Development and implementation of a pneumatic micro-feeder for poorly-flowing solid pharmaceutical materials.

Consistent powder micro-feeding (<100 g/h) is a significant challenge in manufacturing solid oral dosage forms. The low dose feeding can well control the content consistency of the dosage forms, which improves drug efficiency and reduces manufacturing waste. Current commercial micro-feeders are limited in their ability to feed < 20 g/h of cohesive (i.e. powders of poor flowability) active pharmaceutical ingredients (API) and excipients (e.g. lubricants) with low fluctuation. To breach this gap, this study presents an advanced micro-feeder design capable of feeding a range of pharmaceutical-grade powders consistently at flow rates as low as 0.7 g/h with <20 % flow rate variation. This was possible due to a novel powder conveying concept utilising particle re-entrainment to minimise flow rate variations. This work details the design of this pneumatic micro-feeder and its excellent micro-feeding performance even for cohesive powders. The experimental studies investigated the influence of the process parameters (air pressure and air flow rate) and equipment configurations (insert size and plug position) on the feeding performance of different pharmaceutical-relevant powders, i.e., microcrystalline cellulose (MCC), croscarmellose sodium (CCS), crospovidone (XPVP) and paracetamol (APAP). It was shown that the system is capable of delivering consistent powder flow rates with good repeatability and stability.

Micro-feeding and dosing of powders via a small-scale powder pump.

Robust and accurate powder micro-feeding (<100mg/s) and micro-dosing (<5 mg) are major challenges, especially with regard to regulatory limitations applicable to pharmaceutical development and production. Since known micro-feeders that yield feed rates below 5mg/s use gravimetric feeding principles, feed rates depend primarily on powder properties. In contrast, volumetric powder feeders do not require regular calibration because their feed rates are primarily determined by the feeder's characteristic volume replacement. In this paper, we present a volumetric micro-feeder based on a cylinder piston system (i.e., a powder pump), which allows accurate micro-feeding and feed rates of a few grams per hours even for very fine powders. Our experimental studies addressed the influence of cylinder geometries, the initial conditions of bulk powder, and the piston speeds. Additional computational studies via Discrete Element Method simulations offered a better understanding of the feeding process, its possible limitations and ways to overcome them. The powder pump is a simple yet valuable tool for accurate powder feeding at feed rates of several orders of magnitude.

Continuous feeding of low-dose APIs via periodic micro dosing.

Precise and effective feeding of small powder quantities remains a challenge in many fields, including pharmaceutical development and production. This paper demonstrates that a simple feeding principle can be applied to accomplish stable micro feeding (<100mg/s) and describes a gravimetric powder feeding system with a vibratory sieve mounted on a chute. Feeding was induced via vertical vibrations that can be adjusted within a broad range of frequencies and amplitudes. The feeding system was studied using different frequencies, amplitudes, sieves and powder properties. Feeding was characterized by means of a dynamic scale and high-speed camera recordings. The feeding system provided effective powder feeding even in a range of 1-2mg/s. It was shown that powder properties require special attention when the vibratory sieve-chute system operates at higher feed rates (or feeding times >30min), i.e., feeding at a higher throughput. A combination of discrete element method (DEM) simulations and compartment population balance model (PBM) was used to incorporate the proposed micro feed system into a continuous powder mixer (Gerike GCM250; Gerike Holding LTD., Regensdorf, Switzerland). It illustrates how oscillating feeding rates (the latter is a characteristic of the studied micro feeding system) affect the content uniformity of low dose blends, i.e., powder mixtures with a relatively low fraction of active pharmaceutical ingredient.

Accuracy of micro powder dosing via a vibratory sieve-chute system.

This paper describes a powder dosing system with a vibratory sieve mounted on a chute that doses particles into a capsule. Vertical vibration occurred with a broad range of frequencies and amplitudes. During dosing events, the fill weight was accurately recorded via a capacitance sensor, covering the capsules and making it possible to analyze filling characteristics, that is, the fill rates and their robustness. The range of frequencies and amplitudes was screened for settings that facilitated reasonable (no blocking, no spilling) fill rates for three lactose powders. The filling characteristics were studied within this operating space. The results reveal similar operating spaces for all investigated powders. The fill rate robustness varied distinctly in the operating space, which is of prime importance for selecting the settings for continuous feeding applications. In addition, we present accurate dosing studies utilizing the knowledge about the filling characteristics of each powder.

Continuous API-crystal coating via coacervation in a tubular reactor.

We present a proof-of-concept study of a continuous coating process of single API crystals in a tubular reactor using coacervation as a microencapsulation technique. Continuous API crystal coating can have several advantages, as in a single step (following crystallization) individual crystals can be prepared with a functional coating, either to change the release behavior, to protect the API from gastric juice or to modify the surface energetics of the API (i.e., to tailor the hydrophobic/hydrophilic characteristics, flowability or agglomeration tendency, etc.). The coating process was developed for the microencapsulation of a lipophilic core material (ibuprofen crystals of 20 µm- to 100 µm-size), with either hypromellose phthalate (HPMCP) or Eudragit L100-55. The core material was suspended in an aqueous solution containing one of these enteric polymers, fed into the tubing and mixed continuously with a sodium sulfate solution as an antisolvent to induce coacervation. A subsequent temperature treatment was applied to optimize the microencapsulation of crystals via the polymer-rich coacervate phase. Cross-linking of the coating shell was achieved by mixing the processed material with an acidic solution (pH<3). Flow rates, temperature profiles and polymer-to-antisolvent ratios had to be tightly controlled to avoid excessive aggregation, leading to pipe plugging. This work demonstrates the potential of a tubular reactor design for continuous coating applications and is the basis for future work, combining continuous crystallization and coating.