Narciclasine_COA_24132_MedChemExpress

合集下载

Gelucire-14-44-SDS-MedChemExpress

Inhibitors, Agonists, Screening LibrariesSafety Data Sheet Revision Date:Nov.-23-2018Print Date:Nov.-23-20181. PRODUCT AND COMPANY IDENTIFICATION1.1 Product identifierProduct name :Gelucire 14/44Catalog No. :HY-Y1892CAS No. :121548-04-71.2 Relevant identified uses of the substance or mixture and uses advised againstIdentified uses :Laboratory chemicals, manufacture of substances.1.3 Details of the supplier of the safety data sheetCompany:MedChemExpress USATel:609-228-6898Fax:609-228-5909E-mail:sales@1.4 Emergency telephone numberEmergency Phone #:609-228-68982. HAZARDS IDENTIFICATION2.1 Classification of the substance or mixtureNot a hazardous substance or mixture.2.2 GHS Label elements, including precautionary statementsNot a hazardous substance or mixture.2.3 Other hazardsNone.3. COMPOSITION/INFORMATION ON INGREDIENTS3.1 SubstancesSynonyms:NoneFormula:N/AMolecular Weight:N/ACAS No. :121548-04-74. FIRST AID MEASURES4.1 Description of first aid measuresEye contactRemove any contact lenses, locate eye-wash station, and flush eyes immediately with large amounts of water. Separate eyelids with fingers to ensure adequate flushing. Promptly call a physician.Skin contactRinse skin thoroughly with large amounts of water. Remove contaminated clothing and shoes and call a physician.InhalationImmediately relocate self or casualty to fresh air. If breathing is difficult, give cardiopulmonary resuscitation (CPR). Avoid mouth-to-mouth resuscitation.IngestionWash out mouth with water; Do NOT induce vomiting; call a physician.4.2 Most important symptoms and effects, both acute and delayedThe most important known symptoms and effects are described in the labelling (see section 2.2).4.3 Indication of any immediate medical attention and special treatment neededTreat symptomatically.5. FIRE FIGHTING MEASURES5.1 Extinguishing mediaSuitable extinguishing mediaUse water spray, dry chemical, foam, and carbon dioxide fire extinguisher.5.2 Special hazards arising from the substance or mixtureDuring combustion, may emit irritant fumes.5.3 Advice for firefightersWear self-contained breathing apparatus and protective clothing.6. ACCIDENTAL RELEASE MEASURES6.1 Personal precautions, protective equipment and emergency proceduresUse full personal protective equipment. Avoid breathing vapors, mist, dust or gas. Ensure adequate ventilation. Evacuate personnel to safe areas.Refer to protective measures listed in sections 8.6.2 Environmental precautionsTry to prevent further leakage or spillage. Keep the product away from drains or water courses.6.3 Methods and materials for containment and cleaning upAbsorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); Decontaminate surfaces and equipment by scrubbing with alcohol; Dispose of contaminated material according to Section 13.7. HANDLING AND STORAGE7.1 Precautions for safe handlingAvoid inhalation, contact with eyes and skin. Avoid dust and aerosol formation. Use only in areas with appropriate exhaust ventilation.7.2 Conditions for safe storage, including any incompatibilitiesKeep container tightly sealed in cool, well-ventilated area. Keep away from direct sunlight and sources of ignition.Recommended storage temperature:Pure form-20°C 3 years4°C 2 yearsIn solvent-80°C 6 months-20°C 1 monthShipping at room temperature if less than 2 weeks.7.3 Specific end use(s)No data available.8. EXPOSURE CONTROLS/PERSONAL PROTECTION8.1 Control parametersComponents with workplace control parametersThis product contains no substances with occupational exposure limit values.8.2 Exposure controlsEngineering controlsEnsure adequate ventilation. Provide accessible safety shower and eye wash station.Personal protective equipmentEye protection Safety goggles with side-shields.Hand protection Protective gloves.Skin and body protection Impervious clothing.Respiratory protection Suitable respirator.Environmental exposure controls Keep the product away from drains, water courses or the soil. Cleanspillages in a safe way as soon as possible.9. PHYSICAL AND CHEMICAL PROPERTIES9.1 Information on basic physical and chemical propertiesAppearance White to off-white (Oil)Odor No data availableOdor threshold No data availablepH No data availableMelting/freezing point No data availableBoiling point/range No data availableFlash point No data availableEvaporation rate No data availableFlammability (solid, gas)No data availableUpper/lower flammability or explosive limits No data availableVapor pressure No data availableVapor density No data availableRelative density No data availableWater Solubility No data availablePartition coefficient No data availableAuto-ignition temperature No data availableDecomposition temperature No data availableViscosity No data availableExplosive properties No data availableOxidizing properties No data available9.2 Other safety informationNo data available.10. STABILITY AND REACTIVITY10.1 ReactivityNo data available.10.2 Chemical stabilityStable under recommended storage conditions.10.3 Possibility of hazardous reactionsNo data available.10.4 Conditions to avoidNo data available.10.5 Incompatible materialsStrong acids/alkalis, strong oxidising/reducing agents.10.6 Hazardous decomposition productsUnder fire conditions, may decompose and emit toxic fumes.Other decomposition products - no data available.11.TOXICOLOGICAL INFORMATION11.1 Information on toxicological effectsAcute toxicityClassified based on available data. For more details, see section 2Skin corrosion/irritationClassified based on available data. For more details, see section 2Serious eye damage/irritationClassified based on available data. For more details, see section 2Respiratory or skin sensitizationClassified based on available data. For more details, see section 2Germ cell mutagenicityClassified based on available data. For more details, see section 2CarcinogenicityIARC: No component of this product present at a level equal to or greater than 0.1% is identified as probable, possible or confirmed human carcinogen by IARC.ACGIH: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by ACGIH.NTP: No component of this product present at a level equal to or greater than 0.1% is identified as a anticipated or confirmed carcinogen by NTP.OSHA: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by OSHA.Reproductive toxicityClassified based on available data. For more details, see section 2Specific target organ toxicity - single exposureClassified based on available data. For more details, see section 2Specific target organ toxicity - repeated exposureClassified based on available data. For more details, see section 2Aspiration hazardClassified based on available data. For more details, see section 212. ECOLOGICAL INFORMATION12.1 ToxicityNo data available.12.2 Persistence and degradabilityNo data available.12.3 Bioaccumlative potentialNo data available.12.4 Mobility in soilNo data available.12.5 Results of PBT and vPvB assessmentPBT/vPvB assessment unavailable as chemical safety assessment not required or not conducted.12.6 Other adverse effectsNo data available.13. DISPOSAL CONSIDERATIONS13.1 Waste treatment methodsProductDispose substance in accordance with prevailing country, federal, state and local regulations.Contaminated packagingConduct recycling or disposal in accordance with prevailing country, federal, state and local regulations.14. TRANSPORT INFORMATIONDOT (US)This substance is considered to be non-hazardous for transport.IMDGThis substance is considered to be non-hazardous for transport.IATAThis substance is considered to be non-hazardous for transport.15. REGULATORY INFORMATIONSARA 302 Components:No chemicals in this material are subject to the reporting requirements of SARA Title III, Section 302.SARA 313 Components:This material does not contain any chemical components with known CAS numbers that exceed the threshold (De Minimis) reporting levels established by SARA Title III, Section 313.SARA 311/312 Hazards:No SARA Hazards.Massachusetts Right To Know Components:No components are subject to the Massachusetts Right to Know Act.Pennsylvania Right To Know Components:No components are subject to the Pennsylvania Right to Know Act.New Jersey Right To Know Components:No components are subject to the New Jersey Right to Know Act.California Prop. 65 Components:This product does not contain any chemicals known to State of California to cause cancer, birth defects, or anyother reproductive harm.16. OTHER INFORMATIONCopyright 2018 MedChemExpress. The above information is correct to the best of our present knowledge but does not purport to be all inclusive and should be used only as a guide. The product is for research use only and for experienced personnel. It must only be handled by suitably qualified experienced scientists in appropriately equipped and authorized facilities. The burden of safe use of this material rests entirely with the user. MedChemExpress disclaims all liability for any damage resulting from handling or from contact with this product.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: tech@Address: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USA。

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::。

阿西替尼片剂的实验设计

班级: xxxx 学号: 1234567 姓名 : xxx 阿西替尼红膜包衣片剂的实验设计一．立题目的和依据1.阿西替尼的相关性质中文化学名称:N-甲基-2-((3-((1E)-2-(吡啶-2-基)乙烯)- 1H-吲唑-6-基)硫)苯甲酰胺; 英文化学名称:N-methyl-2-((3-((1E)-2-(pyridin-2-yl)ethenyl)-1H-indazol-6-yl)sul-fanyl)benzamide; 分子式: C22 H18 N4OS; 分子量:386.47。

物理性状及指标：外观：类白色至浅黄色粉末溶解性：溶于DMSO (42 mg/ml，25 °C)，水(<1 mg/ml，25 °C)，乙醇(<1mg/ml，25 °C)，甲醇和DMF (~0.25 mg/ml). 在水介质中溶解度范围跨度pH 1.1至pH 7.8是超过0.2 μg/mL。

分配系数(正辛醇/水)是3.5。

密度：~1.4 g/cm3 (预测)干燥失重：≤0.5%含量：99.0%~101.0%2.用途及药理作用的描述阿西替尼能够抑??制受体酪氨酸激酶，选择性作用于VEGF受体1、2和3等靶点。

这些受体已被证实在病理性血管生成、肿瘤的生长和癌症发展中起到作用。

同时也是一种科研试剂，广泛应用于分子生物学，药理学等科研方面。

阿西替尼主要靶向于VEGFR酪酸激酶、抑制血管生成的小分子抗癌药。

药理作用：研究表明，阿西替尼能强效、选择性的抑制VEGF依赖性受体磷酸化，对VEGFR-1、VEGFR-2、EGFR-3的半数抑制浓度（IC50）分别为1.2，0.25和0.29nmol/L。

