Candesartan Cilexetil

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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C₃₃H₃₄N₆O₆ 610.67 (USP 1-Dec-2022)

1H-Benzimidazole-7-carboxylic acid, 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-, 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester, (±);

(±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester);

1-Cyclohexyloxycarbonyloxyethyl 2-ethoxy-1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}benzimidazole-7-carboxylate (USP 1-Dec-2022) CAS

RN®: 145040-37-5; UNII: R85M2X0D68.

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1 DEFINITION

Candesartan cilexetil contains NLT 98.0% (USP 1-Dec-2022) and NMT 102.0% (USP 1-Dec-2022) of candesartan cilexetil (C₃₃H₃₄N₆O₆), calculated on anhydrous basis.

2 IDENTIFICATION

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A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or (USP 1-Dec-2022) 197K. If the spectra obtained show differences, proceed with the samples prepared as follows. Separately dissolve a quantity of USP Candesartan Cilexetil RS and Candesartan Cilexetil in alcohol. [Note—Heating the solution may be necessary for complete dissolution.] Cool the solution in an ice bath, filter the crystals, and dry at 105°.

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B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. (USP 1-Dec-2022)

3 ASSAY

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Procedure

Solution A: Acetonitrile and water (57:43). To each liter, add 10 mL of glacial acetic acid.

Solution B: Acetonitrile and water (90:10). To each liter, add 10 mL of glacial acetic acid.

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and water (60:40)

Standard solution: 0.04 mg/mL of USP Candesartan Cilexetil RS in Diluent. Sonicate as necessary.

Sample solution: 0.04 mg/mL of Candesartan Cilexetil in Diluent. Sonicate as necessary.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 3.9-mm × 15-cm; 4-μm packing L1

Flow rate: 0.8 mL/min

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of candesartan cilexetil (C₃₃H₃₄N₆O₆) in the portion of Candesartan Cilexetil taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of candesartan cilexetil from the Sample solution

r_S = peak response of candesartan cilexetil from the Standard solution

C_S = concentration of USP Candesartan Cilexetil RS in the Standard solution (mg/mL)

C_U = concentration of Candesartan Cilexetil in the Sample solution (mg/mL) (USP 1-Dec-2022)

Acceptance criteria: 98.0%–102.0% (USP 1-Dec-2022) on the anhydrous basis

4 IMPURITIES

Residue on Ignition 〈281〉

Sample: 1 g

Acceptance criteria: NMT 0.1%

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Organic Impurities

Solution A, Solution B, Mobile phase, Diluent, and Chromatographic system: Proceed as directed in the Assay. (USP 1-Dec-2022)

System suitability solution: 0.4 mg/mL of USP Candesartan Cilexetil RS, and 0.4 μg/mL each of USP Candesartan Cilexetil Related

Compound A RS, USP Candesartan Cilexetil Related Compound B RS, USP Candesartan Cilexetil Related Compound D RS, USP Candesartan

Cilexetil Related Compound F RS, and USP Candesartan Cilexetil Related Compound G RS in Diluent (USP 1-Dec-2022)

Standard solution: 0.4 μg/mL (USP 1-Dec-2022) of USP Candesartan Cilexetil RS in Diluent

Sensitivity solution: 0.2 μg/mL of USP Candesartan Cilexetil RS in Diluent, from Standard solution (USP 1-Dec-2022)

Sample solution: 0.4 mg/mL of Candesartan Cilexetil in Diluent (USP 1-Dec-2022)

System suitability

(USP 1-Dec-2022)

Samples: System suitability solution, Standard solution, and Sensitivity solution

[Note—See Table 2 for the relative retention times.] (USP 1-Dec-2022)

Suitability requirements

Resolution: NLT 4.0 between candesartan cilexetil related compound A and candesartan cilexetil related compound B; NLT 2.0 between

candesartan cilexetil and candesartan cilexetil related compound D, System suitability solution (USP 1-Dec-2022)

Tailing factor: NMT 1.5 for candesartan cilexetil, Standard solution (USP 1-Dec-2022)

Relative standard deviation: NMT 5.0% (USP 1-Dec-2022) for candesartan cilexetil, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution (USP 1-Dec-2022)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any specified and unspecified (USP 1-Dec-2022) impurity in the portion of Candesartan Cilexetil taken:

Result = (r_U/r_S) x (C_S/C_U) × (1/F) _{(USP 1-Dec-2022)} × 100

r_U = peak response of any specified or unspecified (USP 1-Dec-2022) impurity from the Sample solution

r_S = peak response of candesartan cilexetil from the Standard solution

C_S = concentration of USP Candesartan Cilexetil RS in the Standard solution (mg/mL)

C_U = concentration of Candesartan Cilexetil in the Sample solution (mg/mL)

F = relative response factor (see Table 2) (USP 1-Dec-2022)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%. (USP 1-Dec-2022)

Table 2

^a 1-Cyclohexyloxycarbonyloxyethyl 2-ethoxy-1-{[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}benzimidazole-7-carboxylate.

5 SPECIFIC TESTS

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Water Determination 〈921〉, Method I, Method Ia (USP 1-Dec-2022) : NMT 0.3%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.

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USP Reference Standards 〈11〉

USP Candesartan Cilexetil RS

USP Candesartan Cilexetil Related Compound A RS

Ethyl 2-ethoxy-1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}benzimidazole-7-carboxylate;

Also known as (Ethyl 1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-2-ethoxybenzimidazole-7-carboxylate).

C₂₆H₂₄N₆O₃ 468.52

USP Candesartan Cilexetil Related Compound B RS

1-Cyclohexyloxycarbonyloxyethyl 1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-2-oxo-2,3-dihydrobenzimidazole-7-carboxylate;

Also known as (1-{[(Cyclohexyloxy)carbonyl]oxy}ethyl 3-({2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl}methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate).

C₃₁H₃₀N₆O₆ 582.62

USP Candesartan Cilexetil Related Compound D RS

1-{[(Cyclohexyloxy)carbonyl]oxy}ethyl 1-{[2’-(2-ethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl}-2-oxo-2,3-dihydrobenzimidazole-7-carboxylate;

Also known as 1-{[(Cyclohexyloxy)carbonyl]oxy}ethyl 3-({2'-(2-ethyl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl}methyl)-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate).

C₃₃H₃₄N₆O₆ 610.67

USP Candesartan Cilexetil Related Compound F RS

1-Cyclohexyloxycarbonyloxyethyl 2-ethoxy-1-{[2’-(2-ethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl}benzimidazole-7-carboxylate;

Also known as (1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-{[2'-(2-ethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate).

C₃₅H₃₈N₆O₆ 638.73

USP Candesartan Cilexetil Related Compound G RS

2-Ethoxy-1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}benzimidazole-7-carboxylic acid;

Also known as 1-{[2’-(1H-Tetrazol-5-yl)biphenyl-4-yl]methyl}-2-ethoxybenzimidazole-7-carboxylic acid.

C₂₄H₂₀N₆O₃ 440.46 (USP 1-Dec-2022)