Excision methods for high resolution shock capturing schemes applied to general relativisti

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香精油中农药残留

香精油中农药残留

Determination of Pesticide Minimum Residue Limits in Essential OilsReport No 3A report for the Rural Industries Research andDevelopment CorporationBy Professor R. C. Menary & Ms S. M. GarlandJune 2004RIRDC Publication No 04/023RIRDC Project No UT-23A© 2004 Rural Industries Research and Development Corporation.All rights reserved.ISBN 0642 58733 7ISSN 1440-6845‘Determination of pesticide minimum residue limits in essential oils’, Report No 3Publication No 04/023Project no.UT-23AThe views expressed and the conclusions reached in this publication are those of the author and not necessarily those of persons consulted. RIRDC shall not be responsible in any way whatsoever to any person who relies in whole or in part on the contents of this report.This publication is copyright. However, RIRDC encourages wide dissemination of its research, providing the Corporation is clearly acknowledged. For any other enquiries concerning reproduction, contact the Publications Manager on phone 02 6272 3186.Researcher Contact DetailsProfessor R. C. Menary & Ms S. M. GarlandSchool of Agricultural ScienceUniversity of TasmaniaGPO Box 252-54HobartTasmania 7001AustraliaPhone: (03) 6226 2723Fax: (03) 6226 7609Email: r.menary@.auIn submitting this report, the researcher has agreed to RIRDC publishing this material in its edited form.RIRDC Contact DetailsRural Industries Research and Development CorporationLevel 1, AMA House42 Macquarie StreetBARTON ACT 2600PO Box 4776KINGSTON ACT 2604Phone: 02 6272 4819Fax: 02 6272 5877Email: rirdc@.auWebsite: .auPublished in June 2004Printed on environmentally friendly paper by Canprint.FOREWORDInternational regulatory authorities are standardising the levels of pesticide residues present in products on the world market which are considered acceptable. The analytical methods to be used to confirm residue levels are also being standardised. To constructively participate in these processes, Australia must have a research base capable of constructively contributing to the establishment of methodologies and must be in a position to assess the levels of contamination within our own products.Methods for the analysis for pesticide residues rarely deal with their detection in the matrix of essential oils. This project is designed to develop and validate analytical methods and apply that methodology to monitor pesticide levels in oils produced from commercial harvests. This will provide an overview of the levels of pesticide residues we can expect in our produce when normal pesticide management programs are adhered to.The proposal to produce a manual which deals with the specific problems associated with detection of pesticide residues in essential oils is intended to benefit the essential oil industry throughout Australia and may prove useful to other horticultural products.This report is the third in a series of four project reports presented to RIRDC on this subject. It is accompanied by a technical manual detailing methodologies appropriate to the analysis for pesticide residues in essential oils.This project was part funded from RIRDC Core Funds which are provided by the Australian Government. Funding was also provided by Essential Oils of Tasmania and Natural Plant Extracts Cooperative Society Ltd.This report, an addition to RIRDC’s diverse range of over 1000 research publications, forms part of our Essential Oils and Plant Extracts R&D program, which aims for an Australian essential oils and plant extracts industry that has established international leadership in production, value adding and marketing.Most of our publications are available for viewing, downloading or purchasing online through our website:•downloads at .au/fullreports/index.html•purchases at .au/eshopSimon HearnManaging DirectorRural Industries Research and Development CorporationAcknowledgementsOur gratitude and recognition is extended to Dr. Noel Davies (Central Science Laboratories, University of Tasmania) who provided considerable expertise in establishing procedures for chromatography mass spectrometry.The contribution to extraction methodologies and experimental work-up of Mr Garth Oliver, Research Assistant, cannot be underestimated and we gratefully acknowledge his enthusiasm and novel approaches.Financial and ‘in kind’ support was provided by Essential Oils Industry of Tasmania, (EOT).AbbreviationsADI Average Daily IntakeAGAL Australian Government Analytical Laboratoriesingredientai activeAPCI Atmospheric Pressure Chemical IonisationBAP Best Agricultural PracticesenergyCE collisionDETA DiethylenetriamineECD Electron Capture DetectorionisationESI ElectrosprayFPD Flame Photometric DetectionChromatographyGC GasResolutionHR HighChromatographyLC LiquidLC MSMS Liquid Chromatography with detection monitoring the fragments of Mass Selected ionsMRL Maximum Residue LimitSpectrometryMS MassNRA National Registration AuthorityR.S.D. Relative Standard DeviationSFE Supercritical Fluid ExtractionSIM Single Ion MonitoringSPE Solid Phase ExtractionTIC Total Ion ChromatogramContents FOREWORD (III)ACKNOWLEDGEMENTS (IV)ABBREVIATIONS (V)CONTENTS (VI)EXECUTIVE SUMMARY (VII)1. INTRODUCTION (1)1.1B ACKGROUND TO THE P ROJECT (1)1.2O BJECTIVES (2)1.3M ETHODOLOGY (2)2. EXPERIMENTAL PROTOCOLS & DETAILED RESULTS (3)2.1M ETHOD D EVELOPMENT (3)2.2M ONITORING OF H ARVESTS (42)2.3P RODUCTION OF M ANUAL (46)3. CONCLUSIONS (47)IMPLICATIONS & RECOMMENDATIONS (50)BIBLIOGRAPHY (50)Executive SummaryThe main objective of this project was to continue method development for the detection of pesticide residues in essential oils, to apply those methodologies to screen oils produced by major growers in the industry and to produce a manual to consolidate and coordinate the results of the research. Method development focussed on the effectiveness of clean-up techniques, validation of existing techniques, the assessment of the application of gas chromatography (GC) with detection using electron capture detectors (ECD), flame photometric detectors (FPD) and high pressure liquid chromatography (HPLC) with ion trap mass selective (MS) detection.The capacity of disposable C18 cartridges to separate components of boronia oil was found to be limited with the majority of boronia components being eluted on the solvent front, with little to no separation achieved. The cartridges were useful, however, in establishing the likely interaction of reverse phases (RP) C18 columns with components of essential oils, using polar mobile phases . The loading of large amounts of oil onto RP HPLC columns presents the risk of permanently contaminating the bonded phases. The lack of retention of components on disposable SPE C18 cartridges, despite the highly polar mobile phase, presented a good indication that essential oils would not accumulate on HPLC RP columns.The removal of non-polar essential oil components by solvent partitioning of distilled oils was minimal, with the recovery of pesticides equivalent to that recorded for the essential oil components. However application of this technique was of advantage in the analysis of solvent extracted essential oils such as those produced from boronia and blackcurrant.ECD was found to be successful in the detection of terbacil, bromacil, haloxyfop ester, propiconazole, tebuconazole and difenaconzole. However, analysis of pesticide residues in essential oils by application of GC ECD is not sufficiently sensitive to allow for a definitive identification of any contaminant. As a screen, ECD will only be effective in establishing that, in the absence of a peak eluting with the correct retention time, no gross contamination of pesticide residues in an essential oil has occurred . In the situation where a peak is recorded with the correct elution characteristics, and which is enhanced when the sample is fortified with the target analyte, a second means of contaminant identification would be required. ECD, then, can only be used to rule out significant contamination and could not in itself be adequate for a positive identification of pesticide contamination.Benchtop GC daughter, daughter mass spectrometry (MSMS) was assessed and was not considered practical for the detection of pesticide residues within the matrix of essential oils without comprehensive clean-up methodologies. The elution of all components into the mass spectrometer would quickly lead to detector contamination.Method validation for the detection of 6 common pesticides in boronia oil using GC high resolution mass spectrometry was completed. An analytical technique for the detection of monocrotophos in essential oils was developed using LC with detection by MSMS. The methodology included an aqueous extraction step which removed many essential oil components from the sample.Further method development of LC MSMS included the assessment of electrospray ionisation (ESI) and atmospheric pressure chemical ionisation (APCI. For the chemicals trialed, ESI has limited application. No response was recorded for some of the most commonly used pesticides in the essential oil industry, such as linuron, oxyflurofen, and bromacil. Overall, there was very little difference between the sensitivity for ESI and APCI. However, APCI was slightly more sensitive for the commonly used pesticides, tebuconazole and propiconazole, and showed a response, though poor, to linuron and oxyflurofen. In addition, APCI was the preferred ionisation method for the following reasons,♦APCI uses less nitrogen gas compared to ESI, making overnight runs less costly;♦APCI does not have the high back pressure associated with ionisation by ESI such that APCI can be run in conjunction with UV-VIS without risk of fracturing the cell, which is pressure sensitive. Analytes that ionised in the negative APCI mode were incorporated into a separate screen which included bromacil, terbacil, and the esters of the fluazifop and haloxyfop acids. Further work using APCI in the positive mode formed the basis for the inclusion of monocrotophos, pirimicarb, propazine and difenaconazole into the standard screen already established. Acephate, carbaryl, dimethoate, ethofumesate and pendimethalin all required further work for enhanced ionisation and / or improved elution profiles. Negative ionisation mode for APCI gave improved characteristics for dicamba, procymidone, MCPA and mecoprop.The thirteen pesticides included in this general screen were monocrotophos, simazine, cyanazine, pirimicarb, propazine, sethoxydim, prometryb, tebuconazole, propiconazole, , difenoconazole and the esters of fluroxypyr, fluazifop and haloxyfop.. Bromacil and terbacil were not included as both require negative ionisation and elute within the same time window as simazine, which requires positive ionisation. Cycling the MS between the two modes was not practical.The method validation was tested against three oils, peppermint, parsley and fennel.Detection limits ranged from 0.1 to 0.5 mgkg-1 within the matrix of the essential oils, with a linear relationship established between pesticide concentration and peak height (r2 greater than 0.997) and repeatabilities, as described by the relative standard deviation (r.s.d), ranging from 3 to 19%. The type of oil analysed had minimal effect on the response function as expressed by slope of the standard curve.The pesticides which have an carboxylic acid moiety such as fluazifop, haloxyfop and fluroxypyr, present several complications in any analytical method development. The commercial preparations usually have the carboxylic acid in the ester form, which is hydrolysed to the active acidic form on contact with soil and vegetation. In addition, the esters may be present in several forms, such as the ethoxy ethyl or butyl esters. Detection using ESI was tested. Preliminary results indicate that ESI is unsuitable for haloxyfop and fluroxypyr ester. Fluazifop possessed good ionisation characteristics using ESI, with responses approximately thirty times that recorded for haxloyfop. Poor chromatography and response necessitated improved mobile phase and the effect of pH on elution characteristics was considered the most critical parameter. The inclusion of acetic acid improved peak resolution.The LC MSMS method for the detection of dicamba, fluroxypyr, MCPA, mecoprop and haloxyfop in peppermint and fennel distilled oils underwent the validation process. Detection limits ranged from 0.01 to 0.1 mgkg-1Extraction protocols and LC MSMS methods for the detection of paraquat and diquat were developed. ESI produced excellent responses for both paraquat and diquat, after some modifications of the mobile phase. Extraction methodology using aqueous phases were developed. Extraction with carbonate buffer proved to be the most effective in terms of recovery and robustness. A total ion chromatogram of the LC run of an aqueous extract of essential oil was recorded and detection using a photodiode array detector confirmed that very little essential oil matrix was co-extracted. The low background noise indicated that samples could be introduced directly into the MS. This presented a most efficient and rapid way for analysis of paraquat and diquat, avoiding the need for specialised columns or modifiers to be included in the mobile phase to instigate ion exchange.The adsorbtion of paraquat and diquat onto glass and other surfaces was reduced by the inclusion of diethylenetriamine (DETA). DETA preferentially accumulates on the surfaces of sample containers, competitively binding to the adsorption sites. All glassware used in the paraquat diquat analysis were washed in a 5% solution of 0.1M DETA, DETA was included in all standard curve preparations, oils were extracted with aqueous DETA and the mobile phase was changed to 50:50 DETA / methanol. The stainless steel tubing on the switching valve was replaced with teflon, further improvingreproducibility. Method validation was undertaken of the analysis of paraquat and diquat using the protocols established. The relationship between analyte concentration and peak area was not linear at low concentrations, with adsorption more pronounced for paraquat, such that the response for this analyte was half that seen for diquat and the 0.1 mgkg-1 level.The development of a method for the detection of the dithiocarbamate, mancozeb was commenced. Disodium N, N'-ethylenebis(dithiocarbamate) was synthesised as a standard for the derivatised final analytical product. An LC method, with detection using MSMS, was successfully completed. The inclusion of a phase transfer reagent, tetrabutylammonium hyrdrogen sulfate, required in the derivatisation step, contaminated the LC MSMS system, such that any signal from the target analyte was masked. Alternatives to the phase transfer reagent are now being investigated.Monitoring of harvests were undertaken for the years spanning 1998 to 2001. Screens were conducted covering a range of solvent extracted and distilled oils. Residues tested for included tebuconazole, simazine, terbacil, bromacil, sethoxydim, prometryn, oxyflurofen, pirimicarb, difenaconazole, the herbicides with acidic moieties and paraquat and diquat. Problems continued for residues of propiconazole in boronia in the 1998 / 1999 year with levels to 1 mgkg-1 still being detected. Prometryn residues were detected in a large number of samples of parsley oil.Finally the information gleaned over years of research was collated into a manual designed to allow intending analysts to determine methodologies and equipment most suited to the type of the pesticide of interest and the applicability of analytical equipment generally available.1. Introduction1.1 Background to the ProjectResearch undertaken by the Horticultural Research Group at the University of Tasmania, into pesticide residues in essential oils has been ongoing for several years and has dealt with the problems specific to the analysis of residues within the matrix of essential oils. Analytical methods for pesticides have been developed exploiting the high degree of specificity and selectivity afforded by high resolution gas chromatography mass spectrometry. Standard curves, reproducibility and detection limits were established for each. Chemicals, otherwise not amenable to gas chromatography, were derivatised and incorporated into a separate screen to cover pesticides with acidic moieties.Research has been conducted into low resolution GC mass selective detectors (MSD and GC ECD. Low resolution GC MSD achieved detection to levels of 1 mgkg-1 in boronia oil, whilst analysis using GC ECD require a clean-up step to effectively detect halogenated chemicals below 1mgkg-1.Dithane (mancozeb) residues were digested using acidified stannous chloride and the carbon disulphide generated from this reaction analysed by GC coupled to FPD in the sulphur mode.Field trials in peppermint crops were established in accordance with the guidelines published by the National Registration Authority (NRA), monitoring the dissipation of Tilt and Folicur residues in peppermint leaves and the co-distillation of these residues with hydro-distilled peppermint oils were assessed.Development of extraction protocols, analytical methods, harvest monitoring and field trials were continued and were detailed in a subsequent report. Solvent-based extractions and supercritical fluid extraction (SFE) was found to have limited application in the clean-up of essential oilsIn conjunction with Essential Oils of Tasmania (EOT), the contamination risk, associated with the introduction of a range of herbicides, was assessed through a series of field trials. This required analytical method development to detect residues in boronia flowers, leaf and oil. The methodology for a further nine pesticides was successful applied. Detection limits for these chemicals ranged from 0.002 mgkg-1 to 0.1 mgkg-1. In addition, methods were developed to analyse for herbicides with active ingredients (ai) whose structure contained acidic functional groups. Two methods of pesticide application were trialed. Directed sprays refer to those directed on the stems and leaves of weeds at the base of boronia trees throughout the trial plot. Cover sprays were applied over the entire canopy. For all herbicides for which significant residues were detected, it was evident that cover sprays resulted in contamination levels ten times those occurring as a result of directed spraying in some instances. Chloropropham, terbacil and simazine presented potentially serious residue problems, with translocation of the chemical from vegetative material to the flower clearly evident.Directed spray applications of diuron and dimethenamid presented only low residue levels in extracted flowers with adequate control of weeds. Oxyflurofen and the mixture of bromacil and diuron (Krovar) presented only low levels of residues when used as a directed spray and were effective as both post and pre-emergent herbicides. Only very low levels of residues of both sethoxydim and norflurazon were detected in boronia oil produced in crops treated with directed spray applications. Sethoxydim was effective as a cover spray for grasses whilst norflurazon showed potential as herbicide to be used in combination with other chemicals such as diuron, paraquat and diquat. Little contamination of boronia oils by herbicides with acidic moieties was found. This advantage, however, appears to be offset by the relatively poor weed control. Both pendimethalin and haloxyfop showed good weed control. Both, however, present problems with chemical residues in boronia oil and should only be used as a directed sprayThe stability of tebuconazole, monocrotophos and propiconazole in boronia under standard storage conditions was investigated. Field trials of tebuconazole and propiconazole were established in commercial boronia crops and the dissipation of both were monitored over time. The amount of pesticide detected in the oils was related to that originally present in the flowers from which the oils were produced.Experiments were conducted to determine whether the accumulation of terbacil residues in peppermint was retarding plant vigour. The level recorded in the peppermint leaves were comparatively low. Itis unlikely that terbacil carry over is the cause for the lack of vigour in young peppermint plants.Boronia oils produced in 1996, 1997 and 1998 were screened for pesticides using the analytical methods developed. High levels of residues of propiconazole were shown to persist in crops harvested up until 1998. Field trials have shown that propiconazole residues should not present problems if the fungicide is used as recommended by the manufacturers.1.2 Objectives♦Provide the industry, including the Standards Association of Australia Committee CH21, with a concise practical reference, immediately relevant to the Australian essential oil industry♦Facilitate the transfer of technology from a research base to practical application in routine monitoring programs♦Continue the development of analytical methods for the detection of metabolites of the active ingredients of pesticide in essential oils.♦Validate the methods developed.♦Provide industry with data supporting assurances of quality for all exported products.♦Provide a benchmark from which Australia may negotiate the setting of a realistic maximum residue limit (MRL)♦Determine whether the rate of uptake is relative to the concentration of active ingredient on the leaf surface may establish the minimum application rates for effective pest control.1.3 MethodologyThree approaches were used to achieve the objectives set out above.♦Continue the development and validation of analytical methods for the detection of pesticide residues in essential oils. Analytical methods were developed using gas chromatography high resolution mass spectrometry (GC HR MS), GC ECD, GC FPD and high pressure liquid chromatography with detection using MSMS.♦Provide industry with data supporting assurances of quality for all exported products.♦Coordinate research results into a comprehensive manual outlining practical approaches to the development of analytical proceduresOne aspect of the commissioning of this project was to provide a cost effective analytical resource to assess the degree of the pesticide contamination already occurring in the essential oils industry using standard pesticide regimens. Oil samples from annual harvests were analysed for the presence of pesticide residues. Data from preceding years were collated to determine the progress or otherwise, in the application of best agricultural practice (BAP).2. Experimental Protocols & Detailed ResultsThe experimental conditions and results are presented under the following headings:♦Method Development♦Monitoring of Commercial Harvests♦Production of a Manual2.1 Method DevelopmentMethod development focussed on the effectiveness of clean-up techniques, validation of existing techniques, the assessment of the application of GC ECD and FPD and high pressure liquid chromatography with ion trap MS, MS detection.2.1.1 Clean-up Methodologies2.1.1.i. Application of Disposable SPE cartridges in the clean-up of pesticide residues in essentialoilsLiterature reviews provided limited information with regards to the separation of contaminants within essential oils. The retention characteristics of disposable C18 cartridges were trialed.Experiment 1;Aim : To assess the capacity of disposable C18 cartridges to the separation of boronia oil components. Experimental : Boronia concrete (49.8 mg) was dissolved in 0.5 mL of acetone and 0.4 mL of chloroform was added. 1mg of octadecane was added as an internal standard. A C18 Sep-Pak Classic cartridge (short body) was pre- conditioned with 1.25 mL of methanol, which was passed through the column at 7.5 mLmin-1, followed by 1.25 mL of acetone, at the same flow rate. The boronia samplewas then applied to the column at 2 mLmin-1 flow and eluted with 1.25 mL of acetone / chloroform (5/ 4) and then eluted with a further 2.5 mL of chloroform. 5 fractions of 25 drops each were collected. The fractions were analysed by GC FID using the following parametersAnalytical parameters6890PackardHewlettGCcolumn: Hewlett Packard 5MS 30m, i.d 0.32µmcarrier gas instrument grade nitrogeninjection volume: 1µL (split)injector temp: 250°Cdetector temp: 280°Cinital temp: 50°C (3 min), 10°Cmin-1 to 270°C (7 mins)head pressure : 10psi.Results : Table 1 record the percentage volatiles detected in the fractions collectedFraction 1 2 3 4 5 % components eluting 18 67 13 2636%monoterpenes 15%sesquiquiterpenes 33 65 2%high M.W components 1 43 47 9Table 1. Percentage volatiles eluting from SPE C18 cartridgesDiscussion : The majority of boronia components eluted on the solvent front, effecting minimal separation. This area of SPE clean-up of essential oils requires a wide ranging investigation, varying parameters such as cartridge type and polarity of mobile phase.Experiment 2.Aim : For the development of methods using LC MSMS without clean-up steps, the potential for oil components to accumulate on the reverse phase (RP) column must be assessed. The retention of essential oil components on SPE C18 cartridges, using the same mobile phase as that to be used in theLC system, would provide a good indication as to the risk of contamination of the LC columns withoil components.Experimental: Parsley oil (20-30 mg) was weighed into a GC vial. 200 µL of a 10 µgmL-1 solution (equivalent to 100mgkg-1 in oil) of each of sethoxydim, simazine, terbacil, prometryn, tebuconazoleand propiconazole were used to spike the oil, which was then dissolved in 1.0 mL of acetonitrile. The solution was then slowly introduced to the C18 cartridge (Waters Sep Pac 'classic' C18 #51910) using a disposable luer lock, 10 mL syringe, under constant manual pressure, and eluted with 9 mLs of acetonitrile. Ten, 1 mL fractions were collected and transferred to GC vials. 1mg of octadecane was added to each vial and the samples were analysed by GC FID under the conditions described in experiment 1.The experiment was repeated using C18 cartridges which had been pre-conditioned with distilled waterfor 15 mins. Again, parsley oil, spiked with pesticides was eluted with acetonitrile and 5 x 1 mL fractions collected.Results: The majority of oil components and pesticides were eluted from the C18 cartridge in the firsttwo fractions. Little to no separation of the target pesticides from the oil matrix was achieved. Table2 lists the distribution of essential oil components in the fractions collected.Fraction 1 2 3 4 5 % components eluting 18 67 13 2663%monoterpenes 15%sesquiquiterpenes 33 65 2%high M.W components 1 43 47 9water conditioned% components eluting 35 56 8 12%monoterpenes 3068%sesquiquiterpenes 60 39 1 0%high M.W components 0 50 42 7Table 2. Percentage volatiles eluting for SPE C18 cartridgesFigure 1 shows a histogram of the percentage distribution of components from the oil in each of the four fractions.Figure 1. Histogram of the percentage of volatiles of distilled oils in each of four fraction elutedon SPE C18 cartridges (non-preconditioned)Figure 2. Histogram of the percentage of volatiles of distilled oils in each of four fraction elutedon SPE C18 cartridges (preconditioned)Discussion : The chemical properties of many of the target pesticides, including polarity, solubility in organic solvents and chromatographic behaviour, are similar to the majority of essential oil components. This precludes the effective separation of analytes from such matrices through the use of standard techniques, where the major focus is pre-concentration of pesticide residues from water or water based vegetative material. However, this experiment served to provide a good indication that under HPLC conditions, where a reverse phase C18 column is used in conjunction with acetonitrile / water based mobile phases, essential oil components do not remain on the column.。

