SIMULTANEOUS TRACE LEVEL DETERMINATION OF BENZENE AND 1, 2-DICHLOROETHANE BY GC-HS/GC-MS IN SEVERAL PHARMACEUTICAL DRUG SUBSTANCES

Objective: We herein report the simultaneous trace level determination of benzene and 1,2-dichloroethane in several active pharmaceutical substances by GC-HS (gas chromatograph-head space) using a DB-624 column.Methods: This GC-HS method was developed based on an oven-programmed approach using nitrogen gas as the mobile phase. Our method is also compatible with the GC-MS (gas chromatography-mass spectrometry) technique using helium as the mobile phase instead of nitrogen. The successful separation of benzene and 1,2-dichloroethane was established by confirmation of their corresponding specific molecular masses.Results: The retention time of benzene and 1,2-dichloroethane were found to be 34.8 min and 35.6 min, respectively. The linearity was found in the range of concentration of 0.63-4.22 ppm and 1.49-9.96 ppm for benzene and 1,2-dichloroethane. The detection limit and quantification limit for benzene were 0.2 and 0.6 ppm, while those of 1,2-dichloroethane were 0.6 ppm and 1.5 ppm. These values were calculated using our developed method with respect to the test concentration of 500 mg/ml. The recovery of benzene and 1,2-dichloroethane were found to be 89–110% and 91–105%, respectively for the various pharmaceutical drug substances. The specificity of the method was studied using 20 solvents which include benzene and 1,2-dichloroethane.Conclusion: We expect that our method will be applicable for the simultaneous trace level determination of benzene and 1,2-dichloroethane during the control of manufacturing processes, and for use in rapid analysis for quality control in the pharmaceutical industry. Finally, this method was validated according to the International Conference on Harmonization (ICH) Validation Guidelines Q2 (R1)

SENSITIVE DETERMINATION OF RELATED SUBSTANCES IN PIOGLITAZONE HYDROCHLORIDE BY HPLC

Objective: An efficient, high performance liquid chromatographic method has been developed and validated for the quantification of related substances in pioglitazone hydrochloride drug substance.Methods: This method includes the determination of three related substances in pioglitazone hydrochloride. The mobile phase A is 0.1% w/v triethylamine in water with pH 2.5 adjusted by dilute phosphoric acid. The mobile phase B is premixed and degassed mixtures of acetonitrile and methanol. The flow rate was 1 ml/min. The elution used was gradient mode. The HPLC column used for the analysis was symmetry C18 with a length of 250 mm, the internal diameter of 4.6 mm and particle size of 5.0 microns.Results: The developed method was found to be linear with the range of 0.006-250% with a coefficient of correlation 0.99. The precision study revealed that the percentage relative standard deviation was within the acceptable limit. The limit of detection and limit of quantitation of the impurities was less than 0.002%and 0.006% with respect to pioglitazone hydrochloride test concentration of 2000 µg/ml respectively. This method has been validated as per ICH guidelines Q2 (R1).Conclusion: A reliable, economical HPLC method was magnificently established for quantitative analysis of related substances of pioglitazone hydrochloride drug substance

ULTRA HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC DETERMINATION OF GENOTOXIC IMPURITIES IN FEBUXOSTAT DRUG SUBSTANCE AND PRODUCTS

Objective: An efficient ultra-high performance liquid chromatographic (UHPLC or Infinity LC 1290) method has been developed and validated for the quantification of possible carcinogenic or genotoxic impurities in febuxostat drug substances and drug products at 18 µg/ml level.Methods: This method includes the conclusion of four potential genotoxic impurities in febuxostat. The mobile phase is trifluoroacetic acid, acetonitrile, and water with linear gradient elution. The UHPLC column used for the analysis was zorbax RRHD eclipse plus C18 with a length of100 mm, internal diameter of 2.1 mm, and particle size of 1.8 µ.Results: The limit of detection and limit of quantitation of the impurities are <0.1 (0.00001%) and 0.3 µg/ml (0.00003%) with respect to febuxostat test concentration of 1000 µg/ml, respectively. This method has been validated as per ICH guidelines Q2 (R1).Conclusion: A rapid, cost-effective infinity LC method was wonderfully established for quantitative analysis of possible genotoxic impurities of febuxostat drug substance and drug products.Keywords: Febuxostat, Genotoxic impurities, Ultra-high performance liquid chromatograph, Infinity-LC 1290, Validatio

TRACE LEVEL DETERMINATION AND QUANTIFICATION OF POTENTIAL GENOTOXIC IMPURITIES IN DASATINIB DRUG SUBSTANCE BY UHPLC/INFINITY LC

