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USP 35 Official Monographs / Diclofenac 2881

obtained from the Assay preparation and the Standard prepara- tion of about 0.75 mg per mL. Quantitatively dilute an accu-
tion, respectively. rately measured volume of this stock solution with Diluent to
obtain a solution having a known concentration of about 1.5
µg per mL.
Resolution solution—Prepare a solution in Diluent containing
20 µg of diethyl phthalate, 7.5 µg of USP Diclofenac Related
Diclofenac Sodium
.

Compound A RS , and 0.75 mg of USP Diclofenac Sodium RS

per mL.
Test solution—Transfer about 75 mg of Diclofenac Sodium,
accurately weighed, to a 100-mL volumetric flask, dissolve in
and dilute with Diluent to volume, and mix.
Chromatographic system (see Chromatography 〈621〉)—The
liquid chromatograph is equipped with a 254-nm detector and
C14H10Cl2NNaO2 318.13 a 4.6-mm × 25-cm column containing packing L7 (end-
Benzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]-, mono- capped). The flow rate is about 1 mL per minute. Chromato-
sodium salt. graph the Resolution solution, and record the peak responses as
Sodium [o-(2,6-dichloroanilino)phenyl]acetate [15307-79-6]. directed for Procedure: the relative retention times are about 0.5
for diethyl phthalate, 0.6 for diclofenac related compound A,
» Diclofenac Sodium contains not less than 99.0 and 1.0 for diclofenac; and the resolution, R, between diethyl
phthalate and diclofenac related compound A is not less than
percent and not more than 101.0 per cent of 2.2, and that between diclofenac related compound A and
C14H10Cl2NNaO2, calculated on the dried basis. diclofenac is not less than 6.5. Chromatograph the Standard
solution, and record the peak responses as directed for Proce-
Packaging and storage—Preserve in tight, light-resistant dure: the relative standard deviation for replicate injections is
containers. not more than 5%.
USP Reference standards 〈11〉— Procedure—Separately inject equal volumes (about 10 µL) of
USP Diclofenac Sodium RS the Standard solution and the Test solution into the chromato-
USP Diclofenac Related Compound A RS graph, record the chromatograms, and measure the peak re-
N-(2,6-Dichlorophenyl)indolin-2-one. sponses over a period of 2.5 times the retention time of
C14H9Cl2NO 278.14 diclofenac. Calculate the per centage of diclofenac related com-
Identification— pound A in the portion of Diclofenac Sodium taken by the
formula:
A: Infrared Absorption 〈197K〉.
B: The retention time of the diclofenac peak in the chromat- 10(C / W)(rU / rS)
ogram of the Test solution corresponds to that of the Resolution
solution as obtained in the test for Chromatographic purity. in which C is the concentration, in µg per mL, of USP
C: The residue obtained by igniting it responds to the flame Diclofenac Related Compound A RS in the Standard solution; W
test for Sodium 〈191〉. is the quantity, in mg, of Diclofenac Sodium taken to prepare
Color of solution—A 1 in 20 solution of it in methanol is the Test solution; and rU and rS are the diclofenac related com-
colorless to faintly yellow, and the absorbance of the solution, pound A peak responses obtained from the Test solution and
determined in a 1-cm cell at 440 nm, is not more than 0.050, the Standard solution, respectively: not more than 0.2% is
methanol being used as the blank. found. Calculate the per centage of each other impurity in the
portion of Diclofenac Sodium taken by the formula:
Clarity of solution—The solution prepared as directed under
Color of solution is not significantly less clear than an equal vol- 10(C / W)(ri / rS)
ume of methanol contained in a similar vessel and examined
similarly. in which ri is the response of an individual impurity peak ob-
pH 〈791〉: between 7.0 and 8.5, in a solution (1 in 100). tained from the Test solution, and the other terms are as defined
Loss on drying 〈731〉—Dry it at 105 ° to 110 ° for 3 hours: it above: not more than 0.2% of any individual impurity is found.
loses not more than 0.5% of its weight. The sum of all of the impurities found is not more than 0.5%.
Heavy metals, Method II 〈231〉—To prepare the Test Prepara- Assay—Dissolve about 450 mg of Diclofenac Sodium, accu-
tion, use a 100-mL borosilicate glass beaker or a quartz crucible. rately weighed, in 25 mL of glacial acetic acid, and titrate with
If the residue is not completely white after the ignition at 500 ° 0.1 N per chloric acid VS, determining the endpoint potentio-
to 600°, add enough hydrogen peroxide to dissolve it, heat metrically. Perform a blank determination, and make any neces-
gently until dr y, and ignite for 1 hour. Repeat the hydrogen sary correction. Each mL of 0.1 N per chloric acid is equivalent
peroxide treatment and ignition until the residue is completely to 31.81 mg of C 14H10Cl2NNaO2.
white. Proceed as directed in Test Preparation, beginning with
“Cool, add 4 mL of 6 N hydrochloric acid.” The limit is
0.001%.
Chromatographic purity— Diclofenac Sodium Delayed-Release
.