针刺方法中英文对照

针刺方法中英文对照
Evaluation of therapeutic effect of acupuncture and moxibustion on diarrhea In China, the efficacy evaluation of acupuncture and moxibustion in the treatment of diarrhea is mainly based on the improvement of patients' symptoms, the change of stool frequency and shape. In English speaking countries, the efficacy evaluation of acupuncture and moxibustion in the treatment of diarrhea is usually based on internationally accepted clinical efficacy evaluation criteria, including evaluation scale, quality of life questionnaire, etc.
04
By inserting needs into these points, acquisition can restore balance and harmony in the body, leading to improved health and well being
Principles of Acquisition
Needlework technique
Needlework technique
Different cupping methods

BS EN 12845-2004+A2-2009 固定式消防系统.自动喷水系统设计,安装和维修

BS EN 12845-2004+A2-2009 固定式消防系统.自动喷水系统设计,安装和维修
批注本地保存成功开通会员云端永久保存去开通
BRITISH STANDARD
BS EN 12845:2004 +A2:2009
Incorporating Corrigendum August 2009
Fixed firefighting systems — Automatic sprinkler systems — Design, installation and maintenance
1 2 3 4 4.1 4.2 4.3 4.4 4.4.1 4.4.2 4.4.3 4.4.4 5 5.1 5.1.1 5.1.2 5.2 5.3 5.4 5.5 6 6.1 6.2 6.2.1 6.2.2 6.2.3 6.3 6.3.1 6.3.2 7 7.1 7.2 7.2.1 7.2.2 7.2.3 7.3 7.3.1 7.3.2
介绍 Introduction ................................................................................................................................................. 10
This British Standard was published under the authority of the Standards Policy and Strategy Committee on 16 November 2004
Amendments/corrigenda issued since publication Date 31 July 2009 Comments Implementation of CEN amendment A2:2009 Correction to National foreword

稳定性英文版

稳定性英文版

HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationFLUOXETINE HClC17H18F3NO•HClM.W. = 345.79CAS — 59333-67-4STABILITY INDICATINGA S S A Y V A L I D A T I O NMethod is suitable for:ýIn-process controlþProduct ReleaseþStability indicating analysis (Suitability - US/EU Product) CAUTIONFLUOXETINE HYDROCHLORIDE IS A HAZARDOUS CHEMICAL AND SHOULD BE HANDLED ONLY UNDER CONDITIONS SUITABLE FOR HAZARDOUS WORK.IT IS HIGHLY PRESSURE SENSITIVE AND ADEQUATE PRECAUTIONS SHOULD BE TAKEN TO AVOID ANY MECHANICAL FORCE (SUCH AS GRINDING, CRUSHING, ETC.) ON THE POWDER.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationTABLE OF CONTENTS INTRODUCTION........................................................................................................................ PRECISION............................................................................................................................... System Repeatability ................................................................................................................ Method Repeatability................................................................................................................. Intermediate Precision .............................................................................................................. LINEARITY................................................................................................................................ RANGE...................................................................................................................................... ACCURACY............................................................................................................................... Accuracy of Standard Injections................................................................................................ Accuracy of the Drug Product.................................................................................................... VALIDATION OF FLUOXETINE HCl AT LOW CONCENTRATION........................................... Linearity at Low Concentrations................................................................................................. Accuracy of Fluoxetine HCl at Low Concentration..................................................................... System Repeatability................................................................................................................. Quantitation Limit....................................................................................................................... Detection Limit........................................................................................................................... VALIDATION FOR META-FLUOXETINE HCl (POSSIBLE IMPURITIES).................................. Meta-Fluoxetine HCl linearity at 0.05% - 1.0%........................................................................... Detection Limit for Fluoxetine HCl.............................................................................................. Quantitation Limit for Meta Fluoxetine HCl................................................................................ Accuracy for Meta-Fluoxetine HCl ............................................................................................ Method Repeatability for Meta-Fluoxetine HCl........................................................................... Intermediate Precision for Meta-Fluoxetine HCl......................................................................... SPECIFICITY - STABILITY INDICATING EVALUATION OF THE METHOD............................. FORCED DEGRADATION OF FINISHED PRODUCT AND STANDARD..................................1. Unstressed analysis...............................................................................................................2. Acid Hydrolysis stressed analysis..........................................................................................3. Base hydrolysis stressed analysis.........................................................................................4. Oxidation stressed analysis...................................................................................................5. Sunlight stressed analysis.....................................................................................................6. Heat of solution stressed analysis.........................................................................................7. Heat of powder stressed analysis.......................................................................................... System Suitability stressed analysis.......................................................................................... Placebo...................................................................................................................................... STABILITY OF STANDARD AND SAMPLE SOLUTIONS......................................................... Standard Solution...................................................................................................................... Sample Solutions....................................................................................................................... ROBUSTNESS.......................................................................................................................... Extraction................................................................................................................................... Factorial Design......................................................................................................................... CONCLUSION...........................................................................................................................ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationBACKGROUNDTherapeutically, Fluoxetine hydrochloride is a classified as a selective serotonin-reuptake inhibitor. Effectively used for the treatment of various depressions. Fluoxetine hydrochloride has been shown to have comparable efficacy to tricyclic antidepressants but with fewer anticholinergic side effects. The patent expiry becomes effective in 2001 (US). INTRODUCTIONFluoxetine capsules were prepared in two dosage strengths: 10mg and 20mg dosage strengths with the same capsule weight. The formulas are essentially similar and geometrically equivalent with the same ingredients and proportions. Minor changes in non-active proportions account for the change in active ingredient amounts from the 10 and 20 mg strength.The following validation, for the method SI-IAG-206-02 , includes assay and determination of Meta-Fluoxetine by HPLC, is based on the analytical method validation SI-IAG-209-06. Currently the method is the in-house method performed for Stability Studies. The Validation was performed on the 20mg dosage samples, IAG-21-001 and IAG-21-002.In the forced degradation studies, the two placebo samples were also used. PRECISIONSYSTEM REPEATABILITYFive replicate injections of the standard solution at the concentration of 0.4242mg/mL as described in method SI-IAG-206-02 were made and the relative standard deviation (RSD) of the peak areas was calculated.SAMPLE PEAK AREA#15390#25406#35405#45405#55406Average5402.7SD 6.1% RSD0.1ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::PRECISION - Method RepeatabilityThe full HPLC method as described in SI-IAG-206-02 was carried-out on the finished product IAG-21-001 for the 20mg dosage form. The method repeated six times and the relative standard deviation (RSD) was calculated.SAMPLENumber%ASSAYof labeled amountI 96.9II 97.8III 98.2IV 97.4V 97.7VI 98.5(%) Average97.7SD 0.6(%) RSD0.6PRECISION - Intermediate PrecisionThe full method as described in SI-IAG-206-02 was carried-out on the finished product IAG-21-001 for the 20mg dosage form. The method was repeated six times by a second analyst on a different day using a different HPLC instrument. The average assay and the relative standard deviation (RSD) were calculated.SAMPLENumber% ASSAYof labeled amountI 98.3II 96.3III 94.6IV 96.3V 97.8VI 93.3Average (%)96.1SD 2.0RSD (%)2.1The difference between the average results of method repeatability and the intermediate precision is 1.7%.HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationLINEARITYStandard solutions were prepared at 50% to 200% of the nominal concentration required by the assay procedure. Linear regression analysis demonstrated acceptability of the method for quantitative analysis over the concentration range required. Y-Intercept was found to be insignificant.RANGEDifferent concentrations of the sample (IAG-21-001) for the 20mg dosage form were prepared, covering between 50% - 200% of the nominal weight of the sample.Conc. (%)Conc. (mg/mL)Peak Area% Assayof labeled amount500.20116235096.7700.27935334099.21000.39734463296.61500.64480757797.52000.79448939497.9(%) Average97.6SD 1.0(%) RSD 1.0ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::RANGE (cont.)The results demonstrate linearity as well over the specified range.Correlation coefficient (RSQ)0.99981 Slope11808.3Y -Interceptresponse at 100%* 100 (%) 0.3%ACCURACYACCURACY OF STANDARD INJECTIONSFive (5) replicate injections of the working standard solution at concentration of 0.4242mg/mL, as described in method SI-IAG-206-02 were made.INJECTIONNO.PEAK AREA%ACCURACYI 539299.7II 540599.9III 540499.9IV 5406100.0V 5407100.0Average 5402.899.9%SD 6.10.1RSD, (%)0.10.1The percent deviation from the true value wasdetermined from the linear regression lineHPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::ACCURACY OF THE DRUG PRODUCTAdmixtures of non-actives (placebo, batch IAG-21-001 ) with Fluoxetine HCl were prepared at the same proportion as in a capsule (70%-180% of the nominal concentration).Three preparations were made for each concentration and the recovery was calculated.Conc.(%)Placebo Wt.(mg)Fluoxetine HCl Wt.(mg)Peak Area%Accuracy Average (%)70%7079.477.843465102.27079.687.873427100.77079.618.013465100.0101.0100%10079.6211.25476397.910080.8011.42491799.610079.6011.42485498.398.6130%13079.7214.90640599.413080.3114.75632899.213081.3314.766402100.399.618079.9920.10863699.318079.3820.45879499.418080.0820.32874899.599.4Placebo, Batch Lot IAG-21-001HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::VALIDATION OF FLUOXETINE HClAT LOW CONCENTRATIONLINEARITY AT LOW CONCENTRATIONSStandard solution of Fluoxetine were prepared at approximately 0.02%-1.0% of the working concentration required by the method SI-IAG-206-02. Linear regression analysis demonstrated acceptability of the method for quantitative analysis over this range.ACCURACY OF FLUOXETINE HCl AT LOW CONCENTRATIONThe peak areas of the standard solution at the working concentration were measured and the percent deviation from the true value, as determined from the linear regression was calculated.SAMPLECONC.µg/100mLAREA FOUND%ACCURACYI 470.56258499.7II 470.56359098.1III 470.561585101.3IV 470.561940100.7V 470.56252599.8VI 470.56271599.5(%) AverageSlope = 132.7395299.9SD Y-Intercept = -65.872371.1(%) RSD1.1HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSystem RepeatabilitySix replicate injections of standard solution at 0.02% and 0.05% of working concentration as described in method SI-IAG-206-02 were made and the relative standard deviation was calculated.SAMPLE FLUOXETINE HCl AREA0.02%0.05%I10173623II11503731III10103475IV10623390V10393315VI10953235Average10623462RSD, (%) 5.0 5.4Quantitation Limit - QLThe quantitation limit ( QL) was established by determining the minimum level at which the analyte was quantified. The quantitation limit for Fluoxetine HCl is 0.02% of the working standard concentration with resulting RSD (for six injections) of 5.0%. Detection Limit - DLThe detection limit (DL) was established by determining the minimum level at which the analyte was reliably detected. The detection limit of Fluoxetine HCl is about 0.01% of the working standard concentration.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::VALIDATION FOR META-FLUOXETINE HCl(EVALUATING POSSIBLE IMPURITIES)Meta-Fluoxetine HCl linearity at 0.05% - 1.0%Relative Response Factor (F)Relative response factor for Meta-Fluoxetine HCl was determined as slope of Fluoxetine HCl divided by the slope of Meta-Fluoxetine HCl from the linearity graphs (analysed at the same time).F =132.7395274.859534= 1.8Detection Limit (DL) for Fluoxetine HClThe detection limit (DL) was established by determining the minimum level at which the analyte was reliably detected.Detection limit for Meta Fluoxetine HCl is about 0.02%.Quantitation Limit (QL) for Meta-Fluoxetine HClThe QL is determined by the analysis of samples with known concentration of Meta-Fluoxetine HCl and by establishing the minimum level at which the Meta-Fluoxetine HCl can be quantified with acceptable accuracy and precision.Six individual preparations of standard and placebo spiked with Meta-Fluoxetine HCl solution to give solution with 0.05% of Meta Fluoxetine HCl, were injected into the HPLC and the recovery was calculated.HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::META-FLUOXETINE HCl[RECOVERY IN SPIKED SAMPLES].Approx.Conc.(%)Known Conc.(µg/100ml)Area in SpikedSampleFound Conc.(µg/100mL)Recovery (%)0.0521.783326125.735118.10.0521.783326825.821118.50.0521.783292021.55799.00.0521.783324125.490117.00.0521.783287220.96996.30.0521.783328526.030119.5(%) AVERAGE111.4SD The recovery result of 6 samples is between 80%-120%.10.7(%) RSDQL for Meta Fluoxetine HCl is 0.05%.9.6Accuracy for Meta Fluoxetine HClDetermination of Accuracy for Meta-Fluoxetine HCl impurity was assessed using triplicate samples (of the drug product) spiked with known quantities of Meta Fluoxetine HCl impurity at three concentrations levels (namely 80%, 100% and 120% of the specified limit - 0.05%).The results are within specifications:For 0.4% and 0.5% recovery of 85% -115%For 0.6% recovery of 90%-110%HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::META-FLUOXETINE HCl[RECOVERY IN SPIKED SAMPLES]Approx.Conc.(%)Known Conc.(µg/100mL)Area in spikedSample Found Conc.(µg/100mL)Recovery (%)[0.4%]0.4174.2614283182.66104.820.4174.2614606187.11107.370.4174.2614351183.59105.36[0.5%]0.5217.8317344224.85103.220.5217.8316713216.1599.230.5217.8317341224.81103.20[0.6%]0.6261.3918367238.9591.420.6261.3920606269.81103.220.6261.3920237264.73101.28RECOVERY DATA DETERMINED IN SPIKED SAMPLESHPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::REPEATABILITYMethod Repeatability - Meta Fluoxetine HClThe full method (as described in SI-IAG-206-02) was carried out on the finished drug product representing lot number IAG-21-001-(1). The HPLC method repeated serially, six times and the relative standard deviation (RSD) was calculated.IAG-21-001 20mg CAPSULES - FLUOXETINESample% Meta Fluoxetine % Meta-Fluoxetine 1 in Spiked Solution10.0260.09520.0270.08630.0320.07740.0300.07450.0240.09060.0280.063AVERAGE (%)0.0280.081SD 0.0030.012RSD, (%)10.314.51NOTE :All results are less than QL (0.05%) therefore spiked samples with 0.05% Meta Fluoxetine HCl were injected.HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::Intermediate Precision - Meta-Fluoxetine HClThe full method as described in SI-IAG-206-02 was applied on the finished product IAG-21-001-(1) .It was repeated six times, with a different analyst on a different day using a different HPLC instrument.The difference between the average results obtained by the method repeatability and the intermediate precision was less than 30.0%, (11.4% for Meta-Fluoxetine HCl as is and 28.5% for spiked solution).IAG-21-001 20mg - CAPSULES FLUOXETINESample N o:Percentage Meta-fluoxetine% Meta-fluoxetine 1 in spiked solution10.0260.06920.0270.05730.0120.06140.0210.05850.0360.05560.0270.079(%) AVERAGE0.0250.063SD 0.0080.009(%) RSD31.514.51NOTE:All results obtained were well below the QL (0.05%) thus spiked samples slightly greater than 0.05% Meta-Fluoxetine HCl were injected. The RSD at the QL of the spiked solution was 14.5%HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSPECIFICITY - STABILITY INDICATING EVALUATIONDemonstration of the Stability Indicating parameters of the HPLC assay method [SI-IAG-206-02] for Fluoxetine 10 & 20mg capsules, a suitable photo-diode array detector was incorporated utilizing a commercial chromatography software managing system2, and applied to analyze a range of stressed samples of the finished drug product.GLOSSARY of PEAK PURITY RESULT NOTATION (as reported2):Purity Angle-is a measure of spectral non-homogeneity across a peak, i.e. the weighed average of all spectral contrast angles calculated by comparing all spectra in the integrated peak against the peak apex spectrum.Purity Threshold-is the sum of noise angle3 and solvent angle4. It is the limit of detection of shape differences between two spectra.Match Angle-is a comparison of the spectrum at the peak apex against a library spectrum.Match Threshold-is the sum of the match noise angle3 and match solvent angle4.3Noise Angle-is a measure of spectral non-homogeneity caused by system noise.4Solvent Angle-is a measure of spectral non-homogeneity caused by solvent composition.OVERVIEWT he assay of the main peak in each stressed solution is calculated according to the assay method SI-IAG-206-02, against the Standard Solution, injected on the same day.I f the Purity Angle is smaller than the Purity Threshold and the Match Angle is smaller than the Match Threshold, no significant differences between spectra can be detected. As a result no spectroscopic evidence for co-elution is evident and the peak is considered to be pure.T he stressed condition study indicated that the Fluoxetine peak is free from any appreciable degradation interference under the stressed conditions tested. Observed degradation products peaks were well separated from the main peak.1® PDA-996 Waters™ ; 2[Millennium 2010]ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationFORCED DEGRADATION OF FINISHED PRODUCT & STANDARD 1.UNSTRESSED SAMPLE1.1.Sample IAG-21-001 (2) (20mg/capsule) was prepared as stated in SI-IAG-206-02 and injected into the HPLC system. The calculated assay is 98.5%.SAMPLE - UNSTRESSEDFluoxetine:Purity Angle:0.075Match Angle:0.407Purity Threshold:0.142Match Threshold:0.4251.2.Standard solution was prepared as stated in method SI-IAG-206-02 and injected into the HPLC system. The calculated assay is 100.0%.Fluoxetine:Purity Angle:0.078Match Angle:0.379Purity Threshold:0.146Match Threshold:0.4272.ACID HYDROLYSIS2.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as in method SI-IAG-206-02 : An amount equivalent to 20mg Fluoxetine was weighed into a 50mL volumetric flask. 20mL Diluent was added and the solution sonicated for 10 minutes. 1mL of conc. HCl was added to this solution The solution was allowed to stand for 18 hours, then adjusted to about pH = 5.5 with NaOH 10N, made up to volume with Diluent and injected into the HPLC system after filtration.Fluoxetine peak intensity did NOT decrease. Assay result obtained - 98.8%.SAMPLE- ACID HYDROLYSISFluoxetine peak:Purity Angle:0.055Match Angle:0.143Purity Threshold:0.096Match Threshold:0.3712.2.Standard solution was prepared as in method SI-IAG-206-02 : about 22mg Fluoxetine HCl were weighed into a 50mL volumetric flask. 20mL Diluent were added. 2mL of conc. HCl were added to this solution. The solution was allowed to stand for 18 hours, then adjusted to about pH = 5.5 with NaOH 10N, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity did NOT decrease. Assay result obtained - 97.2%.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSTANDARD - ACID HYDROLYSISFluoxetine peak:Purity Angle:0.060Match Angle:0.060Purity Threshold:0.099Match Threshold:0.3713.BASE HYDROLYSIS3.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as per method SI-IAG-206-02 : An amount equivalent to 20mg Fluoxetine was weight into a 50mL volumetric flask. 20mL Diluent was added and the solution sonicated for 10 minutes. 1mL of 5N NaOH was added to this solution. The solution was allowed to stand for 18 hours, then adjusted to about pH = 5.5 with 5N HCl, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity did NOT decrease. Assay result obtained - 99.3%.SAMPLE - BASE HYDROLYSISFluoxetine peak:Purity Angle:0.063Match Angle:0.065Purity Threshold:0.099Match Threshold:0.3623.2.Standard stock solution was prepared as per method SI-IAG-206-02 : About 22mg Fluoxetine HCl was weighed into a 50mL volumetric flask. 20mL Diluent was added. 2mL of 5N NaOH was added to this solution. The solution was allowed to stand for 18 hours, then adjusted to about pH=5.5 with 5N HCl, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity did NOT decrease - 99.5%.STANDARD - BASE HYDROLYSISFluoxetine peak:Purity Angle:0.081Match Angle:0.096Purity Threshold:0.103Match Threshold:0.3634.OXIDATION4.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as per method SI-IAG-206-02. An equivalent to 20mg Fluoxetine was weighed into a 50mL volumetric flask. 20mL Diluent added and the solution sonicated for 10 minutes.1.0mL of 30% H2O2 was added to the solution and allowed to stand for 5 hours, then made up to volume with Diluent, filtered and injected into HPLC system.Fluoxetine peak intensity decreased to 95.2%.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSAMPLE - OXIDATIONFluoxetine peak:Purity Angle:0.090Match Angle:0.400Purity Threshold:0.154Match Threshold:0.4294.2.Standard solution was prepared as in method SI-IAG-206-02 : about 22mg Fluoxetine HCl were weighed into a 50mL volumetric flask and 25mL Diluent were added. 2mL of 30% H2O2 were added to this solution which was standing for 5 hours, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity decreased to 95.8%.STANDARD - OXIDATIONFluoxetine peak:Purity Angle:0.083Match Angle:0.416Purity Threshold:0.153Match Threshold:0.4295.SUNLIGHT5.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as in method SI-IAG-206-02 . The solution was exposed to 500w/hr. cell sunlight for 1hour. The BST was set to 35°C and the ACT was 45°C. The vials were placed in a horizontal position (4mm vials, National + Septum were used). A Dark control solution was tested. A 2%w/v quinine solution was used as the reference absorbance solution.Fluoxetine peak decreased to 91.2% and the dark control solution showed assay of 97.0%. The difference in the absorbance in the quinine solution is 0.4227AU.Additional peak was observed at RRT of 1.5 (2.7%).The total percent of Fluoxetine peak with the degradation peak is about 93.9%.SAMPLE - SUNLIGHTFluoxetine peak:Purity Angle:0.093Match Angle:0.583Purity Threshold:0.148Match Threshold:0.825 ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSUNLIGHT (Cont.)5.2.Working standard solution was prepared as in method SI-IAG-206-02 . The solution was exposed to 500w/hr. cell sunlight for 1.5 hour. The BST was set to 35°C and the ACT was 42°C. The vials were placed in a horizontal position (4mm vials, National + Septum were used). A Dark control solution was tested. A 2%w/v quinine solution was used as the reference absorbance solution.Fluoxetine peak was decreased to 95.2% and the dark control solution showed assay of 99.5%.The difference in the absorbance in the quinine solution is 0.4227AU.Additional peak were observed at RRT of 1.5 (2.3).The total percent of Fluoxetine peak with the degradation peak is about 97.5%. STANDARD - SUNLIGHTFluoxetine peak:Purity Angle:0.067Match Angle:0.389Purity Threshold:0.134Match Threshold:0.8196.HEAT OF SOLUTION6.1.Sample solution of IAG-21-001-(2) (20 mg/capsule) was prepared as in method SI-IAG-206-02 . Equivalent to 20mg Fluoxetine was weighed into a 50mL volumetric flask. 20mL Diluent was added and the solution was sonicated for 10 minutes and made up to volume with Diluent. 4mL solution was transferred into a suitable crucible, heated at 105°C in an oven for 2 hours. The sample was cooled to ambient temperature, filtered and injected into the HPLC system.Fluoxetine peak was decreased to 93.3%.SAMPLE - HEAT OF SOLUTION [105o C]Fluoxetine peak:Purity Angle:0.062Match Angle:0.460Purity Threshold:0.131Match Threshold:0.8186.2.Standard Working Solution (WS) was prepared under method SI-IAG-206-02 . 4mL of the working solution was transferred into a suitable crucible, placed in an oven at 105°C for 2 hours, cooled to ambient temperature and injected into the HPLC system.Fluoxetine peak intensity did not decrease - 100.5%.ED. N0: 04Effective Date:APPROVED::。

