Candesartan Cilexetil and Hydrochlorothiazide Tablets

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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1 DEFINITION

Candesartan cilexetil and Hydrochlorothiazide Tablets contain NLT 90.0% and NMT 110.0% each of the labeled amount of candesartan cilexetil. (C₃₃H₃₄N₆O₆) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂).

2 IDENTIFICATION

A. The retention times of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay. 

B. The UV absorption spectra of the major peaks of the Sample solution exhibit maxima and minima at the same wavelengths as those of the Standard solution, as obtained in the Assay.

3 ASSAY

Change to read:

Procedure

Solution A: Acetonitrile and water (10:90). To each liter, add 1.0 mL of trifluoroacetic acid. (USP 1-Aug-2024)

Solution B: Acetonitrile and water (90:10). To each liter, add 1.0 mL of trifluoroacetic acid. (USP 1-Aug-2024)

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and water (70:30)

Standard solution: Prepare solutions of USP Candesartan Cilexetil RS and USP Hydrochlorothiazide RS in Diluent as follows, at concentrations as given in Table 2. Transfer suitable amounts of USP Candesartan Cilexetil RS and USP Hydrochlorothiazide RS to a suitable volumetric flask. Add Diluent to about 50% of the total volume and sonicate to dissolve. Dilute with Diluent to volume. (USP 1-Aug-2024)

Table 2

Sample solution: Nominally equivalent to the concentrations as given in Table 2. prepared as follows. Transfer NLT 5 Tablets to a suitable volumetric flask. Add Diluent to about 60% of the total volume and sonicate for about 25 min with intermittent shaking. Cool to room temperature and dilute with Diluent to volume. Pass through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 282 nm. For Identification B, use a diode array detector in the range of 210-400 nm. (USP 1-Aug-2024)

Column: 4.6-mm x 15-cm; 5-µm packing 17

Column temperature: 30°

Flow rate: 1 mL/min.

Injection volume: 10 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention times for hydrochlorothiazide and candesartan cilexetil are 0.4 and 1.0, respectively. (USP 1-Aug-2024)

Suitability requirements

Tailing factor: NMT 2.0 for candesartan cilexetil and hydrochlorothiazide

Relative standard deviation: NMT 1.0% (USP 1-Aug-2024) for candesartan cilexetil and hydrochlorothiazide

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of candesartan cilexetil (C₃₃H₃₄N₆O₆) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂) in the portion of Tablets taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of candesartan cilexetil or hydrochlorothiazide from the Sample solution

r_s = peak response of candesartan cilexetil or hydrochlorothiazide from the Standard solution

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

C_u = nominal concentration of candesartan cilexetil or hydrochlorothiazide in the Sample solution (mg/mL) lorothiazide in

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

DISSOLUTION (711)

Medium

For Tablets labeled to contain 16 mg/12.5 mg of candesartan cilexetil/hydrochlorothiazide: 0.35% polysorbate 20 in 0.05 M phosphate

buffer, pH 6.5 (dissolve 6.8 g of potassium phosphate, monobasic in a suitable container containing 500 mL of water; add 3.5 mL of polysorbate 20 and dilute with water to 1 L; adjust with 2 N sodium hydroxide solution to a pH of 6.5); (USP 1-Aug-2024) 900 mL

For Tablets labeled to contain 32 mg/12.5 mg and 32 mg/25 mg of candesartan cilexetil/hydrochlorothiazide: 0.70% polysorbate 20 in 0.05 M phosphate buffer, pH 6.5 (dissolve 6.8 g of potassium phosphate, monobasic in a suitable container containing 500 mL. of water; add 7.0 mL of polysorbate 20 and dilute with water to 1 L; adjust with 2 N sodium hydroxide solution to a pH of 6.5); (USP 1-Aug-2024) 900 mL

Apparatus 2: 50 rpm

Time: 45 min

Solution A and Solution B: Prepare as directed in the Assay.

Mobile phase: See Table 3.

Table 3

Standard stock solution A: 0.72 mg/mL of USP Candesartan Cilexetil RS in acetonitrile. Sonicate to dissolve, if necessary. (USP 1-Aug-2024)

Standard stock solution B: 0.28 mg/mL of USP Hydrochlorothiazide RS in acetonitrile. Sonicate to dissolve, if necessary. (USP 1-Aug-2024)

Standard solution: Prepare solutions of USP Candesartan Cilexetil RS and USP Hydrochlorothiazide RS from Standard stock solution A and

Standard stock solution B in the appropriate Medium, at concentrations as given in Table 4.(USP 1-Aug-2024)

Table 4

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 264 nm

Column: 4.6-mm x 15-cm; 5-µm packing LZ

Autosampler temperature: 10°

Flow rate: 1 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for candesartan cilexetil and hydrochlorothiazide

Relative standard deviation: NMT 2.0% for candesartan cilexetil and hydrochlorothiazide

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of candesartan cilexetil (C₃₃H₃₄N₆O₆) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂) dissolved:

Result = (r_U/r_S) x C_S x V x (1/L) × 100

r_U = peak response of candesartan cilexetil or hydrochlorothiazide from the Sample solution

r_S = peak response of candesartan cilexetil or hydrochlorothiazide from the Standard solution s

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) the labeled amount of candesartan cilexetil (C₃₃H₃₄N₆O₆) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂₂) are dissolved

UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements

5 IMPURITIES

Change to read:

ORGANIC IMPURITIES

Solution A and Solution B: Prepare as directed in the Assay.

Mobile phase: See Table 5.

