Highly potent active pharmaceutical ingredients (APIs) and low-dose excipients, or excipients with very low density, are notoriously hard to feed with currently available commercial technology. The micro-feeder system presented in this work is capable of feeding low-dose rates of powders with different particle sizes and flow properties. Two different grades of lactose, di-calcium phosphate, croscarmellose sodium, silicon dioxide, a spray-dried intermediate, and an active ingredient were studied to vary material properties to test performance of the system. The current micro-feeder system is a volumetric feeder combined with a weighing balance at the outlet that measures feeder output rates. Feeding results are shown as a so-called “displacement-feed factor” curve for each material. Since the powder mass and volume are known in the micro-feeder system, in this work, we characterized an observed density variation during processing via a “displacement-feed factor” profile for each of the fed powders. This curve can be later used for calibrating the system to ensure an accurate, constant feed rate and in addition predicting feeding performance for that material at any feed rate. There is a relation between powder properties and feeding performance. Powders with finer particles and higher compressibility show densification during their feeding process. However, powders with larger particles and lower compressibility show both “densification” and “powder bed expansion,” which is the manifestation of dilation and elastic recovery of particles during the micro-feeding process. Through the application of the displacement-feed factor, it is possible to provide precise feeding accuracy of low-dose materials.
Graphical abstract
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.
Purpose Accurate and reliable feeding of small quantities of powder is crucial in many industries. It is particularly true in the case of pharmaceutical manufacturing. First, the exact dosage of highly potent active pharmaceutical ingredients (APIs) is essential. Second, due to the shift towards continuous manufacturing, processing agents must be supplied continuously. Last, with regard to personalized medicine products, small doses of API have to be processed with high flexibility. In all these applications, a few grams of powder or less per hour have to be fed, which makes processing very challenging. The common route of pre-blending causes additional effort in processing and quality control compared to direct continuous feeding, while material properties influence the performance of conventional feeders with conveying screw elements. Methods In this study, a novel micro-feeding system based on active volumetric displacement is investigated and compared to commercial LIW feeders of various scales. In the micro-feeder, the powder is filled into a cylindrical cartridge and pushed towards the process by a piston in a controlled manner. Tests are carried out with a free-flowing grade of lactose and croscarmellose sodium as an example of cohesive powder. Results At feed rates of a few grams per hour, for the investigated materials, the system has at least the same performance as conventional feeders at significantly higher feed rates. Especially at low feed rates, less fluctuations are obvious and accuracy and precision of the micro-feeder are at the same level as for the established feeding technology at rates ten times higher. Conclusion For the two types of investigated materials (free-flowing and cohesive), the micro-feeding system shows similar or better performance than conventional and commercially applied LIW feeders. The technology offers the potential for highly accurate, continuous feeding in the low-dose range.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.