Niederquell, Andreas
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Niederquell, Andreas
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- PublikationUltra-sub-stoichiometric “Dynamic” Bioconjugation Reduces Viscosity by Disrupting Immunoglobulin Oligomerization(American Chemical Society, 09.09.2019) Gong, Yuhui; Niederquell, Andreas; Kuentz, Martin [in: Biomacromolecules]Monoclonal antibodies (mAb) are a major focus of the pharmaceutical industry, and polyclonal immunoglobulin G (IgG) therapy is used to treat a wide variety of health conditions. As some individuals require mAb/IgG therapy their entire life, there is currently a great desire to formulate antibodies for bolus injection rather than infusion. However, to achieve the required doses, very concentrated antibody solutions may be required. Unfortunately, mAb/IgG self-assembly at high concentration can produce an unacceptably high viscosity for injection. To address this challenge, this study expands the concept of "dynamic covalent chemistry" to "dynamic bioconjugation" in order to reduce viscosity by interfering with antibody-antibody interactions. Ultra-sub-stoichiometric amounts of dynamic PEGylation agents (down to the nanomolar) significantly reduced the viscosity of concentrated antibody solutions by interfering with oligomerization.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationPartial Solvation Parameters of Drugs as a New Thermodynamic Tool for Pharmaceutics(Elsevier, 04.01.2019) Niederquell, Andreas; Kuentz, Martin [in: Pharmaceutics]Partial 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 Zeitschrift
- PublikationA Relative Permittivity Approach for Fast Drug Solubility Screening of Solvents and Excipients in Lipid-Based Delivery(Elsevier, 2019) Niederquell, Andreas; Kuentz, Martin [in: Journal of Pharmaceutical Sciences]Drug 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 Zeitschrift
- PublikationNew 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
- PublikationTemperature-Induced Surface Effects on Drug Nanosuspensions(Springer, 02/2018) Aleandri, Simone; Schönenberger, Monica; Niederquell, Andreas; Kuentz, Martin [in: Pharmaceutical Research]Purpose The trial-and-error approach is still predominantly used in pharmaceutical development of nanosuspensions. Physicochemical dispersion stability is a primary focus and therefore, various analytical bulk methods are commonly employed. Clearly less attention is directed to surface changes of nanoparticles even though such interface effects can be of pharmaceutical relevance. Such potential effects in drug nanosuspensions were to be studied for temperatures of 25 and 37°C by using complementary surface analytical methods. Methods Atomic force microscopy, inverse gas chromatography and UV surface dissolution imaging were used together for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Fenofibrate and bezafibrate were selected as model drugs in presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively. Results It was demonstrated that in case of bezafibrate nanosuspension, a surface modification occurred at 37°C compared to 25°C, which notably affected dissolution rate. By contrast, no similar effect was observed in case of fenofibrate nanoparticles. Conclusions The combined usage of analytical surface methods provides the basis for a better understanding of phenomena that take place on drug surfaces. Such understanding is of importance for pharmaceutical development to achieve desirable quality attributes of nanosuspensions.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationA diffusing wave spectroscopy study of pharmaceutical emulsions for physical stability assessment(Elsevier, 2017) Niederquell, Andreas; Machado, Alexandra H.E.; Kuentz, Martin [in: International Journal of Pharmaceutics]Emulsions are broadly used in pharmaceutics either as intermediate products or as final dosage forms. Such disperse systems are only kinetically stabilized and therefore early detection of physical instability is highly desirable. This work employed diffusing wave spectroscopy (DWS) to study a series of model emulsions that were categorized, based on their composition, as either “simple” or “complex”. DWS data were compared with results of droplet size imaging, apparent viscosity obtained by microfluidics, and near-infrared (NIR) analytical centrifugation. A mathematical model of the droplet mean square displacement (MSD) was modified by us regarding improved fitting of experimental data. Although the emulsions showed different types of instability like creaming and sedimentation, a good rank correlation was found between the DWS parameters and results from the comparative stability methods. Our findings indicate that DWS provides a highly attractive method for stability analysis of pharmaceutical emulsions because it requires only low sample volumes, is rapid and non-invasive. The proposed data modeling provides the means for a better understanding of emulsion microstructure that in turn will help designing quality into pharmaceutical dispersions.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationBiorelevant drug solubility enhancement modeled by a linear solvation energy relationship(Elsevier, 2017) Niederquell, Andreas; Kuentz, Martin [in: Journal of Pharmaceutical Sciences]It 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