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The aim of this study is to increase process understanding of the granulation mechanism in twin-screw melt granulation by evaluating the influence of different screw configurations on granule formation and granule temperature via thermal imaging. The study used a Design of Experiments (DoE) to process a miscible and immiscible formulation (85% API/binder w/w) using a twin-screw extruder with varying screw configurations. The barrel temperature (°C), screw speed (rpm), throughput (kg/h), and kneading zone (direction and stagger angle) were varied. Granule and process properties were evaluated for samples collected at four different locations along the length of the granulation barrel to visualize the granule formation, and granule temperature was monitored by an infrared camera to measure heat transfer on the granules. The resulting temperature was linked to the granule properties and the granule formation along the length of the barrel. The most influencing factors on the granule temperature are the direction of the kneading zone and the set barrel temperature. It was observed that granule formation mainly occurred in the zones that apply more kneading on the granules. The highest temperature increase was observed when the smallest stagger angle in reverse configuration was used, and could be linked to better granule quality attributes.

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Anaerobic ammonium oxidation (anammox) granulation which contributed to system stabilization and performance improvement has great potential in the field of wastewater nitrogen removal. The researchers fractionated anammox granules into small-size (0.5-0.9 mm), medium-size (1.8-2.2 mm), and large-size (2.8-3.5 mm) categories to examine their properties and mechanisms. Various analyses, including high-throughput sequencing, determination of inorganic elements and extracellular polymeric substances (EPS), and microbial function prediction, were conducted to characterize these granules and understand their impact. The results revealed distinct characteristics among the different-sized granules. Medium-size granules exhibited the highest sphericity, EPS content, and anammox abundance. In contrast, large-size granules had the highest specific surface area, heme c content, specific anammox activity, biodiversity, and abundance of filamentous bacteria. Furthermore, the precipitates within the granules were identified as CaCO3 and MgCO3, with the highest inorganic element content found in the large-size granules. Microbial community and function annotation also varied with granule size. Based on systematic analysis, the researchers concluded that cell growth, chemical precipitation, EPS secretion, and interspecies interaction all played a role in granulation. Small-size granules were primarily formed through cell growth and biofilm formation. As granule size increased, EPS secretion and chemical precipitation became more influential in the granulation process. In the large-size granules, chemical precipitation and interspecies interaction, including synergistic effects with nitrifying, denitrifying, and filamentous bacteria, as well as metabolic cross-feeding, played significant roles in aggregation. This interplay ultimately contributed to higher anammox activity in the large-size granules. By fully understanding the mechanisms involved in granulation, this study provides valuable insights for the acclimation of anammox granules with optimal sizes under different operational conditions.

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In the pharmaceutical industry, innovative continuous manufacturing technologies such as twin-screw melt granulation (TSMG) are gaining more and more interest to process challenging formulations. To enable the implementation of TSMG, more elucidation of the process is required and this study provides a better understanding of the granule formation along the length of the barrel. By sampling at four different zones, the influence of screw configuration, process parameters and formulation is investigated for the granule properties next to the residence time distribution. It showed that conveying elements initiate the granulation by providing a limited heat transfer into the powder bed. In the kneading zones, the consolidation stage takes place, shear elongation combined with breakage and layering is occurring for the reversed configurations and densification with breakage and layering for the forward and neutral configurations. Due to the material build-up in the reversed configurations, these granules are larger, stronger, more elongated and less porous due to the higher degree of shear and densification. This configuration also shows a significantly longer residence time compared to the forward configuration. Hence, the higher level of shear and the longer period of time enables more melting of the binder resulting in successful granulation.

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Wastewater containing antibiotics can pose a significant threat to biological wastewater treatment processes. This study investigated the establishment and stable operation of enhanced biological phosphorus removal (EBPR) by aerobic granular sludge (AGS) under mixed stress conditions induced by tetracycline (TC), sulfamethoxazole (SMX), ofloxacin (OFL), and roxithromycin (ROX). The results show that the AGS system was efficient in removing TP (98.0%), COD (96.1%), and NH4+-N (99.6%). The average removal efficiencies of the four antibiotics were 79.17% (TC), 70.86% (SMX), 25.73% (OFL), and 88.93% (ROX), respectively. The microorganisms in the AGS system secreted more polysaccharides, which contributed to the reactor's tolerance to antibiotics and facilitated granulation by enhancing the production of protein, particularly loosely bound protein. Illumina MiSeq sequencing revealed that putative phosphate accumulating organisms (PAOs)-related genera (Pseudomonas and Flavobacterium) were enormously beneficial to the mature AGS for TP removal. Based on the analysis of extracellular polymeric substances, extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) theory, and microbial community, a three-stage granulation mechanism was proposed including adaption to the stress environment, formation of early aggregates and maturation of PAOs enriched microbial granules. Overall, the study demonstrated the stability of EBPR-AGS under mixed antibiotics pressure, providing insight into the granulation mechanism and the potential use of AGS for wastewater treatment containing antibiotics.

