Kuentz, Martin

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Kuentz
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Martin
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Kuentz, Martin

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2016 - 20182
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Autor:in: Wyttenbach, Nicole × Thema: in silico prediction ×

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  • Vorschaubild nicht verfügbar
    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
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    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