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Publikation Predictive computational models for assessing the impact of co-milling on drug dissolution(Elsevier, 07/2024) Pätzmann, Nicolas; O'Dwyer, Patrick J.; Beránek, Josef; Kuentz, Martin; Griffin, Brendan T.Co-milling is an effective technique for improving dissolution rate limited absorption characteristics of poorly water-soluble drugs. However, there is a scarcity of models available to forecast the magnitude of dissolution rate improvement caused by co-milling. Therefore, this study endeavoured to quantitatively predict the increase in dissolution by co-milling based on drug properties. Using a biorelevant dissolution setup, a series of 29 structurally diverse and crystalline drugs were screened in co-milled and physically blended mixtures with Polyvinylpyrrolidone K25. Co-Milling Dissolution Ratios after 15 min (COMDR15 min) and 60 min (COMDR60 min) drug release were predicted by variable selection in the framework of a partial least squares (PLS) regression. The model forecasts the COMDR15 min (R2 = 0.82 and Q2 = 0.77) and COMDR60 min (R2 = 0.87 and Q2 = 0.84) with small differences in root mean square errors of training and test sets by selecting four drug properties. Based on three of these selected variables, applicable multiple linear regression equations were developed with a high predictive power of R2 = 0.83 (COMDR15 min) and R2 = 0.84 (COMDR60 min). The most influential predictor variable was the median drug particle size before milling, followed by the calculated drug logD6.5 value, the calculated molecular descriptor Kappa 3 and the apparent solubility of drugs after 24 h dissolution. The study demonstrates the feasibility of forecasting the dissolution rate improvements of poorly water-solube drugs through co-milling. These models can be applied as computational tools to guide formulation in early stage development.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Comparison of protein-like model particles fabricated by micro 3D printing to established standard particles(Elsevier, 08/2024) Amara, Ilias; Germershaus, Oliver; Lentes, Christopher; Sass, Steffen; Youmto, Stephany Mamdjo; Stracke, Jan Olaf; Clemens-Hemmelmann, Mirjam; Assfalg, AnaceliaInnovative analytical instruments and development of new methods has provided a better understanding of protein particle formation in biopharmaceuticals but have also challenged the ability to obtain reproducible and reliable measurements. The need for protein-like particle standards mimicking the irregular shape, translucent nature and near-to-neutral buoyancy of protein particles remained one of the hot topics in the field of particle detection and characterization in biopharmaceutical formulations. An innovative protein-like particle model has been developed using two photo polymerization (2PP) printing allowing to fabricate irregularly shaped particles with similar properties as protein particles at precise size of 50 µm and 150 µm, representative of subvisible particles and visible particles, respectively. A study was conducted to compare the morphological, physical, and optical properties of artificially generated protein particles, polystyrene spheres, ETFE, and SU-8 particle standards, along with newly developed protein-like model particles manufactured using 2PP printing. Our results suggest that 2PP printing can be used to produce protein-like particle standards that might facilitate harmonization and standardization of subvisible and visible protein particle characterization across laboratories and organizations.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Technical note: development of a simulation framework, enabling the investigation of locally tuned single energy proton radiography(IOP Publishing, 07.02.2024) Lundberg, Måns; Meijers, Arturs; Souris, Kevin; Deffet, Sylvain; Weber, Damien C; Lomax, Antony; Knopf, AntjeRange uncertainties remain a limitation for the confined dose distribution that proton therapy can offer. The uncertainty stems from the ambiguity when translating CT Hounsfield Units (HU) into proton stopping powers. Proton Radiography (PR) can be used to verify the proton range. Specifically, PR can be used as a quality-control tool for CBCT-based synthetic CTs. An essential part of the work illustrating the potential of PR has been conducted using multi-layer ionization chamber (MLIC) detectors and mono-energetic PR. Due to the dimensions of commercially available MLICs, clinical adoption is cumbersome. Here, we present a simulation framework