Institut für Pharma Technology

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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. [in: European Journal of Pharmaceutical Sciences]
01A - Beitrag in wissenschaftlicher Zeitschrift
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. [in: European Journal of Pharmaceutical Sciences]
01A - Beitrag in wissenschaftlicher Zeitschrift
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, Georgios [in: Journal of Controlled Release]
01A - Beitrag in wissenschaftlicher Zeitschrift
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-Marc [in: Biochemical Engineering Journal]
01A - Beitrag in wissenschaftlicher Zeitschrift
Tablet formulation with dual control concept for efficient colonic drug delivery
(Elsevier, 25.01.2023) Doggwiler, Viviane; Lanz, Michael; Paredes, Valeria; Lipps, Georg; Imanidis, Georgios [in: International Journal of Pharmaceutics]
01A - Beitrag in wissenschaftlicher Zeitschrift
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, Ivan [in: Microorganisms]
The 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 Zeitschrift
Using a laser monitoring technique for dissolution and thermodynamic study of celecoxib in 2-propanol and propylene glycol mixtures
(Dissolution Technologies, 2023) Jouyban-Gharamaleki, Vahid; Martinez, Fleming; Kuentz, Martin; Rahimpour, Elaheh; Jouyban, Abolghasem [in: Dissolution Technologies]
01A - Beitrag in wissenschaftlicher Zeitschrift
Study of disordered mesoporous silica regarding intrinsic compound affinity to the carrier and drug-accessible surface area
(ACS, 2023) Niederquell, Andreas; Vraníková, Barbora; Kuentz, Martin [in: Molecular Pharmaceutics]
There is increasing research interest in using mesoporous silica for the delivery of poorly water-soluble drugs that are stabilized in a noncrystalline form. Most research has been done on ordered silica, whereas far fewer studies have been published on using nonordered mesoporous silica, and little is known about intrinsic drug affinity to the silica surface. The present mechanistic study uses inverse gas chromatography (IGC) to analyze the surface energies of three different commercially available disordered mesoporous silica grades in the gas phase. Using the more drug-like probe molecule octane instead of nitrogen, the concept of a “drug-accessible surface area” is hereby introduced, and the effect on drug monolayer capacity is addressed. In addition, enthalpic interactions of molecules with the silica surface were calculated based on molecular mechanics, and entropic energy contributions of volatiles were estimated considering molecular flexibility. These free energy contributions were used in a regression model, giving a successful comparison with experimental desorption energies from IGC. It is proposed that a simplified model for drugs based only on the enthalpic interactions can provide an affinity ranking to the silica surface. Following this preformulation research on mesoporous silica, future studies may harness the presented concepts to guide formulation scientists. © 2023 American Chemical Society.
01A - Beitrag in wissenschaftlicher Zeitschrift
Corrigendum to “Powder cohesion and energy to break an avalanche. Can we address surface heterogeneity?” [Int. J. Pharm. 626 (2022) 122198]
(Elsevier, 2023) Brokešová, Jana; Niederquell, Andreas; Kuentz, Martin; Zámostný, Petr; Vraníková, Barbora; Šklubalová, Zdenka [in: International Journal of Pharmaceutics]
01A - Beitrag in wissenschaftlicher Zeitschrift
Isolation and characterization of pancreatic lipase inhibitor from rapeseed seeds
(Oles Honchar Dnipro National University, 2023) Krusir, Galyna; Pylypenko, Liudmyla; Sevastyanova, Elena; Mazurenko, Kseniia; Moshtakov, Serhii; Shunko, Hanna; Vitiuk, Antonina; Shpyrko, Tetyana; Zdoryk, Oleksandr [in: Journal of Chemistry and Technologies]
Digestive enzymes and inhibitors of digestive enzymes are effective correctors of digestive processes in the body, the violation of which leads to various diseases (diabetes, hyperlipidemia, cardiovascular diseases, neoplasms and others). The present study identified the most promising plant objects characterized by the highest antilipolytic activity (ALA) in relation to pancreatic lipase. The experimental results indicate that the inhibitory activity (IA) of phenolic compounds of rapeseed is so much high and comparable to ALA "Orlistat", reaching 95.5 % of its activity. This determines the potential possibility of using the phenolic complex of rapeseed as an alternative to anti-lipolytic drugs of synthetic origin. The predominant component of the phenolic complex is low molecular weight phenolic compounds; polyphenolic compounds are almost equally represented by tannins – condensed and hydrolyzable. According to TLC data, the main components of low molecular weight phenols are glucopyranosylsinapate, sinapic acid and sinapin. Among the phenolic compounds of rapeseed seeds, sinapine and hydrolyzable tannins have the highest anti lipolytic activity against lipase. Significant ability to inhibit the action of pancreatic lipase is characterized by both low molecular weight and high molecular weight phenolic compounds of rapeseed.
