High Level Of Quality Control Research Articles

Continuous Manufacturing of Graphene-Contact Ion-Selective Electrodes Using Roll-to-Roll Processes: The Case for Nitrate Sensors

Soil contains various species of nitrogen, which is crucial for plant growth. Nitrate ion (NO3 -) is essential for promoting high crop yields and is widely used in fertilizers, however groundwater can be polluted by the overuse of nitrate. “Smart agriculture” can be supported by monitoring NO3 - in ground-soil using a distributed network of disposable potentiometric sensors. We have found the performance of such sensors to be enhanced by adding graphene nanoplatelets (GrNPs) as a conductive yet hydrophobic solid contact between the electrode and ion-selective membrane. Exfoliated GrNPs can be stably dispersed in ethyl acetate by liquid-assisted ball-milling, then deposited using methods compatible with the scalable roll-to-roll (R2R) production of ion-selective electrodes (ISEs). Ultra thin layers of GrNPs were formed by spray-coating onto a moving web of screen-printed Ag electrodes on polyethylene terephthalate (PET), followed by in-line deposition of a NO3 - selective membrane and silicone sealant then oven drying. Multiple electrodes from each production run were conditioned in aqueous KNO3 solutions and potentiometric characterizations of sensitivity, selectivity and stability were completed using an 80-channel analyzer. The GrNP layer serves as a hydrophobic transducer of ion adsorption and provides a high capacitance for stable potentiometric signals while also protecting SC-ISEs from damage caused by water permeation. We find that R2R processes can successfully produce graphene-contact NO3 - ISEs for agricultural applications, with extended operational lifetimes and high levels of quality control.

Improved and extended tide gauge records for the British Isles leading to more consistent estimates of sea level rise and acceleration since 1958

This paper describes methods of obtaining improved estimates of long-term sea level trends for the British Isles. This is achieved by lengthening the sea level records where possible, then removing known sources of variability, and then further adjusting for datum errors that are revealed by the previous processes after verification using metadata from archived sources. Local sea level variability is accounted for using a tide and surge model. Far field variability is accounted for using a “common mode”. This combination reduces the residual variability seen at tide gauges around the coast of the British Isles to the point that a number of previously unrecognised steps in individual records become apparent, permitting a higher level of quality control to be applied. A comprehensive data archaeology exercise was carried out which showed that these step-like errors are mostly coincident with recorded site-specific changes in instrumentation, and that in many cases the periodic tide gauge calibration records can be used to quantify these steps. A smaller number of steps are confirmed by “buddy-checking” against neighbouring tide gauges. After accounting for the observed steps, using levelling information where possible and an empirical fit otherwise, the records become significantly more consistent. The steps are not found to make a large difference to the trend and acceleration observed in UK sea level overall, but their correction results in much more consistent estimates of first order (Sea Level Rise) and second order (Sea Level Acceleration) trends over this 60-year period. We find a mean rate of sea level rise of 2.39 ± 0.27 mm yr−1, and an acceleration of 0.058 ± 0.030 mm yr−2 between Jan. 1958 and Dec. 2018. The cleaner dataset also permits us to show more clearly that the variability other than that derived from local meteorology is indeed consistent around the UK, and relates to sea level changes along the eastern boundary of the North Atlantic.

CFD modelling for dams and reservoirs – best practice workflows, specification and review

This paper identifies the need for industry guidance for the application of computational fluid dynamics (CFD) to the dams and reservoirs industry and lays out the primary components of such a model study, providing guidance for procurement and review. First, workflow is discussed to give an overview to those unfamiliar with the process. The key areas are explicitly explained for the layperson. The later part of the paper identifies key issues that reviewers should focus on and discusses areas such as accuracy. Support is offered to owners and those procuring model studies in the form of sample text recommended for specifying CFD studies. Finally, the paper recommends a high level of quality control and expert review when issues of dam safety are concerned.

