Rivastigmine Tartrate
C14H22N2O2·C4H6O6 400.42
Ethylmethylcarbamic acid, 3-[(S)-1-(dimethylamino)ethyl]phenyl ester, (2R,3R)-2,3-dihydroxybutanedioate;
(S)-3-[1-(Dimethylamino)ethyl]phenyl ethylmethylcarbamate, hydrogen tartrate
[129101-54-8].
Rivastigmine 250.34[123441-03-2].
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C14H22N2O2·C4H6O6 400.42
Ethylmethylcarbamic acid, 3-[(S)-1-(dimethylamino)ethyl]phenyl ester, (2R,3R)-2,3-dihydroxybutanedioate;
(S)-3-[1-(Dimethylamino)ethyl]phenyl ethylmethylcarbamate, hydrogen tartrate
[129101-54-8].Rivastigmine 250.34
[123441-03-2].DEFINITION
Rivastigmine Tartrate contains NLT 98.0% and NMT 102.0% of the labeled amount of C14H22N2O2·C4H6O6, calculated on the anhydrous basis.
IDENTIFICATION
• A. Infrared Absorption 
197K
197K
• B.
The retention time of the major peak of the Sample solution corresponds to that of the System suitability solution, as obtained in the test for Organic Impurities, Procedure 2: Enantiomeric Purity.
ASSAY
• Procedure
Buffer:
8.6 mg/mL of monobasic ammonium phosphate. Adjust with ammonia solution to a pH of 7.0.
Mobile phase:
Methanol, acetonitrile, and Buffer (15:15:70)
System suitability solution:
0.05 mg/mL each of USP Rivastigmine Related Compound A RS and USP Rivastigmine Related Compound B RS in Mobile phase
Standard solution:
0.2 mg/mL of USP Rivastigmine Tartrate RS in Mobile phase
Sample solution:
0.2 mg/mL of Rivastigmine Tartrate in Mobile phase
Chromatographic system
Mode:
LC
Detector:
UV 215 nm
Column:
4.6-mm × 25-cm; 5-µm packing L7
Flow rate:
1.2 mL/min
Injection size:
20 µL
[Note—The flow rate may be adjusted to 1.5 mL/min, if needed, to achieve a recommended retention time of rivastigmine at about 10 min. ]
System suitability
Samples:
System suitability solution and Standard solution
Suitability requirements
Resolution:
NLT 1.5 between rivastigmine related compound A and rivastigmine related compound B, System suitability solution
Column efficiency:
NLT 5000 theoretical plates, Standard solution
Tailing factor:
NMT 3.0, Standard solution
Relative standard deviation:
NMT 2.0%, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C14H22N2O2·C4H6O6 in the portion of Rivastigmine Tartrate 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%–102.0% on the anhydrous basis
IMPURITIES
Organic Impurities
• Procedure 1
Mobile phase and System suitability solution:
Proceed as directed in the Assay.
Standard solution:
1.0 µg/mL of USP Rivastigmine Tartrate RS in Mobile phase
Sample solution:
1.0 mg/mL of Rivastigmine Tartrate in Mobile phase
Chromatographic system:
Proceed as directed in the Assay.
System suitability
Samples:
System suitability solution and Standard solution
Suitability requirements
Resolution:
NLT 1.5 between rivastigmine related compound A and rivastigmine related compound B, System suitability solution
Relative standard deviation:
NMT 10%, Standard solution
Analysis
[Note—The run time is 8 times the retention time of the rivastigmine peak. ]
Samples:
Standard solution and Sample solution
Calculate the percentage of any individual impurity in the portion of Rivastigmine Tartrate taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
| rU | = | = peak response for each impurity from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Rivastigmine Tartrate RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Rivastigmine Tartrate in the Sample solution (mg/mL) |
| F | = | = relative response factor (see Impurity Table 1) |
Acceptance criteria
Individual impurities:
See Impurity Table 1.