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The high-efficiency and additionally economic benefits generated from aerobic granular sludge (AGS) wastewater treatment have led to its increasing popularity among academics and industrial players. The AGS process can recycle high value-added biomaterials including extracellular polymeric substances (EPS), sodium alginate-like external polymer (ALE), polyhydroxyfatty acid (PHA), and phosphorus (P), etc., which can serve various fields including agriculture, construction, and chemical while removing pollutants from wastewaters. The effects of various key operation parameters on formation and structural stability of AGS are comprehensively summarized. The degradable metabolism of typical pollutants and corresponding microbial diversity and succession in the AGS wastewater treatment system are also discussed, especially with a focus on emerging contaminants removal. In addition, recent attempts for potentially effective production of high value-added biomaterials from AGS are proposed, particularly concerning improving the yield, quality, and application of these biomaterials. This review aims to provide a reference for in-depth research on the AGS process, suggesting a new alternative for wastewater treatment recycling.

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Twin-screw melt granulation (TSMG) is a promising continuous manufacturing technology for the processing of high drug load formulations and to formulate heat- and moisture-sensitive active pharmaceutical ingredients (APIs). This study evaluates the influence of process parameters for TSMG, mainly focusing on the effect of the screw configuration combined with screw speed, throughput and barrel temperature, to elucidate the melt granulation mechanisms. For the kneading zone, the stagger angle was varied between 30°, 60° and 90°, and investigated for both the forward and the reversed direction. In addition to the process parameters, the influence of the formulation differing in their API-binder miscibility was evaluated. As responses, the granule (size, friability and porosity) and process properties such as torque were evaluated, indicating that the screw configuration is the most influential factor. Nucleation, consolidation and breakage are the granulation mechanisms for the forward and the neutral configuration, while consolidation and densification with shear elongation are identified for the reversed configuration. The formulations differ mainly in the forward and neutral configuration since the immiscible formulation shows a bimodal granule size distribution with a larger fraction of fines and weaker granules is obtained. For the reversed configuration, similar granulation mechanisms are seen for both formulations.

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In this study, the strengthening effect of bio-carrier inoculation in the process of aerobic granulation and its influence on the microbial secretion of extracellular polymeric substances (EPS) has been systematically explored, to further understand and perfect the rapid granulation mechanism. Complete granulation was achieved within 15 days, and the granule morphology realized in a reactor inoculated with the bio-carrier (R1) was better than that in the control group (R2), in which complete granulation was not achieved during the entire operation period. However, AGS gradually disintegrated after the 20th day because of the strong shearing force, the crushed AGS enhanced granulation, however did not ensure stability. The average EPS content in R1 20 mg﹒gVSS-1 higher than that in R2, and the protein (PN) content changes around 41.23-82.56 mg﹒gVSS-1 during the granulation process. This indicates that the bio-carrier stimulates microorganisms to secrete more EPS, and PN may have a greater effect on the aggregation of microorganisms. The results showed that the addition of the bio-carrier shortened the AGS granulation time, and increased the EPS content, and the broken AGS played an auxiliary role as the nucleus for floc attachment.

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Due to the trend of continuous pharmaceutical manufacturing, twin screw wet granulation (TSWG), a continuous process, has gained increased research interest as a potential substitution of traditional batch granulation processes. Despite the complex nature of TSWG, its mechanisms have been gradually unveiled with the aid of innovative research strategies. This review synthesizes these recent findings to provide a comprehensive and mechanistic understanding of TSWG. We explain the impact of screw profiles (i.e. conveying, kneading, turbine mixing, and screw mixing elements) and process conditions (i.e. screw speed, feed rate, and liquid-to-solid ratio) on TSWG mixing performance and granule growth along the barrel, both of which ultimately affect critical granule attributes such as content uniformity, size distribution, strength, and compaction properties.

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This study investigated nutrient removal characteristics and the related pathways in aerobic granular reactors using three pilot-scale granular sequencing batch reactors (GSBRs) treating wastewaters of diverse carbon and nutrient strength. The GSBRs were operated with alternating (AN/O/AX/O_SBR and AN/O_SBR) and purely-aerobic (O_SBR) operation modes. Mineral-rich aerobic granules with hydroxyapatite (HAp) core were cultivated in all the three GSBRs. The highest nitrogen removal efficiency (75%) was achieved in AN/O/AX/O_SBR and O_SBR and the lowest (22%) in AN/O_SBR, establishing a quasi-linear relationship with organic loading rate (OLR). Phosphorus removal efficiencies of 55-63% were achieved in the GSBRs despite different influent PO4-P concentrations. Heterotrophic nitrification and biologically-induced phosphate precipitation (BIPP) became the dominant nutrient depletion pathways, contributing 61-84% and 39-96% to overall ammonium nitrogen and phosphorus removal, respectively. A direct relation was noted between heterotrophic nitrification efficiency (ηHeterotrophic nitrification) and nutrient availability, as nitrification efficiencies of 18 and 64% were observed for COD:Ninf of 5 and 20, respectively. Whereas, BIPP efficiency (ηBIPP) established inverse relation with (COD:P)inf and (Ca:P)inf and direct relation with phosphorus concentration beyond microbial growth requirement. Core heterotrophic nitrifiers and bio-calcifying species were identified as {Thauera and Flavobacterium} and {Flavobacterium, Acinetobacter, Pseudomonas, and Corynebacterium}, respectively. Ca-P crystallization was proposed to be via phosphate precipitation on calcite surfaces. Granulation mechanism was proposed as crystallization on bio-aggregates' periphery and then crystal growth toward the core.

