Second Supplement to USP 38–NF 33
`
`Official Monographs / Ketorolac 8129
`
`rU
`
`rS
`
`CS
`
`CU
`
`ketorolac related compound C peaks, System suitabil-
`ity solution
`Column efficiency: NLT 2700 theoretical plates,
`Standard solution
`Tailing factor: NMT 1.5, Standard solution
`Relative standard deviation: NMT 1.5%, Standard
`solution
`Analysis
`Samples: Standard solution and Sample solution
`Calculate the percentage of the labeled amount of
`ketorolac tromethamine (C15H13NO3 · C4H11NO3) in the
`portion of Tablets taken:
`Result = (rU/rS) · (C S/CU) · 100
`= response of the ketorolac peak from the
`Sample solution
`= response of the ketorolac peak 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%
`PERFORMANCE TESTS
`• DISSOLUTION Æ711æ
`Medium: Water; 600 mL
`Apparatus 2: 50 rpm
`Time: 45 min
`Standard solution: USP Ketorolac Tromethamine RS in
`Medium
`Sample solution: Sample per Dissolution Æ711æ. Dilute
`with Medium to a concentration that is similar to the
`Standard solution.
`Instrumental conditions
`Mode: UV absorption spectroscopy
`Analytical wavelength: 322 nm
`Tolerances: NLT 75% (Q) of the labeled amount of
`ketorolac tromethamine (C15H13NO3 · C4H11NO3) is
`dissolved.
`• UNIFORMITY OF DOSAGE UNITS Æ905æ
`Procedure for content uniformity
`Blank: Methanol
`Standard solution: 12 mg/mL of USP Ketorolac
`Tromethamine RS in methanol
`Sample solution: Transfer 1 Tablet to a suitable volu-
`metric flask that will provide a final concentration of
`about 0.1 mg/mL of ketorolac tromethamine. Add a
`quantity of water equivalent to about 10% of the vol-
`ume of the flask, and sonicate until the Tablet is disin-
`tegrated. Add a quantity of methanol equivalent to
`40% of the volume of the flask, and sonicate for about
`10 min to dissolve the ketorolac tromethamine. Cool
`to ambient temperature, dilute with methanol to vol-
`ume, and mix. Centrifuge or allow to settle. Transfer
`6.0 mL of the clear supernatant to a 50-mL volumetric
`flask, and dilute with methanol to volume.
`Instrumental conditions
`Mode: UV absorption spectroscopy
`Analytical wavelength: UV 322 nm
`Calculate the percentage of the labeled amount of
`ketorolac tromethamine (C15H13NO3 · C4H11NO3) in the
`portion of Tablets taken:
`Result = (AU/AS) · (C S/CU) · 100
`= absorbance of the Sample solution
`
`cis-1-(p-{[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-
`1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)-
`4-isopropylpiperazine.
`C26H31Cl2N5O3
`532.46n2S (USP38)
`
`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 solution
`corresponds to that of the Standard solution, as obtained
`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 the ketoro-
`lac peak
`System suitability
`Samples: Standard solution and System suitability
`solution
`[NOTE—The relative retention times for the ketorolac re-
`lated compound B and ketorolac peaks are 0.8 and
`1.0, respectively.]
`Suitability requirements
`Resolution: NLT 1.5 each between the ketorolac and
`ketorolac related compound B, and ketorolac and
`
`AU
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`SENJU EXHIBIT 2289
`LUPIN v. SENJU
`IPR2015-01100
`
`Page 1 of 2
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`8130 Ketorolac / Official Monographs
`
`Second Supplement to USP 38–NF 33
`
`CU
`
`AS
`CS
`
`= absorbance of 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: Meet the requirements
`IMPURITIES
`
`358.39
`C19H22N2O5
`USP Ketorolac Related Compound B RS
`5-Benzoyl-2,3-dihydro-1H-pyrrolizin-1-ol.
`C14H13NO2
`227.26
`USP Ketorolac Related Compound C RS
`5-Benzoyl-2,3-dihydro-1H-pyrrolizin-1-one.
`C14H11NO2
`225.24
`USP Ketorolac Related Compound D RS
`5-Benzoyl-2,3-dihydro-1H-pyrrolizine.