exploring locally-tuned single energy (LTSE) proton radiography and corresponding potential compact PR detector designs. Based on a planning CT data set, the presented framework models the water equivalent thickness. Subsequently, it analyses the proton energies required to pass through the geometry within a defined ROI. In the final step, an LTSE PR is simulated using the MCsquare Monte Carlo code. In an anatomical head phantom, we illustrate that LTSE PR allows for a significantly shorter longitudinal dimension of MLICs. We compared PR simulations for two exemplary 30 × 30 mm2proton fields passing the phantom at a 90° angle at an anterior and a posterior location in an iso-centric setup. The longitudinal distance over which all spots per field range out is significantly reduced for LTSE PR compared to mono-energetic PR. In addition, we illustrate the difference in shape of integral depth dose (IDD) when using constrained PR energies. Finally, we demonstrate the accordance of simulated and experimentally acquired IDDs for an LTSE PR acquisition. As the next steps, the framework will be used to investigate the sensitivity of LTSE PR to various sources of errors. Furthermore, we will use the framework to systematically explore the dimensions of an optimized MLIC design for daily clinical use.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Computational support to explore ternary solid dispersions of challenging drugs using coformer and hydroxypropyl cellulose(American Chemical Society, 10.10.2024) Niederquell, Andreas; Herzig, Susanne; Schönenberger, Monica; Stoyanov, Edmont; Kuentz, MartinA majority of drugs marketed in amorphous formulations have a good glass-forming ability, while compounds less stable in the amorphous state still pose a formulation challenge. This work explores ternary solid dispersions of two model drugs with a polymer (i.e., hydroxypropyl cellulose) and a coformer as stabilizing excipients. The aim was to introduce a computational approach by preselecting additives using solubility parameter intervals (i.e., overlap range of solubility parameter, ORSP) followed by more advanced COSMO-RS theory modeling. Thus, a mapping of calculated mixing enthalpy and melting points is proposed for in silico evaluation prior to hot melt extrusion. Following experimental testing of process feasibility, the selected formulations were tested for their physical stability using conventional bulk analytics and by confocal laser scanning and atomic force microscopy imaging. In line with the in silico screening, dl-malic and l-tartaric acid (20%, w/w) in HPC formulations showed no signs of early drug crystallization after 3 months. However, l-tartaric acid formulations displayed few crystals on the surface, which was likely a humidity-induced surface phenomenon. Although more research is needed, the conclusion is that the proposed computational small-scale extrusion approach of ternary solid dispersion has great potential in the formulation development of challenging drugs.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Insecticide exposure alters flight-dependent gene-expression in honey bees, Apis mellifera(Elsevier, 12/2024) Christen, Verena; Jeker, Lukas; Lim, Ka S.; Menz, Myles H.M.; Straub, LarsThe increased reports of wild bee declines and annual losses of managed bees pose a significant threat to biodiversity and agricultural productivity. While these losses and declines are likely driven by various factors, the exposure of bees to agrochemicals has raised significant concern due to their ubiquitous use and potential adverse effects. Despite numerous studies suggesting neonicotinoids can negatively affect bees at the behavioral and molecular level, data linking these two factors remains sparse. Here we provide data on the impact of an acute dose of the neonicotinoid thiamethoxam on the flight performance and molecular transcription profiles of foraging honey bees (Apis mellifera). Using a controlled experimental design with tethered flight mills, we measured flight distance, duration, and speed, alongside the expression of genes involved in energy metabolism, hormone regulation, and biosynthesis. Acute thiamethoxam exposure resulted in hyperactive flight behavior but led to significant dysregulation of genes associated with oxidative phosphorylation, indicating potential disruptions in cellular energy production. These molecular changes were particularly evident when bees engaged in flight activities, suggesting that the combined stress of pesticide exposure and physical exertion exacerbates negative outcomes. Our study provides new insights into the molecular mechanisms underlying neonicotinoid-induced impairments in bee physiology that can help understand the potential long-term consequences of xenobiotic exposure on the foraging abilities of bees and ultimately fitness.