VEGFR被抑制后，下游的信号传递继而被中段，最终导致细胞无法增殖、甚至死亡。

但阿西替尼对成纤维细胞生长因子引起的细胞生长没有抑制作用。

3.研究依据和立题目的近年来，在抗肿瘤药的研制中,靶向血管生成和血管内皮生长因子(VEGF)的药物已成为热点。

UHPLC－MS

基因毒性杂质研究专栏㊀基金项目:中国食品药品检定研究院关键技术研究基金(Ｎｏ.ＧＪＪＳ－２０２２－４－１)ꎻ＃同为第一作者ꎬ∗同为通信作者作者简介:黄海伟ꎬ男ꎬ副主任药师ꎬ研究方向:药品质量安全研究ꎬＥ－ｍａｉｌ:ｈｕａｎｇｈｗ＠ｎｉｆｄｃ.ｏｒｇ.ｃｎꎻ袁松ꎬ男ꎬ助理研究员ꎬ研究方向:化学药品质量控制研究ꎬＥ－ｍａｉｌ:ｙｕａｎｓｏｎｇ＠ｎｉｆｄｃ.ｏｒｇ.ｃｎ通信作者:刘阳ꎬ男ꎬ研究员ꎬ研究方向:药品质量安全研究ꎬＴｅｌ:０１０－５３８５１５７１ꎬＥ－ｍａｉｌ:ｙａｎｇｌｉｕ＠ｎｉｆｄｃ.ｏｒｇ.ｃｎꎻ张庆生ꎬ男ꎬ主任药师ꎬ研究方向:药品质量安全研究ꎬＴｅｌ:０１０－５３８５１３７５ꎬＥ－ｍａｉｌ:ｚｑｓ＠ｎｉｆｄｃ.ｏｒｇ.ｃｎＵＨＰＬＣ－ＭＳ/ＭＳ法测定盐酸普萘洛尔缓释片中基因毒性杂质Ｎ－亚硝基普萘洛尔黄海伟＃ꎬ袁松＃ꎬ张娜ꎬ张龙浩ꎬ刘阳∗ꎬ张庆生∗(中国食品药品检定研究院ꎬ国家药品监督管理局化学药品质量研究与评价重点实验室ꎬ北京１０２６２９)摘要:目的㊀建立盐酸普萘洛尔缓释片中基因毒性杂质Ｎ－亚硝基普萘洛尔的超高效液相色谱－串联质谱(ＵＨＰＬＣ－ＭＳ/ＭＳ)检测方法ꎮ方法㊀ＷａｔｅｒｓＡＣＱＵＩＴＹＵＰＬＣＣＳＨＴＭＣ１８色谱柱(３.０ｍｍˑ１５０ｍｍꎬ１.７μｍ)ꎬ１０ｍｍｏｌＬ－１甲酸铵的水溶液(含０.１％甲酸)作为流动相Ａꎬ乙腈溶液(含０.１％甲酸)作为流动相Ｂꎬ梯度洗脱ꎬ流速为０.５ｍＬｍｉｎ－１ꎬ柱温为５０ħꎬ进样器温度为５ħꎬ进样体积为１０μＬꎬ采用多反应监测(ＭＲＭ)模式ꎬ对盐酸普萘洛尔缓释片中的Ｎ－亚硝基普萘洛尔进行定量检测ꎮ结果㊀Ｎ－亚硝基普萘洛尔在１~２０ｎｇｍＬ－１范围内具有良好的线性关系ꎮ低㊁中㊁高３个浓度的加样回收率(ｎ＝３)在９８.４％~１０３.２％之间ꎬＲＳＤɤ２.７％ꎮ检测限和定量限分别为０.０９ｎｇｍＬ－１和０.３ｎｇｍＬ－１ꎮ检出盐酸普萘洛尔缓释片中基因毒性杂质Ｎ－亚硝基普萘洛尔含量为１.８μｇｇ－１ꎮ结论㊀该方法灵敏度高㊁专属性强ꎬ可用于测定盐酸普萘洛尔缓释片中的Ｎ－亚硝基普萘洛尔ꎬ为盐酸普萘洛尔缓释片的质量控制提供参考ꎮ关键词:Ｎ－亚硝基普萘洛尔ꎻ基因毒杂质ꎻ盐酸普萘洛尔缓释片ꎻ含量测定ꎻ超高效液相色谱－串联质谱中图分类号:Ｒ９２７.１㊀文献标志码:Ａ㊀文章编号:２０９５－５３７５(２０２３)０７－０４８１－００４ｄｏｉ:１０.１３５０６/ｊ.ｃｎｋｉ.ｊｐｒ.２０２３.０７.００９ＤｅｔｅｒｍｉｎａｔｉｏｎｏｆｇｅｎｏｔｏｘｉｃｉｍｐｕｒｉｔｙＮ－ｎｉｔｒｏｓｏ－ｐｒｏｐｒａｎｏｌｏｌｉｎＰｒｏｐｒａｎｏｌｏｌＨｙｄｒｏｃｈｌｏｒｉｄｅＳｕｓｔａｉｎｅｄ－ｒｅｌｅａｓｅＴａｂｌｅｔｓｂｙＵＨＰＬＣ－ＭＳ/ＭＳＨＵＡＮＧＨａｉｗｅｉ＃ꎬＹＵＡＮＳｏｎｇ＃ꎬＺＨＡＮＧＮａꎬＺＨＡＮＧＬｏｎｇｈａｏꎬＬＩＵＹａｎｇ∗ꎬＺＨＡＮＧＱｉｎｇｓｈｅｎｇ∗(ＮＭＰＡＫｅｙＬａｂｏｒａｔｏｒｙｆｏｒＱｕａｌｉｔｙＲｅｓｅａｒｃｈａｎｄＥｖａｌｕａｔｉｏｎｏｆＣｈｅｍｉｃａｌＤｒｕｇｓꎬＮａｔｉｏｎａｌＩｎｓｔｉｔｕｔｅｆｏｒＦｏｏｄａｎｄＤｒｕｇＣｏｎｔｒｏｌꎬＢｅｉｊｉｎｇ１０２６２９ꎬＣｈｉｎａ)Ａｂｓｔｒａｃｔ:Ｏｂｊｅｃｔｉｖｅ㊀ＴｏｅｓｔａｂｌｉｓｈａｎＵＨＰＬＣ－ＭＳ/ＭＳｍｅｔｈｏｄｆｏｒｄｅｔｅｒｍｉｎａｔｉｏｎｏｆＮ－ｎｉｔｒｏｓｏ－ｐｒｏｐｒａｎｏｌｏｌｉｎＰｒｏｐ￣ｒａｎｏｌｏｌＨｙｄｒｏｃｈｌｏｒｉｄｅＳｕｓｔａｉｎｅｄ－ｒｅｌｅａｓｅＴａｂｌｅｔｓ.Ｍｅｔｈｏｄｓ㊀ＴｈｅｓｅｐａｒａｔｉｏｎｏｆＮ－ｎｉｔｒｏｓｏ－ｐｒｏｐｒａｎｏｌｏｌｗａｓｐｅｒｆｏｒｍｅｄｏｎａＷａｔｅｒｓＡＣＱＵＩＴＹＵＰＬＣＣＳＨＴＭＣ１８ｃｏｌｕｍｎ(１５０ｍｍˑ３.０ｍｍꎬ１.７μｍ)ｗｉｔｈ１０ｍｍｏｌＬ－１ａｍｍｏｎｉｕｍｆｏｒｍａｔｅａｑｕｅｏｕｓｓｏ￣ｌｕｔｉｏｎ(ｃｏｎｔａｉｎｉｎｇ０.１％ｆｏｒｍｉｃａｃｉｄ)ａｓｍｏｂｉｌｅｐｈａｓｅＡａｎｄａｃｅｔｏｎｉｔｒｉｌｅｓｏｌｕｔｉｏｎ(ｃｏｎｔａｉｎｉｎｇ０.１％ｆｏｒｍｉｃａｃｉｄ)ａｓｍｏｂｉｌｅｐｈａｓｅＢｕｎｄｅｒａｇｒａｄｉｅｎｔｅｌｕｔｉｏｎａｔａｆｌｏｗｒａｔｅｏｆ０.５ｍＬｍｉｎ－１ａｎｄａｃｏｌｕｍｎｔｅｍｐｅｒａｔｕｒｅｏｆ５０ħ.Ｍｕｌｔｉｐｌｅｒｅａｃｔｉｏｎｍｏｎｉ￣ｔｏｒｉｎｇ(ＭＲＭ)ｗａｓｐｅｒｆｏｒｍｅｄｏｎａｔｒｉｐｌｅｑｕａｄｒｕｐｏｌｅｍａｓｓｓｐｅｃｔｒｏｍｅｔｅｒｉｎｐｏｓｉｔｉｖｅｍｏｄｅ.Ｒｅｓｕｌｔｓ㊀Ｔｈｅｃａｌｉｂｒａｔｉｏｎｃｕｒｖｅｓｗａｓｉｎｇｏｏｄｌｉｎｅａｒｉｔｙｉｎｔｈｅｒａｎｇｅｏｆ１~２０ｎｇｍＬ－１.Ｔｈｅｒｅｃｏｖｅｒｉｅｓ(ｎ＝３)ａｔｌｏｗꎬｍｉｄｄｌｅａｎｄｈｉｇｈｓｐｉｋｅｄｃｏｎｃｅｎｔｒａｔｉｏｎｓｗｅｒｅｗｉｔｈｉｎ９８.４％~１０３.２％ｗｉｔｈＲＳＤｕｎｄｅｒ２.７％.Ｔｈｅｌｉｍｉｔｏｆｄｅｔｅｃｔｉｏｎｗａｓ０.０９ｎｇｍＬ－１ꎬａｎｄｔｈｅｌｉｍｉｔｏｆｑｕａｎｔｉｆｉｃａｔｉｏｎｗａｓ０.３ｎｇｍＬ－１.ＵｓｉｎｇｔｈｅｄｅｖｅｌｏｐｅｄｍｅｔｈｏｄꎬｗｅｄｅｔｅｃｔｅｄｔｈｅＮ－ｎｉｔｒｏｓｏ－ｐｒｏｐｒａｎｏｌｏｌｉｎＰｒｏｐｒａｎｏｌｏｌＨｙｄｒｏｃｈｌｏｒｉｄｅＳｕｓ￣ｔａｉｎｅｄ－ｒｅｌｅａｓｅＴａｂｌｅｔｓｗａｓ１.８μｇｇ－１.Ｃｏｎｃｌｕｓｉｏｎ㊀ＴｈｅｍｅｔｈｏｄｗａｓｓｅｎｓｉｔｉｖｅａｎｄａｃｃｕｒａｔｅꎬｗｈｉｃｈｃａｎｂｅａｐｐｌｉｅｄｆｏｒｔｈｅｑｕａｎｔｉｆｉｃａｔｉｏｎｓｏｆＮ－ｎｉｔｒｏｓｏ－ｐｒｏｐｒａｎｏｌｏｌｉｎＰｒｏｐｒａｎｏｌｏｌＨｙｄｒｏｃｈｌｏｒｉｄｅＳｕｓｔａｉｎｅｄ－ｒｅｌｅａｓｅＴａｂｌｅｔｓꎬｐｒｏｖｉｄｉｎｇｒｅｆｅｒｅｎｃｅｆｏｒｑｕａｌｉｔｙｃｏｎｔｒｏｌｏｆＰｒｏｐｒａｎｏｌｏｌＨｙｄｒｏｃｈｌｏｒｉｄｅＳｕｓｔａｉｎｅｄＲｅｌｅａｓｅｔａｂｌｅｔｓ.Ｋｅｙｗｏｒｄｓ:Ｎ－ｎｉｔｒｏｓｏ－ｐｒｏｐｒａｎｏｌｏｌꎻＧｅｎｏｔｏｘｉｃｉｍｐｕｒｉｔｙꎻＰｒｏｐｒａｎｏｌｏｌｈｙｄｒｏｃｈｌｏｒｉｄｅｅｘｔｅｎｄｅｄ－ｒｅｌｅａｓｅｔａｂｌｅｔｓꎻＡｓｓａｙꎻＵＨＰＬＣ－ＭＳ/ＭＳ㊀㊀盐酸普萘洛尔化学名称为１－异丙基－３－(１－萘氧基)－２－丙醇盐酸盐(见图１Ａ)ꎬ盐酸普萘洛尔为非选择性竞争抑制β受体阻滞剂[１]ꎬ临床上常用于高血压㊁心律失常和心绞痛的治疗[２－３]ꎮ２０２２年３月加拿大卫生部(ＨｅａｌｔｈＣａｎａｄａ)发布通告ꎬ辉瑞制药公司自愿召回６０㊁８０㊁１２０㊁１６０ｍｇ４种规格共２９批次盐酸普萘洛尔缓释胶囊ꎬ此次召回是因为在这些批次中检测出超过每天允许摄入量的Ｎ－亚硝基普萘洛尔(见图１Ｂ)[４－５]ꎮＮ－亚硝基类化合物具有直接或间接的致癌作用ꎬ长期小剂量接触或单次较大剂量接触都可能致癌[６－８]ꎬ亚硝胺类化合物是由于药物生产过程中发生了某些副反应而产生ꎮ自２０１８年缬沙坦中Ｎ－二甲基亚硝胺(ＮＤＭＡ)检出以来ꎬ又有Ｎ－二乙基亚硝胺(ＮＤＥＡ)㊁Ｎ－亚硝基－Ｎ－甲基－４－氨基丁酸(ＮＭＢＡ)等杂质陆续在药品中检出ꎬ国家药品监督管理局㊁美国食品药品监督管理局(ＦＤＡ)以及欧洲药品管理局(ＥＭＡ)都发布了有关药品中遗传毒性杂质控制策略㊁检测方法以及限度要求等指导原则ꎬ多个药品因Ｎ－亚硝基类化合物超出每日允许摄入量被召回[９－１１]ꎮ已报道的Ｎ－亚硝基类化合物主要分为两类ꎬ一类与药物本身结构无关ꎬ在药品生产过程中由残留溶剂等引入ꎬ例如ＮＤＭＡ㊁ＮＤＥＡ等ꎻ一类则直接与药物本身相关ꎬ通常是原料药中的仲胺结构与微量残留的亚硝酸盐反应生成相应的杂质[１２－１４]ꎮＮ－亚硝基普萘洛尔属于上述的第二类杂质ꎬ只在普萘洛尔相关制剂中被发现ꎮ目前尚无该基因毒性杂质检测及限度的相关报道ꎬ本文拟采用超高效液相色谱－串联质谱(ＵＨＰＬＣ－ＭＳ/ＭＳ)建立盐酸普萘洛尔缓释片中Ｎ－亚硝基普萘洛尔的检测方法ꎬ为盐酸普萘洛尔中遗传毒性杂质检查和质量控制提供参考依据ꎮ１㊀材料１.１㊀仪器㊀Ａｇｉｌｅｎｔ１２９０－６４７０液相色谱－串联三重四级杆质谱仪(美国Ａｇｉｌｅｎｔ公司)ꎬ配备电喷雾离子源(ＥＳＩ)和Ｍａｓｓｈｕｎｔｅｒ数据处理系统ꎻＸＰ２０５ＤＲ型电子分析天平(瑞士Ｍｅｔｔｌｅｒ公司)ꎬＭｉｌｌｉ－Ｑ超纯水纯化系统(美国Ｍｉｌｌｉｐｏｒｅ公司)ꎮ１.２㊀药物与试剂㊀甲醇(质谱级ꎬ美国ＦｉｓｈｅｒＳｃｉｅｎ￣图１㊀盐酸普萘洛尔(Ａ)及Ｎ－亚硝酸普萘洛尔(Ｂ)的结构式ｔｉｆｉｃ公司)ꎬ乙腈(质谱级ꎬ美国Ｓｉｇｍａ－Ａｌｄｒｉｃｈ公司)ꎬ甲酸(质谱级ꎬ德国Ｍｅｒｃｋ公司)ꎬ甲酸铵(质谱级ꎬ美国ＦｉｓｈｅｒＳｃｉｅｎｔｉｆｉｃ公司)ꎬ水为超纯水ꎬＮ－亚硝基普萘洛尔对照品(批号:ＰＮ２０２２０３１２ꎬＰＥＲＩＤＡ公司ꎬ纯度９６.８％)ꎬ盐酸普萘洛尔缓释片(市场采购)ꎮ２㊀方法与结果２.１㊀溶液制备㊀２.１.１㊀标准曲线对照品溶液制备㊀精密称取Ｎ－亚硝基普萘洛尔对照品１０.４３ｍｇꎬ置１００ｍＬ量瓶中ꎬ加甲醇使溶解并稀释至刻度ꎬ摇匀ꎬ作为对照品储备液ꎮ精密量取对照品储备液０.１ｍＬꎬ置１００ｍＬ量瓶中ꎬ用甲醇稀释至刻度ꎬ摇匀ꎬ精密量取１.０㊁２.０㊁５.０㊁７.０㊁１０.０㊁１０.０ｍＬ上述溶液分别置１００㊁１００㊁１００㊁１００㊁１００㊁５０ｍＬ量瓶中ꎬ用甲醇稀释至刻度ꎬ摇匀ꎬ作为浓度分别约为１.０㊁２.０㊁５.０㊁７.０㊁１０.０㊁２０.０ｎｇｍＬ－１的系列线性溶液ꎮ２.１.２㊀供试品溶液制备㊀取本品１０片ꎬ精密称定ꎬ研细ꎬ混匀ꎬ精密称取约相当于盐酸普萘洛尔２０ｍｇ的细粉ꎬ置１５ｍＬ离心管中ꎬ精密加入甲醇５ｍＬꎬ涡旋３ｍｉｎꎬ滤过ꎬ取续滤液作为供试品溶液ꎮ２.２㊀色谱及质谱条件㊀２.２.１㊀色谱条件㊀采用ＷａｔｅｒｓＡＣＱＵＩＴＹＵＰＬＣＣＳＨＴＭＣ１８(１５０ｍｍˑ３.０ｍｍꎬ１.７μｍ)色谱柱ꎻ以１０ｍｍｏｌＬ－１甲酸铵的水溶液(含０.１％甲酸)作为流动相Ａꎬ乙腈溶液(含０.１％甲酸)作为流动相Ｂꎬ梯度洗脱:０.０~５.０ｍｉｎꎬ５０％Ｂꎻ５.０~７.０ｍｉｎꎬ５０％Ｂң７０％Ｂꎻ７.０~９.０ｍｉｎꎬ７０％Ｂꎻ９.０~９.０ｍｉｎꎬ７０％Ｂң５０％Ｂꎻ９.０~１３.０ｍｉｎꎬ５０％Ｂꎻ流速为０.５ｍＬｍｉｎ－１ꎬ柱温为５０ħꎬ进样器温度为５ħꎬ进样体积为１０μＬꎮ２.２.２㊀质谱条件㊀采用电喷雾离子源(ｅｌｅｃｔｒｏｓｐｒａｙＩｏｎｉｚａｔｉｏｎＳｏｕｒｃｅꎬＥＳＩ)ꎬ正离子检测模式ꎬ干燥气温度为３００ħꎬ干燥气流量为６Ｌｍｉｎ－１ꎬ喷雾电压为３５ｐｓｉꎬ鞘气温度为３５０ħꎬ鞘气流量为１０Ｌｍｉｎ－１ꎬ毛细管电压为４５００Ｖꎮ采集方式为多反应监测(ＭｕｌｔｉｐｌｅｒｅａｃｔｉｏｎｍｏｎｉｔｏｒꎬＭＲＭ)模式ꎬ以ｍ/ｚ２８９.２ң７２.２作为定量离子对ꎬ碎裂电压为７８Ｖꎬ碰撞电压为１２Ｖꎬ以ｍ/ｚ２８９.２ң１４５.１作为定性离子对ꎬ碎裂电压为７８Ｖꎬ碰撞电压为１２Ｖꎮ２.３㊀方法学考察㊀２.