Tiamulin Fumarate Click to View Image C28H47NO4S·C4H4O4 609.82
Acetic acid,[[2-(diethylaminoethyl]thio]-,6-ethenyl-decahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl ester [3aS-(3aa,4b,5a,6a,8b,9a,9ab,10S*)]-,(E)-2-butenedioate (1:1)(salt).
[[2-(Diethylamino)ethyl]thio]acetic acid 8-ester with (3aS,4R,5S,6S,8R,9R,9aR,10R)-octahydro-5,8-dihydroxy-4,6,9,10-tetramethyl-6-vinyl-3a,9-propano-3aH-cyclopentacycloocten-1(4H)-one fumarate (1:1)(salt) [55297-96-6]. »Tiamulin Fumarate contains not less than 98.0percent and not more than 102.0percent of C28H47NO4S·C4H4O4,calculated on the dried basis. Packaging and storage— Preserve in tight,light-resistant containers,and store at room temperature. Labeling— Label it to indicate that it is for veterinary use only. Change to read: USP Reference standards á11ñ USP Tiamulin Fumarate RS.USP Tiamulin Related Compound A RS.USP28 Color and clarity of solution— Transfer about 5.0g of Tiamulin Fumarate to a 100-mLvolumetric flask,and dissolve in and dilute with water to volume:the solution is clear and colorless,and the absorbance of the solution,determined in a 1-cm cell at 400and 650nm,is not greater than 0.150and 0.030absorbance units,respectively. Identification— A: Infrared Absorption á197Kñ. B: The retention time of the tiamulin fumarate peak in the chromatogram of the Assay preparationcorresponds to that in the chromatogram of the Standard preparation,as obtained in the Assay. Melting temperature á741ñ: between 143and 149. Specific rotation á781Sñ: between +24and +28,on the dried basis,measured at 20. Test solution: 5.0mg per mL,in dioxane. pHá791ñ: between 3.1and 4.1. Test solution: 1.0g per 100mLof water. Loss on drying á731ñ Dry it in vacuum at 105for 3hours:it loses not more than 0.5%of its weight. Residue on ignition á281ñ: not more than 0.1%. Heavy metals,Method IIá231ñ: not more than 0.001%. Limit of residual solvents Internal standard solution— Dilute 0.3mLof n-butanol to 1000mL. Standard solution— Transfer about 500mg each of acetone,ethyl acetate,and isobutyl acetate,each accurately weighed,to a 250-mLvolumetric flask,dilute with theInternal standard solutionto volume,and mix.Transfer 2.5mLof the solution so obtained to a 20-mLvolumetric flask,dilute with theInternal standard solutionto volume,and mix. Test solution— Transfer about 1g of Tiamulin Fumarate,accurately weighed,to a 20-mLvolumetric flask,dissolve in and dilute with theInternal standard solution to volume,and mix. Chromatographic system (see Chromatography á621ñ)— The gas chromatograph is equipped with a flame-ionization detector and a 0.25-mm ×30-m capillary column coated with a 0.5-µm film of phase G16.The carrier gas is helium,flowing at a rate of 1.07mLper minute,and the split flow ratio is 50:1.The column temperature is maintained at 75,the injection port temperature is maintained at 250,and the detector temperature is maintained at 300.Chromatograph theStandard solution,and record the peak responses as directed for Procedure:the relative retention times are about 0.34,0.38,0.57,and 1.0for acetone,ethyl acetate,isobutyl acetate,and n-butanol,respectively;the resolution,R,between acetone and ethyl acetate is not less than 2.0;the tailing factor for each of the analyte peaks is not more than 2;and the relative standard deviation for replicate injections is not more than 2%. Procedure— Separately inject equal volumes (about 1.0µL)of the Standard solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure the peak responses for acetone,ethyl acetate,isobutyl acetate,and n-butanol.Calculate the percentages of acetone,ethyl acetate and isobutyl acetate in the portion of Tiamulin Fumarate taken by the formula: 1.25(WS/WU)(RU/RS), in whichWSis the weight,in mg,of the solvent of interest taken to prepare theStandard solution;WUis the weight,in mg,of Tiamulin Fumarate taken to prepare theTest solution;andRUandRSare the peak response ratios of the solvent of interest to the internal standard obtained from theTest solution and theStandard solution,respectively:not more than 0.5%each of acetone,ethyl acetate,and isobutyl acetate is found;and the sum of the percentages of acetone,ethyl acetate,and isobutyl acetate is not more than 0.5%. Change to read: Chromatographic purity— Dilute perchloric acid solution,Buffer solution,Mobile phase,System suitability solution,and Chromatographic system— Proceed as directed in the Assay. Standard solution— Use theStandard preparationprepared as directed in theAssay. Test solution— Use the Assay preparationprepared as directed in the Assay. Procedure— Separately inject equal volumes (about 20µL)of theStandard solutionand theTest solutioninto the chromatograph,record the chromatogram,identify the tiamulin fumarate peak,and measure all the peak responses.