Accessed from 10.6.1.1 by apman3 on Fri Feb 05 18:46:15 EST 2016
`
`3088 Diclofenac / Official Monographs
`
`USP 38
`
`rS
`
`make any necessary correction. Each mL of 0.1 N perchloric
`acid is equivalent to 31.81 mg of C14H10Cl2NNaO2.
`
`.
`
`Diclofenac Sodium Delayed-Release
`Tablets
`
` It meets
`
`DEFINITION
`Diclofenac Sodium Delayed-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 diclofenac peak of the Sam-
`ple solution corresponds to that of the Standard solution,
`as obtained in the Assay.
`• B. IDENTIFICATION TESTS—GENERAL, Sodium Æ191æ:
`the requirements of the flame test.
`ASSAY
`• PROCEDURE
`Solution A: Mix equal volumes of 0.01 M phosphoric
`acid and 0.01 M monobasic sodium phosphate. If nec-
`essary, adjust with additional portions of the appropri-
`ate component to a pH of 2.5 – 0.2.
`Mobile phase: Methanol and Solution A (7:3)
`[NOTE—Increasing the proportion of buffer increases
`resolution.]
`Diluent: Methanol and water (7:3)
`System suitability solution: 20 mg/mL of diethyl
`phthalate, 7.5 mg/mL of USP Diclofenac Related Com-
`pound A RS, and 0.75 mg/mL of USP Diclofenac So-
`dium RS in Diluent
`Standard solution: 0.75 mg/mL of USP Diclofenac So-
`dium RS in Diluent
`Sample solution: Transfer 20 Tablets to a volumetric
`flask of such capacity that when filled to volume, a con-
`centration of 0.75 mg/mL of diclofenac sodium is ob-
`tained. Add Diluent to about 70% of the capacity of the
`flask, and shake by mechanical means for NLT 30 min
`to disintegrate the Tablets. Cool to room temperature,
`and dilute with Diluent to volume. Pass a portion of the
`solution through a filter of 0.5-mm or finer pore size,
`and use the filtrate as the Sample solution.
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 254 nm
`Column: 4.6-mm · 25-cm; packing L7 (end-capped)
`Flow rate: 1 mL/min
`Injection size: 10 mL
`System suitability
`Samples: System suitability solution and Standard
`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; NLT 6.5
`between the diclofenac related compound A and
`diclofenac peaks, System suitability solution
`Relative standard deviation: NMT 2.0%, 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
`
`rU
`
`USP Monographs
`
`CS
`
`CU
`
` Meet the
`
`= 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:
` Proceed as directed for Procedure, Ap-
`paratus 1 and Apparatus 2, Delayed-Release Dosage Forms,
`Method B to determine the amount of C14H10Cl2NNaO2
`dissolved.
`Acid stage
`Medium: 0.1 N hydrochloric acid; 900 mL
`Apparatus 2: 50 rpm, paddles constructed of (or
`coated with) polytef being used
`Time: 2 h
`Detector: UV maxima at about 276 nm
`Standard solution: Transfer 68 mg of USP Diclofenac
`Sodium RS to a 100-mL volumetric flask, add 10.0 mL
`of 0.1 N sodium hydroxide, and dilute with water to
`volume. Transfer 2.0 mL of this solution to a second
`100-mL volumetric flask, dilute with a mixture of 0.1
`N hydrochloric acid and 5 N sodium hydroxide
`(900:20) to volume, and mix. This Standard solution
`contains 13.6 mg/mL of USP Diclofenac Sodium RS.
`Sample solution: At the end of 2 h, remove each Tab-
`let, or the major portion thereof if the Tablet is not
`intact, from the individual vessels, and subject them to
`the test under Buffer stage. To the 0.1 N hydrochloric
`acid remaining in each vessel, add 20.0 mL of 5 N so-
`dium hydroxide, and stir for 5 min.