３.１㊀专属性试验㊀取甲醇作为空白溶剂和２.１.１项下１ｎｇｍＬ－１的对照品溶液ꎬ分别进样ꎬ记录色谱图(见图２)ꎬ在所建立的色谱和质谱条件下ꎬＮ－亚硝基普萘洛尔的保留时间为６.７４ｍｉｎꎬ峰型良好ꎬ空白溶剂对检测无干扰ꎮＡ.甲醇溶液ꎻＢ.对照品溶液图２㊀甲醇和对照品溶液提取离子流色谱图２.３.２㊀检测限与定量限试验㊀取２.１.１项下１ｎｇｍＬ－１的线性溶液ꎬ以甲醇为稀释剂逐步稀释ꎬ分别在信噪比(Ｓ/Ｎ)为１０ʒ１和３ʒ１时作为定量限和检测限ꎬ测得Ｎ－亚硝基普萘洛尔的定量限和检测限分别为０.３㊁０.０９ｎｇｍＬ－１ꎮ２.３.３㊀线性关系考察㊀精密量取２.１.１项下系列线性溶液ꎬ进样检测ꎬ记录色谱图ꎮ以Ｎ－亚硝基普萘洛尔峰面积Ｙ为纵坐标ꎬ以质量浓度Ｘ(ｎｇｍＬ－１)为横坐标进行线性回归ꎬ得Ｎ－亚硝基普萘洛尔的线性回归方程为Ｙ＝２５６３.３８Ｘ－１６１.３８(ｒ＝０.９９９９)ꎬ结果表明在１.０１~２０.１９ｎｇｍＬ－１浓度范围内ꎬＮ－亚硝基普萘洛尔峰面积与质量浓度之间呈良好的线性关系ꎮ２.３.４㊀精密度和重复性试验㊀取２.１.１项下５.０ｎｇｍＬ－１的线性溶液连续进样６次ꎬ得Ｎ－亚硝基普萘洛尔峰面积的ＲＳＤ为１.１３％ꎬ结果表明系统精密度良好ꎮ取盐酸普萘洛尔缓释片ꎬ按２.１.２项下方法平行制备６份供试品溶液ꎬ进样检测ꎬ按标准曲线法计算Ｎ－亚硝基普萘洛尔含量ꎬ计算得６份供试品溶液中Ｎ－亚硝基普萘洛尔含量的ＲＳＤ为３.５８％ꎮ结果表明方法具有良好的重复性ꎮ２.３.５㊀稳定性试验㊀取２.１.１项下５.０ｎｇｍＬ－１的线性溶液ꎬ放置于进样盘ꎬ分别在０㊁８ｈ进样检测ꎬ结果Ｎ－亚硝基普萘洛尔峰面积的相对偏差为２.９６％ꎬ结果表明５ħ条件下对照品溶液在８ｈ内稳定ꎻ取２.３.４项下１份重复性试验供试溶液ꎬ放置于进样盘ꎬ分别在０㊁２㊁５㊁７ｈ进样检测ꎮ结果Ｎ－亚硝基普萘洛尔峰面积的ＲＳＤ(ｎ＝４)为２.６６％ꎬ结果表明５ħ条件下供试品溶液在７ｈ内稳定ꎮ２.３.６㊀提取效率试验㊀取盐酸普萘洛尔缓释片ꎬ按２.１.２项下方法平行制备２份供试品溶液ꎬ其中１份涡旋３ｍｉｎꎬ另一份涡旋１０ｍｉｎꎬ进样检测ꎬ按标准曲线法计算Ｎ－亚硝基普萘洛尔含量ꎬ计算得２份供试品溶液中Ｎ－亚硝基普萘洛尔含量相对标对偏差为３.７７％ꎮ结果表明涡旋３ｍｉｎ可提取完全ꎮ２.３.７㊀回收率试验㊀取盐酸普萘洛尔缓释片ꎬ精密称定ꎬ研细ꎬ混匀ꎬ精密称取细粉约５７ｍｇ(约相当于盐酸普萘洛尔２０ｍｇ)ꎬ置１５ｍＬ离心管中ꎬ精密加入２.１.１项下１０ｎｇｍＬ－１(高浓度)㊁５ｎｇｍＬ－１(中浓度)㊁２ｎｇｍＬ－１(低浓度)的线性溶液５ｍＬꎬ涡旋３ｍｉｎꎬ滤过ꎬ取续滤液作为回收率溶液ꎬ每个浓度点平行制备３份ꎬ进样检测ꎬ结果见表１ꎬ低㊁中㊁高浓度点的回收率分别为９８.４％(ＲＳＤ２.７％ꎬｎ＝３)㊁１０１.６％(ＲＳＤ１.１％ꎬｎ＝３)㊁１０３.２％(ＲＳＤ１.５％ꎬｎ＝３)ꎬ结果表明回收率良好ꎮ表１㊀加样回收率结果编号加入量检测量本底回收率平均回收ＲＳＤ５２６.１０６１.７４３５.１８１０１.７６１０１.６１.１２.４㊀样品测定㊀按２.１项下制备盐酸普萘洛尔缓释片供试品溶液ꎬ照２.２项下条件进样检测ꎬ记录色谱图ꎬ以峰面积按标准曲线法计算供试品溶液中Ｎ－亚硝基普萘洛尔的含量ꎬ测得盐酸普萘洛尔缓释片中Ｎ－亚硝基普萘洛尔含量为１.８μｇｇ－１ꎮ３㊀讨论由于盐酸普萘洛尔供试品溶液浓度较高ꎬ普萘洛尔峰与Ｎ－亚硝基普萘洛尔峰需要达到较大的分离度ꎬ才能将普萘洛尔峰切入废液不至于干扰杂质的检测ꎬ所以首先对不同类型的色谱柱进行了考察ꎬ最终选用ＷａｔｅｒｓＡＣＱＵＩＴＹＵＰＬＣＣＳＨＴＭＣ１８色谱柱ꎬＮ－亚硝基普萘洛尔峰型良好ꎬ且可与普萘洛尔峰完全分离ꎬ但两者洗脱时间较长ꎬ为提高实验效率在此基础上对色谱条件进行优化ꎬ增加有机相比例以缩短分析时间ꎻ不同流动相系统对色谱保留和杂质的质谱响应影响非常大ꎬ对流动相系统进行了考察ꎬ当采用乙腈为流动相时体系ꎬＮ－亚硝基普萘洛尔出峰较快ꎬ且质谱响应增强ꎬ可满足分析的分离度要求ꎮ前期的试验显示Ｎ－亚硝基普萘洛尔在甲醇中易溶ꎬ在乙腈中微溶ꎬ以甲醇－水作为溶剂为较优选择ꎬ但缓释片加极少量水后即成凝胶状无法进样检测ꎬ为保证提取完全和样品检测的准确性ꎬ选择了以甲醇作为溶剂ꎬ以甲醇作为溶剂时ꎬ存在一定的溶剂效应ꎬＮ－亚硝基普萘洛尔峰前沿ꎬ峰形变宽ꎬ灵敏度降低ꎬ为此ꎬ采用较大内径的色谱柱ꎬ并增加进样体积至１０μＬꎬ即可满足Ｎ－亚硝基普萘洛尔检测灵敏度的要求ꎮ目前未见Ｎ－亚硝基普萘洛尔的毒理学数据ꎬ暂无明确控制限度ꎬ提示药品研发生产㊁相关科研机构应对杂质进行深入的毒理研究以建立合理的控制限度ꎬ保障用药安全ꎮ４㊀结论本研究建立了盐酸普萘洛尔缓释片中Ｎ－亚硝基普萘洛尔的ＵＨＰＬＣ－ＭＳ/ＭＳ检测方法ꎬ并进行了相关方法学验证ꎬ结果表明ꎬ所建立的方法具有良好的专属性㊁灵敏度和准确度ꎬ可准确测定盐酸普萘洛尔缓释片中潜在的Ｎ－亚硝基普萘洛尔的含量ꎬ有助于盐酸普萘洛尔缓释片的市场监管ꎬ保障药品质量安全ꎮ参考文献:[１]㊀ＧＲＥＣＯＡꎬＤᶄＥＲＭＥＡＭꎬＧＡＬＬＡＲＡＴＩＢＺꎬｅｔａｌ.Ａｆｕｒ￣ｔｈｅｒｅｘｐｅｒｉｅｎｃｅｏｆｐｒｏｐｒａｎｏｌｏｌｆｏｒｓｅｖｅｒｅｉｎｆａｎｔｉｌｅｈｅｍａｎ￣ｇｉｏｍａｓｏｆｔｈｅｆａｃｅ:ａｎｏｂｓｅｒｖａｔｉｏｎａｌｓｔｕｄｙ[Ｊ].ＤｅｒｍａｔｏｌＴ￣ｈｅｒꎬ２０１４ꎬ２７(４):１９８－２０２.[２]ＣＨＯＢＡＮＩＡＮＡＶꎬＢＡＫＲＩＳＧＬꎬＢＬＡＣＫＨＲꎬｅｔａｌ.ＴｈｅｓｅｖｅｎｔｈｒｅｐｏｒｔｏｆｔｈｅＪｏｉｎｔｎａｔｉｏｎａｌｃｏｍｍｉｔｔｅｅｏｎｐｒｅｖｅｎ￣ｔｉｏｎꎬｄｅｔｅｃｔｉｏｎꎬｅｖａｌｕａｔｉｏｎꎬａｎｄｔｒｅａｔｍｅｎｔｏｆｈｉｇｈｂｌｏｏｄｐｒｅｓｓｕｒｅ－ＴｈｅＪＮＣ７ｒｅｐｏｒｔ[Ｊ].ＪＡＭＡꎬ２００３ꎬ２８９(１９):２５６０－２５７２.[３]汪传辉.普萘洛尔在临床上的合理应用[Ｊ].中国药业ꎬ１９９７(１０):２７－２８.[４]ＨｅａｌｔｈＣａｎａｄａ.Ｐｆｉｚｅｒｒｅｃａｌｌｓｄｅｒａｌ－ＬＡ(ＰｒｏｐｒａｎｏｌｏｌＨｙｄｒｏ￣ｃｈｌｏｒｉｄｅ)ｃａｐｓｕｌｅｓｄｕｅｔｏａｎｉｔｒｏｓａｍｉｎｅｉｍｐｕｒｉｔｙ[Ｊ/ＯＬ].[２０２１－０３－０１].ｈｔｔｐｓ://ｒｅｃａｌｌｓ－ｒａｐｐｅｌｓ.ｃａｎａｄａ.ｃａ/ｅｎ/ａｌｅｒｔ－ｒｅｃａｌｌ/ｐｆｉｚｅｒ－ｒｅｃａｌｌｓ－ｉｎｄｅｒａｌ－ｐｒｏｐｒａｎｏｌｏｌ－ｈｙｄｒｏｃｈｌｏｒｉｄｅ－ｃａｐｓｕｌｅｓ－ｄｕｅ－ｎｉｔｒｏｓａｍｉｎｅ－ｉｍｐｕｒｉｔｙ＃ｗｂ－ａｕｔｏ－２. [５]ＨｅａｌｔｈＣａｎａｄａ.Ｉｎｄｅｒａｌ－ＬＡ:ＮｉｔｒｏｓａｍｉｎｅＩｍｐｕｒｉｔｙ[Ｊ/ＯＬ].[２０２１－０３－０２].ｈｔｔｐｓ://ｒｅｃａｌｌｓ－ｒａｐｐｅｌｓ.ｃａｎａｄａ.ｃａ/ｅｎ/ａｌｅｒｔ－ｒｅｃａｌｌ/ｉｎｄｅｒａｌ－ｎｉｔｒｏｓａｍｉｎｅ－ｉｍｐｕｒｉｔｙ. [６]ＡＮＤＲＺＥＪＥＷＳＫＩＰꎬＫＡＳＰＲＺＹＫ－ＨＯＲＤＥＲＮＢꎬＮＡＷＲＯＣＫＩＪ.ＴｈｅｈａｚａｒｄｏｆＮ－ｎｉｔｒｏｓｏｄｉｍｅｔｈｙｌａｍｉｎｅ(ＮＤＭＡ)ｆｏｒｍａｔｉｏｎｄｕｒｉｎｇｗａｔｅｒｄｉｓｉｎｆｅｃｔｉｏｎｗｉｔｈｓｔｒｏｎｇｏｘｉｄａｎｔｓ[Ｊ].Ｄｅｓａｌｉｎａｔｉｏｎꎬ２００５ꎬ１７６(１/２/３):３７－４５. [７]ＳＥＮＴＨＯＮＧＰꎬＢＯＲＩＢＯＯＮＵ.Ｅｖａｌｕａｔｉｏｎｏｆｏｃｃｕｐａｔｉｏｎａｌｅｘｐｏｓｕｒｅｔｏｎｉｔｒｏｓａｍｉｎｅꎬｃａｒｂｏｎｂｌａｃｋａｎｄｄｕｓｔｉｎｒｕｂｂｅｒｐｒｏｃｅｓｓｉｎｇｉｎｄｕｓｔｒｙ[Ｊ].ＩｎｔＪＯｃｃｕｐＥｎｖｉｒｏｎＭｅｄꎬ２０１７ꎬ８(３):１８１－１８３.[８]ＰＲＥＵＳＳＭＡＮＮＲ.ＣａｒｃｉｎｏｇｅｎｉｃＮ－ｎｉｔｒｏｓｏｃｏｍｐｏｕｎｄｓａｎｄｔｈｅｉｒｅｎｖｉｒｏｎｍｅｎｔａｌｓｉｇｎｉｆｉｃａｎｃｅ[Ｊ].Ｎａｔｕｒｗｉｓｓｅｎｓｃｈａｆｔｅｎꎬ１９８４ꎬ７１(１):２５－３０.[９]ＦＤＡ.ＬｕｐｉｎＰｈａｒｍａｃｅｕｔｉｃａｌｓꎬＩｎｃ.ＩｓｓｕｅｓＶｏｌｕｎｔａｒｉｌｙＮａｔｉｏｎｗｉｄｅＲｅｃａｌｌｏｆＯｎｅＬｏｔｏｆＭｅｔｆｏｒｍｉｎＨｙｄｒｏｃｈｌｏｒｉｄｅＥｘｔｅｎｄｅｄ－ＲｅｌｅａｓｅＴａｂｌｅｔｓＵＳＰꎬ５００ｍｇＤｕｅｔｏｔｈｅＤｅｔｅｃｔｉｏｎｏｆＮ－Ｎｉｔｒｏｓｏｄｉｍｅｔｈｙｌａｍｉｎｅ(ＮＤＭＡ)[Ｊ/ＯＬ].[２０２０－０６－１１].ｈｔｔｐｓ://ｗｗｗ.ｐｒｎｅｗｓｗｉｒｅ.ｃｏｍ/ｎｅｗｓ－ｒｅｌｅａｓｅｓ/ｌｕｐｉｎ－ｐｈａｒｍａｃｅｕｔｉｃａｌｓ－ｉｎｃ－ｉｓｓｕｅｓ－ｖｏｌｕｎｔａｒｉｌｙ－ｎａｔｉｏｎｗｉｄｅ－ｒｅｃａｌｌ－ｏｆ－ｏｎｅ－ｌｏｔ－ｏｆ－ｍｅｔｆｏｒｍｉｎ－ｈｙｄｒｏｃｈｌｏｒｉｄｅ－ｅｘｔｅｎｄｅｄ－ｒｅｌｅａｓｅ－ｔａｂｌｅｔｓ－ｕｓｐ－５００ｍｇ－ｄｕｅ－ｔｏ－ｔｈｅ－ｄｅｔｅｃｔｉｏｎ－ｏｆ－ｎ－ｎｉ￣ｔｒｏｓｏｄｉｍｅｔｈｙｌａｍｉｎｅ－ｎｄｍａ－３０１０７４１８９.ｈｔｍｌ.[１０]ＨｅａｌｔｈＣａｎａｄａ.ＡｕｒｏＰｈａｒｍａＩｎｃ.ｖｏｌｕｎｔａｒｉｌｙｒｅｃａｌｌｓｏｎｅｌｏｔｏｆＡｕｒｏ－ＩｒｂｅｓａｒｔａｎＨＣＴｔａｂｌｅｔｓｂｅｃａｕｓｅｏｆｎｉｔｒｏｓａｍｉｎｅｉｍｐｕｒｉｔｙ[Ｊ/ＯＬ].[２０１９－０４－１８].ＡｕｒｏＰｈａｒｍａＩｎｃ.ｖｏｌ￣ｕｎｔａｒｉｌｙｒｅｃａｌｌｓｏｎｅｌｏｔｏｆＡｕｒｏ－ＩｒｂｅｓａｒｔａｎＨＣＴｔａｂｌｅｔｓｂｅｃａｕｓｅｏｆｎｉｔｒｏｓａｍｉｎｅｉｍｐｕｒｉｔｙ－Ｃａｎａｄａ.ｃａ.[１１]ＦＤＡ.ＰｆｉｚｅｒＩｓｓｕｅｓａＶｏｌｕｎｔａｒｙＮａｔｉｏｎｗｉｄｅＲｅｃａｌｌｆｏｒＴｗｅｌｖｅＬｏｔｓｏｆＣＨＡＮＴＩＸ(Ｖａｒｅｎｉｃｌｉｎｅ)ＴａｂｌｅｔｓＤｕｅｔｏＮ－ＮｉｔｒｏｓｏＶａｒｅｎｉｃｌｉｎｅＣｏｎｔｅｎｔ[Ｊ/ＯＬ].[２０２１－０７－１９].ｈｔ￣ｔｐｓ://ｗｗｗ.ｆｄａ.ｇｏｖ/ｓａｆｅｔｙ/ｒｅｃａｌｌｓ－ｍａｒｋｅｔ－ｗｉｔｈｄｒａｗａｌｓ－ｓａｆｅｔｙ－ａｌｅｒｔｓ/ｐｆｉｚｅｒ－ｉｓｓｕｅｓ－ｖｏｌｕｎｔａｒｙ－ｎａｔｉｏｎｗｉｄｅ－ｒｅｃａｌｌ－ｔｗｅｌｖｅ－ｌｏｔｓ－ｃｈａｎｔｉｘｒ－ｖａｒｅｎｉｃｌｉｎｅ－ｔａｂｌｅｔｓ－ｄｕｅ－ｎ－ｎｉｔｒｏｓｏ. [１２]ＫＡＯＹＴꎬＷＡＮＧＳＦꎬＷＵＭＨ.ｅｔａｌ.Ａｓｕｂｓｔｒｕｃｔｕｒｅ－ｂａｓｅｄｓｃｒｅｅｎｉｎｇａｐｐｒｏａｃｈｔｏｕｎｃｏｖｅｒＮ－ｎｉｔｒｏｓａｍｉｎｅｓｉｎｄｒｕｇｓｕｂ￣ｓｔａｎｃｅｓ[Ｊ].ＪＦｏｏｄＤｒｕｇＡｎａｌꎬ２０２２ꎬ３０(１):１５０－１６２. [１３]ＢＯＤＩＮＴꎬＶＯＲＡＳＩＴＶ.ＮｉｔｒｏｓａｍｉｎｅＣｏｎｔａｍｉｎａｔｉｏｎｉｎＰｈａｒｍａｃｅｕｔｉｃａｌｓ:ＴｈｒｅａｔꎬＩｍｐａｃｔꎬａｎｄＣｏｎｔｒｏｌ[Ｊ].ＪＰｈａｒｍＳｃｉꎬ２０２１ꎬ１１０(９):３１１８－３１２８.[１４]ＳＯＮＡＬＩＳＢ.Ｃｒｉｔｉｃａｌａｎａｌｙｓｉｓｏｆｄｒｕｇｐｒｏｄｕｃｔｒｅｃａｌｌｓｄｕｅｔｏｎｉｔｒｏｓａｍｉｎｅｉｍｐｕｒｉｔｉｅｓ[Ｊ].ＪＭｅｄＣｈｅｍꎬ２０２１ꎬ６４(６):２９２３－２９３６.(收稿日期:２０２３－０２－２５)。

