A Validated Chiral LC Method for the Enantiomeric Separation of Nateglinide and the Quantitative Determination of Its l-Enantiomer

A simple and accurate chiral liquid chromatographic method was developed for the enantiomeric purity determination of d-nateglinide and quantitative determination of l-nateglinide in bulk drug samples. Good resolution (R _s  > 6.0) between d-enantiomer and l-enantiomer of nateglinide were achieved with Chiralpak AD-H (250 × 4.6 mm, 5 μm particle size) column using hexane and ethanol (90:10 v/v) as mobile phase at 25 °C temperature. Flow rate was kept as 1.0 mL min^?1 and elution was monitored at 210 nm. The effects of the mobile phase composition, the flow rate and the temperature on the chromatographic separation were investigated. Developed method is capable to detect (LOD) and quantitate (LOQ) l-nateglinide to the levels of 0.3 and 1.0 μg mL^?1 respectively, for 10 μL injection volume. The percentage RSD of the peak area of six replicate injections of l-nateglinide at LOQ concentration was 5.2. The percentage recoveries of l-nateglinide from d-nateglinide ranged from 97.9 to 99.7. The test solution and mobile phase was found to be stable up to 24 h after preparation. The developed method was validated with respect to LOD, LOQ, precision, linearity, accuracy, robustness and ruggedness.     

Chow-Witt groups and Grothendieck-Witt groups of regular schemes

Let A be a noetherian commutative Z[1/2]-algebra of Krull dimension d and let P be a projective A-module of rank d. We use derived Grothendieck-Witt groups and Euler classes to detect some obstructions for P to split off a free factor of rank one. If d?3, we show that the vanishing of its Euler class in the corresponding Grothendieck-Witt group is a necessary and sufficient condition for P to have a free factor of rank one. If d is odd, we also get some results in that direction. If A is regular, we show that the Chow-Witt groups defined by Morel and Barge appear naturally as some homology groups of a Gersten-type complex in Grothendieck-Witt theory. From this, we deduce that if d=3 then the vanishing of the Euler class of P in the corresponding Chow-Witt group is a necessary and sufficient condition for P to have a free factor of rank one.     

A disaster queue with Markovian arrivals and impatient customers

We consider a single server queueing system in which arrivals occur according to a Markovian arrival process. The system is subject to disastrous failures at which times all customers in the system are lost. Arrivals occurring during the time the system undergoes repair are stored in a buffer of finite capacity. These customers can become impatient after waiting a random amount of time and leave the system. However, these customers do not become impatient once the system becomes operable. When the system is operable, there is no limit on the number of customers who can be admitted. The structure of this queueing model is of GI/M/1-type that has been extensively studied by Neuts and others. The model is analyzed in steady state by exploiting the special nature of this type queueing model. A number of useful performance measures along with some illustrative examples are reported.     

New experiments on HNCSe and HCNSe radical cations

Dissociative ionization of the selenourea Se=C(NH(2))(2) (2) conveniently generates beams of pure isocyanoselenic acid radical cations. The HNCSe(.+) connectivity is established by collisional activation and by associative ion-molecule reactions with dimethyl sulfide or nitric oxide using a large-scale hybrid mass spectrometer.     

Short-time behavior of mixed diffusion-barrier controlled adsorption

This paper focuses on the short-time adsorption kinetics of nonionic surfactants onto water/air surfaces, analyzed in the context of the mixed diffusion-barrier controlled adsorption modeling framework. Specifically, we reconcile the apparent contradiction between theoretical prediction and experimental observations on the adsorption kinetics mechanism at short times: while the mixed diffusion-barrier controlled model predicts a barrier-controlled adsorption, as well as the impossibility of a diffusion-controlled adsorption at asymptotic short times, the short-time experimental dynamic surface tension (DST) behavior of many nonionic surfactants has been interpreted to result from diffusion-controlled adsorption at asymptotic short times. This is because the short-time experimental DST of these surfactants displays a t variation, which is considered as a fingerprint for the existence of diffusion-controlled adsorption, based on the short-time asymptotic behavior of the diffusion-controlled adsorption model. As a result of this interpretation, the fundamental physical nature of the energy barrier has been proposed to be associated with high surfactant surface concentrations. In this paper, we derive a new nonasymptotic short-time formalism of the mixed diffusion-barrier controlled model to describe surfactant adsorption onto a spherical pendant-bubble surface, including determining the ranges of time and surfactant surface concentration values where the short-time formalism is applicable. Based on this formalism, we find that one can expect to observe an apparent t variation of the DST at short times even for the mixed diffusion-barrier controlled adsorption model. We analyze the consequence of this finding by re-evaluating the existing notions of the energy barrier. We conclude that the energy barrier is associated with the adsorption of a single surfactant molecule onto a clean surface.     