`Buffer stage
`Medium: pH 6.8 phosphate buffer; 900 mL
`Apparatus 2: 50 rpm
`Time: 45 min
`Detector: UV maxima at about 276 nm
`Solution A: 76 mg/mL of tribasic sodium phosphate
`pH 6.8 phosphate buffer: Solution A and 0.1 N hydro-
`chloric acid (1:3), adjusted with 2 N hydrochloric acid
`or 2 N sodium hydroxide to a pH of 6.8 – 0.05, if
`necessary
`Standard solution: Transfer 68 mg of USP Diclofenac
`Sodium RS to a 100-mL volumetric flask. Add 10.0 mL
`of 0.1 N sodium hydroxide, dilute with water to vol-
`ume, and mix. Transfer 3.0 mL of this solution to a
`100-mL volumetric flask, dilute with Buffer stage Me-
`dium to volume, and mix. The final concentration is
`about 0.0204 mg/mL of diclofenac sodium.
`Sample solution: Sample per Dissolution Æ711æ. Dilute
`with Medium to a concentration similar to that of the
`Standard solution.
`Tolerances: NLT 75% (Q) of the labeled amount of
`C14H10Cl2NNaO2 is dissolved.
`• UNIFORMITY OF DOSAGE UNITS Æ905æ:
`requirements
`IMPURITIES
`Organic Impurities
`• PROCEDURE
`Solution A, Mobile phase, Diluent, System suitability
`solution, Sample solution, Chromatographic system,
`and System suitability: Proceed as directed in the
`Assay.
`Standard stock solution: 0.8 mg/mL of USP Diclofenac
`Related Compound A RS in methanol
`Standard solution: 4 mg/mL of USP Diclofenac Related
`Compound A RS from the Standard stock solution in
`Diluent
`Analysis: Measure the peak responses over a period of
`40 min.
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`SENJU EXHIBIT 2284
`LUPIN v. SENJU
`IPR2015-01105
`
`Page 1 of 2
`
`
`
`3088 Diclofenac / Official Monographs
`
`USP 38
`
`rS
`
`make any necessary correction. Each mL of 0.1 N perchloric
`acid is equivalent to 31.81 mg of C14H10Cl2NNaO2.
`
`.
`
`Diclofenac Sodium Delayed-Release
`Tablets
`
` It meets
`
`DEFINITION
`Diclofenac Sodium Delayed-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 diclofenac peak of the Sam-
`ple solution corresponds to that of the Standard solution,
`as obtained in the Assay.
`• B. IDENTIFICATION TESTS—GENERAL, Sodium Æ191æ:
`the requirements of the flame test.
`ASSAY
`• PROCEDURE
`Solution A: Mix equal volumes of 0.01 M phosphoric
`acid and 0.01 M monobasic sodium phosphate. If nec-
`essary, adjust with additional portions of the appropri-
`ate component to a pH of 2.5 – 0.2.
`Mobile phase: Methanol and Solution A (7:3)
`[NOTE—Increasing the proportion of buffer increases
`resolution.]
`Diluent: Methanol and water (7:3)
`System suitability solution: 20 mg/mL of diethyl
`phthalate, 7.5 mg/mL of USP Diclofenac Related Com-
`pound A RS, and 0.75 mg/mL of USP Diclofenac So-
`dium RS in Diluent
`Standard solution: 0.75 mg/mL of USP Diclofenac So-
`dium RS in Diluent
`Sample solution: Transfer 20 Tablets to a volumetric
`flask of such capacity that when filled to volume, a con-
`centration of 0.75 mg/mL of diclofenac sodium is ob-
`tained. Add Diluent to about 70% of the capacity of the
`flask, and shake by mechanical means for NLT 30 min
`to disintegrate the Tablets. Cool to room temperature,
`and dilute with Diluent to volume. Pass a portion of the
`solution through a filter of 0.5-mm or finer pore size,
`and use the filtrate as the Sample solution.
