USP 38
`
`Official Monographs / Diclofenac 3089
`
`USP Monographs
`
`ASSAY
`• PROCEDURE
`[NOTE—Protect the Standard solution, System suitability
`solution, and Sample solution from light.]
`Diluent: Methanol and water (7:3)
`Buffer: 0.01 M phosphoric acid and 0.01 M monobasic
`sodium phosphate. Adjust with appropriate component
`to a pH of 2.5.
`Mobile phase: Methanol and Buffer (7:3)
`Standard solution: 0.5 mg/mL of USP Diclofenac So-
`dium RS in Diluent
`Resolution solution: 20 mg/mL of diethyl phthalate,
`7.5 mg/mL of USP Diclofenac Related Compound A RS,
`and 0.75 mg/mL of USP Diclofenac Sodium RS in
`Diluent
`Sample solution: Powder NLT 20 Tablets, and transfer
`a weighed portion of the powder, equivalent to 100 mg
`of diclofenac sodium, to a 200-mL volumetric flask, and
`add 150 mL of Diluent. Heat on a steam bath for 3–5
`min, and sonicate for 20 min. Cool to room tempera-
`ture, and dilute with Diluent to volume. Place the flask
`in an ice bath for 45 min, shaking occasionally to pre-
`cipitate out any undissolved waxy material. Pass a por-
`tion of the chilled solution through a filter of 0.45-mm
`or finer pore size. Allow the filtrate to reach room tem-
`perature before using.
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 254 nm
`Column: 4.6-mm · 25-cm; packing L7
`Flow rate: 1 mL/min
`Injection size: 10 mL
`System suitability
`Samples: Standard solution and Resolution solution
`[NOTE—The relative retention times for diethyl phthal-
`ate, diclofenac related compound A, and diclofenac
`are 0.5, 0.6, and 1.0, respectively.]
`Suitability requirements
`Resolution: NLT 2.2 between the diethyl phthalate
`and diclofenac related compound A peaks, and NLT
`3.8 between the diclofenac related compound A and
`diclofenac peaks, Resolution solution
`Relative standard deviation: NMT 2.0% for
`diclofenac, Standard solution
`Analysis
`Samples: Standard solution and Sample solution
`Calculate the percentage of C14H10Cl2NNaO2 in the
`portion of Tablets taken:
`Result = (rU/rS) · (C S/CU) · 100
`= peak response of diclofenac from the Sample
`solution
`= peak response of diclofenac from the Standard
`solution
`= concentration of USP Diclofenac Sodium RS in
`the Standard solution (mg/mL)
`= nominal concentration of diclofenac sodium in
`the Sample solution (mg/mL)
`Acceptance criteria: 90.0%–110.0%
`PERFORMANCE TESTS
`• DISSOLUTION Æ711æ
`Test 1
`Medium: 0.05 M phosphate buffer, pH 7.5; 900 mL
`Apparatus 2: 50 rpm; use wire sinkers.
`Times: 1, 5, 10, 16, and 24 h
`Detector: UV 276 nm
`Standard solution: USP Diclofenac Sodium RS in
`Medium
`Analysis: Pass portions of the solution under test
`through a suitable filter. Dilute with Medium, if neces-
`sary, to a concentration similar to that of the Standard
`solution.
`
`CS
`
`CU
`
`rU
`
`rS
`
`rU
`
`rS
`
`CS
`
`CU
`
`Calculate the percentage of diclofenac related com-
`pound A in relation to the quantity of diclofenac so-
`dium in the portion of Tablets taken:
`Result = (rU/rS) · (C S/CU) · 100
`= peak response of diclofenac related
`compound A from the Sample solution
`= peak response of diclofenac related
`compound A from the Standard solution
`= concentration of USP Diclofenac Related
`Compound A RS in the Standard solution
`(mg/mL)
`= nominal concentration of diclofenac sodium
`in the Sample solution (mg/mL)
`Calculate the percentage of each impurity other than
`diethyl phthalate, if present, in relation to the
`diclofenac sodium in the portion of Tablets taken:
`Result = (rU/rS) · (C S/CU) · 100
`= peak response for each impurity from the
`Sample solution
`= peak response of diclofenac related
`compound A from the Standard solution
`= concentration of USP Diclofenac Related
`Compound A RS in the Standard solution
`(mg/mL)
`= nominal concentration of diclofenac sodium
`in the Sample solution (mg/mL)
`Acceptance criteria
`Individual impurities: NMT 0.5% of diclofenac re-
`lated compound A; NMT 1.0% of any other individ-
`ual impurity
`Total impurities: NMT 1.5%
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in tight, light-resistant
`containers.
`• USP REFERENCE STANDARDS Æ11æ
`USP Diclofenac Sodium RS
`USP Diclofenac Related Compound A RS
`N-(2,6-Dichlorophenyl)indolin-2-one.
`C14H9Cl2NO 278.14
`
`rU
`
`rS
`
`CS
`
`CU
`
`Diclofenac Sodium Extended-Release
`Tablets
`
`DEFINITION
`Diclofenac Sodium Extended-Release Tablets contain NLT
`90.0% and NMT 110.0% of the labeled amount of
`diclofenac sodium (C14H10Cl2NNaO2).
`IDENTIFICATION
`• A. The retention time of the Sample solution corresponds
`to that of the Standard solution, as obtained in the Assay.
`• B. THIN-LAYER CHROMATOGRAPHIC IDENTIFICATION TEST
`Æ201æ
`Standard solution: 2.0 mg/mL of USP Diclofenac So-
`dium RS in methanol. [NOTE—Shake by mechanical
`means for 10 min before makeup to final volume.]
