The approaches applied for micro-feeding include an auger method (Coperion, 2013; Amouzegar et al., 2000), vibratory channels (Tardos and Lu, 1996), micro-dosing (MG2, 2023; Besenhard et al., 2016), a pneumatic method (DEC Group, 2023; Bellon et al., 2013) or a rotor vane feeder (LCI Corporation, 2020). However, only a few commercial feeders can continuously feed the powder material at very low flow rates (<50 g/h) while the majority of these feeders struggle to handle cohesive or non-flowing materials (Nowak, 2015; Kruisz et al., 2021; Jones-Salkey et al., 2023; Kerins et al., 2023). Table 1 presents an overview of the feeding mechanisms of various existing feeders and recent advancements in feeding technologies. The screw feeder has seen improvements with twin screws and agitation mechanisms to address flow inconsistency and blockage issues (De Souter et al., 2023, Engisch and Muzzio, 2015, Fernandez et al., 2011, Santos et al., 2018). Vibratory feeders, which rely on vibrations to move powders, have been optimised by adjusting vibration frequency and amplitude to better handle different material characteristics (Besenhard et al., 2016, Besenhard et al., 2015, Horio et al., 2014, Zainuddin et al., 2012). The screw-brush feeder combines a screw feeder with a brush conveyor to stabilise powder flow, though it faces challenges such as particle grinding and contamination (Barati Dalenjan et al., 2015). Fluidised feeders, using fluidisation principles, provide precise control over feed rates, but issues like segregation and control complexity persist (P Hou et al., 2023, Suri and Horio, 2009, Tang and Chen, 1999). Powder pumps, utilising cylinder-piston systems, achieve low flow rates with minimal fluctuation but are less suitable for continuous processes due to powder compaction and refilling needs (Besenhard et al., 2017, Fathollahi et al., 2021, Fathollahi et al., 2020). Slide feeders, employing a double-acting air-driven mechanism, have demonstrated good reproducibility and reliability for various powders (Pohořelý et al., 2004).

Publication year	Author	Investigated materials	Feed rates	Variation	Concept
Mechanical feeder
2011 2020 2020	Fernandez, Cleary & McBride, Minglani et al., Li et al.				Applying DEM to study flow behaviour in diverse screw designs can inform the development of an improved screw for powder feeding.
2015	Barati Dalenjan, Jamshidi & Ale Ebrahim	Zinc oxide	72–630 g/h	2–14 %	The screw-brush feeding system utilises a brush conveyor to stabilise the powder flow rate downstream of a single screw feeder.
2017 2020 2021	Besenhard et al., Fathollahi et al.,. Fathollahi et al.	α-lactose monohydrate powders, API and spray-dried intermediate	1–100 g/h	4–20 %	Powder pump, a cylinder-piston feeder, loads powder into a cartridge and uses a motorised plunger and scraper to control the flow rate via adjustable speed settings.
Vibratory feeder
2012	Chen, Seyfang & Steckel	Lactose Powder	3.6–36 g/h	< 3 %	Vibrating capillary − Through the employment of a vibrating capillary and modulation of both frequency and amplitude, the regulation of flow rate and variability was achieved.
2012 2014	Zainuddin et al.; Horio, Yasuda & Matsusaka	Microcrystalline cellulose	86.4–306 g/h	3–5 %	Vibration shear tube method − The study expelled powder through a narrow gap between a vibrating tube and a flat surface, subjecting each particle to high shear forces to overcome adhesion and friction. The powder flow rate was regulated by controlling the vibration amplitude.
2015 2016	Besenhard et al.	Inhalac 230 Respitose SV003	3.6 – 7.2 g/h	4.6–12 %	Vibratory sieve chute system − to transfer powder from chute to receiver using vibration. The feeder achieved continuous feeding of pharmaceutical materials by regulating frequencies and amplitudes.
2018	Wang et al.	Respitose SV003 Granulac 230	1.4–1.8 g/h	< 12 %	The pulse inertia force was utilised to effectuate the vibration and transportation of the powder, with the flow rate of the powder being regulated by controlling the frequency of the applied force.
Pneumatic/Fluidised feeder
1986	Wibberley & Phong-Anant	Coal	2.0–97.2 g/h		The study employed a motorised screw jack to narrow the fluidised chamber, while carrier gas was used to fluidise the powder and prevent compaction. Top carrier gas was used to blank the gas-powder mixture.
1991	Burch et al.	Geldart A particles: coal and coal-derived char particles. Geldard C particles: coal-derived ashes and CaO powders	1.2–12 g/h	Short term:  < 12 % Long Term: > 15 %	This method strips particles from the powder surface by passing a carrier gas through a narrow gap between a cylindrical piston and the reservoir wall, then carries them through a feed tube when the reservoir is elevated. The flow rate is adjustable through gas flow and reservoir motion.
1999	Tang & Chen	Geldart A particles: coal and coal-derived char particles. Geldard C particles: coal-derived ashes and CaO powders	0.6–31.8 g/h	Short term:  < 3 % Long Term: > 5 %	Modified Burch et al. (1991) 's design
2004	Michael Pohořelý et al	Silica sand, g-alumina, ceramsite (fired claystone), digested and dried municipal sewage sludge, and shredded hard wood.	100–1800 g/h	0.14 % − 15 %	Slide feeder − filling two containers with powder and then using two pockets on the side plate to dispense and receive powder into the pneumatic transport pipe. The powder is then transported by constant pressure air.
2009	Suri & Horio	Charcoal, glass beads, Neo beads	36–3852 g/h		The study improved upon Wen & Simons (1959) ’s work by using a cartridge as a closed fluidised bed for powder fluidisation from the bottom.
2023	P. Hou et al.	Microcrystalline cellulose croscarmellose sodium, crospovidone, and paracetamol	0.7 – 20 g/h	5 %–20 %	Using adjustable cross-sectional area in the entrainment zone to entrain the particle. By adjusting the air flow rate to maintain the powder flow rate.

Adapted from (Besenhard et al., 2016Hou et al., 2023).

This study introduces a new micro-feeder technology that combines an inclined screw feeder with a double-screw agitated hopper to enable highly consistent feeding of typical pharmaceutical materials at rates below 10 g/h. The double screw agitator speed controls the powder flow rate, while the feeding screw speed minimises powder flow rate variation. The effects of feeding screw pitches, agitator speed, and screw speed are investigated. The feeding performance and the mechanisms of the micro-feeder are evaluated and investigated in relation to three common pharmaceutical materials: croscarmellose sodium (CCS, cohesive), magnesium stearate (MgSt, very cohesive), and paracetamol (APAP, non-flowing).

2.1. Materials

Three different powders were used: croscarmellose sodium (CCS, JRS pharma, Germany), magnesium stearate (MgSt, LIGAMED MF-2-V from Peter Greven Nederland C.V., Nederland), and an active pharmaceutical ingredient, paracetamol (APAP, Ph Eur Powder from Mallinckrodt Pharmaceuticals, Ireland). Table 2 summarises the powder properties of the investigated materials.

Download the full study Pre-proof as PDF here: A continuous micro-feeder for cohesive pharmaceutical materials (Pre-proof)

or read it here

P. Hou, M.O. Besenhard, G. Halbert, M. Naftaly, D. Markl, A continuous micro-feeder for cohesive pharmaceutical materials, International Journal of Pharmaceutics, 2024, 124528, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2024.124528.