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Definition of the binding specificity of the T7 bacteriophage primase by analysis of a protein binding microarray using a thermodynamic model(Oxford University Press, 10.04.2024) Lipps, GeorgProtein binding microarrays (PBM), SELEX, RNAcompete and chromatin-immunoprecipitation have been intensively used to determine the specificity of nucleic acid binding proteins. While the specificity of proteins with pronounced sequence specificity is straightforward, the determination of the sequence specificity of proteins of modest sequence specificity is more difficult. In this work, an explorative data analysis workflow for nucleic acid binding data was developed that can be used by scientists that want to analyse their binding data. The workflow is based on a regressor realized in scikit-learn, the major machine learning module for the scripting language Python. The regressor is built on a thermodynamic model of nucleic acid binding and describes the sequence specificity with base- and position-specific energies. The regressor was used to determine the binding specificity of the T7 primase. For this, we reanalysed the binding data of the T7 primase obtained with a custom PBM. The binding specificity of the T7 primase agrees with the priming specificity (5′-GTC) and the template (5′-GGGTC) for the preferentially synthesized tetraribonucleotide primer (5′-pppACCC) but is more relaxed. The dominant contribution of two positions in the motif can be explained by the involvement of the initiating and elongating nucleotides for template binding.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation In situ minimally invasive 3D printing for bone and cartilage regeneration - a scoping review(De Gruyter, 14.09.2024) Maintz, Michaela; Tomooka, Yukiko; Eugster, Manuela; Gerig, Nicolas; Sharma, Neha; Thieringer, Florian M.; Rauter, GeorgAdvancements in personalized medicine, three-dimensional (3D) printing, miniaturization, and robot-assistedsurgery are driving innovation in tissue engineering. A novelapproach, known asin situprinting, focuses on the direct depo-sition of materials at the surgical site. Using thein situprintingapproach, bone and/or cartilage defects can be addressed withhigh precision. Furthermore, highly customized 3D printed tis-sue constructs or implants can be deposited directly insidethe body. Currently, most applications ofin situprinting arelimited to areas near the skin or open surgeries. Even thougha minimally invasive approach would bring clinical benefits,only a few research groups have focused on this field. In thisscoping review, we provide an overview of the current stateofin situminimally invasive 3D printing technology for boneand cartilage regeneration and discuss its advantages and cur-rent challenges.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Amorphous solid dispersion of a binary formulation with felodipine and HPMC for 3D printed floating tablets(Elsevier, 06/2024) Mora-Castaño, Gloria; Millán-Jiménez, Mónica; Niederquell, Andreas; Schönenberger, Monica; Shojaie, Fatemeh; Kuentz, Martin; Caraballo, IsidoroThis study focuses on the combination of three-dimensional printing (3DP) and amorphous solid dispersion (ASD) technologies for the manufacturing of gastroretentive floating tablets. Employing hot melt extrusion (HME) and fused deposition modeling (FDM), the study investigates the development of drug-loaded filaments and 3D printed (3DP) tablets containing felodipine as model drug and hydroxypropyl methylcellulose (HPMC) as the polymeric carrier. Prior to fabrication, solubility parameter estimation and molecular dynamics simulations were applied to predict drug-polymer interactions, which are crucial for ASD formation. Physical bulk and surface characterization complemented the quality control of both drug-loaded filaments and 3DP tablets. The analysis confirmed a successful amorphous dispersion of felodipine within the polymeric matrix. Furthermore, the low infill percentage and enclosed design of the 3DP tablet allowed for obtaining low-density systems. This structure resulted in buoyancy during the entire drug release process until a complete dissolution of the 3DP tablets (more than 8 h) was attained. The particular design made it possible for a single polymer to achieve a zero-order controlled release of the drug, which is considered the ideal kinetics for a gastroretentive system. Accordingly, this study can be seen as an advancement in ASD formulation for 3DP technology within pharmaceutics.