4010 Ketoprofen / Official Monographs
`
`USP 38
`
` NMT 3.0%
`
`SPECIFIC TESTS
`• WATER DETERMINATION, Method I Æ921æ:
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in tight containers,
`and store at controlled room temperature.
`• USP REFERENCE STANDARDS Æ11æ
`USP Ketoprofen RS
`USP Ketoprofen Related Compound A RS
`a-Methyl-3-(4-methylbenzoyl) benzeneacetic acid.
`
`Ketorolac Tromethamine
`
`
`
`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) [74103-07-4].
`DEFINITION
`Ketorolac Tromethamine contains NLT 98.5% and NMT
`101.5% of ketorolac tromethamine (C15H13NO3 ·
`C4H11NO3), calculated on the dried basis.
`IDENTIFICATION
`• A. INFRARED ABSORPTION Æ197Kæ
`• B. ULTRAVIOLET ABSORPTION Æ197Uæ
`Sample solution: 10 mg/mL
`Medium: Methanol
`Acceptance criteria: Meets the requirements
`• 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 Æ621æ, Thin-Layer Chromato-
`graphy.)
`Mode: TLC
`Adsorbent: 0.25-mm layer of chromatographic silica
`gel mixture
`Application volume: 40 mL
`Developing solvent system: Dichloromethane, ace-
`tone, and glacial acetic acid (95:5:2)
`Spray reagent: Freshly prepared alcoholic solution
`containing 30 mg of ninhydrin/mL
`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 rea-
`gent, and heat the plate at about 150(cid:176) 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.
`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.
`
`AU
`ACB
`CS
`
`Calculate the concentration, in mg/mL, of ketoprofen in
`the sample withdrawn at each time point:
`Result = (AU - A CB) · (C S/AS)
`= absorbance of the Sample solution
`= absorbance of the Capsule blank
`= concentration of USP Ketoprofen RS in the
`Standard solution (mg/mL)
`= absorbance of the Standard solution
`AS
`Calculate the percentage of ketoprofen dissolved at
`each time point:
`Result = (D + SR) · 100/L
`= [amount dissolved (mg)] = volume (mL)
`remaining before draw · concentration
`(mg/mL) of sample withdrawn at the
`sampling time point
`= [amount removed (mg)] = volume (mL) of
`sample withdrawn · concentration (mg/mL)
`of sample withdrawn at each time point
`= conversion factor for percentage
`100
`= Capsule label claim (mg)
`L
`Tolerances: The percentage of the labeled amount of
`ketoprofen released at the times specified conforms to
`Acceptance Table 2.
`
`D
`
`R
`
`Amount Dissolved
`10%–25%
`55%–80%
`NLT 80%
`
` Meet the
`
`Time
`(h)
`1
`4
`8
`• UNIFORMITY OF DOSAGE UNITS Æ905æ:
`requirements
`Procedure for content uniformity: [NOTE—Protect the
`Standard solution and Sample solution from light.]
`Mobile phase, Standard solution, System suitability
`solution, and Chromatographic system: Proceed as
`directed in the Assay.
`Sample solution: Transfer the contents of 10 Capsules,
`1 Capsule each, to each of 10 250-mL volumetric flasks,
`add about 150 mL of Mobile phase to each flask, and
`stir for 2 h. Dilute with Mobile phase to volume, and
`mix. Centrifuge, and pipet a volume of clear superna-
`tant that contains about 2.4 mg of ketoprofen into a
`100-mL volumetric flask. Dilute with Mobile phase to
`volume.
