Kuentz, Martin

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Kuentz
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Martin
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Kuentz, Martin

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2020 - 202232
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Enddatum: 2022 × Anfangsdatum: 2020 × Institut: Institut für Pharma Technology ×

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  • Vorschaubild
    Publikation
    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
  • Vorschaubild nicht verfügbar
    Publikation
    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
  • Vorschaubild
    Publikation
    Mechanistic study of dissolution enhancement by interactive mixtures of chitosan with meloxicam as model
    (Elsevier, 01.02.2022) Kuentz, Martin; Brokesova, Jana; Slamova, Michaela; Zamostny, Petr; Koktan, Jakub; Kreicik, Lukas; Svacinova, Petra; Sklubalova, Zdenka; Vraníková, Barbora [in: European Journal of Pharmaceutical Sciences]
    To enhance dissolution rate of meloxicam (MX), a poorly soluble model drug, a natural polysaccharide excipient chitosan (CH) is employed in this work as a carrier to prepare binary interactive mixtures by either mixing or co-milling techniques. The MX-CH mixtures of three different drug loads were characterized for morphological, granulometric, and thermal properties as well as drug crystallinity. The relative dissolution rate of MX was determined in phosphate buffer of pH 6.8 using the USP-4 apparatus; a significant increase in MX dissolution rate was observed for both mixed and co-milled mixtures comparing to the raw drug. Higher dissolution rate of MX was evidently connected to surface activation by mixing or milling, which was pronounced by the higher specific surface energy as detected by inverse gas chromatography. In addition to the particle size reduction, the carrier effect of the CH was confirmed for co-milling by linear regression between the MX maximum relative dissolution rate and the total surface area of the mixture (R2 = 0.863). No MX amorphization or crystalline structure change were detected. The work of adhesion/cohesion ratio of 0.9 supports the existence of preferential adherence of MX to the coarse particles of CH to form stable interactive mixtures.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Hydroxypropyl Cellulose for Drug Precipitation Inhibition: From the Potential of Molecular Interactions to Performance Considering Microrheology
    (American Chemical Society, 10.01.2022) Stoyanov, Edmont; Niederquell, Andreas; Kuentz, Martin [in: Molecular Pharmaceutics]
    There has been recent interest in using hydroxypropyl cellulose (HPC) for supersaturating drug formulations. This study investigated the potential for molecular HPC interactions with the model drug celecoxib by integrating novel approaches in the field of drug supersaturation analysis. Following an initial polymer characterization study, quantum-chemical calculations and molecular dynamics simulations were complemented with results of inverse gas chromatography and broadband diffusing wave spectroscopy. HPC performance was studied regarding drug solubilization and kinetics of desupersaturation using different grades (i.e., HPC-UL, SSL, SL, and L). The results suggested that the potential contribution of dispersive interactions and hydrogen bonding depended strongly on the absence or presence of the aqueous phase. It was proposed that aggregation of HPC polymer chains provided a complex heterogeneity of molecular environments with more or less excluded water for drug interaction. In precipitation experiments at a low aqueous polymer concentration (i.e., 0.01%, w/w), grades L and SL appeared to sustain drug supersaturation better than SSL and UL. However, UL was particularly effective in drug solubilization at pH 6.8. Thus, a better understanding of drug–polymer interactions is important for formulation development, and polymer blends may be used to harness the combined advantages of individual polymer grades.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Evaluation of gravitational consolidation of binary powder mixtures by modified Heckel equation
    (Elsevier, 2022) Svačinová, Petra; Macho, Oliver; Jarolímová, Žofie; Gabrišová, Ľudmila; Šklubalová, Zdenka; Kuentz, Martin [in: Powder Technology]
    Consolidation of powders by tapping is an important quality test but it is time and material consuming, which encourages the use of mathematical modelling. This article aims to study this gravitational consolidation dynamics by using nine binary mixtures consisting of cellets and powdered microcrystalline cellulose (MCC102), differing in size, shape, and consolidation properties. To describe the correlation between number of taps and powder bed density/ porosity, the modified Heckel equation. (MH) was newly introduced and compared to the models by Kawakita (KW) and Varthalis & Pilpel (VP). High coefficients of determination were observed by applying the traditional KW model up to 80% of cellets, while a comparable fitting adequacy was obtained with the MH equation up to 50% of cellets in the mixtures. An increased content of MCC102 increased fitting adequacy in the MH and KW model, whereas a nearly opposite mixture trend was observed for the VP model.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Lipophilic salts and lipid-based formulations for bridging the food effect gap of venetoclax
    (Elsevier, 01/2022) Koehl, Niklas; Henze, Laura; Holm, Rene; Kuentz, Martin; Keating, John; De Vijlder, Thomas; Marx, Andreas; Griffin, Brendan [in: Journal of Pharmaceutical Sciences]
