Niederquell, Andreas

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Niederquell
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Andreas
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Niederquell, Andreas

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2017 - 201972020 - 202411

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  • Vorschaubild
    Publikation
    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, Martin
    A 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 Zeitschrift
  • Vorschaubild
    Publikation
    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, Isidoro
    This 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 Zeitschrift
  • Kein Vorschaubild vorhanden
    Publikation
    Comparison of the liquisolid technique and co-milling for loading of a poorly soluble drug in inorganic porous excipients
    (Elsevier, 01/2024) Ogadah, Chiazor Ugo; Mrštná, Kristýna; Matysová, Ludmila; Müllertz, Anette; Rades, Thomas; Niederquell, Andreas; Šklubalová, Zdenka; Vraníková, Barbora
    Drug loading into mesoporous carriers may help to improve the dissolution of poorly aqueous-soluble drugs. However, both preparation method and carrier properties influence loading efficiency and drug release. Accordingly, this study aimed to compare two preparation methods: formulation into liquisolid systems (LSS) and co-milling for their efficiency in loading the poorly soluble model drug cyclosporine A (CyA) into mesoporous magnesium aluminometasilicate Neusilin® US2 (NEU) or functionalized calcium carbonate (FCC). Scanning electron microscopy was used to visualize the morphology of the samples and evaluate the changes that occurred during the drug loading process. The solid-state characteristics and physical stability of the formulations, prepared at different drug concentrations, were determined using X-ray powder diffraction. In vitro release of the drug was evaluated in biorelevant media simulating intestinal fluid. The obtained results revealed improved drug release profiles of the formulations when compared to the milled (amorphous) CyA alone. The dissolution of CyA from LSS was faster in comparison to the co-milled formulations. Higher drug release was achieved from NEU than FCC formulations presumably due to the higher pore volume and larger surface area of NEU.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Kein Vorschaubild vorhanden
    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
    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
  • Kein Vorschaubild vorhanden
    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
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Kein Vorschaubild vorhanden
    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
    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
  • Kein Vorschaubild vorhanden
    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
    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
  • Kein Vorschaubild vorhanden
    Publikation
    Relevance of the theoretical critical pore radius in mesoporous silica for fast crystallizing drugs
    (Elsevier, 26.10.2020) Vraníková, Barbora; Niederquell, Andreas; Kuentz, Martin
    Formulation of poorly water-soluble drugs with mesoporous silica has become a thriving field of pharmaceutics. The theoretical critical pore diameter has been introduced as a maximum value below which an undesired drug crystallization is suppressed by spatial confinement. Currently, only few values have been reported and study of fast crystallising drugs is missing especially at relevant storage temperatures. This study investigated the critical pore diameter of three model drugs with a poor glass-forming ability (i.e. haloperidol, carbamazepine and benzamide) using different mesoporous carriers (Parteck® SLC 500, Neusilin® US2, Syloid® XDP 3050 and Aeroperl® 300 Pharma) and subsequently monitored physical formulation stability over three months by X-ray powder diffraction. The selected drugs showed clear differences in their estimated critical pore diameters, whereas a temperature dependence was barely relevant for pharmaceutical storage conditions. Superior stability was noted for the formulations containing benzamide in line with its predicted relatively large critical pore diameter of 29.5 nm. Contrarily, impaired physical stability depending on drug loading was observed in the case of haloperidol representing a compound with a rather small critical pore diameter (8.4 nm). These findings confirm the importance of estimating the critical pore diameter, especially for poor glass-forming drugs.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Kein Vorschaubild vorhanden
    Publikation
    Machine Estimation of Drug Melting Properties and Influence on Solubility Prediction
    (American Chemical Society, 04.06.2020) Wyttenbach, Nicole; Niederquell, Andreas; Kuentz, Martin
    There has been much recent interest in machine learning (ML) and molecular quantitative structure property relationships (QSPR). The present research evaluated modern ML-based methods implemented in commercial software (COSMOquick and Molecular Modeling Pro), compared to a classical group contribution approach (Joback and Reid method), to estimate melting points and enthalpy of fusion values. A broad data set of market compounds was gathered from the literature, together with new data measured by differential scanning calorimetry for drug candidates. The highest prediction accuracy was achieved by QSPR using stochastic gradient boosting. The model deviations were discussed, particularly the implications on thermodynamic solubility modeling, as this typically requires estimation of both melting point and enthalpy of fusion. The results suggested that despite considerable advancement in prediction accuracy, there are still limitations especially with complex drug candidates. It is recommended that in such cases, melting properties obtained in silico should be used carefully as input data for thermodynamic solubility modeling. Future research will show how the prediction limits of thermophysical drug properties can be further advanced by even larger data sets and other ML algorithms or also by using molecular simulations.
    01A - Beitrag in wissenschaftlicher Zeitschrift