Development of a Controlled Continuous Low-Dose Feeding Process.

This paper proposes a feed rate control strategy for a novel volumetric micro-feeder, which can accomplish low-dose feeding of pharmaceutical raw materials with significantly different powder properties. The developed feed-forward control strategy enables a constant feed rate with a minimum deviation from the set-point, even for materials that are typically difficult to accurately feed (e.g., due to high cohesion or low density) using conventional continuous feeders. Density variations observed during the feeding process were characterized via a displacement feed factor profile for each powder. The characterized effective displacement density profile was applied in the micro-feeder system to proactively control the feed rate by manipulating the powder displacement rate (i.e., computing the feed rate from the powder displacement rate). Based on the displacement feed factor profile, the feed rate can be predicted during the feeding process and at any feed rate set-point. Three pharmaceutically relevant materials were used for the micro-feeder evaluation: di-calcium phosphate (large-particle system, high density), croscarmellose sodium (small-particle system, medium density), and barium sulfate (very small-particle <10 µm, high density). A significant improvement in the feeding performance was achieved for all investigated materials. The feed rate deviation from the set-point and its relative standard deviation were minimal compared to operations without the control strategy.

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.

Single-tablet-scale direct-compression: An on-demand manufacturing route for personalized tablets.

Today's pharmaceutical industry is facing various challenges. Two of them are issues with supply chain security and the increasing demand for personalized medicine. Both can be addressed by increasing flexibility and a more decentralized approach to pharmaceutical manufacturing. In this study, we present a setup that provides flexibility in terms of supplied raw materials and the product, i.e., a direct-compression setup for personalized tablets operating at a single-tablet-scale. The performance of the implemented single-tablet-scale technology for dosing and mixing was investigated. In addition, an analysis of the critical quality attributes (CQAs) of immediate release ibuprofen and loratadine tablets was performed. The developed dosing device achieved acceptance rates of > 90 % for doses ≥ 20 mg for various pharmaceutical powders. Regarding the vibratory mixing process, a dependency of the performance on the applied frequencies and acceleration was observed, with 100 Hz and âˆ¼ 90 G performing best, yet still exhibiting varying mixing efficacies depending on the granular system. The tablets produced met U.S. Pharmacopeia requirements regarding mechanical stability and dissolution characteristics. Given these results, we consider the developed setup a proof of concept of a tool to provide personalized tablets to patients while minimizing the dependency on complex supply chains.

Optimization of key energy and performance metrics for drug product manufacturing.

During the development of pharmaceutical manufacturing processes, detailed systems-based analysis and optimization are required to control and regulate critical quality attributes within specific ranges, to maintain product performance. As discussions on carbon footprint, sustainability, and energy efficiency are gaining prominence, the development and utilization of these concepts in pharmaceutical manufacturing are seldom reported, which limits the potential of pharmaceutical industry in maximizing key energy and performance metrics. Based on an integrated modeling and techno-economic analysis framework previously developed by the authors (Sampat et al., 2022), this study presents the development of a combined sensitivity analysis and optimization approach to minimize energy consumption while maintaining product quality and meeting operational constraints in a pharmaceutical process. The optimal input process conditions identified were validated against experiments and good agreement resulted between simulated and experimental data. The results also allowed for a comparison of the capital and operational costs for batch and continuous manufacturing schemes under nominal and optimized conditions. Using the nominal batch operations as a basis, the optimized batch operation results in a 71.7% reduction of energy consumption, whereas the optimized continuous case results in an energy saving of 83.3%.

Ibuprofen-loaded calcium stearate pellets: drying-induced variations in dosage form properties.

Pellets intended for oral dosing are frequently produced via extrusion/spheronization followed by drying. Typically, the last active process step, i.e., drying, is assumed to have little effect on the final dosage form properties (e.g., dissolution characteristics). Thus, there exist only a few studies of this subject. In the present study, calcium stearate/ibuprofen pellets were used as model system to investigate the impact of the drying conditions. Lipophilic calcium stearate matrix pellets containing 20% ibuprofen were prepared via wet extrusion/spheronization. Subsequently, desiccation, fluid-bed drying, and lyophilization were applied for granulation liquid removal. The impact of these drying techniques on the final pellet properties was evaluated. The in vitro dissolution behavior was dramatically altered by the drying techniques that were considered. The investigated pellets showed drug release rates that varied as much as 100%. As no polymorphic transitions occurred during drying, we focused on two possible explanations: (a) a change in the drug distribution within the pellets and (b) a change in pellet micro-structure (porosity, pore size). The ibuprofen distribution proved to be homogeneous regardless of the drying conditions. Pellet porosity and pore sizes, however, were modified by the drying process. Our results clearly demonstrate that a single process step, such as drying, can play a crucial role in achieving desired pellet properties and release profiles.

A Taylor vortex analogy in granular flows.

Fluids sheared between concentric rotating cylinders undergo a series of three-dimensional instabilities. Since Taylor's archetypal 1923 study, these have proved pivotal to understanding how fluid flows become unstable and eventually undergo transitions to chaotic or turbulent states. In contrast, predicting the dynamics of granular systems--from nano-sized particles to debris flows--is far less reliable. Under shear these materials resemble fluids, but solid-like responses, non-equilibrium structures and segregation patterns develop unexpectedly. As a result, the analysis of geophysical events and the performance of largely empirical particle technologies might suffer. Here, using gas fluidization to overcome jamming, we show experimentally that granular materials develop vortices consistent with the primary Taylor instability in fluids. However, the vortices observed in our fluidized granular bed are unlike those in fluids in that they are accompanied by novel mixing-segregation transitions. The vortices seem to alleviate increased strain by spawning new vortices, directly modifying the scale of kinetic interactions. Our observations provide insights into the mechanisms of shear transmission by particles and their consequent convective mixing.