Critical quality evaluation and application value of network Meta-analyses in traditional Chinese medicine

To introduce the application status of network Meta-analysis( NMA) in the field of traditional Chinese medicine,and to discuss the application value of NMA in the field of traditional Chinese medicine,this study comprehensively reviewed the systematic reviews with application of NMA in the field of traditional Chinese medicine. CNKI,Wan Fang,Sino Med,VIP,Embase,PubMed and Cochrane Library and the reference list of previous studies were searched. The AMSTAR scale was used to evaluate the quality of literature methodology,and PRISMA-NMA checklist was used to measure the degree of report specification. Overall,122 articles were included,including 80 in Chinese and 42 in English. The included studies centered on cancer,bone and joint disease,cardiovascular disease,respiratory disease,mental disease and digestive disease. Additionally,the intervention can be categorized into three groups,traditional Chinese medicine injection,oral Chinese medicine or prescription,and traditional physical therapy including acupuncture.Nearly one-third of the researches' intervention program is aimed at comparing the effect of Chinese and Western combined therapy and monotherapy. The overall methodology quality grade is medium and the report quality is average,with methodology reporting and result reporting especially need to be improved. The subgroup analysis shows that the methodology quality of the English literatures is evidently higher than Chinese literatures,and the quality of the literatures published after 2015 is higher than those published in or before 2015.This study indicates that the NMA can compare multiple treatments simultaneously,which accords with characteristics of the clinical practice in traditional Chinese medicine that is complex and individual. NMA in the field of traditional Chinese medicine is still in the process of development. With higher level of quality control and reporting as well as the improvement of the statistical methodology and the accumulation of original researches,NMA application in the field of traditional Chinese medicine will be promising.

Simultaneous determination of bisphenol A and its chlorinated derivatives in human plasma: Development, validation and application of a UHPLC-MS/MS method.

Bisphenol A (BPA) is a well-known ubiquitous chemical found in polycarbonate, polysulfone and epoxy resins, used in mass production for many consumer products. BPA exhibits endocrine disruptor properties that can potentially induce adverse health effects. In aquatic environments, it can react with chlorine to produce chlorinated derivatives (ClxBPAs). ClxBPAs exhibit oestrogenic activity 10 to 105 times higher than BPA itself. Assessing human exposure to endocrine disrupting chemicals is mandatory to assess health risk. Blood, as well as urine matrix, are commonly used to perform human biomonitoring. We therefore developed, fully validated and applied a method based on Ultra High Performance Liquid Chromatography couples to a Triple Quad Mass Spectrometer to determine BPA, monochlorobisphenol A (MCBPA), dichlorobisphenol A (DCBPA), trichlorobisphenol A (TCBPA) and tetrachlorobisphenol A (TTCBPA) in human blood plasma. The European Medicines Agency guidelines for bioanalytical method validation have been applied. Precision and trueness of the method were <15% at medium and high levels of quality control and <20% at the limits of quantification (LOQs). The LOQs were settled at 0.1 ng/mL for BPA, 0.02 ng/mL for TTCBPA and 0.005 ng/mL for MCBPA, DCBPA, and TCBPA. The analytical method was applied to ten patients suffering from end stage renal disease. BPA was quantified in all ten patients while MCBPA, DCBPA and TTCBPA were determined in three and TCBPA in four. In conclusion, we have successfully developed a highly sensitive method to determine BPA and ClxBPAs in human plasma. Thanks to this method, for the first time, we could demonstrate ClxBPAs occurrence in human blood.