药理学与毒理学ESI收录期刊

期刊全称期刊简称Aaps Journal AAPS JAaps Pharmscitech AAPS PHARMSCITECHActa Pharmaceutica ACTA PHARMACEUTActa Pharmacologica Sinica ACTA PHARMACOL SINActa Poloniae Pharmaceutica ACTA POL PHARMAdvanced Drug Delivery Reviews ADV DRUG DELIVER REVAdvances in Therapy ADV THERAlimentary Pharmacology & Therapeutics ALIMENT PHARM THERAmerican Journal of Cardiovascular Drugs AM J CARDIOVASC DRUGAmerican Journal of Health-System Pharmacy AM J HEALTH-SYST PHAmerican Journal of Pharmaceutical Education AM J PHARM EDUCAmerican Journal of Therapeutics AM J THERAnnals of Occupational Hygiene ANN OCCUP HYGAnnals of Pharmacotherapy ANN PHARMACOTHER Annual Reports in Medicinal Chemistry ANNU REP MED CHEM Annual Review of Pharmacology and Toxicology ANNU REV PHARMACOLAnti-Cancer Agents in Medicinal Chemistry ANTI-CANCER AGENT MEAnti-Cancer Drugs ANTI-CANCER DRUG Antimicrobial Agents and Chemotherapy ANTIMICROB AGENTS CHAntiviral Research ANTIVIR RESAntiviral Therapy ANTIVIR THERArchiv Der Pharmazie ARCH PHARMArchives of Pharmacal Research ARCH PHARM RESArchives of Toxicology ARCH TOXICOL Arhiv Za Higijenu Rada I Toksikologiju-Archives of Industrial Hygiene and Toxicology ARH HIG RADA TOKSIKO Assay and Drug Development Technologies ASSAY DRUG DEV TECHN Bangladesh Journal of Pharmacology BANGL J PHARMACOL Basic & Clinical Pharmacology & Toxicology BASIC CLIN PHARMACOLBiochemical Pharmacology BIOCHEM PHARMACOLBiodrugs BIODRUGSBiological & Pharmaceutical Bulletin BIOL PHARM BULLBiologicals BIOLOGICALSBiomarkers BIOMARKERSBiomedicine & Pharmacotherapy BIOMED PHARMACOTHERBiomolecules & Therapeutics BIOMOL THERBiopharm International BIOPHARM INTBiopharmaceutics & Drug Disposition BIOPHARM DRUG DISPOSBmc Pharmacology & Toxicology BMC PHARMACOL TOXICO Boletin Latinoamericano Y Del Caribe De Plantas Medicinales Y Aromaticas B LATINOAM CARIBE PL Brazilian Journal of Pharmaceutical Sciences BRAZ J PHARM SCIBritish Journal of Clinical Pharmacology BRIT J CLIN PHARMACO British Journal of Pharmacology BRIT J PHARMACOLBulletin of Pharmaceutical Sciences B PHARM SCI Canadian Journal of Physiology and Pharmacology CAN J PHYSIOL PHARMCanadian Pharmacists Journal CAN PHARM J Cancer Biotherapy and Radiopharmaceuticals CANCER BIOTHER RADIO Cardiovascular Drugs and Therapy CARDIOVASC DRUG THER Cardiovascular Therapeutics CARDIOVASC THERCardiovascular Toxicology CARDIOVASC TOXICOL Chemical Research in Toxicology CHEM RES TOXICOLChemico-Biological Interactions CHEM-BIOL INTERACTChemmedchem CHEMMEDCHEMChemotherapy CHEMOTHERAPY Chinese Journal of Natural Medicines CHIN J NAT MEDICINES Chinese Medicine CHIN MED-UK Clinical and Experimental Hypertension CLIN EXP HYPERTENS Clinical and Experimental Pharmacology and Physiology CLIN EXP PHARMACOL P Clinical Drug Investigation CLIN DRUG INVESTClinical Pharmacokinetics CLIN PHARMACOKINET Clinical Pharmacology & Therapeutics CLIN PHARMACOL THER Clinical Therapeutics CLIN THERClinical Toxicology CLIN TOXICOL Cns & Neurological Disorders-Drug Targets CNS NEUROL DISORD-DR Cns Neuroscience & Therapeutics CNS NEUROSCI THER Critical Reviews in Therapeutic Drug Carrier Systems CRIT REV THER DRUG Critical Reviews in Toxicology CRIT REV TOXICOLCurrent Cancer Drug Targets CURR CANCER DRUG TAR Current Computer-Aided Drug Design CURR COMPUT-AID DRUG Current Drug Delivery CURR DRUG DELIVCurrent Drug Metabolism CURR DRUG METABCurrent Drug Targets CURR DRUG TARGETS Current Medicinal Chemistry CURR MED CHEMCurrent Neuropharmacology CURR NEUROPHARMACOLCurrent Opinion in Pharmacology CURR OPIN PHARMACOLCurrent Pharmaceutical Analysis CURR PHARM ANAL Current Pharmaceutical Biotechnology CURR PHARM BIOTECHNO Current Pharmaceutical Design CURR PHARM DESIGN Current Topics in Nutraceutical Research CURR TOP NUTRACEUT R Current Vascular Pharmacology CURR VASC PHARMACOLCutaneous and Ocular Toxicology CUTAN OCUL TOXICOL Daru-Journal of Pharmaceutical Sciences DARUDissolution Technologies DISSOLUT TECHNOLDose-Response DOSE-RESPONSE Drug and Chemical Toxicology DRUG CHEM TOXICOL Drug Delivery DRUG DELIV Drug Design Development and Therapy DRUG DES DEV THERDrug Development and Industrial Pharmacy DRUG DEV IND PHARM Drug Development Research DRUG DEVELOP RES Drug Discovery Today DRUG DISCOV TODAY Drug Metabolism and Disposition DRUG METAB DISPOS Drug Metabolism and Pharmacokinetics DRUG METAB PHARMACOK Drug Metabolism Reviews DRUG METAB REVDrug Research DRUG RESDrug Resistance Updates DRUG RESIST UPDATEDrug Safety DRUG SAFETY Drug Testing and Analysis DRUG TEST ANALDrugs DRUGSDrugs & Aging DRUG AGINGDrugs of the Future DRUG FUTUREDrugs of Today DRUG TODAY Endocrine Metabolic & Immune Disorders-Drug Targets ENDOCR METAB IMMUNE Environmental Toxicology and Pharmacology ENVIRON TOXICOL PHAR European Journal of Clinical Pharmacology EUR J CLIN PHARMACOL European Journal of Drug Metabolism and Pharmacokinetics EUR J DRUG METAB PH European Journal of Hospital Pharmacy-Science and Practice EUR J HOSP PHARM-S PEuropean Journal of Pharmaceutical Sciences EUR J PHARM SCI European Journal of Pharmaceutics and Biopharmaceutics EUR J PHARM BIOPHARM European Journal of Pharmacology EUR J PHARMACOL European Review For Medical and Pharmacological Sciences EUR REV MED PHARMACO Experimental and Toxicologic Pathology EXP TOXICOL PATHOL Expert Opinion On Drug Delivery EXPERT OPIN DRUG DELExpert Opinion On Drug Discovery EXPERT OPIN DRUG DIS Expert Opinion On Drug Metabolism & Toxicology EXPERT OPIN DRUG MET Expert Opinion On Drug Safety EXPERT OPIN DRUG SAFExpert Opinion On Emerging Drugs EXPERT OPIN EMERG DRExpert Opinion On Investigational Drugs EXPERT OPIN INV DRUG Expert Opinion On Orphan Drugs EXPERT OPIN ORPHAN DExpert Opinion On Pharmacotherapy EXPERT OPIN PHARMACOExpert Opinion On Therapeutic Patents EXPERT OPIN THER PATExpert Opinion On Therapeutic Targets EXPERT OPIN THER TARExpert Review of Anti-Infective Therapy EXPERT REV ANTI-INFEExpert Review of Clinical Pharmacology EXPERT REV CLIN PHAR Expert Review of Pharmacoeconomics & Outcomes Research EXPERT REV PHARM OUTFarmacia FARMACIAFitoterapia FITOTERAPIAForensic Toxicology FORENSIC TOXICOL Frontiers in Pharmacology FRONT PHARMACOL Fundamental & Clinical Pharmacology FUND CLIN PHARMACOLHuman & Experimental Toxicology HUM EXP TOXICOL Indian Journal of Pharmaceutical Education and Research INDIAN J PHARM EDUC Indian Journal of Pharmaceutical Sciences INDIAN J PHARM SCI Indian Journal of Pharmacology INDIAN J PHARMACOL Inflammopharmacology INFLAMMOPHARMACOLOGYInhalation Toxicology INHAL TOXICOL Integrative Cancer Therapies INTEGR CANCER THER International Immunopharmacology INT IMMUNOPHARMACOL International Journal of Antimicrobial Agents INT J ANTIMICROB AG International Journal of Clinical Pharmacology and Therapeutics INT J CLIN PHARM TH International Journal of Clinical Pharmacy INT J CLIN PHARM-NET International Journal of Drug Policy INT J DRUG POLICY International Journal of Immunopathology and Pharmacology INT J IMMUNOPATH PH International Journal of Medicinal Mushrooms INT J MED MUSHROOMS International Journal of Nanomedicine INT J NANOMEDInternational Journal of Pharmaceutics INT J PHARMACEUTInternational Journal of Pharmacology INT J PHARMACOLInternational Journal of Toxicology INT J TOXICOL Investigational New Drugs INVEST NEW DRUG Iranian Journal of Basic Medical Sciences IRAN J BASIC MED SCIIranian Journal of Pharmaceutical Research IRAN J PHARM RES Journal of Antibiotics J ANTIBIOT Journal of Antimicrobial Chemotherapy J ANTIMICROB CHEMOTH Journal of Applied Biomedicine J APPL BIOMEDJournal of Applied Toxicology J APPL TOXICOL Journal of Asian Natural Products Research J ASIAN NAT PROD RES Journal of Biochemical and Molecular Toxicology J BIOCHEM MOL TOXIC Journal of Biopharmaceutical Statistics J BIOPHARM STATJournal of Cardiovascular Pharmacology J CARDIOVASC PHARM Journal of Cardiovascular Pharmacology and Therapeutics J CARDIOVASC PHARM TJournal of Chemotherapy J CHEMOTHERAPYJournal of Clinical Lipidology J CLIN LIPIDOLJournal of Clinical Pharmacology J CLIN PHARMACOL Journal of Clinical Pharmacy and Therapeutics J CLIN PHARM THER Journal of Controlled Release J CONTROL RELEASE Journal of Drug Delivery Science and Technology J DRUG DELIV SCI TEC Journal of Drug Targeting J DRUG TARGET Journal of Environmental Pathology Toxicology and Oncology J ENVIRON PATHOL TOX Journal of Ethnobiology and Ethnomedicine J ETHNOBIOL ETHNOMED Journal of Ethnopharmacology J ETHNOPHARMACOLJournal of Food and Drug Analysis J FOOD DRUG ANAL Journal of Ginseng Research J GINSENG RESJournal of Immunotoxicology J IMMUNOTOXICOL Journal of Infection and Chemotherapy J INFECT CHEMOTHERJournal of Managed Care Pharmacy J MANAGE CARE PHARMJournal of Microencapsulation J MICROENCAPSULJournal of Natural Medicines J NAT MED-TOKYOJournal of Natural Products J NAT PROD Journal of Neuroimmune Pharmacology J NEUROIMMUNE PHARM Journal of Ocular Pharmacology and Therapeutics J OCUL PHARMACOL TH Journal of Pharmaceutical and Biomedical Analysis J PHARMACEUT BIOMED Journal of Pharmaceutical Innovation J PHARM INNOVJournal of Pharmaceutical Sciences J PHARM SCI-US Journal of Pharmacokinetics and Pharmacodynamics J PHARMACOKINET PHAR Journal of Pharmacological and Toxicological Methods J PHARMACOL TOX MET Journal of Pharmacological Sciences J PHARMACOL SCI Journal of Pharmacology and Experimental Therapeutics J PHARMACOL EXP THER Journal of Pharmacy and Pharmaceutical Sciences J PHARM PHARM SCI Journal of Pharmacy and Pharmacology J PHARM PHARMACOL Journal of the American Pharmacists Association J AM PHARM ASSOC Journal of Toxicologic Pathology J TOXICOL PATHOLJournal of Toxicological Sciences J TOXICOL SCI Journal of Traditional Chinese Medicine J TRADIT CHIN MED Korean Journal of Physiology & Pharmacology KOREAN J PHYSIOL PHA Latin American Journal of Pharmacy LAT AM J PHARMLetters in Drug Design & Discovery LETT DRUG DES DISCOV Marine Drugs MAR DRUGSMedchemcomm MEDCHEMCOMM Medical Letter On Drugs and Therapeutics MED LETT DRUGS THER Medicinal Chemistry MED CHEM Medicinal Chemistry Research MED CHEM RESMedicinal Research Reviews MED RES REVMicrobial Drug Resistance MICROB DRUG RESIST Mini-Reviews in Medicinal Chemistry MINI-REV MED CHEMMolecular & Cellular Toxicology MOL CELL TOXICOLMolecular Diagnosis & Therapy MOL DIAGN THER Molecular Diversity MOL DIVERSMolecular Informatics MOL INFORMMolecular Pharmaceutics MOL PHARMACEUTMolecular Pharmacology MOL PHARMACOLNanotoxicology NANOTOXICOLOGY Natural Product Communications NAT PROD COMMUN Natural Product Reports NAT PROD REPNatural Product Research NAT PROD RES Nature Reviews Drug Discovery NAT REV DRUG DISCOV Naunyn-Schmiedebergs Archives of Pharmacology N-S ARCH PHARMACOL Pakistan Journal of Pharmaceutical Sciences PAK J PHARM SCI Particle and Fibre Toxicology PART FIBRE TOXICOLPediatric Drugs PEDIATR DRUGSPharmaceutical Biology PHARM BIOL Pharmaceutical Chemistry Journal PHARM CHEM J+ Pharmaceutical Development and Technology PHARM DEV TECHNOL Pharmaceutical Research PHARM RES-DORDRPharmaceutical Statistics PHARM STAT Pharmacoepidemiology and Drug Safety PHARMACOEPIDEM DR S Pharmacogenetics and Genomics PHARMACOGENET GENOM Pharmacogenomics PHARMACOGENOMICS Pharmacogenomics Journal PHARMACOGENOMICS JPharmacognosy Magazine PHARMACOGN MAGPharmacological Reports PHARMACOL REPPharmacological Research PHARMACOL RESPharmacological Reviews PHARMACOL REVPharmacology PHARMACOLOGY Pharmacology & Therapeutics PHARMACOL THERAPEUTPharmacotherapy PHARMACOTHERAPYPharmazie PHARMAZIEPhytomedicine PHYTOMEDICINEPhytotherapy Research PHYTOTHER RESPlanta Medica PLANTA MED Recent Patents On Anti-Cancer Drug Discovery RECENT PAT ANTI-CANC Records of Natural Products REC NAT PROD Regulatory Toxicology and Pharmacology REGUL TOXICOL PHARM Reproductive Toxicology REPROD TOXICOL Revista Brasileira De Farmacognosia-Brazilian Journal of Pharmacognosy REV BRAS FARMACOGN Revista Espanola De Quimioterapia REV ESP QUIMSaudi Pharmaceutical Journal SAUDI PHARM J Skin Pharmacology and Physiology SKIN PHARMACOL PHYS Therapeutic Drug Monitoring THER DRUG MONIT Therapeutic Innovation & Regulatory Science THER INNOV REGUL SCITherapie THERAPIEToxicologic Pathology TOXICOL PATHOLToxicological Sciences