Accessed from 10.6.1.1 by apman3 on Fri Feb 05 18:44:09 EST 2016
`
`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.
`
`SENJU EXHIBIT 2288
`LUPIN v. SENJU
`IPR2015-01105
`
`Page 1 of 2
`
`
`
`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.
`
`SENJU EXHIBIT 2288
`LUPIN v. SENJU
`IPR2015-01105
`
`Page 1 of 2
`
`
`
`Accessed from 10.6.1.1 by apman3 on Fri Feb 05 18:44:09 EST 2016
`
`4012 Ketorolac / Official Monographs
`
`USP 38
`
`• USP REFERENCE STANDARDS Æ11æ
`USP Endotoxin RS
`USP Ketorolac Tromethamine RS
`
`.
`
`Ketorolac Tromethamine Tablets
`
`DEFINITION
`Ketorolac Tromethamine Tablets contain NLT 90.0% and
`NMT 110.0% of the labeled amount of ketorolac
`tromethamine (C15H13NO3 · C4H11NO3).
`IDENTIFICATION
`• The retention time of the major peak of the Sample solu-
`tion corresponds to that of the Standard solution, as ob-
`tained in the Assay.
`ASSAY
`• PROCEDURE
`Mobile phase: Methanol, water, and glacial acetic acid
`(55:44:1)
`Diluent: Methanol and water (1:1). [NOTE—Protect all
`volumetric solutions from light.]
`Standard stock solution: 0.24 mg/mL of USP Ketorolac
`Tromethamine RS in methanol
`Standard solution: 24 mg/mL of USP Ketorolac
`Tromethamine RS in Diluent from Standard stock solution
`System suitability stock solution: 25 mg/mL each of
`USP Ketorolac Tromethamine RS, USP Ketorolac Related
`Compound A RS, USP Ketorolac Related Compound B
`RS, USP Ketorolac Related Compound C RS, and USP
`Ketorolac Related Compound D RS in methanol
`System suitability solution: 0.25 mg/mL each of USP
`Ketorolac Tromethamine RS, USP Ketorolac Related
`Compound A RS, USP Ketorolac Related Compound B
`RS, USP Ketorolac Related Compound C RS, and USP
`Ketorolac Related Compound D RS in Standard solution
`from System suitability stock solution
`Sample stock solution: 0.2 mg/mL of ketorolac
`tromethamine prepared as follows. Transfer 10 Tablets
`to a suitable volumetric flask. Add a quantity of water
`equivalent to about 10% of the volume of the flask,
`and sonicate until the Tablets are disintegrated. Add a
`quantity of methanol equivalent to 40% of the volume
`of the flask, and sonicate for 10 min to dissolve the
`ketorolac tromethamine. Cool to ambient temperature,
`dilute with methanol to volume, and mix. Centrifuge,
`or allow to settle.
`Sample solution: 0.02 mg/mL of ketorolac
`tromethamine in Diluent from Sample stock solution
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 254 nm
`Column: 4.6-mm · 25-cm; 5-mm packing L1
`Flow rate: 1.2 mL/min
`Injection volume: 100 mL
`Run time: 3.8 times the retention time of ketorolac
`peak
`System suitability
`Samples: System suitability solution and Standard
`solution
`[NOTE—The relative retention times are 0.8 for ketorolac
`related compound B and 1.0 for the ketorolac peaks.]
`Suitability requirements
`Resolution: NLT 1.5 each between the keterolac and
`ketorolac related compound B and ketotolac and
`ketorolac related compound C peaks, System suitabil-
`ity solution
`Column efficiency: NLT 2700 theoretical plates,
`Standard solution
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`RU
`
`USP Monographs
`
`Acceptance criteria: The chromatogram obtained ex-
`hibits two main peaks corresponding to ketorolac and
`the internal standard.
`ASSAY
`• PROCEDURE
`[NOTE—Protect all the solutions from light.]
`Mobile phase: Methanol, water, and glacial acetic acid
`(55:44:1)
`Diluent: Methanol and water (1:1). [NOTE—Resolution
`may be increased by increasing the proportion of water
`in the Mobile phase.]
`Internal standard solution: 0.3 mg/mL of naproxen in
`methanol
`Standard stock solution: 0.24 mg/mL of USP Ketorolac
`Tromethamine RS in methanol
`Standard solution: 0.024 mg/mL of USP Ketorolac
`Tromethamine RS from the Standard stock solution and
`0.03 mg/mL of Internal standard solution in Diluent
`Sample stock solution: Nominally 0.24 mg/mL of
`ketorolac tromethamine in methanol, from an equiva-
`lent volume of Injection.
`Sample solution: Transfer 5.0 mL of the Sample stock
`solution and 5.0 mL of the Internal standard solution to a
`50-mL volumetric flask, and dilute with Diluent to
`volume.
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 254 nm
`Column: 4.6-mm · 25-cm; 5-mm packing L1
`Flow rate: 1.2 mL/min
`Injection volume: 100 mL
`System suitability
`Sample: Standard solution
`[NOTE—The relative retention times for ketorolac and
`naproxen are 0.7 and 1.0, respectively.]
`Resolution: NLT 5.4 between ketorolac and naproxen
`Column efficiency: NLT 2700 theoretical plates for the
`ketorolac peak
`Tailing factor: NMT 1.5 for the ketorolac peak
`Relative standard deviation: NMT 1.5%
`Analysis
`Samples: Standard solution and Sample solution
`Calculate the percentage of ketorolac tromethamine
`(C15H13NO3 · C4H11NO3) in each mL of Injection taken:
`Result = (RU/RS) · (C S/CU) · 100
`= peak response ratio of ketorolac to naproxen
`from the Sample solution
`= peak response ratio of ketorolac to naproxen
`from the Standard solution
`= concentration of USP Ketorolac Tromethamine
`RS in the Standard solution (mg/mL)
`= nominal concentration of ketorolac
`tromethamine in the Sample solution
`(mg/mL)
`Acceptance criteria: 90.0%–110.0%
`SPECIFIC TESTS
`• PH Æ791æ:
` 6.9–7.9
`• BACTERIAL ENDOTOXINS TEST Æ85æ:
` It contains NMT 5.8
`USP Endotoxin Units/mg of ketorolac tromethamine.
`• STERILITY TESTS Æ71æ:
` Meets the requirements for Test for
`Sterility of the Product to Be Examined, Membrane Filtration
`• PARTICULATE MATTER IN INJECTIONS Æ788æ:
` Meets the re-
`quirements for small-volume injections
`• OTHER REQUIREMENTS: Meets the requirements for Injec-
`tions Æ1æ
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in single-dose contain-
`ers, preferably of Type I glass, protected from light, and
`store at controlled room temperature.
`
`RS
`
`CS
`
`CU
`
`Page 2 of 2
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