Sensitivity of a continuous hot-melt extrusion and strand pelletization line to control actions and composition variation.

The purpose of this work was to develop a robust hot-melt extrusion and strand pelletization process for manufacturing pellets with an immediate release (IR) of a poorly water-soluble active pharmaceutical ingredient (API), nimodipine. The robustness of pharmaceutical continuous manufacturing processes and of its control strategy is vital for competitiveness to traditional batch-manufacturing. Therefore, first the sensitivity of product quality, process stability, and process monitoring tools to i) parameter changes due to control actions and ii) typical process deviations, i.e., feeding errors, was investigated in a design of experiments (DoE). Thereby, die melt pressure was found to be highly sensitive to composition deviations, i.e. a limiting factor for process stability. Especially critical were deviations to increased HPMC content, since it behaved as a filler in the melt. Pelletization, or pellet size and size distribution respectively, were found to be sensitive to an increased throughput, due to the resulting insufficient strand cooling before the pelletizer. API dissolution in contrast, was found to be robust across the entire investigated range of formulation and process settings. Second, a design space for the production of IR pellets for subsequent tableting was established, and finally, a technical control strategy was developed to ensure a robust process. Near-infrared (NIR) spectroscopy was applied to monitor API content and the sensitivity of the residence time distribution (RTD) was investigated by means of tracer measurements. NIR-based API content monitoring and RTD models for material tracking were found to be at risk after processing melt with high HPMC content, due to a lack of purging by less viscous formulation compositions.

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.

Continuous monitoring of API content, API distribution and crushing strength after tableting via near-infrared chemical imaging.

Near-infrared chemical imaging (NIR-CI) with high-speed cameras based on the push-broom acquisition principle is a rapidly-evolving and can be used for a variety of purposes, from classification (and sorting) of products to mapping spatial distribution of materials. The present study examined if NIR-CI is suitable for tablet manufacturing. To that end, the tablets were introduced into the CI system via a flat belt conveyor. A formulation, which consisted of 4wt.%-6wt.% caffeine, 5wt.% crospovidone as a disintegrant, 88wt.%-90wt.% lactose as a filler and 1wt.% magnesium stearate as a lubricator, was tableted at compression forces ranging from 5kN to 30kN. The intra- and inter-tablet homogeneity of caffeine and the tablet's hardness were analyzed via NIR-CI. For the homogeneity evaluation, two methods were applied: standard deviation (SD) and distributional homogeneity index (DHI). The results showed that the SD of caffeine in a single tablet increased with an increase in the caffeine content. This was attributed to natural variations in a binary mixture of caffeine and excipients. Overall, the chosen NIR-CI setup has strong potential to be transferred to the production scale to monitor all tablets in a production stream.

Small- and wide-angle X-ray scattering (SWAXS) for quantification of aspirin content in a binary powder mixture.

This article presents a novel application of small and wide angle X-ray scattering (SWAXS) in the assessment of aspirin and lactose content in a binary pharmaceutical powder formulation. It is shown that the content correlates with the intensity of the SAXS signal and the intensity of polymorph fingerprints in the WAXS spectra that are collected from the same samples. Because the polymorph WAXS fingerprints and the SAXS signal are two independent characteristics of the same sample, simultaneous SWAXS analysis provides the basis for a dual independent assessment of the same contents.