Objective: A simple, cost-effective and mass compatible ultra-high fast performance liquid chromatographic (Agilent-Infinity LC 1290) method has been developed and validated for the determination of potentially genotoxic impurities in dasatinib active pharmaceutical ingredients.Methods: This method comprises the determination of three possible genotoxic impurities in dasatinib. The mobile phase is trifluoroacetic acid, acetonitrile and water with linear gradient elution curve number 6. The column used for the development and validation is zorbax RRHD eclipse plus C18 with the length of 50 mm, the internal diameter of 2.1 mm and particle size of 1.8 microns.Results: The limit of detection of the potential genotoxic impurities are less than 0.1 µg/ml with respect to dasatinib test concentration of 1000 µg/ml. The limit of quantification of the potential genotoxic impurities is less than 0.3 µg/ml with respect to dasatinib test concentration of 1000 µg/ml.Conclusion: This method has been validated as per ICH guidelines Q2 (R1). These three potential mutagenic impurities are not degradant impurities of dasatinib and its only process related impurities. The method development has been approached using the QbD principle

A design for testability scheme for modular and non-modular quantum dot cellular automata (QCA) employing stuck-at fault model

Today leading VLSI experts predict a hard wall for CMOS and other conventional fabrication technology due to fundamental physical limits (ultra-thin gate oxide, short channel effects, doping fluctuations, etc.), and increasingly difficult and expensive lithography in nanoscale. Extensive research conducted in recent years at nanoscale aiming to surpass CMOS has proposed Quantum Dot Cellular Automata as a viable alternative for nanoscale computing. Quantum Dot Cellular Automata (QCA) paradigm is an innovatory approach to computing, which encodes binary information by means of charge configuration of nanostructures instead of current switching devices. The fundamental building block of QCA devices is the QCA cell, and electrostatic interaction between neighboring cells governs the design of all QCA wires and logic gates. The two primary logic elements in QCA technology are: majority voter and inverter. Binary wires and inverter chains are used for interconnection purposes. Logic operation AND, and OR can be achieved by maneuvering inputs to the majority voter. Clocking enables precise control over timing and data flow direction, as well as power gain in QCA circuits. Also proper clocking can achieve computational pipelining and can drastically reduce circuit power dissipation. Manufacturing of a QCA cell is expected to result in defects like cell displacement, misalignment, and absence of cell or additional cell in circuitry, causing the circuit to exhibit faulty behavior. So a well-defined testing scheme becomes necessary for this technology. Though the technology is different from conventional CMOS design, it is shown to be effective and realistic to use existing testing schemes at this stage. Stuck-at (s-a-v) fault model is quite acceptable in this regard in spite of the fact, that this model does not incorporate all the defective behaviors occurring in the fabrication process. With this in view, single stuck-at value faults have been considered for testing QCA circuits. In this thesis a new strategy for designing QCA logic, exhaustively testable for single s-a-v faults, is presented. In particular, the method facilitates QCA functionality testing. Any combinational logic can be implemented using only AND-OR gates (with negated signals available), and in QCA this generally results in reduced test set for exhaustive fault detection within the data path. Previously this strategy was used for QCA logic testing considering only primary inputs (either true or complemented, but not both) feeding different majority voters, which fails for general circuits where fanouts are allowed for primary inputs and their complement. Here, a design scheme has been proposed which makes testing possible for any combinational QCA circuit. The extension to modular design testing is also presented. Two design approaches are proposed for testing modular and non-modular logic. The first design uses 2 n ( n = primary inputs) ' Test Enable ' majority voters, and is tested with two 4-bit vectors regardless of complexity of design and the input size. Second design employs n majority voters for the same purpose, thus requiring lesser number of majority voters, but at the price of increased vector length. Application specific conditions would decide which design becomes optimal. Without going into the features of a particular QCA fabrication, errors on logic level is addressed, such that the approach achieves generality, and could be applied to any particular implementation of QCA. Also to overcome the fault masking in modular circuit design, a solution has been presented. To verify the scheme, a simulation and layout tool, QCADesigner version 2.0.3 was used. First the fault free circuit was designed and simulated. Then random s-a-v faults were injected in different locations of data path. In all cases, 100% fault coverage was achieved confirming the validity of proposed approac

Changes in shoot density, biomass and leaf area of Zostera caulescens Miki from Summer to Autumn in Funakoshi Bay of the Sanriku Coast, Japan

