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Background/Objectives: Amorphization of an active pharmaceutical ingredient (API) can improve its dissolution and enhance bioavailability. Avoiding solvents for drug amorphization is beneficial due to environmental issues and potential solvent residues in the final product. Methods: Dry amorphization using a twin-screw extruder is presented in this paper. A blend of mesoporous silica particles and crystalline itraconazole was processed using a pharma-grade laboratory scale twin-screw extruder. The influence of different screw configurations and process parameters was tested. Particle size and shape are compared in scanning electron microscopy (SEM) images. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) are used to determine the residual amount of crystalline itraconazole in the final product. Results: An optimized screw configuration for the process was found which leads to more than 90% amorphous API when processed at room temperature. Full amorphization was reached at 70 °C. The specific mechanic energy ( SME ) introduced into the material during twin-screw processing is crucial for the dry amorphization. The higher the SME , the lower the residual amount of crystalline API. Two months after processing, however, recrystallization was observed by XRD. Conclusions: Dry processing using a twin-screw extruder is continuous, free of solvents and can be performed at low temperatures. This study proves the concept of twin-screw processing with mesoporous silica for dry amorphization of itraconazole.

The respiratory health effects of Synthetic Amorphous Silica (SAS) have been studied in human epidemiological research. This article presents a historical overview and review of nine occupational worker studies that have been conducted so far on this topic. The combined study population of all of these studies included 1172 employees, and exposure concentrations ranged from < 1 mg/m 3 to 100 mg/m 3 . In two studies with a total of 293 workers, the incidence of silicosis was investigated after long-term exposure to precipitated SAS, and no cases of silicosis were found (Plunkett and Dewitt, 1962; Volk, 1960). In another study, the spirometry results of 40 workers were normal (Vitums et al., 1977). In a study of 28 workers, 4 cases of silicosis were identified, but it is possible that contamination with cristobalite occurred and detailed information about the amorphous silica origin was not provided (Mohrmann and Kahn, 1985). Ferch et al. (1987) found that lung impairment was associated with confounding factors (smoking) but not with exposure to precipitated SAS in a study of 143 workers. Choudat et al. (1990) reported a reduction in forced expiratory flow in a group exposed to precipitated SAS compared to a control group. Still, they found no correlation between the extent of exposure and pulmonary function was found in a study of 131 workers. Wilson et al. (1979) also failed to show a significant association between the degree of exposure to precipitated SAS and annual changes in lung function in a study of 165 workers. In the most recent and most extensive study (Taeger et al., 2016; Yong et al., 2022) in Germany, involving 462 factory workers, no association between inhalable or respirable SAS dust exposure and respiratory health was reported. Based on the available data, there is no evidence-base to support a relationship between SAS and respiratory health in humans., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Synthetic amorphous silica (SAS) is used as additive in a variety of industrial applications for many decades and has been approved to be used in food, food contact materials, pharmaceuticals, and cosmetics. Due its internal structure, SAS is considered as a nanomaterial, thus it is affected by a general safety discussion. Based on the production process, SAS for cosmetic application is a nanomaterial by the EU Recommendation, although it was not considered as such, because the solely size-dependent definitions of the term "nanomaterial" emerged in recent times first in Recommendation 2011/696/EU. Therefore, former physicochemical and toxicological evaluations of SAS were already performed on nanomaterials, however, without being addressed as such. Safety concerns can only emerge if two criteria, (toxicological) hazard and exposure towards the substance is fulfilled at the same time. In case of SAS, the Scientific Committee on Consumer Safety (SCCS) challenged provided data to be insufficient to draw a conclusion regarding the safety of SAS and thus, requested further investigations, in particular by exploring skin penetration of particulate SAS.Investigation of specific particulate substances in skin penetration tests is an analytical challenge. The number of available analytical techniques that are capable to detect nanomaterials in complex matrices, like receptor fluids from skin penetration testing, are limited and still emerging. In the new studies, a comprehensive set of analytical techniques were used to investigate the skin penetration potential of SAS. Particle-sensitive, element and particle-specific combinations of techniques and different sample preparation procedures, that respected the particulate