TOXICOL SCIToxicology TOXICOLOGY Toxicology and Applied Pharmacology TOXICOL APPL PHARM Toxicology and Industrial Health TOXICOL IND HEALTHToxicology in Vitro TOXICOL IN VITROToxicology Letters TOXICOL LETT Toxicology Mechanisms and Methods TOXICOL MECH METHOD Toxicology Research TOXICOL RES-UKToxicon TOXICONToxin Reviews TOXIN REVToxins TOXINSTrends in Pharmacological Sciences TRENDS PHARMACOL SCI Tropical Journal of Pharmaceutical Research TROP J PHARM RESValue in Health VALUE HEALTHVascular Pharmacology VASC PHARMACOLXenobiotica XENOBIOTICA Yakugaku Zasshi-Journal of the Pharmaceutical Society of Japan YAKUGAKU ZASSHIISSN EISSN ESI学科名称1550-74161550-7416PHARMACOLOGY & TOXICOLOGY 1530-99321530-9932PHARMACOLOGY & TOXICOLOGY 1330-00751846-9558PHARMACOLOGY & TOXICOLOGY 1671-40831745-7254PHARMACOLOGY & TOXICOLOGY 0001-6837null PHARMACOLOGY & TOXICOLOGY 0169-409X1872-8294PHARMACOLOGY & TOXICOLOGY 0741-238X1865-8652PHARMACOLOGY & TOXICOLOGY 0269-28131365-2036PHARMACOLOGY & TOXICOLOGY 1175-32771179-187X PHARMACOLOGY & TOXICOLOGY 1079-20821535-2900PHARMACOLOGY & TOXICOLOGY 0002-94591553-6467PHARMACOLOGY & TOXICOLOGY 1075-27651536-3686PHARMACOLOGY & TOXICOLOGY 0003-48781475-3162PHARMACOLOGY & TOXICOLOGY 1060-02801542-6270PHARMACOLOGY & TOXICOLOGY 0065-7743null PHARMACOLOGY & TOXICOLOGY 0362-1642null PHARMACOLOGY & TOXICOLOGY 1871-52061875-5992PHARMACOLOGY & TOXICOLOGY 0959-49731473-5741PHARMACOLOGY & TOXICOLOGY 0066-48041098-6596PHARMACOLOGY & TOXICOLOGY 0166-35421872-9096PHARMACOLOGY & TOXICOLOGY 1359-6535null PHARMACOLOGY & TOXICOLOGY 0365-62331521-4184PHARMACOLOGY & TOXICOLOGY 0253-62691976-3786PHARMACOLOGY & TOXICOLOGY 0340-57611432-0738PHARMACOLOGY & TOXICOLOGY 0004-12541848-6312PHARMACOLOGY & TOXICOLOGY 1540-658X1557-8127PHARMACOLOGY & TOXICOLOGY 1991-007X1991-0088PHARMACOLOGY & TOXICOLOGY 1742-78351742-7843PHARMACOLOGY & TOXICOLOGY 0006-29521873-2968PHARMACOLOGY & TOXICOLOGY 1173-88041179-190X PHARMACOLOGY & TOXICOLOGY 0918-6158null PHARMACOLOGY & TOXICOLOGY 1045-10561095-8320PHARMACOLOGY & TOXICOLOGY 1354-750X1366-5804PHARMACOLOGY & TOXICOLOGY 0753-********-6007PHARMACOLOGY & TOXICOLOGY 1976-91482005-4483PHARMACOLOGY & TOXICOLOGY 1542-166X1939-1862PHARMACOLOGY & TOXICOLOGY 0142-27821099-081X PHARMACOLOGY & TOXICOLOGY 1471-2210null PHARMACOLOGY & TOXICOLOGY 0717-********-7917PHARMACOLOGY & TOXICOLOGY 1984-82502175-9790PHARMACOLOGY & TOXICOLOGY 0306-52511365-2125PHARMACOLOGY & TOXICOLOGY 0007-11881476-5381PHARMACOLOGY & TOXICOLOGY 1110-0052null PHARMACOLOGY & TOXICOLOGY 0008-42121205-7541PHARMACOLOGY & TOXICOLOGY 1715-16351913-701X PHARMACOLOGY & TOXICOLOGY 1084-97851557-8852PHARMACOLOGY & TOXICOLOGY 0920-32061573-7241PHARMACOLOGY & TOXICOLOGY 1755-59141755-5922PHARMACOLOGY & TOXICOLOGY 1530-79051559-0259PHARMACOLOGY & TOXICOLOGY 0893-228X1520-5010PHARMACOLOGY & TOXICOLOGY 0009-27971872-7786PHARMACOLOGY & TOXICOLOGY 1860-71791860-7187PHARMACOLOGY & TOXICOLOGY0009-31571421-9794PHARMACOLOGY & TOXICOLOGY 2095-69751875-5364PHARMACOLOGY & TOXICOLOGY 1749-85461749-8546PHARMACOLOGY & TOXICOLOGY 1064-19631525-6006PHARMACOLOGY & TOXICOLOGY 1440-16811440-1681PHARMACOLOGY & TOXICOLOGY 1173-25631179-1918PHARMACOLOGY & TOXICOLOGY 0312-********-1926PHARMACOLOGY & TOXICOLOGY 0009-92361532-6535PHARMACOLOGY & TOXICOLOGY 0149-29181879-114X PHARMACOLOGY & TOXICOLOGY 1556-36501556-9519PHARMACOLOGY & TOXICOLOGY 1871-52731996-3181PHARMACOLOGY & TOXICOLOGY 1755-59301755-5949PHARMACOLOGY & TOXICOLOGY 0743-********-660X PHARMACOLOGY & TOXICOLOGY 1040-84441547-6898PHARMACOLOGY & TOXICOLOGY 1568-00961873-5576PHARMACOLOGY & TOXICOLOGY 1573-40991875-6697PHARMACOLOGY & TOXICOLOGY 1567-20181875-5704PHARMACOLOGY & TOXICOLOGY 1389-20021875-5453PHARMACOLOGY & TOXICOLOGY 1389-45011873-5592PHARMACOLOGY & TOXICOLOGY 0929-86731875-533X PHARMACOLOGY & TOXICOLOGY 1570-159X1875-6190PHARMACOLOGY & TOXICOLOGY 1471-48921471-4973PHARMACOLOGY & TOXICOLOGY 1573-41291875-676X PHARMACOLOGY & TOXICOLOGY 1389-20101873-4316PHARMACOLOGY & TOXICOLOGY 1381-61281873-4286PHARMACOLOGY & TOXICOLOGY 1540-7535null PHARMACOLOGY & TOXICOLOGY 1570-16111875-6212PHARMACOLOGY & TOXICOLOGY 1556-95271556-9535PHARMACOLOGY & TOXICOLOGY 1560-81151560-8115PHARMACOLOGY & TOXICOLOGY 1521-298X null PHARMACOLOGY & TOXICOLOGY 1559-32581559-3258PHARMACOLOGY & TOXICOLOGY 0148-05451525-6014PHARMACOLOGY & TOXICOLOGY 1071-75441521-0464PHARMACOLOGY & TOXICOLOGY 1177-8881null PHARMACOLOGY & TOXICOLOGY 0363-90451520-5762PHARMACOLOGY & TOXICOLOGY 0272-43911098-2299PHARMACOLOGY & TOXICOLOGY 1359-64461878-5832PHARMACOLOGY & TOXICOLOGY 0090-95561521-009X PHARMACOLOGY & TOXICOLOGY 1347-43671880-0920PHARMACOLOGY & TOXICOLOGY 0360-25321097-9883PHARMACOLOGY & TOXICOLOGY 2194-93792194-9387PHARMACOLOGY & TOXICOLOGY 1368-76461532-2084PHARMACOLOGY & TOXICOLOGY 0114-59161179-1942PHARMACOLOGY & TOXICOLOGY 1942-76031942-7611PHARMACOLOGY & TOXICOLOGY 0012-66671179-1950PHARMACOLOGY & TOXICOLOGY 1170-229X1179-1969PHARMACOLOGY & TOXICOLOGY 0377-********-0368PHARMACOLOGY & TOXICOLOGY 1699-39931699-4019PHARMACOLOGY & TOXICOLOGY 1871-53032212-3873PHARMACOLOGY & TOXICOLOGY 1382-66891872-7077PHARMACOLOGY & TOXICOLOGY 0031-69701432-1041PHARMACOLOGY & TOXICOLOGY 0378-********-0180PHARMACOLOGY & TOXICOLOGY 2047-99562047-9964PHARMACOLOGY & TOXICOLOGY0928-09871879-0720PHARMACOLOGY & TOXICOLOGY 0939-64111873-3441PHARMACOLOGY & TOXICOLOGY 0014-29991879-0712PHARMACOLOGY & TOXICOLOGY 1128-36021128-3602PHARMACOLOGY & TOXICOLOGY 0940-29931618-1433PHARMACOLOGY & TOXICOLOGY 1742-52471744-7593PHARMACOLOGY & TOXICOLOGY 1746-04411746-045X PHARMACOLOGY & TOXICOLOGY 1742-52551744-7607PHARMACOLOGY & TOXICOLOGY 1474-03381744-764X PHARMACOLOGY & TOXICOLOGY 1472-82141744-7623PHARMACOLOGY & TOXICOLOGY 1354-37841744-7658PHARMACOLOGY & TOXICOLOGY 2167-87072167-8707PHARMACOLOGY & TOXICOLOGY 1465-65661744-7666PHARMACOLOGY & TOXICOLOGY 1354-37761744-7674PHARMACOLOGY & TOXICOLOGY 1472-82221744-7631PHARMACOLOGY & TOXICOLOGY 1478-72101744-8336PHARMACOLOGY & TOXICOLOGY 1751-24331751-2441PHARMACOLOGY & TOXICOLOGY 1473-71671744-8379PHARMACOLOGY & TOXICOLOGY 0014-82372065-0019PHARMACOLOGY & TOXICOLOGY 0367-326X1873-6971PHARMACOLOGY & TOXICOLOGY 1860-89651860-8973PHARMACOLOGY & TOXICOLOGY 1663-98121663-9812PHARMACOLOGY & TOXICOLOGY 0767-39811472-8206PHARMACOLOGY & TOXICOLOGY 0960-32711477-0903PHARMACOLOGY & TOXICOLOGY 0019-54640019-5464PHARMACOLOGY & TOXICOLOGY 0250-474X1998-3743PHARMACOLOGY & TOXICOLOGY 0253-76131998-3751PHARMACOLOGY & TOXICOLOGY 0925-46921568-5608PHARMACOLOGY & TOXICOLOGY 0895-83781091-7691PHARMACOLOGY & TOXICOLOGY 1534-73541552-695X PHARMACOLOGY & TOXICOLOGY 1567-57691878-1705PHARMACOLOGY & TOXICOLOGY 0924-85791872-7913PHARMACOLOGY & TOXICOLOGY 0946-1965null PHARMACOLOGY & TOXICOLOGY 2210-77032210-7711PHARMACOLOGY & TOXICOLOGY 0955-39591873-4758PHARMACOLOGY & TOXICOLOGY 0394-6320null PHARMACOLOGY & TOXICOLOGY 1521-94371940-4344PHARMACOLOGY & TOXICOLOGY 1178-20131178-2013PHARMACOLOGY & TOXICOLOGY 0378-********-3476PHARMACOLOGY & TOXICOLOGY 1811-77751812-5700PHARMACOLOGY & TOXICOLOGY 1091-58181092-874X PHARMACOLOGY & TOXICOLOGY 0167-69971573-0646PHARMACOLOGY & TOXICOLOGY 2008-38662008-3874PHARMACOLOGY & TOXICOLOGY 1735-03281726-6890PHARMACOLOGY & TOXICOLOGY 0021-88200021-8820PHARMACOLOGY & TOXICOLOGY 0305-74531460-2091PHARMACOLOGY & TOXICOLOGY 1214-021X1214-0287PHARMACOLOGY & TOXICOLOGY 0260-437X1099-1263PHARMACOLOGY & TOXICOLOGY 1028-60201477-2213PHARMACOLOGY & TOXICOLOGY 1095-66701099-0461PHARMACOLOGY & TOXICOLOGY 1054-34061520-5711PHARMACOLOGY & TOXICOLOGY 0160-24461533-4023PHARMACOLOGY & TOXICOLOGY 1074-24841940-4034PHARMACOLOGY & TOXICOLOGY1120-009X1973-9478PHARMACOLOGY & TOXICOLOGY 1933-28741876-4789PHARMACOLOGY & TOXICOLOGY 0091-27001552-4604PHARMACOLOGY & TOXICOLOGY 0269-47271365-2710PHARMACOLOGY & TOXICOLOGY 0168-36591873-4995PHARMACOLOGY & TOXICOLOGY 1773-2247null PHARMACOLOGY & TOXICOLOGY 1061-186X1029-2330PHARMACOLOGY & TOXICOLOGY 0731-********-6537PHARMACOLOGY & TOXICOLOGY 1746-4269null PHARMACOLOGY & TOXICOLOGY 0378-8741null PHARMACOLOGY & TOXICOLOGY 1021-9498null PHARMACOLOGY & TOXICOLOGY 1226-84532093-4947PHARMACOLOGY & TOXICOLOGY 1547-691X1547-6901PHARMACOLOGY & TOXICOLOGY 1341-321X1437-7780PHARMACOLOGY & TOXICOLOGY 1083-4087null PHARMACOLOGY & TOXICOLOGY 0265-20481464-5246PHARMACOLOGY & TOXICOLOGY 1340-34431861-0293PHARMACOLOGY & TOXICOLOGY 0163-38641520-6025PHARMACOLOGY & TOXICOLOGY 1557-18901557-1904PHARMACOLOGY & TOXICOLOGY 1080-76831557-7732PHARMACOLOGY & TOXICOLOGY 0731-********-264X PHARMACOLOGY & TOXICOLOGY 1872-51201939-8042PHARMACOLOGY & TOXICOLOGY 0022-35491520-6017PHARMACOLOGY & TOXICOLOGY 1567-567X1573-8744PHARMACOLOGY & TOXICOLOGY 1056-87191873-488X PHARMACOLOGY & TOXICOLOGY 1347-86131347-8648PHARMACOLOGY & TOXICOLOGY 0022-35651521-0103PHARMACOLOGY & TOXICOLOGY 1482-1826null PHARMACOLOGY & TOXICOLOGY 0022-35732042-7158PHARMACOLOGY & TOXICOLOGY 1544-31911544-3450PHARMACOLOGY & TOXICOLOGY 0914-********-915X PHARMACOLOGY & TOXICOLOGY 0388-13501880-3989PHARMACOLOGY & TOXICOLOGY 0255-29221577-7014PHARMACOLOGY & TOXICOLOGY 1226-45122093-3827PHARMACOLOGY & TOXICOLOGY 0326-2383null PHARMACOLOGY & TOXICOLOGY 1570-18081875-628X PHARMACOLOGY & TOXICOLOGY 1660-33971660-3397PHARMACOLOGY & TOXICOLOGY 2040-25032040-2511PHARMACOLOGY & TOXICOLOGY 0025-732X1523-2859PHARMACOLOGY & TOXICOLOGY 1573-40641875-6638PHARMACOLOGY & TOXICOLOGY 1054-25231554-8120PHARMACOLOGY & TOXICOLOGY 0198-63251098-1128PHARMACOLOGY & TOXICOLOGY 1076-62941931-8448PHARMACOLOGY & TOXICOLOGY 1389-55751875-5607PHARMACOLOGY & TOXICOLOGY 1738-642X2092-8467PHARMACOLOGY & TOXICOLOGY 1177-10621179-2000PHARMACOLOGY & TOXICOLOGY 1381-19911573-501X PHARMACOLOGY & TOXICOLOGY 1868-17431868-1751PHARMACOLOGY & TOXICOLOGY 1543-8384null PHARMACOLOGY & TOXICOLOGY 0026-895X1521-0111PHARMACOLOGY & TOXICOLOGY 1743-53901743-5404PHARMACOLOGY & TOXICOLOGY 1934-578X1555-9475PHARMACOLOGY & TOXICOLOGY 0265-05681460-4752PHARMACOLOGY & TOXICOLOGY1478-64191478-6427PHARMACOLOGY & TOXICOLOGY 1474-17761474-1784PHARMACOLOGY & TOXICOLOGY 0028-12981432-1912PHARMACOLOGY & TOXICOLOGY 1011-601X null PHARMACOLOGY & TOXICOLOGY 1743-89771743-8977PHARMACOLOGY & TOXICOLOGY 1174-58781179-2019PHARMACOLOGY & TOXICOLOGY 1388-02091744-5116PHARMACOLOGY & TOXICOLOGY 0091-150X1573-9031PHARMACOLOGY & TOXICOLOGY 1083-74501097-9867PHARMACOLOGY & TOXICOLOGY 0724-********-904X PHARMACOLOGY & TOXICOLOGY 1539-16041539-1612PHARMACOLOGY & TOXICOLOGY 1053-85691099-1557PHARMACOLOGY & TOXICOLOGY 1744-68721744-6880PHARMACOLOGY & TOXICOLOGY 1462-24161744-8042PHARMACOLOGY & TOXICOLOGY 1470-269X1473-1150PHARMACOLOGY & TOXICOLOGY 0973-********-4062PHARMACOLOGY & TOXICOLOGY 1734-11401734-1140PHARMACOLOGY & TOXICOLOGY 1043-6618null PHARMACOLOGY & TOXICOLOGY 0031-69971521-0081PHARMACOLOGY & TOXICOLOGY 0031-70121423-0313PHARMACOLOGY & TOXICOLOGY 0163-7258null PHARMACOLOGY & TOXICOLOGY 0277-00081875-9114PHARMACOLOGY & TOXICOLOGY 0031-71440031-7144PHARMACOLOGY & TOXICOLOGY 0944-71131618-095X PHARMACOLOGY & TOXICOLOGY 0951-418X1099-1573PHARMACOLOGY & TOXICOLOGY 0032-09431439-0221PHARMACOLOGY & TOXICOLOGY 1574-89282212-3970PHARMACOLOGY & TOXICOLOGY 1307-6167null PHARMACOLOGY & TOXICOLOGY 0273-23001096-0295PHARMACOLOGY & TOXICOLOGY 0890-6238null PHARMACOLOGY & TOXICOLOGY 0102-695X null PHARMACOLOGY & TOXICOLOGY 0214-34291988-9518PHARMACOLOGY & TOXICOLOGY 1319-01642213-7475PHARMACOLOGY & TOXICOLOGY 1660-55271660-5535PHARMACOLOGY & TOXICOLOGY 0163-43561536-3694PHARMACOLOGY & TOXICOLOGY 2168-47902168-4804PHARMACOLOGY & TOXICOLOGY 0040-59571958-5578PHARMACOLOGY & TOXICOLOGY 0192-62331533-1601PHARMACOLOGY & TOXICOLOGY 1096-60801096-0929PHARMACOLOGY & TOXICOLOGY 0300-483X null PHARMACOLOGY & TOXICOLOGY 0041-008X1096-0333PHARMACOLOGY & TOXICOLOGY 0748-23371477-0393PHARMACOLOGY & TOXICOLOGY 0887-2333null PHARMACOLOGY & TOXICOLOGY 0378-********-3169PHARMACOLOGY & TOXICOLOGY 1537-65161537-6524PHARMACOLOGY & TOXICOLOGY 2045-452X2045-4538PHARMACOLOGY & TOXICOLOGY 0041-0101null PHARMACOLOGY & TOXICOLOGY 1556-95431556-9551PHARMACOLOGY & TOXICOLOGY 2072-66512072-6651PHARMACOLOGY & TOXICOLOGY 0165-6147null PHARMACOLOGY & TOXICOLOGY 1596-5996null PHARMACOLOGY & TOXICOLOGY 1098-30151524-4733PHARMACOLOGY & TOXICOLOGY 1537-18911879-3649PHARMACOLOGY & TOXICOLOGY0049-82541366-5928PHARMACOLOGY & TOXICOLOGY 0031-6903null PHARMACOLOGY & TOXICOLOGY。