Total syntheses of the highly potent anti-cancer polyacetylenes, (S)-18-hydroxyminquartynoic acid, (S)-minquartynoic acid and (E)-15,16-dihydrominquartynoic acid

The total syntheses of three polyacetylenic natural products, (S)-18-hydroxyminquartynoic acid (1), (S)-minquartynoic acid (2) and (E)-15,16-dihydrominquartynoic acid (3), has been achieved. The Cadiot-Chodkiewicz cross-coupling reaction was used as the key step for the construction of tetrayne and triyne units.     

Synthesis of novel halogenated cryptolepine analogues

Cryptolepine (5‐N‐methyl‐10‐H‐indolo[3,2‐b]quinoline) is an indoloquinoline alkaloid present in the roots of Cryptolepis Sanguinolenta. In its hydrochloride form the alkaloid presents a number of bioactivities. The alkaloid also has cytotoxic properties that are likely to be due to its abilities to intercalate into DNA and inhibit the enzyme topoisomerase II, as well as the synthesis of DNA. In this research project five novel analogues of cryptolepine were chosen for synthesis.     

A practical synthesis of 5‐(4′‐methylbiphenyl‐2‐yl)‐1H‐tetrazole

Practical synthesis of 5‐(4′‐methylbiphenyl‐2‐yl)‐1H‐tetrazole, key intermediate in several angiotensin II receptor antagonists from 2‐fluorobenzonitrile in excellent yields and very high purity is described.     

Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations

The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development culminating in a marketing approval. Although the bioanalytical procedure(s) originally developed during the discovery stage may not necessarily be fit to support the drug development scenario, they may be suitably modified and validated, as deemed necessary. Several reviews have appeared over the years describing analytical approaches including various techniques, detection systems, automation tools that are available for an effective separation, enhanced selectivity and sensitivity for quantitation of many analytes. The intention of this review is to cover various key areas where analytical method development becomes necessary during different stages of drug discovery research and development process. The key areas covered in this article with relevant case studies include: (a) simultaneous assay for parent compound and metabolites that are purported to display pharmacological activity; (b) bioanalytical procedures for determination of multiple drugs in combating a disease; (c) analytical measurement of chirality aspects in the pharmacokinetics, metabolism and biotransformation investigations; (d) drug monitoring for therapeutic benefits and/or occupational hazard; (e) analysis of drugs from complex and/or less frequently used matrices; (f) analytical determination during in vitro experiments (metabolism and permeability related) and in situ intestinal perfusion experiments; (g) determination of a major metabolite as a surrogate for the parent molecule; (h) analytical approaches for universal determination of CYP450 probe substrates and metabolites; (i) analytical applicability to prodrug evaluations-simultaneous determination of prodrug, parent and metabolites; (j) quantitative determination of parent compound and/or phase II metabolite(s) via direct or indirect approaches; (k) applicability in analysis of multiple compounds in select disease areas and/or in clinically important drug-drug interaction studies. A tabular representation of select examples of analysis is provided covering areas of separation conditions, validation aspects and applicable conclusion. A limited discussion is provided on relevant aspects of the need for developing bioanalytical procedures for speedy drug discovery and development. Additionally, some key elements such as internal standard selection, likely issues of mass detection, matrix effect, chiral aspects etc. are provided for consideration during method development.     

Propagation of a cleavage crack front across a field of persistent grain boundaries

The nonuniform propagation of a cleavage front across a field of persistent grain boundaries is analyzed. When a cleavage crack advances in a field of grains, some of the grain boundaries cannot be directly broken through, which interrupts the crack growth process. When the crack front bypasses such persistent grain boundaries (PGB), the overall crack growth driving force must be increased so that the local stress intensity can overcome the local fracture resistance. A theoretical model is developed based on the R-curve analysis. A closed-form expression of the critical stress intensity factor is given as a function of the line content of PGB.