Batch vs. continuous direct compression - a comparison of material processability and final tablet quality.

In this study, an in-depth comparison was made between batch and continuous direct compression using similar compression set-ups. The overall material processability and final tablet quality were compared and evaluated. Correlations between material properties, process parameters and final tablet properties were made via multivariate data analyses. In total, 10 low-dosed (1% w/w) and 10 high-dosed (40% w/w) formulations were processed, using a total of 10 different fillers/filler combinations. The trials indicated that the impact of filler type, drug load or process settings was similar for batch and continuous direct compression. The main differentiator between batch and continuous was the flow dynamics in the operating system, where properties related to flow, compressibility and permeability played a crucial role. The less consistent flow throughout a batch process resulted in a significantly higher variability within the tablet press (σCF) and for the tablet quality responses (σMass, σTS). However, the better controlled blending procedure prior to batch processing was reflected in a more consistent API concentration variability. Overall, the comparison showed the benefits of selecting appropriate excipients and process settings to achieve a specific outcome, keeping in mind some key differentiators between both processes.

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.