Kuentz, Martin

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Kuentz, Martin

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  • Vorschaubild nicht verfügbar
    Publikation
    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
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    Publikation
    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
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    Publikation
    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
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    Publikation
    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
  • 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
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    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
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    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
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    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
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    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
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    Publikation
    Synergistic Computational Modeling Approaches as Team Players in the Game of Solubility Predictions
    (Elsevier, 17.11.2020) Kuentz, Martin [in: Journal of Pharmaceutical Sciences]
    Several approaches to predict and model drug solubility have been used in the drug discovery and development processes during the last decades. Each of these approaches have their own benefits and place, and are typically used as standalone approaches rather than in concert. The synergistic effects of these are often overlooked, partly due to the need of computational experts to perform the modeling and simulations as well as analyzing the data obtained. Here we provide our views on how these different approaches can be used to retrieve more information on drug solubility, ranging from multivariate data analysis over thermodynamic cycle modeling to molecular dynamics simulations. We are discussing aqueous solubility as well as solubility in more complex mixed solvents and media with colloidal structures present. We conclude that the field of computational pharmaceutics is in its early days but with a bright future ahead. However, education of computational formulators with broad knowledge of modeling and simulation approaches is imperative if computational pharmaceutics is to reach its full potential.
    01A - Beitrag in wissenschaftlicher Zeitschrift