Rivastigmine Tartrate
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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
•  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
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.1%
•  Heavy Metals, Method II 231: NMT 20 ppm
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
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers, and store at room temperature.
•  USP Reference Standards 11
USP Rivastigmine Tartrate RS
USP Rivastigmine Related Compound A RS
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
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
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USP35–NF30 Page 4580
Pharmacopeial Forum: Volume No. 35(6) Page 1476