Candesartan Cilexetil Tablets Type of Posting Revision Bulletin Posting Date 18–Nov–2016 Official Date 01–Dec–2016 Expert Committee Chemical Medicines Monographs 2 Reason for Revision Compliance In accordance with the Rules and Procedures of the 2015-2020 Council of Experts, the Chemical Medicines Monographs 2 Expert Committee has revised the Candesartan Cilexetil Tablets monograph. The purpose of this revision is to widen the total impurities limit from NMT 3.0% to NMT 4.0% in accordance with the FDA-approved drug products. Minor editorial changes have been made to update the monograph to the current USP style. The Candesartan Cilexetil Tablets Revision Bulletin supersedes the currently official Candesartan Cilexetil Tablets monograph. The Revision Bulletin will be incorporated in the Second supplement to USP 40–NF 35. Should you have any questions, please contact Sujatha Ramakrishna, Ph.D., MBA. Senior Scientific Liaison (301–816–8349 or sxr@usp.org).

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Revision BulletinOfficial December 1, 2016 Candesartan 1

. rU = peak response from the Sample solutionrS = peak response from the Standard solutionCandesartan Cilexetil Tablets CS = concentration of USP Candesartan Cilexetil RS

in the Standard solution (mg/mL)DEFINITION CU = nominal concentration of candesartan cilexetilCandesartan Cilexetil Tablets contain NLT 90.0% and NMT in the Sample solution (mg/mL)110.0% of the labeled amount of candesartan cilexetil Acceptance criteria: 90.0%–110.0%(C33H34N6O6).PERFORMANCE TESTSIDENTIFICATION • DISSOLUTION ⟨711⟩• A. The retention time of the major peak of the Sample Medium for Tablets labeled to contain 4 mg, 8 mg,solution corresponds to that of the Standard solution, as and 16 mg: 0.35% polysorbate 20 in 0.05 M phos-obtained in the Assay. phate buffer, pH 6.5; 900 mL• B. The UV absorption spectra of the major peak of the Medium for Tablets labeled to contain 32 mg:Sample solution exhibit maxima and minima at the same 0.70% polysorbate 20 in 0.05 M phosphate buffer, pHwavelengths as those of the corresponding peak from 6.5; 900 mLthe Standard solution, as obtained in the Assay. Apparatus 2: 50 rpm

Time: 45 minASSAYMobile phase: Acetonitrile, trifluoroacetic acid, and• PROCEDUREwater (550:1:450)Mobile phase: Acetonitrile, trifluoroacetic acid, and

Standard stock solution: 0.45 mg/mL of USPwater (550:1:450)Candesartan Cilexetil RS in acetonitrile. Sonication mayDiluent: Acetonitrile and water (70:30)be necessary for complete dissolution.Standard solution: 0.8 mg/mL of USP Candesartan

Standard solution: Prepare solutions in Medium fromCilexetil RS in Diluent. Sonication may be necessary forStandard stock solution (see Table 2 for concentrations).complete dissolution. Pass through a suitable filter of

0.45-µm pore size.Sample solution: Nominally 0.8 mg/mL of candesartan Table 2cilexetil in Diluent prepared as follows. Transfer a num- Tablet Strength Concentrationber of Tablets (see Table 1) to a suitable volumetric (mg) (mg/mL)flask.

4 0.00458 0.009

Table 116 0.018

Number of 32 0.036Tablet Strength Tablets

(mg) (NLT) Sample solution: Pass a portion of solution under test4 10 through a suitable filter of 0.45-µm pore size.

Chromatographic system8 10(See Chromatography ⟨621⟩, System Suitability.)16 5Mode: LC

32 5 Detector: UV 254 nmColumn: 4.6-mm × 15-cm; 5-µm packing L7Add Diluent to fill about 70% of the total volume, andColumn temperature: 30°sonicate for about 25 min with intermittent shaking.Flow rate: 1.5 mL/minAllow to cool and dilute with Diluent to volume. PassInjection volume: 50 µLthrough a suitable filter of 0.45-µm pore size.Run time: NLT 1.8 times the retention time ofChromatographic systemcandesartan cilexetil(See Chromatography ⟨621⟩, System Suitability.)