nature of SAS, were used to detect SAS in receptor fluids directly. In addition, electron microscopic techniques were used to examine different layers of skin to detect adsorbed SAS.The combination of Asymmetric Flow Field-Flow Fractionation (AF4) in combination with Inductively Coupled Plasma Mass Spectrometry (ICP-MS) for examination of receptor fluids and Scanning Electron Microscopy coupled with Energy Dispersive X-ray spectroscopy (SEM/EDX) for examination of skin itself, were identified as suitable techniques for the detection of SAS in skin penetration tests. Data from literature was used to compare the results of the studies with the outcome of other test systems (other particles, other techniques). Both, the test results, and literature evaluation led to the conclusion, that SAS does not penetrate skin. Based on this outcome and local and systemic dermal toxicity review of SAS, it can be concluded that dermal application of SAS in cosmetic formulations is negligible., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Axel Bosch reports financial support was provided by SASFORREACH, a consortium of the producers of synthetic amorphous silica. Each author certifies that their freedom to design, conduct, interpret, and publish research was not compromised by the sponsor., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ecotoxicology studies were performed in the earthworm Eisenia fetida with four different synthetic amorphous silica (SAS) (SYLOID® AL-1 FP, SYLOID® MX 107, LUDOX® P T-40 F, and HDK® N20) mixed into artificial soil to determine a NOEC/LOEC for effects on reproduction (56 days after application), mortality and biomass development (28 days after application) using a standardized artificial soil with 10% peat. The LC50 for test-item effects on adult mortality, and an EC10 and EC50 for reproduction were also determined. Furthermore, earthworms underwent histopathology evaluation, and the amount of silica in different organs from these organisms was evaluated using EDX (Energy Dispersive X-ray Spectroscopy). Histopathology revealed no findings in any organ of the earthworms, except for desiccated dissepiments in evaluated decedents at extremely high SAS doses. To measure SAS uptake into the organs, a fully quantitative method for silica was established and validated using standards containing known concentrations of silica to ensure the accuracy of the analyses undertaken. Results from EDX analysis demonstrated the negligible presence of silicon within the brain ganglia and gonads of adult earthworms comparable to controls. Therefore, any deposition of the test items within these two organs was excluded. In contrast, traces of silicon higher than in controls were found in the intestinal lumina of the earthworms due to ingestion of SAS with soil and feed, but not in other organs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors reports financial support was provided by SASforREACH, a consortium of the producers of synthetic amorphous silica. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Reproducible aerosol generation in combination with stable aerosol properties are essential prerequisites for compliant performance of acute or repeated inhalation toxicity tests of particulate materials according to OECD TG 403, 436, 412, or 413. A frequent problem of powder aerosol generation is the formation of coarse agglomerates with low shear resistance, which are beyond the tolerable size range but not detected by the prescribed aerodynamic measurement techniques by cascade impactor as the measurement conditions cause a disintegration into smaller fragments. But such agglomerates are observed during the transport to the inhalation chambers. These effects particularly apply to high mass concentrations and low-density powders, i.e., pyrogenic oxides. This study describes the transport influence in the airflow on the change of powder aerosols and on their respirability. A simplified short tube set-up was developed for the aerosol transport pre-tests, which allows the determination of the optimal aerosol formation conditions for the inhalation tests. The particles were measured with low shear using laser diffraction measurement or optical particle counters. The calculation of the aerodynamic particle sizes prescribed in the guidelines requires knowledge of the effective particle density of the porous aerosol particles. A practicable method for determining these is presented and described. In the outlook, first low concentration measurements show that clear agglomeration effects can also occur at particle concentrations around 20 mg/m³., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors reports financial support was provided by SASFORREACH, a consortium of the producers of synthetic amorphous silica. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Each author certifies that their freedom to design, conduct, interpret, and publish research was not compromised by the sponsor., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