Effect of Cutter Soil Mixing (CSM) method and curing pressures on the tensile strength of a treated soft clay

This study presents a set of laboratory experiments to investigate the effect of Cutter Soil Mixing (CSM) method and curing pressures on the tensile strength of a soft clay treated with Air Cooled Blast Furnace Slag (ACBFS) and Industrial Hydrated Lime (IHL). High productivity, minimum vibration, using the in-situ soil as construction material, and high level of quality control are some of the main benefits of CSM method. Three different slurries containing various percentages of ACBFS and IHL were mixed with saturated soft clay due to CSM method to enhance its tensile strength and make it suitable for the construction of deep CSM panels. To simulate high pressure due to the self-weight of the deep CSM panels in the field, a number of high pressure curing devices were designed and built in the laboratory and used for 28 and 56 day pressurised curing of the treated samples. Then an indirect tensile strength test was performed on the treated samples to investigate the effect of mixing method, ACBFS-IHL content, curing pressure and curing time on the tensile strength of the treated material. Finally, X-Ray Diffraction (XRD) and Scanning Electron Microscopy (SEM) analysis were conducted to investigate the microstructural and properties of the treated clay. The outcomes demonstrate that using CSM method and curing pressures along with ACBFS-IHL as a chemical stabiliser, increases the tensile strength of treated soft clay up to 35 times, which is significantly higher than the use of chemical stabiliser alone. Moreover, the microstructural analysis results revealed that the main hydration products in the clay treated with ACBFS-IHL is gismondine (C–A–S–H) which is also considered to be responsible for the higher tensile development.

Synthesis and characterization of nanometer-sized liposomes for encapsulation and microRNA transfer to breast cancer cells.

Introduction: The use of liposomes as a drug delivery carrier (DDC) for the treatment of various diseases, especially cancer, is rapidly increasing, requiring more stringent synthesis, formulation, and preservation techniques to bolster safety and efficacy. Liposomes otherwise referred to as phospholipid vesicles are self-assembled colloidal particles. When formed in either the micrometer or nanometer size range, they are ideal candidates as DDC because of their biological availability, performance, activity, and compatibility. Defining and addressing the critical quality attributes (CQAs) along the pharmaceutical production scale will enable a higher level of quality control for reproducibility. More specifically, understanding the CQAs of nanoliposomes that dictate its homogeneity and stability has the potential to widen applications in biomedical science.Methods: To this end, we designed a study that aimed to define synthesis, characterization, formulation (encapsulation), preservation, and cargo delivery and trafficking as the major components within a target product profile for nanoliposomes. A series of synthetic schemes were employed to measure physicochemical properties relevant to nanomaterial drug product development, including concentration gradients, probe versus bath sonication, and storage temperature measured by microscopy (electron and light) and dynamic light scattering.Results: Concentration was found to be a vital CQA as reducing concentrations resulted in nanometer-sized liposomes of <350 nm. Liposomes were loaded with microRNA and fluorescence spectroscopy was used to determine loading efficacy and stability over time. Lyophilization was used to create a dry powder formulation that was then assessed for stability for 6 months. Lastly, breast cancer cell lines were used to ensure efficacy of microRNA delivery and localization.Conclusion: We conclude that microRNA can be loaded into nanometer-sized liposomes, preserved for months in a dried form, and maintain encapsulation after extended time periods in storage.

Raman spectroscopy-based identification of toxoid vaccine products

Vaccines are complex biomedicines. Manufacturing is time consuming and requires a high level of quality control (QC) to guarantee consistent safety and potency. An increasing global demand has led to the need to reduce time and cost of manufacturing. The evolving concepts for QC and the upcoming threat of falsification of biomedicines define a new need for methods that allow the fast and reliable identification of vaccines. Raman spectroscopy is a non-destructive technology already established in QC of classical medicines. We hypothesized that Raman spectroscopy could be used for identification and differentiation of vaccine products. Raman maps obtained from air-dried samples of combination vaccines containing antigens from tetanus, diphtheria and pertussis (DTaP vaccines) were summarized to compile product-specific Raman signatures. Sources of technical variance were emphasized to evaluate the robustness and sensitivity in downstream data analysis. The data management approach corrects for spatial inhomogeneities in the dried sample while offering a proper representation of the original samples inherent chemical signature. Reproducibility of the identification was validated by a leave-one-replicate-out cross-validation. The results highlighted the high specificity and sensitivity of Raman measurements in identifying DTaP vaccine products. The results pave the way for further exploitation of the Raman technology for identification of vaccines in batch release and cases of suspected falsification.

