Abstract A simple and convenient method was developed for the introduction of a 2,2,2‐trifluoroethoxy group to various aromatic and heteroaromatic systems. The novel process utilizes aromatic chlorides as substrates, and tetrakis(2,2,2‐trifluoroethoxy) borate salt as an inexpensive and readily available fluoroalkoxy source in a palladium‐catalyzed cross‐coupling reaction. The power of the developed methodology was demonstrated in the synthesis of a fluorous derivative of Sildenafil.
The knowledge on human serum albumin (HSA) binding is of utmost importance as it affects pharmacokinetic behavior and bioavailability of drugs. In this article, we report a novel method to screen for ionizable molecules with high HSA binding affinity based on pKa shifts using UV-pH titration. We investigated the HSA binding of 27 drugs and compared the results to experimental data from conventional methods. In most cases, significant shifts (ΔpKa > 0.1) were observed for drugs with high HSA binding, while no change could be detected for low-affinity binders. We showed the pivotal role of ionization centers in the formation of strong interactions between drug and HSA using molecular docking studies. We also verified our findings by testing five modified analogues designed by structural considerations. Significant decreases in their HSA binding proved that the UV-pH titration method combined with an in silico support can be used as a medicinal chemistry tool to assist rational molecular design.
Zusammenfassung: Ziel der Studie war die Pruning der Freisetzung von zwei verschiedenen Antimykotika aus sieben verschiedenen Salbengrundlagen, teils Grundlagen industriell konfektionierter Zubereitungen, teils DAB‐Grundlagen. Die Prüning wurde vergleichend auf isolierter Schweinehaut, über die bereits Erfahrungen anderer Autoren vorliegen, und auf einem selbst entwickelten Lipid‐Agar vorgenommen, der Gelatine, Lecithin, synthetisches Schweineschmalz (Capryl/Caprin‐/Stearinsäure Trigrycerid) und Hornmehl enthäli Als Prüfstanun wurde Trichophyton mentagrophytes 100/25 Hoechst verwendet. Vorläufige Ergebnisse zeigen eine gute Korrelation zwischen den beiden Prüfsystemen. Von zwei geprüften handelsüblichen Antimykotika‐Salben erwies sich ein Präparat als hinsichtlich der Wirkstoffliberation galenisch optimal formuliert; das weitere ließ eine nicht‐optimale Wirkstoffliberation erkennen. Die praktische Bedeutung dieser Befunde wird diskutiert. Summary: Purpose of this study was to test the release of two different antimycotics from seven different ointment bases. The bases were industrial preparations or ointment bases according to DAB (Deutsches Arzneibuch). The tests were made on samples of isolated pig skins, as described previously by other authors, and on a newly developed lipid‐agar, which contains gelatine, lecithin, synthetic pig lard (Caprylic/Capric/Stearic Triglyceride) and hoof powder. Trichophyton mentagrophytes 100/25 Hoechst was used as test strain. The results show a good correlation between the two test‐systems. One of two antimycotic preparations tested showed an optimal drug release, the other one was not satifactory in this respect. The practical use of these results is discussed.
The pharmacokinetics and the relative bioavailability of iron and of folic acid was investigated in a randomized, balanced 2-way cross-over study with 14 healthy male participants. The drugs were given in a combined preparation dragée (Ferro-Folsan) containing 100 mg of ferrous-II-sulfate x 1.5 H2O (CAS 13463-43-9) and 0.85 mg of folic acid (CAS 59-30-3). Other established preparations were used as reference drugs. All subjects had a normal iron body level and were brought to a saturated folic acid level prior to the investigation. After administration of 2 dragées of the test medication and determination of serum iron level until 9 h p.a., a relative bioavailability of 64%, compared to an equal dose of a ferrous-II-sulfate-ascorbic acid reference solution, was calculated. From the serum folate AUC (0-9 h) the relative bioavailability was evaluated with 97% for the oral formulation compared to the i.m. administration. The ratio of the cumulative renal folate excretion in the 0-9 h interval amounted to 76% for the oral compared to the i.m. administration. However, in order to understand this differing result it should be kept in mind that during the first hours following parenteral administration a greater amount of the unchanged compound is renally excreted than after oral dosing. This is presumably based upon the different rate of absorption following both administrations with a steeper absorption phase following the parenteral dose.
