Carvedilol
C24H26N2O4 406.47
2-Propanol, 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-, (±)-;
(±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol
[72956-09-3].
(kar' ve dil'' ol).
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C24H26N2O4 406.47
2-Propanol, 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-, (±)-;
(±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol
[72956-09-3].DEFINITION
Carvedilol contains NLT 98.0% and NMT 102.0% of C24H26N2O4, calculated on the dried basis.
IDENTIFICATION
• B.
The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
• 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
Chromatographic system
Mode:
LC
Detector:
UV 240 nm
Column:
4.6-mm × 15-cm; 5-µm packing L7
Column temperature:
55
Flow rate:
1 mL/min
Run time:
60 min
Injection size:
10 µL
System suitability
Sample:
System suitability solution
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%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of carvedilol (C24H26N2O4) in the portion of the sample taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of carvedilol from the Sample solution |
| rS | = | = peak response of carvedilol from the Standard solution |
| CS | = | = concentration of carvedilol in the Standard solution (mg/mL) |
| CU | = | = concentration of Carvedilol in the Sample solution (mg/mL) |
Acceptance criteria:
98.0%–102.0% on the dried basis
IMPURITIES
• Residue on Ignition 
281
:
NMT 0.1% from 1 g
281:
NMT 0.1% from 1 g
• Heavy Metals, Method II 231:
NMT 10 ppm
231:
NMT 10 ppm
• 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
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 × 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 = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of the corresponding related compound or any other impurity from the Sample solution |
| rS | = | = 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. |
| CS | = | = concentration of the corresponding related compound in the Standard solution (mg/mL). To calculate the percentage of any other impurities for CS, use the concentration of USP Carvedilol RS. |
| CU | = | = concentration of Carvedilol in the Sample solution (mg/mL) |
Acceptance criteria:
See Table 1.
Table 1
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|
|---|---|---|---|
| Carvedilol related compound Ea | 0.35 | 0.1 | |
| Carvedilol related compound Ab | 0.52 | 0.1 | |
| Carvedilol bisalkylpyrocatechol derivative (if present)c | 0.70 | 0.15 | |
| Carvedilol | 1.0 | — | |
| Carvedilol related compound Cd | 3.6 | 0.02 | |
| Carvedilol related compound De | 5.0 | 0.1 | |
| Carvedilol related compound Bf | 8.5 | 0.1 | |
| Any other individual impurity | — | 0.10 | |
| Total impurities | — | 0.5g | |
|
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-yloxy)propan-2-ol).
g
Disregard any impurity less than 0.01%.
|
|||
• 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.
Table 2
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 22 | 78 |
| 20 | 22 | 78 |
| 33 | 38 | 62 |
| 45 | 38 | 62 |
| 55 | 55 | 45 |
| 65 | 55 | 45 |
| 68 | 22 | 78 |
| 80 | 22 | 78 |
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
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 = (rU/rT) × 100
| rU | = | = peak response for each impurity in the Sample solution |
| rT | = | = sum of all the peak responses in the Sample solution |
Acceptance criteria:
See Table 3.
Table 3
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|
|---|---|---|---|
| Carvedilol related compound Aa | 0.7 | 0.1 | |
| Carvedilol | 1.0 | — | |
| Carvedilol related compound Fb | 1.2 | 0.1c | |
| N-Isopropylcarvedilold | 1.6 | 0.1 | |
| Carvedilol related compound Ce | 1.8 | 0.02 | |
| Carvedilol related compound Bf | 2.1 | 0.1 | |
| Biscarbazoleg | 3 | 0.1 | |
| Any other individual impurity | — | 0.1 | |
| Total impurities | — | 0.5 | |
|
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-(6,7,8,9-tetrahydro-5H-carbazol-4-yloxy)propan-2-ol.
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. Use about 1.9 mL of Diluent per mg of the Carvedilol, and sonicate briefly to facilitate dissolution.
Chromatographic system
Mode:
LC
Detector:
UV 226 nm
Column:
4.6-mm × 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 = (rU/rT) × (1/F) × 100
| rU | = | = peak response of carvedilol related compound F from the Sample solution |
| rT | = | = 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%
SPECIFIC TESTS
• Loss on Drying 731:
Dry a sample at 105 for 3 h: it loses NMT 0.5% of its weight.
731:
Dry a sample at 105 for 3 h: it loses NMT 0.5% of its weight.
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.
• USP Reference Standards 11
11
USP Carvedilol RS 
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USP Carvedilol Related Compound A RS
1-(4-(2-Hydroxy-3-(2-(2-methoxyphenoxy)ethylamino)propoxy)-9H-carbazol-9-yl)-3-(2-(2-methoxyphenoxy)ethylamino) propan-2-ol.
C36H43N3O7 629.74
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1-(4-(2-Hydroxy-3-(2-(2-methoxyphenoxy)ethylamino)propoxy)-9H-carbazol-9-yl)-3-(2-(2-methoxyphenoxy)ethylamino) propan-2-ol.
C36H43N3O7 629.74
USP Carvedilol Related Compound B RS
3,3'-(2-(2-Methoxyphenoxy)ethylazanediyl)bis(1-(9H-carbazol-4-yloxy)propan-2-ol).
C39H39N3O6 645.74
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3,3'-(2-(2-Methoxyphenoxy)ethylazanediyl)bis(1-(9H-carbazol-4-yloxy)propan-2-ol).
C39H39N3O6 645.74
USP Carvedilol Related Compound C RS
1-(9H-Carbazol-4-yloxy)-3-(benzyl(2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol.
C31H32N2O4 496.60
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1-(9H-Carbazol-4-yloxy)-3-(benzyl(2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol.
C31H32N2O4 496.60
USP Carvedilol Related Compound D RS
4-(Oxiran-2-ylmethoxy)-9H-carbazole.
C15H13NO2 239.27
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4-(Oxiran-2-ylmethoxy)-9H-carbazole.
C15H13NO2 239.27
USP Carvedilol Related Compound E RS
2-(2-Methoxyphenoxy)ethyl amine.
C9H13NO2 167.21
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2-(2-Methoxyphenoxy)ethyl amine.
C9H13NO2 167.21
USP Carvedilol System Suitability Mixture RS
Mixture of approximately 0.1% carvedilol related compound F (1-(2-(2-Methoxyphenoxy)ethylamino)-3-(2,3,4,9-tetrahydro-1H-carbazol-5-yloxy)propan-2-ol) in a matrix of carvedilol drug substance.
Mixture of approximately 0.1% carvedilol related compound F (1-(2-(2-Methoxyphenoxy)ethylamino)-3-(2,3,4,9-tetrahydro-1H-carbazol-5-yloxy)propan-2-ol) in a matrix of carvedilol drug substance.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Sujatha Ramakrishna, Ph.D.
Senior Scientific Liaison 1-301-816-8349 |
(SM22010) Monographs - Small Molecules 2 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 2513
Pharmacopeial Forum: Volume No. 34(3) Page 574