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Towards quantitative microplastic analysis using pyrolysis-gas chromatography coupled with mass spectrometry(Elsevier, 11/2024) Grafinger, Katharina Elisabeth; Ochiai, Celandin; Zhou, Huan-Xiao; Hettich, Timm; Büttler, Andre; Álvarez Troncoso, Romina; Zenker, Armin; Gaugler, StefanMicroplastic pollution from everyday plastic items has increased tremendously worldwide. Pyrolysis gas chromatography coupled to mass spectrometry (Py-GC/MS) has been widely investigated for the qualitative and quantitative analysis of microplastics in environmental samples. However, there are several pitfalls to consider when developing an appropriate protocol for their analysis. This study aimed at the development of an in-house database of primary (single) polymers, binary (two) polymers and tertiary (three) polymer mixtures. In this context the potential occurrence of gas phase reactions during pyrolysis of binary and tertiary polymers were investigated. Further, different diluters were tested for the accurate preparation of calibration standards for quantification purposes. Seven different polymers were included in this study, which were chosen due to their prevalence in daily plastic appliances. For each single polymer specific peaks could be identified and recommendation for quantifier analytes given. The analysis of binary polymer mixtures revealed gas phase reactions for PET with PVC, PVC with MDI-PU and PE with PVC. For these binary polymers, several different novel pyrolysis products, specific for the according binary polymer mixture, could be identified. These results confirmed that especially PVC exhibits strong interactions during co-pyrolysis with ester- and ether-based polymers. Similar results were obtained for tertiary polymers. For accurate preparation of calibration standards different diluters (silica, deactivated silica, calcium carbonate, THF and HFIP) were tested. It was observed that deactivated silica had only an influence on the pyrolysis of PET. Whereas, dilution with silica affected PA-6/66, PE, PET and MDI-PU. Only PVC was not influenced by dilution with silica. In conclusion, our results highlight the necessity of an international standard of reference material as well as a standardized analytical protocol for the analysis and quantification of polymers in environmental samples. It is crucial to use diluters suitable for the specific polymer, to exclude potential interactions of diluters with the polymer. The present work has to be seen as a foundation, but future work is needed to adequately address the quantification of polymers in environmental samples.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Initial primer synthesis of a DNA primase monitored by real-time NMR spectroscopy(American Chemical Society, 27.03.2024) Wu, Pengzhi; Zehnder, Johannes; Schröder, Nina; Blümmel, Pascal E. W.; Salmon, Loïc; Damberger, Fred. F.; Lipps, Georg; Allain, Frédéric H.-T.; Wiegand, ThomasPrimases are crucial enzymes for DNA replication, as they synthesize a short primer required for initiating DNA replication. We herein present time-resolved nuclear magnetic resonance (NMR) spectroscopy in solution and in the solid state to study the initial dinucleotide formation reaction of archaeal pRN1 primase. Our findings show that the helix-bundle domain (HBD) of pRN1 primase prepares the two substrates and then hands them over to the catalytic domain to initiate the reaction. By using nucleotide triphosphate analogues, the reaction is substantially slowed down, allowing us to study the initial dinucleotide formation in real time. We show that the sedimented protein–DNA complex remains active in the solid-state NMR rotor and that time-resolved 31P-detected cross-polarization experiments allow monitoring the kinetics of dinucleotide formation. The kinetics in the sedimented protein sample are comparable to those determined by solution-state NMR. Protein conformational changes during primer synthesis are observed in time-resolved 1H-detected experiments at fast magic-angle spinning frequencies (100 kHz). A significant number of spectral changes cluster in the HBD pointing to the importance of the HBD for positioning the nucleotides and the dinucleotide.01A - Beitrag in wissenschaftlicher Zeitschrift