High concentrations of low-density particles may cause effects in acute inhalation toxicity studies which can be easily underestimated or misinterpreted following strictly the OECD TG 436, i.e., limited parameters as mortality and gross lesions will be evaluated only. Seven particle types (synthetic amorphous silica (SAS) HMDZ-SAS, silica gel, pyrogenic SAS, and precipitated SAS, calcium carbonate, aluminum oxide pyrogenic alumina, organic red pigment) were chosen at the highest technically feasible concentration of approximately 500 mg/m 3 for acute inhalation studies with an expanded endpoint setup. Therefore additional parameters and a thorough histopathological evaluation of an extensive set of organs, including the respiratory tract emphasizing the nasal cavities were added. Six Crl:WI rats per study were exposed for four hours from which three animals were sacrificed after 24 hours and three animals after 14 days. HMDZ-SAS caused early death in all animals due to blockage of the nasal passages caused by its hydrophobicity. For all other Si-containing compounds, histology revealed minor inflammatory and reactive lesions in lungs after 24 hours that were still present after 14 days, except in silica gel-treated animals. After 14 days, for pyrogenic SAS, precipitated SAS, and pyrogenic alumina, granulomas formed in the BALT and lung-associated lymph nodes. In contrast, the calcium carbonate induced almost no findings, and the red pigment (also tested for the additional dose of 1000 mg/m 3 ) stuck partially to the nasal mucosa without causing pathological damage and partly entered the lungs without showing any adverse effects. The results of the present study highlight the advantage of improving the rather simple study design of acute inhalation studies by implementing an extended study design., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors reports financial support was provided by SASFORREACH, a consortium of the producers of synthetic amorphous silica. Each author certifies that their freedom to design, conduct, interpret, and publish research was not compromised by the sponsor. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Inhalation toxicity testing of particulate materials is mandated for classification. According to CLP, particulate materials should be tested as marketed and many particulate materials are marketed as non-respirable particles. However, OECD TG 413 requires exposure to particle sizes that are respirable and reach the alveoli. The requirement for exposure of rats to respirable particles is thus in contrast to CLP and requires the application of high shear forces. The exposure to artificially small particles causes a number of issues that hamper the interpretation of the results of the testing. These issues are aerosol altering in the exposure system, assessment of the adversity of the inflammatory lung responses, inclusion of recovery groups, and extrapolation of the results to humans exposed under occupational condition. In addition, effects of many particulate materials after testing according to OECD 413 are not intrinsic properties, but a general reaction of the lung to the deposited material, show very similar NOAECs for chemical diverse materials, and often are completely reversible., Competing Interests: Declaration of Competing Interest Each author certifies that their freedom to design, conduct, interpret, and publish research was not compromised by the sponsor., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The article by Balwierz et al [...].

Synthetic amorphous silica (SAS) is industrially relevant material whose bioactivity in vitro is strongly diminished, for example, by protein binding to the particle surface. Here, we investigated the in vitro bioactivity of fourteen SAS (pyrogenic, precipitated, or colloidal), nine of which were surface-treated with organosilanes, using alveolar macrophages as a highly sensitive test system. Dispersion of the hydrophobic SAS required pre-wetting with ethanol and extensive ultrasonic treatment in the presence of 0.05% BSA (Protocol 1). Hydrophilic SAS was suspended by moderate ultrasonic treatment (Protocol 2) and also by Protocol 1. The suspensions were administered to NR8383 alveolar macrophages under serum-free conditions for 16 h, and the release of LDH, GLU, H 2 O 2 , and TNFα was measured in cell culture supernatants. While seven surface-treated hydrophobic SAS exhibited virtually no bioactivity, two materials (AEROSIL® R 504 and AEROSIL® R 816) had minimal effects on NR8383 cells. In contrast, non-treated SAS elicited considerable increases in LDH, GLU, and TNFα, while the release of H 2 O 2 was low except for CAB-O-SIL® S17D Fumed Silica. Dispersing hydrophilic SAS with Protocol 1 gradually reduced the bioactivity but did not abolish it. The results show that hydrophobic coating reagents, which bind covalently to the SAS surface, abrogate the bioactivity of SAS even under serum-free in vitro conditions. The results may have implications for the hazard assessment of hydrophobic surface-treated SAS in the lung., Competing Interests: MW and AV were employed by IBE R&D Institute for Lung Health gGmbH, a non-profit research institute, and received funding from the Evonik Operations GmbH for conducting the study and preparing the manuscript. TS and NK were employed by Evonik Operations GmbH. JN was employed by Grace Europe Holding GmbH., (Copyright © 2022 Wiemann, Vennemann, Schuster, Nolde and Krueger.)

