Transport through a correlated polar side-coupled quantum dot transistor in the presence of a magnetic field and dissipation.

Non-equilibrium magneto-transport properties of a quantum dot dimer transistor are studied in the presence of electron-electron and electron-phonon interactions and the interaction of the dimer phonons with the substrate phonon bath that gives rise to dissipation. The entire system is modeled by the Anderson-Holstein-Caldeira-Leggett Hamiltonian where the Caldeira-Leggett term takes care of the damping. The electron-phonon interaction is dealt with the Lang-Firsov transformation and the electron-electron interaction is treated at the mean-field level. The transport problem is studied using the Keldysh non-equilibrium Green function theory and the effects of electron-electron interaction, external magnetic field, electron-phonon interaction and damping on spectral function, tunneling current and differential conductance of the dimer transistor are calculated.

Spin-Hall conductivity and Hall angle in a two-dimensional system with impurities in the presence of spin-orbit interactions.

We investigate the spin-torque-dependent Spin Hall phenomenon in a two-dimensional tight-binding system in the presence of Rashba and Dresselhaus spin-orbit interactions and random static impurities. We employ the Matsubara Green function techniques to calculate the relaxation time caused by the scattering of electrons by impurities. The longitudinal and transverse conductivities are next calculated with the help of the Kubo formalism. We have also calculated the spin Hall angle for the present model and studied its dependence on spin-orbit interactions and impurity strength. Finally, we explore the effect of interplay between the Rashba and Dresselhaus interactions on the spin-Hall effect.

Development and validation of a novel stability-indicating reverse phase HPLC method for the determination of sacubitril-valsartan premix stereoisomers: Cellulose tris(4-methyl benzoate) stationary phase.

A new stability indicating reverse phase HPLC method has been developed and validated as per International Conference on Harmonization guidelines for the determination of sacubitril-valsartan premix stereoisomers, namely, (2R)-valsartan, (2S,4S)-sacubitril, (2R,4S)-sacubitril, and (2R,4R)-sacubitril. Primarily, stability indicating separation study was done on reverse phase LC conditions; it was described by peak homogeneity of sacubitril-valsartan and its stereoisomers. Cellulose tris(4-methylbenzoate) packing column Chiralcel OJ-RH(150 mm × 4.6 mm), 5 µm provided better resolution than those of amylose based stationary phase's. Resolution between two arbitrary adjacent analyte was found to be more than 2.0 with 0.1% trifluoroacetic acid in water as mobile phase-A and mobile phase-B consisting of acetonitrile, methanol, and trifluoroacetic acid (90:10:0.1, v/v/v). Gradient elution was performed at a flow rate of 1.0 ml/min, column temperature 20°C, injection volume 10 µl, UV detection at 254 nm and run time was 52 min. The detector response linearity of stereoisomers found to be linear (R2  ≥ 0.9998), limit of detection (0.290 µg/ml, 0.122 µg/ml, 0.123 µg/ml, and 0.124 µg/ml), and limit of quantification (0.878 µg/ml, 0.370 µg/ml, 0.373 µg/ml, and 0.375 µg/ml), respectively. Percentage recovery was found to be 98-105. Finally, the proposed method is user friendly and can be used in bulk drugs analysis.

Novel and Potential Small Molecule Scaffolds as DYRK1A Inhibitors by Integrated Molecular Docking-Based Virtual Screening and Dynamics Simulation Study.

The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a novel, promising and emerging biological target for therapeutic intervention in neurodegenerative diseases, especially in Alzheimer's disease (AD). The molMall database, comprising rare, diverse and unique compounds, was explored for molecular docking-based virtual screening against the DYRK1A protein, in order to find out potential inhibitors. Ligands exhibiting hydrogen bond interactions with key amino acid residues such as Ile165, Lys188 (catalytic), Glu239 (gk+1), Leu241 (gk+3), Ser242, Asn244, and Asp307, of the target protein, were considered potential ligands. Hydrogen bond interactions with Leu241 (gk+3) were considered key determinants for the selection. High scoring structures were also docked by Glide XP docking in the active sites of twelve DYRK1A related protein kinases, viz. DYRK1B, DYRK2, CDK5/p25, CK1, CLK1, CLK3, GSK3ß, MAPK2, MAPK10, PIM1, PKA, and PKCα, in order to find selective DYRK1A inhibitors. MM/GBSA binding free energies of selected ligand-protein complexes were also calculated in order to remove false positive hits. Physicochemical and pharmacokinetic properties of the selected six hit ligands were also computed and related with the proposed limits for orally active CNS drugs. The computational toxicity webserver ProTox-II was used to predict the toxicity profile of selected six hits (molmall IDs 9539, 11352, 15938, 19037, 21830 and 21878). The selected six docked ligand-protein systems were exposed to 100 ns molecular dynamics (MD) simulations to validate their mechanism of interactions and stability in the ATP pocket of human DYRK1A kinase. All six ligands were found to be stable in the ATP binding pocket of DYRK1A kinase.

Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase.

Ten benzoxazole clubbed 2-pyrrolidinones (11-20) as human monoacylglycerol lipase inhibitors were designed on the criteria fulfilling the structural requirements and on the basis of previously reported inhibitors. The designed, synthesized, and characterized compounds (11-20) were screened against monoacylglycerol lipase (MAGL) in order to find potential inhibitors. Compounds 19 (4-NO2 derivative) and 20 (4-SO2NH2 derivative), with an IC50 value of 8.4 and 7.6 nM, were found most active, respectively. Both of them showed micromolar potency (IC50 value above 50 µM) against a close analogue, fatty acid amide hydrolase (FAAH), therefore considered as selective inhibitors of MAGL. Molecular docking studies of compounds 19 and 20 revealed that carbonyl of 2-pyrrolidinone moiety sited at the oxyanion hole of catalytic site of the enzyme stabilized with three hydrogen bonds (~2 Å) with Ala51, Met123, and Ser122, the amino acid residues responsible for the catalytic function of the enzyme. Remarkably, the physiochemical and pharmacokinetic properties of compounds 19 and 20, computed by QikProp, were found to be in the qualifying range as per the proposed guideline for good orally bioactive CNS drugs. In formalin-induced nociception test, compound 20 reduced the pain response in acute and late stages in a dose-dependent manner. They significantly demonstrated the reduction in pain response, having better potency than the positive control gabapentin (GBP), at 30 mg/kg dose. Compounds 19 and 20 were submitted to NCI, USA, for anticancer activity screening. Compounds 19 (NSC: 778839) and 20 (NSC: 778842) were found to have good anticancer activity on SNB-75 cell line of CNS cancer, exhibiting 35.49 and 31.88% growth inhibition (% GI), respectively.

Comparative evaluation of elastic recovery of three different elastomeric impression materials on chemical disinfection and autoclaving: An in vitro study.

AIM: The aim of the study was to investigate the effect of disinfection and steam autoclaving on the elastic recovery of three different elastomeric impression materials. SETTINGS AND DESIGN: In vivo - comparative study. MATERIALS AND METHODS: Ninety dumbbell-shaped specimens of commercially available two addition-cured silicones (AFFINIS and AQUASIL) and one condensation-cured silicone (SPEEDEX) impression materials were prepared and treated with chemical disinfectant and steam autoclaving. Specimens were seal packed and sent to laboratory for testing elastic recovery. After the specimen had been pulled to failure, the broken parts were fitted back together, and the distance between the marks was measured using an electronic Vernier caliper. STATISTICAL ANALYSIS USED: one-way analysis of variance test and Tukey post hoc test for multiple comparisons. RESULTS: The result showed significant difference in elastic recovery of AFFINIS when it was disinfected and steam autoclaved whereas elastic recovery showed no significant difference when SPEEDEX and AQUASIL were disinfected and steam autoclaved. Similarly, results were alike when AFFINIS, SPEEDEX, and AQUASIL were compared on disinfection. However, significant difference was noted on steam autoclaving, highest being the mean value of AFFINIS. CONCLUSION: Within the limitations of this in vitro study, conclusion was made that the elastic recovery of AFFINIS was the least which improved with disinfection and autoclaving. Elastic recovery of SPEEDEX and AQUASIL was similar. However, all the three materials used in the study can be safely sterilized after clinical use and before being sent to the laboratory without significantly affecting their elastic recovery.

