Bisoprolol Fumarate
Click to View Image
(C18H31NO4)2·C4H4O4 766.96
2-Propanol,1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-,(±)-,(E)-2-butenedioate (2:1)(salt).
(±)-1-[[a-(2-Isoproproxyethoxy)-p-tolyl]oxy]-3-(isopropylamino)-2-propanol fumarate (2:1)(salt) [104344-23-2].
»Bisoprolol Fumarate contains not less than 97.5percent and not more than 102.0percent of (C18H31NO4)2·C4H4O4,calculated on the anhydrous basis.
Packaging and storage— Preserve in tight,light-resistant containers.Store at controlled room temperature.
Identification—
A:Infrared Absorption á197Kñ.
B: The retention time of the major peak in the chromatogram of the Assay preparationcorresponds to that in the chromatogram of the Standard preparation,as obtained in the Assay.
Specific rotation á781ñ: between -2and +2.
Test solution: 10mg per mL,in methanol.
Water,Method Iá921ñ: not more than 0.5%.
Residue on ignition á281ñ: not more than 0.1%.
Chromatographic purity—
Diluent,Mobile phase,System suitability solution,and Chromatographic system— Proceed as directed in the Assay.
Standard solution— Prepare as directed for Standard preparationin the Assay.
Test solution— Prepare as directed for Assay preparationin the Assay.
Procedure— Inject a volume (about 10µL)of the Test solutioninto the chromatograph,record the chromatogram,and measure the peak areas.Calculate the percentage of total impurities in the portion of Bisoprolol Fumarate taken by the formula:
100(ri/rs),
in which riis the sum of areas for all the peaks,excluding the fumaric acid and bisoprolol peaks;and rsis the sum of the areas of all the peaks in the chromatogram:not more than 0.5%of total impurities is found.
Content of fumaric acid— Transfer about 500mg of Bisoprolol Fumarate,accurately weighed,to a beaker,and dissolve in 70mLof dehydrated alcohol.Add 8.0mLof 0.1Ntetrabutylammonium hydroxide VS,and stir for 2minutes.Titrate with 0.1Ntetrabutylammonium hydroxide VS,determining the endpoint potentiometrically,using a glass-calomel electrode system.Perform a blank determination,and make any necessary correction (see Titrimetry á541ñ).Each mLof 0.1Ntetrabutylammonium hydroxide is equivalent to 5.804mg of fumaric acid:not less than 14.8%and not more than 15.4%of fumaric acid is found,calculated on the anhydrous basis.
Assay—
Diluent— Prepare a mixture of water and acetonitrile (65:35).
Mobile phase— To a 1-Lportion of Diluentadd 5mLof heptafluorobutyric acid,5mLof diethylamine,and 2.5mLof formic acid.Mix,filter,and degas.Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
System suitability solution— Prepare a solution in Diluentcontaining about 0.5mg of propranolol hydrochloride and 1mg of Bisoprolol Fumarate per mL.
Standard preparation— Quantitatively dissolve an accurately weighed quantity of USP Bisoprolol Fumarate RSin Diluentto obtain a solution having a known concentration of about 1mg per mL.
Assay preparation— Transfer about 50mg of Bisoprolol Fumarate,accurately weighed,to a 50-mLvolumetric flask.Dissolve in and dilute with Diluentto volume,and mix.
Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 273-nm detector and a 4.6-mm ×12.5-cm column that contains packing L7.The flow rate is about 1mLper minute.Chromatograph the System suitability solution,and record the peak areas as directed for Procedure:the resolution,R,between bisoprolol and propranolol is not less than 7.0.Chromatograph the Standard preparation,and record the peak areas as directed for Procedure: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 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the areas for the major peaks.Calculate the quantity,in mg,of (C18H31NO4)2·C4H4O4in the portion of Bisoprolol Fumarate taken by the formula:
50C(rU/rS),
in which Cis the concentration,in mg per mL,of USP Bisoprolol Fumarate RSin the Standard preparation;and rUand rSare the peak areas obtained from the Assay preparationand the Standard preparation,respectively.
Auxiliary Information— Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(PA5)Pharmaceutical Analysis 5
USP28–NF23Page 268
Pharmacopeial Forum:Volume No.29(3)Page 609
Phone Number:1-301-816-8305