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In this study, an expanded granular sludge blanket (EGSB) reactor was used for the treatment of low-strength domestic sewage and the sludge granulation process was systematically investigated. At an optimized hydraulic retention time (HRT) of 5 h, up-flow velocity (Vup) of 1.9 m/h, and organic loading rate (OLR) of 2.16 kg COD/m3/d, the average COD removal efficiency was 71.5 ±â€¯2.3%. Completely granular sludge can be observed after 107 d of continuous operation. Analysis of the distribution and composition of the extracellular polymeric substances (EPS) indicates that the tightly bound EPS (TB-EPS) content shows an increasing trend, while the loosely bound EPS (LB-EPS) content did not significantly alter after the granular sludge was formed. The three-dimensional excitation-emission matrix technique (3D-EEM) confirms that aromatic protein-like substances are of key importance to sludge granulation. High-throughput sequencing analysis indicates that the metabolism shifted from hydrogenotrophic (Methanobaterium) to aceticlastic methanogens (Methanosaeta) during sludge granulation.

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Recently, we have developed a novel granulation technology to manufacture hollow spherical granules (HSGs) for controlled-release formulations; however, the mechanism of the granulation is still unclear. The aim of this study is to determine the mechanism of the formation of the HSGs using a high shear granulator. Samples of granulated material were collected at various times during granulation and were investigated using scanning electron microscope and X-ray computed tomography. It was observed that the granulation proceeded by drug layering to the polymer, followed by formation of a hollow in the granule. In addition, it was also found that generation of a crack in the adhered drug layer and air flow into the granules might be involved in forming the hollow in the structure. Observation of the granulation of formulations with different types of drugs and polymers indicated that negative pressure in the granules occurred and the granules caved in when the hollow was formed. The hollow-forming speed and the shell density of the hollow granules depended on the particular drug and polymer. Taken together, the granulation mechanism of HSGs was determined and this information will be valuable for HSGs technology development.

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Although near infrared (NIR) spectra are primarily influenced by undesired variations, i.e., baseline shifts and non-linearity, and many applications of NIR spectroscopy to the real-time monitoring of wet granulation processes have been reported, the granulation mechanisms behind these variations have not been fully discussed. These variations of NIR spectra can be canceled out using appropriate pre-processing techniques prior to spectral analysis. The present study assessed the feasibility of directly using baseline shifts in NIR spectra to monitor granulation processes, because such shifts can reflect changes in the physical properties of the granular material, including particle size, shape, density, and refractive index. Specifically, OPUSGRAN®, a novel granulation technology, was investigated by in-line NIR monitoring. NIR spectra were collected using a NIR diffuse reflectance fiber optic probe immersed in a high-shear granulator while simultaneously examining the morphology, particle size, density, strength, and Raman images of the mixture during granulation. The NIR baseline shift pattern was found to be characteristic of the OPUSGRAN® technology and was attributed to variations in the light transmittance, reflection, and scattering resulting from changes in the physicochemical properties of the samples during granulation. The baseline shift also exhibited an inflection point around the completion of granulation, and therefore may be used to determine the endpoint of the process. These results suggest that a specific pattern of NIR baseline shifts are associated with the unique OPUSGRAN® granulation mechanism and can be applied to monitor the manufacturing process and determine the endpoint.

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This study is concerned with identifying the design space of two different continuous granulators and their respective granulation mechanisms. Performance of a continuous high shear granulator and a twin screw granulator with paracetamol formulations were examined by face-centered cubic design, which focused on investigating key performance metrics, namely, granule size, porosity, flowability and particle morphology of granules as a function of essential input process parameters (liquid content, throughput and rotation speed). Liquid and residence time distribution tests were also performed to gain insights into the liquid-powder mixing and flow behavior. The results indicated that continuous high shear granulation was more sensitive to process variation and produced spherical granules with monomodal size distribution and distinct internal structure and strength variation. Twin screw granulation with such a particular screw configuration showed narrower design space and granules were featured with multimodal size distribution, irregular shape, less detectible porosity difference and tighter range of strength. Granulation mechanisms explored on the basis of nucleation and growth regime maps revealed that for most cases liquid binder was uniformly distributed with fast droplet penetration into the powder bed and that granule consolidation and coalescence mainly took place in the nucleation, steady growth and rapid growth regimes.

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