A new stability indicating reverse phase high performance liquid chromatography method for the determination of enantiomeric purity of a DPP-4 inhibitor drug linagliptin.

A simple, sensitive, and stability indicating isocratic reverse phase high performance liquid chromatography method has been developed, optimized and validated for the separation and quantification of S-enantiomer in linagliptin (R-enantiomer) drug substance. Enantiomeric separation was achieved on a Cellulose tris(4-chloro-3-methylphenylcarbamate) stationary phase. Mobile phase consists of aqueous diammonium hydrogen phosphate buffer and acetonitrile in the ratio of 35:65 v/v. Isocratic elution was performed at a flow rate of 1.0 mL/min, the column oven temperature was set at 40°C and detection was at 226 nm. The resolution between R and S enantiomers is found to be more than 4.0. The impact of mobile phase composition, pH of buffer and temperature on the resolution has been studied. The detector response is found to be linear over the concentration range of 0.17-1.7 µg/mL. LOD and LOQ levels of S-enantiomer are found to be 0.057 and 0.172 µg/mL respectively. The recovery of S-enantiomer is 99.8% w/w. The proposed method is validated for specificity, precision, linearity, accuracy and robustness.

A Validated GC-MS Method for the Determination of Genotoxic Impurities in Divalproex Sodium Drug Substance.

A specific GC-MS method has been developed, optimized and validated for the determination of five genotoxic impurities namely Methyl bromide (Me.-Br), Ethyl bromide (Et.-Br), Isopropyl bromide (Ipr.-Br), n-Propyl bromide (n-Pr.-Br) and n-Butyl bromide (n-But.-Br) in Divalproex sodium (DPS) drug substance. Chromatographic separation of five genotoxic impurities was achieved on DB-1 column (30 m × 0.32 mm, 3.0 µm), consists of 100% dimethyl polysiloxane as stationary phase and passing helium carrier gas. The mass fragments (m/z) were selected for the quantification of Me.-Br (m/z 94), Et.-Br (m/z 108), Ipr.-Br (m/z 122), n-Pr.-Br (m/z 122) and n-But.-Br (m/z 136). Bromide ion (m/z 79) was the qualifier ion for the analytes [(Me.-Br), (Et.-Br), (Ipr.-Br), (n-Pr.-Br) and (n-But.-Br)]. The performance of the method was assessed by evaluating the specificity, linearity, sensitivity, precision and accuracy experiments. The established limit of detection and limit of quantification values for the genotoxic impurities were in the range of 0.005-0.019 µg mL-1. The correlation coefficient values of the linearity experiment were in the range of 0.9947-0.9983. The average recoveries for the accuracy were in the range of 97.6-111.3%. The results proved that the method is suitable for the determination of Me.-Br, Et.-Br, Ipr.-Br, n-Pr.-Br and n-But.-Br contents in divalproex sodium.

Reliable GC Method for Related Substances in Divalproex Sodium Drug.

A specific GC method has been developed, optimized and validated for the determination of seven related substances namely N,N-dimethyl valpronamide, valeric acid, 2-methyl valeric acid, 2-ethyl valeric acid, 2-isopropyl valeric acid, 2-n-butyl valeric acid and 2-propyl-2-pentenoic acid in divalproex sodium (DPS) drug substance. Chromatographic separations of these seven impurities were achieved on DB-FFAP column (30 m × 0.53 mm, 1.0 µm), which consists nitroterephthalic acid modified polyethylene glycol material as stationary phase. DPS is a coordination complex of the sodium valproate and valproic acid (VPA). Nonanoic acid is used as internal standard. All the seven related substances, VPA and nonanoic acid were extracted into dichloromethane and monitored by GC with flame ionization detector. The performance of the developed method was assessed by evaluating specificity, linearity, sensitivity, precision, accuracy and robustness. Forced degradation experiments were conducted to evaluate the degradation behavior of DPS. The established limits of detection (LODs) and limits of quantification (LOQs) values for the related substances were in the ranges of 4-5 and 12-15 µg mL-1, respectively. Further, for VPA, LOD and LOQ values were 4 and 12 µg mL-1, respectively. The correction factors of these related substances with respect to VPA and lie between 0.92 and 1.44. The average recoveries were in the range of 92.4-108.4%.