含萘三氮唑甲烷骨架的硫代乙酸类尿酸转运体1(URAT1)抑制剂的合成及其构效关系

含萘三氮唑甲烷骨架的硫代乙酸类尿酸转运体1(URAT1)抑制剂的合成及其构效关系辛晓;刘巍;谢亚非;刘长鹰;汤立达;徐为人;赵桂龙【摘要】分别以1-溴萘和酮或1-萘甲醛及有机金属试剂为原料,经12步反应合成了8个含萘三氮唑甲烷骨架的硫代乙酸类尿酸转运体1(URAT1)抑制剂(1h～1o),其结构经1H NMR,13C NMR和MS (ESI)表征.体外活性测试结果显示:对URAT1的抑制活性最强的是1k,是阳性对照药lesinurad的133倍[IC50=0.054 μmol·L-1(1k),7.18 μmol·L-1(lesinurad)].%Eight naphthyltriazolylmethane-based thioacetic acids(1h ～ 1o) were synthesized as uric acid transporter 1 (URAT1) inhibitors by 12 steps using 1-bromonaphthalene and ketones or 1-naphth-aldehyde and alkyl organometallic reagents as starting materials.The structures were characterized by 1H NMR,13C NMR and MS(ESI).In vitro URAT1 inhibitory assay showed that 1k was the most potent URAT1 inhibitor among target compounds,which was 133-fold more potent than positive contr ol lesinurad(IC5o =0.054 μmol · L-1 for 1k against human URAT1 vs 7.18 μmol · L-1 for lesinurad).【期刊名称】《合成化学》【年(卷),期】2017(025)006【总页数】14页(P461-474)【关键词】1-溴萘;1-萘甲醛;痛风;高尿酸血症;尿酸转运体1 (URAT1);合成;lesinurad;构效关系【作者】辛晓;刘巍;谢亚非;刘长鹰;汤立达;徐为人;赵桂龙【作者单位】天津中医药大学研究生院,天津300193;天津药物研究院天津市新药设计与发现重点实验室,天津300193;天津药物研究院天津市新药设计与发现重点实验室,天津300193;天津药物研究院天津市新药设计与发现重点实验室,天津300193;天津药物研究院天津市新药设计与发现重点实验室,天津300193;天津药物研究院天津市新药设计与发现重点实验室,天津300193;天津中医药大学研究生院,天津300193;天津药物研究院天津市新药设计与发现重点实验室,天津300193;天津药物研究院天津市新药设计与发现重点实验室,天津300193【正文语种】中文【中图分类】O623.626;O621.3痛风是困扰人类最古老的疾病之一[1]，是由于尿酸单钠盐(MSU)在关节和关节周围的组织等部位沉积引起的，是最常见的类风性关节炎。

顶空固相微萃取_气相色谱法测定鱼腥草注射液中甲基正壬酮含量

△[基金项目]　陈可冀中西医结合发展基金、福建省高校中药学重点实验室开放课题基金资助项目(30002905012020)[通讯作者]　3李颖,E 2mail:L iying830221@1631com 。

顶空固相微萃取-气相色谱法测定鱼腥草注射液中甲基正壬酮含量△李颖13,郑申西2,李宗3(11福建中医学院药学系,福建　福州　350003;21福州市疾病预防控制中心,福建　福州　350003;31福建省药品不良反应监测中心,福建　福州　350001)[摘要]目的:建立顶空固相微萃取-气相色谱法测定鱼腥草注射液中甲基正壬酮含量的方法,并与传统水蒸气蒸馏法提取结果进行比较。

方法:采用固相微萃取器在样品瓶顶空吸附样品,对鱼腥草注射液样品进行提取,在气相色谱仪进样口高温下解吸附,并用毛细管气相色谱法分离甲基正壬酮。

色谱柱为DB 21毛细管柱(30m ×0125mm ,0125μm );载气:高纯氮(纯度≥991999%);柱温130℃;不分流进样,进样口温度200℃;F I D 检测器,温度200℃;流速110mL ・m in-1。

结果:甲基正壬酮在1107～25191μg 呈良好线性关系,r =019996;平均加样回收率为99177%,RS D =2124%。

含量测定结果与水蒸气蒸馏法(S D )无显著差异。

结论:本方法简便、快速、准确、灵敏度高、重现性好,可取代S D 2GC 法用于鱼腥草注射液中甲基正壬酮的含量分析。

[关键词]顶空固相微萃取;气相色谱法;鱼腥草注射液;甲基正壬酮鱼腥草注射液是鲜鱼腥草(国家规定使用鲜鱼腥草,国内亦有厂家用干草)经水蒸气蒸馏的挥发油饱和水溶液经灭菌制成的注射液。

鱼腥草注射液的主要有效成分为甲基正壬酮、月桂烯、葵醛等[1,2],具有抗病毒、抗菌、增强机体免疫功能、抑制炎症导致的毛细血管通透性增加、镇痛、抗过敏、平喘、止咳祛痰等作用[325]。

以往鱼腥草注射液含量测定的前处理方法主要有液-液萃取法及水蒸气蒸馏法等,传统方法操作繁琐、成分提取不够完全、重现性较差,在应用、推广上存在较多局限。

超高效液相色谱-串联质谱法测定化妆品中15种N-亚硝胺化合物

第42 卷第 11 期2023 年11 月Vol.42 No.111469~1478分析测试学报FENXI CESHI XUEBAO（Journal of Instrumental Analysis）超高效液相色谱-串联质谱法测定化妆品中15种N-亚硝胺化合物汪毅1，梁文耀1，何国山1，陈张好2，周智明2，吴谦1，席绍峰1，谭建华1*（1．广州质量监督检测研究院，国家化妆品质量检验检测中心（广州），广东广州511447；2．广东省药品检验所，广东广州510663）摘要：采用超高效液相色谱-串联质谱（UPLC-MS/MS）建立了化妆品中15种痕量N-亚硝胺化合物的分析方法。

水剂样品以水或乙腈分组超声提取，膏霜乳液样品采用亚铁氰化钾-乙酸锌溶液沉淀大分子或者饱和氯化钠-乙腈盐析分组处理后，以Agilent Poroshell 120 SB-Aq（100 mm×3.0 mm，2.7 μm）色谱柱分离，经大气压化学电离源（APCI）电离，多反应监测模式检测，以同位素内标法定量。

结果表明，15种N-亚硝胺化合物在相应质量浓度范围内线性关系良好（r2＞0.995），检出限和定量下限分别为5~15 ng/g和15~45 ng/g。

水、乳、膏霜3种化妆品基质在25、50、100 ng/g加标水平下的平均回收率为88.0%~111%，相对标准偏差（RSD，n=6）为1.4%~9.8%。

该方法用于市售化妆品检测，发现13批次样品检出N-亚硝基二乙醇胺（NDELA），其中1批次超限量值。

方法的专属性强，灵敏度高，精密度好，解决了N-亚硝胺化合物稳定性差、易被干扰等问题，适用于化妆品中15种N-亚硝胺化合物的痕量测定。

关键词：N-亚硝胺化合物；化妆品；超高效液相色谱-串联质谱法（UPLC-MS/MS）；大气压化学电离源中图分类号：O657.63；O623.732文献标识码：A 文章编号：1004-4957（2023）11-1469-10 Determination of Fifteen N-nitrosamine Compounds in Cosmetics by Ultra Performance Liquid Chromatography-TandemMass SpectrometryWANG Yi1，LIANG Wen-yao1，HE Guo-shan1，CHEN Zhang-hao2，ZHOU Zhi-ming2，WU Qian1，XI Shao-feng1，TAN Jian-hua1*（1．Guangzhou Quality Supervision and Testing Institute，National Quality Supervision and Testing Center for Cosmetics（Guangzhou），Guangzhou　511447，China；2．Guangdong Institute for Drug Control，Guangzhou　510663）Abstract：An ultra performance liquid chromatography-tandem mass spectrometric（UPLC-MS/MS）method was established for detecting 15 trace N-nitrosamine compounds in cosmetics. The final estab⁃lished method involved ultrasonic extraction of cosmetics using water or acetonitrile for different com⁃pounds. The samples were treated with potassium ferrocyanide-zinc acetate solution for precipitating macromolecules or saturated sodium chloride-acetonitrile for salting out.An Agilent Poroshell 120 SB-Aq（100 mm × 3.0 mm，2.7 μm） chromatography column was used for separation，followed by atmospheric pressure chemical ionization（APCI） source and multiple reaction monitoring mode detec⁃tion in the isotope internal standard method for quantification. The result showed good linearity（r2> 0.995） for the 15 N-nitrosamine compounds in their respective concentration ranges，with detection and quantitation limits of 5-15 ng/g and 15-45 ng/g，respectively.The average recoveries for the three cosmetic matrices（aqueous，emulsion，cream） at spiked levels of 25，50，100 ng/g were be⁃tween 88.0% and 111%，with relative standard deviations（RSD，n=6） of 1.4%-9.8%. The method was applied to the detection of commercial cosmetics and N-nitrosodiethanolamine（NDELA） was de⁃tected in 13 batches，with one batch exceeding the limit. The strong specificity，high sensitivity，and good precision made the method could solve the problems of poor stability and easy interference ofdoi：10.19969/j.fxcsxb.23051602收稿日期：2023－05－16；修回日期：2023－06－10基金项目：广东省药品监督管理局化妆品风险评估重点实验室专项（2021ZDZ03）；广东省市场监督管理局科技项目（2022CZ06）∗通讯作者：谭建华，博士，正高级工程师，研究方向：色谱－质谱检测技术研究，E-mail：tanjianhua0734@第 42 卷分析测试学报N-nitrosamine compounds，and was suitable for the trace determination of 15 N-nitrosamine com⁃pounds in cosmetics.Key words：N-nitrosamine compounds；cosmetics；ultra performance liquid chromatography-tan⁃dem mass spectrometry（UPLC-MS/MS）；atmospheric pressure chemical ionization（APCI） sourceN-亚硝胺化合物是一类具有N-亚硝基结构的化合物，因取代基的不同，形成了种类繁多的同系物，目前已发现超过300种［1］。

抗过敏药物盐酸松齐拉敏的合成

Chenmical Intermediate当代化工研究138生物制药与研究2017·03抗过敏药物盐酸松齐拉敏的合成＊王碧玉（泉州师范学院化工与材料学院福建 362000）摘要：抗过敏药物是医院日常医疗过程中比较常用的一种药物，对患者病情的康复有着重大作用，不仅是医院，就连小的诊所和药店里面也广泛应用到了抗过敏药物。

抗过敏药物的种类繁多，不同的抗敏药物其抗敏效果不一样，有时为了更好的治疗疾病，减轻患者的病痛，医院会利用多种药物合成更有利于患者治疗的新型抗过敏药物，盐酸松齐拉敏就是一种常见的合成抗过敏药物，合成的原料包括2-氨基嘧啶、对甲氧基氯苄和N，N-二甲基-2-氯乙胺，其合成步骤为两次N-烃基化反应，其合成后的总收率为79.2%，最终合成功的结构要通过1H NMR，13C NMR和HR-MS(ESI)确证。