Total impurities:
NMT 0.5%
Impurity Table 1
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| Tartrate | 0.18 | — | Disregard |
| Phenol impuritya | 0.28 | 1.6 | 0.3 |
| DPTTAb | 0.46 | 0.83 | 0.15 |
| Nor impurityc | 0.57 | 1.2 | 0.15 |
| Rivastigmine | 1.0 | 1.0 | — |
| Carbamate impurityd | 4.1 | 1.3 | 0.15 |
| Ether impuritye | 6.5 | 1.4 | 0.15 |
| Any other impurity | — | 1.0 | 0.1 |
|
a
(S)-3-[1-(Dimethylamino)ethyl]phenol.
b
(+)-Di-(p-toluoyl)-d-tartaric acid (rivastigmine related compound A).
c
(S)-3-[1-(Dimethylamino)ethyl]phenyl dimethylcarbamate (rivastigmine related compound B).
d
3-Nitrophenyl ethyl(methyl)carbamate.
e
(S)-N,N-Dimethyl-1-[3-(4-nitrophenoxy)phenyl]ethanamine.
|
|||
• Procedure 2: Enantiomeric Purity
Buffer:
Transfer 1.78 g of dibasic sodium phosphate dihydrate and 1.38 g of monobasic sodium phosphate into a 1000-mL volumetric flask. Dissolve in and dilute with water to volume. Adjust with phosphoric acid to a pH of 6.0.
Mobile phase:
Transfer 20 mL of acetonitrile and 205 µL of N,N-dimethyloctylamine to a 1000-mL volumetric flask, and dilute with Buffer to volume.
Standard solution:
0.1 µg/mL of USP Rivastigmine Tartrate R-Isomer RS in Mobile phase
Sensitivity solution:
0.05 µg/mL of USP Rivastigmine Tartrate R-Isomer RS in Mobile phase, Standard solution
System suitability solution:
100 µg/mL of USP Rivastigmine Tartrate RS and 0.1 µg/mL of USP Rivastigmine Tartrate R-Isomer RS in Mobile phase
Sample solution:
100 µg/mL of Rivastigmine Tartrate in Mobile phase
Chromatographic system
Mode:
LC
Detector:
UV 200 nm
Column:
4.0-mm × 10-cm; packing L41
Flow rate:
0.5 mL/min
Injection size:
20 µL
System suitability
Samples:
Standard solution, Sensitivity solution, and System suitability solution
Suitability requirements
Resolution:
NLT 0.8 between the enantiomer peaks, System suitability solution
[Note—The elution order is the R-enantiomer, followed by the rivastigmine peak, which is the S-enantiomer. ]
Signal-to-noise ratio:
NLT 10, Sensitivity solution
Relative standard deviation:
NMT 10%, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of the R-enantiomer in the portion of Rivastigmine Tartrate taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of R-enantiomer from the Sample solution |
| rS | = | = peak response of R-enantiomer from the Standard solution |
| CS | = | = concentration of R-enantiomer in the Standard solution (µg/mL) |
| CU | = | = concentration of Rivastigmine Tartrate in the Sample solution (µg/mL) |
Acceptance criteria:
NMT 0.3% of the R-enantiomer
SPECIFIC TESTS
• Water Determination, Method Ia 921:
NMT 0.5%
921:
NMT 0.5%
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers, and store at room temperature.
• USP Reference Standards 11
11
USP Rivastigmine Tartrate RS
USP Rivastigmine Related Compound A RS
Di-p-toluoyl-d-(+)-tartaric acid monohydrate.
C20H20O9 404.37
Di-p-toluoyl-d-(+)-tartaric acid monohydrate.
C20H20O9 404.37
USP Rivastigmine Related Compound B RS
N,N-Dimethylcarbamic acid-3-[1-(dimethylamino)ethyl]phenyl ester.
C13H20N2O2 236.32
N,N-Dimethylcarbamic acid-3-[1-(dimethylamino)ethyl]phenyl ester.
C13H20N2O2 236.32
USP Rivastigmine Tartrate R-Isomer RS
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 4580
Pharmacopeial Forum: Volume No. 35(6) Page 1476