Gadopentetate Dimeglumine Injection
»Gadopentetate Dimeglumine Injection is a sterile solution of gadopentetate dimeglumine in Water for Injection.It contains not less than 90.0percent and not more than 110.0percent of the labeled amount of gadopentetate dimeglumine (C14H20GdN3O10·2C7H17NO5).It may contain small amounts of Meglumine and Pentetic Acid as stabilizers,and it may contain suitable buffers.Gadopentetate Dimeglumine Injection intended for intravascular use contains no antimicrobial agents.
Packaging and storage Preserve in single-dose containers,preferably of Type Iglass,protected from light.Store at controlled room temperature.
Labeling Label containers of Injection intended for intravascular injection to direct the user to discard any unused portion remaining in the container.
A: Ultraviolet Absorption á197Uñ
Solutions: 74mg of USP Gadopentetate Monomeglumine RSper mL,and 94mg of Gadopentetate Dimeglumine per mL.
B: Dilute a volume of Injection with water to obtain a test solution having a concentration of 35mg per mL.Separately apply 10µLof this solution and 10µLof a Standard solution containing 28mg of USP Gadopentetate Monomeglumine RSper mLin a meglumine solution (0.075in 1000)to a thin-layer chromatographic plate (see Chromatography á621ñ)coated with a 0.25-mm layer of chromatographic silica gel mixture.Allow the spots to dry,and develop the chromatogram in a solvent system consisting of a mixture of 1,4-dioxane,water,and ammonium hydroxide (70:30:2)until the solvent front has moved about three-fourths of the length of the plate.Remove the plate from the developing chamber,mark the solvent front,and allow the solvent to evaporate.Dip the plate in a detection reagent prepared by mixing 100mg of ninhydrin and 250mg of cadmium acetate with 1.0mLof glacial acetic acid and diluting with alcohol to 50mL.Heat the plate at 120for 10minutes,and locate the spots by examining the plate in daylight:the principal spot obtained from the test solution corresponds in appearance and RFvalue to the principal spot obtained from the Standard solution (presence of meglumine).
C: Prepare the test solution and Standard solution as directed for Identificationtest A.Transfer 500mLof 1Nsulfuric acid at 0to a 1000-mLconical flask,immerse in an ice bath,and add 50g of ceric sulfate tetrahydrate.Mix until dissolved,filter,and refrigerate (Stock solution A).Transfer 325mLof 2Nsulfuric acid at 0to a 500-mLvolumetric flask.To 25g of sodium arsenite,add 150mLof 1Nsodium hydroxide,mix,and add in small portions to the sulfuric acid.Dilute with water to volume,and refrigerate (Stock solution B).Just prior to use,prepare a spray reagent by mixing equal volumes of Stock solution Aand Stock solution Bat a temperature not lower than 10.[NOTEUse the spray reagent within five minutes.]Proceed as directed under Thin-layer Chromatographic Identification Test á201ñ,except to spray the plate first with the spray reagent and then with a 1%solution of 1,2-phenylenediamine in acetone.Locate the spots by examining the plate in daylight:the principal spot obtained from the test solution corresponds in appearance and RFvalue to the principal spot obtained from the Standard solution (presence of gadopentetate).
Bacterial endotoxins á85ñ It contains not more than 25USP Endotoxin Units per mLof Injection.
pHá791ñ: between 6.5and 8.0.
Heavy metals á231ñ
Test preparation In a 50-mLcolor-comparison tube,mix a volume of Injection,equivalent to 1.0g of gadopentetate dimeglumine,with 5mLof 1Nsodium hydroxide,dilute with water to 40mL,and mix.
Meglumine content Proceed as directed in the test for Meglumine contentunder Diatrizoate Meglumine Injection.The meglumine content is between 37.4%and 45.8%of the labeled amount of gadopentetate dimeglumine.
Content of gadolinium
Cesium chloride solution Dissolve 10.0g of cesium chloride in 100.0mLof water,and mix.
Blank solution Transfer 10.0mLof Cesium chloride solutionand 1.0mLof hydrochloric acid (spectrophotometric grade)to a 100-mLvolumetric flask,dilute with water to volume,and mix.
Standard solutions Transfer about 1.153g of gadolinium (III)oxide,accurately weighed,to a 100-mLvolumetric flask,add 2.0mLof hydrochloric acid to dissolve,dilute with water to volume,and mix.Transfer 3.0,4.0,and 5.0mLof this stock solution to separate 50-mLvolumetric flasks,and to each flask add 5.0mLof Cesium chloride solutionand 0.5mLof hydrochloric acid (spectrophotometric grade).Dilute the contents of each flask with water to volume,and mix.These Standard solutionscontain,respectively,600,800,and 1000µg of gadolinium per mL.