01A - Beitrag in wissenschaftlicher Zeitschrift
Physiological buffer effects in drug supersaturation - a mechanistic study of hydroxypropyl cellulose as precipitation inhibitor
(2023) Niederquell, Andreas; Stoyanov, Edmont; Kuentz, Martin [in: Journal of Pharmaceutical Sciences]
01A - Beitrag in wissenschaftlicher Zeitschrift
Analysis of the physical characteristics of an anhydrous vehicle for compounded pediatric oral liquids
(MDPI, 2023) Banov, Daniel; Liu, Yi; Ip, Kendice; Shan, Ashley; Vu, Christine; Zdoryk, Oleksandr; Bassani, August S.; Carvalho, Maria [in: Pharmaceutics]
The paucity of suitable drug formulations for pediatric patients generates a need for customized, compounded medications. This research study was set out to comprehensively analyze the physical properties of the new, proprietary anhydrous oral vehicle SuspendIt® Anhydrous, which was designed for compounding pediatric oral liquids. A wide range of tests was used, including sedimentation volume, viscosity, droplet size after dispersion in simulated gastric fluid, microscopic examination and content uniformity measurements to evaluate the properties of the anhydrous vehicle. The results showed that the vehicle exhibited consistent physical properties under varying conditions and maintained stability over time. This can be attributed to the unique blend of excipients in its formulation, which not only maintain its viscosity but also confer thixotropic behavior. The unique combination of viscous, thixotropic and self-emulsifying properties allows for rapid redispersibility, sedimentation stability, accurate dosing, potential drug solubility, dispersion and promotion of enhanced gastrointestinal distribution and absorption. Furthermore, the vehicle demonstrated long-term sedimentation stability and content uniformity for a list of 13 anhydrous suspensions. These results suggest that the anhydrous oral vehicle could serve as a versatile base for pediatric formulation, potentially filling an important gap in pediatric drug delivery. Future studies can further investigate its compatibility, stability and performance with other drugs and in different clinical scenarios.
01A - Beitrag in wissenschaftlicher Zeitschrift
How technical innovations may help to prevent drug shortages in switzerland
(Schweizerische Chemische Gesellschaft, 2023) Gygax, Daniel; Eigenmann, Kaspar; Suter, Christian; Hürzeler Müller, Marianne; Mahmoud, Ahmed; Mosbacher, Johannes; Pöllinger, Norbert [in: Chimia]
In this work, we investigated the technical feasibility of 'on-demand' production of selected drugs to cover their demand for a time window of 90 days. We focused on two sub-processes 'automated chemical synthesis' and 'formulation in micropellets' to enable personalized dosing. The production of drugs 'on-demand' is challenging, important, but also attractive. Switzerland could thus gain access to an additional instrument for increasing resilience for supply-critical drugs. The biggest challenge in the case study presented here is the scalability of automated chemical synthesis and the application range of micropellet formulations.
01A - Beitrag in wissenschaftlicher Zeitschrift
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. [in: European Journal of Pharmaceutical Sciences]
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. © 2023
01A - Beitrag in wissenschaftlicher Zeitschrift
Comparative drug solubility studies using shake-flask versus a laser-based robotic method
(Springer, 2023) Rahimpour, Elaheh; Moradi, Milad; Sheikhi-Sovari, Atefeh; Rezaei, Homa; Rezaei, Hadis; Jouyban-Gharamaleki, Vahid; Kuentz, Martin; Jouyban, Abolghasem [in: AAPS PharmSciTech]
Drug solubility is of central importance to the pharmaceutical sciences, but reported values often show discrepancies. Various factors have been discussed in the literature to account for such differences, but the influence of manual testing in comparison to a robotic system has not been studied adequately before. In this study, four expert researchers were asked to measure the solubility of four drugs with various solubility behaviors (i.e., paracetamol, mesalazine, lamotrigine, and ketoconazole) in the same laboratory with the same instruments, method, and material sources and repeated their measurements after a time interval. In addition, the same solubility data were determined using an automated laser-based setup. The results suggest that manual testing leads to a handling influence on measured solubility values, and the results were discussed in more detail as compared to the automated laser-based system. Within the framework of unavoidable uncertainties of solubility testing, it is a possibility to combine minimal experimental testing that is preferably automated with mathematical modeling. That is a practical suggestion to support future pharmaceutical development in a more efficient way. © 2023, The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.