Simultaneous Determination of Genotoxic Impurities in Fudosteine Drugs by GC-MS.

A simple, sensitive and reliable gas chromatography mass spectrometry (GC-MS) method has been developed, optimized and validated for the simultaneous determination of 3-chloro-1-propanol (CHP), 1,3-dichloropropane (DCP), 3-chloropropylacetate (CPA) and chloropropyl hydroxypropyl ether (CHE) contents in fudosteine, using chlorobenzene as internal standard. Efficient chromatographic separations were achieved on an Agilent J&W DB-WAXetr, 30 m long with 0.32 mm i.d., 1.0 µm particle diameter column that consists of bonded and cross-linked polyethylene glycol as a stationary phase by passing helium as the carrier gas. The analytes were extracted in dichloromethane and monitored by gas chromatography electron ionization mass spectrometry (GC-EI-MS) with selective ion monitoring (SIM) mode. The performance of the method was assessed by evaluating specificity, precision (repeatability and reproducibility), sensitivity, linearity and accuracy. The limit of detection and limit of quantification established for CHP, DCP, CPA and CHE were in the range of 0.05-0.08 µg mL(-1) and 0.10-0.17 µg mL(-1), respectively. The recoveries for CHP, DCP, CPA and CHE were in the range of 92.0-101.5%. The results proved that the method is suitable for the simultaneous determination of contents of CHP, DCP, CPA and CHE in fudosteine.

Identification, Isolation, and Characterization of a New Degradation Impurity in Nafcillin Sodium.

A new degradant of Nafcillin Sodium was found at a level of 1.8% w/w during the gradient reversed-phase HPLC analysis in stability storage samples. This impurity was identified by LC-MS and was characterized by (1)H-NMR, (13)C-NMR, LC/MS/MS, elemental analysis, and IR techniques. Based on the structural elucidation data, this impurity was named as N-[(2S)-2-carboxy-2-{[(2-ethoxynaphthalen-1-yl)carbonyl]amino}ethylidene]-3-({N-[(2-ethoxynaphthalen-1-yl)carbonyl]glycyl}sulfanyl)-D-valine. This impurity was prepared by isolation and was co-injected into the HPLC system to confirm the retention time. To the best of our knowledge, this impurity has not been reported elsewhere. The identification and structural elucidation of this degradant impurity has been discussed in detail.

Self-administered tuberculosis treatment outcomes in a tribal population on the indo-myanmar border, Nagaland, India.

BACKGROUND: Multiple strategies are being adopted by national tuberculosis (TB) programmes to achieve universal coverage of tuberculosis treatment. However, populations living in 'hard-to-reach' areas of north-east India have poor access to health services. Our study aimed to detail treatment outcomes in TB program supported by Médecins Sans Frontières (MSF) and using an alternative model of TB treatment delivery in Mon district, Nagaland, India. METHODS: This was a retrospective cohort study of TB patients, initiated on self-administered therapy (SAT) through Mon District Hospital, Nagaland, India between April 2012 and March 2013. RESULTS: A total of 238 tuberculosis patients had final TB treatment outcomes during the study period, including 82 and 156 from semi-urban and rural areas respectively. The majority of patients (62%, 147/238) were suffering from pulmonary, smear-positive tuberculosis. Overall, 74% of patients (175/238) had successful outcomes, being cured or having completed their treatment. Females (81%), pulmonary TB patients (75%) and those on a Category I regimen (79%) had better treatment success rates than males (67%), extra-pulmonary TB patients (62%) and patients on a Category II regimen (61%). The univariate and bivariate analyses found age, sex and TB treatment regimen significantly associated with unsuccessful TB treatment outcomes (defined as death, loss-to-follow-up and failure). However, only older age showed significance in a multivariate binary logistic regression model. CONCLUSION: Our study suggests that self-administered TB treatment is feasible for patients living in areas with limited or no access to health services. The relatively low number of patients with adverse outcomes suggests that SAT models are safe; other advantages include the need for fewer resources and less frequent movements by patients. National TB programmes should consider allowing SAT strategies for delivery of TB treatment to 'hard-to-reach' populations, which could in turn help to achieve universal coverage and contribute to global TB elimination by 2050.

