(kee'' toe role' ak troe meth' a meen).
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 98.5 percent and not more than 101.5 percent of C15H13NO3·C4H11NO3, calculated on the dried basis.
Packaging and storage Preserve in tight, light-resistant containers. Store at 25, excursions permitted between 15 and 30.
USP Reference standards 11
B: Ultraviolet Absorption 197U
Solution: 10 µg per mL.
C: Tromethamine test Prepare a Standard solution of USP Ketorolac Tromethamine RS in a mixture of dichloromethane and methanol (2:1) containing 5 mg per mL. Similarly prepare a test solution of Ketorolac Tromethamine containing 5 mg per mL. Apply 40-µL volumes of the Standard solution and the test solution to a thin-layer chromatographic plate (see Chromatography 621) 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 30 mg of ninhydrin per mL, and heat the plate at about 150 for 2 to 5 minutes. Yellow spots with pink to purple borders develop on the plate in the areas where the Standard solution and the test solution were applied.
pH 791: between 5.7 and 6.7, in a solution (1 in 100).
Loss on drying 731 Dry it in vacuum at 60 for 3 hours: it loses not more than 0.5% of its weight.
Residue on ignition 281: not more than 0.1%.
Heavy metals, Method II 231: 0.002%.
Mobile phase, Solvent mixture, Standard preparation, Resolution solution, and Chromatographic system Proceed as directed in the Assay.
Test solution Use the Assay preparation.
Procedure Chromatograph the Test solution as directed for Procedure in the Assay, 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 which rfi is the response factor of each individual impurity peak relative to that of ketorolac; ri is the peak response for each impurity; and rs is the sum of all the peak responses of the impurity peaks and the major ketorolac peak. The rfi values are 0.52 for the ketorolac 1-keto analog, 0.67 for the ketorolac 1-hydroxy analog, 2.2 for the impurity peak having a retention time of 0.54 relative to that of ketorolac, and 0.91 for 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 5.75 g of monobasic ammonium phosphate in 1000 mL of water, and adjust with phosphoric acid to a pH of 3.0. Prepare a filtered and degassed mixture of this buffer solution and tetrahydrofuran (70:30). Make adjustments if necessary (see System Suitability under Chromatography 621) to achieve a retention time for ketorolac of about 8 to 12 minutes.
Solvent mixture Prepare a mixture of water and tetrahydrofuran (70:30).
Standard preparation Quantitatively dissolve an accurately weighed quantity of USP Ketorolac Tromethamine RS in Solvent mixture to obtain a solution having a known concentration of about 0.4 mg per mL. [noteProtect this solution from light. ]
Assay preparation Transfer about 20 mg of Ketorolac Tromethamine, accurately weighed, to a 50-mL volumetric flask, dilute with Solvent mixture to volume, and mix. [noteProtect this solution from light. ]
Resolution solution In a 250-mL separator mix 100 mL of water, 100 mL of dichloromethane, 30 mg of USP Ketorolac Tromethamine RS, and 1 mL of 1 N hydrochloric 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 10 to 15 minutes. Transfer 1.0 mL of the solution to a vial, evaporate in a current of air or in a stream of nitrogen to dryness, add 1.0 mL of Solvent mixture, and swirl to dissolve. [noteThis solution may be stored under refrigeration and used as long as the chromatogram obtained as directed for Procedure is 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 621) The liquid chromatograph is equipped with a 313-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L7 and is maintained at a constant temperature of about 40. The flow rate is about 1.5 mL per minute. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the relative retention times are about 0.63 for the ketorolac 1-hydroxy analog, 0.89 for the ketorolac 1-keto analog, and 1.0 for ketorolac; and the resolution, R, between the ketorolac 1-keto analog and ketorolac is not less than 1.5. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the column efficiency is not less than 5500 theoretical plates; and the relative standard deviation for replicate injections is not more than 1.5%.
Procedure Separately inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of C15H13NO3·C4H11NO3 in the portion of Ketorolac Tromethamine taken by the formula:
50C(rU / rS)in which C is the concentration, in mg per mL, of USP Ketorolac Tromethamine RS in the Standard preparation; and rU and rS are the ketorolac peak responses obtained from the Assay preparation and the Standard preparation, respectively.
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USP35NF30 Page 3623Pharmacopeial Forum: Volume No. 29(6) Page 1915