[NOTE—Possible tiamulin fumarate impurities include,but are not limited to,pleuromutilin,mutilin,14-acetyl mutilin,11-monoacetyl mutilin,tiamulin related compound A,USP2811,14-diacetyl mutilin,8-dimethylderivative,bisdimethylthioderivative,and 11-ketoderivative,their retention times,relative to tiamulin fumarate,being about 0.25,0.3,0.5,0.6,0.8,1.1,1.3,1.4,and 2.3,respectively.]Calculate the area percentage of each impurity,relative to tiamulin fumarate,in the portion of Tiamulin Fumarate taken by the formula: 100(ri/rU), in which riand rUare the peak responses of each impurity and tiamulin fumarate,respectively:not more than 1.0%of any identified impurity is found;not more than 0.5%of any unidentified impurity is found;and not more than 2.0%of total impurities is found. Content of fumarate— Dissolve about 450mg of Tiamulin Fumarate,accurately weighed,in 60mLof a mixture of alcohol and water (1:1).Titrate with 0.1Nsodium hydroxide VS,determining the endpoint potentiometrically,using a glass–calomel electrode (see Titrimetry á541ñ).Perform a blank determination,and make any necessary correction.Each mLof 0.1Nsodium hydroxide is equivalent to 5.8mg of fumarate:between 83.7and 87.3mg of fumarate is found. Change to read: Assay— Dilute perchloric acid solution— Prepare a solution containing 6%of perchloric acid. Buffer solution— Transfer 10g of ammonium carbonate to a 1000-mLvolumetric flask,and dissolve in about 800mLof water.Add 24mLofDilute perchloric acid solution,dilute with water to volume,mix,and filter. Mobile phase— Prepare a mixture of methanol,Buffer solution,and acetonitrile,(49:28:23),filter,and degas. System suitability solution— Dissolve accurately weighed quantities of USP Tiamulin Fumarate RSand USP Tiamulin Related Compound A RSUSP28inMobile phase to obtain a solution having known concentrations of about 0.08mg of each per mL. Standard preparation— Dissolve an accurately weighed quantity of USP Tiamulin Fumarate RSinMobile phaseto obtain a solution having a known concentration of about 4mg per mL. Assay preparation— Transfer about 200mg,accurately weighed,to a 50-mLvolumetric flask,dissolve in and dilute with Mobile phaseto volume,and mix. Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 212-nm detector and a 4.6-mm ×25-cm column that contains 5-µm packing L1.The flow rate is about 1.2mLper minute.The column temperature is maintained at 30±3.Chromatograph the Standard preparation and the System suitability solution,and record the peak responses as directed forProcedure:the tiamulin related compound AUSP28peak elutes prior to the tiamulin fumarate peak;the resolution,R,between tiamulin related compound AUSP28and tiamulin fumarate is not less than 2.0;the capacity factor,k¢,determined from the tiamulin fumarate peak,is not less than 2.0;the column efficiency is not less than 14,000theoretical plates;the tailing factor is not more than 2.0;and the relative standard deviation for replicate injections is not more than 2.0%. Procedure— Separately inject equal volumes (about 20µL)of theStandard preparation and theAssay preparation into the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in mg,of C28H47NO4S·C4H4O4in the portion of Tiamulin Fumarate taken by the formula: 50C(rU/rS), in which Cis the concentration,in mg per mL,of USP Tiamulin Fumarate RSin the Standard preparation;and rUand rSare the tiamulin fumarate peak responses obtained from theAssay preparation and theStandard preparation,respectively. Auxiliary Information— Staff Liaison:Ian DeVeau,Ph.D.,Senior Scientist Expert Committee:(VET)Veterinary Drugs USP28–NF23Page 1926 Pharmacopeial Forum:Volume No.30(3)Page 938 Phone Number:1-301-816-8178