Development and validation of a gas chromatography method for the trace level determination of allylamine in sevelamer hydrochloride and sevelamer carbonate drug substances.

A capillary gas chromatography method using a flame ionization detector has been developed for the trace analysis of allylamine (AA) in sevelamer hydrochloride (SVH) and sevelamer carbonate (SVC) drug substances. The method utilized a mega bore capillary column DB-CAM (30 m × 0.53 mm × 1.0 µm) with a bonded and cross-linked, base-deactivated polyethylene glycol stationary phase and was validated for specificity, sensitivity, precision, linearity, and accuracy. The detection and quantitation limits obtained for allylamine were 2 µg/g and 6 µg/g, respectively. The method was found to be linear in the range between 6 µg/g and 148 µg/g with a correlation coefficient of 0.9990. The average recoveries obtained in SVH and SVC were 93.9% and 99.1%, respectively. The developed method was found to be robust for the determination of AA in sevelamer drug substances and also the specificity was demonstrated with a gas chromatograph coupled with a mass spectrometer.

The relationship between time to surgical debridement and incidence of infection in grade III open fractures.

OBJECTIVE: The purpose of this study was to determine the association between time to initial debridement and infection rate in high-energy (grade III) open fractures of tibia. METHODS: All patients presenting with open fractures were included in the study. The inclusion criteria were Gustilo III A, B and C open fractures of tibia. Time of injury, time of arrival to the hospital, time of initial debridement and subsequent soft tissue procedures were recorded. The primary outcome measure was a diagnosis of infection or osteomyelitis at 1 year. Secondary outcome measure was fracture union at 1 year. RESULTS: Sixty-seven (67) patients with grade III open fractures were included; the mean age was 32.4 years (54 males and 13 females). Eight patients (12 %) in this study went on to develop a deep infection, and there were 6 (8.4 %) non-unions. The infection rate for patients in the group who underwent debridement in less than 6 h and those greater than 6 h was 13.1 and 10.8 %, respectively. No statistically significant difference could be demonstrated between the two groups (p = 0.56). While there was no significant relationship between grade of fracture and infection rate (p = 0.07), the relationship between grade of fracture and non-union was significant (p = 0.02). CONCLUSION: Our study shows that the risk of developing an infection was not increased if the primary surgical management was delayed more than 6 h after injury. Therefore, reasonable delays in surgical treatment for patients with open fractures may be justified in order to provide an optimal operating environment.

Simple and sensitive stability-indicating ion chromatography method for the determination of cyclopropylamine in nevirapine and moxifloxacin hydrochloride drug substances.

A simple and sensitive ion chromatography method has been developed for the determination of cyclopropylamine (CPA) in nevirapine (NEV) and moxifloxacin HCl (MOX) pharmaceutical drug substances. Efficient chromatographic separation was achieved on a Metrosep C4, 5 µm (250 mm × 4.0 mm) column. The mobile phase consists of 5 mM hydrochloric acid containing 10% (v/v) acetonitrile and was delivered in an isocratic mode at a flow rate of 0.9 mL min(-1) at 27°C. A conductometric detector was used for the detection of the analyte. The drug substances were subjected to stress conditions including oxidation, thermal, photolytic and humidity for the evaluation of the stability-indicating nature of the method. The method was validated for specificity, precision, linearity, accuracy and solution stability. The limit of detection (LOD) and limit of quantification (LOQ) values are 0.10 µg mL(-1) and 0.37 µg mL(-1) respectively. The linearity range of the method is between 0.37 µg mL(-1) and 1.5 µg mL(-1) and the correlation coefficient is found to be 0.9971. The average recoveries of CPA in NEV and MOX are 97.0% and 98.0%, respectively.

Identification of oxidative degradation impurities of olanzapine drug substance as well as drug product.

Impurities found in stressed and stability studies of olanzapine (polymorphic form-I) [1-7] in both drug substance and drug product are described. These impurities are identified as 4-(4-methyl-1-piperazinyl)-3-hydroxymethylidene-1H-benzo[b][1,4]diazepine-2(3H)-thione (hydroxymethylidene thione) and (Z)-4-(4-methyl-1-piperazinyl)-3-acetoxymethylidene-1H-benzo[b][1,4]diazapine-2(3H)-thione (acetoxymethylidene thione). An oxidative degradation pathway of olanzapine, for the formation of these impurities, has been proposed.