    Lipid based formulations (LBF) have shown to overcome food dependent bioavailability for some poorly water-soluble drugs. However, the utility of LBFs can be limited by low dose loading due to a low drug solubility in LBF vehicles. This study investigated the solubility and drug loading increases in LBFs using lipophilic counterions to form lipophilic salts of venetoclax. Venetoclax docusate was formed from venetoclax free base and verified by 1H NMR. Formation of stable venetoclax-fatty acid associations with either oleic acid or decanoic acid were attempted, however, the molecular associations were less consistent based on 1H NMR. Venetoclax docusate displayed a up to 6.2-fold higher solubility in self-emulsifying drug delivery systems (SEDDS) when compared to the venetoclax free base solubility resulting in a higher dose loading. A subsequent bioavailability study in landrace pigs demonstrated a 2.5-fold higher bioavailability for the lipophilic salt containing long chain SEDDS compared to the commercially available solid dispersion Venclyxto® in the fasted state. The bioavailability of all lipophilic salt SEDDS in the fasted state was similar to Venclyxto® in the fed state. This study confirmed that lipophilic drug salts increase the dose loading in LBFs and showed that lipophilic salt-SEDDS combinations may be able to overcome bioavailability limitations of drugs with low inherent dose loading in lipid vehicles. Furthermore, the present study demonstrated the utility of a LBF approach, in combination with lipophilic salts, to overcome food dependent variable oral bioavailability of drugs.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    Artificial neural networks to predict the apparent degree of supersaturation in supersaturated lipid-based formulations. A pilot study
    (MDPI, 05.09.2021) Bennett-Lenane, Harriett; O'Shea, Joseph; Murray, Jack; Ilie, Alexandra Roxana; Holm, Rene; Kuentz, Martin; Griffin, Brendan [in: Pharmaceutics]
    In response to the increasing application of machine learning (ML) across many facets of pharmaceutical development, this pilot study investigated if ML, using artificial neural networks (ANNs), could predict the apparent degree of supersaturation (aDS) from two supersaturated LBFs (sLBFs). Accuracy was compared to partial least squares (PLS) regression models. Equilibrium solubility in Capmul MCM and Maisine CC was obtained for 21 poorly water-soluble drugs at ambient temperature and 60 °C to calculate the aDS ratio. These aDS ratios and drug descriptors were used to train the ML models. When compared, the ANNs outperformed PLS for both sLBFCapmulMC (r2 0.90 vs. 0.56) and sLBFMaisineLC (r2 0.83 vs. 0.62), displaying smaller root mean square errors (RMSEs) and residuals upon training and testing. Across all the models, the descriptors involving reactivity and electron density were most important for prediction. This pilot study showed that ML can be employed to predict the propensity for supersaturation in LBFs, but even larger datasets need to be evaluated to draw final conclusions.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Rational selection of bio-enabling oral drug formulations. A PEARRL commentary
    (Elsevier, 05/2021) Kuentz, Martin; Kronseder, Christian; Holm, Rene; Saal, Christoph; Griffin, Brendan [in: Journal of Pharmaceutical Sciences]
    New drug candidates often require bio-enabling formation technologies such as lipid-based formulations, solid dispersions, or nanosized drug formulations. Development of such more sophisticated delivery systems generally requires higher resource investment compared to a conventional oral dosage form, which might slow down clinical development. To achieve the biopharmaceutical objectives while enabling rapid cost effective development, it is imperative to identify a suitable formulation technique for a given drug candidate as early as possible. Hence many companies have developed internal decision trees based mostly on prior organizational experience, though they also contain some arbitrary elements. As part of the EU funded PEARRL project, a number of new decision trees are here proposed that reflect both the current scientific state of the art and a consensus among the industrial project partners. This commentary presents and discusses these, while also going beyond this classical expert approach with a pilot study using emerging machine learning, where the computer suggests formulation strategy based on the physicochemical and biopharmaceutical properties of a molecule. Current limitations are discussed and an outlook is provided for likely future developments in this emerging field of pharmaceutics.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    In Silico, In Vitro, and In Vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax
    (American Chemical Society, 23.04.2021) Koehl, Niklas; Henze, Laura; Bennett-Lenane, Harriett; Faisal, Waleed; Price, Daniel J.; Holm, Rene; Kuentz, Martin; Griffin, Brendan [in: Molecular Pharmaceutics]
    The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico–in vitro–in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug–excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    Current challenges and future perspectives in oral absorption research. An opinion of the UNGAP network
    (Elsevier, 04/2021) Kuentz, Martin; Vinarov, Zahari; Bertil, Abrahamsson; Artursson, Per; Batchelor, Hannah; Berben, Philippe; Bernkop-Schnürch, Andreas; Butler, James; Ceulemans, Jens; Davies, Nigel; Dupont, Didier; Eide Flaten, Goril; Fotaki, Nikoleta; Jannin, Vincent; Keemink, Janneke; Kesisoglou, Filippos; Koziolek, Mirko; Augustijns, Patrick; Griffin, Brendan [in: Advanced Drug Delivery Reviews]
    Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
    01A - Beitrag in wissenschaftlicher Zeitschrift