运动强度与成人高血压患者C反应蛋白的关系

运动强度与成人高血压患者C反应蛋白的关系

论著·临床辅助检查CHINESE COMMUNITY DOCTORS 中国社区医师2018年第34卷第14期原发性高血压的进程是一种炎性反应性疾病的过程;C 反应蛋白(hs-CRP)是一种参与炎症的重要急性期蛋白,在炎症与高血压的关联中研究最多,大量研究结果支持hs-CRP 是高血压的独立预测因子[1,2];同时充分肯定运动明显降低血清超敏hs-CRP 水平及血压,减少心血管事件风险,给高血压个体带来益处[3]。

本研究探讨运动强度与成人高血压患者血清hs-CRP 浓度的关系,为运动强度的制定提供试验依据。

资料与方法研究对象纳入标准:①符合成人原发性高血压的诊断标准,年龄20~60周岁,且用药后血压控制在<140/90mmHg;②县城所在地、乐里镇辖区内居民;③入选前,试验对象运动量未达到中小运动量标准(每天运动<30min,每次运动心率的提高很少>20%)[4];④主观上自愿接受试验规定的运动强度。

排除标准:①运动高血压;②肝、肾功能不全;③慢性炎症和免疫功能低下;④不能耐受试验规定运动量的其他疾病;⑤自动退出试验的其他情况。

共选入72例原发性高血压患者参与本次研究,其中男47例,女25例。

方法:第1年中小运动量,每周从事轻到中等强度运动≥2.5h,运动的标准是锻炼时心跳加速,心率增加>20%并可能出汗,但运动时心率应在<70%最大心率(210-年龄),以患者能耐受且不感到疲劳为宜[4]。

试验前测量血清hs-CRP 浓度,以后第3个月、第6个doi:10.3969/j.issn.1007-614x.2018.14.073科研项目广西壮族自治区卫生和计划生育委员会自筹经费科研课题。

合同号:Z2016002摘要目的:探讨运动强度与成人高血压患者血清C 反应蛋白(hs-CRP)浓度的相关性。

方法:选择年龄20~60周岁,且用药后血压控制在<140/90mmHg,平时运动未达中小运动量标准的原发性高血压患者72例,试验前测量血清hs-CRP 浓度。

高分辨率熔解曲线实验优化建议

高分辨率熔解曲线实验优化建议

High Resolution Melting高分辨率熔解曲线实验优化建议picture placeholderApplication Support Center Roche Applied Science Hotline: 800 820 0577Email: asc.support@饱和双链DNA结合染料减少非特异性产物和引物二聚体引物模板Mg 2+ PCR 程序•引物设计–引物退火温度 Tm~60o C–扩增片段长度 <250bp,通常在100-150bp左右–使用专业的引物设计软件;利用BLAST(/BLAST) 来确保引物与模板DNA结合的特异性•引物纯度–使用HPLC纯化级别的高纯度引物•引物浓度–为了避免引物二聚体的生成,使用较低的引物浓度:例如 200nM each•核酸提取–确保所有样品的提纯方法都是一样的–使用高质量的核酸提纯方法。

例如:商业化的手动核酸提取试剂盒或者全自动核酸提取仪•模板浓度–建议模板起始浓度在5-30ng/20ul,扩增曲线的Cp值<30–用吸光度方法计算待测样品的核酸浓度,调整模板浓度使它们的起始浓度相同167 bp PCR FragmentMgCl2 Titration 1.0 – 4.0 mMPCR Primers: 200 nM each Touchdown PCR Protocol (64 – 54°C)MWMPCR Products (+ NTC 4.0 mM)MWM50 bp4.04.03.53.02.52.01.51.050 bpMgCl 2 ConcentrationAgarose Gel 2%Touchdown PCR•用于:当无法进一步调节引物退火温度时•原理:先在较高的温度退火,保证产物的特异性;在后面的循环中,退火温度逐渐降低,保证有足够的产物总量•局限性:Touchdown PCR 不适用于定量实验Example 1: Touchdown PCR with40 Cycles and 0.5 °C step sizeExample 2:Touchdown PCR with45 Cycles and 1°C step size在 LC Nano中编辑 Touchdown PCR•问题:丰度低的突变基因在PCR扩增中很难被检测到•解决方法:选择性的扩增突变序列•Fast COLD PCR原理:–适用于 G/C → A/T 的突变,Tm(wt)>Tm(mut)–变性温度设在Tm(mut)附近,保证在这个温度下只有突变型发生变性•实验必备条件:–精确的温度控制–孔间温差尽量小,保证样品中突变型扩增的富集程度一致•其他应用:–Fast COLD-PCR:优先扩增 Tm 低于野生型 homoduplexes,适用于 (G/C → A/T, 占突变的84%)–Full COLD-PCR:优先扩增 heteroduplexes, 适用于所有突变–Ice-COLD-PCR:与 Full COLD-PCR 相同, 但使用了 reference sequence(RS) oligo, 提高heteroduplex 的突变检出率HRM优化 - Spiking方法区分纯合子样品•问题:纯合野生型和纯合突变型的Tm接近,分组不清晰•解决方法:向所有样品中加入20%纯合野生型样品–Homozygous WT:组分不变–Homozygous MT:含有20% WT–heterozygous:组分不变,仍然是heterozygousAAA B + AABB + AA AAA BBB20% AA20% AA20% AA内容小结•HRM实验优化建议–引物–模板–Mg2+浓度–PCR程序: Touchdown PCR, COLD PCR •Spiking方法区分纯合子样品We Innovate Healthcare。

文档:色谱法英文

文档:色谱法英文

“固定相分子筛载气归一化法微量进样器进样保留时间峰面积The stationary phase is the substance which is fixed in place for the chromatography procedure.A molecular sieve is a material containing tiny pores of a precise and uniform size that is used as an adsorbent for gases and liquids.When the mobile phase is gas, it is called eluant gas.The mobile phase is the phase which moves in a definite direction. In statistics, normalization refers to the division of multiple sets of data by a common variable in order to negate that variable's effect on the data, thus allowing underlying characteristics of the data sets to be compared.Microinjector is a kind of injector which can make injection in a very small volumn. An injector, ejector, steam ejector or steam injector is a pump-like device that uses the Venturi effect of a converging-diverging nozzle to convert the pressure energy of a motive fluid to velocity energy which creates a low pressure zone that draws in and entrains a suction fluid and then recompresses the mixed fluids by converting velocity energy back into pressure energy.Injection is a method of putting sample into the column with a syringe or injectorThe retention time is the characteristic time it takes for a particular analyte to pass through the system (from the column inlet to the detector) under set conditions.The area of a peak is called peak area.色谱图 chromatogram色谱峰 chromatographic peak峰底 peak base峰高 h,peak height峰宽 W,peak width半高峰宽 Wh/2,peak width at half height峰面积 A,peak area拖尾峰 tailing area前伸峰 leading area假峰 ghost peak畸峰 distorted peak反峰 negative peak拐点 inflection point原点 origin斑点 spot区带 zone复班 multiple spot区带脱尾 zone tailing基线 base line基线漂移 baseline drift基线噪声 N,baseline noise统计矩 moment一阶原点矩γ1,first origin moment二阶中心矩μ2,second central moment三阶中心矩μ3,third central moment液相色谱法 liquid chromatography,LC液液色谱法 liquid liquid chromatography,LLC液固色谱法 liquid solid chromatography,LSC正相液相色谱法 normal phase liquidchromatography反相液相色谱法 reversed phase liquidchromatography,RPLC柱液相色谱法 liquid column chromatography高效液相色谱法 high performance liquidchromatography,HPLC尺寸排除色谱法 size exclusion chromatography,SEC凝胶过滤色谱法 gel filtration chromatography凝胶渗透色谱法 gel permeation chromatography,GPC亲和色谱法 affinity chromatography离子交换色谱法 ion exchange chromatography,IEC离子色谱法 ion chromatography离子抑制色谱法 ion suppression chromatography离子对色谱法 ion pair chromatography疏水作用色谱法 hydrophobic interactionchromatography制备液相色谱法 preparative liquid chromatography平面色谱法 planar chromatography纸色谱法 paper chromatography薄层色谱法 thin layer chromatography,TLC高效薄层色谱法 high performance thin layerchromatography,HPTLC 浸渍薄层色谱法 impregnated thin layerchromatography凝胶薄层色谱法 gel thin layer chromatography离子交换薄层色谱法 ion exchange thin layerchromatography制备薄层色谱法 preparative thin layerchromatography薄层棒色谱法 thin layer rod chromatography液相色谱仪 liquid chromatograph制备液相色谱仪 preparative liquid chromatograph凝胶渗透色谱仪 gel permeation chromatograph涂布器 spreader点样器 sample applicator色谱柱 chromatographic column棒状色谱柱 monolith column monolith column微粒柱 microparticle column填充毛细管柱 packed capillary column空心柱 open tubular column微径柱 microbore column混合柱 mixed column组合柱 coupled column预柱 precolumn保护柱 guard column预饱和柱 presaturation column浓缩柱 concentrating column抑制柱 suppression column薄层板 thin layer plate浓缩区薄层板 concentrating thin layer plate荧光薄层板 fluorescence thin layer plate反相薄层板 reversed phase thin layer plate梯度薄层板 gradient thin layer plate烧结板 sintered plate展开室 development chamber往复泵 reciprocating pump注射泵 syringe pump气动泵 pneumatic pump蠕动泵 peristaltic pump检测器 detector微分检测器 differential detector积分检测器 integral detector总体性能检测器 bulk property detector溶质性能检测器 solute property detector(示差)折光率检测器 [differential] refractive indexdetector 荧光检测器 fluorescence detector紫外可见光检测器 ultraviolet visible detector电化学检测器 electrochemical detector蒸发(激光)光散射检测器 [laser] light scatteringdetector光密度计 densitometer薄层扫描仪 thin layer scanner柱后反应器 post-column reactor体积标记器 volume marker记录器 recorder积分仪 integrator馏分收集器 fraction collector工作站 work station固定相 stationary phase固定液 stationary liquid载体 support柱填充剂 column packing化学键合相填充剂 chemically bonded phasepacking薄壳型填充剂 pellicular packing多孔型填充剂 porous packing吸附剂 adsorbent离子交换剂 ion exchanger基体 matrix载板 support plate粘合剂 binder流动相 mobile phase洗脱(淋洗)剂 eluant,eluent展开剂 developer等水容剂 isohydric solvent改性剂 modifier显色剂 color [developing] agent死时间 t0,dead time保留时间 tR,retention time调整保留时间 t&#39;R,adjusted retention time死体积 V0,dead volume保留体积 vR,retention volume调整保留体积 v&#39;R,adjusted retention volume柱外体积 Vext,extra-column volune粒间体积 V0,interstitial volume(多孔填充剂的)孔体积 VP,pore volume of porouspacking 液相总体积 Vtol,total liquid volume洗脱体积 ve,elution volume流体力学体积 vh,hydrodynamic volume相对保留值 ri.s,relative retention value分离因子α,separation factor流动相迁移距离 dm,mobile phase migrationdistance流动相前沿 mobile phase front溶质迁移距离 ds,solute migration distance比移值 Rf,Rf value高比移值 hRf,high Rf value相对比移值 Ri.s,relative Rf value保留常数值 Rm,Rm value板效能 plate efficiency折合板高 hr,reduced plate height分离度 R,resolution液相载荷量 liquid phase loading离子交换容量 ion exchange capacity负载容量 loading capacity渗透极限 permeability limit排除极限 Vh,max,exclusion limit拖尾因子 T,tailing factor柱外效应 extra-column effect管壁效应 wall effect间隔臂效应 spacer arm effect边缘效应 edge effect斑点定位法 localization of spot放射自显影法 autoradiography原位定量 in situ quantitation生物自显影法 bioautography归一法 normalization method内标法 internal standard method外标法 external standard method叠加法 addition method普适校准(曲线、函数) calibration function or curve谱带扩展(加宽) band broadening(分离作用的)校准函数或校准曲线 universalcalibration function or curve [of separation] 加宽校正 broadening correction加宽校正因子 broadening correction factor溶剂强度参数ε0,solvent strength parameter洗脱序列 eluotropic series洗脱(淋洗) elution等度洗脱 gradient elution梯度洗脱 gradient elution(再)循环洗脱 recycling elution线性溶剂强度洗脱 linear solvent strength gradient程序溶剂 programmed solvent程序压力 programmed pressure程序流速 programmed flow展开 development上行展开 ascending development下行展开 descending development双向展开 two dimensional development环形展开 circular development离心展开 centrifugal development向心展开 centripetal development径向展开 radial development多次展开 multiple development分步展开 stepwise development连续展开 continuous development梯度展开 gradient development匀浆填充 slurry packing停流进样 stop-flow injection阀进样 valve injection柱上富集 on-column enrichment流出液 eluate柱上检测 on-column detection柱寿命 column life柱流失 column bleeding显谱 visualization活化 activation反冲 back flushing脱气 degassing 沟流 channeling 过载 overloading。