INCREASE OF STIMULANT INFLUENCE REMITTANCES FROM ABROAD

Introduction. The transition to the program budget in the public finance sector, the strengthening of the fight against corruption and offenses in the budget sphere attach particular importance to the problems of improving the management of financial resources. In this regard, the problem of efficient formation and spending of budgetary funds is relevant. Purpose.The purpose of the article is to reveal the essence of the state financial control in the budget sphere and develop practical proposals for its development. Results.The main problems of the state financial control in Ukraine should include: the fiscal nature of the overwhelming majority of control procedures; absence of system control, where the main is further control, and the procedures of preliminary and ongoing control are rather weak and unregulated; not awareness of the importance of internal financial control both in the system of management of public finances and managers of enterprises, institutions, organizations; the low level of effectiveness of the administrative penalty mechanism, when the amount of the fine for misuse or illegal use of budget funds is considerably less than the amount of budget funds that the state loses due to abuse of officials and can not provide full compensation for these losses; growth of financial irregularities in the use of budget funds; unregulated activity and cross-section of the functions of the subjects of financial control; weak interaction between externaland internal control bodies. The formation of the mechanism for its implementation should be based on a set of principles that reflect the main properties of the system being created in the scientific, methodological, legal and organizational aspects. It is this hierarchy of structuring that is justified and rational. The group of scientific and methodological principles include the following: systemic, complexity, purposefulness, continuity. The set of legal principles includes: legality, unity, prerogative of national interests. Our organizational principles include: parity, objectivity and competence, budget efficiency, preventive, interaction between public authorities and local self-government. In the process of forming a mechanism for the implementation of financial control must take into account its dual economic orientation. First, it must ensure the rational use of financial resources, which is expressed in minimizing budget expenditures. Secondly, the effectiveness of control activities manifests itself in the strictly targeted use of state resources with high economic efficiency of the corresponding investments. Thus, the criterion for evaluating the rationality of the implementation of financial control is the quantitatively expressed correlation between the target consumption of public funds and the stable replenishment of budgetary resources. Conclusion. The current practice of conducting financial audits confirms the existence of complex problems in the budget sphere. The following typical violations such as non-targeted, unlawful and inefficient spending of public funds are fairly common. At present, in the arsenal of controlling bodies, largely outdated forms and methods of audits and audits prevail. Their focus is mainly on identifying the facts of violations, and not the reasons for their occurrence, which does not contribute to successfully overcoming the disadvantages of using budget funds. A transition to a higher level of quality control and revision work with the use of modern instruments of monitoring and auditing, achievements of domestic and foreign economic science is necessary. Continuing scientific research, it is advisable to focus on the mechanisms of using new approaches to the management of the system of state financial control bodies as a practical tool for ensuring the efficiency of spending budget funds.

A RAPID, SENSITIVE AND VALIDATED ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY AND TANDEM MASS SPECTROMETRY METHOD FOR DETERMINATION OF PAROMOMYCIN IN MICE PLASMA: APPLICATION TO PHARMACOKINETIC STUDY

Objective: To develop and validate simple, sensitive, accurate and selective UPLC-MS/MS method for quantification of paromomycin (PARO) in mice plasma.Methods: Precipitation method was used for the extraction of plasma samples, an aliquot of 25 µl plasma samples was extracted using 10% perchloric acid in water. Chromatographic separation was performed using waters acquity ultra-performance liquid chromatography (UPLC) columns, BEH HILIC (50 mm× 2.1 mm, 1.7 µm) by a gradient mixture of acetonitrile and water (both containing 0.005% v/v trifluro acetic acid) as a mobile phase at the flow rate of 0.2 ml/min. The analyte was protonated in the positive electrospray ionization (ESI) interface and detected in multiple reactions monitoring (MRM) modes using the transition m/z 308.60-455.30.Results: The method had a short chromatographic run time of 3 min. Calibration curves were linear over wide ranges of 50.51-5019.22 ng/ml. The between and within-batch precision and accuracy of the method was determined by using 4 quality control samples, the highest % CV observed was 11.06. The mean recovery values are 78.17, 101.17 and 92.58 at low, medium and high-quality control levels; respectively.Conclusion: It was concluded that the developed and validated UPLC-MS/MS method was rapid, sensitive, accurate, precise, linear, and specific. Therefore, this method can be used for quantification of PARO in mice plasma with various advantages over the reported methods.