pH 2.5 Phosphate buffer—Mix equal volumes of 0.01 M Tablets

phosphoric acid and 0.01 M monobasic sodium phosphate. If
necessary, adjust with additional portions of the appropriate
component to a pH of 2.5 ± 0.2. DEFINITION
Diclofenac Sodium Delayed-Release T ablets contain NLT 90.0%
Mobile phase—Prepare a filtered and degassed mixture of and NMT 110.0% of the labeled amount of diclofenac so-
methanol and pH 2.5 Phosphate buffer (700:300). Make adjust- dium (C 14H10Cl2NNaO2).
ments if necessar y (see System Suitability under Chromatography
〈621〉). [ NOTE—Increasing the proportion of buffer increases res- IDENTIFICATION
olution.] • A. The retention time of the diclofenac peak of the Sample
Diluent—Prepare a mixture of methanol and water (70:30). solution corresponds to that of the Standard solution, as ob-
Standard solution—Prepare a solution of USP Diclofenac Re- tained in the Assay.
lated Compound A RS in methanol having a known concentra- • B. IDENTIFICATION TESTS—GENERAL, Sodium 〈191〉: It meets
the requirements of the flame test.

Official from May 1, 2012

Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
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2882 Diclofenac / Official Monographs USP 35

ASSAY volumetric flask, dilute with a mixture of 0.1 N

• PROCEDURE hydrochloric acid and 5 N sodium hydroxide (900:20) to
Solution A: Mix equal volumes of 0.01 M phosphoric acid volume, and mix. This Standard solution contains 13.6
and 0.01 M monobasic sodium phosphate. If necessar y, ad- µg/mL of USP Diclofenac Sodium RS.
just with additional portions of the appropriate component Sample solution: At the end of 2 h, remove each T ablet,
to a pH of 2.5 ± 0.2. or the major portion thereof if the T ablet is not intact, from
Mobile phase: Methanol and Solution A (7:3) the individual vessels, and subject them to the test under
[NOTE—Increasing the proportion of buffer increases Buffer stage. To the 0.1 N hydrochloric acid remaining in
resolution.] each vessel, add 20.0 mL of 5 N sodium hydroxide, and stir
Diluent: Methanol and water (7:3) for 5 min.
System suitability solution: 20 µg/mL of diethyl phthalate, Buffer stage
7.5 µg/mL of USP Diclofenac Related Compound A RS, and Medium: pH 6.8 phosphate buffer; 900 mL
0.75 mg/mL of USP Diclofenac Sodium RS in Diluent Apparatus 2: 50 rpm
Standard solution: 0.75 mg/mL of USP Diclofenac Sodium Time: 45 min
RS in Diluent Detector: UV maxima at about 276 nm
Sample solution: Transfer 20 Tablets to a volumetric flask of Solution A: 76 mg/mL of tribasic sodium phosphate
such capacity that when filled to volume, a concentration of pH 6.8 phosphate buffer: Solution A and 0.1 N
0.75 mg/mL of diclofenac sodium is obtained. Add Diluent hydrochloric acid (1:3), adjusted with 2 N hydrochloric acid
to about 70% of the capacity of the flask, and shake by or 2 N sodium hydroxide to a pH of 6.8 ± 0.05, if
mechanical means for NL T 30 min to disintegrate the T ab- necessary
lets. Cool to room temperature, and dilute with Diluent to Standard solution: Transfer 68 mg of USP Diclofenac
volume. Pass a portion of the solution through a filter of Sodium RS to a 100-mL volumetric flask. Add 10.0 mL of
0.5-µm or finer pore size, and use the filtrate as the Sample 0.1 N sodium hydroxide, dilute with water to volume, and
solution. mix. Transfer 3.0 mL of this solution to a 100-mL
Chromatographic system volumetric flask, dilute with Buffer stage Medium to volume,
(See Chromatography 〈621〉, System Suitability.) and mix. The final concentration is about 0.0204 mg/mL of
Mode: LC diclofenac sodium.
Detector: UV 254 nm Sample solution: Sample per Dissolution 〈711〉. Dilute with
Column: 4.6-mm × 25-cm; packing L7 (end-capped) Medium to a concentration similar to that of the Standard
Flow rate: 1 mL/min solution.
Injection size: 10 µL Tolerances: NLT 75% (Q) of the labeled amount of
System suitability C14H10Cl2NNaO2 is dissolved.
Samples: System suitability solution and Standard solution • UNIFORMITY OF DOSAGE UNITS 〈905〉: Meet the requirements
[NOTE—The relative retention times for diethyl phthalate,
diclofenac related compound A, and diclofenac are 0.5, IMPURITIES
0.6, and 1.0, respectively.] Organic Impurities
Suitability requirements • PROCEDURE
Resolution: NLT 2.2 between the diethyl phthalate and Solution A, Mobile phase, Diluent, System suitability
diclofenac related compound A peaks; NL T 6.5 between solution, Sample solution, Chromatographic system, and
the diclofenac related compound A and diclofenac peaks, System suitability: Proceed as directed in the Assay.
System suitability solution Standard stock solution: 0.8 mg/mL of USP Diclofenac
Relative standard deviation: NMT 2.0%, Standard Related Compound A RS in methanol
solution Standard solution: 4 µg/mL of USP Diclofenac Related
Analysis Compound A RS from the Standard stock solution in Diluent
Samples: Standard solution and Sample solution Analysis: Measure the peak responses over a period of 40
Calculate the per centage of C 14H10Cl2NNaO2 in the portion min.
of Tablets taken: Calculate the per centage of diclofenac related compound A
in relation to the quantity of diclofenac sodium in the
Result = (r U/rS) × (C S/CU) × 100 portion of Tablets taken:

