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ANALYTICAL METHOD SOP # S PROCEDURES …

SOP # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8. ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/MM/2000 AnneANALYSTB ellaSUPERVISORE dannaQCCarolHEADSTRUCTURAL FORMULA( 1S-(2-[N-3-(2-oxotetrahydro thienyl)]acetamido)-thioglycolic acid) = :White to ivory whiteAppearance:Microcrystalline powderSOLUBILITYS lightly soluble in methanol, ethanol, acetone, # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8. ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/ SpectrumThe infrared spectrum of a nujol homogeneous dispersion of the testmaterial, exhibits maxima only at the same wavelengths as that of a similarpreparation of an Erdosteine retention time of the major peak in the chromatogram of the Samplepreparation corresponds to that of the Standard Preparation, obtained asdirected in the of solutionA test solution ( w)

sop # s-230-04-0600 analytical method procedures total number of pages 8. erdosteine - monograph. ed. n0: 04 effective date: iagim approved: iag-si -10846 erdosteine 04 active drug substance monograph

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Transcription of ANALYTICAL METHOD SOP # S PROCEDURES …

1 SOP # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8. ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/MM/2000 AnneANALYSTB ellaSUPERVISORE dannaQCCarolHEADSTRUCTURAL FORMULA( 1S-(2-[N-3-(2-oxotetrahydro thienyl)]acetamido)-thioglycolic acid) = :White to ivory whiteAppearance:Microcrystalline powderSOLUBILITYS lightly soluble in methanol, ethanol, acetone, # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8. ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/ SpectrumThe infrared spectrum of a nujol homogeneous dispersion of the testmaterial, exhibits maxima only at the same wavelengths as that of a similarpreparation of an Erdosteine retention time of the major peak in the chromatogram of the Samplepreparation corresponds to that of the Standard Preparation, obtained asdirected in the of solutionA test solution ( w/v in Methanol) is clear and colorless, according on dryingDetermined on a sample of about , exactly weighed, in oven at 105 Cup to constant weight, according to USP METHOD <731>.

2 Specification: Not more than on ignitionDetermined on a sample of about , exactly weighed, according to USPM ethod <281>.Specification: Not more than metalsDetermined on a sample of about 2g, exactly weighed, according to USPM ethod II <231>.Specification: Not more than # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8. ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/ purity by HPLC (Limit Test)The potential related substances most likely to be present are as follows:-Homocysteine thiolactone (raw material)-Homocysteine (coming from homocysteine thiolactone)-N-chloro-acetyl-homocystein e thiolactone (RV 142) (synthesis intermediate)-Thiodiglycolic acid (degradation impurity during synthesis)-N-thiodiglycolyl homocysteine (Metabolite 1, corresponding to theErdosteine cycleopening)-Thioglycolic acid.

3 (raw material)-S-{2-[N-3-(2-oxotetrahydro thienyl] acetamido}-N(carboxymethyl thioacetyl)-homocysteine (RV 201) (synthesis secondary product)-Bis N-(2-oxo-3-tetrahydrothienylthiodiglycol ylamide (EP 21506) (Synthesissecondaryproduct). (The presence of two peaks in the graph is due to the fact that EP21506 is a mixture of 4 diastereoisomers). THIS TEST SHOULD BE CARRIED-OUT AS RAPIDLY AS POSSIBLE. STANDARD SOLUTIONS SHOULD BE PREPARED PROMPTLY AND PROTECTEDFROM LIGHT. THE MOBILE PHASE USED FOR MAKING DILUTIONS MUST BE EQUAL TO THEONE PASSING ON THE COLUMN. THE USE OF AN AUTOSAMPLER WITH REFRIGERATION IS # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8.))

4 ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/MM/2000 AnneANALYSTB ellaSUPERVISORE dannaQCCarolHEADHPLC ConditionsColumn:Eurospher 100 C18, 25 x , 5 Column Temperature:30 CMobile Phase:Acetonitrile:Solution A* (11:89 v/v)Flow :UV at 220nm, AUFS Value:20 L *Solution A - Buffer solution pH :Dissolve Potassium dihydrogen phosphate (KH2PO4) and Heptanesulphonic acid Sodium salt in about 500mL water. Add of a 25% (w/v)Phosphoric acid and make up to 1L with water. Adjust to pH with a 10 NSodium hydroxide phase proportions and flow rate may be varied in order to achieve the requiredsystem SOLVENTS USED MUST BE OF HPLC GRADEI mpurities stock solutions' and standard preparation:Homocysteine SolutionAccurately weigh about 18mg Homocysteine into a 50mL volumetric in and make up to volume with mobile Thiolactone SolutionAccurately weigh about 18 Homocysteine Thiolactone into a 50 mL volumetricflask.