Effect of chemical inhomogeneity in the bismuth-based copper oxide superconductors

Effect of chemical inhomogeneity in the bismuth-based copper oxide superconductors

a r X i v :c o n d -m a t /0312570v 1 [c o n d -m a t .s u p r -c o n ] 22 D e c 2003Effect of chemical inhomogeneity in the bismuth-based copper oxide superconductorsH.Eisaki,∗N.Kaneko,†D.L.Feng,‡A.Damascelli,§P.K.Mang,K.M.Shen,Z.-X.Shen,and M.GrevenDepartment of Applied Physics,Physics,and Stanford Synchrotron Radiation Laboratory,Stanford University,Stanford CA,94305(Dated:February 2,2008)We examine the effect on the superconducting transition temperature (T c )of chemical inhomo-geneities in Bi 2Sr 2CuO 6+δand Bi 2Sr 2CaCu 2O 8+δsingle crystals.Cation disorder at the Sr crystal-lographic site is inherent in these materials and strongly affects the value of T c .Partial substitution of Sr by Ln (Ln =La,Pr,Nd,Sm,Eu,Gd,and Bi)in Bi 2Sr 1.6Ln 0.4CuO 6+δresults in a monotonic decrease of T c with increasing ionic radius mismatch.By minimizing Sr site disorder at the expense of Ca site disorder,we demonstrate that the T c of Bi 2Sr 2CaCu 2O 8+δcan be increased to 96K.Based on these results we discuss the effects of chemical inhomogeneity in other bulk high-temperature superconductors.PACS numbers:74.62.-c,74.62.Bf,74.62.Dh,74.72.HsI.INTRODUCTIONThe possible existence of nanoscale electronic inho-mogeneity —the propensity of charge carriers doped into the CuO 2plane to form nanoscale structures —has drawn much attention in the field of high-T c su-perconductivity.Neutron scattering studies on Nd co-doped La 2−x Sr x CuO 4(Nd-LSCO)1and STM/STS stud-ies on Bi 2Sr 2CaCu 2O 8+δ(Bi2212)2have led to sug-gestions that such self-organization may manifest it-self as one-dimensional “stripes”in Nd-LSCO,or two-dimensional “patches”in Bi2212.In the former case,the inter-stripe spacing in the superconducting regime is reported to be approximately four times the in-plane lat-tice constant,about 1.5nm,and in the latter case the patches are estimated to be 1-3nm across.Many the-oretical studies suggest that the spatial electronic inho-mogeneity in the hole-doped CuO 2planes is an essential part of high-T c physics 3.However,at present,the im-portance of,or even the existence of generic nanoscale electronic inhomogeneity remains controversial 4,5.If nanoscale electronic inhomogeneity exists in the su-perconducting cuprates,the doped holes will distribute themselves in the CuO 2planes so as to minimize their to-tal energy.In real materials,the CuO 2planes are usually inhomogeneous due to local lattice distortions and/or the random Coulomb potential resulting from chemical disor-der,which differs from system to system.Therefore,even if electronic inhomogeneity may itself be a genuine prop-erty of doped CuO 2planes,the spatial variation of doped holes will likely depend on the details of each material.For example,in the framework of the stripe model 1,in-commensurate spin and charge correlations are stabilized in Nd-LSCO by the long-range distortion of the CuO 6oc-tahedra in the low-temperature tetragonal phase,which creates one-dimensional potential wells.For Bi2212,it is argued that the random Coulomb potential caused by ex-cess oxygen atoms in the BiO planes pins the doped holes,thus creating patch-shaped inhomogeneities 2.These ob-servations suggest that electronic and chemical inhomo-geneity are inseparable from each other ,and that the un-derstanding of the latter is imperative for an understand-ing of the former.Motivated by this line of reasoning,we have exam-ined the effects of chemical inhomogeneity in single-layer Bi 2Sr 2CuO 6+δ(Bi2201)and double-layer Bi2212.Al-though widely used for surface sensitive measurements such as STM 2and angle-resolved photoemission spec-troscopy (ARPES)6,a detailed understanding of their materials properties is very limited,when compared to other materials such as LSCO or YBa 2Cu 3O 7−δ.The Bi-based cuprates contain excess oxygens in BiO planes and one can change their carrier concentration by changing the amount,δ.The excess oxygen would engender a random Coulomb potential in the CuO 2planes.Besides the oxygen nonstoichiometry in BiO planes,there exists another source of chemical inhomo-geneity which inherently exists in typical samples.Al-though referred to as Bi2201and Bi2212,it is empir-ically known that stoichiometric Bi 2.0Sr 2.0CuO 6+δand Bi 2.0Sr 2.0CaCu 2O 8+δare very difficult to synthesize 7,8,even in a polycrystalline form.In order to more eas-ily form the crystal structure,one usually replaces Sr 2+ions by trivalent ions,such as excess Bi 3+ions or La 3+ions,forming Bi 2+x Sr 2−x CuO 6+δ,Bi 2Sr 2−x La x CuO 6+δ,and Bi 2+x Sr 2−x CaCu 2O 8+δ.As listed up in Ref.9,a typical Bi:Sr nonstoichiometry,x ,for Bi2212is around 0.1,which yields a T c =89-91K.To our knowledge,the highest T c reported in the literature is 95K (Ref.9(g),(i)).For Bi2201,T c of Bi 2+x Sr 2−x CuO 6+δis around 10K for x (Bi)=0.1,whereas La substituted Bi2201(Bi 2Sr 2−x La x CuO 6+δ)has a higher T c >30K for x (La)≈0.410.Since the Sr atom is located next to the apical oxygen which is just above the Cu atoms,the effect of Sr site (also referred to as the A-site)cation inhomogeneity is expected to be stronger than that of the excess oxy-gens in BiO planes.Note that BiO planes are located relatively far away from CuO 2planes,with SrO planes in between.In this study,we evaluate the effect of chemical inho-mogeniety in the Bi-based cuprates.For Bi2201,we have grown a series of Bi 2Sr 1.6Ln 0.4CuO 6+δcrystals with var-2ious trivalent rare earth(Ln)ions.In this series,the magnitude of the local lattice distortion can be changed systematically by making use of the different ionic radii of the substituted Ln ions.Wefind that T c monoton-ically decreases with increasing ionic radius mismatch. For Bi2212,a series of Bi2+x Sr2−x CaCu2O8+δcrystals with varying values of x were grown in order to evalu-ate the effect of Bi:Sr nonstoichiometry.In addition,we also have grown Bi2Sr2Ca1−y Y y Cu2O8+δ,andfind that substitution of Y for Ca site helps to enforce Bi:Sr stoi-chiometry and to raise T c to96K for y=0.08.Our results demonstrate that the cation disorder,in particular that located at the Sr site,significantly affects the maximum attainable T c(T c,max)in the Bi-based su-perconductors.In order to explain our results we use a conceptual hierarchy that classifies and ranks the princi-pal kinds of chemical disorder possible in these systems. We then extend our arguments to other cuprates to ex-amine whether a general trend exists in the hole-doped high-T c superconductors.This paper is organized as follows:Section II contains detailed information about sample preparation and char-acterization.The experimental results are presented in Section III and discussed in Section IV,while the effects of disorder in other cuprates is addressed in Section V.II.SAMPLE PREPARATIONSingle crystals of Bi2201and Bi2212were grown us-ing the travelling-solventfloating-zone technique,which is now the preferred method for synthesizing high-purity single crystals of many transition metal oxides.This technique allows for greater control of the growth con-ditions than is possible either by standard solid state re-actions or by theflux method.Powders of Bi2O3,SrCO3,CaCO3,Ln2O3(Ln=La, Pr,Nd,Sm,Eu,Gd,Y),and CuO(all of99.99%or higher purity)were well dried and mixed in the desired cation ratio(Bi:Sr:Ln:Cu=2:2−x:x:1for Bi2201and Bi:Sr:Ca:Cu=2+x:2−x:1:2for Bi2212),and then repeatedly calcinated at about800◦C with intermediate grinding.Eventually,the powder wasfinely ground and formed into a100mm long rod with a diameter of5mm. The crystal growth was performed using a Crystal Sys-tems Inc.infrared radiation furnace equipped with four 150W halogen lamps.Except for nearly-stoichiometric (x=0)Bi2212,the rods were premelted at18mm/h to form dense feed rods.The crystal growth was carried out without the use of a solvent and at a growth speed of 0.3-0.4mm/h for Bi2201and0.15-0.2mm/h for Bi2212. The growth atmospheres adopted for the Bi2212growth are listed in Table1.Bi2201single crystals were grown in1atm offlowing O2.The growth condition for the x=0Bi2212sample was more stringent than for the other samples.In or-der to obtain homogeneous polycrystalline feed rods,a mixture of starting powders with the stoichiometric ra-tio Bi:Sr:Ca:Cu=2:2:1:2was calcinated in stages,at tem-peratures increasing from770◦C to870◦C in10◦C incre-ments,with intermediate grindings.Thefinal calcina-tion temperature(870◦C)was set to be just below the composition’s melting temperature(875◦C).The dura-tion of each calcination was about20hours.To avoid possible compositionalfluctuation in the feed rod,in-stead of premelting,the feed rod was sintered four times in thefloating-zone furnace at a speed of50mm/h.This process allowed us to obtain dense feed rods,approxi-mately95%of the ideal density.The atmosphere re-quired for stable crystal growth was7±3%O2,a range much narrower than for nonstoichiometric or Y-doped Bi2212.The grown crystal rod contained small amounts of a single-crystalline SrCuO2secondary phase,indicat-ing that the sample still suffers from Bi:Sr nonstoichiom-etry.Single-phase Bi2212single crystals could be cleaved from the grown rod.No traces of impurity phases were found in other compositions.Inductively coupled plasma(ICP)spectroscopy was carried out to determine the chemical compositions of the crystals.Additional electron-probe microanalysis (EPMA)was also carried out on the Bi2201crystals.The results confirm that the actual compositions follow the nominal compositions,as listed in Table1for Bi2212. Hereafter,we basically denote the samples by nominal composition to avoid confusion.In order to determine the maximum T c for each cation composition(i.e.,to achieve optimal hole concentration),the Bi2212samples were annealed at various temperatures and oxygen par-tial pressures using a tube furnace equipped with an oxy-gen monitor and a sample transfer arm,which allowed us to rapidly quench the annealed samples from high tem-peratures within a closed environment.This procedure ensures that the variation of T c among the samples is primarily due to cation nonstoichiometry and not due to differing hole concentrations.Annealing conditions for obtaining optimal(OP),and typical underdoped(UD) and overdoped(OD)samples are listed in Table1.The results for Bi2201are on the as-grown crystals and ac-cordingly may not exactly reflect T c,max.However,by carrying out a series of annealing studies,we have con-firmed that the systematic change of T c among our sam-ples is not due to different hole concentrations,but due to the different Ln ions.Superconducting transition temperatures were deter-mined by AC susceptibility measurements using a Quan-tum Design Physical Properties Measurement System (PPMS).The transition temperatures reported here cor-respond to the onset of a diamagnetic signal.We note that the different definition of T c(such as the interecept between the superconducting transition slope and the χ=0axis)does not affect our conclusions due to the sharp superconducting transition(less than2K for most samples),as shown below.Although it is hard to de-termine the exact superconducting fraction due to the demagnetization factor of the plate-shaped crystals,the magnitude of the superconducting signal suggests the3 TABLE I:Sample preparation conditions and crystal compositions derived from the ICP analysis for Bi2212single crystals. The ICP analysis on the third sample in the Table was done on cleaved,single-phase samples from an ingot containing a small amount of SrCuO2secondary phase.annealing condition nominal composition ICP results Bi:Sr ratio growth atmosphere UD OP OD4M /H (a r b .u n i t s )Temperature (K)FIG.2:Bi 2+x Sr 2−x Ca 1−y Y y Cu 2O 8+δsusceptibility curves,normalized to -1at the lowest temperature.Data for optimally-doped (OP),underdoped (UD),and overdoped (OD)samples are indicated for each cation composition by closed circles,open squares,and open triangles,respectively.of Bi 2+x Sr 2−x CaCu 2O 8+δ.By adopting the methods de-scribed in Sec.II,we have managed to grow single crys-tals over the range 0.0<x ≤0.2.In Figs.2(a)-(c),we present magnetic susceptibility data for three differ-ent crystals with compositions x =0.2,0.04,and ≃0,respectively (ǫin the chemical formula for the nominal x =0sample (Fig.2(c))implies the presence of resid-ual nonstoichiometry in our sample,as discussed in the previous section).In the figures,OP indicates optimally-doped samples,which possess T c ,max for a given cation composition.Representative data for underdoped (UD)and overdoped (OD)samples,which were obtained by reducing and oxidizing OP samples,are also plotted to demonstrate successful control of the hole concentration over a wide range.As the Bi:Sr ratio approaches 1:1,T c ,max increases from 82.4K for x =0.2,to 91.4K for x =0.07(not shown),92.6K for x =0.04,and eventually to 94.0K for the sample closest to the stoichiometric composition that we could grow.We note that most of the samples studied in the literature contain a nonstoichiometry of x ∼0.1with T c =89−91K 9,consistent with the present results.Although T c of Bi2212can be raised by trying to en-force Bi:Sr stoichiometry,the preparation of nearly sto-ichiometric samples becomes much more difficult than when nonstoichiometry is allowed.This could be due to agreater stability of the crystal structure when it contains additional positive charges,which are usually introduced by allowing the Bi 3+:Sr 2+ratio to be larger than one,as discussed in Ref.8.If this is indeed the case,one might expect to be able to synthesize higher-T c ,max sam-ples more easily by introducing extra positive charges via cation substitution that causes disorder less severe than substitution of Bi 3+ions at the Sr site.In the case of Bi2201we observed that the substitution of additional Ln atoms can eliminate excess Bi atoms from the unfavorable Sr site position,effectively lower-ing the magnitude of disorder and raising T c .In the double-layer material Bi2212,there is an additional crys-tallographic site,the Ca site located between the CuO 2planes,which can also accept trivalent dopant ions.One might expect Ln 3+ions at the Ca site to be a weaker type of disorder than Bi 3+ions at the Sr site,since there are no apical oxygens in the Ca planes that could couple to Cu atoms in the CuO 2planes.To test this idea we have also grown Y-substituted Bi 2Sr 2Ca 1−y Y y Cu 2O 8+δcrystals.We find that this com-pound is as easy to prepare as ordinary (nonstoichiomet-ric)Bi2212,and that for Y-Bi2212the Bi:Sr ratio indeed tends to be stoichiometric.Furthermore,as shown in Fig.2(d),T c ,max for the y =0.08sample was increased to 96.0K,a value higher than for any other Bi2212sam-ple reported in the literature.9We also grew y =0.10and y =0.12samples and confirmed that T c ,max >95K in both cases.IV.DISCUSSIONThe effect on T c of structural distortions associated with cation substitution has been extensively studied in LSCO-based materials 13,and it is established that T c strongly depends on the A-site (La site)ionic ra-dius mismatch.For instance,Attfield et ed si-multaneous co-substitution of several alkaline earth and Ln ions to hold the average A-site ionic radius constant while systematically controlling the variance of the A-site ionic radius,and found that T c is affected not just by the average radius,but also by the degree of disorder (the variance)at that crystallographic site.Our study of single-layer Bi2201continues this line of inquiry to a different superconducting material and demonstrates a similar sensitivity of T c to A-site disorder.We note that our results qualitatively agree with those of a previous study on polycrystalline Bi2201samples 14.One can see the same trend in Bi2212crystals with varying degrees of chemical inhomogeniety.As expected,we find that T c is strongly dependent on the A-site dis-order introduced by the Bi:Sr nonstoichiometry.Fur-thermore,we also demonstrate that by the seemingly counter-intuitive method of introducing additional Y 3+ions,and hence a new type of disorder,we can raise T c ,max to 96K while minimizing A-site disorder.This suggests that,although the minimization of chemical dis-5order is important for raising T c,different types of dis-order are not equally harmful.This is consistent with the observation15that by carefully controlling disorder in the triple-layer material TlBa2Ca2Cu3O9+δ(Tl1223) T c can be raised from∼120K to133.5K,a new record for that system,and that Ba site(the A-site in this sys-tem)cation disorder(deficiency)has the strongest effect on T c.Numerous experiments on Bi2212have suggested non-uniformity in its electronic properties.These include broad linewidths seen in inelastic neutron scattering ex-periments16,residual low-energy excitations in the super-conducting state observed in penetration depth measure-ments17,finite spin susceptibility at low temperatures observed in NMR studies18,and short quasiparticle life-times detected by complex conductivity experiments19. The most recent of these are STM/STS measurements2 that purport to directly image patch-shaped,electroni-cally inhomogeneous regions.The Bi:Sr nonstoichiome-try which inherently exists in most samples may be par-tially responsible for these experimental observations. Although the present results do not directly prove the presence of nanoscale electronic inhomogeneity,they can be taken as a circumstantial supporting evidence,since they successfully prove the existence of nanoscale chemi-cal inhomogeneity which potentially pins down electronic inhomogeneity.To explain their STM/STS results,Pan et al.2attribute the source of pinning centers to excess oxygen in the BiO planes.Although the overall frame-work addressed by Pan et al.should still hold,we con-sider that the Bi ions on the Sr site are more effective as pinning centers since they are closer to the CuO2planes and affect T c more directly.Indeed,assuming a random distribution of Bi ions on the Sr site and a nonstoichiom-etry of x=0.10,the average separation between Bi ions is∼1−2nm,comparable with the length scale observed in the STM/STS studies.Recent89Y NMR experiments on YBCO indicate that the spatial inhomogeniety in this system is much less severe than in LSCO or Bi22125.This is reasonable since the latter two systems exhibit a much higher degree of disorder located at the A-site(La site(LSCO)and Sr site(Bi2212)),whereas YBCO(Ba site)is thought to be free from such cation disorder.Indeed,recent penetration depth measurements on the YBCO variant Nd1+x Ba2−x Cu3O7−δ,with cationic disorder at the Ba site,demonstrate that the superconducting properties of this system change quite sensitively with the degree of Nd/Ba nonstoichiometry20.V.DISORDER EFFECTS IN THE CUPRATES The two main lessons to be learned from our Bi2201 and Bi2212case studies are that(1)chemical inhomo-geneity affects T c,max and that(2)the effect of disorder differs depending on its location.In the following,we attempt to classify the various sites at which chemical disorder is possible and categorize other superconducting families on the basis of which kind of disorder is prevalentin each system.In Fig.3,we classify25cuprate superconductors basedon the pattern of the chemical disorder and the number of CuO2planes in the unit cell.21In thefirst row,we il-lustrate three possible locations of chemical disorder rel-ative to the CuO5pyramids in multilayer materials,orto the CuO6octahedra in single-layer materials.Pattern (a)corresponds to the Bi:Sr nonstoichiometry in Bi2201and Bi2212,or Sr2+ions doped into the La site in LSCO, referred to as A-site disorder so far.The disorder is lo-cated next to the apical oxygen.Pattern(b)corresponds to Y3+substitution for Ca2+in Bi2212and representsdisorder located next to the CuO2plane,but at a posi-tion where there are no apical oxygen atoms with whichto bond.There is no corresponding(b)site in single-layer materials.Pattern(c)disorder is further awayfrom the CuO2plane.We include excess oxygenδin Bi-and Tl-based cuprates,oxygen defects in CuO chains in YBa2Cu3O7−δ,and Hg deficiency y as well as excessoxygenδin Hg1−y Ba2Ca n−1Cu n O2n+2+δin this cate-gory.We note that the materials are catalogued basedon the primary form of disorder that they are believed to exhibit.As demonstrated in the present case study,the effect of the chemical disorder is expected to be stronger for pat-tern(a)than for pattern(b),which is reasonable consid-ering the role of the apical oxygen atom in passing on theeffect of disorder to nearby Cu atoms.First,the random Coulomb potential caused by type(a)disorder changesthe energy levels of the apical oxygen orbitals,which can be transmitted to CuO2planes through the hybridizationbetween the apical O(2p z)orbital and the Cu(3d r2−3z2) orbital.Second,the displacement of the apical oxygencaused by type(a)disorder brings about a local lattice distortion to the CuO2planes.The effect of pattern(c)disorder is expected to be weakest since the disorder is located relatively far away from the CuO2plane.The number of CuO2planes per unit cell may be re-garded as another parameter that,in effect,determines the magnitude of the chemical disorder.As demonstrated in Bi2212,multilayer materials can accommodate het-erovalent ions by making use of type(b)substitution whose effect on T c was seen to be weaker than type(a) substitution.Furthermore,the space between the CuO2 planes forming a multilayer may buffer the impact of the disorder.For instance,in single-layer materials,any dis-placement of the“upper”apical oxygen in a CuO6octa-hedron creates stress in the CuO2plane because the mo-tion of the octahedron is constrained by the“lower”api-cal oxygen.Double-layer materials contain CuO5pyra-mids rather than CuO6octahedra,and the separation between CuO2planes relieves this stress,reducing the effects of type(a)disorder.This buffer zone between the outer CuO2planes is further increased in triple-layer ma-terials,with the additional benefit that the middle layer is somewhat“protected”from the direct effects of pat-6tern(a)(and(c))disorder.Cursory examination of Fig.3reveals that T c,max gen-erally increases both across the rows and down the columns of the chart.Indeed,there is no material in (a-1)which possesses a T c,max higher than50K.Fur-thermore,Bi2201in column(a)has a lower T c,max than Tl2201in column(c),despite their similar crystal struc-tures.Similarly,T c,max of TlBa1+x La1−x CuO5(Tl1201) is lower than that of HgBa2CuO4+δ(Hg1201).This trend is closely obeyed when one concentrates on the variation within a single family of materials,each denoted by a different color in the chart.For exam-ple,across thefirst row,oxygen-intercalated La2CuO4+δlocated in(c-1)has higher T c,max than Sr-substituted La2CuO4(a-1).Down the column,T c,max of the bilayer La-based system La2−x Sr x CaCu2O6(a-2)is higher than that of its single-layer cousin.The classification suggests a negative correlation between the effective magnitude of chemical disorder and T c,max.Additional remarks are made in Ref.s22,23,24.We note that one may also have to consider other fac-tors which characterize the global materials properties and are likely to play a significant role as well in de-termining T c,max,such as Madelung potential26,bond valence sum25,band structure27,block layer28,multi layer29etc.Although the present scheme is somewhat oversimplified and does not take account of these param-eters,we believe it serves as a useful framework within which to consider the chemical disorder effects prevalent in these materials,at least some of which,if ignored, have the potential to lead to the misinterpretation of ex-perimental data.Finally,similar to previous work on Tl122315and to the present work on Bi2212,it might be possible to raise T c,max of certain other cuprates by minimizing the effects of chemical disorder.VI.SUMMARYIn summary,we present case studies of the effects of chemical disorder on the superconducting transition tem-perature of the single-layer and double-layer Bi-based cuprate superconductors.Wefind that the supercon-ducting transition temperature of Bi2212can be in-creased up to96K by lowering the impact of Sr site disorder,the primary type of disorder inherent to the bismuth family of materials,at the expense of Ca site dis-order.Based on these experimental results,we present a qualitative hierarchy of possible disorder sites,and then proceed to categorize the hole-doped high-temperature superconductors on that basis.AcknowledgmentsWe thank G.Blumberg,J.Burgy,E.Dagotto,J.C. 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保留时间

