Development and validation of a bioanalytical method by LC‐MS/MS for the quantification of the LAFIS 10 – an antimalarial candidate – and its pharmacokinetics first evaluation

A rapid and highly sensitive method by LC‐MS/MS was developed and validated for the quantification of an antimalarial candidate (LAFIS10) in rat plasma using dexamethasone as internal standard (IS). The chromatographic separation was performed with a Poroshell 120 EC‐C₁₈ column. The mobile phase consisted of water (A) and acetonitrile (B), both containing 10 m m of ammonium formate and 0.1% formic acid, delivered in the form of elution gradient. The LAFIS10 was monitored using an electrospray ionization interface operating in the positive mode in multiple reaction monitoring mode, monitoring the transitions 681.47 → 538.2 for LAFIS10 and 393.20 → 355.30 for the IS. The flow rate was 500 μL/min. The column temperature was kept at 40 °C and the injection volume was 2 μL. The lower limit of quantification was of 10 ng/mL and linearity between 10 and 1000 ng/mL was observed, with an R² > 0.99. The accuracy of the method was >90%. The relative standard deviations intra‐ and interday were <8.80 and <6.37%, respectively. The method showed sensitivity, linearity, precision, accuracy and selectivity required to quantify LAFIS 10 in preclinical pharmacokinetic studies according to criteria established by the US Food and Drug Administration and European Medicines Agency. Copyright © 2014 John Wiley & Sons, Ltd.     

Rapid and sensitive ultra‐high‐pressure liquid chromatography method for quantification of antichagasic benznidazole in plasma: application in a preclinical pharmacokinetic study

Benznidazole (BNZ) and nifurtimox are the only drugs available for treating Chagas disease. In this work, we validated a bioanalytical method for the quantification of BNZ in plasma aimed at improving sensitivity and time of analysis compared with the assays already published. Furthermore, we demonstrated the application of the method in a preclinical pharmacokinetic study after administration of a single oral dose of BNZ in Wistar rats. A Waters® Acquity UHPLC system equipped with a UV–vis detector was employed. The method was established using an Acquity® UHPLC HSS SB C₁₈ protected by an Acquity® UHPLC HSS SB C₁₈ VanGuard guard column and detection at 324 nm_. The mobile phase consisted of ultrapure water–acetonitrile (65:35), and elution was isocratic. The mobile phase flow rate was 0.55 mL/min, the volume of injection was 1 μL, and the run time was just 2 min. The samples were kept at 25°C until injection and the column at 45°C for the chromatographic separation. The sample preparation was performed by a rapid protein precipitation with acetonitrile. The linear concentration range was 0.15–20 µg/mL. The pharmacokinetic parameters of BNZ in rats were determined and the method was considered sensitive, fast and suitable for application in pharmacokinetic studies. Copyright © 2014 John Wiley & Sons, Ltd.     

Single Crystal to Single Crystal (SC‐to‐SC) Transformation from a Nonporous to Porous Metal–Organic Framework and Its Application Potential in Gas Adsorption and Suzuki Coupling Reaction through Postmodification

A new amino‐functionalized strontium–carboxylate‐based metal–organic framework (MOF) has been synthesized that undergoes single crystal to single crystal (SC‐to‐SC) transformation upon desolvation. Both structures have been characterized by single‐crystal X‐ray analysis. The desolvated structure shows an interesting 3D porous structure with pendent ?NH₂ groups inside the pore wall, whereas the solvated compound possesses a nonporous structure with DMF molecules on the metal centers. The amino group was postmodified through Schiff base condensation by pyridine‐2‐carboxaldehyde and palladium was anchored on that site. The modified framework has been utilized for the Suzuki cross‐coupling reaction. The compound shows high activity towards the C?C cross‐coupling reaction with good yields and turnover frequencies. Gas adsorption studies showed that the desolvated compound had permanent porosity and was microporous in nature with a BET surface area of 2052 m² g^?1. The material also possesses good CO₂ (8 wt %) and H₂ (1.87 wt %) adsorption capabilities.     

“(Diphosphine)Nickel”‐Catalyzed Negishi Cross‐Coupling: An Experimental and Theoretical Study

The use of a strongly donating “(bis‐dialkylphosphine)Ni” fragment promotes the catalytic coupling of a large range of ArCl and ArZnCl derivatives under mild conditions. Stoichiometric mechanistic investigations and DFT calculations prove that a Ni⁰/Ni^II cycle is operative in this system.     