The world\u27s longest seagrass, Zostera caulescens Miki, is found in Funakoshi Bay along the Sanriku Coast of Honshu Island, Japan. Our study describes the changes in vertical distribution of shoot density, leaf area index (LAI) and biomass of Z. caulescens from summer (flowering season) to autumn (preparing for overwintering) in Funakoshi Bay. The samples were collected from a 0.5×0.5m quadrat at depths of 4.4m, 10.9m, 13.3m, 14.3m and 15.3m in July, and, for October, at 5.4m, 7.4m, 9.2m, 12.9m, and 15.7m. Above- and below-ground biomass, and flowering and vegetative shoot densities decreased with increasing bottom depth in both summer and autumn seasons except at the shallowest sampling depth, while the maximum above-ground biomass in both seasons was 187.3gDW/m^2 at the depth of 7.4m and 213.5gDW/m^2 at the depth of 10.9m, respectively. Densities of vegetative shoots were greater than those of flowering shoots at each sampling depth in both seasons except a bottom depth of 15.3m in July. The maximum length of flowering shoots in autumn (737cm) was greater than in summer (546cm), and the range of shoot lengths in autumn was wider than in summer. Biomass and densities of vegetative shoots at different depths in autumn were higher than those in summer, and Leaf Area Indices (LAI) of flowering and vegetative shoots at different depths in summer were higher than those in autumn. In addition, the mean LAIs of individual flowering and vegetative shoots in summer were greater than those in autumn as well. These results suggest that Z. caulescens has a higher LAI in summer when there is low seawater transparency and after ripening from summer to autumn, it also makes vegetative shoots in preparation for growth during the next spring

Angiogenic factors and their soluble receptors predict organ dysfunction and mortality in post-cardiac arrest syndrome

INTRODUCTION: Post-cardiac arrest syndrome (PCAS) often leads to multiple organ dysfunction syndrome (MODS) with a poor prognosis. Endothelial and leukocyte activation after whole-body ischemia/reperfusion following resuscitation from cardiac arrest is a critical step in endothelial injury and related organ damage. Angiogenic factors, including vascular endothelial growth factor (VEGF) and angiopoietin (Ang), and their receptors play crucial roles in endothelial growth, survival signals, pathological angiogenesis and microvascular permeability. The aim of this study was to confirm the efficacy of angiogenic factors and their soluble receptors in predicting organ dysfunction and mortality in patients with PCAS. METHODS: A total of 52 resuscitated patients were divided into two subgroups: 23 survivors and 29 non-survivors. The serum levels of VEGF, soluble VEGF receptor (sVEGFR)1, sVEGFR2, Ang1, Ang2 and soluble Tie2 (sTie2) were measured at the time of admission (Day 1) and on Day 3 and Day 5. The ratio of Ang2 to Ang1 (Ang2/Ang1) was also calculated. This study compared the levels of angiogenic factors and their soluble receptors between survivors and non-survivors, and evaluated the predictive value of these factors for organ dysfunction and 28-day mortality. RESULTS: The non-survivors demonstrated more severe degrees of organ dysfunction and a higher prevalence of MODS. Non-survivors showed significant increases in the Ang2 levels and the Ang2/Ang1 ratios compared to survivors. A stepwise logistic regression analysis demonstrated that the Ang2 levels or the Ang2/Ang1 ratios on Day 1 independently predicted the 28-day mortality. The receiver operating characteristic curves of the Ang2 levels, and the Ang2/Ang1 ratios on Day 1 were good predictors of 28-day mortality. The Ang2 levels also independently predicted increases in the Sequential Organ Failure Assessment (SOFA) scores. CONCLUSIONS: We observed a marked imbalance between Ang1 and Ang2 in favor of Ang2 in PCAS patients, and the effect was more prominent in non-survivors. Angiogenic factors and their soluble receptors, particularly Ang2 and Ang2/Ang1, are considered to be valuable predictive biomarkers in the development of organ dysfunction and poor outcomes in PCAS patients

Hydro-acoustic methods as a practical tool for cartography of seagrass beds

Cartography of seagrass beds is very important for management and conservation of sound littoral ecosystems and sustainable fisheries in the coastal waters. The cartographical methods to map spatial distribution of seagrass beds are reviewed. They are classified into two categories. One is a direct method by visual observation and the other is an indirect method using a remote sensing apparatus. Indirect methods are divided into optical or hydro-acoustic methods. Indirect methods require sea truth by direct methods. Optical methods are image analysis of aerial photography or satellite imagery. They are effective for mapping broad areas but limited to shallow waters due to light attenuation in waters. Hydro-acoustic methods such as an echosounder and a side scan sonar have no limitation of turbidity. The echosounder is practical to map vertically density and height distributions of seagrass beds. The side scan sonar and multi-beam sonar are appropriate for mapping broad horizontal distributions. Coupling of several indirect mapping methods is more useful than using only one method