保留时间

保留时间 retention time被分离样品组分从进样开始到柱后出现该组分浓度极大值时的时间,也既从进样开始到出现某组分色谱峰的顶点时为止所经历的时间,称为此组分的保留时间,用tR表示,常以分(min)为时间单位。

保留时间是由色谱过程中的热力学因素所决定,在一定的色谱操作条件下,任何一种物质都有一确定的保留时间,可作为定性的依据。

 半峰宽 peak width at half-height又称半宽度、半峰宽度、区域宽度、区域半宽度,是色谱峰高一半处的峰宽度,用y1/2(或W1/2)表示。

半峰宽与标准偏差的关系为: 倍频 overtune基频以外的其他振动能级跃迁产生的红外吸收频率统称为倍频。

v=0至v=2的跃迁称为第一个倍频2n,相应地3n,4n……等均称为倍频。

 表面增强拉曼Surface-Enhanced Raman Scattering简称SERS。

用通常的拉曼光谱法测定吸附在胶质金属颗粒如银、金或铜表面的样品,或吸附在这些金属片的粗糙表面上的样品。

尽管原因尚不明朗,人们发现被吸附的样品其拉曼光谱的强度可提高103-106倍。

主要用于吸附物种的状态解析等。

 薄膜法thin film method适用于高分子化合物的红外光谱测定。

将样品溶于挥发性溶剂后倒在洁净的玻璃板上,在减压干燥器中使溶剂挥发后形成薄膜,固定后进行测定。

top 差示分光光度法 differential spectrophotometry分光光度法中,样品中被测组分浓度过大或浓度过小(吸光度过高或过低)时,测量误差均较大。

为克服这种缺点而改用浓度比样品稍低或稍高的标准溶液代替试剂空白来调节仪器的100%透光率(对浓溶液)或0%透光率(对稀溶液)以提高分光光度法精密度、准确度和灵敏度的方法,称为差示分光光度法。

差示分光光度法又可分高吸光度差示法,低吸光度差示法,精密差示分光光度法等。

 超临界流体色谱 supercritical fluid chromatography,SFC以超临界流体作流动相,以固体吸附剂(如硅胶)或键合在载体(或毛细管壁)上的有机高分子聚合物作固定相的色谱方法。

High Resolution Imaging(高清晰度成像技术)

High Resolution Imaging(高清晰度成像技术)
High Resolution Imaging
0
Outline
• Motivation • Historical Evolution of Ideas • Imaging with Quadratic Regularization
• • • • Regularized Least Squares Migration (RLSM) Preconditioned Least Squares Migration (PLSM) Synthetics Case study (WCSB)
5300 4800 4300 3800 3300 2800 2300 1800 1300
Depth (km)
1
AVA Target
2
0 3 4 Horizontal distance (km) 5 6 7 8
m/s
3
1.0 1
kg/m^3
0.8 0.6 0.4 x10 4
Depth (km)
2 3
21

AVA/AVP Imaging:
• For angle dependent images, m(x,z,p), we attempt to impose horizontal smoothness along CIGs:
J || W ( L m d) || || Dh m( x, z, ph ) ||
[??]
Resolution
4
A Simple Analogy
5
Convolution / Cross-correlation / Deconv
Convolution
Cross-correlation
Wr s ~ r W 's

O3说明书

O3说明书
1.1.1 量程Range ......................................................................................................1 1.1.2 噪声Noise (RMS) ...........................................................................................1 1.1.3 最低检测限Lower Detectable Limit ..............................................................1 1.1.4 零漂Zero Drift ................................................................................................2 1.1.5 量程漂移Span Drift........................................................................................2 1.1.6 延迟时间Lag Time .........................................................................................2 1.1.7 上升/下降时间,终值的 95% Rise/Fall Time, 95% of Final Value..............2 1.1.8 精度Precision.......................................................

High Resolution Surface Mass Spectrometry by TOF-SIMS - CEAC:高分辨率质谱-通过TOF-SIMS的表面

High Resolution Surface Mass Spectrometry by TOF-SIMS - CEAC:高分辨率质谱-通过TOF-SIMS的表面
High transformation probabilities High transmission mass spectrometer High sensitivity secondary ion detection
Monolayer Sputtering
θ(t) = θ(0) . exp (- σ .ν . t)
(Sample provided by the University of Antwerp, Belgium (Prof. Gijbels))
Deth resolution
B monolayer in Si
intensity In t e n s it y
B concentration / atoms/cm3
TOF-SIMS
Main features of TOF-SIMS
Parallel mass detection High (unlimited) mass range High mass resolution > 10 000 High mass accuracy (1-10 ppm) High transmission for high masses and at high mass resolution
➢ Perspectives
Key questions in nanoanalysis
• Identification (What?) • Localisation (Where?) • Quantification (How much?)
Nanotechnology
Definition: In at least one dimension <100nm
Ag catalyst