System suitabilityMode: LCSample: Standard solutionDetectorsSuitability requirementsAssay: UV 282 nmTailing factor: NMT 2.0Identification test B: Diode arrayRelative standard deviation: NMT 2.0%Column: 4.6-mm × 15-cm; 5-µm packing L7

AnalysisColumn temperature: 30°Samples: Standard solution and Sample solutionFlow rate: 1.5 mL/minCalculate the percentage of the labeled amount ofInjection volume: 10 µLcandesartan cilexetil (C33H34N6O6) dissolved:Run time: NLT 2.7 times the retention time of

candesartan cilexetil Result = (rU/rS) × CS × V × (1/L) × 100System suitabilitySample: Standard solution rU = peak response from the Sample solutionSuitability requirements rS = peak response from the Standard solutionTailing factor: NMT 2.0 CS = concentration of the Standard solutionRelative standard deviation: NMT 2.0% (mg/mL)Analysis V = volume of medium, 900 mLSamples: Standard solution and Sample solution L = label claim (mg/Tablet)Calculate the percentage of the labeled amount of Tolerances: NLT 80% (Q) of the labeled amount ofcandesartan cilexetil (C33H34N6O6) in the portion of candesartan cilexetil (C33H34N6O6) is dissolved.Tablets taken: • UNIFORMITY OF DOSAGE UNITS ⟨905⟩: Meet the

requirementsResult = (rU/rS) × (CS/CU) × 100

2016 The United States Pharmacopeial Convention All Rights Reserved.

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Revision Bulletin2 Candesartan Official December 1, 2016

IMPURITIES Relative standard deviation: NMT 10.0% forcandesartan cilexetil peak, Standard solution

AnalysisChange to read: Samples: Standard solution and Sample solutionCalculate the percentage of each impurity in the por-

• ORGANIC IMPURITIES tion of Tablets taken:Solution A: Acetonitrile, trifluoroacetic acid, and water(10: 0.1: 90) Result = (rU/rS) × (CS/CU) × (1/F) × 100

Solution B: Acetonitrile, trifluoroacetic acid, and water(90: 0.1: 10) rU = peak response of each impurity from the

Mobile phase: See Table 3. Sample solutionrS = peak response of candesartan cilexetil from

the Standard solutionTable 3CS = concentration of USP Candesartan Cilexetil RS

Time Solution A Solution B in the Standard solution (mg/mL)(min) (%) (%) CU = nominal concentration of candesartan cilexetil

0 65 35 in the Sample solution (mg/mL)F = relative response factor of each impurity (see30 5 95

Table 4)45 5 95Acceptance criteria: See Table 4.50 65 35

55 65 35Table 4

System suitability stock solution A: 0.05 mg/mL each Relative Accep-of USP Candesartan Cilexetil Related Compound A RS, Reten- Relative tanceUSP Candesartan Cilexetil Related Compound B RS, tion Response Criteria,USP Candesartan Cilexetil Related Compound D RS, Name Time Factor NMT (%)and USP Candesartan Cilexetil Related Compound F RSCandesartan cilexetilin acetonitrilerelated compound Ga

. 0.17 1.30 1.0System suitability stock solution B: 0.1 mg/mL of USPCandesartanCandesartan Cilexetil RS in acetonitrilecilexetil related —System suitability stock solution C: 0.5 mg/mL ofcompound Ab

.