Gradient RP-HPLC method for the determination of potential impurities in atazanavir sulfate.

This paper proposes a simple and selective RP-HPLC method for the determination of process impurities and degradation products (degradants) of atazanavir sulfate (ATV) drug substance. Chromatographic separation was achieved on Ascentis(®) Express C8, (150mm×4.6mm, 2.7µm) column thermostated at 30°C under gradient elution by a binary mixture of potassium dihydrogen phosphate (pH 3.5, 0.02M) and ACN at a flow rate of 1.0ml/min. A photodiode array (PDA) detector set at 250nm was used for detection. Stress testing (forced degradation) of ATV was carried out under acidic, alkaline, oxidative, photolytic, thermal and humidity conditions. In presence of alkali, ATV transformed into cyclized products and the order of degradation reaction is determined by the method of initial rates. The unknown process impurities and alkaline degradants are isolated by preparative LC and characterized by ESI-MS/MS, (1)H NMR, and FT-IR spectral data. The developed method is validated with respect to sensitivity (lod and loq), linearity, precision, accuracy and robustness and can be implemented for routine quality control analysis and stability testing of ATV.

Identification, isolation and characterization of a new degradation product in sultamicillin drug substance.

A new degradant of sultamicillin drug substance was found during the gradient reverse phase HPLC analysis of stability storage samples. The level of this degradant impurity was observed up to 1.0%. The impurity (formaldehyde adduct with 5-oxo-4-phenylimidazolidin-1-yl moiety) was identified by LC/MS and was characterized by ((1)H NMR, (13)C NMR, 2D-NMR ((1)H-(1)H COSY, NOESY, HSQC and HMBC), LC/MS/MS, MS/TOF, elemental analysis and IR. This impurity was prepared by isolation and co-injected into HPLC system to confirm the retention time.

Stability indicating ion chromatography method for the simultaneous determination of ibandronate sodium drug substance and its impurities.

A simple and sensitive ion chromatography method has been developed for the simultaneous assay of ibandronate sodium drug substance and the determination of its impurities. The separation was achieved on Allsep™ anion column 150 mm × 4.6 mm, 7 µm particle diameter. The mobile phase consisted of 1% (v/v) aqueous formic acid and acetone 98:2% (v/v); flow rate 1.0 ml min(-1) at ambient temperature. The analytes were monitored by conductometric detector. The drug substance was subjected to stress conditions of hydrolysis, oxidation, photolytic, thermal and humidity degradation. Considerable degradation was achieved only under oxidative conditions. Mass balance was demonstrated in all stress conditions. The method was validated for specificity, precision, linearity, solution stability and accuracy. The limits of detection (LOD) and limits of quantification (LOQ) for impurities were in the range of 0.36-0.80 µg ml(-1) and 1.00-2.40 µg ml(-1), respectively. For ibandronate LOD was 38 µg ml(-1) and LOQ was 113 µg ml(-1). The average recoveries for impurities and ibandronate were in the range of 99.0-103.1% and the method can be successfully applied for the routine analysis of ibandronate sodium drug substance.

Identification, isolation and characterization of a new impurity in drug substance resulting from stress stability studies.

A new unknown impurity of cefoxitin formed during a gradient reverse phase high performance liquid chromatography (HPLC) analysis of stress stability samples of the drug substance cefoxitin, and the level of this impurity was found at up to 0.9%. This impurity was identified by LC-MS and characterized by (1H NMR, 13C NMR, LC/MS/MS, elemental analysis and FT-IR). Based on the spectral data, the impurity was named as, 3-[[(2R,3S)-[3-methoxy-3-N-[2-(thiophen-2-yl)acetamido]]-4-oxoazetidin-2-ylthio]-2-[(carbamoyloxy)methyl]]-acrylic acid. The structure of this impurity was also established unambiguously, prepared by isolation and co-injected into HPLC to confirm the retention time. To the best of our knowledge, this impurity has not been reported elsewhere. Structural elucidation of the impurity by spectral data is discussed in detail.