Ketorolac Tromethamine

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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C₁₅H₁₃NO₃· C₄H₁₁NO₃        376.40

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) CAS RN®: 74103-

07-4; UNII: 4EVE5946BQ.

1 DEFINITION

Ketorolac Tromethamine contains NLT 98.5% and NMT 101.5% of ketorolac tromethamine (C₁₅H₁₃NO₃· C₄H₁₁NO₃), calculated on the dried basis.

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

C. Thin-Layer Chromatography, Tromethamine Test

Diluent: Dichloromethane and methanol (2:1)

Standard solution: 5 mg/mL of USP Ketorolac Tromethamine RS in Diluent

Sample solution: 5 mg/mL of Ketorolac Tromethamine in Diluent

Chromatographic system

(See Chromatography 〈621〉, Thin-Layer Chromatography.)

Mode: TLC

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

Application volume: 40 μL

Developing solvent system: Dichloromethane, acetone, and glacial acetic acid (95:5:2)

Spray reagent: Freshly prepared alcoholic solution containing 30 mg/mL of ninhydrin

Analysis

Samples: Standard solution and Sample solution

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 Spray reagent, and heat the plate at about 150° for 2–5 min.

Acceptance criteria: Yellow spots with pink to purple borders develop on the plate in the areas where the Standard solution and the Sample solution were applied.

3 ASSAY

Procedure

Protect all the solutions from light.

Buffer: 5.75 g/L of monobasic ammonium phosphate. Adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Tetrahydrofuran and Buffer (30:70)

Diluent: Tetrahydrofuran and water (30:70)

System suitability 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 10–15 min.

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 Diluent, and swirl to dissolve. [Note—This solution may be stored under refrigeration and used as long as the chromatogram obtained as directed for Analysis 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.]

Standard solution: 0.4 mg/mL of USP Ketorolac Tromethamine RS in Diluent

Sample solution: 0.4 mg/mL of Ketorolac Tromethamine in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 313 nm

Column: 4.6-mm × 25-cm; 5-μm packing L7

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for the ketorolac 1-hydroxy analog, the ketorolac 1-keto analog, and ketorolac are about 0.63, 0.89, and 1.0, respectively. Make adjustments, if necessary, to achieve a retention time for ketorolac of about 8–12 min.]

Suitability requirements

Resolution: NLT 1.5 between ketorolac 1-keto analog and ketorolac, System suitability solution

Column efficiency: NLT 5500 theoretical plates, Standard solution

Relative standard deviation: NMT 1.5%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ketorolac tromethamine (C₁₅H₁₃NO₃· C₄H₁₁NO₃) in the portion of Ketorolac Tromethamine taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak area from the Sample solution

r_S = peak area from the Standard solution

C_S = concentration of USP Ketorolac Tromethamine RS in the Standard solution (mg/mL)

C_U = concentration of Ketorolac Tromethamine in the Sample solution (mg/mL)

Acceptance criteria: 98.5%–101.5% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Change to read:

Organic Impurities

Mobile phase, Diluent, System suitability solution, Standard solution,

(ERR 1-Jul-2021) Sample solution, and System suitability: (ERR 1-

Jul-2021) Proceed as directed in the Assay.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 313 nm

Column: 4.6-mm × 25-cm; 5-μm packing L7

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

Run time: 3 times the retention time of ketorolac

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of Ketorolac Tromethamine taken:

Result = (r_U/r_T) × F × 100

r_U = peak response of each individual impurity from the Sample solution

r_T = sum of all the peak responses from the Sample solution

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1.

Table 1

5 SPECIFIC TESTS

pH 〈791〉

Sample solution: 10 mg/mL

Acceptance criteria: 5.7–6.7

Loss on Drying 〈731〉

Analysis: Dry under vacuum at 60° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers. Store at 25°, excursions permitted between 15° and 30°.

USP Reference Standards 〈11〉

USP Ketorolac Tromethamine RS