Otto Scheibelhofer

Monitoring Blending of Pharmaceutical Powders with Multipoint NIR Spectroscopy

Blending of powders is a crucial step in the production of pharmaceutical solid dosage forms. The active pharmaceutical ingredient (API) is often a powder that is blended with other powders (excipients) in order to produce tablets. The blending efficiency is influenced by several external factors, such as the desired degree of homogeneity and the required blending time, which mainly depend on the properties of the blended materials and on the geometry of the blender. This experimental study investigates the mixing behavior of acetyl salicylic acid as an API and α-lactose monohydrate as an excipient for different filling orders and filling levels in a blender. A multiple near-infrared probe setup on a laboratory-scale blender is used to observe the powder composition quasi-simultaneously and in-line in up to six different positions of the blender. Partial least squares regression modeling was used for a quantitative analysis of the powder compositions in the different measurement positions. The end point for the investigated mixtures and measurement positions was determined via moving block standard deviation. Observing blending in different positions helped to detect good and poor mixing positions inside the blender that are affected by convective and diffusive mixing.

A Review of PAT Strategies in Secondary Solid Oral Dosage Manufacturing of Small Molecules

Pharmaceutical solid oral dosage product manufacturing is a well-established, yet revolutionizing area. To this end, process analytical technology (PAT) involves interdisciplinary and multivariate (chemical, physical, microbiological, and mathematical) methods for material (e.g., materials, intermediates, products) and process (e.g., temperature, pressure, throughput, etc.) analysis. This supports rational process modeling and enhanced control strategies for improved product quality and process efficiency. Therefore, it is often difficult to orient and find the relevant, integrated aspects of the current state-of-the-art. Especially, the link between fundamental research, in terms of sensor and control system development, to the application both in laboratory and manufacturing scale, is difficult to comprehend. This review compiles a nonexhaustive overview on current approaches from the recognized academia and industrial practices of PAT, including screening, selection, and final implementations in solid oral dosage manufacturing, through a wide diversity of use cases. Finally, the authors attempt to extract a common consensus toward developing PAT application guidance for different unit operations of drug product manufacturing.

Automatic correction for window fouling of near infrared probes in fluidised systems

Near infrared (NIR) spectroscopy is a versatile, non-invasive and non-destructive tool that is often used for process monitoring in the pharmaceutical industry. Often, equipment window fouling or probe fouling of in-situ NIR probes occurs, leading to biased spectra and wrong interpretations (e.g. process-state estimation). Physical counter measures, including self-cleaning probes and geometrical considerations, are called for. This paper presents a mathematical solution to the problem of window fouling for an NIR-monitored process: by determining the distance to the particles, we established which part of the signal was missing owing to the coating accumulation on the probe window. The proposed approach is illustrated with the example of hot-melt coating in a fluidised bed, during which coating buildup on substrate particles was monitored despite window fouling.

Monitoring of a Hot Melt Coating Process via a Novel Multipoint Near-Infrared Spectrometer

The aim of the present work was to develop a PAT strategy for the supervision of hot melt coating processes. Optical fibers were placed at various positions in the process chamber of a fluid bed device. Experiments were performed to determine the most suitable position for in-line process monitoring, taking into account such requirements as a good signal to noise ratio, the mitigation of dead zones, the ability to monitor the product over the entire process, and reproducibility. The experimental evidence suggested that the position at medium fluid bed height, looking towards the center, i.e., normal to particle movement, proved to be the most reliable position. In this study, the advantages of multipoint monitoring are shown, and an in-line-implementation was created. This enabled the real-time supervision of the process, including the fast detection of inhomogeneities and disturbances in the process chamber, and the compensation of sensor malfunction. In addition, a model for estimating the particle size distribution via NIR was successfully created. This ensures that the quality of the product and the endpoint of the coating process can be determined correctly.

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 tablets 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.

Microphase separation in solid lipid dosage forms as the cause of drug release instability

Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40°C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage.

Designed Blending for Near Infrared Calibration

Spectroscopic methods are increasingly used for monitoring pharmaceutical manufacturing unit operations that involve powder handling and processing. With that regard, chemometric models are required to interpret the obtained spectra. There are many ways to prepare artificial powder blend samples used in a chemometric model for predicting the chemical content. Basically, an infinite number of possible concentration levels exist in terms of the individual components. In our study, design of experiments for ternary mixtures was used to establish a suitable number of blend compositions that represents the entire mixture region of interest for a three component blend. Various experimental designs and their effect on the predictive power of a chemometric model for near infrared spectra were investigated. It was determined that a particular choice of experimental design could change the predictive power of a model, even with the same number of calibration experiments.

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.

Fast real-time monitoring of entacapone crystallization and characterization of polymorphs via Raman spectroscopy, statistics and SWAXS

Abstract Crystallization of the drug entacapone from binary solvent mixtures was monitored in situ using a Raman optical probe. The recorded Raman spectra and statistical analysis, which included the principal components method and indirect hard modeling made it possible to estimate the starting point of crystallization, to assess crystallization temperatures and to provide information on the polymorphic content of the mixture. It was established that crystallization temperatures were proportional to the volume content of the solvent in mixtures. The samples were also evaluated off-line via Raman spectroscopy and SWAXS. The collected data showed the presence of forms b and g in all solvent mixtures. In a toluene/methanol 30:70 mixture, in addition to forms b and g, at least one of the forms A, D or a was also indicated by SWAXS. The results have shown that the presence of a particular polymorph is strongly dependent on the nature and portion of the solvent in the binary solvent mixture.

The influence of residual water on the secondary structure and crystallinity of freeze-dried fibrinogen

The purpose of this work was to investigate the influence of water content on the secondary structure of a freeze-dried protein (fibrinogen) after a storage period of two weeks. To that end, attenuated reflectance Fourier transformed infrared (ATR-FTIR) and Raman spectra were generated and evaluated and the crystalline state of the fibrinogen bulks was determined via X-ray diffraction. First, a PCA (principal component analysis) of the spectral data was performed. While the α-helix and β-turn contents were increasing with the increasing water content, the β-sheet content was decreasing. A partial least squares (PLS) model was developed to correlate the mid-infrared and Raman spectral changes with the degree of crystallinity. The obtained R(2) value of 0.953 confirmed a correlation between changes in the secondary structure and crystallinity of the samples. The results demonstrated that the combined ATR-FTIR and Raman approach could be used to predict the crystalline state in freeze-dried fibrinogen products.