Micro-dosing of powders into capsules using a new automated micro-dosing system: effect of powder characteristics and operating conditions on the filling of 0.5 mg-100 mg weights.

OBJECTIVE: To demonstrate the applicability of a novel micro-dosing system for precisely filling low powder doses (down to a few mg) into capsules along with weighing the filled powder mass accurately. METHODS: Ten commonly used pharmaceutical powders, ranging from cohesive to free-flowing, were selected and filled at three target fill weights (0.5, 1, and 10 mg), to investigate the effect of distinct powder properties on the filling performance. The fill weight and variability, filling speed and yield (% and number of conforming capsules out of all capsules collected), as well as the system's long-term performance were assessed. RESULTS: The filling accuracy was found to be good for all investigated powders. In particular, the results demonstrate that the tested powders, including the challenging cohesive ones, could be dosed at standard deviations within 0.23 mg at a 10 mg target weight, within 0.07 mg at a 1 mg target weight, and within 0.05 mg at a 0.5 mg target weight. In all cases, free-flowing powders showed lower standard deviations. Intermediate and cohesive powders had slightly higher standard deviations but were still within an acceptable range. CONCLUSION: The study shows the suitability of the tested micro-dosing system for filling low powder doses into capsules, which is of particular importance for dosing active pharmaceutical ingredients (APIs) directly in capsules, i.e. an API-in-capsule (AIC) approach for clinical trials (often in conjunction with highly potent APIs), and for low-dose powder filling for inhalation applications.

Study of a low-dose capsule filling process by dynamic and static tests for advanced process understanding.

Precise filling of capsules with doses in the mg-range requires a good understanding of the filling process. Therefore, we investigated the various process steps of the filling process by dynamic and static mode tests. Dynamic tests refer to filling of capsules in a regular laboratory dosator filling machine. Static tests were conducted using a novel filling system developed by us. Three grades of lactose excipients were filled into size 3 capsules with different dosing chamber lengths, nozzle diameters and powder bed heights, and, in the dynamic mode, with two filling speeds (500, 3000 caps/h). The influence of the gap at the bottom of the powder container on the fill weight and variability was assessed. Different gaps resulted in a change in fill weight in all materials, although in different ways. In all cases, the fill weight of highly cohesive Lactohale 220 increased when decreasing the gap. Furthermore, experiments with the stand-alone static test tool indicated that this very challenging powder could successfully be filled without any pre-compression in the range of 5 mg-20 mg with acceptable RSDs. This finding is of great importance since for very fine lactose powders high compression ratios (dosing-chamber-length-to-powder-bed height compression ratios) may result in jamming of the piston. Moreover, it shows that the static mode setup is suitable for studying fill weight and variability. Since cohesive powders, such as Lactohale 220, are hard to fill, we investigated the impact of vibration on the process. Interestingly, we found no correlation between the reported fill weight changes in dynamic mode at 3000 cph and static mode using similar vibration. However, we could show that vibrations during sampling in the static mode dramatically reduced fill weight variability. Overall, our results indicate that by fine-tuning instrumental settings even very challenging powders can be filled with a low-dose dosator capsule filling machine. This study is a further step towards a scientific qualification of dosator nozzles for low-fill weight (1-45 mg) capsule filling.

Performance indicators for carrier-based DPIs: Carrier surface properties for capsule filling and API properties for in vitro aerosolisation.

This study investigates engineered carrier, as well as engineered API particles, and shows that there are distinct performance indicators of particle engineering for carrier-based dry powder inhalers (DPIs). Spray dried (SDSS) and jet-milled (JMSS) salbutamol sulphate (SS) was blended with untreated α-lactose monohydrate (LAC_R) and α-lactose monohydrate engineered (LAC_E). Subsequent capsule filling was performed with different process settings on a dosator nozzle capsule filling machine in order to reach a target fill weight of 20-25 mg. To evaluate the performance of the different mixtures, in vitro lung deposition experiments were carried out with a next generation impactor, the emitted dose (ED) and fine particle fraction (FPF) were calculated based on the specification of the European pharmacopoeia. The FPF of micronised powder blends is significantly higher (20%) compared to the FPF of spray dried blends (5%). Compared to API engineering, carrier engineering had a positive effect on the capsule filling performance (weight variability and mean fill weight) at lower compression ratios (setting 1). Results further showed that higher compression ratios appear to be beneficial in terms of capsule filling performance (higher fill weight and less fill weight variation). Concluding, it can be stated that the carrier engineering, or generally carrier properties, govern downstream processing, whereas the API engineering and API properties govern the aerosolisation performance and thereby significantly affect the dose delivery to the lungs.