A RAPID, SENSITIVE AND VALIDATED ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY AND TANDEM MASS SPECTROMETRY METHOD FOR DETERMINATION OF RIFAMPICIN IN RAT PLASMA: APPLICATION TO PHARMACOKINETIC STUDY

&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To develop and validate simple, sensitive and selective ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS) method for quantification of rifampicin (RIF) in rat plasma and its application to pharmacokinetics study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Precipitation method was used for the extraction of plasma samples, an aliquot of 25 µl plasma samples was extracted using acetonitrile precipitation technique. Chromatographic separation was performed usingWaters Acquity&lt;sup&gt;TM&lt;/sup&gt;UPLC columns, BEH C18 (50 mm× 2.1 mm, 1.7 µm) by a gradient mixture of acetonitrile and water (both containing 0.1 % formic acid) as a mobile phase at the flow rate of 0.7 ml/min.The analyte was protonated in the positive ESI (electrospray ionization interface) and detected in MRM (multiple reactions monitoring) modes using the transition m/z 308.60-455.30.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The method had a short chromatography run time of 1.8 min with improved sensitivity over existing methods. Calibration curves been linear over the wide range of 1.97-5047.00 ng/ml. The between and within-batch precision and accuracy of the method was determined by using 4 quality control samples; the highest %CV observed was10.11. The mean recovery values are 74.26, 82.77 and 101.73 at low, medium and high-quality control levels; respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;It was concluded that the developed and validated UPLC-MS/MS method was sensitive,specific, precise, linear, and rapid. Therefore, the method can be used for quantification of RIFin rat plasma with various advantages over the reported methods. RIF is widely recommended by US-FDAguidance for industry on drug interaction studies and the developed method can be used to explore drug interaction studies in drug discovery and development.&lt;/p&gt;

OPTIMIZATION OF SALARY CALCULATIONS AND EMPLOYEES’ LABOUR PRODUCTIVITY STIMULATION AT THE ENTERPRISE

The purposes of the paper are: the detailed analysis of salary calculations, the evaluation of the effectiveness of employees’ work, the development of optimizing mechanisms of salary calculations by increasing productivity and implementation of the methods of employees’ labour stimulation. Methodology. The study is based on an analysis of different groups of enterprises, including agricultural ones. It is analysed that for today the efficiency of labour at some enterprises drops due to low wages and the lack of employees’ motivation mechanism. Results. The study found that the process of salary calculations has a lot of problematic aspects, such as a deficient work organization, insufficient stimulation of workers, poorly composed documents, etc. To improve such a situation, it is suggested an introduction of automation in order to reduce the wasting of working time for data processing of an accounting department and to improve significantly the quality and speed of information transfer to the head of an enterprise and external users. It is offered to use a labour ball to improve employees’ motivation, which is a form of accounting for the work varying on quality and quantity that was contributed to production. According to the scoring results, a mechanism of bonuses for employees is suggested. Practical implications. We suggested entering new documents to control the number of issued orders – “Registration Book of Issued Orders”. To provide a high level of quality control of executed works, it is suggested to display data in a special primary document “Record Sheet of Performance Quality”. It is offered to use partial salary payment for unprofitable enterprises through payment in kind. Value/originality. At first, the results will allow increasing the firm’s performance quality without losing employees, and subsequently – allow increasing the profitability of the enterprise.