Table 5

Diluent A: Acetonitrile and water (70:30)

Diluent B: Acetonitrile and water (50:50)

Peak identification stock solution A: 0.05 mg/mL each of USP Candesartan Cilexetil Related Compound A RS, USP Candesartan Cilexetil Related Compound B.RS, USP Candesartan Cilexetil Related Compound D RS, and USP Candesartan Cilexetil Related Compound F RS in acetonitrile

Peak identification stock solution B: 0.1 mg/mL of USP Candesartan Cilexetil RS in acetonitrile

Peak identification stock solution C: 0.5 mg/mL of USP Candesartan Cilexetil Related Compound G RS in methanol

Peak identification solution: 0.0015 mg/mL each of USP Candesartan Cilexetil Related Compound A RS, USP Candesartan Cilexetil Related Compound B RS, USP Candesartan Cilexetil Related Compound D RS, and USP Candesartan Cilexetil Related Compound F.RS; 0.001 mg/mL of USP Candesartan Cilexetil RS; and 0.005 mg/mL of USP Candesartan Cilexetil Related Compound G RS from Peak identification stock solution A, Peak identification stock solution B, and Peak identification stock solution C in acetonitrile

System suitability stock solution: 0.05 mg/mL each of USP Benzothiadiazine Related Compound A RS and USP Hydrochlorothiazide RS, and 0.1 mg/mL of USP Chlorothiazide RS in Diluent B

System suitability solution: 2.5 µg/mL each of USP Benzothiadiazine Related Compound A RS and USP Hydrochlorothiazide RS and 5 µg/mL of USP Chlorothiazide RS in Diluent A, from System suitability stock solution (USP 1-Aug-2024)

Standard solution: 0.008 mg/mL of USP Candesartan Cilexetil RS and 0.003 mg/mL of USP Hydrochlorothiazide RS in Diluent A. Sonicate to dissolve, if necessary. (USP 1-Aug-2024)

Sample solution: Nominally 1.5 mg/mL of candesartan cilexetil in acetonitrile prepared as follows. Transfer about 75 mg of candesartan cilexetil, from finely powdered Tablets (NLT 20), to a 50-mL volumetric flask. Add 30 mL of Diluent A and sonicate for 20 min with intermittent shaking in cold water. Allow it to reach room temperature, dilute with Diluent A to volume, and pass through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 265 nm

Column: 4.6-mm x 25-cm; 5-µm packing LZ

Column temperature: 35°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

System suitability

Samples: Peak identification solution, (USP 1-Aug-2024) System suitability solution, and Standard solution

[NOTE-See Table 6 for the relative retention times.) (USP 1-AUG-2024)

Suitability requirements

Resolution: NLT 1.5 between benzothiadiazine related compound A and chlorothiazide; NLT 1.5 between chlorothiazide and hydrochlorothiazide, System suitability solution

Tailing factor: NMT 2.0 for candesartan cilexetil and hydrochlorothiazide, Standard solution

Relative standard deviation: NMT 5.0% (USP 1-Aug-2024) for candesartan cilexetil and hydrochlorothiazide, Standard solution

Signal-to-noise ratio: NLT 10 for candesartan cilexetil, Peak identification solution (USP 1-Aug-2024)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each specified degradation product (USP 1-Aug-2024) of candesartan cilexetil and any unspecified

degradation product (USP 1-Aug-2024) in the portion of Tablets taken:

Result = (r_u/r_s) × (C_s/C_u) × (1/F) × 100

r_u  = peak response of each specified degradation product of candesartan cilexetil or any unspecified degradation product (USP 1-Aug-2024) 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 = nominal concentration of candesartan cilexetil in the Sample solution (mg/mL)

F = relative response factor (see Table 6)

Calculate the percentage of benzothiadiazine related compound A and chlorothiazide in the portion of Tablets taken:

Result = (r_u/r_s) × (C_s/C_u)  × (1/F) × 100

r_u = peak response of benzothiadiazine related compound Aor (USP 1-Aug-2024) chlorothiazide from the Sample solution

r_s = peak response of hydrochlorothiazide from the Standard solution

C_s = concentration of USP Hydrochlorothiazide RS in the Standard solution (mg/mL)

C_u = nominal concentration of hydrochlorothiazide in the Sample solution (mg/mL)

F = relative response factor (see Table 6)

Acceptance criteria: See Table 6. The reporting threshold is 0.1% (USP 1-Aug-2024)

Table 6

^aProcess-related impurity is not included in total degradation products (USP 1-Aug-2024)

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers. Store at controlled room temperature.

Change to read:

USP REFERENCE STANDARDS (11)

USP Benzothiadiazine Related Compound A RS

4-Amino-6-chloro-1,3-benzenedisulfonamide. C₆H₈CIN₃O₄S₂ 285.73

USP Candesartan Cilexetil RS

USP Candesartan Cilexetil Related Compound A RS

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

C₂₆H₂₄N₆O₃ 468.51

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] oxyethyl 3-((2-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (USP 1-Aug-2024)

C₃₁H₃₀N₆O₆. 582.62 (USP 1-Aug-2024)

USP Candesartan Cilexetil Related Compound D RS

1-{[(Cyclohexyloxy) carbonyl]oxyethyl 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 (USP 1-Aug-2024)

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]methylbenzimidazole-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. (USP 1-Aug-2024)

C₃₅H₃₈N₆O₆ 638.73 (USP 1-Aug-2024)

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 (USP 1-Aug-2024) 1-[2-(1H-Tetrazol-5-yl)biphenyl-4-yl]methyl)-2-ethoxybenzimidazole-7-carboxylic acid.

C₂₄H₂₀N₆O₃ 440.46 (USP 1-Aug-2024)

USP Chlorothiazide RS

USP Hydrochlorothiazide RS