Test solution Treat an accurately measured volume of Injection,equivalent to about 469mg of gadopentetate dimeglumine,with 0.2mLof nitric acid in a porcelain crucible,concentrate on a hot plate,char with a burner,and ignite in a muffle furnace at 800until all black particles disappear (approximately 1hour).Allow the residue to cool on a refractory surface for about 5minutes,then equilibrate to room temperature in a desiccator.Dissolve the white residue so obtained in a mixture of 1.0mLof water and 1.0mLof hydrochloric acid (spectrophotometric grade)with heating.Transfer this solution to a 100-mLvolumetric flask,add 10.0mLof Cesium chloride solution,dilute with water to volume,and mix.
Procedure Concomitantly determine the absorbances of the Standard solutionsand the Test solutionat the gadolinium emission line at 368.4nm,with a suitable atomic absorption spectrophotometer (see Spectrophotometry and Light-scattering á851ñ)equipped with a gadolinium hollow-cathode lamp and a nitrous oxideacetylene flame,using the Blank solutionas the blank.Plot the absorbances of the Standard solutionsversus their concentrations,in µg per mL,of gadolinium,and draw the straight line best fitting the three plotted points.From the graph so obtained and the absorbance of the Test solution,determine the concentration,in µg per mL,of gadolinium in the Test solution.Calculate the quantity,in µg,of gadolinium in each mLof the Injection taken by the formula:
100C/V,in which Cis the concentration,in µg per mL,of gadolinium in the Test solution;and Vis the volume,in mL,of Injection taken.The gadolinium content is between 15.1%and 18.4%of the labeled amount of gadopentetate dimeglumine.
Content of pentetic acid
Stock solution A Transfer about 50g of sodium acetate and 10mLof glacial acetic acid to a 1000-mLvolumetric flask,and dilute with degassed water to volume.Adjust with 0.1Nsodium hydroxide or glacial acetic acid to a pHof 5.
Stock solution B Transfer about 50.8mg of xylenol orange to a 100-mLvolumetric flask,and add degassed water to volume.
Diluting solution Transfer 30mLof Stock Solution Aand 3mLof Stock Solution Bto a 200-mLvolumetric flask,and dilute with degassed water to volume.
Procedure Transfer an accurately measured volume of Injection,equivalent to about 938mg of gadopentetate dimeglumine,to a suitable container,add 20mLof water and 10mLof Diluting solution,and mix.Adjust with 0.1Nsodium hydroxide or glacial acetic acid to a pHof 5.Titrate with 0.001Mgadolinium sulfate solution until the color changes from yellow to reddish violet.Each mLof 0.001Mgadolinium sulfate consumed is equivalent to 0.7867mg of pentetic acid (C14H23N3O10).The pentetic acid content is between 0.027%and 0.04%.
Other requirements It meets the requirements under Injections á1ñ.
Mobile phase Prepare a filtered and degassed mixture containing about 1.37g of tetrabutylammonium perchlorate in a mixture of acetonitrile and water (120:880).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Standard preparation Transfer about 46.43mg of USP Gadopentetate monomeglumine RS,accurately weighed,to a 25-mLvolumetric flask containing 12.5mLof 0.1%meglumine solution.Dilute with water to volume,and mix.
Assay preparation Transfer an accurately measured volume of Injection,equivalent to about 469mg of gadopentetate dimeglumine,to a 200-mLvolumetric flask.Dilute with water to volume,and mix.
Chromatographic system (see Chromatography á621ñ)The liquid chromatograph is equipped with a 195-nm detector and a 4.6-mm ×12.5-cm column that contains 5-µm packing L7.The flow rate is about 1.5mLper minute.Chromatograph the Standard preparation,and record the peak responses as directed under Procedure:the column efficiency is not less than 800theoretical plates,the tailing factor is not more than 3.5,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 responses for the major peaks.Calculate the quantity,in mg,of C14H20GdN3O10·2C7H17NO5in the portion of Injection taken by the formula:
(938.02/742.80)(200C)(RU/RS),in which 938.02and 742.80are the molecular weights of gadopentetate dimeglumine and gadopentetate monomeglumine,respectively;Cis the concentration,in mg per mL,of USP Gadopentetate Monomeglumine RSin the Standard preparation;and RUand RSare the peak responses obtained from the Assay preparationand the Standard preparation,respectively.
Auxiliary Information Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(RMI)Radiopharmaceuticals and Medical Imaging Agents