Stereochemical analysis of N-cyclohexylidene-N-(1-phenylethyl)amine derivatives

The configurational properties of a series of cyclohexylidene imines are discussed on the basis of their 1H, 13C and 15N NMR spectral data.     

Ultra-high-speed liquid chromatography combined with mass spectrometry detection analytical methods for the determination of nitrosamine drug substance-related impurities

In the present study, five simple, feasible, and sensitive Ultra-high-speed liquid chromatography combined with mass spectrometry detection methods, using electrospray ionization are proposed. These methods were developed and validated for the determination of four different nitrosamine drug substance-related impurities—N-nitrosoacebutolol, N-nitrosobisoprolol, N-nitrosometoprolol, and N-nitrososotalol—in five beta blockers active pharmaceutical ingredients—acebutolol HCl, bisoprolol fumarate, metoprolol tartrate, metoprolol succinate, and sotalol HCl. The proposed methods were validated as per regulatory guidelines. Acquity HSS T3 (3.0 × 100 mm, 1.8 μm) column and formic acid 0.1% in water combined with methanol or acetonitrile were used for chromatographic separation in all methods. The limit of detection and the limit of quantification were found to be in the range of 0.02–1.2 and 2–20 parts per billion, respectively. The accuracy and precision of the five methods have been demonstrated in the working range of each one, giving values of recovery within the range of 64.1%–113.3%, and the regression coefficients (R) were found to be in the range of 0.9978–0.9999. These methods could be used for controlling nitrosamine drug substance-related impurities content for beta blockers drug substances batches manufactured at Moehs group.     

Expanded Conformations of Monomeric Tau Initiate Its Amyloidogenesis**

Understanding early amyloidogenesis is key to rationally develop therapeutic strategies. Tau protein forms well-characterized pathological deposits but its aggregation mechanism is still poorly understood. Using single-molecule force spectroscopy based on a mechanical protection strategy, we studied the conformational landscape of the monomeric tau repeat domain (tau-RD_244-368). We found two sets of conformational states, whose frequency is influenced by mutations and the chemical context. While pathological mutations Δ280K and P301L and a pro-amyloidogenic milieu favored expanded conformations and destabilized local structures, an anti-amyloidogenic environment promoted a compact ensemble, including a conformer whose topology might mask two amyloidogenic segments. Our results reveal that to initiate aggregation, monomeric tau-RD_244-368 decreases its polymorphism adopting expanded conformations. This could account for the distinct structures found in vitro and across tauopathies.     

On some properties of the entropy of a system containing a black hole

We show that the entropy of a system constituted by a massive Schwarzschild black hole in stable thermal equilibrium with black body radiation is superadditive in Landsberg's sense. Furthermore, we comment on some consequences arising from the negative character of the heat capacity of that system.     

Aqueous amphiphilic drug (amitriptyline hydrochloride)-bile salt mixtures at different temperatures

The formation of mixed micelles built of 7,12-dioxolithocholic and the following hydrophobic bile acids was examined by conductometric method: cholic (C), deoxycholic (D), chenodeoxycholic (CD), 12-oxolithocholic (12-oxoL), 7-oxolithocholic (7-oxoL), ursodeoxycholic (UD) and hiodeoxycholic (HD). Interaction parameter (β) in the studied binary mixed micelles had negative value, suggesting synergism between micelle building units. Based on β value, the hydrophobic bile acids formed two groups: group I (C, D and CD) and group II (12-oxoL, 7-oxoL, UD and HD). Bile acids from group II had more negative β values than bile acids from group I. Also, bile acids from group II formed intermolecular hydrogen bonds in aggregates with both smaller (2) and higher (4) aggregation numbers, according to the analysis of their stereochemical (conformational) structures and possible structures of mixed micelles built of these bile acids and 7,12-dioxolithocholic acid. Haemolytic potential and partition coefficient of nitrazepam were higher in mixed micelles built of the more hydrophobic bile acids (C, D, CD) and 7,12-dioxolithocholic acid than in micelles built only of 7,12-dioxolithocholic acid. On the other hand, these mixed micelles still had lower values of haemolytic potential than micelles built of C, D or CD. The mixed micelles that included bile acids: 12-oxoL, 7-oxoL, UD or HD did not significantly differ from the micelles of 7,12-dioxolithocholic acid, observing the values of their haemolytic potential.     

New green synthesis and formulations of acyclovir prodrugs

Different green synthesis of alkyl esters of acyclovir (acyclovir prodrugs) is described. Hexanoic, decanoic, dodecanoic and tetradecanoic acyclovir esters were synthesized reacting acyclovir and the respective acid anhydride in dimethyl sulfoxide (DMSO), in solvents from renewable sources and without solvent (T=30 °C). Yields in prodrugs after 10 min of reaction were >95% using DMSO as solvent. The purification methodology was very simple, shorter and greener than previously described. The biosolvent, N,N-dimethylamide of decanoic acid, let us to obtain >95% yield at 24 h. This oily biosolvent is not dermotoxic and the reaction crude can directly be used in topic formulations. Syntheses without solvent proceeded successfully for acyclovir esters. Indeed, dodecanoate and tetradecanoate yielding >98% conversion of reactants in 30 min. In spite of requiring mild temperature (65 °C), substrate molar ratios were lowered to 1 : 1, thus conducing to a more efficient use of raw materials. The synthetic procedures were scaled up to a 300 g batch (yield 98-99% isolated ester). These esters can be used as acyclovir prodrugs in topic formulations. The esters release from an oil/water micro-emulsion and a hydrogel formulation were tested with good results.     

The through-space transmission of 13C19F coupling constants via an intermediate bond: A polarization propagator analysis

Inner projections of the polarization propagator were used to study the indirect through-space transmission of the Fermi contact term of CF couplings via a CX (X = F, H) intermediate bond. When X = H a large capability for transmitting this component is observed. But for X = F a notable inhibition of this transmission mechanism is observed. The role of the fluorine lone pairs in this behaviour is discussed.