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Publikation Advancing algorithmic drug product development. Recommendations for machine learning approaches in drug formulation(Elsevier, 2023) Murray, Jack D.; Lange, Justus J.; Bennett-Lenane, Harriet; Holm, René; Kuentz, Martin; O'Dwyer, Patrick J.; Griffin, Brendan T.Artificial intelligence is a rapidly expanding area of research, with the disruptive potential to transform traditional approaches in the pharmaceutical industry, from drug discovery and development to clinical practice. Machine learning, a subfield of artificial intelligence, has fundamentally transformed in silico modelling and has the capacity to streamline clinical translation. This paper reviews data-driven modelling methodologies with a focus on drug formulation development. Despite recent advances, there is limited modelling guidance specific to drug product development and a trend towards suboptimal modelling practices, resulting in models that may not give reliable predictions in practice. There is an overwhelming focus on benchtop experimental outcomes obtained for a specific modelling aim, leaving the capabilities of data scraping or the use of combined modelling approaches yet to be fully explored. Moreover, the preference for high accuracy can lead to a reliance on black box methods over interpretable models. This further limits the widespread adoption of machine learning as black boxes yield models that cannot be easily understood for the purposes of enhancing product performance. In this review, recommendations for conducting machine learning research for drug product development to ensure trustworthiness, transparency, and reliability of the models produced are presented. Finally, possible future directions on how research in this area might develop are discussed to aim for models that provide useful and robust guidance to formulators. © 202301A - Beitrag in wissenschaftlicher ZeitschriftPublikation Co‐current filtrate flow in TFF perfusion processes. Decoupling transmembrane pressure from crossflow to improve product sieving(Wiley, 2023) Romann, Patrick; Giller, Philip; Sibilia, Antony; Herwig, Christoph; Zydney, Andrew L.; Perilleux, Arnaud; Souquet, Jonathan; Bielser, Jean‐Marc; Villiger, ThomasHollow fiber‐based membrane filtration has emerged as the dominant technology for cell retention in perfusion processes yet significant challenges in alleviating filter fouling remain unsolved. In this work, the benefits of co‐current filtrate flow applied to a tangential flow filtration (TFF) module to reduce or even completely remove Starling recirculation caused by the axial pressure drop within the module was studied by pressure characterization experiments and perfusion cell culture runs. Additionally, a novel concept to achieve alternating Starling flow within unidirectional TFF was investigated. Pressure profiles demonstrated that precise flow control can be achieved with both lab‐scale and manufacturing‐scale filters. TFF systems with co‐current flow showed up to 40% higher product sieving compared to standard TFF. The decoupling of transmembrane pressure from crossflow velocity and filter characteristics in co‐current TFF alleviates common challenges for hollow fiber‐based systems such as limited crossflow rates and relatively short filter module lengths, both of which are currently used to avoid extensive pressure drop along the filtration module. Therefore, co‐current filtrate flow in unidirectional TFF systems represents an interesting and scalable alternative to standard TFF or alternating TFF operation with additional possibilities to control Starling recirculation flow.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Tablet formulation with dual control concept for efficient colonic drug delivery(Elsevier, 25.01.2023) Doggwiler, Viviane; Lanz, Michael; Paredes, Valeria; Lipps, Georg; Imanidis, Georgios01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Efficient colonic drug delivery in domestic pigs employing a tablet formulation with dual control concept(Elsevier, 06/2023) Doggwiler, Viviane; Puorger, Chasper; Paredes, Valeria; Lanz, Michael; Nuss, Katja M.; Lipps, Georg; Imanidis, Georgios01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Indigenous yeasts from rose oil distillation wastewater and their capacity for biotransformation of phenolics(MDPI, 12.01.2023) Rusanova, Mila; Rusanov, Krasimir; Butterweck, Veronika; Atanassov, IvanThe indigenous yeasts associated with the spontaneous fermentation of phenolic-rich rose oil distillation wastewater (RODW) generated after the