Kuentz, Martin

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Martin
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Kuentz, Martin

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  • Publikation
    New prediction methods for solubility parameters based on molecular sigma profiles using pharmaceutical materials
    (Bioinfo Publications, 07/2018) Niederquell, Andreas; Wyttenbach, Nicole; Kuentz, Martin [in: International Journal of Pharmaceuticals]
    Solubility parameters have been applied extensively in the chemical and pharmaceutical sciences. Particularly attractive is calculation of solubility parameters based on chemical structure and recently, new in silico methods have been proposed. Thus, screening charge densities of molecular surfaces (i.e. so-called σ-profiles) are used by the conductor-like screening model for real solvents (COSMO-RS) and can be employed in a quantitative structure property relationship (QSPR) to predict solubility parameters. In the current study, it was aimed to compare both in silico methods with an experimental dataset of pharmaceutical compounds, which was complemented with own measurements by inverse gas chromatography. An initial evaluation of the total solubility parameters of reference solvents resulted in excellent predictions (observed versus predicted values) with R2 of 0.855 (COSMO-RS) and 0.945 (QSPR). The subsequent main study of pharmaceutical compounds exhibited R2 values of 0.701 (COSMO-RS) and 0.717 (QSPR). The comparatively lower prediction was to some extent due to the solid state of pharmaceuticals with known conceptual limitations of the solubility parameter and possible experimental bias. Total solubility parameters were also estimated by classical group contribution methods, which had comparatively lower prediction power. Therefore, the new in silico methods are highly promising for pharmaceutical applications.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Publikation
    Interactions of dimethylaminoethyl methacrylate copolymer with non-acidic drugs demonstrated high solubilization in vitro and pronounced sustained release
    (Elsevier, 04/2018) Saal, Wiebke; Wyttenbach, Nicole; Alsenz, Jochem; Kuentz, Martin [in: European Journal of Pharmaceutics and Biopharmaceutics]
    Recent work demonstrated remarkable solubilization effects of methacrylate-copolymer Eudragit EPO (EPO) not only with acidic drugs but interestingly also with poorly soluble basic compounds. The current work studied EPO-mediated solubilization effects first in vitro using felodipine (FLP) and tamoxifen (TMX) as model compounds. EPO-containing solutions were subsequently compared in a rat pharmacokinetic study against reference solutions and suspensions. Surprisingly, solution formulations with EPO did not result in an increased relative oral bioavailability. Exposure was reduced for both drugs and plasma-profiles of the EPO solutions showed a delayed and lower maximum plasma concentration compared to the reference formulations. This sustained in vivo release was likely due to combined effects of strong drug-polymer interactions and pH-dependent precipitation of the polymer in the rat intestine. Remarkable was that in vitro drug-polymer coprecipitates did not reveal crystalline drug by polarized light microscopy. Thus, such a formulation approach provides a rather simple opportunity to modify drug release in vivo. However, this may be rather an approach for preclinical formulations, if high peak-to-trough ratios of plasma levels are problematic regarding adverse effects related to Cmax or if plasma concentrations drop too fast below required pharmacological concentrations
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Publikation
    Glass-forming ability of compounds in marketed amorphous drug products
    (Elsevier, 03/2017) Wyttenbach, Nicole; Kuentz, Martin [in: European Journal of Pharmaceutics and Biopharmaceutics]
    This note is about the glass-forming ability (GFA) of drugs marketed as amorphous solid dispersions or as pure amorphous compounds. A thermoanalytical method was complemented with an in silico study, which made use of molecular properties that were identified earlier as being relevant for GFA. Thus, molar volume together with effective numbers of torsional bonds and hydrogen bonding were used to map drugs that are as amorphous products on the market either as solid dispersion of without co-processed carrier as amorphous drug in a solid dosage form. Differential scanning calorimetry experiments showed that most compounds were stable glass formers (GFs) (class III) followed by so-called unstable GFs (class II) and finally, only vemurafenib was found in class I with increased crystallization propensity. The in silico results, however showed that all drugs were either clearly in the chemical space expected for GFs or they were borderline to the region that holds for high crystallization tendency. Interestingly, the pure amorphous compounds scattered in a very confined region of the molecular predictors. These findings can guide amorphous product development of future drug candidates. Based on the compound location in the given chemical space, amorphous formulation opportunities can be balanced against the risks of physical instability upon storage.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Publikation
    Can we estimate the critical micelle concentration of amphiphilic drug bases from molecular connectivity indices?