rU = peak response of diclofenac from the Sample Result = (r U/rS) × (C S/CU) × 100
solution
rS = peak response of diclofenac from the Standard rU = peak response of diclofenac related compound A
solution from the Sample solution
CS = concentration of USP Diclofenac Sodium RS in rS = peak response of diclofenac related compound A
the Standard solution (mg/mL) from the Standard solution
CU = nominal concentration of diclofenac sodium in CS = concentration of USP Diclofenac Related
the Sample solution (mg/mL) Compound A RS in the Standard solution
Acceptance criteria: 90.0%–110.0% (mg/mL)
CU = nominal concentration of diclofenac sodium in
PERFORMANCE TESTS the Sample solution (mg/mL)
• DISSOLUTION 〈711〉: Proceed as directed for Procedure, Calculate the per centage of each impurity other than
Apparatus 1 and Apparatus 2, Delayed-Release Dosage Forms, diethyl phthalate, if present, in relation to the diclofenac
Method B to determine the amount of C 14H10Cl2NNaO2 sodium in the portion of T ablets taken:
dissolved.
Acid stage Result = (r U/rS) × (C S/CU) × 100
Medium: 0.1 N hydrochloric acid; 900 mL
Apparatus 2: 50 rpm, paddles constructed of (or coated rU = peak response for each impurity from the Sample
with) polytef being used solution
Time: 2 h rS = peak response for each impurity from the
Detector: UV maxima at about 276 nm Standard solution
Standard solution: Transfer 68 mg of USP Diclofenac CS = concentration of USP Diclofenac Related
Sodium RS to a 100-mL volumetric flask, add 10.0 mL of Compound A RS in the Standard solution
0.1 N sodium hydroxide, and dilute with water to volume. (mg/mL)
Transfer 2.0 mL of this solution to a second 100-mL

Official from May 1, 2012

Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 128.83.63.20 by nEwp0rt1 on Wed Nov 23 22:23:09 EST 2011

USP 35 Official Monographs / Diclofenac 2883

CU = nominal concentration of diclofenac sodium in Mode: LC

the Sample solution (mg/mL) Detector: UV 254 nm
Acceptance criteria Column: 4.6-mm × 25-cm; packing L7
Individual impurities: NMT 0.5% of diclofenac related Flow rate: 1 mL/min
compound A; NMT 1.0% of any other individual Injection size: 10 µL
impurity System suitability
Total impurities: NMT 1.5% Samples: Standard solution and Resolution solution
[NOTE—The relative retention times for diethyl phthalate,
ADDITIONAL REQUIREMENTS diclofenac related compound A, and diclofenac are 0.5,
• PACKAGING AND STORAGE: Preserve in tight, light-resistant 0.6, and 1.0, respectively.]
containers. Suitability requirements
• USP REFERENCE STANDARDS 〈11〉 Resolution: NLT 2.2 between the diethyl phthalate and
USP Diclofenac Sodium RS diclofenac related compound A peaks, and NL T 3.8 be-
USP Diclofenac Related Compound A RS tween the diclofenac related compound A and diclofenac
N-(2,6-Dichlorophenyl)indolin-2-one. peaks, Resolution solution
C14H9Cl2NO 278.14 Relative standard deviation: NMT 2.0% for diclofenac,
Standard solution
Analysis
Samples: Standard solution and Sample solution
Calculate the per centage of C 14H10Cl2NNaO2 in the portion
.