Low density powders have a bulk density of less than 100 kg/m3 and are produced technically by flame pyrolysis of silicon tetrachloride (pyrogenic powders such as pyrogenic silica) or wet-chemically by sol-gel processes (e.g. silica-gel) or precipitation reactions using sodium silicate solution and a mineral acid. The transport and alteration behavior of aerosols from low density powders was investigated in a device for toxicological inhalation studies. The test conditions corresponded to those for acute toxicology studies according to OECD Guideline 436. The use of cascade impactors, required by guideline, has not proven successful for low density powders as the fragile agglomerate structures are destroyed during the measurement. As an alternative and non-invasive measurement method, laser diffraction spectroscopy has proved very successful in the present investigations. In particular, aerosols from pyrogenic powders of low density showed a distinctive tendency to re-agglomerate, especially at concentrations >500 mg/m 3 mm 3 . Investigation results indicate that aerosol particle size must be monitored over the entire acute inhalation test period for acute inhalation studies to be performed reliably., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wessely, Stintz, Nolde and Creutzenberg.)

The aim of the present study was to understand the mechanism of lethality associated with high dose inhalation of a low-density hydrophobic surface-treated SAS observed in some acute inhalation studies. It was demonstrated that physical obstruction of the upper respiratory tract (nasal cavities) caused the effects observed. Hydrophobic surface-treated SAS was inhaled (flow-past, nose-only) by six Wistar rats (three males and three females) in an acute toxicity study at a concentration of ~500 mg/m 3 for an intended 4-hr exposure. Under the conditions of the test set-up, the concentration applied was found to be the highest that can be delivered to the test animal port without significant alteration of the aerosol size distribution over time. None of the test- material-exposed animals survived the planned observation time of 4 h; three animals died between 2 3 4 h after starting exposure and cessation of exposure at 3 1 4 h, two died after transfer to their cages and the remaining animal was sacrificed due to its poor condition and welfare considerations. Histology accomplished by energy dispersive X-ray (EDX) analysis demonstrated that test material particles agglomerated and formed a gel-like substrate that ultimately blocked the upper respiratory airways, which proved fatal for the rat as an obligatory nose breather. This observation is in line with the findings reported by Hofmann et al. showing a correlation between lethality and hydrophobicity determined by contact angle measurement. The aerosol characterizations associated with this study are provided in detail by Wessely et al., Competing Interests: NK and TS are employed by Evonik Operations GmbH. KW, NW, and AV are employed by AnaPath Services GmbH. JN is employed by Grace Europe Holding GmbH. GG and OC are employed by Fraunhofer Institute for Toxicology and Experimental Medicine. BW and MS are employed by Technische Universität Dresden. VM is employed by Cabot Corporation. MK is employed by Wacker Chemie AG., (Copyright © 2022 Krueger, Weber, Warfving, Vitali, Nolde, Schuster, Bruer, Creutzenberg, Wessely, Stintz, Moise and Kellert.)