Redox‐responsive core cross‐linked micelles of poly(ethylene oxide)‐b‐poly(furfuryl methacrylate) by Diels‐Alder reaction for doxorubicin release

Redox‐responsive core cross‐linked (CCL) micelles of poly(ethylene oxide)‐b‐poly(furfuryl methacrylate) (PEO‐b‐PFMA) block copolymers were prepared by the Diels‐Alder click‐type reaction. First, the PEO‐b‐PFMA amphiphilic block copolymer was synthesized by the reversible addition‐fragmentation chain transfer polymerization. The hydrophobic blocks of PFMA were employed to encapsulate the doxorubicin (DOX) drug, and they were cross‐linked using dithiobismaleimidoethane at 60 °C without any catalyst. Under physiological circumstance, the CCL micelles demonstrated the enhanced structural stability of the micelles, whereas dissociation of the micelles took place rapidly through the breaking of disulfide bonds in the cross‐linking linkages under reduction environment. The core‐cross‐linked micelles showed fine spherical distribution with hydrodynamic diameter of 68 ± 2.9  nm. The in vitro drug release profiles presented a slight release of DOX at pH 7.4, while a significant release of DOX was observed at pH 5.0 in the presence of 1,4‐dithiothreitol. MTT assays demonstrated that the block copolymer did not have any practically cytotoxicity against the normal HEK293 cell line while DOX‐loaded CCL micelles exhibited a high antitumor activity towards HepG2 cells. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3741–3750     

DOSY NMR as a tool for predicting optimal conditions for hydrogel formation: The case of a hyperbranched polyglycidol cross‐linked with boronic acids

This article demonstrates the utility of DOSY NMR for the determination of the optimal conditions for the efficient covalent, reversible cross‐linking of macromolecules in water for hydrogel formation. The studied model system was hyperbranched polyglycidol (HbPGL) containing numerous diol groups in peripheral regions and two types of boronic acids, that is, B(OH)₄^? and benzene‐1,4‐boronic diacid, as cross‐linking agents. Diffusion coefficient changes of a polymer in solution, under the influence of various concentrations of cross‐linking agent and pH, which influences the equilibrium of the reaction between boronic acids and diols, were recorded. These data are consistent with the rheological properties, namely the G′_max(ω) of hydrogels prepared under analogous conditions, from more concentrated solutions of HbPGL. This approach appears to be promising as it facilitates avoiding the loss of a large amount of polymer that is necessary for the elaboration of appropriate conditions for network formation in aqueous media. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 2171–2178     

Quantitation of memantine hydrochloride bulk drug and its tablet formulation using proton nuclear magnetic resonance spectrometry

The use of quantitative nuclear magnetic resonance spectrometry for the determination of non‐UV active memantine hydrochloride with relative simplicity and precision has been demonstrated in this study. The method was developed on a 500 MHz NMR instrument and was applied to determination of the drug in a tablet formulation. The analysis was performed by taking caffeine as an internal standard and D₂O as the NMR solvent. The signal of methyl protons of memantine hydrochloride appeared at 0.75 ppm (singlet) relative to the signal of caffeine (internal standard) at 3.13 ppm (singlet). The method was found to be linear (r² = 0.9989) in the drug concentration range of 0.025 to 0.80 mg/ml. The maximum relative standard deviation for accuracy and precision was <2. The limits of detection and quantification were 0.04 and 0.11 mg/ml, respectively. The robustness of the method was revealed by changing nine different parameters. The deviation for each parameter was also within the acceptable limits. The study highlighted possibility of direct determination of memantine hydrochloride in pure form and in its marketed tablet formulation by the use of quantitative NMR, without the need of derivatization, as is the requirement in HPLC studies. Copyright © 2016 John Wiley & Sons, Ltd.     

From Minutes to Years: Predicting Organotrifluoroborate Solvolysis Rates

Organotrifluoroborates solvolyze in water at rates that vary over five orders of magnitude. The negative logarithm of the solvolytic rate constant, pk_(B?F), correlates exceptionally well with the pK_a of the analogous carboxylic acid (R²=0.984). This unforeseen correlation may be of predictive value for several applications including Suzuki–Miyaura cross‐coupling reactions and the design of ¹⁸F‐organotrifluoroborate radioprosthetic groups.     

Catalytic Activity of Cationic and Neutral Silver(I)–XPhos Complexes with Nitrogen Ligands or Tolylsulfonate for Mannich and Aza‐Diels–Alder Coupling Reactions

Cationic and neutral silver(I)–L complexes (L=Buchwald‐type biaryl phosphanes) with nitrogen co‐ligands or organosulfonate counter ions have been synthesised and characterised through their structural and spectroscopic properties. At room temperature, both cationic and neutral silver(I)–L complexes are extremely active catalysts in the promotion of the single and double A³ coupling of terminal (di)alkynes, pyrrolidine and formaldehyde. In addition, the aza‐Diels–Alder two‐ and three‐component coupling reactions of Danishefsky’s diene with an imine or amine and aldehyde are efficiently catalysed by these cationic or neutral silver(I)–L complexes. The solvent influences the catalytic performance due to limited complex solubility or solvent decomposition and reactivity. The isolation of new silver(I)–L complexes with reagents as ligands lends support to mechanistic proposals for such catalytic processes. The activity, stability and metal–distal arene interaction of these silver(I)–L catalysts have been compared with those of analogous cationic gold(I) and copper(I) complexes.