`Sample solution: Equivalent to 2.0 mg/mL of
`diclofenac sodium from a portion of the powder (NLT
`10 Tablets) in methanol. [NOTE—Sonicate for 10 min,
`and shake by mechanical means for 10 min before
`makeup to final volume. Centrifuge this solution, and
`use the clear supernatant.]
`Developing solvent system: Methanol, toluene, and
`glacial acetic acid (8:12:0.1)
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`SENJU EXHIBIT 2285
`LUPIN v. SENJU
`IPR2015-01100
`
`Page 1 of 2
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`3090 Diclofenac / Official Monographs
`
`USP 38
`
`Standard stock solution: 0.8 mg/mL of USP Diclofenac
`Related Compound A RS in Diluent
`Standard solution: 4 mg/mL of USP Diclofenac Related
`Compound A RS, made by diluting a measured volume
`of Standard stock solution with Diluent
`System suitability solution: 0.5 mg/mL of USP
`Diclofenac Sodium RS in Diluent
`System suitability
`Samples: Resolution solution and System suitability
`solution
`[NOTE—The relative retention times for diethyl phthal-
`ate, diclofenac related compound A, and diclofenac
`are 0.5, 0.6, and 1.0, respectively.]
`Suitability requirements
`Resolution: NLT 2.2 between the diethyl phthalate
`and diclofenac related compound A peaks; and NLT
`3.8 between the diclofenac related compound A
`and the diclofenac peaks, Resolution solution
`Standard deviation: NMT 2.0% for the diclofenac
`peak, System suitability solution
`Analysis
`Samples: Sample solution and Standard solution
`Calculate the percentage of each impurity in the por-
`tion of Tablets taken:
`Result = (rU/rS) · (C S/CU) ·100
`= peak response for any impurity from the
`Sample solution
`= peak response for USP Diclofenac Related
`Compound A RS from the Standard solution
`= concentration (mg/mL) of USP Diclofenac
`Related Compound A RS in the Standard
`solution
`= concentration (mg/mL) of diclofenac sodium
`in the Sample solution
`Acceptance criteria
`Total impurities: NMT 1.5%
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in well-closed contain-
`ers. Store at controlled room temperature, and protect
`from light.
`• LABELING: When more than one Dissolution test is given,
`the labeling states the test used only if Test 1 is not used.
`• USP REFERENCE STANDARDS Æ11æ
`USP Diclofenac Sodium RS
`USP Diclofenac Related Compound A RS
`N-(2,6-Dichlorophenyl)indolin-2-one.
`C14H9Cl2NO 278.14
`
`CS
`
`CU
`
`rU
`
`rS
`
`Dicloxacillin Sodium
`
`C19H16Cl2N3NaO5S · H2O 510.32
`4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,
`6-[[[3-(2,6-dichlorophenyl)-5-methyl-
`4-isoxazolyl]carbonyl]amino]-3,3-dimethyl-7-oxo-,
`monosodium salt, monohydrate, [2S-(2a,5a,6
`b )]-.
`Monosodium (2S,5R,6R)-6-[3-(2,6-dichlorophenyl)-5-methyl-
`4-isoxazolecarboxamido]-3,3-dimethyl-7-oxo-4-thia-
`1-azabicyclo[3.2.0]heptane-2-carboxylate monohydrate
`[13412-64-1].
`Anhydrous 492.32 [343-55-5].
`
`Tolerances: The percentages of the labeled amount of
`C14H10Cl2NNaO2 dissolved at the times specified con-
`form to Acceptance Table 2.
`
`Time
`(h)
`1
`5
`10
`16
`24
`
`Amount Dissolved
`
`15%–35%
` 45%–65%
` 65%–85%
` 75%–95%
`NLT 80%
`
`Test 2: If the product complies with this test, the label-
`ing indicates that it meets USP Dissolution Test 2.
`Medium, Apparatus, and Analysis: Proceed as di-
`rected for Dissolution Test 1.
`Times: 1, 2, 4, 6, and 10 h
`Tolerances: The percentages of the labeled amount of
`C14H10Cl2NNaO2 dissolved at the times specified con-
`form to Acceptance Table 2.
`
`Time
`(h)
`1
`2
`4
`6
`10
`
`Amount Dissolved
`
`NMT 28%
` 20%–40%
` 35%–60%
` 50%–80%
`NLT 65%
`
`Test 3: If the product complies with this test, the label-
`ing indicates that it meets USP Dissolution Test 3.
`Medium and Analysis: Proceed as directed for Dissolu-
`tion Test 1.
`Apparatus 1: 100 rpm
`Times: 2, 4, 8, and 16 h
`Tolerances: The percentages of the labeled amount of
`C14H10Cl2NNaO2 dissolved at the times specified con-
`form to Acceptance Table 2.
`
`Time
`(h)
`2
`4
`8
`16
`
`Amount Dissolved
`
`22%–42%
` 34%–61%
`52%–82%
`NLT 73%
`
`Test 4: If the product complies with this test, the label-
`ing indicates that it meets USP Dissolution Test 4.
`Medium and Analysis: Proceed as directed for Test 1.
`Apparatus 1: 100 rpm
`Times: 2, 4, 8, and 16 h
`Tolerances: The percentages of the labeled amount of
`C14H10Cl2NNaO2 dissolved at the times specified con-
`form to Acceptance Table 2.
`
`USP Monographs
`
`Amount Dissolved
`
`Time
`(h)
`2
`4
`8
`16
`• UNIFORMITY OF DOSAGE UNITS Æ905æ:
`requirements
`IMPURITIES
`Organic Impurities
`• PROCEDURE
`Diluent, Buffer, Mobile phase, Resolution solution,
`Sample solution, Chromatographic system, and Sys-
`tem suitability: Proceed as directed in the Assay.
`
`20%–40%
` 35%–55%
`60%–85%
`NLT 85%
`
` Meet the
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`Page 2 of 2