1H-Pyrrolizine-1-carboxylic acid,5-benzoyl-2,3-dihydro,(±)-,compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1).
(±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid,compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) [74103-07-4].
»Ketorolac Tromethamine contains not less than 98.5percent and not more than 101.5percent of C15H13NO3·C4H11NO3,calculated on the dried basis.
Packaging and storage Preserve in tight,light-resistant containers.Store at 25,excursions permitted between 15and 30.
B:Ultraviolet Absorption á197Uñ
Solution: 10µg per mL.
C:Tromethamine test Prepare a Standard solution of USP Ketorolac Tromethamine RSin a mixture of dichloromethane and methanol (2:1)containing 5mg per mL.Similarly prepare a test solution of Ketorolac Tromethamine containing 5mg per mL.Apply 40-µLvolumes of the Standard solution and the test solution to a thin-layer chromatographic plate (seeChromatography á621ñ)coated with a 0.25-mm layer of chromatographic silica gel mixture.Place the plate in a chromatographic chamber previously equilibrated with a mixture of dichloromethane,acetone,and glacial acetic acid (95:5:2).Seal the chamber,and develop the chromatogram until the solvent front has moved about three-fourths of the length of the plate.Remove the plate from the chamber,and allow the solvent to evaporate.Spray the plate with a freshly prepared alcoholic solution containing 30mg of ninhydrin per mL,and heat the plate at about 150for 2to 5minutes.Yellow spots with pink to purple borders develop on the plate in the areas where the Standard solution and the test solution were applied.
pHá791ñ: between 5.7and 6.7,in a solution (1in 100).
Loss on drying á731ñ Dry it in vacuum at 60for 3hours:it loses not more than 0.5%of its weight.
Residue on ignition á281ñ: not more than 0.1%.
Heavy metals,Method IIá231ñ: 0.002%.
Organic volatile impurities,Method Vá467ñ: meets the requirements.
Mobile phase,Solvent mixture,Standard preparation,Resolution solution,and Chromatographic system Proceed as directed in theAssay.
Test solution Use theAssay preparation.
Procedure Chromatograph theTest solutionas directed forProcedurein theAssay,allowing the chromatography to extend to three times the retention time of ketorolac.Measure the responses of all the peaks.Calculate the percentage of each individual impurity in the portion of Ketorolac Tromethamine taken by the formula:
100rfi(ri/rs),in whichrfiis the response factor of each individual impurity peak relative to that of ketorolac;riis the peak response for each impurity;andrsis the sum of all the peak responses of the impurity peaks and the major ketorolac peak.Therfivalues are 0.52for the ketorolac 1-keto analog,0.67for the ketorolac 1-hydroxy analog,2.2for the impurity peak having a retention time of 0.54relative to that of ketorolac,and 0.91for the impurity peak at a relative retention time of 0.66.Not more than 0.1%of the ketorolac 1-keto analog or of the ketorolac 1-hydroxy analog is found;not more than 0.5%of any other impurity is found;and the sum of all impurities is not more than 1.0%.
Mobile phase Dissolve 5.75g of monobasic ammonium phosphate in 1000mLof water,and adjust with phosphoric acid to a pHof 3.0.Prepare a filtered and degassed mixture of this buffer solution and tetrahydrofuran (70:30).Make adjustments if necessary (seeSystem Suitability underChromatography á621ñ)to achieve a retention time for ketorolac of about 8to 12minutes.
Solvent mixture Prepare a mixture of water and tetrahydrofuran (70:30).
Standard preparation Quantitatively dissolve an accurately weighed quantity of USP Ketorolac Tromethamine RSinSolvent mixtureto obtain a solution having a known concentration of about 0.4mg per mL.[NOTEProtect this solution from light.]
Assay preparation Transfer about 20mg of Ketorolac Tromethamine,accurately weighed,to a 50-mLvolumetric flask,dilute withSolvent mixtureto volume,and mix.[NOTEProtect this solution from light.]
Resolution solution In a 250-mLseparator mix 100mLof water,100mLof dichloromethane,30mg of USP Ketorolac Tromethamine RS,and 1mLof 1Nhydrochloric acid.Insert the stopper,shake,and allow the layers to separate.Transfer the lower dichloromethane layer to a stoppered borosilicate glass flask,and discard the upper layer.Expose the dichloromethane solution to direct sunlight for 10to 15minutes.Transfer 1.0mLof the solution to a vial,evaporate in a current of air or in a stream of nitrogen to dryness,add 1.0mLof Solvent mixture,and swirl to dissolve.[NOTEThis solution may be stored under refrigeration and used as long as the chromatogram obtained as directed forProcedureis suitable for identifying the peaks due to the ketorolac 1-keto analog and ketorolac 1-hydroxy analog,and for the measurement of the resolution between the ketorolac 1-keto analog and ketorolac.]
Chromatographic system(see Chromatography á621ñ) The liquid chromatograph is equipped with a 313-nm detector and a 4.6-mm ×25-cm column that contains 5-µm packing L7and is maintained at a constant temperature of about 40.The flow rate is about 1.5mLper minute.Chromatograph theResolution solution,and record the peak responses as directed forProcedure:the relative retention times are about 0.63for the ketorolac 1-hydroxy analog,0.89for the ketorolac 1-keto analog,and 1.0for ketorolac;and the resolution,R,between the ketorolac 1-keto analog and ketorolac is not less than 1.5.Chromatograph theStandard preparation,and record the peak responses as directed forProcedure:the column efficiency is not less than 5500theoretical plates;and the relative standard deviation for replicate injections is not more than 1.5%.
Procedure Separately inject equal volumes (about 10µL)of theStandard preparationand theAssay preparationinto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in mg,of C15H13NO3·C4H11NO3in the portion of Ketorolac Tromethamine taken by the formula:
50C(rU/rS),in whichCis the concentration,in mg per mL,of USP Ketorolac Tromethamine RSin theStandard preparation;andrUandrSare the ketorolac peak responses obtained from theAssay preparationand theStandard preparation,respectively.
Auxiliary Information Staff Liaison:Clydewyn M.Anthony,Ph.D.,Scientist
Expert Committee:(PA2)Pharmaceutical Analysis 2
USP28NF23Page 1100Pharmacopeial Forum:Volume No.29(6)Page 1915