Diclofenac Sodium Extended-Release of Tablets taken:

Tablets
Result = (r U/rS) × (C S/CU) × 100
DEFINITION
Diclofenac Sodium Extended-Release T ablets contain NLT 90.0% rU = peak response of diclofenac from the Sample
and NMT 110.0% of the labeled amount of diclofenac so- solution
dium (C 14H10Cl2NNaO2). rS = peak response of diclofenac from the Standard
solution
IDENTIFICATION CS = concentration of USP Diclofenac Sodium RS in
• A. The retention time of the Sample solution corresponds to the Standard solution (mg/mL)
that of the Standard solution, as obtained in the Assay. CU = nominal concentration of diclofenac sodium in
• B. THIN-LAYER CHROMATOGRAPHIC IDENTIFICATION TEST 〈201〉 the Sample solution (mg/mL)
Standard solution: 2.0 mg/mL of USP Diclofenac Sodium Acceptance criteria: 90.0%–110.0%
RS in methanol. [ NOTE—Shake by mechanical means for 10
min before makeup to final volume.] PERFORMANCE TESTS
Sample solution: Equivalent to 2.0 mg/mL of diclofenac so- • DISSOLUTION 〈711〉
dium from a portion of the powder (NL T 10 Tablets) in Test 1
methanol. [NOTE—Sonicate for 10 min, and shake by me- Medium: 0.05 M phosphate buffer, pH 7.5; 900 mL
chanical means for 10 min before makeup to final volume. Apparatus 2: 50 rpm; use wire sinkers.
Centrifuge this solution, and use the clear supernatant.] Times: 1, 5, 10, 16, and 24 h
Developing solvent system: Methanol, toluene, and glacial Detector: UV 276 nm
acetic acid (8:12:0.1) Standard solution: USP Diclofenac Sodium RS in Medium
Analysis: Pass portions of the solution under test through a
ASSAY suitable filter. Dilute with Medium, if necessar y, to a
• PROCEDURE concentration similar to that of the Standard solution.
[NOTE—Protect the Standard solution, System suitability solu- Tolerances: The per centages of the labeled amount of
tion, and Sample solution from light.] C14H10Cl2NNaO2 dissolved at the times specified conform to
Diluent: Methanol and water (7:3) Acceptance Table 2.
Buffer: 0.01 M phosphoric acid and 0.01 M monobasic so-
dium phosphate. Adjust with appropriate component to a Time
pH of 2.5. Amount Dissolved
(h)
Mobile phase: Methanol and Buffer (7:3) 1 15%–35%
Standard solution: 0.5 mg/mL of USP Diclofenac Sodium 5 45%–65%
RS in Diluent
Resolution solution: 20 µg/mL of diethyl phthalate, 7.5 10 65%–85%
µg/mL of USP Diclofenac Related Compound A RS, and 0.75 16 75%–95%
mg/mL of USP Diclofenac Sodium RS in Diluent 24 NLT 80%
Sample solution: Powder NLT 20 Tablets, and transfer a
weighed portion of the powder, equivalent to 100 mg of Test 2: If the product complies with this test, the labeling
diclofenac sodium, to a 200-mL volumetric flask, and add indicates that it meets USP Dissolution Test 2.
150 mL of Diluent. Heat on a steam bath for 3–5 min, and Medium, Apparatus, and Analysis: Proceed as directed for
sonicate for 20 min. Cool to room temperature, and dilute Dissolution Test 1.
with Diluent to volume. Place the flask in an ice bath for 45 Times: 1, 2, 4, 6, and 10 h
min, shaking occasionally to precipitate out any undissolved Tolerances: The per centages of the labeled amount of
waxy material. Pass a portion of the chilled solution through C14H10Cl2NNaO2 dissolved at the times specified conform to
a filter of 0.45- µm or finer pore size. Allow the filtrate to Acceptance Table 2.
reach room temperature before using.
Chromatographic system Time
(See Chromatography 〈621〉, System Suitability.) Amount Dissolved
(h)
1 NMT 28%
2 20%–40%
4 35%–60%
6 50%–80%
10 NLT 65%

Official from May 1, 2012

Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.