Fibre orientation measurement modelling

Fibre orientation  measurement  modelling

P u b l i s h e d b y M a n e y P u b l i s h i n g (c ) I O M C o m m u n i c a t i o n s L t dFibre orientation:measurement,modelling and knowledge based designP.Hine *1,R.A.Duckett 1,P.Caton-Rose 2,P.D.Coates 2,P.Jittman 3,C.Chapman 3and G.Smith 3In this paper the authors describe the results of a research programme which has investigated the links between the orientation distribution of short fibre reinforced composites produced during injection moulding and the mechanical properties of the resulting moulded components.A variety of injection moulded parts,including both model shapes (e.g.,a transverse ribbed plate)and commercial products,has been manufactured and studied,both experimentally and using simulation.The fibre orientation distribution (FOD)has been characterised for each component at a number of chosen locations using an in-house developed image analyser.Measurement of the FOD for a range of different component shapes has led to the proposal of a number of preliminary design rules,which have been incorporated into a knowledge based engineering (KBE)design package.A crucial component of the KBE design optimisation is the use of a simulation package to predict the FOD for any component shape.Therefore,the accuracy of the principal commercial simulation package for FOD prediction,Moldflow,has been investigated by comparison with the experimentally measured FODs.Finally,the link between FOD and mechanical properties (both elastic modulus and fracture)has been studied by comparing analytical predictions with mechanical measurements.Keywords:Fibre orientation measurement,KBE,Design automation,Short fibre compositesIntroductionShort glass fibre reinforcement of polymers is well established as a means of significantly improving mechanical performance without compromising proces-sability,and many glass filled polymer grades and products are commercially available.A key issue for the most effective use of these materials is how to optimise design for an injection moulded product.The mechan-ical properties of the final component are crucially dependent on the fibre orientation distribution devel-oped during the process,in addition to the fibre,matrix and interfacial properties.A perceived knowledge gap is how to control fibre orientation for delivering the desired performance.In order to help close this gap,a 2year Faraday Plastics EPSRC sponsored project has recently been undertaken to address this important link between orientation and product properties (‘Design–process–performance interactions for precision pro-ducts’),and in the present study,the most important results of this programme are reported.The most important variable,arguably,is the fibre orientation distribution produced in a component during the injection moulding process,which depends on a number of factors,most notably the mould cavity geometry.The importance of being able to predict and obtain the correct orientation is indicated in Fig.1,which shows specific stiffness versus fibre volume fraction for a typical fibre aspect ratio of 25and three different orientation states.Specific stiffness (modulus/density)is seen to always increase with fibre volume fraction for all three orientation states as a result of the modulus rising faster than density.However,fibre orientation has a notable effect:if the fibres are preferentially aligned,which is generally the case for injection moulded products,then the specific stiffness can be twice as high as for 3D random alignment.Thus,if the fibre orientation produced during processing can be accurately predicted,a more optimised design can be made, e.g.stiffness may be significantly increased,or weight significantly reduced.The key connections,of which the present study describes,are therefore between the original design shape (which controls the cavity geometry)and the resulting fibre orientation distribution (FOD)and between the FOD and the final component properties.A key aspect of the work was to combine all the acquired information into a design package based on Knowledge Based Engineering (KBE).1IRC in Polymer Science and Technology,School of Physics and Astronomy,University of Leeds,Leeds LS29JT,UK 2IRC in Polymer Science and Technology,School of Engineering,Design and Technology,University of Bradford,Bradford BD71DP,UK 3KBPD Laboratory,WMG,University of Warwick,Coventry CV47AL,UK *Corresponding author,email p.j.hine@ß2005Institute of Materials,Minerals and Mining Published by Maney on behalf of the InstituteReceived 5July 2005;accepted 13September 2005DOI 10.1179/174328905X71986Plastics,Rubber and Composites 2005VOL34NO9417P u b l i s h e d b y M a n e y P u b l i s h i n g (c ) I O M C o m m u n i c a t i o n s L t dThe philosophy has been to address the two links in the Design–Process–Performance chain individually.A number of injection moulded components,including both model shapes (flat plates and ribbed plates)and commercial products,have been either injection moulded at Bradford or supplied by commercial collaborators.The work has mainly concentrated on short glass filled polyamides (a major commercial material for safety critical products).The FOD of each component has then been measured using the estab-lished image analysis system (Leeds)using fibre section ellipticity parison of the various FOD for the different component shapes has led to the development of a number of design rules which have subsequently been incorporated directly into a KBE design package by the Knowledge Based Product Development Laboratory at Warwick.A very important aspect of the work has been to compare the measured FOD with that predicted by the leading commercial software,Moldflow (made available by the company for this project),in order to assess the accuracy of the model predictions.This has been investigated in both 2D and 3D flow situations,and for both model and commercial products.This link is vital,because an integrated design tool based on a KBE system requires an accurate computer based prediction of the FOD for any particular component shape and processing history.Finally,the link between FOD and mechanical proper-ties has been developed.Previous work at Leeds led to the development of an analytical modelling route for the prediction of the elastic properties of short fibre reinforced polymers,1which has been further validated in this work.A new aspect has been to investigate the effect of the FOD on crack resistance.ResultsMeasurements of FOD in injection moulded componentsThe first area of study was to extend previous studies,which have concentrated mainly on 2D components,to components whose geometry led to 3D fibre orientation distributions (FOD):as before,simple plaques were thestarting point for the studies,then model rib sections and finally commercial products.Examples of the components that have been investi-gated are shown in Fig.2,and they include a transverse ribbed plate,a multi-ribbed plate 2and a commercial automotive control pedal.The transverse ribbed plate on the left has been studied most extensively,forming a link between the research at the three sites on modelling (Bradford),experimental characterisation and mechanical properties (Leeds)and design (Warwick),for a 40%w/w glass filled Nylon (Rhodia Technyl C216V40)used extensively in this work.In initial studies,a 4mm thick plate,with a 3mm thick rib was explored and some of this work has already been published.3Fibre orientation was char-acterised from examination of three 2D sections:(i)perpendicular to the flow direction and 16mm from the gate (i.e.in front of the rib);(ii)perpendicular to the flow direction and 25mm behind the rib;(iii)along the centre line of the plate,including the rib.As is common with injection moulded plates,measurements showed there to be a centrally located core region,where the fibres were aligned transverse to the flow direction,surrounded by outer shell regions where the fibres were aligned preferential to the flow direction.It was found that the level of orientation in the shell and core regions was relatively constant along the length of the plate,but that the proportion of the shell region increased with distance from the gate (45%at 16mm from the gate and 75%at 65mm from the gate).For this reason,the stiffness of the plate in the flow direction also increased with distance from the gate.For the next set of experiments,a 2mm thick plain plate was moulded,using the same 40%w/w glass filled Nylon.FOD analysis at the same positions as for the 4mm plate showed first,at a reasonable distance from the gate,that the absolute value of the flow direction aligned shell layer was very similar in the 2mm and 4mm plate,at around 0.8mm each side,resulting in much higher stiffness in the flow direction;second,the level of orientation in the shell layer was very similar in the 2mm and 4mm plate;third,the thickness of the shell layer saturated much more quickly in the 2mm plate,with the result that there was much less change in FOD and properties along the plate length.Twoother1Effect of orientation on specific stiffnessversusvolume fraction for glass fibre filledPPP u b l i s h e d b y M a n e y P u b l i s h i n g (c ) I O M C o m m u n i c a t i o n s L t dflat plate samples,of 3and 6mm thickness,were also examined (the 3mm multi-ribbed plate is shown in Fig.2b ).Although made of different material combina-tions (30%w/w glass/PBT and 40%w/w glass/Nylon),results followed a similar trend,with regard to an absolute value for the shell thickness of around 0.8mm.Figure 3shows the value of the second order orientation tensor (X here is the flow direction and Y is perpendicular to X in the plane of the plate)averaged across the sample width and thickness for the four thickness plates and three materials studied.It is seen that there is a clear trend between plate thickness and the preferred level of orientation (and hence flow direction stiffness),owing to combination of the constant absolute value of the shell layer,and the approximately constant levels of orientation in the shell and core regions.Analysis of the various ribbed plates (with ribs of various aspect ratios)showed a number of other general trends.It was found that for a rib transverse to the flow direction,the thicker the rib,the higher the degree of preferred orientation along the rib itself.It is possible that a thicker transverse rib forces the flow front to experience some transverse flow and hence causes some flow alignment along the length of the rib.This was borne out by the subsequent Moldflow simulations of the flow front shape as it passed the rib for the two sample thicknesses.Increasing the rib height leads to a more preferred orientation normal to the plate.In fact,the orientation in a longitudinal rib is very similar to that of the plate itself,albeit rotated by 90u .Finally,if the rib is placed parallel to the flow direction,then fibres are more highly aligned along its length compared to a transverse rib.From these studies and product assessments,pre-liminary design rules were proposed for incorporation into the KBE design package:(i)Thinner plates give higher alignment (and hencestiffness)in the flow direction(ii)Thinner plates show less variation along theflow path(iii)Taller ribs are more preferentially aligned alongtheir height(iv)Thicker transverse ribs are more preferentiallyaligned along their length(v)Longitudinal ribs are more highly aligned alongtheir length compared to transverse ribs.The final set of experiments concerned FOD measure-ments on commercial products,for comparison with Moldflow simulations,including the automotive pedal shown in Fig.2c .Three sections were taken,two on flat 2D sections similar to those described above for the model components,and a third at an intersection of two ribs (shown by the white area on the image inFig.2c )to help assess the 3D prediction capabilities of Moldflow.FOD simulation studies using MoldflowComputer simulations corresponding to the components described in the preceding section were constructed using commercially available software (Moldflow)allowing direct comparison of measured and predicted FOD.In the first instance,components were described using a ‘midplane’or 2K D model,where a specimen thickness is described in terms of a number of layers above and below a central plane.This method has significant computational cost benefits over a complete 3D analysis,although the more complex 3D route was also explored during the present study.The software was capable of predicting the flow front profiles displayed during short shot injection of the two model plate geometries described above.Altering the ratio of cavity height (i.e.product thickness)to gate height near the gate region showed that thinner plates with more constrictive gate profiles (4:1cavity/gate height ratio)produced linear flow front profiles resulting in highly aligned shell regions,whereas thicker plates with cavity/gate height ratios of the order of 2:1exhibited fountain flow type behaviour and a thick,transversely aligned core.This effect of cavity thickness on flow front profile was well predicted by Moldflow.FOD predictions in most commercial software are based on the fibre mechanics analysis of Folgar and Tucker,4but their representation is recognised to be inaccurate for highly filled systems.In the current absence of a complete,rigorous multi-body mechanics solution,the scientifically unsatisfactory route (but practically necessary,and useful for design rule explora-tion)of additional semi-empirical coefficients,‘fibre orientation coefficient’,c i and ‘thickness moment of interaction’D z is employed;these are available in Moldflow MPI software.Values for c i and D z can be chosen within each analysis,to attempt to account for fibre–fibre interactions during complex flows.Previous work by Bay 5proposed a link between fibre aspect ratio,fibre volume fraction and c i .FOD predictions using Bay’s value c i 50.0003for the material used in the present study were found to be in good agreement with experimental data for sections close to the gate region.However,further down the flow length of both model geometries (both 2and 4mm thick plates),the accuracy of predictions diminished.The combined effect of c i and the additional ‘thickness moment of interaction’coeffi-cient D z ,was explored for various materials and geometries.Figure 4shows the FOD comparisons for two locations in the 4mm thick ribbed plate 16mm from the gate (Fig.4a )and 25mm behind the rib (Fig.4b).a Transverse ribbed plate;b Multi-ribbed plate;c Automotive control pedal 2Example products investigatedHine et al.Fibre orientation:measurement,modelling and knowledge based designPlastics,Rubber and Composites 2005VOL34NO9419P u b l i s h e d b y M a n e y P u b l i s h i n g (c ) I O M C o m m u n i c a t i o n s L t dD z was fixed at 1.0(the original Folgar and Tucker model)and c i was optimised at the first position (16mm from the gate)to give the best fit to the measured image analysis results.This gave a value for c i of 0.00006,which is less than but of a similar order to that predicted by the equation of Bay .It is seen that,although the FOD can be predicted reasonably well near the gate,the same values of c i and D z did not predict the FOD at the second position so well.Further optimisation of these parameters could not improve this issue.In general,the Folgar and Tucker theory over-predicted the levels of orientation within the shell regions of all flat plate geometries analysed using the midplane technique.Modification of this analysis,available within Moldflow through the D z parameter,did not significantly improve FOD predictions,reflect-ing shortcomings of the current theory.A more significant effect of the FOD overprediction is that resultant composite material properties will be at variance with the actual properties.Using the ‘optimum’fibre interaction coefficient (c i 50.00006)obtained during midplane analyses,gate sections of the two plates were analysed in full 3D as the non-symmetric gate used for these mouldings could not be analysed using the symmetric midplane visualisation.Three locations across the sample width were selected for FOD analysis:the centreline,the quarter line and near the outer edge.Figure 5a shows a typical orienta-tion map for the 4mm plate where white corresponds to alignment along the flow direction and blacktoa 16mm from gate;b 25mm behind rib4FOD comparisons for two locations in 4mm ribbed plate for D z 51.0and c i 50.000065Orientation map from a FOD measurements and b MPI 3D analysis,for 4mm plate near gateHine et al.Fibre orientation:measurement,modelling and knowledge based design420Plastics,Rubber and Composites 2005VOL34NO9P u b l i s h e d b y M a n e y P u b l i s h i n g (c ) I O M C o m m u n i c a t i o n s L t dalignment perpendicular to the flow for the experimental data.The corresponding plot of predicted orientation (Fig.5b )shows a similar pattern,although there are interesting differences which are under further investigation.For all locations across the sample width,it was clear that the 3D predictions of orientation conveyed the features of measured orientation reasonably.However,the analysis produced significantly higher levels of alignment than seen experimentally,as with the mid-plane pared to the midplane technique,additional computational costs of the 3D analysis,and the limited gains in accuracy of the fibre orientation predictions,it was concluded that for larger sections,the midplane technique is currently optimum.Both the midplane and 3D analyses have been studied for commercial products,which have complex FODs in addition to the typical shell–core–shell structure for flat plates.The automotive pedal made from the Rhodia 40wt-%glass filled polyamide was sectioned in three locations,two on flat 2D sections and a third at an intersection of two ribs as shown in Fig.6(and the white lines on Fig.2c earlier).Analysis of the two flat regions produced the standard shell–core–shell structure pre-viously described for flat plates.The third section (Fig.7:the white colour indicates orientation parallel to the flow direction as shown by the arrow in Fig.6)displayed a more complex FOD resulting in a plate like formation on the outer walls as well as a shell–core–shell–core–shell distribution at the rib cross over region (shown by the dotted box in Fig.7).It is unlikely that such an effect would be apparent within a midplane analysis and demonstrates the potential of the 3D approach.However,as with the plate analyses,both the midplane and 3D predictions showed higher levels of orientation than measured and would result in higher elastic composite material properties in the direction of flow.To summarise the simulation studies,it was found that the commercial software was able to predict the filling of the mould,and the effect of mould thickness on flow front shape,very well.In terms of FOD prediction,a value of c i could be chosen that would predict therelative proportions of the core and shell regions quite well:however,the orientation in the shell layer was often an overprediction.Simulation of 3D flow is in its infancy.Further development of physical modelling based on FOD–product strength interactionsPrevious studies at Leeds and ETH Zurich 1have shown that if the fibre orientation structure in a component can either be measured or accurately predicted,then the elastic and thermoelastic properties of the component can be calculated with very acceptable accuracy using micromechanical models.In particular,the elastic properties at a particular position are well described by averaging the fibre orientation over the measured volume.With strength and,in particular,crack propa-gation resistance,the important measurement is now the local fibre orientation state at a stress concentration or at the tip of an incipient crack.As part of this work,an assessment of the ideas of Friedrich 6has been carried out,who proposed that the crack resistance of a short fibre reinforced material depends on the number of fibres that are perpendicular to the crack tip.Friedrich proposed that the strain energy release rate G c ,or the energy to propagate a crack through the material,takes the form :G c 5af peff z b where a accounts for the energy absorbing processes as a result of the fibres (pull out,etc.)and b the energy absorbing process due to the matrix:here f peff would be an average fibre orientation across the sample thickness at the crack tip.Friedrich8Location of fracturesamples7FOD map for pedal section shown in Fig.66Cut plane (arrow shows view direction for Fig.7)Hine et al.Fibre orientation:measurement,modelling and knowledge based designPlastics,Rubber and Composites 2005VOL34NO9421P u b l i s h e d b y M a n e y P u b l i s h i n g (c ) I O M C o m m u n i c a t i o n s L t dthen proposed an empirical form for f pefff peff ~a ½1z tanh (b f p ) where a ~0:5and b ~0to5and f p 5(2,cos 2h cpn .–1)where ,cos 2h cpn .is the average value of the second order orientation average with respect to the crack plane normal,i.e.when ,cos 2h cpn .51,all the fibres lie perpendicular to the crack direction and f p 51.The transverse rib sample produced for this pro-gramme and discussed in the earlier sections,proved an ideal component for the present study,due to the changes in fibre orientation structure,in particular the core/shell proportions,along its length.Three point bend fracture samples were cut from various positions across the ribbed plate (Fig.8),in order to sample different proportions of fibres that are parallel or perpendicular to the crack tip.The chosen sections were again 16mm from the gate (55%core,45%shell)and 25mm behind the rib (75%shell and 25%core).Samples were cut with the crack running parallel to the flow direction (L sample),and transverse to the flow direction (T sample).Samples were also cut with the crack located in the aligned shell region (TT sample).Figure 9shows a comparison between the measured fracture toughness values (solid squares)and the best fit to the Friedrich equation.The proposed empirical theory fits the measured behaviour very well;the higher values of toughness are seen when the fibres are perpendicular to the crack tip (or parallel to the crack tip normal).The value of b controls whether the relationship is symmetric about the endpoints:a value of 0.5gives a symmetric shape.For the results shown in Fig.8,a floating fit of this parameter gave a value of 0.499,i.e.safely considered as 0.5.Three independent parameters are therefore controlling the shape of the relationship:a ,the fracture energy due to the fibres when all the fibres are perpendicular to the crack tip;b ,the fracture energy due to the matrix when all the fibres are parallel to thecrack propagation direction;b which controls how sharp the transition is between the endpoints.From the fitted data,for this polymer and this fibre volume fraction,the values obtained were a 516.6kJ m –2,b 55.1kJ m –2and b 52.1.Future work will be aimed at establishing whether these three parameters can be predicted from physical principles,which would then transform the empirical relationship into a predictive theory.This work suggests another rule for the KBE design:(i)At positions of stress intensity,the local fibreorientation should be parallel to the stress direction (i.e.perpendicular to the likely crack propagation direction).Evaluation of links between computer modelling of FOD and product propertiesTo arrive at an optimal design,it is important to be able to accurately predict the FOD as a result of processing (as described in the section ‘FOD simulation studies using Moldflow’above)but also to be secure in the link between the resulting FOD and product properties.To further validate this important stage in the design process,experimental measurements have been combined with both analytical and finite element approaches (Abaqus).Once again,the model transverse ribbed plate was used for these studies.Three point bend samples were cut to enable the bending modulus at the chosen positions of 16mm from the gate and 25mm behind the rib to be measured.The image analysis results for this product (see section ‘Measurements of FOD in injection moulded components’above)were then used,together with the micromechanical models,to predict the bending modulus of the ribbed plate at the same locations.The modelling approach has previously been validated using finite element techniques in collaboration with the group of Andrei Gusev at ETH Zurich,and combines the work of Qui and Weng 7to determine the properties of the composite unit together with an aggregate model to model the effects of disorientation (e.g.Brody and Ward 8or Camacho and Tucker 9).For predicting the bending modulus of the samples,the through thickness orientation of the plates at the two positions was split into 10layers and the modulus of each of these layers was averaged through the thickness according to Freudenthal.10The results in Table 1show that the agreement between the micro-mechanical model results and predicted bending mod-ulus at these two positions is excellent,showing that if the fibre orientation can be accurately predicted,then the elastic properties will follow.The modelling route,which has been found to be the best,is also that used by Moldflow.For the modulus variation through the thickness of the plate (at 25mm behind the rib),the FE predictions (Moldflow)are seen to be different (Fig.10)from those calculated from the micromechanical model based on the measured FOD.It can be proposed that this isTable 1Measured and predicted bending modulus16mm from gate E YY ,GPa25mm from rib E YY ,GPa 25mm from rib E XX ,GPa Measured 3.32¡0.282.60¡0.167.18¡0.19Predicted3.44¡0.162.74¡0.046.97¡0.029Fracture measurements (&)and best fit to FriedrichequationHine et al.Fibre orientation:measurement,modelling and knowledge based design422Plastics,Rubber and Composites 2005VOL34NO9P u b l i s h e d b y M a n e y P u b l i s h i n g (c ) I O M C o m m u n i c a t i o n s L t dbecause of the difference in the predicted and actual FOD.Overprediction of the shell layer orientation leads to a higher predicted modulus in this layer.Implementation of knowledge based design strategy (KBE)for short fibre productsInitial Knowledge Based Engineering (KBE)studies have been undertaken,incorporating the design rules as described in the section ‘Results’above.KBE is based on an object-oriented programming language,allowing necessary knowledge and experience in engineering design to be captured and deployed.Stored product information is not only geometric but also non-geometric such as weight,material,performance,and the technique used to design,analyse and manufacture the product.KBE also has generative and integrated modelling capabilities.Generative modelling updates design representation,or a product model,immediately as product requirements are changed.This is controlled by engineering rules encoded in a KBE system including product geometry,manufacturing instruc-tions,costs,etc.,and,depending on the construction of the generative model,this directly affects all features of the component,subassembly,assembly and product.Integrated modelling capability allows a KBE system to include additional rules in the generative model to create supporting data automatically,for example,finite element meshes,process plans,or cost models.In addition,as it is a single product model that is used to generate the outputs,consistency can be assured.In the present study,flat plates and ribbed plates were modelled using modelling tools of the KBE Adaptive Modelling Language (AML)from Technosoft.11The relationship between product model geometry and FOD,as a result of the injection moulding process used,was evaluated using Moldflow finite element analysis software and the relationship between process and performance,which in these initial studies was displacement under specified load,was undertaken using Nastran in the KBE shell.Both software packages were fully integrated into and controlled by the AML.All necessary information for fibre orientation distributionand displacement analysis such as geometry,material,injection locations,constraint areas and applied load,were automatically generated by the system depending on design specifications input by users.Engineering rules –some of which have been generated in this work,as discussed in the section ‘Measurements of FOD in injection moulded components’above (AIM1and AIM3)–were coded into the system.Design specifica-tions such as the size of the plate,material used,and applied load on the product can be changed via the graphical user interface (GUI)(Fig.11).The strength of the KBE approach is that it integrates the prediction of FOD and the subsequent prediction of elastic properties,which is key for injection moulded components where the FOD is generally inhomogeneous.Three types of applied load:tensile load,longitudinal bending load (applied to longitudinal ribbed plates)and transverse bending load (transverse ribbed plates)were explored.The system outputs a maximum displacement value due to the chosen applied load.The KBE system could also be used for design optimisation of short glass fibre filled injection moulding using the optimisation software,Design Optimisation Tool (DOT),one of the built-in software modules of AML.In this case,additional design specifications such as maximum and minimum values of plate thicknesses,maximum and minimum values of rib height (only for bending load)and a critically allowed displacement value had to be input into the system.After that,the system iterates until an optimal design is obtained,i.e.the product model which has a maximum displacement not more than the critical value under the specified condition,and also has minimum weight.For example,the optimal design obtained from the KBE system for a 40612064mm plate made of 40%glass fibre filled Nylon subjected to 40000N tensile load or 1000N bending load with 1mm critical displacement is shown in Table 2.It should be noted that in the case of tensile load,no rib was added,while in the case of bending load,a rib was added with its length and thickness set to be equal to the plate width and thickness,respectively.It can be seen that the KBE system can be efficiently used to evaluate and investigate,and to optimise the design of short glass fibre filled injection moulding.Withthis11Graphical user interface (GUI)of KBEsystem10Modulus through ribbed plate thicknessHine et al.Fibre orientation:measurement,modelling and knowledge based designPlastics,Rubber and Composites 2005VOL34NO9423。

开启片剂完整性的窗户(中英文对照)

开启片剂完整性的窗户(中英文对照)

开启片剂完整性的窗户日本东芝公司,剑桥大学摘要:由日本东芝公司和剑桥大学合作成立的公司向《医药技术》解释了FDA支持的技术如何在不损坏片剂的情况下测定其完整性。

太赫脉冲成像的一个应用是检查肠溶制剂的完整性,以确保它们在到达肠溶之前不会溶解。

关键词:片剂完整性,太赫脉冲成像。

能够检测片剂的结构完整性和化学成分而无需将它们打碎的一种技术,已经通过了概念验证阶段,正在进行法规申请。

由英国私募Teraview公司研发并且以太赫光(介于无线电波和光波之间)为基础。

该成像技术为配方研发和质量控制中的湿溶出试验提供了一个更好的选择。

该技术还可以缩短新产品的研发时间,并且根据厂商的情况,随时间推移甚至可能发展成为一个用于制药生产线的实时片剂检测系统。

TPI技术通过发射太赫射线绘制出片剂和涂层厚度的三维差异图谱,在有结构或化学变化时太赫射线被反射回。

反射脉冲的时间延迟累加成该片剂的三维图像。

该系统使用太赫发射极,采用一个机器臂捡起片剂并且使其通过太赫光束,用一个扫描仪收集反射光并且建成三维图像(见图)。

技术研发太赫技术发源于二十世纪九十年代中期13本东芝公司位于英国的东芝欧洲研究中心,该中心与剑桥大学的物理学系有着密切的联系。

日本东芝公司当时正在研究新一代的半导体,研究的副产品是发现了这些半导体实际上是太赫光非常好的发射源和检测器。

二十世纪九十年代后期,日本东芝公司授权研究小组寻求该技术可能的应用,包括成像和化学传感光谱学,并与葛兰素史克和辉瑞以及其它公司建立了关系,以探讨其在制药业的应用。

虽然早期的结果表明该技术有前景,但日本东芝公司却不愿深入研究下去,原因是此应用与日本东芝公司在消费电子行业的任何业务兴趣都没有交叉。

这一决定的结果是研究中心的首席执行官DonArnone和剑桥桥大学物理学系的教授Michael Pepper先生于2001年成立了Teraview公司一作为研究中心的子公司。

TPI imaga 2000是第一个商品化太赫成像系统,该系统经优化用于成品片剂及其核心完整性和性能的无破坏检测。

高效液相色谱验证-英文 (免费,不消耗积分)