关键词：2-氨基嘧啶；对甲氧基氯苄；N，N-二甲基-2-氯乙胺中图分类号：T 文献标识码：ASynthesis of Anti-allergic Medicine Hydrochloric Acid ThonzylamineWang Biyu（Chemical Engineering and Material College, Quanzhou Normal University, Fujian, 362000）Abstract ：Anti-allergic medicine is the common used medicine in hospitals’ daily medical process and has important function on the recovery ofpatients,besides,it not only has application in hospitals, but also in small clinics and pharmacies. The drug categories are of a great variety and the anti-allergic effect of different anti-allergic medicines is different, sometimes,in order to better treat the isease and release patients’ pain, the hospital will use many kinds of medicines to make new-type anti-allergic synthetic medicine that is more helpful to patients.Hydrochloric acid is one common seen synthetic anti-allergic medicine and its synthetic materials include 2-aminopyrimidine ，methoxybenzyl chloride and N,N-dimethyl-2-chloroethylamine, besides,its synthetic step is two-time N-alkylation, which total recovery rate after synthesis is 79.2%, finally, the structure of synthetic work needs to be confirmed by 1HNMR ，13C NMR and HR-MS(ESI).Key words ：2-aminopyrimidine ；methoxybenzyl chloride ；N,N-dimethyl-2-chloroethylamine据相关研究资料显示，抗过敏要求盐酸松齐拉敏的合成方法一共有两种，一种就是以2-氯嘧啶、对甲氧基氯苄[N'-(4-甲氧基苄基)]和N，N-二甲基乙二胺为原料，经过两次N-烃基化反应合成的方法，另一种则是以4，6-二氯-N-［(4-甲氧基苄基) 甲基］嘧啶-2-胺为原料的合成方法，其中第一种合成方法的总收率为70%～90%，而第二种的为45%～70%。

乙酰胆碱酯酶抑制剂

上海应用技术学院研究生课程《高等天然产物化学》试卷2014 / 2015 学年第1 学期课程代码：NX0702013论文题目：乙酰胆碱酯酶抑制剂的研究进展姓名：芮银146061414康满满146061409专业：制药工程学院：化工学院乙酰胆碱酯酶抑制剂的研究进展芮银，陈祎桐，康满满摘要：本文阐述了乙酰胆碱酯酶抑制剂(AChEI)的研究进展，介绍了用于药物治疗的乙酰胆碱酯酶抑制剂的各种来源如植物、微生物等，及其抑制乙酰胆碱的活性物质。

在此基础上，总结了几种现代分析技术，对AChEIs进行筛选，大大加快AD药物资源的开发利用进程。

这些方法主要有基于比色法的Ellman's法及相关的改进方法、薄层显色法、荧光显色法、电喷雾质谱法等。

但是，到目前为止，现代分析技术在AD药物资源中的应用还处在起步阶段。

关键词：乙酰胆碱酯酶抑制剂，筛选方法，薄层显色法，荧光显色法The progress of acetylcholinesteraseinhibitorsRui Yin, Chen Yitong, Kang ManmanAbstract：In this artical, the research elaborates progress of acetylcholinesterase inhibitors (AChEI), and introduces a variety of sources for drug treatment acetylcholinesterase inhibitors such as plants, microorganisms, and its active ingredients. On this basis, the review summarizes several modern analytic techniques such as Ellman's method which based on the colorimetric method, TLC chromogenic method, fluorescent color method, Electrospray ionization mass spectrometry and so on. However, at present, the application of modern analytic techniques in AD drug resources is still in infancy.Key word: Acetylcholinesterase inhibitors, Screening Methods, TLC chromogenic method, Fluorescent color method目录摘要.................................................................................................错误!未定义书签。

Bioorg. Med. Chem. Lett. 17 (2007) 3317-3321

Design and synthesis of urea and thiourea derivatives and their inhibitory activities on lipopolysaccharide-inducedNO productionYoon Jung Kim,Jae-Ha Ryu,Ye Jin Cheon,Hyo Jin Lim and Raok Jeon *College of Pharmacy,Sookmyung Women’s University,52Hyochangwon-Gil,Yongsan-Ku,Seoul 140-742,Republic of KoreaReceived 17November 2006;revised 20March 2007;accepted 2April 2007Available online 6April 2007Abstract—Series of ureas and thioureas were designed and synthesized,and their inhibitory activities of NO production in lipopoly-saccharide-activated macrophages were evaluated.We found several essential moieties in the structure of the prepared compounds for the activity.Thiourea derivatives revealed higher inhibitory activity than the corresponding urea derivatives.Among these com-pounds,7e having carboxymethyl group at N3position of thiourea was the most potent in the inhibition of NO production.They inhibited NO production through the suppression of iNOS protein and mRNA expression.Ó2007Elsevier Ltd.All rights reserved.The critical role of nitric oxide (NO)in various patho-logical conditions has led to the discovery of new inhib-itors of NO production as potential therapeutic agents.NO,a gaseous free radical,is produced through the oxi-dation of L -arginine by three isoforms of nitric oxide synthase (NOS).1The constitutive NOS (cNOS)found in neuronal tissues (nNOS,type I)and vascular endo-thelium (eNOS,type III)is Ca 2+-dependent and releases small amounts of NO required for homeostatic func-tion.2Meanwhile,inducible NOS (iNOS,type II),which can be induced by lipopolysaccharide (LPS)and various cytokines such as IFN-a ,IL-1b ,and TNF-a ,is Ca 2+-independent and produces micromolar levels of NO.3Low concentrations of NO produced by iNOS possess beneﬁcial roles in antimicrobial activity of macrophages against pathogens,4while the overproduction of NO and its derivatives,such as peroxynitrite and nitrogen diox-ide,has been suggested to be mutagenic in vivo and to provoke the pathogenesis of septic shock and various inﬂammatory processes.5Furthermore,NO and its oxi-dized forms have also been known to be carcinogenic.6Among the many strategies for providing rational con-trol of NO levels,the eﬀorts have been mainly directed toward development of selective inhibitor of iNOS thatcan be applied for the treatment of diseases accompany-ing high levels of NO.Regulation of iNOS can be achieved by the control of expression level and/or enzy-matic activity of iNOS.Many classes of iNOS inhibitors can be classiﬁed according to their structural features,such as,amino acid analogues,7amino heterocycles,8amidines,9guanidines,10isoquinolinamines,11and isot-hiourea.12,13But most of the inhibitors are neither po-tent nor selective enough against NOS isoforms,that limited the application of them in vivo.Only one class of iNOS inhibitors,L -lysine analogue,was reported to enter the clinical trial in human.14Urea was known to inhibit not only the activity of iNOS in macrophages during the uremia,15but also the expres-sion of iNOS in LPS-activated macrophages.16Urea was suggested as an important modulator for renal function through the ﬁne tuning of NO production.17Several groups have reported that urea and thiourea 18or iso-thiourea 12,13,19inhibit iNOS expression and/or NO pro-duction.Based on these reports,we tried to investigate urea and thiourea derivatives as novel inhibitors having mechanism for enzymatic inhibition and/or downregula-tion of iNOS expression.Herein,we report the design and synthesis of urea and thiourea derivatives as depicted in Figure 1.Their eﬀects on the NO production and expression of iNOS were evaluated in LPS-activated macrophage cell culture system.0960-894X/$-see front matter Ó2007Elsevier Ltd.All rights reserved.doi:10.1016/j.bmcl.2007.04.005Keywords :Urea;Thiourea;Carbazole;Nitric oxide synthase;Nitric oxide;Inhibitor.*Corresponding author.Tel.:+8227109571;fax:+8227159571;e-mail:rjeon@sookmyung.ac.krBioorganic &Medicinal Chemistry Letters 17(2007)3317–3321The preparation of the carbazole-linked urea and thio-urea derivatives is outlined in Schemes 1and 2.Hydroxy ethyl group was introduced at nitrogen of carbazole and the resulting alcohol 2was mesylated to obtain com-pound 3.Alkylation of 4-nitrophenol by treatment of compound 3in the presence of NaH gave compound 4.Following reduction of nitro compound 4over 10%Pd/C under atmospheric pressure of hydrogen gas pro-vided amine 5.Condensation of amine 5with the appro-priate isocyanates or isothiocyanates oﬀered the desired compounds 6and 7.The activities of the prepared compounds were evalu-ated for the inhibition of NO production in LPS-acti-vated macrophages.Murine macrophage cell line,RAW 264.7cells,was stimulated with 1l g/mL of LPS in the presence of samples for 20h.The amounts of NO released into culture media were determined by the Griess method 20in the form of nitrite.21The inhibitory activities of the prepared compounds on the NO production are given in Table 1.Aminoguani-dine,a well-known speciﬁc inhibitor of iNOS,was usedas positive control that showed 85%inhibition of NO production at 0.1l M.Most of the thiourea derivatives revealed higher activity than the corresponding urea derivatives.For example,thioureas 7a ,7c ,7e ,and 7f showed signiﬁcantly higher activities than ureas 6a ,6b ,6g ,and 6i ,respectively.Eﬀects of the alkyl substituents at the N1and N3posi-tion of urea 6a and thiourea 7a were investigated.Intro-duction of methyl group 6h at the N1position of urea 6a lowered the activity,while introduction of bulkier sub-stituent retrieved the pound 6i with ethyl group showed the similar activity as 6a .Meanwhile,activity of compound 6j with cyclopropylmethyl at N1became 2.5-fold higher than that of 6a .On the other hand,thiourea derivatives 7f substituted with ethyl and 7g with cyclopropylmethyl at N1of 7a revealed 2-fold lower activity than 7a .The eﬀects of substituents at N3position were consider-ably diﬀerent between urea and thiourea derivatives.While the substitution at N3of urea derivatives 6b–6g showed no signiﬁcant eﬀects on the activity,the alkyl substitution of thiourea greatly enhanced the pounds 7b ,7c ,7e with methyl,ethyl,or carboxym-ethyl group at N3revealed similar activity ranging from 80%to 90%inhibition of NO production at 5l M con-centration.In both cases of ureas and thioureas,the carboxymethyl was the best substituent at N3for the improvement of activity.IC 50values of 6j ,7a–7c ,and3318Y.J.Kim et al./Bioorg.Med.Chem.Lett.17(2007)3317–33217e,which showed more than50%inhibitory responses at 5l M,were determined as3.12,5.31,0.73,0.90,and 0.15l M,respectively.In order toﬁnd the inﬂuence of lipophilic tail on the activity,carbazolylmethyl group of thiourea derivatives 7b–7c was eliminated.These compounds showed lower activities,less than15%inhibition of NO production at5l M,than the corresponding carbazole-linked thiou-reas.It has been reported that a carbazole derivative inhibited iNOS expression in the LPS-activated macro-phage.22Our results also demonstrated that both thio-urea and carbazole moieties might play an important role for their activities although carbazole moiety devoid of thiourea group revealed no activity.We expect to potentiate the activity by the structural modiﬁcation of thiourea and lipophilic segment.For the further biological study of our derivatives,we examined the eﬀects of6j,7a–7c,and7e on the expres-sion of iNOS protein and mRNA in LPS-activated RAW264.7cells.The amounts of iNOS protein were analyzed in Western blot analysis after20-h incubation with compounds during LPS(1l g/mL)activation ofmacrophages.23Compounds7b and7e signiﬁcantly reduced the amounts of iNOS at10l M(Fig.2).At RT-PCR analysis,24the expression level of iNOS mRNA was increased markedly by LPS-activation for pounds7b and7e suppressed the induction of iNOS mRNA at10l M(Fig.3).These results indicated that the inhibition of NO production by thiourea deriv-atives resulted from the suppression of iNOS protein and mRNA.When we treated the compounds after the completion of iNOS induction by LPS(post-treatment),they showed weak activity compared with the results of the co-treat-ment of compounds with LPS.Even the most potent compound7e showed12%inhibition at10l M by post-treatment.These results suggested that thiourea derivatives exhibited their activities mainly through the inhibition of iNOS expression with marginal inhibi-tion against enzymatic activity.It has been reported that urea itself inhibited the activity of iNOS by transcrip-tional15and post-transcriptional16mechanisms.Many of thioureas and isothioureas were reported12,25as inhibitors of iNOS enzyme devoid of controlling the expression step.In addition,a carbazole compound,Table1.Inhibitory activities of carbazole-linked phenylureas and phenylthioureas on the NO production in LPS-induced NO productionNO NHNXR1R2R1, R2=H,alkylX = O, SCompound R1R2X Inhibition a(%)IC50b(nM) 6a H H O246b H Et O306c H Pro O146d H i-Pro O156e H Ph O286f H CH2CO2Et O386g H CH2CO2H O436h Me H O86i Et H O256j Cyclopropylmethyl H O613120±2507a H H S555310±7027b H Me S80730±1807c H Et S90901±2117d H CH2CO2Et S417e H CH2CO2H S87153±837f Et H S337g Cyclopropylmethyl H S34a Values mean the inhibition(%)of NO production at5l M concentration of compounds relative to the LPS control(n=3).b Values are means±SD of three experiments.Y.J.Kim et al./Bioorg.Med.Chem.Lett.17(2007)3317–332133199-(2-chlorobenzyl)-9H-carbazole-3-carbaldehyde,was reported as an inhibitor of iNOS mRNA expression through a signaling pathway that does not involve NF-j B pathway.22The exact diﬀerence between the mecha-nism of our compounds and that of the reported thioureas and carbazole derivative was not explained in this report. The study of the mechanism for the iNOS inhibition by our compounds might be worthy to pursue further.In conclusion,we prepared a series of urea and thiourea derivatives and evaluated their inhibitory activities of NO production in LPS-activated macrophages.They suppressed the release of NO into culture media through the suppression of iNOS protein and mRNA expression. The SAR studies demonstrated that thiourea is superior to urea and N3substitution of thiourea with alkyl group is highly beneﬁcial for their activity.Further study of the other biological activities related with the overproduc-tion of NO,and the detailed mechanism for the activities of these derivatives,is in progress.Our thiourea deriva-tives that can control the expression of iNOS can be good leads for the development of therapeutic agents for the management of NO-related diseases.AcknowledgmentThis work was supported by the SRC program of MOST/KOSEF(R11-2005-017,RESEARCH CEN-TER FOR WOMEN’S DISEASES).Supplementary data Supplementary data associated with this article can be found,in the online version,at doi:10.1016/j.bmcl. 2007.04.005.References and notes1.Forstermann,U.;Schmidt,H.H.;Pollock,J.S.;Sheng,H.;Mitchell,J.A.;Warner,T.D.;Nakane,M.;Murad,F.Biochem.Pharmacol.1991,42,1849.2.Bredt,D.S.;Snyder,S.H.Proc.Natl.Acad.Sci.U.S.A.1990,87,682.3.Lowenstein,C.J.;Glatt,C.S.;Bredt,D.S.;Snyder,S.H.Proc.Natl.Acad.Sci.U.S.A.1992,89,6711.4.Cook,H.T.;Cattell,V.Clin.Sci.(Lond.)1996,91,375.5.Thiemermann,C.;Szabo,C.;Mitchell,J.A.;Vane,J.R.Proc.Natl.Acad.Sci.U.S.A.1993,90,267.6.Halliwell,ncet1994,344,721.7.Moore,W.M.;Webber,R.K.;Jerome,G.M.;Tjoeng,F.S.;Misko,T.P.;Currie,M.G.J.Med.Chem.1994,37, 3886.8.Hagen,T.J.;Bergmanis,A.A.;Kramer,S.W.;Fok,K.F.;Schmelzer,A.E.;Pitzele,B.S.;Swenton,L.;Jerome,G.M.;Kornmeier,C.M.;Moore,W.M.;Branson,L.F.;Connor,J.R.;Manning,P.T.;Currie,M.G.;Hallinan,E.A.J.Med.Chem.1998,41,3675.9.Moore,W.M.;Webber,R.K.;Fok,K.F.;Jerome,G.M.;Kornmeier, C.M.;Tjoeng, F.S.;Currie,M.G.Bioorg.Med.Chem.1996,4,1559.10.Bryk,R.;Wolﬀ,D.J.Biochemistry1998,37,4844.11.Beaton,H.;Hamley,P.;Nicholls,D.J.;Tinker,A.C.;Wallace,A.V.Bioorg.Med.Chem.Lett.2001,11,1023.12.Paesano,N.;Marzocco,S.;Vicidomini,C.;Saturnino,C.;Autore,G.;De Martino,G.;Sbardella,G.Bioorg.Med.Chem.Lett.2005,15,539.13.Raman,C.S.;Li,H.;Martasek,P.;Babu,B.R.;Griﬃth,O.W.;Masters,B.S.;Poulos,T.L.J.Biol.Chem.2001, 276,26486.14.Hansel,T.T.;Kharitonov,S.A.;Donnelly,L.E.;Erin,E.M.;Currie,M.G.;Moore,W.M.;Manning,P.T.;Recker,D.P.;Barnes,P.J.FASEB J.2003,17,1298.15.Moeslinger,T.;Friedl,R.;Volf,I.;Brunner,M.;Baran,H.;Koller,E.;Spieckermann,P.G.Kidney Int.1999,56,581.16.Prabhakar,S.S.;Zeballos,G.A.;Montoya-Zavala,M.;Leonard,C.Am.J.Physiol.1997,273,C1882.17.Wang,W.;Jittikanont,S.;Falk,S.A.;Li,P.;Feng,L.;Gengaro,P.E.;Poole,B.D.;Bowler,R.P.;Day,B.J.;Crapo,J.D.;Schrier,R.W.Am.J.Physiol.Renal Physiol.2003,284,F532.18.Goodyer,C.L.M.;Chinje,E.C.;Jaﬀar,M.;Stratford,I.J.;Threadgill,M.D.Bioorg.Med.Chem.2003,11,4189.19.Shearer,B.G.;Lee,S.;Oplinger,J.A.;Frick,L.W.;Garvey,E.P.;Furﬁne,E.S.J.Med.Chem.1997,40,1901.20.Green,L.C.;Wagner,D.A.;Glogowski,J.;Skipper,P.L.;Wishnok,J.S.;Tannenbaum,S.R.Anal.Biochem.1982,126,131.21.Cell culture and nitrite assay in LPS-activated RAW264.7cells—cells in10%fetal bovine serum(FBS)–DMEM, were plated in48-well plates(1·105cells/mL)and then incubated for24h.The cells were replaced with fresh media with1%FBS and then incubated for20h in the presence or absence of test compounds with LPS(1l g/ mL).NO production in each well was assessed by measuring the accumulated nitrite in culture supernatant.Samples(100l L)of media were incubated with Griess reagent(150l L)for10min at room temperature in96-well microplate.Absorbance at570nm was read using an ELISA plate reader.A standard calibration curve was prepared using sodium nitrite as a standard.A dose–response curve was prepared,and the results were typically expressed as IC50values.22.Tsao,L.T.;Lee,C.Y.;Huang,L.J.;Kuo,S.C.;Wang,J.P.Biochem.Pharmacol.2002,63,1961.LPS-+ + + + ++Sample 6j 7a 7b7c 7eFigure3.Eﬀects of the prepared compounds on the expression3320Y.J.Kim et al./Bioorg.Med.Chem.Lett.17(2007)3317–332123.Western blot analysis of iNOS protein expression—RAW264.7cells(1.5·106cells/60-mm dish)were stimulated with LPS(1l g/mL)in the presence or absence of test compounds.After incubation for20h,the cells were washed and lysed with lysis buﬀer.Twenty l g protein of cell lysates was applied on8%SDS–polyacrylamide gels and transferred to PVDF membrane by a standard method.The membrane was probed with antibody for anti-mouse iNOS(Transduction Laboratories,Lexington, KY)and anti-actin(Sigma,St.Louis,MO).The bands were visualized using an enhanced chemiluminescence (ECL)detection kit(Amersham Bioscience,Piscataway, NJ)according to the manufacturer’s instruction.24.Reverse transcription-polymerase chain reaction(RT-PCR)analysis of iNOS mRNA expression—RAW264.7 cells(1.8·106cells/60-mm dish)were stimulated for6h with LPS(1l g/mL)in the presence or absence of test compounds.After washing twice with phosphate-buﬀered saline,total RNA was isolated from cell pellet,using an RNA isolation reagent(Trizol,Invitrogen,Carlsbad,CA).Two micrograms of RNA was reverse transcribed into cDNA using reverse transcriptase and random hexamer.The PCR samples,contained in the reaction mixture,were comprised of mixture buﬀer,dNTP,Taq DNA polymerase (Promega,Madison,WI),and primers(sense and antisense).The sense and antisense primers for iNOS were50-ATGTCCGAAGCAAACATCAC-30and50-TAATGTCCAGGAAGTAGGTG-30,respectively.The sense and antisense primers for b-actin were50-TGT GATGGTGGGAATGGGTCAG-30and50-TTTGATGT CACGCACGATTTCC-30,respectively.The PCR ampli-ﬁcation was performed under following conditions;25 cycles of denaturation at94°C for30s,annealing at55°C for30s,and extension at72°C for30s,using thermal cycler(Gene Amp PCR system2400,Applied Biosystems, Foster City,CA).The ampliﬁed PCR products were separated on a2%agarose gel.25.Garvey,E.P.;Oplinger,J.A.;Tanoury,G.J.;Sherman,P.A.;Fowler,M.;Marshall,S.;Harmon,M.F.;Paith,J.E.;Furﬁne,E.S.J.Biol.Chem.1994,269,26669.Y.J.Kim et al./Bioorg.Med.Chem.Lett.17(2007)3317–33213321。