Simultaneous Quantification of Baricitinib and Methotrexate in Rat Plasma by LC-MS/MS: Application to a Pharmacokinetic Study.

Efficacy assessments using a combination of baricitinib and methotrexate necessitate the development of an analytical method for the determination of both drugs in plasma with precision. A high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of baricitinib and methotrexate in rat plasma. Extraction of baricitinib, methotrexate, and tolbutamide (internal standard; IS) from 50 µL of rat plasma was carried out by protein precipitation with methanol. Chromatographic separation of the analytes was performed on the YMC pack ODS AM (150 mm × 4.6 mm, 5 µm) column under gradient conditions with methanol: 2.0 mM ammonium acetate buffer as the mobile phases at a flow rate of 1 mL/min. The precursor ion and product ion transition for both analytes and IS were monitored on a triple quadrupole mass spectrometer, operated with selective reaction monitoring in positive ionization mode. The method was validated over a concentration range of 0.5–250.00 ng/mL for baricitinib and methotrexate. Mean extraction recoveries for baricitinib, methotrexate, and IS of 86.8%, 89.4%, and 91.8% were consistent across low, medium, and high QC levels, respectively. Precision and accuracy at low, medium, and high quality control levels were less than 15% across the analytes. Benchtop, wet, freeze-thaw, and long-term stability were evaluated for both of the analytes. The analytical method was applied to support the pharmacokinetic study of simultaneous estimation of baricitinib and methotrexate in Wistar rats. Assay reproducibility was demonstrated by reanalysis of 18 incurred samples

In-line and real-time prediction of recombinant antibody titer by in situ Raman spectroscopy

The Food and Drug Administration's (FDA) process analytical technology (PAT) framework has been initiated to encourage drug manufacturers to develop innovative techniques in order to better understand their processes and institute high level quality control which allows action at any point in the manufacturing process. While Raman spectroscopy and chemometrics have been successfully used to predict concentration of conventional metabolites in cell cultures, it is really not the case for active substances. Thus, we propose, for the first time, an in-line and real-time prediction of recombinant antibody titer using an immersion probe link to a spectrometer without the tacking of samples. A good robustness of the method is observed on different culture batches and the contamination risk is drastically reduced which is an important issue in biotechnology manufacturing processes.

Automatic inversion of deep-directional-resistivity measurements for well placement and reservoir description

Deep-directional-resistivity (DDR) logging-while-drilling (LWD) technology has gained acceptance as an efficient method for horizontal well landing, geosteering, and reservoir and fluid-contact mapping. The largest part of the value lies in the automatic inversion of the measurements, improving the detection of geologic and fluid boundaries within a radius of investigation of more than 30 m around the wellbore in real time. The tool and its sensors were designed to acquire a data set with sensitivity to a number of formation properties ensuring the concurrent deployment of a robust inversion. Based on this, an inversion method implemented on computer clusters statistically samples (or explores) the multidimensional inversion space, returning the distribution of formation models that fit the available data. The most noticeable aspect to operators is that this is done without introducing bias. There is no need to commit to a number of layers or to the position, thickness, resistivity, or dip of the layers to generate the continuous images on which all DDR interpretation is based, which translates into several theoretical and practical advantages. In practice, this gives users a higher level of quality control and more confidence in interpreting the subsurface within a larger diameter around the wellbore, which is useful for integrating the information into a geomodel. This derisks current and future operation, improves real-time and planning decisions, and ultimately drives better well placement, completion, production, and return on investment.