高效液相色谱验证-英文 (免费,不消耗积分)

3METHOD V ALIDATION FORHPLC ANALYSIS OF RELATED SUBSTANCES IN PHARMACEUTICAL DRUG PRODUCTSY.C.L EE,P H.D.Patheon YM,Inc.3.1INTRODUCTIONIn this chapter we outline the general requirements for analytical method valida-tion for HPLC analysis of related substances in pharmaceutical products.Most of the discussion is based on method validation for pharmaceutical products of synthetic origin.Even though most of the requirements are similar for other types of pharmaceutical drug products(e.g.,biopharmaceutical drug products),detailed discussion of method validation for other types of pharmaceutical drug products is outside the scope of this chapter.The discussion focuses on current regulatory requirements in the pharmaceutical industry.Since the expectations for method validation are different at different stages of the product development process, the information given in this chapter is most suitable forfinal method valida-tion according to the ICH requirements to prepare for regulatory submissions (e.g.,NDA).Even though the method validation is related to HPLC analysis, most of the principles are also applicable to other analytical techniques(e.g., TLC,UV).Analytical Method Validation and Instrument Performance Verification,Edited by Chung Chow Chan,Herman Lam,Y.C.Lee,and Xue-Ming ZhangISBN0-471-25953-5Copyright 2004John Wiley&Sons,Inc.2728METHOD V ALIDATION FOR HPLC ANALYSIS OF RELATED SUBSTANCES3.2BACKGROUND INFORMATION3.2.1DefinitionsDefinitions for some of the commonly used terms in this chapter are given below.žDrug substance(active pharmaceutical ingredient):a pharmaceutical active ingredient.žRelated substances:impurities derived from the drug substance and there-fore not including impurities from excipients.Related substances include degradation products,synthetic impurities of drug substance,and manufac-turing process impurities from the drug product.žAuthentic sample:a purified and characterized sample of a related substance.Unlike reference standards,authentic samples may not be of high purity.However,the purity of an authentic sample has to be determined before use.Authentic samples are used in method development to identify related substances in the analysis.In addition,they are used extensively to prepare the spiked samples in method validation.žSpiked sample:a sample added with a known amount of related substances, prepared from authentic samples during method development or validation.žControl sample:a representative batch of drug substance(or drug product).Typically,control samples are tested in all analyses to ensure consistency in method performance across different runs.Sometimes,they are used as part of the system suitability test to establish the run-to-run precision(e.g., intermediate precision,reproducibility).žResponse factor:the response of drug substance or related substances per unit weight.Typically,the response factor of drug substance(or related substance)can be calculated by the following equation:Response factor=response(in response units) concentration(in mg/mL)žRelative response factor:the ratio of the response factor of individual related substance to that of a drug substance to correct for differences in the response of related substances and that of the drug substance.It can be determined using the following equation:Relative response factor=response factor of individual related substance response factor of drug substanceIf a linearity curve(Figure3.1)is constructed for both the related substance and the drug substance by plotting the response versus the concentration, the relative response factor can also be determined byRelative response factor=slope related substance slope drug substanceBACKGROUND INFORMATION 29P e a k a r e a Concentration (mg/mL)Figure 3.1.Relative response factor.3.2.2Different Types of Related Substance AnalysisArea Percent.In this approach,the level of an individual related substance is calculated by the following equation:%related substance =area related substance total area×100%where the area related substance is the peak area of the individual related substance and the total area is the peak area (i.e.,response)of the drug substance plus the peak areas of all related substances.This is one of the simplest approaches for related substance analysis because there is no need for a reference standard.This is particularly important during the early phase of the project when a highly purified reference standard is not available.It is the preferred approach as long as the method performance meets the criteria described below.Linearity over a Wide Range of Concentration .Since the areas of the related sub-stances (typically,less than 1%)and drug substance (typically,more than 95%)are summed,it is important that the method is linear from the concentration of related substances (e.g.,1%)to that of the drug substance (e.g.,95%).However,in some cases,the peak shape of the drug substance may not be totally sym-metrical at such a high concentration.Therefore,the response may not be linear in such a wide concentration range,and the use of area percentage may not be appropriate.If the response of the analyte is nonlinear at higher concentrations,the related substances would be overestimated.Although this is conservative from a safety perspective,it is inaccurate and therefore unacceptable.Sample Concentration (Method Sensitivity).To maintain linearity at the con-centration range of the drug substance,scientists may try to lower the sample concentration to improve peak shape for the drug substance.However,if the sample concentration is too low,it will affect the method sensitivity,and the ability to detect low levels of related substances may not be adequate.30METHOD V ALIDATION FOR HPLC ANALYSIS OF RELATED SUBSTANCESResponse Factor .The response factors of the related substances should be sim-ilar to that of the drug substance (i.e.,relative response factors close to unity).Otherwise,a response factor correction must be used in the calculation.High–Low.This approach can be used to overcome the limitation of linear range in the area percent method discussed above.In this approach,samples are prepared at a concentration (i.e.,high concentration)similar to that of the area percent method (Figure 3.2).In addition,the high concentration sample solutions are diluted further,to low concentrations (Figure 3.3).Samples from both high-and low-concentration solutions are injected for analysis.In the injections of the high concentration,the responses of all related substances are determined as these small peaks are detectable.The high sample concentration is used to allow all related substances to be detected and quantitated.In the injection of Peak area for related substancesTime (min)A b s o r b a n c e (m A U )510152025010203040506070Figure 3.2.chromatogram from high concentration.Time (min)A b s o r b a n c e (m A U )010203040506070Figure 3.3.chromatogram from low concentration.BACKGROUND INFORMATION 31low-concentration sample,the response of the drug substance is determined.Low concentration is used to ensure that the response of the drug substance is within the linearity range.After dilution,response of the drug substance in the low-concentration sample is similar to that of related substance in the high-concentration sample.Therefore,only a small linearity range is required for this method.In addition,since high sample concentration is used for the determination of related substances,high method sensitivity can be achieved.The limitation of the high–low approach is that each sample is injected at least twice (i.e.,high and low concentrations)and the total analysis time will be doubled.In addition,an additional step is required to dilute the high concentration to a low concentration,and dilution error can occur during the second dilution.External Standard.In this approach,related substance levels are determined by calculation using a standard curve.The concentration of related substance is determined by the response (i.e.,peak area of individual related substance)and the calibration curve.A reference standard of the drug substance is typically used in the calibration.Therefore,a response factor correction may be required if the response of related substance is very different from that of the drug substance.A single-point standard curve (Figure 3.4)is appropriate when there is no significant y -intercept.Otherwise,a multipoint calibration curve (Figure 3.5)has to be used.Different types of calibration are discussed in Section 3.2.3.The external standard approach offers several advantages over the area per-cent method,as discussed below.Reduced Linear Range .Unlike the area percent and high–low methods,which use the response of the drug substance in sample injections for calculation,an external standard method uses a standard curve.Typically,the concentration range of the calibration curve is similar to that of related substances in the sample (e.g.,1to 5%of the nominal sample concentration).Therefore,this method requires a small linear range.P e a k a r e a Concentration (% related substance)Reference standard calibration curveArea found Figure 3.4.Single-point calibration.32METHOD V ALIDATION FOR HPLC ANALYSIS OF RELATED SUBSTANCESConcentration (% related substance)% related substance foundat different levelsP e a k a r e a Area found Figure 3.5.Multi-point calibration.Improved Method Sensitivity .In this approach,only the responses of individual related substances are used in the calculation.Since the area of drug substance peak in the sample injections is not necessary for the calculation,high sample concentrations can be used without worrying about the off-scale response of the drug substance.This approach is particularly useful when the scientists want to improve the method sensitivity by increasing the sample concentration.Reference Standard .One of the limitations of the external standard method is that a well-characterized reference standard is essential.In addition,each anal-ysis requires accurate weighings of small quantities (e.g.,10mg)of reference standard.Therefore,weighing error can affect method precision and accuracy.3.2.3Suitability of Related Substance AnalysisAs discussed in Section 3.2.2,linear range is a critical factor for determining the suitable type of related substance analysis.The following are different situations to illustrate the rationales.Typically,the low end of a linearity curve is about 50%of the ICH reporting limit (e.g.,50%of 0.1%=0.05%).This is to ensure that the method will be able to calculate results accurately below the ICH reporting limit.The high end of the linearity curve is the nominal concentration (i.e.,100%).This is the target sample concentration for the drug substance.Case 1.Linearity demonstrated from 50%of the ICH reporting limit to a nominal concentration of drug substance in the sample solution.In addition,no signif-icant y -intercept is observed (Figure 3.6).In this case,area percent calculation is suitable because the linearity range covers the responses of related substances and that of the drug substance in the sample solution.Therefore,these responses can be used directly to calculate the area percentage of each related substance.Case 2.Linearity demonstrated from 50%of the ICH reporting limit to 150%of the shelf life specification of related substance.No significant y -intercept is observed (Figure 3.7).In this case,a high–low calculation is more suitable,asBACKGROUND INFORMATION33P e a k a r e a Concentration (% related substance)ICH reporting limitFigure 3.6.Linearity:case 1.Concentration (% related substance)reporting limitP e a k a r e a Figure 3.7.Linearity:case 2.the response is linear only up to the shelf life specification level.Drug substance concentration in sample solution (high concentration)should be diluted to the linear range to obtain the low-concentration solution.Therefore,the response of drug substance in low concentration will be within the linearity range and suitable for calculation.Alternatively,a single-point external standard calibration of concentration within the linearity range can also be used.Case 3.Linearity demonstrated from 50%of the ICH reporting limit to 150%of the shelf life specification of a related substance,and a significant y -intercept is observed (Figure 3.8).Due to the significant y -intercept,a single-point cali-bration (e.g.,high–low or one-point external standard calibration)is not suitable.In this case,multiple-point external standard calibration is the most appropriate.See Section 3.3.3for more discussion of the significant y -intercept.3.2.4Preparation before Method ValidationCritical Related Substances.Critical related substances are those that may exist at significant levels in the drug product.Authentic samples of these critical related34METHOD V ALIDATION FOR HPLC ANALYSIS OF RELATED SUBSTANCESConcentration (% related substance)ICH reporting limit P e a k a r e a Figure 3.8.Linearity:case 3.substances should be available for method validation.According to the ICH guidelines,all related substances at a level exceeding the identification threshold have to be identified.These related substances should be considered critical and included in the method validation.To determine the critical related substances,one can review the related sub-stance profile when the drug substance (or drug product)is subject to stress testing.The most significant related substances in stress testing should be con-sidered critical.In addition,significant related substances (i.e.,greater than ICH identification threshold)observed in stability studies during product development should also be included in the method validation.The related substance method has to be validated with respect to each critical related substance;therefore,the workload associated with method validation will increase drastically if the number of critical related substances is large.Lower and Upper Concentration Range for Method Validation.The concentra-tion range of related substances is typically related to the targeted quantitation limit (QL)at the low end and the proposed shelf life specification at the high end.Therefore,it is important to have a good estimate of these limits;otherwise,inappropriate concentrations may be used in method validation.Even though ICH proposes a method validation range from the ICH reporting limit to 120%of specification,one would want to extend the range to 50%of the ICH report-ing limit to 150%of specification to ensure that the method is suitable for most intended uses.The ICH reporting limit is given in Table 3.1.In general,the quantitation limit should be lower than the corresponding ICH reporting limit.This is to ensure that the method is accurate and precise enough to report results at the level of the ICH reporting limit.Method Procedure.Since the method procedure is undergoing constant modifi-cations during method development,it is very important to define the procedure before method validation.This will ensure that the same method procedure will be used in all method validation experiments.METHOD V ALIDATION EXPERIMENTS35 Table3.1.Various ICH Thresholds Regarding Degra-dation Products in New Drug Products as Stated inthe Current ICH Guidelines Q3B(R)Maximum Daily Dose a Threshold bThresholds for Reporting≤1g0.1%>1g0.05%Thresholds for Identification<1mg 1.0%or5µg TDI c whicheveris lower1–10mg0.5%or20µg TDI,whicheveris lower>10mg–2g0.2%or2mg TDI,whicheveris lower>2g0.1%Thresholds for Qualification<10mg 1.0%or50µg TDI,whicheveris lower10–100mg0.5%or200µg TDI,whichever is lower>100mg–2g0.2%or2mg TDI,whicheveris lower>2g0.1%a The amount of drug substance administered per day.b Threshold is based on percent of the drug substance.c Total daily intake.Critical Experimental Parameters for Robustness.Critical experimental param-eters should be identified during method development,and they will be investi-gated in the robustness experiments.System Suitability Tests.The appropriate system suitability tests should be defi-ned before method validation(e.g.,precision,resolution of critical related sub-stances,tailing,detector sensitivity).These system suitability tests should be performed in each method validation experiments.System suitability results from the method validation experiment can be used to determine the appropriate system suitability acceptance criteria.3.3METHOD V ALIDATION EXPERIMENTSIn this section we outline the requirements for method validation according to current ICH guidelines.36METHOD V ALIDATION FOR HPLC ANALYSIS OF RELATED SUBSTANCES3.3.1SpecificityICH definition:Specificity is the ability to assess unequivocally the analyte in the presence of components that may be expected to be present.Most related substance methods will be used in a stability study,and therefore they have to be stability indicating.Stability indicating means that the method has sufficient specificity to resolve all related substances and the drug substance from each other.Typically,for the related substance method for a drug product, degradation products are the most critical related substances.Therefore,as a minimum requirement,the method should have sufficient specificity to resolve the degradation products and the drug substance.In addition,all degradation products should be resolved from potential interference with the excipients. Samples for SpecificityžBlank solution to show no interference with any HPLC system artifact peak.žPlacebo to demonstrate the lack of interference from excipients.žDrug substance to show that all significant related substances are resolved from the drug substance.žAuthentic samples of critical related substances to show that all known related substances are resolved from each other.žTypically,a stressed sample of about10to20%degradation is used to demonstrate the resolution among degradation products.A10to20%de-graded sample is used because it has a sufficiently high concentration level of critical related substance.Therefore,these related substances can be detected easily.In addition,10to20%degradation is not too excessive,and the related substance profile should be close to that of a typical stability sample.žStressed placebo to show that the degradation products from the excipients will not interfere with the degradation products of the drug substance. Different Approaches1.When authentic samples of related substance are available.Analyzestressed drug product,placebo,drug substance,stressed placebo,and solutions spiked with authentic samples of related substances.The HPLC chromatograms are used to show the resolution among related substances, drug substance,and other potential interferences.In addition,check the peak homogeneity of the significant degradation products and drug substance by a photodiode array detector(PDA)or mass spectrometer.This verifies that no significant related substance coelute with each other.2.When authentic samples of impurities are not available.A stressed drugproduct can be analyzed to show separation of the most significant related substances.In addition,the peak homogeneity of the stressed sample should be investigated by PDA or mass spectrometry.Alternatively,one may use an orthogonal procedure to verify the method specificity.The orthogonalMETHOD V ALIDATION EXPERIMENTS37method can be a different technique(e.g.,capillary electrophoresis,thin-layer chromatography)or different type of HPLC analysis(e.g.,reversed phase versus normal phase).For example,compare the related substance profile in the original HPLC method and that of the orthogonal method.To demonstrate method specificity,the significant related substances should be consistent in these methods.3.3.2Quantitation Limit(and/or Detection Limit)ICH definition:The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be determined quantitatively with suitable precision and accuracy.The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be detected but not necessarily quantitated as an exact value.Two types of approaches can be used to determine the quantitation limit or detection limit,as described below.Signal-to-Noise Approach.Quantitation limit(QL;Figure3.9)is defined as the concentration of related substance in the sample that will give a signal-to-noise (S/N)ratio of10:1.Detection limit(DL)corresponds to the concentration that will give a signal-to-noise ratio of3:1.The quantitation limit of a method is affected by both the detector sensitivity and the accuracy of sample preparation at such a low concentration.In practice,the quantitation limit should be lower than the corresponding ICH reporting limit(Table3.1).To investigate the effect of both factors(i.e.,sample preparation and detector sensitivity),solutions of different concentrations near the ICH reporting limits are prepared by spiking known amounts of related substances into excipients. Each solution is prepared according to the procedure and analyzed repeatedly to determine the S/N ratio.The average S/N ratio from all analyses at each concen-tration level is used to calculate the QL or DL.The following equation can be used to estimate the QL at each concentration level.Since different concentration levels give different QLs,typically the worst-case QL will be reported as the QL of the method.QL at each concentration=10×concentration(in%related substance) S/N(average at each concentration)Noise (N) Figure3.9.Quantitation limit.38METHOD V ALIDATION FOR HPLC ANALYSIS OF RELATED SUBSTANCES Alternatively,the spike solution can be diluted serially to lower concentrations. The S/N ratio at each concentration level is determined.The concentration level (in percent related substance)that gives an S/N value of about10will be reported as the QL.Standard Deviation Approach.The following equations can be used to deter-mine quantitation limit and detection limit by standard deviation of the response at low concentrations:QL=10×SD SDL=3.3×SD Swhere SD is the standard deviation of the response near QL and S is the slope of the linearity curve near QL.There are two ways to determine SD:ing experiments similar to those given for the signal-to-noise approach,determine the standard deviation of the responses by repeat analysis of a solution near the targeted QL.2.Construct a calibration curve near the targeted QL:a.Determine the residual standard deviation of the regression line of cal-ibration,orb.Determine the standard deviation of the y-intercept.Other Considerations for QL.To account for instrument-to-instrument variation, one may need to verify the QL in multiple runs using different instruments. The desired QL should be less than the ICH reporting limit(e.g.,50%of ICH reporting limit).QL should be appropriate;too high indicates that the method is not sensitive enough to report results at the ICH reporting limit.Too low indicates that insignificant degradation products,even though much lower than the ICH reporting limit,may need to be reported.To ensure that the HPLC system in each analysis is sufficiently sensitive to report results at the ICH reporting limit,one may use a detector sensitivity solution as part of the system suitability test.Since the ICH reporting limit corresponds to QL(i.e.,S/N=10),one-third of the ICH reporting limit should correspond to DL(i.e.,S/N=3).Therefore,as part of the system suitability test, a detector sensitivity solution of a concentration of about one-third of the ICH reporting limit level would be injected.The response of the detector sensitivity solution should meet the detection limit and should be visually distinguishable from baseline.Alternatively,one may evaluate the S/N ratio of the standard solution during method development or validation.Part of the routine system suitability test is toMETHOD V ALIDATION EXPERIMENTS39 determine the S/N of the standard solution before each analysis.Therefore,the S/N of each analysis needs to be greater than the established limit.3.3.3LinearityICH definition:The linearity of an analytical procedure is its ability(within a given range)to obtain test results that are directly proportional to the concentra-tion(amount)of analyte in the sample.General RequirementsRange.Ideally,linearity should be established from50%of the ICH reporting limit to the nominal concentration of drug substance in the sample solution(for area percent method).If the linearity does not support such a wide range of concentration,determine the linearity from50%of the ICH reporting level to 150%of the proposed shelf life specifications of the related substance(for the high–low and external standard methods)as a minimum.This will ensure a linear response for related substances at all concentration levels to be detected during stability.Experimental Requirements.Solutions of known concentrations are used to deter-mine the linearity.A plot of peak area versus concentration(in percent related substance)is used to demonstrate the linearity.Authentic samples of related sub-stances with known purity are used to prepare these solutions.In most cases,for the linearity of a drug product,spiking the related substance authentic sample into excipients is not necessary,as the matrix effect should be investigated in method accuracy.Acceptance Criteria.Visual inspection is the most sensitive method for detecting nonlinearity.Therefore,the plot has to be linear by visual inspection.In addition, according to ICH guidelines,the following results should be reported:slope, correlation coefficient,y-intercept,and residual sum of squares.y-Intercept.There are several approaches to evaluating the significance of the y-intercept.žIntercept/slope ratio.The intercept/slope ratio is used to convert the y-intercept from the response unit(peak area)to the unit of percent related substance.The intercept/slope ratio should be compared to the proposed specifications to determine its significance.For example,if the shelf life specification is2.0%,an intercept/slope ratio of0.2%may be considered significant,as0.2%represents10%relative to the specification.žStatistical approach.The linearity results can be subjected to statistical analysis(e.g.,use of statistical analysis in an Excel spreadsheet).The p-value of the y-intercept can be used to determine if the intercept is sta-tistically significant.In general,when the p-value is less than0.05,the40METHOD V ALIDATION FOR HPLC ANALYSIS OF RELATED SUBSTANCES y-intercept is considered statistically significant.The p-value,which com-pares the y-intercept with the variation of responses,indicates the probability that the y-intercept to be not equal to zero.For example,when the p-value is less than0.05,this indicates that it is95%confident that the y-intercept is not equal to zero.In other words,it is95%certain that the y-intercept is significant.Typically,a positive y-intercept indicates the existence of interference with the response or the saturation of responses at high concentrations.A negative y-intercept indicates the possibility of method sensitivity problem(i.e.,a low response cannot be detected)or analytes get retained in the glassware or HPLC system(i.e.,a compatibility issue between sample solvent and mobile phase). Different Approaches for Linearity Determination.Thefirst approach is to weigh different amounts of authentic sample directly to prepare linearity solu-tions of different concentrations.Since solutions of different concentration are prepared separately from different weights,if the related substances reach their solubility limit,they will not be completely dissolved and will be shown as a nonlinear response in the plot.However,this is not suitable to prepare solutions of very low concentration,as the weighing error will be relatively high at such a low concentration.In general,this approach will be affected significantly by weighing error in the preparation.Another approach is to prepare a stock solution of high concentration,then perform serial dilution from the stock solution to obtain solutions of lower con-centrations for linearity determination.This is a more popular approach,as serial dilution can be used to prepare solutions of very low concentrations.Since the low concentrations are prepared by serial dilution,this approach does not need to weigh a very small quantity of related substance.In addition,since all solutions are diluted from the same stock solution,weighing error in preparing the stock solution will not affect the linearity determination.Relative Response Factor.The relative response factor(RRF)can be used to correct for differences in relative response between the related substances and the drug substance.In the area percent and high–low method,the related sub-stances are calculated against the response of the drug substance.In the external standard calculation,the standard curve of drug substance is generally used in the calculation.Since the related substances are calibrated by the response of the drug substance,it is necessary to determine the relative response of the related substance to that of the drug substance.After the linearity of the related sub-stances and the drug substance are determined,one can calculate the relative response factor by comparing the slope of the related substance to that of the drug substance.If the relative response factor is significantly different from unity, a correction factor may need to be used in the calculation.Otherwise,the reported results will be grossly over-or underestimated(Figure3.10).。