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.

The effect of material attributes and process parameters on the powder bed uniformity during a low-dose dosator capsule filling process.

The objective of this work was to assess the effect of process parameters of a dosator nozzle machine on the powder bed uniformity of inhalation powders with various characteristics during a low-dose dosator capsule filling process. Three grades of lactose excipients were extensively characterized and filled into size 3 capsules using different dosing chamber lengths (2.5, 5mm), nozzle diameters (1.9, 3.4mm), powder bed heights (5, 10mm) and filling speeds (500, 3000capsules/h). The fill weight and the weight variability of Lactohale 100 (large particles, good flowability, low cohesion) remained almost the same, regardless of the process parameters throughout the capsule filling run time. Moreover, for this powder an increase in the fill weight at a higher filling speed was observed in all cases. Fill weight variability was significantly higher for lower dosing chamber volumes at a filling speed of 3000 capsules per hour. Lactohale 220 (small particles, poor flowability, high cohesion) delivered entirely different results. After a certain run time, depending on instrumental settings, a 'steady-state' with constant fill weights and low weight variability was achieved. For this highly cohesive powder, a high dosing chamber volume requires a low filling speed in order for the powder to completely fill the dosator nozzle. Moreover, it was established that a dosing chamber length of 2.5mm and a powder bed height of 10mm were required due to the powder's high fill weight variability over time, while the dosator size had no effect on it. In summary, the layer uniformity, the fill weight and the weight variability strongly depend on the powder characteristics and the instrumental settings. The results indicate that Lactohale 220 requires special attention during low-dose capsule filling. The study presents excellent insights into the effect of material attributes and process parameters on the layer uniformity and the quality of end product.

Multi-methodological investigation of the variability of the microstructure of HPMC hard capsules.

The objective of this study was to analyze differences in the subtle microstructure of three different grades of HMPC hard capsule shells using mechanical, spectroscopic, microscopic and tomographic approaches. Dynamic mechanical analysis (DMA), thermogravimetric analysis (TGA), vibrational spectroscopic, X-Ray scattering techniques as well as environmental scanning electron microscopy (ESEM) and optical coherence tomography (OCT) were used. Two HPMC capsules manufactured via chemical gelling, one capsule shell manufactured via thermal gelling and one thermally gelled transparent capsule were included. Characteristic micro-structural alterations (associated manufacturing processes) such as mechanical and physical properties relevant to capsule performance and processability were thoroughly elucidated with the integration of data obtained from multi-methodological investigations. The physico-chemical and physico-mechanical data obtained from a gamut of techniques implied that thermally gelled HPMC hard capsule shells could offer an advantage in terms of machinability during capsule filling, owing to their superior micro- and macroscopic structure as well as specifically the mechanical stability under dry or humid conditions.

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.

Development of a design space and predictive statistical model for capsule filling of low-fill-weight inhalation products.

The objectives of this study were to develop a predictive statistical model for low-fill-weight capsule filling of inhalation products with dosator nozzles via the quality by design (QbD) approach and based on that to create refined models that include quadratic terms for significant parameters. Various controllable process parameters and uncontrolled material attributes of 12 powders were initially screened using a linear model with partial least square (PLS) regression to determine their effect on the critical quality attributes (CQA; fill weight and weight variability). After identifying critical material attributes (CMAs) and critical process parameters (CPPs) that influenced the CQA, model refinement was performed to study if interactions or quadratic terms influence the model. Based on the assessment of the effects of the CPPs and CMAs on fill weight and weight variability for low-fill-weight inhalation products, we developed an excellent linear predictive model for fill weight (R(2 )= 0.96, Q(2 )= 0.96 for powders with good flow properties and R(2 )= 0.94, Q(2 )= 0.93 for cohesive powders) and a model that provides a good approximation of the fill weight variability for each powder group. We validated the model, established a design space for the performance of different types of inhalation grade lactose on low-fill weight capsule filling and successfully used the CMAs and CPPs to predict fill weight of powders that were not included in the development set.

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.