A Validated Liquid Chromatography-Tandem Mass Spectrometry Coupled with Liquid-Liquid Extraction for Indacaterol Quantitation in Human Plasma

Indacaterol is a recent ultra-long-acting inhaled β2-agonist bronchodilator. The current work validated an in-house developed high performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) bioassay for indacaterol in human plasma. Ethyl acetate was used in a liquid-liquid extraction (LLE) method to extract indacaterol from plasma samples. A 200 μL of the mobile phase (water-methanol (30:70, v/v)) was used to reconstitute the indacaterol dry extract. A 5 μL was then eluted on a C18 column at a mobile phase flow of 1 mL/min. Formoterol was the internal standard (IS). The MS/MS was the detector. Method validation followed the International Guidelines. Indacaterol and IS were detected at a mass to charge ratio of 393.3 and 345.2, respectively. Validated calibration curves were linear over 0.075 - 100 ng/mL. Method specificity was established in 8 different plasma batches. No matrix effect was observed. The intra-batch accuracy (precision) percentages for the lower limit of quantitation (LLOQ), Low, Mid and High quality control levels were 113.6 (10.8), 104.7 (9.1), 99.8 (7.6) and 102.2 (8.5), respectively. The inter-batch accuracy, recovery, short-term and long-term stability results were accepted. Validation has confirmed a specific, accurate and precise HPLC-MS/MS coupled with a simple and fast LLE for indacaterol in human plasma.

Simultaneous quantification of lenalidomide, ibrutinib and its active metabolite PCI-45227 in rat plasma by LC–MS/MS: Application to a pharmacokinetic study

Efficacy assessments using a combination of ibrutinib and lenalidomide necessitate the development of an analytical method for determination of both drugs in plasma with precision. A high performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for the simultaneous determination of lenalidomide, ibrutinib, and its active metabolite PCI45227 in rat plasma. Extraction of lenalidomide, ibrutinib, PCI45227 and tolbutamide (internal standard; IS) from 50μl rat plasma was carried out by liquid–liquid extraction with ethyl acetate:dichloromethane (90:10) ratio. Chromatographic separation of analytes was performed on YMC pack ODS AM (150mm×4.6mm, 5μm) column under gradient conditions with acetonitrile:0.1% formic acid buffer as the mobile phases at a flow rate of 1ml/min. Precursor ion and product ion transition for analytes and IS were monitored on a triple quadrupole mass spectrometer, operated in the selective reaction monitoring with positive ionization mode. Method was validated over a concentration range of 0.72–183.20ng/ml for ibrutinib, 0.76–194.33ng/ml for PCI-45227 and 1.87–479.16ng/ml for lenalidomide. Mean extraction recovery for ibrutinib, PCI-45227, lenalidomide and IS of 75.2%, 84.5%, 97.3% and 92.3% were consistent across low, medium, and high QC levels. Precision and accuracy at low, medium and high quality control levels were less than 15% across analytes. Bench top, wet, freeze–thaw and long term stability was evaluated for all the analytes. The analytical method was applied to support a pharmacokinetic study of simultaneous estimation of lenalidomide, ibrutinib, and its active metabolite PCI-45227 in Wistar rat. Assay reproducibility was demonstrated by re-analysis of 18 incurred samples.

Indacaterol determination in human urine: validation of a liquid-liquid extraction and liquid chromatography-tandem mass spectrometry analytical method.

