Validating a Numerical Simulation of the ConsiGma(R) Coater.

Continuous manufacturing is increasingly used in the pharmaceutical industry, as it promises to deliver better product quality while simultaneously increasing production flexibility. GEA developed a semi-continuous tablet coater which can be integrated into a continuous tableting line, accelerating the switch from traditional batch production to the continuous mode of operation. The latter offers certain advantages over batch production, e.g., operational flexibility, increased process/product quality, and decreased cost. However, process understanding is the key element for process control. In this regard, computational tools can improve the fundamental understanding and process performance, especially those related to new processes, such as continuous tablet coating where process mechanics remain unclear. The discrete element method (DEM) and computational fluid dynamics (CFD) are two methods that allow transition from empirical process design to a mechanistic understanding of the individual process units. The developed coupling model allows to track the heat, mass, and momentum exchange between the tablet and fluid phase. The goal of this work was to develop and validate a high-fidelity CFD-DEM simulation model of the tablet coating process in the GEA ConsiGma® coater. After the model development, simulation results for the tablet movement, coating quality, and heat and mass transfer during the coating process were validated and compared to the experimental outcomes. The experimental and simulation results agreed well on all accounts measured, indicating that the model can be used in further studies to investigate the operating space of the continuous tablet coating process.

Nephroprotective effects of TVP1022, a non-MAO inhibitor S-isomer of rasagiline, in an experimental model of diabetic renal ischemic injury.

Ischemic acute kidney injury (iAKI) in diabetes mellitus is associated with a rapid deterioration of kidney function, more than in nondiabetic subjects. TVP1022, a non-MAO inhibitor S-isomer of rasagiline, possesses antioxidative and antiapoptotic activities. The current study examines the effects of TVP1022 and tempol on iAKI in diabetic rats. Diabetes was induced by streptozotocin. iAKI was induced by clamping the left renal artery for 30 min in both diabetic and nondiabetic rats. The right intact kidney served as a control. Forty-eight hours following ischemia, urinary flow (V), sodium excretion (UNaV), and glomerular filtration rate (GFR) in both ischemic and nonischemic kidneys were determined. The nephroprotective effects of tempol and TVP1022 were examined in these rats. Hematoxylin and eosin staining, 4-hydroxynonenal (4-HNE) immunofluorescence, and nitrotyrosine immunohistochemistry were performed on renal tissues of the various experimental groups. Compared with normoglycemic rats, iAKI in diabetic animals caused more profound reductions in V, UNaV, and GFR. Tempol and TVP1022 treatment increased GFR two- and four-fold in diabetic ischemic kidney, respectively. Besides hemodynamic perturbations, iAKI markedly increased renal immunoreactive 4-HNE and nitrotyrosine staining in both diabetic and nondiabetic rats. Moreover, iAKI increased medullary necrosis, congestion, and casts. Noteworthy, these increases were to a larger extent in ischemic diabetic kidneys. TVP1022, and to a lesser extent tempol, decreased nitrotyrosine and 4-HNE immunoreactivities and necrosis and cast formation in the renal medulla. TVP1022 treatment improves renal dysfunction and histological changes in an iAKI diabetic model and suggests a role for TVP1022 therapy in kidney injury.

Continuous direct compression of a commercially batch-manufactured tablet formulation with two different processing lines.

The transfer from batch-based to continuous tablet manufacturing increases the quality and efficiency of processes. Nonetheless, as in the development of a batch process, the continuous process design requires optimization studies to ensure a robust process. In this study, processing of a commercially batch-manufactured tablet product was tested with two continuous direct compression lines while keeping the original formulation composition and tablet quality requirements. Tableting runs were conducted with different values of process parameters. Changes in parameter settings were found to cause differences in tablet properties. Most of these quality properties could be controlled and maintained within the set limits effortlessly already at this stage of studies. However, the API content and content uniformity seemed to require more investigation. The observed content uniformity challenges were traced to individual tablets with a high amount of API. This was suspected to be caused by API micro-agglomerates since tablet weight variability did not explain the issue. This could be solved by adding a mill between two blenders in the process line. Overall, this case study produced promising results with both tested manufacturing lines since many tablet properties complied with the test result limits without optimization of process parameter settings.

