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1. Pre-Nucleation in High-Shear Wet Granulation

   Kumar, D.S.; Oka, S.; Emady, H.N. (January 2023, Proceedings for 10th International Granulation Workshop)

   Wet granulation can be broken down into three rate processes: Wetting & Nucleation, Consolidation & Growth, and Breakage & Attrition. These stages are often inseparable from each other, which hinders the characterization of the relationship between operating conditions and product properties in wet granulation processes. Single-drop granulation is a form of drop-controlled nucleation intended to isolate the Wetting & Nucleation rate process by allowing a single droplet to form a single granule upon impacting a static powder bed. Single-dropped granules (pre-nucleated granules) were charged to a mixer granulator under varied conditions to observe how the individual rate processes and resulting granulated product are affected by various pre-nucleation conditions. Batches with larger fractions of pre-nucleated granules tended to produce a larger granule size than batches with few or no pre-nucleated granules. Pre-nucleated granules on their own failed to produce a reasonable granular product, but performed well under conditions with standard liquid addition. A difference in granular product can also be identified between the formation mechanisms utilized to produce the pre-nucleated granules. 

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2. Rational Function-Based Approach for Integrating Tableting Reduced-Order Models with Upstream Unit Operations: Dry Granulation Case Study

   https://doi.org/10.3390/ph17091158  

   Bachawala, Sunidhi; Lagare, Rexonni B; Delaney, Abigail B; Nagy, Zoltan K; Reklaitis, Gintaras V; Gonzalez, Marcial (September 2024, Pharmaceuticals)

   We present a systematic and automatic approach for integrating tableting reduced-order models with upstream unit operations. The approach not only identifies the upstream critical material attributes and process parameters that describe the coupling to the first order and, possibly, the second order, but it also selects the mathematical form of such coupling and estimates its parameters. Specifically, we propose that the coupling can be generally described by normalized bivariate rational functions. We demonstrate this approach for dry granulation, a unit operation commonly used to enhance the flowability of pharmaceutical powders by increasing granule size distribution, which, inevitably, negatively impacts tabletability by reducing the particle porosity and imparting plastic work. Granules of different densities and size distributions are made with a 10% w/w acetaminophen and 90% w/w microcrystalline cellulose formulation, and tablets with a wide range of relative densities are fabricated. This approach is based on product and process understanding, and, in turn, it is not only essential to enabling the end-to-end integration, control, and optimization of dry granulation and tableting processes, but it also offers insight into the granule properties that have a dominant effect on each of the four stages of powder compaction, namely die filling, compaction, unloading, and ejection. 

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3. Germ Granule Evolution Provides Mechanistic Insight into Drosophila Germline Development

   https://doi.org/10.1093/molbev/msad174  

   Doyle, Dominique A; Burian, Florencia N; Aharoni, Benjamin; Klinder, Annabelle J; Menzel, Melissa M; Nifras, Gerard Carlo; Shabazz-Henry, Ahad L; Palma, Bianca Ulrich; Hidalgo, Gisselle A; Sottolano, Christopher J; et al (August 2023, Molecular Biology and Evolution)

   True, John (Ed.)

   Abstract The copackaging of mRNAs into biomolecular condensates called germ granules is a conserved strategy to posttranscriptionally regulate germline mRNAs. In Drosophila melanogaster, mRNAs accumulate in germ granules by forming homotypic clusters, aggregates containing multiple transcripts from the same gene. Nucleated by Oskar (Osk), homotypic clusters are generated through a stochastic seeding and self-recruitment process that requires the 3′ untranslated region (UTR) of germ granule mRNAs. Interestingly, the 3′ UTR belonging to germ granule mRNAs, such as nanos (nos), have considerable sequence variations among Drosophila species and we hypothesized that this diversity influences homotypic clustering. To test our hypothesis, we investigated the homotypic clustering of nos and polar granule component (pgc) in four Drosophila species and concluded that clustering is a conserved process used to enrich germ granule mRNAs. However, we discovered germ granule phenotypes that included significant changes in the abundance of transcripts present in species’ homotypic clusters, which also reflected diversity in the number of coalesced primordial germ cells within their embryonic gonads. By integrating biological data with computational modeling, we found that multiple mechanisms underlie naturally occurring germ granule diversity, including changes in nos, pgc, osk levels and/or homotypic clustering efficacy. Furthermore, we demonstrated how the nos 3′ UTR from different species influences nos clustering, causing granules to have ∼70% less nos and increasing the presence of defective primordial germ cells. Our results highlight the impact that evolution has on germ granules, which should provide broader insight into processes that modify compositions and activities of other classes of biomolecular condensate. 

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4. A Machine Learning-assisted Hybrid Model to Predict Ribbon Solid Fraction, Granule Size Distribution and Throughput in a Dry Granulation Process

   Yan-Shu Huang, David Sixon (July 2023, Computer aided chemical engineering)

   Kokossis, A.; Georgiadis, M.C.; Pistikopoulos, E.N. (Ed.)

   A quantitative model can play an essential role in controlling critical quality attributes of products and in designing the associated processes. One of the challenges in designing a dry granulation process is to find the optimal balance between improving powder flowability and sacrificing powder tabletability, both of which are highly affected by ribbon solid fraction and granule size distribution (GSD). This study is focused on developing a hybrid machine learning (ML)-assisted mechanistic model to predict ribbon solid fraction, GSD, and throughput for the purpose of implementing model predictive control of an integrated continuous dry granulation tableting process. It is found that the predictability of ribbon solid fraction and throughput are improved when modification is made to Johanson’s model by incorporating relationships between roll compaction parameters and ribbon elastic recovery. Such relationships typically are either not considered or assumed to be a constant in the models reported in the literature. To describe the nature of the bimodal size distribution of roller compactor granules instead of only using traditional 𝐷𝐷10, 𝐷𝐷50 and 𝐷𝐷90 values, the GSD is represented by a bimodal Weibull distribution with five fitting parameters. Furthermore, these five GSD parameters are predicted by ML models. The results indicate the ribbon solid fraction and screen size are the two most significant factors affecting GSD. 

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5. Binder Jetting Additive Manufacturing of Ceramics: Feedstock Powder Preparation by Spray Freeze Granulation

   Du, W. (June 2019, Proceedings of the ASME 2019 International Manufacturing Science and Engineering Conference (MSEC2019))

   Objective of this study is to prepare the binder jetting feedstock powder by spray freeze drying and study the effects of its parameters on the powder properties. Binder jetting additive manufacturing is a promising technology for fabricating ceramic parts with complex or customized geometries. However, this process is limited by the relatively low density of the fabricated parts even after sintering. The main cause comes from the contradicting requirements of the particle size of the feedstock powder: a large particle size (>5 μm) is required for a high flowability while a small particle size (<1 μm) for a high sinterability. For the first time, a novel technology for the feedstock material preparation, called spray freeze drying, is investigated to address this contradiction. Using raw alumina nanopowder (100 nm), a full factorial design at two levels for two factors (spraying pressure and slurry feed rate) was formed to study their effects on the properties (i.e., granule size, flowability, and sinterability) of the obtained granulated powder. Results show that high pressure and small feed rate lead to small granule size. Compared with the raw powder, the flowability of the granulated powders was significantly increased, and the high sinterability was also maintained. This study proves that spray freeze granulation is a promising technology for the feedstock powder preparation of binder jetting additive manufacturing. 

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