Quantitative on-line vs. off-line NIR analysis of fluidized bed drying with consideration of the spectral background.

Quantitative dehydration studies of dibasic calcium phosphate anhydrous (DCPA) in a small-scale cold-model fluidized bed dryer with process air control were conducted. Near-infrared spectroscopy (NIRS) with partial least squares regression (PLSR) was used to predict DCPAs' residual moisture content. Loss-on-drying (LOD) was employed as a reference method and confirmed the actual moisture content of DCPA. First, dynamic PLSR modeling was carried out, i.e., the NIR spectra were on-line recorded and predicted throughout the drying process. Secondly, PLSR off-line modeling was performed, i.e., samples were consecutively thief-probed from the processor, put into glass vials and analyzed off-line. Furthermore, two background spectra were collected prior to the in- and off-line measurements in an attempt to increase the method's sensitivity, i.e., (i) dry DCPA that was fluidized at respective process air velocity (on-line) or inside a glass vial (off-line) and (ii) Spectralon®--a highly reflecting standard reference material made of fluoropolymer. Benefits and drawbacks of the in- and off-line approaches with different spectral backgrounds are discussed in detail. The results indicated that (i) the thief-probed sample amount from the processor and thus the sample weight and (ii) the downtime between thief-probing a sample and its actual analysis via NIRS and LOD can bias the moisture content predictions.

Microstructure of calcium stearate matrix pellets: a function of the drying process.

Drying is a common pharmaceutical process, whose potential to modify the final drug and/or dosage form properties is often underestimated. In the present study, pellets consisting of the matrix former calcium stearate (CaSt) incorporating the active pharmaceutical ingredient ibuprofen were prepared via wet extrusion and spheronization. Subsequent drying was performed by either desiccation, fluid-bed drying, or lyophilization, and the final pellets were compared with respect to their microstructure. To minimize the effect of solute ibuprofen molecules on the shrinking behavior of the CaSt, low ibuprofen loadings were used, as ibuprofen is soluble in the granulation liquid. Pellet porosity and specific surface area increased during desiccation, fluid-bed drying, and lyophilization. The inlet-air temperature during fluid-bed drying affected the specific surface area, which increased at lower inlet-air temperatures rather than the pellet porosity. The in vitro dissolution profiles were found to be a nonlinear function of the specific surface area. Overall, the microstructure, including porosity, pore size, and specific surface area, of CaSt pellets was a strong function of the drying conditions.

Shape-mediated ordering in granular blends.

Many industries mix granular materials of different sizes and shapes. Product quality and consistency are often compromised by demixing of constituent components. Not only is this practically problematic but it is also philosophically unsettling, for on smaller colloidal scales, systems consisting of particles differing by size and shape display quantitatively predictable transitions between mixed and separated phases. We report here that patterns and segregation transitions analogous to those seen in colloidal systems can be found in granular blends differing in shape, concentration, and temperature. This provides insights into the mechanisms of granular segregation.

Triboelectrification and razorbacks: geophysical patterns produced in dry grains.

Electrostatic interactions between particles can dramatically affect granular flows, creating industrial safety and handling problems [K. N. Palmer, (Chapman and Hall, London, 1973), pp. 388-389]. We present experimental data demonstrating that charging of grains can also cause spontaneous self-assembly that may generate lasting geological patterns under arid conditions. Paradoxically, we find that grains that tribocharge enough to produce small explosions, ejecting grains meters into the air, leave little net charge on grains. Rather, grains charge into strongly heterogeneous polar clusters. These assemble into stereotyped residual structures that resemble geological features, for example, razorbacks observed on Mars ["The Razorback Mystery," July 16, 2004, http://www.jpl.nasa.gov/missions/mer/images.cfm?id=701].

Shear instabilities in granular flows.

Unstable waves have been long studied in fluid shear layers. These waves affect transport in the atmosphere and oceans, in addition to slipstream stability behind ships, aeroplanes and heat-transfer devices. Corresponding instabilities in granular flows have not been previously documented, despite the importance of these flows in geophysical and industrial systems. Here we report that breaking waves can form at the interface between two streams of identical grains flowing on an inclined plane downstream of a splitter plate. Changes in either the shear rate or the angle of incline cause such waves to appear abruptly. We analyse a granular flow model that agrees qualitatively with our experimental data; the model suggests that the waves result from competition between shear and extensional strains in the flowing granular bed. We propose a dimensionless shear number that governs the transition between steady and wavy flows.

Free surface waves in wall-bounded granular flows.

We report free-surface waves in granular flows near boundaries in an inclined chute. The chevron-shaped traveling waves spontaneously develop at inclinations close to the angle of repose for both steady and accelerating flows. Two distinct regimes are characterized by internal angle and frequency variations. Experimental measurements indicate that subsurface circulation driven by velocity gradients near frictional walls plays a central role in the pattern formation mechanism, suggesting that wave generation is controlled by the granular analog of a fluid boundary layer.