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Publikation Evaluating pediatric and adult simulated fluids solubility. Abraham solvation parameters and multivariate analysis(Springer, 2021) Guimaraes, Mariana; Kuentz, Martin; Vertzoni, Maria; Fotaki, NikolettaPurpose: To understand drug solubilization as a function of age and identify drugs at risk of altered drug solubility in pediatric patients. To assess the discrimination ability of the Abraham solvation parameters and age-related changes in simulated media composition to predict in vitro drug solubility differences between pediatric and adult gastrointestinal conditions by multivariate data analysis. Methods: Differences between drug solubility in pediatric and adult biorelevant media were expressed as a % pediatric-to-adult ratio [Sp/Sa (%)]. Solubility ratios of fourteen poorly water-soluble drugs (2 amphoteric; 4 weak acids; 4 weak bases; 4 neutral compounds) were used in the analysis. Partial Least Squares Regression was based on Abraham solvation parameters and age-related changes in simulated gastrointestinal fluids, as well as their interactions, to predict the pediatric-to-adult solubility ratio. Results: The use of Abraham solvation parameters was useful as a theory-informed set of molecular predictors of drug solubility changes between pediatric and adult simulated gastrointestinal fluids. Our findings suggest that the molecular solvation environment in the fasted gastric state was similar in the pediatric age-groups studied, which led to fewer differences in the pediatric-to-adult solubility ratio. In the intestinal fasted and fed state, there was a high relative contribution of the physiologically relevant surfactants to the alteration of drug solubility in the pediatric simulated conditions compared to the adult ones, which confirms the importance of an age-appropriate composition in biorelevant media. Conclusion: Statistical models based on Abraham solvation parameters were applied mostly to better understand drug solubility differences in adult and pediatric biorelevant media.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Synergistic Computational Modeling Approaches as Team Players in the Game of Solubility Predictions(Elsevier, 17.11.2020) Kuentz, MartinSeveral 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 ZeitschriftPublikation Solubility of 5-aminosalicylic acid in {N-methyl-2-pyrrolidone + ethanol} mixtures at T = (293.2 to 313.2) K(Elsevier, 28.02.2020) Moradi, Milad; Kuentz, MartinThe solubility determination of 5-aminosalicylic acid (mesalazine) in the N-methyl-2-pyrrolidone (NMP)/ethanol mixtures was carried out at T = (293.2 to 313.2) K. The solubility data were represented by the Jouyban-Acree, NRTL and UNIQUAC models. Apparent thermodynamic quantities for mesalazine dissolved in NMP/ethanol mixtures were determined. To discuss solute-solvent interactions in the present system, the activity coefficient values for mesalazine were computed. The results revealed that the solubility increases by addition of NMP and reaches a maximum value at neat NMP which is consistent with the minimum values of both Gibbs free energy of dissolution and mesalazine activity coefficient observed at neat NMP. Moreover, this drug is preferentially solvated by ethanol in ethanol-rich mixtures but preferential solvation by NMP in NMP-rich mixtures is observed.01A - Beitrag in wissenschaftlicher Zeitschrift