    (Informa, 2017) Saal, Wiebke; Wyttenbach, Nicole; Alsenz, Jochem; Kuentz, Martin [in: Pharmaceutical Development and Technology]
    Self-aggregation of drugs is since many years an important topic in the pharmaceutical sciences. Drugs can aggregate similar to surfactants and thereby exhibit a critical micelle concentration (CMC). The present work focused on amphiphilic drug bases and it was aimed to predict log(CMC) based on chemical structure alone. A dataset of 35 compounds was gathered mostly form the literature and complemented with own measurements based on ultrasonic resonator technology. The hydrophilic–lipophilic balance (HLB) values of the protonated bases were calculated and provided a range of 22.9–27.4. Based on a hypothesis from surfactant sciences, it was tried to predict log(CMC) with connectivity and shape indices as well as molecular dipole moment. A fairly good model was obtained using the Randix index (RI), 3 D Wiener number (WN) and molecular dipole moment (DM) (R2 = 0.824). Interestingly, a simple linear regression of log(CMC) with the Randic index alone, resulted in an acceptable model (R2 = 0.755). The present work should help with early identification of drug bases that exhibit surfactant-like behavior and an estimation of log(CMC) values is proposed. An improved understanding of drug aggregation and prediction of log(CMC) helps to better cope with physical consequences like, for example, “anomalous” drug solubility in drug discovery and development.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Publikation
    A Systematic Study of Molecular Interactions of Anionic Drugs with a Dimethylaminoethyl Methacrylate Copolymer Regarding Solubility Enhancement
    (American Chemical Society, 2017) Kirchmeyer, Wiebke; Ross, Alfred; Wyttenbach, Nicole; Alsenz, Jochem; Kuentz, Martin [in: Molecular Pharmaceutics]
    The methacrylate-copolymer Eudragit EPO (EPO) has raised interest in solubility enhancement of anionic drugs. Effects on aqueous drug solubility at rather low polymer concentrations are barely known despite their importance upon dissolution and dilution of oral dosage forms. We provide evidence for substantial enhancement (factor 4–230) of aqueous solubility of poorly water-soluble anionic drugs induced by low (0.1–5% (w/w)) concentration of EPO for a panel of seven acidic crystalline drugs. Diffusion data (determined by 1H nuclear magnetic resonance spectroscopy) indicate that the solubility increasing effect monitored by quantitative ultraperformance liquid chromatography was caused primarily by molecular API polymer interactions in the bulk liquid phase. Residual solid API remained unaltered as tested by X-ray powder diffraction. The solubility enhancement (SE) revealed a significant rank correlation (rSpearman = −0.83) with rDiffAPI, where SE and rDiffAPI are defined ratios of solubility and diffusion coefficient in the presence and absence of EPO. SE decreased in the order of indomethacin, mefenamic acid, warfarin, piroxicam, furosemide, bezafibrate, and tolbutamide. The solubilizing effect was attributed to both ionic and hydrophobic interactions between drugs and EPO. The excellent solubilizing properties of EPO are highly promising for pharmaceutical development, and the data set provides first steps toward an understanding of drug–excipient interaction mechanisms.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Publikation
    Unexpected solubility enhancement of drug bases in presence of a dimethylaminoethyl methacrylate copolymer
    (American Chemical Society, 2017) Saal, Wiebke; Ross, Alfred; Wyttenbach, Nicole; Alsenz, Jochem; Kuentz, Martin [in: Molecular Pharmaceutics]
    The methacrylate copolymer Eudragit EPO (EPO) has previously shown to greatly enhance solubilization of acidic drugs via ionic interactions and by multiple hydrophobic contacts with polymeric side chains. The latter type of interaction could also play a role for solubilization of other compounds than acids. The aim of this study was therefore to investigate the solubility of six poorly soluble bases in presence and absence of EPO by quantitative ultrapressure liquid chromatography with concomitant X-ray powder diffraction analysis of the solid state. For a better mechanistic understanding, spectra and diffusion data were obtained by 1H nuclear magnetic resonance (NMR) spectroscopy. Unexpected high solubility enhancement (up to 360-fold) was evidenced in the presence of EPO despite the fact that bases and polymer were both carrying positive charges. This exceptional and unexpected solubilization was not due to a change in the crystalline solid state. NMR spectra and measured diffusion coefficients indicated both strong drug–polymer interactions in the bulk solution, and diffusion data suggested conformational changes of the polymer in solution. Such conformational changes may have increased the accessibility and extent of hydrophobic contacts thereby leading to increased overall molecular interactions. These initially surprising solubilization results demonstrate that excipient selection should not be based solely on simple considerations of, for example, opposite charges of drug and excipient, but it requires a more refined molecular view. Different solution NMR techniques are especially promising tools to gain such mechanistic insights.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Publikation
    The quest for exceptional drug solubilization in diluted surfactant solutions and consideration of residual solid state