5 Dissolve in and make up to volume with mobile acid Solution (Mercaptuacetic acid)Accurately weigh about 18mg Thioglycolic acid into a 50mL volumetric in and make up to volume with mobile acid SolutionAccurately weigh about 18mg Thiodiglycolic acid into a 50mL volumetric in and make up to volume with mobile # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8. ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/MM/2000 AnneANALYSTB ellaSUPERVISORE dannaQCCarolHEADRV 142 SolutionAccurately weigh about 12mg RV 142 into a 25mL volumetric in and make up to volume with mobile Diluted SolutionPipet 1mL each of the impurities stock solutions into a 25mL volumetric flask and make upto volume with mobile stock solutionAccurately weigh about 12mg Erdosteine into a 10mL volumetric in and make up to volume with mobile solutionPipet 1mL of the Impurities Diluted Solution and 4mL of Erdosteine Stock Solution into a50mL volumetric flask and make up to volume with mobile resulting concentrations of the impurities in this solution as percent of

6 Erdosteineconcentration are as suitability testInject the standard solution and run the chromatogram up to 25 minutes. The peaks elutein the following order:PEAK ORDERRRTT hiodiglycolic retention time of the Erdosteine peak is about resolution factor between Homocysteine thiolactone and Erdosteine peaks andbetween Erdosteine and RV 142 should be no less than # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8. ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/MM/2000 AnneANALYSTB ellaSUPERVISORE dannaQCCarolHEADS ample Solution preparationAccurately weigh about 30mg Erdosteine test material into a 25mL volumetricflask.

7 Dissolve in and make up to volume with mobile phase. Pipet 4mL of this solutioninto a 50mL volumetric flask and make up to volume with mobile mobile phase (blank run). Inject the standard and sample solutions and run thechromatogram up to 25 minutes. Determine the peak areas in each solution using asuitable criteriaSubtract any blank peak from the sample solution chromatogram. No peak area in thesample solution chromatogram should be greater than that of the corresponding peak dueto impurities in the standard solution chromatogram. Calculate any other impurities suchas RV 201 (RRT = ), Metabolite 1 (RRT = ) and EP 21506 (double peak at RRT = ) by means of area normalization.

8 If no peak is detected at the corresponding RRT,report it as "Not detected" or "Less than the specified detection limit".SpecificationIMPURITIESSPECIFICAT IONS(UPPER LIMIT) unknown # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8. ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/MM/2000 AnneANALYSTB ellaSUPERVISORE dannaQCCarolHEADASSAY BY HPLCThis test should be carried-out as rapidly as solutions should be prepared promptly and protected from light. Themobile phase used for making dilutions must be equal to the one passing on thecolumn. The use of an autosampler with refrigeration is ConditionsThe same as for Chromatographic Purity ( ).

9 Standard Solution preparationAccurately weigh about 30mg Erdosteine into a 25mL volumetric flask, add about20mL mobile phase and sonicate to dissolve. Make up to volume with mobile phase(standard stock solution). Dilute 4mL of this solution to 50mL with mobile suitability solutionWeigh about 6mg Metabolite 1 into a 50mL volumetric flask. Dissolve in and make up tovolume with mobile phase. Pipet 3mL of this solution and 2mL of the Erdosteine standardstock solution into a 25mL volumetric flask and make up to volume with mobile suitability testInject the system suitability solution. The retention time of the Erdosteine peak is minutes. Metabolite 1 elutes at relative retention time of related to resolution factor between these two peaks (calculated according to USP) should benot less than A relative standard deviation calculated for 5 standard replicateinjections must be not more than Solution preparationAccurately weigh about 30mg Erdosteine test material into a 25mL volumetric flask, addabout 20mL of mobile phase and sonicate to dissolve.

10 Make up to volume with mobilephase. Pipet 4mL of this solution into a 50mL volumetric flask and make up to volume withmobile # S-230-04-0600 ANALYTICAL METHODPROCEDUREST otal Numberof Pages 8. ERDOSTEINE - N0: 04 Effective Date:IAGIMAPPROVED:IAG-SI -10846 ERDOSTEINE 04 ACTIVE DRUG SUBSTANCE MONOGRAPHEd. Status :Supcds 03DD/MM/2000 AnneANALYSTB ellaSUPERVISORE dannaQCCarolHEADP rocedureInject the standard and sample solutions into the chromatograph and determine the peakarea of Erdosteine in each of Erdosteine:Pk area smp x Std wt*(mg) x 100d x smp wt**(mg) % Assay calculated on dry basisPk area st= of Metabolite 1:Pk area smp x Std wt* (mg) x Rf**(mg) x 100d x Smp wt**(mg) % Assay of Metabolite 1 calculated on dry basisPk area st=* std wt - is corrected according to % Water and % Assay** smp wt - is corrected according to % Water** RF = , response factor for calculation of Metabolite 1 = Absorptivity of erdosteineAbsorptivity of metabolite1 = - Erdosteine assay, calculated on dry SIZE (This test is performed only for micronized active drug substance)Apparatus:Computerized inspection systemMethod:By volume distributionSpecifications:100% less than 40


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