Capecitabine
C15H22FN3O6 359.35
Carbamic acid, [1-(5-deoxy-
-d-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidinyl]-, pentyl ester;
Pentyl 1-(5-deoxy--d-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidinecarbamate
[154361-50-9].
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C15H22FN3O6 359.35
Carbamic acid, [1-(5-deoxy-
-d-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidinyl]-, pentyl ester;
Pentyl 1-(5-deoxy-
-d-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidinecarbamate
[154361-50-9].DEFINITION
Capecitabine contains NLT 98.0% and NMT 102.0% of C15H22FN3O6, calculated on the anhydrous and solvent-free basis.
IDENTIFICATION
• A. Infrared Absorption 
197K
197K
Sample:
2 mg of sample in 300 mg of potassium bromide
• 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
Diluent:
Methanol, acetonitrile, and water (7:1:12)
Solution A:
0.1% mixture of glacial acetic acid in water
Solution B:
Methanol, acetonitrile, and Solution A (7:1:12)
Solution C:
Methanol, acetonitrile, and Solution A (16:1:3)
Mobile phase:
See the gradient table below.
| Time (min) |
Solution B (%) |
Solution C (%) |
|---|---|---|
| 0 | 100 | 0 |
| 5 | 100 | 0 |
| 20 | 49 | 51 |
| 30 | 49 | 51 |
| 31 | 100 | 0 |
| 40 | 100 | 0 |
[Note—The following solutions may be sonicated if necessary. ]
System suitability solution:
0.6 µg/mL each of USP Capecitabine RS, USP Capecitabine Related Compound A RS, USP Capecitabine Related Compound B RS, and USP Capecitabine Related Compound C RS in Diluent
Standard solution:
0.6 mg/mL of USP Capecitabine RS in Diluent
Sample solution:
0.6 mg/mL of Capecitabine in Diluent
Chromatographic system
Mode:
LC
Detector:
UV 250 nm
Column:
4.6-mm × 25-cm; 5-µm packing L1
Column temperature:
40
Autosampler temperature:
5
Flow rate:
1 mL/min
Injection size:
10 µL
System suitability
Samples:
System suitability solution and Standard solution
[Note—For the purpose of peak identification, the approximate relative retention times are given in Impurity Table 1. The relative retention times are measured with respect to capecitabine. ]
Suitability requirements
Resolution:
NLT 1.0 between capecitabine related compound A and capecitabine related compound B, System suitability solution
Tailing factor:
NMT 1.5, Standard solution
Relative standard deviation:
NMT 2.0%, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C15H22FN3O6 in the portion of Capecitabine taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Capecitabine RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Capecitabine in the Sample solution (mg/mL) |
Acceptance criteria:
98.0%–102.0% on the anhydrous and solvent-free basis
IMPURITIES
Organic Impurities
• Procedure
Diluent, Solution B, Solution C, System suitability solution, Standard solution, Sample solution, and Chromatographic system:
Proceed as directed in the Assay.
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Capecitabine taken:
Result = (rU/rS) × (CS/CU) × 100/F
| rU | = | = peak response for each impurity from the Sample solution |
| rS | = | = peak response for capecitabine from the Standard solution |
| CS | = | = concentration of USP Capecitabine RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Capecitabine in the Sample solution (mg/mL) |
| F | = | = relative response factor for an impurity, from Impurity Table 1 |
Acceptance criteria
Individual impurities:
See Impurity Table 1.
Total impurities:
NMT 1.5%
Impurity Table 1
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| Capecitabine related compound A | 0.18 | 1.05 | 0.3 |
| Capecitabine related compound B | 0.19 | 0.81 | 0.3 |
| 2¢,3¢-Di-O-acetyl-5¢-deoxy-5-fluorocytidine | 0.36 | 0.89 | 0.1 |
| 5¢-Deoxy-5-fluoro-N4-(2-methyl-1-butyloxycarbonyl)cytidine + 5¢-Deoxy-5-fluoro-N4-(3-methyl-1-butyloxycarbonyl)cytidine | 0.95 | 1.01 | 0.5 |
| Capecitabine | 1.00 | 1.00 | — |
| [1-[5-Deoxy-3-O-(5-deoxy--d-ribofuranosyl)--d-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester |
1.06 | 1.00 | 0.3 |
| [1-[5-Deoxy-2-O-(5-deoxy--d-ribofuranosyl)--d-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester |
1.09 | 1.00 | 0.2 |
| Capecitabine related compound C | 1.11 | 0.91 | 0.3 |
[1-[5-Deoxy-3-O-(5-deoxy- -d-ribofuranosyl)--d-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester |
1.20 | 1.00 | 0.3 |
| 2¢,3¢-Di-O-acetyl-5¢-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine | 1.37 | 0.85 | 0.1 |
| Individual unspecified impurity | — | 1.00 | 0.1 |
SPECIFIC TESTS
• Optical Rotation, Specific Rotation 781S:
+96.0 to +100.0
781S:
+96.0 to +100.0
Sample solution:
10 mg/mL, on the anhydrous and solvent-free basis, in methanol, at 20
• Water Determination, Method Ic 921:
NMT 0.3%
921:
NMT 0.3%
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers. Store at controlled room temperature.
• USP Reference Standards 11
11
USP Capecitabine RS 
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USP Capecitabine Related Compound A RS
5¢-Deoxy-5-fluorocytidine.
C9H12FN3O4 245.21
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5¢-Deoxy-5-fluorocytidine.
C9H12FN3O4 245.21
USP Capecitabine Related Compound B RS
5¢-Deoxy-5-fluorouridine.
C9H11FN2O5 246.19
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5¢-Deoxy-5-fluorouridine.
C9H11FN2O5 246.19
USP Capecitabine Related Compound C RS
2¢,3¢-O-Carbonyl-5¢-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine.
C16H20FN3O7 385.34
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2¢,3¢-O-Carbonyl-5¢-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine.
C16H20FN3O7 385.34
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Feiwen Mao, M.S.
Senior Scientific Liaison 1-301-816-8320 |
(SM32010) Monographs - Small Molecules 3 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 2469
Pharmacopeial Forum: Volume No. 35(4) Page 834