`C14H13NO 211.26
`
`Lactulose Concentrate
`
`Change to read:
`
`
`
`n2S (USP38)
`
`C12H22O11
`342.30
`D-Fructose, 4-O-b -D-galactopyranosyl-;n
`4-O-b -D-Galactopyranosyl-D-fructofuranose [4618-18-2].
`DEFINITION
`Lactulose Concentrate is a solution of sugars prepared from
`Lactose. It consists principally of lactulose together with
`minor quantities of lactose and galactose, and traces of
`other related sugars and water. It contains NLT 95.0%
`and NMT 105.0% of the labeled amount of lactulose
`(C12H22O11). It contains no added substances.
`IDENTIFICATION
`• A. The retention time of the major peak of the Sample
`solution corresponds to that of the Standard solution, as
`obtained in the Assay.
`• B.
`Sample solution: Dilute a portion of Concentrate with
`water (1 in 20).
`Analysis: Add a few drops of the Sample solution to
`5 mL of hot alkaline cupric tartrate TS.
`Acceptance criteria: A red precipitate of cuprous oxide
`is formed.
`ASSAY
`• PROCEDURE
`Buffer: 1.15 g/L of monobasic sodium phosphate in
`water
`Mobile phase: Acetonitrile and Buffer (82:18). Ensure
`that the concentration of acetonitrile in the Mobile
`phase is between 78% and 85% to obtain appropriate
`retention times.
`Standard solution: 40 mg/mL of USP Lactulose RS,
`4.8 mg/mL of USP Anhydrous Lactose RS, and 3.2 mg/
`mL of USP Epilactose RS in a mixture of acetonitrile and
`water (1:1)
`Sample solution: Nominally equivalent to 40 mg/mL of
`lactulose prepared as follows. Transfer a quantity of
`Concentrate containing 2.0 g of lactulose to a 50-mL
`volumetric flask, and dissolve in 20 mL of water. Add
`25.0 mL of acetonitrile, allow the solution to reach am-
`bient temperature, and dilute with water to volume.
`
`Change to read:
`• ORGANIC IMPURITIES
`Mobile phase, Diluent, and System suitability solu-
`tion: Proceed as directed in the Assay.
`Standard solution: Use the System suitability solution,
`prepared as directed in the Assay.
`Sample solution: Proceed as directed for the Sample
`solution in the Assay.
`Chromatographic system and System suitability: Pro-
`ceed as directed in the Assay.
`Analysis
`Samples: Standard solution and Sample solution
`Calculate the percentage of each known impurity in the
`portion of Tablets taken:
`Result = (rU/rS) · (C S/CU) · 100
`= peak response of each known impurity in the
`Sample solution
`= peak response of each known impurity in the
`Standard solution
`= concentration of each impurity in the Standard
`solution (mg/mL)
`= nominal concentration of ketorolac
`tromethamine in the Sample solution
`(mg/mL)
`Calculate the percentage of any other impurity in the
`portion of Tablets taken:
`Result = (rU/rT) · 100
`= peak response of each individual impurity in
`the Sample solution
`= sum of responses for all the peaks in the
`Sample solution
`Acceptance criteria: See Table 1.
`
`rU
`
`rS
`
`CS
`
`CU
`
`rU
`
`rT
`
`Name
`Ketorolac related compound A
`Ketorolac related compound B
`Ketorolac
`Ketorolac related compound C
`Ketorolac related compound D
`Total unspecified impurity
`Total impurities
`
`Table 1
`Relative
`Retention
`Time
`0.5
`0.8
`1.0
`1.2
`2.6
`—
`—
`
`Acceptance
`Criteria,
`NMT (%)
`0.5
`0.5
`—
`•0.8• (RB 1-Feb-2015)
`0.5
`0.5
`1.0
`
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in well-closed contain-
`ers at controlled room temperature, protected from light
`and excessive humidity.
`• USP REFERENCE STANDARDS Æ11æ
`USP Ketorolac Tromethamine RS
`USP Ketorolac Related Compound A RS
`5-Benzoyl-N-[1,3-dihydroxy-2-(hydroxymethyl)propan-
`2-yl]-2,3-dihydro-1H-pyrrolizine-1-carboxamide.
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`Page 2 of 2