Alda-1_DataSheet_MedChemExpress

Inhibitors, Agonists, Screening Libraries Data SheetBIOLOGICAL ACTIVITY:Alda–1 is a potent ALDH2 agonist, which significantly improves ALDH2 activity.In Vivo: Alda–1 treatment results in a significant decrease of 4–HNE–protein content in the plasma of apoE -/- mice. Alda–1administration leads to a slight increase in gene expression related to neurogenesis (Nog ), mitochondrial biogenesis (CYTB , ND1),and apoptosis (Bax , Gsk3b ) in the Hp of apoE -/- mice. Alda–1 administration leads to 2 and 10 differentially expressed proteins in theFCx and Hp of apoE -/- mice, respectively [1]. Alda–1 (1.5 mg/kg, b.w., i.p.) administration significantly increases the climbing time,tends to reduce the immobility time and increases the swimming time of the prenatally stressed rats in the forced swim test.Moreover, treatment of prenatally stressed rats with Alda–1 significantly increases number of entries into the open arms of the maze and the time spent therein, as assessed by elevated plus–maze test [2]. Alda–1 (8.5 mg/kg, i.p.) with glucose significantly lowers 4–HNE and FJB–positive cells in the cerebral cortex of Alda–1–treated rats than in DMSO–treated rats 24 h after glucose administration [3]. Alda–1 (10 mg/kg per day) treatment prevents aldehydic overload, mitochondrial dysfunction and improves ventricular function in post–MI cardiomyopathy rats [4].PROTOCOL (Extracted from published papers and Only for reference)Cell Assay:[2]Spleen cells (4×106 cells/mL) are stimulated by optimal concentrations of concanavalin A (Con A; 2.5μg/mL and 0.6 μg/mL) and lipopolysaccharide (LPS, 5 μg/mL) and are incubated in 96–well plates at final volume of 0.2mL for 72 h. Cell proliferation is determined by adding 0.5 μCi of [3H]–thymidine per well at 16 h before the end of the incubation.The cultures are harvested with an automatic cell harvester, and [3H] thymidine incorporation is assessed using a liquid scintillationcounter.Animal Administration: Alda–1 is dissolved in 1 mL/kg b.w. DMSO/water 50/50.[2]After behavioral verification at three months of age,the animals are divided into the following four groups: control, control + Alda–1, prenatally stressed and prenatally stressed + Alda–1(6 animals per group). Alda–1 injections are given intraperitoneally (i.p.) once daily at a dose of 1.5 mg/kg b.w. (dissolved in 1 mL/kg b.w. DMSO/water 50/50) for 14 days. At the same time, the control and prenatally stressed rats receive 1 mL/kg b.w. DMSO/water 50/50. The injections of Alda–1 and vehicle are given between 10 a.m and 11 a.m. In the last five days of Alda–1 treatment the behavioral parameters in the elevated plus maze test and then in the forced swim test are measured.References:[1]. Stachowicz A, et al. Proteomic Analysis of Mitochondria–Enriched Fraction Isolated from the Frontal Cortex and Hippocampus of Apolipoprotein E Knockout Mice Treated with Alda–1, an Activator of Mitochondrial Aldehyde Dehydrogenase (ALDH2). Int J Mol Sci.[2]. Stachowicz A, et al. The impact of mitochondrial aldehyde dehydrogenase (ALDH2) activation by Alda–1 on the behavioral and biochemical disturbances in animal model of depression. Brain Behav Immun. 2016 Jan;51:144–53.Product Name:Alda–1Cat. No.:HY-18936CAS No.:349438-38-6Molecular Formula:C 15H 11Cl 2NO 3Molecular Weight:324.16Target:Aldehyde Dehydrogenase (ALDH)Pathway:Metabolic Enzyme/Protease Solubility:DMSO: ≥ 51 mg/mL[3]. Ikeda T, et al. Effects of Alda–1, an Aldehyde Dehydrogenase–2 Agonist, on Hypoglycemic Neuronal Death. PLoS One. 2015 Jun 17;10(6):e0128844.[4]. Gomes KM, et al. Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post–myocardial infarction cardiomyopathy: benefits of Alda–1. Int J Cardiol. 2015 Jan 20;179:129–138.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: tech@Address: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USA。

硕士论文--多奈哌齐透皮贴剂的药学研究

ｍａｔｒｉｘ．Ｔｈｉｓｐａｐｅｒｄｅｔｅｒｍｉｎｅｄｔｈｅｐｅｎｅ仃ａｔｉｏｎｐａｒａｍｅｔｅｒｓｏｆＤＰＢｉｎｖｉｔｒｏ．Ｔｈｅｒｅｓｕｌｔｓｓｈｏｗｅｄｔｈａｔｔｈｅｐａｒｔｉｔｉｏｎｃｏｅ伍ｃｉｅｎｔｂｅｔｗｅｅｎｓｔｒａｔｕｍｃｏｒｎｅｕｍａｎｄｖｉａｂｌｅｓｋｉｎｉＳ７．２１，ｗｈｉｃｈｓｈｏｗｅｄ
关键词：多奈哌齐；经皮给药系统；促渗剂；丙烯酸酯压敏胶；药代动力学
多奈哌齐透皮给药研究
ＳｔｕｄｙｏｆＤｏｎｅｐｅｚｉｌＴｒａｎｓｄｅｒｍａｌＰａｔｃｈ
Ａｂｓｔｒａｃｔ
Ｄｏｎｅｐｅｚｉｌ（ＤＰＢ）ｉｓａｐｉｐｅｒｉｄｉｎｅ—ｂａｓｅｄｒｅｖｅｒｓｉｂｌｅａｃｅｔｙ７ｌｃｈｏｌｉｎｅｓｔｅｒａｓｅｉｎｈｉｂｉｔｏｒ．ＣｕｒｒｅｎｔｌｙＤＰＢｉｓｔｈｅｍｏｓｔｐｒｅｓｃｒｉｂｅｄｐｈａｒｍａｃｏｌｏｇｉｃａｌａｇｅｎｔｆｏｒｔｈｅｔｒｅａｔｍｅｎｔｏｆｍｉｌｄｔｏｍｏｄｅｒａｔｅＡｌｚｈｅｉｍｅｒ’Ｓｄｉｓｅａｓｅ．Ｉｔａｌｓｏｐｌａｙｓｔｈｅｉｍｐｏｒｔａｎｔｒｏｌｅｉｎｉｍｐｒｏｖｉｎｇｔｈｅｐａｔｉｅｎｔ’Ｓｍｅｎｔａｌｓｔａｔｅａｎｄｋｅｅｐｉｎｇｔｈｅｂｒａｉｎａｃｔｉｖｅ．ＮｏｗｔｈｅｄｒｕｇｄｏｓａｇｅｆｏｒｍｏｆＤＰＢｈａｓｔａｂｌｅｔｓａｎｄｃａｐｓｕｌｅｓ．Ｒｅｓｅａｒｃｈｅｓｈａｖｅｓｈｏｗｅｄｔｈａｔａｉｚｈｅｉｍｅｒ’Ｓｄｉｓｅａｓｅｉｓｔｈｅｍｏｓｔｃｏｍｍｏｎｃａｕｓｅｏｆ
—ＩＩ—
大连理』大学硕士学位论文ｓｙｓｔｅｍｓｗｅｒｅａｄｍｉｎｉｓｔｅｒｅｄｔｒａｎｓｄｅｒｍａｌｌｙｔｏｒａｔｓｗｈｉｌｅｏｒａｌａｄｍｉｎｉｓｔｒａｔｉｏｎｏｆＤＰＢｓｏｌｕｔｉｏｎｔｏｒａｔｓＷａＳｕｓｅｄ舔ａｃｏｎｔｒ０１．ＴｈｅＰＫｐａｒａｍｅｔｅｒｓ．ｓｕｃｈａｓｔｈｅｔｉｍｅｔｏｒｅａｃｈｔｈｅｐｅａｋｂｌｏｏｄｃｏｎｃｅｎｔｒａｔｉｏｎ（ＭＲＴ）（Ｔｍａｘ），ｔｈｅｍａｘｉｍｕｍｂｌｏｏｄｃｏｎｃｅｎｔｒａｄｏｎ（Ｃｍａｘ）．ｍｅａｎｒｅｓｉｄｅｎｃｅｔｉｍｅ（ＭＲＴ）ａｎｄａｒｅａｕｎｄｅｒｔｈｅｃｕｒｖｅ（ＡＵＣ０ｑ）ｗｅｒｅｓｉｇｎｉｆｉｃａｎｔｌｙｄｉｆｆｅｒｅｎｔｏｆｔｒａｎｓｄｅｒｍａｌａｄｍｉｎｉｓｔｒａｔｉｏｎｃｏｍｐａｒｅｄｗｉｔｈｏｒａｌａｄｍｉｎｉｓｔｒａｔｉｏｎ．Ｉｎｃｏｎｔｒａｓｔｔｏｏｒａｌｄｅｌｉｖｅｒｙ．ａｓｕｓｔａｉｎｅｄａｃｔｉｖｉｔｙＷａＳｏｂｓｅｒｖｅｄｏｖｅｒａｐｅｒｉｏｄｏｆ４８ｈａｆｔｅｒｔｒａｎｓｄｅｒｍａｌａｄｍｉｎｉｓｔｒａｔｉｏｎ．

毕业论文——盐酸普萘洛尔

毕业论文题目盐酸普萘洛尔含量的HPLC测定研究专业应用化学班级091班姓名吴XX指导教师李成平(教授)所在学院生物与环境工程学院完成时间：20XX年6月承诺书我谨此郑重承诺：本毕业设计（论文）是本人在指导老师指导下独立撰写完成的。

凡涉及他人观点和材料，均依据著作规范作了注释。

如有抄袭或其它违反知识产权的情况，本人愿接受学校处分。

承诺人（签名）：年月日盐酸普萘洛尔含量的HPLC测定研究生物与环境工程学院应用化学专业吴XX摘要：本文采用高校液相测定了盐酸普萘洛尔片中盐酸普萘洛尔的含量，固定相为：安捷伦c18(4．6 mill X 250 mm，5urn)，甲醇一醋酸钠缓冲溶液pH=5.51(70：30)为流动相，检测波长为290nm；结果盐酸普萘洛尔在25～125ug/ml范围内呈现良好的线性关系，r=0.9998盐酸普萘洛尔的平均回收率为94.05％，RSD为0.14％(n=9)；此方法简便、准确、重现性好，可用于盐酸普萘洛尔片中盐酸普萘洛尔的含量测定。

关键词高效液相色谱法；盐酸普萘洛尔；含量Determination ofPropranolol Hydrochloride Tablets by HPLCwu hanyu, Major in Chemistry Speciality , College of Biology andEnvironmental EngineeringAbstract: To establish a HPLC method for determination the content of propranolol hydrochloride tablets .Method :Diamonsil C18 column (4.6mm ×150mm ,5 um), was used,the methanol-Sodium acetate solution pH=5.51(70:30) as mobile phase, the flow rate was 1.0 ml· min-1 , the detection wave length was 290 nm. Result :The method showed a good linear relationship within the range of 25~125ug/mL,r=0.9998,the average recovery was 94.05%with RSD0.14％(ｎ=9).Conclusion :the method is simple ,rapid ,reliable .Key words: HPLC ; Propranolol hydrochloride ;Determination目录1 引言 (5)1.1 本课题研究的背景 (5)2 研究内容 .................................................................................. 错误！未定义书签。

1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。