    (Elsevier, 2017) Saal, Wiebke; Alsenz, Jochem; Wyttenbach, Nicole; Kuentz, Martin [in: European Journal of Pharmaceutical Sciences]
    Solubility screening in different surfactant solutions is an important part of pharmaceutical profiling. A particular interest is in low surfactant concentrations that mimic the dilution of an oral dosage form. Despite of intensive previous research on solubilization in micelles, there is only limited data available at low surfactant concentrations and generally missing is a physical state analysis of the residual solid. The present work therefore studied 13 model drugs in 6 different oral surfactant solutions (0.5%, w/w) by concomitant X-ray diffraction (XRPD) analysis to consider effects on solvent-mediated phase transformations. A particular aspect was potential occurrence of exceptionally high drug solubilization. As a result, general solubilization correlations were observed especially between surfactants that share chemical similarity. Exceptional solubility enhancement of several hundred-fold was evidenced in case of sodium dodecyl sulfate solutions with dipyridamole and progesterone. Furthermore, carbamazepine and testosterone showed surfactant-type dependent hydrate formation. The present results are of practical relevance for an optimization of surfactant screenings in preformulation and early development and provide a basis for mechanistic modeling of surfactant effects on solubilization and solid state modifications.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Publikation
    Miniaturized X-ray powder diffraction assay (MixRay) for quantitative kinetic analysis of solvent-mediated phase transformations in pharmaceutics
    (Elsevier, 30.11.2016) Kirchmeyer, Wiebke; Wyttenbach, Nicole; Alsenz, Jochem; Kuentz, Martin; Grassmann, Olaf [in: Journal of Pharmaceutical and Biomedical Analysis]
    Many pharmaceutical compounds exhibit polymorphism, which may result in solvent-mediated phase transformations. Since the polymorphic form has an essential influence on physicochemical characteristics such as solubility or dissolution rate, it is crucial to know the exact polymorphic composition of a drug throughout pharmaceutical development. This study addressed the need to perform quantitative X-ray analysis of polymorphic mixtures on a 96-well scale (MixRay). A calibration of polymorphic mixtures (anhydrate and hydrate) was performed with three model drugs, caffeine, piroxicam, and testosterone, and linear correlations were obtained for all compounds. The MixRay approach for piroxicam was applied to a solubility and residual solid screening assay (SORESOS) to quantify the amount of hydrate and anhydrate corresponding to kinetic bulk concentrations. Changes in these drug concentrations correlated well with the kinetic changes in the residual solid. The influence of excipients on the solid state and kinetic concentrations of piroxicam was also studied. Excipients strongly affected polymorphic transformation kinetics of piroxicam and concentrations after 24h depended on the excipient used. The new calibration X-ray method combined with bulk concentration analysis provides a valuable tool for both pharmaceutical profiling and early formulation development.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Publikation
    Theoretical Considerations of the Prigogine–Defay Ratio with Regard to the Glass-Forming Ability of Drugs from Undercooled Melts
    (American Chemical Society, 2016) Wyttenbach, Nicole; Kirchmeyer, Wiebke; Alsenz, Jochem; Kuentz, Martin [in: Molecular Pharmaceutics]
    Drug behavior in undercooled melts is highly important for pharmaceutics with regard to amorphous solid dispersions, and therefore, categories were recently introduced that differentiate glass formers (GFs) from other drugs that are nonglass formers (nGFs). The present study is based on the assumption that molecular properties relevant for the so-called Prigogine-Defay (PD) ratio would be indicative of a drug's glass-forming ability. The PD ratio depends in theory on the entropy of fusion and molar volume. Experimental data were gathered from a broad set of pharmaceutical compounds (n = 54) using differential scanning calorimetry. The obtained entropy of fusion and molar volume were indeed found to significantly discriminate GFs from nGFs. In a next step, the entropy of fusion was predicted by different in silico methods. A first group contribution method provided rather unreliable estimates for the entropy of fusion, while an alternative in silico approach seemed more promising for drug categorization. Thus, a significant discrimination model employed molar volume, a so-called effective hydrogen bond number, and effective number of torsional bonds (or torsional units) to categorize GFs and nGFs (p ≤ 0.0000). The results led to new insights into drug vitrification and to practical rules of thumb. The latter may serve as guidance in pharmaceutical profiling and early formulation development with respect to amorphous drug formulations.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Publikation
    Influence of Excipients on Solvent-Mediated Hydrate Formation of Piroxicam Studied by Dynamic Imaging and Fractal Analysis
    (American Chemical Society, 2015) Kuentz, Martin; Kirchmeyer, Wiebke; Wyttenbach, Nicole; Alsenz, Jochem [in: Crystal Growth & Design]
    01A - Beitrag in wissenschaftlicher Zeitschrift