Carvedilol

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

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

DOWNLOAD PDF HERE

C₂₄H₂₆N₂O₄ 406.47

2-Propanol, 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl)amino]-, (±)-;

(+)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)eth yl)amino]-2-propanol

CAS RN: 72956-09-3; UNII: 0K47UL67F2.

1 DEFINITION

Carvedilol contains NLT 98.0% and NMT 102.0% of C₂₄H₂₆N₂O₄ calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 PROCEDURE

Buffer: 2.72 g/L of monobasic potassium phosphate. Adjust with dilute phosphoric acid to a pH of 2.0.

Mobile phase: Acetonitrile and Buffer (31:69)

System suitability solution: 0.05 mg/mL each of USP Carvedilol RS and USP Carvedilol Related Compound A RS in Mobile phase

Standard solution: 0.04 mg/mL of USP Carvedilol RS in Mobile phase

Sample solution: 0.04 mg/mL of Carvedilol in Mobile phase

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm x 15-cm; 5-µm packing L7

Column temperature: 55°

Flow rate: 1 mL/min

Run time: 60 min

Injection size: 10 µL

3.3 System suitability

Sample: System suitability solution

3.4 Suitability requirements

Resolution: NLT 4.0 between carvedilol and carvedilol related compound A

Tailing factor: NMT 1.5 for the carvedilol peak

Relative standard deviation: NMT 2%

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of carvedilol (C₂₄H₂₆N₂O₄) in the portion of the sample taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of carvedilol from the Sample solution

r_S = peak response of carvedilol from the Standard solution s

C_S = concentration of carvedilol in the Standard solution (mg/mL)

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

Acceptance criteria: 98.0%-102.0% on the dried basis

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.1% from 1 g

ORGANIC IMPURITIES, PROCEDURE 1: [NOTE-On the basis of the impurities present, perform either Organic Impurities, Procedure 1 or Organic Impurities, Procedure 2. Organic Impurities, Procedure 2 is recommended when carvedilol related compound F is a potential impurity.]

Buffer and Mobile phase: Prepare as directed in the Assay.

System suitability solution: 0.05 mg/mL each of USP Carvedilol RS and USP Carvedilol Related Compound C RS in Mobile phase

Standard solution: 1 µg/mL each of USP Carvedilol RS, USP Carvedilol Related Compound A RS, USP Carvedilol Related Compound B RS, USP Carvedilol Related Compound D RS, and USP Carvedilol Related Compound E RS, and 0.2 µg/mL of USP Carvedilol Related Compound C RS in Mobile phase

Sample solution: 1 mg/mL of Carvedilol in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Dual wavelength, UV 220 and 240 nm. Use 220 nm for quantitating carvedilol related compound E, and use 240 nm for carvedilol and all other related compounds.

Column: 4.6-mm x 15-cm; 5-µm packing L7

Column temperature: 55°

Flow rate: 1 mL/min

Injection size: 20 µL

System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 17 between carvedilol and carvedilol related compound C

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of carvedilol related compound A, carvedilol related compound B, carvedilol related compound C, carvedilol related compound D, carvedilol related compound E, and any other individual impurity in the portion of Carvedilol taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of the corresponding related compound or any other impurity from the Sample solution

r_S = peak response of the corresponding related compound from the Standard solution. To calculate the percentage of any other individual impurity use the peak response of carvedilol.

C_S = concentration of the corresponding related compound in the Standard solution (mg/mL). To calculate the percentage of any other impurities for C use the concentration of USP Carvedilol RS.

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

Acceptance criteria: See Table 1.

Table 1

^a 2-(2-Methoxyphenoxy) ethyl amine.

^b 1-(4-(2-Hydroxy-3-(2-(2-methoxyphenoxy) ethylamino) propoxy)-9H-carbazol-9-yl)-3-(2-(2-methoxyphenoxy) ethylamino) propan-2-ol.

^c 3,3'-(2,2'-[1,2-Phenylenebis(oxy)]bis(ethane-2,1-diyl)}bis(azanediyl)bis(1-(9H-carbazol-4-yloxy)propan-2-ol).

d 1-(9H-Carbazol-4-yloxy)-3-(benzyl (2-(2-methoxyphenoxy)ethyl) amino)propan-2-ol.

^e 4-(Oxiran-2-ylmethoxy)-9H-carbazole.

^f 3,3'-(2-(2-Methoxyphenoxy)ethylazanediyl)bis(1-(9H-carbazol-4-yl oxy)propan-2-ol).

^g Disregard any impurity less than 0.01%.

Change to read:

ORGANIC IMPURITIES, PROCEDURE 2

Solution A: Acetonitrile and trifluoroacetic acid (100:0.1)

Solution B: Trifluoroacetic acid and water (0.1:100)

Diluent: Acetonitrile, trifluoroacetic acid, and water (22:0.1:78)

Mobile phase: See Table 2.

System suitability solution: 1.0 mg/mL of USP Carvedilol System Suitability Mixture RS in Diluent

Sample solution: 1 mg/mL of Carvedilol in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm × 15-cm; 5-μm packing L68

Column temperature: 30°

Flow rate: 1.4 mL/min

Injection size: 20 μL

System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 1.8 between carvedilol and carvedilol related compound F

Analysis

Sample: Sample solution

Calculate the percentage of each impurity in the portion of Carvedilol taken:

Result = (r_U/r_T) × 100

r_U = peak response for each impurity in the Sample solution

r_T = sum of all the peak responses in the Sample solution

Acceptance criteria: See Table 3.