,.

c. 0.46 1.16USP Candesartan Cilexetil Related Compound G RS in

Candesartan cilexetilmethanolrelated compound Bd

. 0.77 1.00 1.5System suitability solution: 0.0015 mg/mL each ofUSP Candesartan Cilexetil Related Compound A RS, Candesartan cilexetil 1.0 — —USP Candesartan Cilexetil Related Compound B RS, Candesartan cilexetilUSP Candesartan Cilexetil Related Compound D RS, related compound De

. 1.15 1.00 0.5and USP Candesartan Cilexetil Related Compound F Candesartan cilexetilRS, 0.001 mg/mL of USP Candesartan Cilexetil RS, related compound Ff

. 1.47 0.88 1.50.005 mg/mL of USP Candesartan Cilexetil RelatedAny unspecifiedCompound G RS from System suitability stock solution —impurity 1.00 0.2A, System suitability stock solution B, and System suitabil- •

.4.0• (RB 1-ity stock solution C in acetonitrile — —Total impurities Dec-2016)Standard solution: 0.001 mg/mL of USP Candesartana

.1-{[2’-(1H-Tetrazol-5-yl)biphenyl-4-yl]methyl}-2-ethoxybenzimidazole-7-Cilexetil RS in acetonitrile from System suitability stockcarboxylic acid.solution Bb

.Ethyl 1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-2-ethox-Sample solution: Nominally 1 mg/mL of candesartan ybenzimidazole-7-carboxylate.cilexetil in acetonitrile prepared as follows. Transfer a c

.Process-related impurity not included in total impurities.suitable quantity of candesartan cilexetil from NLT d

.1-(Cyclohexyloxycarbonyloxy)ethyl 1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-20 powdered Tablets into a suitable volumetric flask. yl]methyl}-2-hydroxybenzimidazole-7-carboxylate.Add acetonitrile to fill 60% of the total volume and e

.1-{[(Cyclohexyloxy)carbonyl]oxy}ethyl 3-({2’-(2-ethyl-1H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl}methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxyl-sonicate for 15 min with intermittent shaking in coldate.water. Dilute with acetonitrile to volume and passf

.1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-{[2’-(2-ethyltetrazol-5-through a suitable filter of 0.45-µm pore size.yl)biphenyl-4-yl]methyl}benzimidazole-7-carboxylate. Chromatographic system

(See Chromatography ⟨621⟩, System Suitability.) ADDITIONAL REQUIREMENTSMode: LC • PACKAGING AND STORAGE: Preserve in tight, light-resistantDetector: UV 254 nm containers. Store at controlled room temperature.Column: 4.6-mm × 10-cm; 3.5-µm packing L1 • USP REFERENCE STANDARDS ⟨11⟩Sample cooler temperature: 10° USP Candesartan Cilexetil RSFlow rate: 1 mL/min USP Candesartan Cilexetil Related Compound A RSInjection volume: 10 µL Ethyl 1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-

System suitability 2-ethoxybenzimidazole-7-carboxylate.Samples: System suitability solution and Standard C26H24N6O3 468.51solution USP Candesartan Cilexetil Related Compound B RS

Suitability requirements 1-(Cyclohexyloxycarbonyloxy)ethyl 1-{[2’-(1H-tetrazol-Resolution: NLT 5.0 between candesartan cilexetil 5-yl)biphenyl-4-yl]methyl}-2-hydroxybenzimidazole-related compound B and candesartan cilexetil, Sys- 7-carboxylate.tem suitability solution C31H30N6O6 582.61

Tailing factor: NMT 2.0 for candesartan cilexetilpeak, Standard solution

2016 The United States Pharmacopeial Convention All Rights Reserved.

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Revision BulletinOfficial December 1, 2016 Candesartan 3

USP Candesartan Cilexetil Related Compound D RS C35H38N6O6 638.711-{[(Cyclohexyloxycarbonyloxy)carbonyl]oxy}ethyl 3-{ USP Candesartan Cilexetil Related Compound G RS[2’-(2-ethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl}- 1-{[2’-(1H-Tetrazol-5-yl)biphenyl-4-yl]methyl}-2-ethox-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate. ybenzimidazole-7-carboxylic acid.

C33H34N6O6 610.67 C24H20N6O3 440.45USP Candesartan Cilexetil Related Compound F RS1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-{[2’-(2-ethyltetrazol-5-yl)biphenyl-4-yl]methyl}benzimidazole-7-carboxylate.

2016 The United States Pharmacopeial Convention All Rights Reserved.

C181881_M12275-CHM22015, Rev. 0 20161118