Repaglinide
C27H36N2O4 452.59
(S)-2-Ethyoxy-4-[2-[[methyl-1-[2-[(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-benzoic acid;
(+)-2-Ethoxy-
-[[(S)--isobutyl-o-piperidinobenzyl]carbamoyl]-p-toluic acid
[135062-02-1].
(re pag' li nide).
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C27H36N2O4 452.59
(S)-2-Ethyoxy-4-[2-[[methyl-1-[2-[(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-benzoic acid;
(+)-2-Ethoxy-
-[[(S)--isobutyl-o-piperidinobenzyl]carbamoyl]-p-toluic acid
[135062-02-1].DEFINITION
Repaglinide contains NLT 98.0% and NMT 101.0% of C27H36N2O4, calculated on the dried basis.
IDENTIFICATION
• B. Ultraviolet Absorption 
197U
197U
Sample solution:
25 µg/mL in methanol
ASSAY
• Procedure
Buffer:
1 mg/mL of monobasic potassium phosphate solution, adjusted with phosphoric acid to a pH of 2.5
Mobile phase:
Methanol and Buffer (8:2)
System suitability solution:
500 µg/mL of USP Repaglinide RS and 40 µg/mL of USP Repaglinide Related Compound B RS in methanol
Standard solution:
500 µg/mL of USP Repaglinide RS in methanol
Sample solution:
0.5 mg/mL of Repaglinide in methanol
Chromatographic system
Mode:
LC
Detector:
UV 240 nm
Column:
4.6-mm × 12.5-cm; 5-µm packing L1
Column temperature:
45
Flow rate:
1 mL/min
Injection size:
10 µL
System suitability
Samples:
System suitability solution and Standard solution
[Note—The relative retention times for repaglinide related compound B and repaglinide are 0.4 and 1.0, respectively, System suitability solution. ]
Suitability requirements
Relative standard deviation:
NMT 2.0% of repaglinide, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C27H36N2O4 in the portion of Repaglinide taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of the Standard solution (mg/mL) |
| CU | = | = concentration of the Sample solution (mg/mL) |
Acceptance criteria:
98.0%–101.0% on the dried basis
IMPURITIES
Inorganic Impurities
• Heavy Metals, Method II 231:
10 ppm
231:
10 ppm
Organic Impurities
• Procedure
Solution A:
3 mg/mL of monobasic potassium phosphate solution, adjusted with 1 N sodium hydroxide to a pH of 7.0
Solution B:
Methanol
System suitability solution:
A solution in methanol, containing 10 mg/mL of USP Repaglinide RS, 100 µg/mL of USP Repaglinide Related Compound A RS, 100 µg/mL of USP Repaglinide Related Compound B RS, and 100 µg/mL of USP Repaglinide Related Compound C RS
Sample solution:
10 mg/mL of Repaglinide in methanol
Standard solution:
0.1 mg/mL of repaglinide in methanol, from the Sample solution
Mobile phase:
See the gradient table below.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 50 | 50 |
| 2 | 30 | 70 |
| 8 | 30 | 70 |
| 12 | 5 | 95 |
| 15 | 5 | 95 |
Chromatographic system
Mode:
LC
Detector:
UV 240 nm
Column:
4.6-mm × 12.5-cm; 5-µm packing L1
Flow rate:
1 mL/min
Column temperature:
45
Injection size:
3 µL
System suitability
Samples:
System suitability solution and Standard solution
[Note—The relative retention times for repaglinide related compound B, repaglinide related compound C, repaglinide, and repaglinide related compound A are 0.3, 0.9, 1.0, and 1.6, respectively. ]
Suitability requirements
Relative standard deviation:
NMT 10% of repaglinide, Standard solution
Analysis
Samples:
Sample solution and Standard solution
Calculate the percentage of each impurity in the portion of Repaglinide taken:
Result = (rU/rS) × (CS/CU) × F × 100
| rU | = | = peak response of each impurity from the Sample solution |
| rS | = | = peak response of repaglinide from the Standard solution |
| CS | = | = concentration of repaglinide in the Standard solution (mg/mL) |
| CU | = | = concentration of Repaglinide in the Sample solution (mg/mL) |
| F | = | = relative response factor (see Impurity Table 1) |
Acceptance criteria
Individual impurities:
See Impurity Table 1.
Impurity Table 1
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| Repaglinide related compound A |
1.6 | 2 | 0.1 |
| Repaglinide related compound B |
0.3 | 1 | 0.1 |
| Repaglinide related compound C |
0.9 | 1 | 0.1 |
| Repaglinide | 1.0 | — | — |
| Total impurities | — | — | 0.5 |
SPECIFIC TESTS
• Optical Rotation, Specific Rotation 781S:
+6.3 to +7.3, at 20
781S:
+6.3 to +7.3, at 20
Sample solution:
50 mg/mL, in methanol
• Loss on Drying 731:
Dry a sample at 105 to constant weight: it loses NMT 0.5% of its weight.
731:
Dry a sample at 105 to constant weight: it loses NMT 0.5% of its weight.
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers.
• USP Reference Standards 11
11
USP Repaglinide RS 
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USP Repaglinide Related Compound A RS
(S)-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine, N-acetyl-l-glutamate salt.
C16H26N2·C7H11NO5 435.6
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(S)-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine, N-acetyl-l-glutamate salt.
C16H26N2·C7H11NO5 435.6
USP Repaglinide Related Compound B RS
3-Ethoxy-4-ethoxycarbonylphenylacetic acid.
C13H16O5 252.27
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3-Ethoxy-4-ethoxycarbonylphenylacetic acid.
C13H16O5 252.27
USP Repaglinide Related Compound C RS
(S)-2-Ethoxy-4-[2-[[2-phenyl-1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]benzoic acid.
C30H34N2O4 486.61
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(S)-2-Ethoxy-4-[2-[[2-phenyl-1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]benzoic acid.
C30H34N2O4 486.61
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Elena Gonikberg, Ph.D.
Principal Scientific Liaison 1-301-816-8251 |
(SM32010) Monographs - Small Molecules 3 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4530
Pharmacopeial Forum: Volume No. 36(2) Page 428