Rivastigmine Tartrate

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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1 DEFINITION

Rivastigmine Tartrate contains NLT 98.0% and NMT 102.0% of the labeled amount of C₁₄H₂₂N₂O₂ · C₄H₆O₆, calculated on the anhydrous basis.

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 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.

3 ASSAY

Procedure

Buffer: 8.6 mg/mL monobasic ammonium phosphate → adjust to pH 7.0 with ammonia solution.

Mobile phase: Methanol, acetonitrile, Buffer (15:15:70)

System suitability solution:

0.05 mg/mL each of

USP Rivastigmine Related Compound A RS

USP Rivastigmine Related Compound B RS

in Mobile phase

Standard solution:

0.2 mg/mL USP Rivastigmine Tartrate RS in Mobile phase

Sample solution:

0.2 mg/mL Rivastigmine Tartrate in Mobile phase

Chromatographic system

Mode: LC

Detector: UV 215 nm

Column: 4.6 mm × 25 cm, 5-µm L7

Flow rate: 1.2 mL/min

Injection size: 20 µL

[Note—Flow may be adjusted to 1.5 mL/min to reach ~10 min retention time.]

System suitability

Samples: System suitability solution + Standard solution

Requirements:

Resolution ≥ 1.5 (related compound A vs B)

Column efficiency ≥ 5000 theoretical plates

Tailing factor ≤ 3.0

RSD ≤ 2.0%, Standard solution

Analysis

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response, Sample solution

rₛ = peak response, Standard solution

Cₛ = concentration of Standard (mg/mL)

Cᵤ = concentration of Sample (mg/mL)

Acceptance criteria: 98.0%–102.0% (anhydrous)

4 IMPURITIES

Inorganic Impurities

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities — Procedure 1

Mobile phase + System suitability solution: as in Assay.

Standard solution:

1.0 µg/mL USP Rivastigmine Tartrate RS in Mobile phase

Sample solution:

1.0 mg/mL Rivastigmine Tartrate in Mobile phase

Chromatographic system: same as Assay.

System suitability

Samples: System suitability solution + Standard solution

Requirements:

Resolution ≥ 1.5 (related compound A vs B)

RSD ≤ 10%, Standard solution

Analysis

[Note—Run time = 8× retention time of rivastigmine peak.]

Calculate impurity %:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (1/F) × 100

rᵤ = impurity peak response (Sample)

rₛ = peak response (Standard)

Cₛ = concentration of Standard (mg/mL)

Cᵤ = concentration in Sample (mg/mL)

F = relative response factor (Impurity Table 1)

ᵃ (S)-3-[1-(Dimethylamino)ethyl]phenol

ᵇ (+)-Di-(p-toluoyl)-D-tartaric acid (related compound A)

ᶜ (S)-3-[1-(Dimethylamino)ethyl]phenyl dimethylcarbamate

ᵈ ▲4-Nitrophenyl ethyl(methyl)carbamate▲ (ERR 1-May-2024)

ᵉ (S)-N,N-Dimethyl-1-[3-(4-nitrophenoxy)phenyl]ethanamine

Organic Impurities — Procedure 2: Enantiomeric Purity

Buffer:

1.78 g dibasic sodium phosphate dihydrate +

1.38 g monobasic sodium phosphate → dilute to 1000 mL → adjust to pH 6.0.

Mobile phase:

20 mL acetonitrile + 205 µL N,N-dimethyloctylamine → dilute to 1000 mL with Buffer.

Standard solution:

0.1 µg/mL USP Rivastigmine Tartrate R-Isomer RS

Sensitivity solution:

0.05 µg/mL USP Rivastigmine Tartrate R-Isomer RS

System suitability solution:

100 µg/mL USP Rivastigmine Tartrate RS +

0.1 µg/mL R-Isomer RS

Sample solution:

100 µg/mL Rivastigmine Tartrate

Chromatographic system

Mode: LC

Detector: UV 200 nm

Column: 4.0 mm × 10 cm, L41

Flow: 0.5 mL/min

Injection: 20 µL

System suitability

Resolution ≥ 0.8 (R-enantiomer then S-enantiomer)

S/N ≥ 10, Sensitivity solution

RSD ≤ 10%, Standard solution

Analysis

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = R-enantiomer peak, Sample

rₛ = R-enantiomer peak, Standard

Cₛ = concentration in Standard (µg/mL)

Cᵤ = concentration in Sample (µg/mL)

Acceptance criteria: NMT 0.3% R-enantiomer

5 SPECIFIC TESTS

Water Determination, Method Ia 〈921〉: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage:

Preserve in tight containers at room temperature.

USP Reference Standards 〈11〉

USP Rivastigmine Tartrate RS

USP Rivastigmine Related Compound A RS

(+)-Di-(p-toluoyl)-D-tartaric acid.

C₂₀H₁₈O₆ 386.35

USP Rivastigmine Related Compound B RS

(RS)-3-[1-(Dimethylamino)ethyl]phenyl dimethylcarbamate.

C₁₃H₁₉N₁O₂ 236.32

USP Rivastigmine Tartrate R-Isomer RS

▲(R)-3-[1-(Dimethylamino)ethyl]phenyl ethylmethylcarbamate, hydrogen tartrate.

C₁₄H₂₂N₂O₂ · C₄H₆O₆ 400.42▲ (ERR 1-May-2024)