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 254 nm
`Column: 4.6-mm · 25-cm; packing L7 (end-capped)
`Flow rate: 1 mL/min
`Injection size: 10 mL
`System suitability
`Samples: System suitability solution and Standard
`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; NLT 6.5
`between the diclofenac related compound A and
`diclofenac peaks, System suitability solution
`Relative standard deviation: NMT 2.0%, 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
`
`rU
`
`USP Monographs
`
`CS
`
`CU
`
` Meet the
`
`= 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:
` Proceed as directed for Procedure, Ap-
`paratus 1 and Apparatus 2, Delayed-Release Dosage Forms,
`Method B to determine the amount of C14H10Cl2NNaO2
`dissolved.
`Acid stage
`Medium: 0.1 N hydrochloric acid; 900 mL
`Apparatus 2: 50 rpm, paddles constructed of (or
`coated with) polytef being used
`Time: 2 h
`Detector: UV maxima at about 276 nm
`Standard solution: Transfer 68 mg of USP Diclofenac
`Sodium RS to a 100-mL volumetric flask, add 10.0 mL
`of 0.1 N sodium hydroxide, and dilute with water to
`volume. Transfer 2.0 mL of this solution to a second
`100-mL volumetric flask, dilute with a mixture of 0.1
`N hydrochloric acid and 5 N sodium hydroxide
`(900:20) to volume, and mix. This Standard solution
`contains 13.6 mg/mL of USP Diclofenac Sodium RS.
`Sample solution: At the end of 2 h, remove each Tab-
`let, or the major portion thereof if the Tablet is not
`intact, from the individual vessels, and subject them to
`the test under Buffer stage. To the 0.1 N hydrochloric
`acid remaining in each vessel, add 20.0 mL of 5 N so-
`dium hydroxide, and stir for 5 min.
`Buffer stage
`Medium: pH 6.8 phosphate buffer; 900 mL
`Apparatus 2: 50 rpm
`Time: 45 min
`Detector: UV maxima at about 276 nm
`Solution A: 76 mg/mL of tribasic sodium phosphate
`pH 6.8 phosphate buffer: Solution A and 0.1 N hydro-
`chloric acid (1:3), adjusted with 2 N hydrochloric acid
`or 2 N sodium hydroxide to a pH of 6.8 – 0.05, if
`necessary
`Standard solution: Transfer 68 mg of USP Diclofenac
`Sodium RS to a 100-mL volumetric flask. Add 10.0 mL
`of 0.1 N sodium hydroxide, dilute with water to vol-
`ume, and mix. Transfer 3.0 mL of this solution to a
`100-mL volumetric flask, dilute with Buffer stage Me-
`dium to volume, and mix. The final concentration is
`about 0.0204 mg/mL of diclofenac sodium.
`Sample solution: Sample per Dissolution Æ711æ. Dilute
`with Medium to a concentration similar to that of the
`Standard solution.
`Tolerances: NLT 75% (Q) of the labeled amount of
`C14H10Cl2NNaO2 is dissolved.
`• UNIFORMITY OF DOSAGE UNITS Æ905æ:
`requirements
`IMPURITIES
`Organic Impurities
`• PROCEDURE
`Solution A, Mobile phase, Diluent, System suitability
`solution, Sample solution, Chromatographic system,
`and System suitability: Proceed as directed in the
`Assay.
`Standard stock solution: 0.8 mg/mL of USP Diclofenac
`Related Compound A RS in methanol
`Standard solution: 4 mg/mL of USP Diclofenac Related
`Compound A RS from the Standard stock solution in
`Diluent
`Analysis: Measure the peak responses over a period of
`40 min.
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`SENJU EXHIBIT 2284
`LUPIN v. SENJU
`IPR2015-01105
`
`Page 1 of 2
`
`
`
`Accessed from 10.6.1.1 by apman3 on Fri Feb 05 18:46:15 EST 2016
`
`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.
`
`Page 2 of 2
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