Indacaterol is a novel once-a-day inhaled ultra-long-acting β2-agonist. Quantitative bioanalysis supports pharmacokinetic and clinical research. The aim of the current work was to validate an in-house developed high performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) analytical method for indacaterol determination in human urine samples. A liquid-liquid extraction method has been developed to extract indacaterol from human urine samples using ethyl acetate. Indacaterol dry extract was reconstituted with 200 μL of the mobile phase (acidified water:methanol (30:70, v/v)) of which 5 μL was needed for the HPLC-MS/MS analysis. Indacaterol was eluted on a reversed C18 stationary phase with an isocratic mobile phase at a flow of 1 mL/min. Formoterol was the internal standard (IS). The MS/MS detection was employed with a turbo-ion spray ionization in the positive ion mode. A consensus of the international Guidelines for Bioanalytical Method Validation was followed. Indacaterol was detected at a mass to charge ratio (m/z) of 393.3 and its MS/MS daughter at 173.2. The retention times of indacaterol and IS were 1.60 and 1.20 min, respectively. Validated calibration curves were linear over a range of 0.075-100 ng/mL with correlation coefficients (r)≥0.990. The curves' regression weighting factor was 1/x. Method specificity was established in six different human urine batches. No matrix interference was observed. The intra- and inter-batch precision and accuracy within±20% (at lower limit) and±15% (other quality control (QC) levels) were confirmed. The indacaterol mean recovery (precision) percentages at Low, Mid, and High QC levels were 93.5 (3.84), 89.8 (2.15), and 92.2 (2.17), respectively. Short-term, long-term, freeze-thaw, and auto-sampler stability results were accepted. A specific, accurate and precise HPLC-MS/MS method has been validated for indacaterol quantification in human urine. This simple method is reproducible and robust to support future, indacaterol-related pharmacokinetic, bioequivalence and clinical studies.

Tropospheric aerosol scattering and absorption over central Europe: a closure study for the dry particle state

Abstract. This work analyses optical properties of the dry tropospheric aerosol measured at the regional Global Atmosphere Watch (GAW) observation site Melpitz in East Germany. For a continuous observation period between 2007 and 2010, we provide representative values of the dry-state scattering coefficient, hemispheric backscattering coefficient, absorption coefficient, single scattering albedo, and scattering Ångström exponent. Besides the direct measurement, the aerosol scattering coefficient was alternatively computed from experimental particle number size distributions using a Mie model. Within pre-defined limits, a closure could be achieved with the direct measurement. The achievement of closure implies that such calculations can be used as a high-level quality control measure for data sets involving multiple instrumentation. All dry-state optical properties show pronounced annual and diurnal variations, which are attributed to the corresponding variations in the regional emission fluxes, the intensity of secondary particle formation, and the mixing layer height. Air mass classification shows that atmospheric stability is a major factor influencing the dry aerosol properties at the GAW station. In the cold season, temperature inversions limit the volume available for atmospheric mixing, so that the dry-state aerosol optical properties near the ground proved quite sensitive to the geographical origin of the air mass. In the warm season, when the atmosphere is usually well-mixed during daytime, considerably less variability was observed for the optical properties between different air masses. This work provides, on the basis of quality-checked in situ measurements, a first step towards a climatological assessment of direct aerosol radiative forcing in the region under study.

Simultaneous quantification of ruxolitinib and nilotinib in rat plasma by LC–MS/MS: Application to a pharmacokinetic study

Efficacy assessments using a combination of ruxolitinib and nilotinib necessitate the development of a high precision analytical method for determination of both drugs in plasma. A high performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for the simultaneous determination of ruxolitinib and nilotinib in rat plasma. Extraction of ruxolitinib, nilotinib and dasatinib (internal standard; IS) from 50μl rat plasma was carried out by protein precipitation with methanol. Chromatographic separation of analytes was performed on YMC pack ODS AM (150mm×4.6mm, 5μm) column under gradient conditions with acetonitrile:2.0mM ammonium acetate buffer as the mobile phase at a flow rate of 1ml/min. Precursor ion and product ion transition for both analytes and IS were monitored on a triple quadrupole mass spectrometer, operated in the selective reaction monitoring with positive ionization mode. Method was validated over a concentration range of 0.16–247ng/ml for ruxolitinib and 0.86–219ng/ml for nilotinib. Mean extraction recovery for ruxolitinib, nilotinib, and IS of 99.6%, 97.6% and 90.3% were consistent across low, medium, and high QC levels. Precision and accuracy at low, medium and high quality control levels were less than 15% across analytes. Bench top, wet, freeze-thaw and long term stability were evaluated for both analytes. The analytical method was applied to support a pharmacokinetic study of simultaneous estimation of ruxolitinib and nilotinib in Wistar rat. Assay reproducibility was demonstrated by re-analysis of 18 incurred samples.