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Ergebnisse nach Hochschule und Institut
Publikation A Relative Permittivity Approach for Fast Drug Solubility Screening of Solvents and Excipients in Lipid-Based Delivery(Elsevier, 2019) Niederquell, Andreas; Kuentz, MartinDrug solubility screening in solvents and lipids is central for the development of lipid-based formulations (LBFs), and any guidance to reduce the experimental workload would be highly desirable. Solubility parameters are interesting as they can be predicted in silico for a drug but they are hardly predictable for complex lipids. This paper uses a new approach to convert an in silico drug solubility parameter to an estimated relative permittivity, εr. Diverse solvents and lipid-based excipients were then experimentally tested for εr and solubility using fenofibrate as model. The typical excipients and solvents used in LBFs showed an εr range of about 2-24, and good solubility of fenofibrate was indeed evidenced in vicinity of its estimated relative permittivity 13.2 ± 2.7. Mixtures of promising excipients were studied subsequently, and the obtained εr was predictable based on the known values of the individual components. The novel permittivity approach has demonstrated its usefulness, it has much potential in early development for ranking of suitable excipients, and it gives an initial orientation to design formulations. Future research may clarify further opportunities and limits of the novel approach for LBFs.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Partial Solvation Parameters of Drugs as a New Thermodynamic Tool for Pharmaceutics(Elsevier, 04.01.2019) Niederquell, Andreas; Kuentz, MartinPartial solvation parameters (PSP) have much in common with the Hansen solubility parameter or with a linear solvation energy relationship (LSER), but there are advantages based on the sound thermodynamic basis. It is, therefore, surprising that PSP has so far not been harnessed in pharmaceutics for the selection of excipients or property estimation of formulations and their components. This work introduces PSP calculation for drugs, where the raw data were obtained from inverse gas chromatography. It was shown that only a few probe gases were needed to get reasonable estimates of the drug PSPs. Interestingly, an alternative calculation of LSER parameters in silico did not reflect the experimentally obtained activity coefficients for all probe gases as well, which was attributed to the complexity of the drug structures. The experimental PSPs were proven to be helpful in predicting drug solubility in various solvents and the PSP framework allowed calculation of the different surface energy contributions. A specific benefit of PSP is that parameters can be readily converted to either classical solubility or LSER parameters. Therefore, PSP is not just about a new definition of solvatochromic parameters, but the underlying thermodynamics provides a unified approach, which holds much promise for broad applications in pharmaceutics.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Biorelevant drug solubility enhancement modeled by a linear solvation energy relationship(Elsevier, 2017) Niederquell, Andreas; Kuentz, MartinIt is for the pharmaceutical sciences of vital importance to understand how drugs are solubilized in biorelevant media. However, the complexity of fasted state simulated intestinal fluid (FaSSIF) has so far hampered adequate solubility modeling. The present study focuses on apparently neutral compounds at physiological pH and a linear free energy relationship is introduced for biorelevant drug solubilization. Based on literature data of 40 compounds, the Abraham solvation descriptors were calculated from chemical structure to then predict the ratio of solubility enhancement log(SE) in FaSSIF compared to aqueous buffer solubility at pH 6.5. A suitable model was obtained with R2 of 0.810 and notable were especially the positive effect of McGowan's characteristic volume and the negative effect of drug basicity. A negative influence on log(SE) was further evidenced for dipolarity/polarizability and for the excess molar refraction descriptor. A positive solubilization effect was obtained for drug acidity and hence the tendency for proton donation, which was likely due to the different proton-accepting moieties of taurocholic acid and lecithin that are both present in the mixed colloids of FaSSIF. Overall, an improved understanding was achieved regarding the molecular features that are driving drug solubilization in biorelevant media.01A - Beitrag in wissenschaftlicher Zeitschrift