01A - Beitrag in wissenschaftlicher Zeitschrift
Not the usual suspects. Alternative surfactants for biopharmaceuticals
(American Chemical Society, 2023) Brosig, Sebastian; Cucuzza, Stefano; Serno, Tim; Bechtold-Peters, Karoline; Buecheler, Jakob; Zivec, Matej; Germershaus, Oliver; Gallou, Fabrice [in: ACS Applied Materials & Interfaces]
01A - Beitrag in wissenschaftlicher Zeitschrift
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, Thomas [in: Biotechnology & Bioengineering]
Hollow 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 Zeitschrift
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, Fritz [in: Crystal Growth & Design]
The 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
Advancing Raman model calibration for perfusion bioprocesses using spiked harvest libraries
(Wiley, 07.08.2022) Kolar, Jakub; Herwig, Christoph; Bielser, Jean‐Marc; Romann, Patrick; Tobler, Daniela; Villiger, Thomas [in: Biotechnology Journal]
Background Raman spectroscopy has gained popularity to monitor multiple process indicators simultaneously in biopharmaceutical processes. However, robust and specific model calibration remains a challenge due to insufficient analyte variability to train the models and high cross-correlation of various media components and artifacts throughout the process. Main Methods A systematic Raman calibration workflow for perfusion processes enabling highly specific and fast model calibration was developed. Harvest libraries consisting of frozen harvest samples from multiple CHO cell culture bioreactors collected at different process times were established. Model calibration was subsequently performed in an offline setup using a flow cell by spiking process harvest with glucose, raffinose, galactose, mannose, and fructose. Major Results In a screening phase, Raman spectroscopy was proven capable not only to distinguish sugars with similar chemical structures in perfusion harvest but also to quantify them independently in process-relevant concentrations. In a second phase, a robust and highly specific calibration model for simultaneous glucose (root mean square error prediction [RMSEP] = 0.32 g L−1) and raffinose (RMSEP = 0.17 g L−1) real-time monitoring was generated and verified in a third phase during a perfusion process. Implication The proposed novel offline calibration workflow allowed proper Raman peak decoupling, reduced calibration time from months down to days, and can be applied to other analytes of interest including lactate, ammonia, amino acids, or product titer. Graphical Abstract and Lay Summary Building accurate and robust Raman models for online monitoring of cell culture processes remains a difficult and time-consuming process, particularly for perfusion processes. In this study, the authors developed a novel offline calibration approach based on design-of-experiment spiking and a harvesting library. The Raman spectra of these spiked harvest samples allowed proper peak decoupling and model generation within days instead of weeks or even months. The approach has been successfully applied to monitor various sugars in perfusion bioreactors and other compounds as well as process modes may equally benefit from the described workflow.
01A - Beitrag in wissenschaftlicher Zeitschrift
Study and computational modeling of fatty acid effects on drug solubility in lipid-based systems
(Elsevier, 06/2022) Wyttenbach, Nicole; Ectors, Philipp; Niederquell, Andreas; Kuentz, Martin [in: Journal of Pharmaceutical Sciences]
Lipid-based systems have many advantages in formulation of poorly water-soluble drugs but issues of a limited solvent capacity are often encountered in development. One of the possible solubilization approaches of especially basic drugs could be the addition of fatty acids to oils but currently, a systematic study is lacking. Therefore, the present work investigated apparently neutral and basic drugs in medium chain triglycerides (MCT) alone and with added either caproic acid (C6), caprylic acid (C8), capric acid (C10) or oleic acid (C18:1) at different levels (5 – 20%, w/w). A miniaturized solubility assay was used together with X-ray diffraction to analyze the residual solid and finally, solubility data were modeled using the conductor-like screening model for real solvents (COSMO-RS). Some drug bases had an MCT solubility of only a few mg/ml or less but addition of fatty acids provided in some formulations exceptional drug loading of up to about 20% (w/w). The solubility changes were in general more pronounced the shorter the chain length was and the longest oleic acid even displayed a negative effect in mixtures of celecoxib and fenofibrate. The COSMO-RS prediction accuracy was highly specific for the given compounds with root mean square errors (RMSE) ranging from an excellent 0.07 to a highest value of 1.12. The latter was obtained with the strongest model base pimozide for which a new solid form was found in some samples. In conclusion, targeting specific molecular interactions with the solute combined with mechanistic modeling provides new tools to advance lipid-based drug delivery.
01A - Beitrag in wissenschaftlicher Zeitschrift

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