^a 1-(4-(2-Hydroxy-3-(2-(2-methoxyphenoxy) ethylamino)propoxy)-9Hcarbazol-9-yl)-3-(2-(2-methoxyphenoxy) ethylamino) propan-2-ol.

^b 1-(2-(2-Methoxyphenoxy) ethylamino)-3-(2,3,4,9-tetrahydro-1H-carbazol-5-yloxy)propan-2-ol. (ERR 1-Jan-2021)

^c This impurity is quantitated using the procedure under Organic Impurities, Procedure 3: Carvedilol Related Compound F.

^d 1-(H-Carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy) ethyl]N-isopropylamino]-2-propanol.

^e 1-(9H-Carbazol-4-yloxy)-3-(benzyl (2-(2-methoxyphenoxy)ethyl)amino) propan-2-ol.

^f 3,3'-(2-(2-Methoxyphenoxy) ethylazanediyl)bis(1-(9H-carbazol-4-yloxy)propan-2-ol).

^g 1,3-Bis-(9H-carbazol-4-yloxy)-2-propanol.

ORGANIC IMPURITIES, PROCEDURE 3: CARVEDILOL RELATED COMPOUND F (if present)

Solution A: Trifluoroacetic acid and water (0.5:100)

Solution B: Methanol and trifluoroacetic acid (100:0.5)

Diluent: Water and acetonitrile (1:1)

Mobile phase: Solution A and Solution B (65:35)

System suitability solution: 1.5 mg/mL of USP Carvedilol System Suitability Mixture RS in Diluent

Sample solution: 1.5 mg/mL of Carvedilol in Diluent prepared as follows. Initially add Diluent to fill about 80% of the total volume. Sonicate briefly to facilitate dissolution. Cool, and dilute with Diluent to volume.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 226 nm

Column: 4.6-mm x 30-mm; 3-µm packing L7

Column temperature: 40°

Flow rate: 2 mL/min

Injection size: 10 µL

System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 2.0 between carvedilol and carvedilol related compound F

Analysis

Sample: Sample solution

Calculate the percentage of carvedilol related compound F in the portion of the sample taken:

Result = (r_U/r_T) x (1/F) x 100

r_U = peak response of carvedilol related compound F from the Sample solution

r_T = sum of the peak responses of carvedilol and carvedilol related compound F from the Sample solution

F = relative response factor, 1.1

Acceptance criteria: NMT 0.1%

5 SPECIFIC TESTS

LOSS ON DRYING (731): Dry a sample at 105" for 3 h: it loses NMT 0.5% of its weight.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers, and store at controlled room temperature.

LABELING: If a test for Organic Impurities by HPLC other than Procedure 1 is used, then the labeling states the test with which the article complies.

Change to read:

USP REFERENCE STANDARDS (11)

USP Carvedilol RS

USP Carvedilol Related Compound A RS

1-(4-(2-Hydroxy-3-(2-(2-methoxy phenoxy)ethylamino)propoxy)-9H-carbazol-9-yl)-3-(2-(2-methoxyphenoxy) ethylamino) propan-2-ol.

C₃₆H₄₃N3O₇ 629.75 (ERR 1-Jan-2021)

USP Carvedilol Related Compound B RS

3,3'-(2-(2-Methoxyphenoxy) ethylazanediyl)bis(1-(9H-carbazol-4-yloxy)propan-2-ol).

C₃₉H₃₉N₃O₆  645.76 (ERR 1-Jan-2021)

USP Carvedilol Related Compound CRS

1-(9H-Carbazol-4-yloxy)-3-(benzyl (2-(2-methoxyphen oxy)ethyl)amino)propan-2-ol.

C₃₁H₃₂N₂O₄ 496.61 (ERR 1-Jan-2021)

USP Carvedilol Related Compound D. RS

4-(Oxiran-2-ylmethoxy)-9H-carbazole.

C₁₅H₁₃NO₂ 239.27

USP Carvedilol Related Compound E RS

[NOTE-This material may be available in the free base or salt form. (ERR 1-2021)

2-(2-Methoxyphenoxy) ethyl amine.

C₉H₁₃NO₂ 167.21

2-(2-Methoxyphenoxy) ethyl amine hydrochloride monohydrate.

C₉H₁₃N₂O₂ . H₂O 221.68 (ERR 1-Jan-2021)

USP Carvedilol System Suitability Mixture RS

Contains a mixture of carvedilol related compound F in a matrix of carvedilol drug substance:

Carvedilol.

Carvedilol related compound F.

[NOTE-This material may be available in the free base or salt form.]

1-(2-(2-Methoxyphenoxy)ethylamino)-3-(2,3,4,9-tetrahydro-1H-carbazol-5-yloxy)propan-2-ol.

C₂₄H₃₀N₂O₄ 410.51

1-(2-(2-Methoxyphenoxy) ethylamino)-3-(2,3,4,9-tetrahydro-1H-carbazol-5-yloxy)propan-2-ol acetate.

C₂₄H₃₀N₂O₄ . C₂H₄O₂ 470.57 (ERR 1-Jan-2021)