HIGH-RESOLUTION MASS SPECTROMETER AND METHODS FOR

HIGH-RESOLUTION MASS SPECTROMETER AND METHODS FOR

专利名称:HIGH-RESOLUTION MASS SPECTROMETERAND METHODS FOR DETERMINING THEISOTOPIC ANATOMY OF ORGANIC ANDVOLATILE MOLECULES发明人:John M. Eiler申请号:US13656447申请日:20121019公开号:US20130103337A1公开日:20130425专利内容由知识产权出版社提供专利附图:摘要:A mass spectrometer including an entrance slit, an energy filter, a momentumfilter and a detector array, the entrance slit, energy filter and momentum filter being configured to provide molecular analyte ions to the detector array at a mass resolution of about 20,000 or greater. A method for determining the isotopic composition of an analyte in a sample includes converting the analyte to molecular analyte ions, separating the molecular analyte ions using an entrance slit, separating the molecular analyte ions according to their energy levels, separating the molecular analyte ions according to their momenta, detecting two or more of the molecular analyte ions at a mass resolution of about 20,000 or greater to produce molecular analyte ion data; and analyzing the molecular analyte data to determine the isotopic composition of at least a portion of the analyte.申请人:John M. Eiler地址:Pasadena CA US国籍:US更多信息请下载全文后查看。

HIGH-RESOLUTION MICROSCOPE AND METHOD FOR DETERMIN

HIGH-RESOLUTION MICROSCOPE AND METHOD FOR DETERMIN

专利名称:HIGH-RESOLUTION MICROSCOPE ANDMETHOD FOR DETERMINING THE TWO- ORTHREE-DIMENSIONAL POSITIONS OFOBJECTS发明人:KALKBRENNER, THOMAS,KALKBRENNER, Thomas,WOLLESCHENSKY,RALF,WOLLESCHENSKY, Ralf申请号:EP2010/007595申请日:20101214公开号:WO2011/085766A1公开日:20110721专利内容由知识产权出版社提供摘要:The invention relates to a high-resolution microscope and to a method for determining the two- or three-dimensional positions of objects, comprising at least one of the following method steps a) - o) : a) the vertical (Z) position of imaged particles or molecules is determined from the orientation and shape thereof by means of an anamorphic lens, preferably a cylindrical lens, in the imaging, b) the detection beam path is split into at least two partial detection beam paths having different optical path lengths, which are detected at an offset on a detector, c) activation or switchover is performed by means of a multi-photon excitation process, preferably a two-photon excitation, d) a point-scanning activation or switchover occurs, e) a line-scanning activation or switchover occurs, f) the sample is excited and the sample light is detected in the wide-field mode, g) manually or automatically predetermined sample regions are activated or switched over, h) the activation or switchover is performed by means of AOTF or SLM orDMD, i) laser pulses for activating or switching are spectrally split by means of a spectrally splitting element, preferably a grating, j) an SLM or DMD in the beam path after the grating performs a controlled selection of split laser pulse fractions, k) the laser wide-field excitation is guided by SLM or DMD, l) ROIs are selected by SLM or DMD, m) a multi-photon switching or activation is performed by means of a microlens array, preferably a cylindrical lens array, n) switching and/or excitation is performed by means of a line scanner, and o) a line detection is performed by means of a spatially resolved sensor, wherein at least two sensor rows, each comprising a plurality of sensors, are illuminated with sample light by means of a slit diaphragm position.申请人:CARL ZEISS MICROIMAGING GMBH,CARL ZEISS MICROIMAGINGGMBH,KALKBRENNER, THOMAS,KALKBRENNER, Thomas,WOLLESCHENSKY,RALF,WOLLESCHENSKY, Ralf地址:Carl-Zeiss-Promenade 10 07745 Jena DE,An der Leutra 6 07743 Jena DE,Ricarda-Huch-Weg 26 07743 Jena DE国籍:DE,DE,DE代理人:HAMPE, Holger更多信息请下载全文后查看。

A threshold selection method from gray-level histograms翻译 中文版

A threshold selection method from gray-level histograms翻译 中文版

从灰度直方图的一个Tlreshold选择方法自动摘要,非参数和非监督方法阈值选取的图像分割相结合。

一个最佳阈值是由选定的判别准则,即以便最大化所得到的类中灰色的可分水平。

该过程是很简单的,仅利用零级和的灰度级直方图的一阶累计瞬间。

这是直白地扩展到多阈值问题的方法。

几种实验结果也列于支持该方法的有效性。

(一)引言重要的是在图像处理以选择一个适当的阈值的灰度级从他们的背景中提取的对象。

一各种技术已经被提出在这方面。

在一个理想的情况下,直方图两者之间的深刻和尖锐的山谷表示对象和背景峰,分别使该阈值可以在这个山谷的底部选择[1]。

然而,对于大多数实际图片,它往往是难以检测的谷底精确,尤其是在这种情况下,如当谷在平坦宽阔,充满了噪声时,或者当两个峰在高度极为不平等的,通常不产生可追溯山谷。

已经出现了,为了克服提出了一些技术这些困难。

它们是,例如,谷锐化技术[2],制约了直方图的像素衍生工具(或拉普拉斯梯度)的大型绝对值和的差值直方图方法[3],它选择在阈的灰度级与差的最大金额。

这些利用在原来的关于相邻像素(或边缘)的信息图像修改的直方图,以使有用的阈值。

另一个类的方法直接处理的通过参数化技术的灰度直方图。

例如,本直方图是由之和近似在最小二乘意义高斯分布,统计决策程序应用[4]。

然而,这种方法需要相当乏味有时不稳定的计算。

此外,在许多情况下,高斯分布变成是微薄的逼近的真实模式。

在任何情况下,门槛不“善”在已评估大多数的方法,到目前为止提出的。

这意味着,它可以得出一个最优阈值法的正确方法建立一个适当的标准,用于评估“善”从更一般的角度来看阈值。

在这种对应关系,我们的讨论将局限在阈值选择的基本情况,其中只有灰度级直方图足够了而没有其他的先验知识。

它不仅重要的,因为一个标准技术在图像处理中,但也在模式识别无人监督的决策问题是必不可少的。

一种新方法是从判别的角度,提出了分析;它直接评估方法的可行性,门槛的“善”,并自动选择最佳门槛。

瑞士制造的完整电阻性解决方案:对混凝土耐久性测试的电阻性检测说明书

瑞士制造的完整电阻性解决方案:对混凝土耐久性测试的电阻性检测说明书

The complete electrical resistivity solution for concrete durability testingThe advanced Resipod family offers a complete solution for measuring the electrical resistivity of concrete both in the laboratory under controlled conditions and on site.The construction industry is rapidly moving towards performance based specifications for concrete durability and this is largely determined by the permeability of the concrete. The electrical resistivity of concrete is determined by the resistivity of fluid in the pores, the pore structure and the degree of saturation. It is therefore directly related to the permeability of the concrete. All of these factors are affected by construction practice and this makes electrical resistivity an ideal test method for use in q uality control programs and performance based specifications.Unmatched FeaturesThe Resipod provides a variety of features that are unique in a concrete surface resistivity instrument:• Simple to use• Fully integrated surface resistivity instrument• Highest resolution available for a surface resistivity instrument (±0.2 kΩcm possible with the full 200µA nominal current)• Surface resistivity (SR) and bulk resistivity (BR) test configurations available• Variable spaced probe version with the automatic correction for sample geometry• Hold, save and delete function, with on-board memory• USB connection and dedicated PC software• Designed to float (waterproof)Made in SwitzerlandMuch faster to performNo sample preparation necessaryTest can be repeated at different ages e.g. 28 days, 56 daysThe same cylinder can be used for compressive strength testingResipod with 1.5” (38mm) probe spacing is fully compliant with the abovementioned standardResipod Geometric (SR) MethodThe AASHTO T 358 standard is limited to particular sample geometries anda maximum aggregate size of 1.5”, 38mm. Resipod Geometric is designed tocomply with the latest research intended to extend the current limits of thisAASHTO standard.Resipod Geometric is supplied with a variable spacing probe that canaccommodate larger aggregate sizes. It also allows the user to enter geometriccorrection factors via the ResipodLink software to give the correct resistivityreading directly on the instrument.Resipod Bulk Resistivity (BR) MethodTechnical Information ResipodLink SoftwareSystem requirements: Windows XP, Windows Vista, Windows 7, Windows 8, USB-Connector. An internet connection is necessary for automatic updates and for firmware updates (using PqUpgrade) if available. PDF Reader is required to show the “Help Manual”.81038102E ver 12 2017 © Proceq SA, Switzerland. All rights reserved.Head Office Proceq SA Ringstrasse 2 CH-8603 Schwerzenbach Switzerland Phone: +41 (0)43 355 38 00 Fax: +41 (0)43 355 38 12 info@ Subject to change without notice.All information contained in this documentation is presented in good faith and believed to be correct. Proceq SA makes no warranties and excludes all liability as to the completeness and/or accuracy of the information. For the use and application of any product manufactured and/or sold by Proceq SA explicit reference is made to the particular applicable operating instructions.Technical Information ResipodResistivity measurementRange1 – ca. 1000 k Ωcm (depending on probe spacing)Accuracy (nominal current 200µA)±0.2 k Ωcm or ±1% (whichever is greater)Accuracy (nominal current 50µA)±0.3 k Ωcm or ±2% (whichever is greater)Accuracy (nominal current <50µA)±2 k Ωcm or ±5% (whichever is greater)Display3½ digit Frequency40 Hz AC MemoryNon volatile, ca. 500 measured values Power Supply>50 hours autonomy Charger connectionUSB type B, (5V , 100mA)Dimensions197 x 53 x 69.7 mm (7.8 x 2.1 x 2.7 inch)Weight318g (11.2 oz)Operating temperature0° to 50°C (32° to 122°F)Storage temperature -10° to 70°C (14° to 158°F)Ordering InformationUnitsDescription 381 10 000Resipod, 50mm probe spacing, test strip, foam contact pads, charger with USB-cable, software, carrying strap, documentation and case 381 20 000Resipod, 38mm (1.5”) probe spacing, test strip, foam contact pads, charger with USB-cable, software, carrying strap, documentation and case 381 30 000Resipod Bulk Resistivity, 50mm probe spacing, test strip, foam contact pads, charger with USB-cable, software, carrying strap, documentation and case, Bulk Resistivity Accessory 381 40 000Resipod Bulk Resistivity, 38mm (1.5”) probe spacing, test strip, foam contact pads, charger with USB-cable, software, carrying strap, documentation and case, Bulk Resistivity Accessory 381 50 000Resipod Geometric, 50mm probe spacing, test strip, foam contact pads, charger with USB-cable, software, carrying strap, documentation and case, Resipod Geometric Accessory 381 60 000Resipod Geometric, 38mm probe spacing, test strip, foam contact pads, charger with USB-cable, software, carrying strap, documentation and case, Resipod Geometric Accessory Parts and Accessories381 01 088Bulk Resistivity Accessory 381 01 094Variable Spacing Probe 381 01 043SSet of replacement foam contact pads (20 pieces)381 01 038Resipod Test strip 381 01 092SBulk Resistivity contact pad (10 pieces)341 80 112USB chargerService and Warranty InformationProceq is committed to providing complete support for the Resipod testing instrument by means of our global service and support facilities. Furthermore, each instrument is backed by the standard Proceq 2-year warranty and extended warranty options.Standard warranty• Electronic portion of the instrument: 24 months• Mechanical portion of the instrument: 6 monthsExtended warrantyWhen purchasing a Resipod, max. 3 additional warranty years can be purchased (for the electronic portion of the instrument). The additional warranty must be requested at time of purchase or within 90 days of purchase.。

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we can observe. The main reason to excise the part of the spacetime containing the singularity is that otherwise steep gradients near the physical singularity form, which numerical codes cannot handle. The only long term stable simulations including black holes performed without excision [6, 7] use techniques that are only applicable when the black hole is present in the initial slice. In contrast most simulations including hydrodynamics have either been performed on a fixed spacetime background, or have only been run until a short time after the formation of the black hole [8]. There have been fully dynamical simulations of matter with black holes in axisymmetry such as [9], but few in 3D [10, 11, 12]. In this paper we will present a simple method for excision boundaries applied to hydrodynamics. The boundary condition is based on High–Resolution Shock– Capturing (HRSC) methods which may be used in a hydrodynamics code, and theoretically could be applied to any system using such HRSC methods. We show how it can be applied to three different, standard reconstruction schemes: TVD, ENO and PPM. Because of some problems found using this boundary condition with the PPM scheme we introduce a modified version of PPM (MPPM), which solves these problems. This excision method, combined with a suitable excision method for the spacetime, allows long term simulations of matter in black hole spacetimes. This has been shown e.g. using our hydrodynamics code called Whisky in [10]. The outline of this paper is as follows. In section II and III respectively we outline the equations and HRSC methods that will be used. The modifications required at excision boundaries are given in section IV. Section V contains the tests used to validate the boundary conditions. Throughout this paper we shall use geometric units where c = G = M⊙ = 1. Greek indices are taken to run from 0 to 3, latin indices from 1 to 3. We adopt the standard convention for the summation over repeated indices. In section III latin indices denote the cell index.
PACS numbers: 02.70.Bf, 04.25.Dm, 04.30.Db, 95.30.Lz, 97.60.Lf
1
arXiv:/0501054v1 18 Jan 2005
I.
INTRODUCTION
With gravitational wave detectors such as LIGO, VIRGO and GEO operational the problem of calculating gravitational wave templates has become even more urgent. Amongst the physical models that are the best candidates for producing detectable wave signals those including highly relativistic matter near black holes stand out. In cases such as black hole / neutron star binaries, binary neutron star systems that collapse promptly to a black hole, accretion flows onto black holes and many models for gamma-ray bursts, detailed numerical simulations will be required to find the impact of varying physical parameters on the gravitational waves produced. Black hole / neutron star binaries are on astrophysical grounds believed to be as likely as binary neutron star mergers, with expected event rates of one per year in a sphere of about 70 Mpc radius [1]. While signals from binary neutron stars are expected to give us information about the masses, spins and locations of the objects, they are not expected to give information about the internal structure of the stars. Signals from mixed binary systems, on the other hand, will provide information about the neutron star structure and equation of state (EOS) [2]. The crucial problem for numerical simulations involving 3D general relativity which must be overcome to simulate such physical systems is stability. With current formulations of the vacuum Einstein equations it is possible to produce long term simulations of black holes in certain situations [3, 4, 5]. These simulations typically require some part of the computational domain inside the black hole to be excised, with an inner boundary condition placed on a surface inside the apparent horizon. This apparent horizon is never outside the event horizon. Because no physical signal can travel outwards from such an horizon, excising the interior (or parts of it) should not affect the exterior spacetime, which is the only region
Max-Planck-Institut f¨ ur Gravitationsphysik, Albert-Einstein-Institut, 14476 Golm, Germany 2 School of Mathematics, University of Southampton, Southampton SO17 1BJ, UK 3 Institute of Cosmology and Gravitation, Mercantile House, Hampshire Terrace, PO1 2EG, Portsmouth UK 4 Center for Relativity, University of Texas at Austin, Austin TX 78712-1081, USA (Dated: February 7, 2008) We present a simple method for applying excision boundary conditions for the relativistic Euler equations. This method depends on the use of Reconstruction-Evolution methods, a standard class of HRSC methods. We test three different reconstruction schemes, namely TVD, PPM and ENO. The method does not require that the coordinate system is adapted to the excision boundary. We demonstrate the effectiveness of our method using tests containing discontinuites, static test-fluid solutions with black holes, and full dynamical collapse of a neutron star to a black hole. A modified PPM scheme is introduced because of problems arisen when matching excision with the original PPM reconstruction scheme.
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