industrial distillation of rose oil were studied. The ITS-rDNA sequence analysis of the samples collected from RODW fermented at semi-sterile conditions, a waste deposition lagoon and endophytic yeasts isolated from industrially cultivated Rosa damascena suggests that the spontaneous RODW fermentation is caused by yeasts from the genus Cyberlindnera found also as endophytes in the rose flowers. Phylogenetic analysis based on the nucleotide sequences of the translation elongation factor (TEF1α) and 18S- and 26S- rRNA genes further confirmed the taxonomic affiliation of the RODW yeast isolates with the genus Cyberlindnera. The RODW fermentation capacity of a selected set of indigenous yeast isolates was studied and compared with those of common yeast strains. The indigenous yeast isolates demonstrated a superior growth rate, resulting in a nearly double reduction in the phenolic content in the fermented RODW. The indigenous yeasts’ fermentation changed the RODW phenolics’ composition. The levels of some particular phenolic glycosides decreased through the depletion and fermentation of their sugar moiety. Hence, the relative abundance of the corresponding aglycons and other phenolic compounds increased. The capacity for the biotransformation of RODW phenolics by indigenous yeasts is discussed.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Physiological buffer effects in drug supersaturation - a mechanistic study of hydroxypropyl cellulose as precipitation inhibitor(2023) Niederquell, Andreas; Stoyanov, Edmont; Kuentz, Martin01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Maximizing yield of perfusion cell culture processes. Evaluation and scale-up of continuous bleed recycling(Elsevier, 04/2023) Romann, Patrick; Kolar, Jakub; Chappuis, Loïc; Herwig, Christoph; Villiger, Thomas; Bielser, Jean-Marc01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Lipid based formulations as supersaturating oral delivery systems. From current to future industrial applications(Elsevier, 01.10.2023) Holm, René; Kuentz, Martin; Ilie-Spiridon, Alexandra-Roxana; Griffin, Brendan T.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Leveraging the use of in vitro and computational methods to support the development of enabling oral drug products. An InPharma commentary(Elsevier, 01.09.2023) Reppas, Christos; Kuentz, Martin; Bauer-Brandl, Annette; Carlert, Sara; Dallmann, André; Dietrich, Shirin; Dressman, Jennifer; Ejskjaer, Lotte; Frechen, Sebastian; Guidetti, Matteo; Holm, René; Holzem, Florentin Lukas; Karlsson, Εva; Kostewicz, Edmund; Panbachi, Shaida; Paulus, Felix; Senniksen, Malte Bøgh; Stillhart, Cordula; Turner, David B.; Vertzoni, Maria; Vrenken, Paul; Zöller, Laurin; Griffin, Brendan T.; O'Dwyer, Patrick J.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Exploring the cocrystal landscape of posaconazole by combining high-throughput screening experimentation with computational chemistry(American Chemical Society, 23.12.2022) Guidetti, Matteo; Hilfiker, Rolf; Kuentz, Martin; Bauer-Brandl, Annette; Blatter, FritzThe development of multicomponent crystal forms, such as cocrystals, represents a means to enhance the dissolution and absorption properties of poorly water-soluble drug compounds. However, the successful discovery of new pharmaceutical cocrystals remains a time- and resource-consuming process. This study proposes the use of a combined computational-experimental high-throughput approach as a tool to accelerate and improve the efficiency of cocrystal screening exemplified by posaconazole. First, we employed the COSMOquick software to preselect and rank cocrystal candidates (coformers). Second, high-throughput crystallization experiments (HTCS) were conducted on the selected coformers. The HTCS results were successfully reproduced by liquid-assisted grinding and reaction crystallization, ultimately leading to the synthesis of thirteen new posaconazole cocrystals (7 anhydrous, 5 hydrates, and 1 solvate). The posaconazole cocrystals were characterized by PXRD, 1H NMR, Fourier transform-Raman, thermogravimetry–Fourier transform infrared spectroscopy, and differential scanning calorimetry. In addition, the prediction performance of COSMOquick was compared to that of two alternative knowledge-based methods: molecular complementarity (MC) and hydrogen bond propensity (HBP). Although HBP does not perform better than random guessing for this case study, both MC and COSMOquick show good discriminatory ability, suggesting their use as a potential virtual tool to improve cocrystal screening.01A - Beitrag in wissenschaftlicher Zeitschrift