`System suitability
`Samples: Standard solution and System suitability
`solution
`Suitability requirements
`Resolution: NLT 3.0 between ketoprofen and
`ketoprofen related compound A, System suitability
`solution
`Tailing factor: NLT 1.5 for the ketoprofen peak, Sys-
`tem suitability solution
`Relative standard deviation: NMT 2.0%, Standard
`solution
`Analysis
`Samples: Standard solution and Sample solution
`Calculate the percentage of C16H14O3 in each Capsule:
`Result = (rU/rS) · (C S/CU) · 100
`= peak response from the Sample solution
`= peak response from the Standard solution
`= concentration of USP Ketoprofen RS in the
`Standard solution (mg/mL)
`= concentration of ketoprofen in the Sample
`solution (mg/mL)
`
`rU
`rS
`CS
`
`CU
`
`USP Monographs
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`SENJU EXHIBIT 2287
`LUPIN v. SENJU
`IPR2015-01100
`
`Page 1 of 2
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`USP 38
`
`Official Monographs / Ketorolac 4011
`
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 313 nm
`Column: 4.6-mm · 25-cm; 5-mm packing L7
`Column temperature: 40(cid:176)
`Flow rate: 1.5 mL/min
`Injection volume: 10 mL
`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 = (rU/rT) · F · 100
`= peak response of each individual impurity
`from the Sample solution
`= sum of all the peak responses from the Sample
`solution
`= relative response factor (see Table 1)
`F
`Acceptance criteria: See Table 1.
`
`rU
`
`rT
`
`USP Monographs
`
`Table 1
`Relative
` Reten-
`tion
` Time
`
`Relative
` Re-
`sponse
` Factor
`
`Acceptance
` Criteria,
` NMT (%)
`
`0.54
`
`0.63
`
`0.66
`
`0.89
`
`1.0
`
`—
`
`2.2
`
`0.67
`
`0.91
`
`0.52
`
`1.0
`
`—
`
`0.5
`
`0.1
`
`0.5
`
`0.1
`
`—
`
`1.0
`
`Name
`Impurity having a 0.54
`relative retention time
`Ketorolac 1-hydroxy an-
`alog
`Impurity having a 0.66
`relative retention time
`Ketorolac 1-keto analog
`
`Ketorolac tromethamine
`
`Total impurities
`
`SPECIFIC TESTS
`• PH Æ791æ
`Sample solution: 10 mg/mL
`Acceptance criteria: 5.7–6.7
`• LOSS ON DRYING Æ731æ
`Analysis: Dry under vacuum at 60(cid:176) for 3 h.
`Acceptance criteria: NMT 0.5%
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in tight, light-resistant
`containers. Store at 25(cid:176), excursions permitted between
`15(cid:176) and 30(cid:176).
`• USP REFERENCE STANDARDS Æ11æ
`USP Ketorolac Tromethamine RS
`
`Ketorolac Tromethamine Injection
`
`DEFINITION
`Ketorolac Tromethamine Injection is a sterile solution of
`Ketorolac Tromethamine. It contains NLT 90.0% and NMT
`110.0% of the labeled amount of ketorolac tromethamine
`(C15H13NO3 · C4H11NO3).
`IDENTIFICATION
`• A.
`Sample: Standard solution and Sample solution (1:1),
`prepared as directed in the Assay
`Analysis: Chromatograph the Sample as directed in the
`Assay.
`
`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 hy-
`drochloric 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 chro-
`matogram 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 Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 313 nm
`Column: 4.6-mm · 25-cm; 5-mm packing L7
`Column temperature: 40(cid:176)
`Flow rate: 1.5 mL/min
`Injection volume: 10 mL
`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 keterolac tromethamine
`(C15H13NO3 · C4H11NO3) in the portion of Keterolac
`Tromethamine taken:
`Result = (rU/rS) · (C S/CU) · 100
`= peak area from the Sample solution
`= peak area from the Standard solution
`= concentration of USP Ketorolac Tromethamine
`RS in the Standard solution (mg/mL)
`= concentration of Ketorolac Tromethamine in
`the Sample solution (mg/mL)
`Acceptance criteria: 98.5%–101.5% on the dried basis
`IMPURITIES
`• RESIDUE ON IGNITION Æ281æ:
`
`rU
`rS
`CS
`
`CU
`
` NMT 0.1%
`
`Delete the following:
`•• HEAVY METALS, Method II Æ231æ:
` 20 ppm• (Official 1-Dec-2015)
`• ORGANIC IMPURITIES
`Mobile phase, Diluent, System suitability solution,
`Standard solution, and Sample solution: Prepare as
`directed in the Assay.
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`Page 2 of 2