Three H-Oil gas oils, heavy atmospheric gas oil (HAGO), light vacuum gas oil (LVGO), heavy vacuum gas oil (HVGO), and two their blends with hydrotreated straight run vacuum gas oils (HTSRVGOs) were cracked on two high unit cell size (UCS) lower porosity commercial catalysts and two low UCS higher porosity commercial catalysts. The cracking experiments were performed in an advanced cracking evaluation fluid catalytic cracking (FCC) laboratory unit at 527 °C, 30 s catalyst time on stream, and catalyst-to-oil (CTO) variation between 3.5 and 7.5 wt/wt The two high UCS lower porosity catalysts were more active and more coke selective. However, the difference between conversion of the more active high UCS lower porosity and low UCS higher porosity catalysts at 7.5 wt/wt CTO decreased in the order 10% (HAGO) > 9% (LVGO) > 6% (HVGO) > 4% (80% HTSRVGO/20% H-Oil VGO). Therefore, the catalyst performance is feedstock-dependent. The four studied catalysts along with a blend of one of them with 2% ZSM-5 were examined in a commercially revamped UOP FCC VSS unit. The lower UCS higher porosity catalysts exhibited operation at a higher CTO ratio achieving a similar conversion level with more active higher UCS lower porosity catalysts. However, the higher UCS lower porosity catalysts made 0.67% Δ coke that was higher than the maximum acceptable limit of 0.64% for this particular commercial FCC unit (FCCU), which required excluding the HVGO from the FCC feed blend. The catalyst system containing ZSM-5 increased the LPG yield but did not have an impact on gasoline octane. It was found that the predominant factor that controls refinery profitability related to the FCCU performance is the FCC slurry oil (bottoms) yield., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Soluble inorganic aluminium compounds like aluminium sulfate or aluminium chloride have been challenged by the European Chemical Agency to induce germ cell mutagenicity. Before conducting mutagenicity tests, the hydrolysis products in water and in physiological solutions should be determined as a function of the concentration and pH. We used different 27 Al NMR spectroscopic techniques (heteronuclear Overhauser effect spectroscopy (HOESY), exchange spectroscopy (EXSY), diffusion ordered (DOSY)) in this work to gain the information to study the aluminium species in solutions with Al₂(SO₄)₃ concentrations of 50.0, 5.0, and 0.5 g/L and their pH and time dependent transformation. At low pH, three different species were present in all physiological solutions and water: [Al(OH) n (H₂O) 6 - n ] (3 - n)+ ( n = 0-2), [Al(H₂O)₅SO₄]⁺, and [Al₂(OH)₂(H₂O)₈] 4+ . Increasing pH reduced the amounts of the two monomer species, with a complete loss at pH 5 for solutions with a concentration of 50.0 g/L and at pH 4 for solutions with a concentration of 5.0 g/L. The dimer species [Al₂(OH)₂(H₂O)₈] 4+ is present in a pH range between 3 and 6. Less symmetric oligomeric and probably asymmetric aluminium species are formed at pH of 5 and 6. The pH value is the driving force for the formation of aluminium species in all media, whereas the specific medium had only minor effect. No conclusive information could be obtained at pH 7 due to signal loss related to fast quadrupole relaxation of asymmetric aluminium species. A slight reduction of the content of the symmetric aluminium species due to the formation of oligomeric species was observed over a period of 6 weeks. Reference 27 Al NMR experiments conducted on saturated water solutions of AlCl₃ and those with a concentration of 50 g/L show that the type of salt/counter ion at the same concentration and pH influences the hydrolysis products formed., Competing Interests: The authors declare no conflict of interest.The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the result.

Rare earth elements (REE) used to be taken as tracers of geological origin for fluvial transport. Nowadays their increased applications in innovative environmental-friendly technology (e.g. in catalysts, superconductors, lasers, batteries) and medical applications (e.g. MRI contrast agent) lead to man-made, elevated levels in the environment. So far, no regulatory thresholds for REE concentrations and emissions to the environment have been set because information on risks from REE is scarce. However, evidence gathers that REE have to be acknowledged as new, emerging contaminants with manifold ways of entry into the environment, e.g. through waste water from hospitals or through industrial effluents. This paper reviews existing information on bioaccumulation and ecotoxicity of lanthanum in the aquatic environment. Lanthanum is of specific interest as one of the major lanthanides in industrial effluents. This review focuses on the freshwater and the marine environment, and tackles the water column and sediments. From these data, methods to derive quality criteria for sediment and water are discussed and preliminary suggestions are made., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)