Predicting powder feedability: A workflow for assessing the risk of flow stagnation and defining the operating space for different powder-feeder combinations.

Powder feeding is of critical importance for continuous manufacturing (CM) since next to in-process segregation it is the phenomenon primarily responsible for fluctuations in content uniformity and for content deviations in the final drug product. So far, feeding studies have focused on the characterization of specific feeders and the prediction of their performance for various materials. This work presents a more holistic approach, an early general assessment of the "feedability" of raw materials. With that regard, we established a workflow to: i) predict potential feeding issues, such as the flow stagnation in the hopper based on both the material attributes and the feeder's geometry; and ii) predict the feed rate space using various feeder/screw combinations for powders with an acceptable risk of hopper flow stagnation. Statistical models were developed for this twofold approach using a dataset comprising nine powders and four different feeders. In order to include different feeding equipment into the statistical models, novel equipment descriptors (capturing the effect of different geometries) and performance indicators (the end fill level as indicator for the risk of powder flow stagnation) were introduced. The application of the workflow was demonstrated for a simple formulation, and model validation was successfully performed for an additional powder that was not contained in the original dataset. Finally, the most relevant material attributes were identified, and reduced material characterization data sets were investigated in terms of effects on the model's prediction performance. The workflow presents a promising tool for initial process assessment in early-phase development.

Loss-in-weight feeding, powder flow and electrostatic evaluation for direct compression hydroxypropyl methylcellulose (HPMC) to support continuous manufacturing.

Minimizing variability in the feeding process is important for continuous manufacturing since materials are fed individually and can impact the final product. This study demonstrates the importance of measuring powder properties and highlights the need to characterize the feeding performance both offline with multiple refills and in the intended configuration for the continuous manufacturing equipment. The standard grade hydroxypropyl methylcellulose (HPMC) had material buildup on the loss-in-weight feeder barrel from triboelectric charging and resulted in more mass flow excursions and failed refills which were not observed with the direct compression grades. The location of the electrostatic buildup changed when the feeder was connected to a hopper instead of feeding offline into a collection bucket. Overall, the direct compression HPMC exhibited better flow which resulted in more accurate loss-in-weight feeding with less excursions from the target mass flow and all refills were completed in the first attempt. The improvements with the direct compression HPMC would be beneficial when running any continuous process (wet granulation, roller compaction, or direct compression) or other processes where loss-in-weight feeding is utilized, such as melt extrusion or twin screw granulation.

Feeding of particle-based materials in continuous solid dosage manufacturing: a material science perspective.

The pharmaceutical industry today is experiencing a paradigm shift from batch to continuous manufacturing, which promises greater flexibility to target diverse populations, as well as more-consistent product quality to ensure best efficacy. However, shifting to continuous processing means that even basic process steps, such as feeding, can become unexpected but are crucially important. In this review, we will present the fundamental differences between dispensing (batch) and feeding (continuous) and how they impact the formulation design space. We will further outline our rational development approach, applicable to continuous unit operations in general, which includes standardized material and process characterization, as well as predictive modeling based on advanced, multidomain simulation tools.

A morphological cline in Eucalyptus: a genetic perspective.

The putative hybrid zone between Eucalyptus populnea and E. brownii is examined using morphological and molecular techniques. This species complex displays continuous morphological variation across the study area, which has been previously interpreted as the product of hybridization between allopatric species. A microsatellite analysis indicates that there was little genetic structuring across the morphological cline and only low levels of population differentiation. The nested clade analysis of the JLA+ region of the chloroplast DNA (cpDNA) indicates that the geographical distribution of cpDNA haplotypes is unlikely to be the result of historical hybridization events, and that restricted seed-mediated gene flow with isolation by distance is responsible for the phylogeographical distribution. A more plausible explanation for the origin and persistence of the morphological cline is that the process of continuous morphological diversification has been promoted by a directional selection gradient. This study addresses species status within Eucalyptus and the belief that hybridization is widespread and is an important process in the group's evolution.