Rivastigmine

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 contains NLT 98.0% and NMT 102.0% of rivastigmine (C₁₄H₂₂N₂O₂), calculated on the anhydrous and solvent-free basis.

2 IDENTIFICATION

Change to read:

A. ▲Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197F▲ (CN 1-May-2020)

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 Enantiomeric Purity.

3 ASSAY

Procedure

[Note—Protect solutions containing rivastigmine from light.]

Buffer: 8.9 g/L dibasic sodium phosphate dihydrate in water (0.05 M)

Mobile phase: Methanol and Buffer (58:42), adjusted to pH 8.45 with phosphoric acid

[Note—Cool to room temperature before pH adjustment.]

System suitability solution:

1 mg/mL USP Rivastigmine Tartrate RS

1 µg/mL each of:

USP Rivastigmine Related Compound B RS

USP Rivastigmine Related Compound C RS

USP Rivastigmine Related Compound D RS

in Mobile phase

Standard solution:

1.0 mg/mL USP Rivastigmine Tartrate RS in Mobile phase

Sample solution:

0.625 mg/mL Rivastigmine in Mobile phase

Chromatographic system

Mode: LC

Detector: UV 214 nm

Column: 4.0 mm × 25 cm; 5-µm L1

Column temperature: 40°

Flow rate: 1.0 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution and Standard solution

[Note—RRTs for related compounds C, D, B, and rivastigmine are 0.37, 0.56, 0.68, 1.0.]

Requirements:

Resolution ≥ 1.5 (compound D vs compound B)

RSD ≤ 1.0%, Standard solution

Analysis

Calculate % rivastigmine:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (Mᵤ / Mₛ) × 100

rᵤ = peak response, Sample

rₛ = peak response, Standard

Cₛ = concentration of USP Rivastigmine Tartrate RS (mg/mL)

Cᵤ = concentration of Rivastigmine in Sample (mg/mL)

Mᵤ = molecular weight of rivastigmine = 250.34

Mₛ = molecular weight of rivastigmine tartrate = 400.42

Acceptance criteria: 98.0%–102.0% (anhydrous + solvent-free)

4 IMPURITIES

Residue on Ignition 〈281〉:

NMT 0.1%

Organic Impurities

[Note—Protect solutions from light.]

Buffer, Mobile phase, System suitability solution, Sample solution, and Chromatographic system:

As in Assay.

Standard solution:

0.0025 mg/mL USP Rivastigmine Tartrate RS

Sensitivity solution:

0.5 µg/mL Rivastigmine Tartrate RS (from Standard)

System suitability

Samples:

System suitability solution

Standard solution

Sensitivity solution

[Note—RRTs for related compounds C, D, B, rivastigmine: 0.37, 0.56, 0.68, 1.0]

Requirements:

Resolution ≥ 1.5 (compound D vs B)

S/N ≥ 10 (rivastigmine, Sensitivity solution)

RSD ≤ 10%, Standard solution

Analysis

Calculate impurity %:

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

rᵤ = impurity peak response, Sample

rₛ = rivastigmine peak response, Standard

Cₛ = concentration of Rivastigmine Tartrate RS (mg/mL)

Cᵤ = concentration of Rivastigmine in Sample

Mᵤ = 250.34

Mₛ = 400.42

F = relative response factor (Table 1)

Acceptance criteria: See Table 1

Disregard peak at RRT ~0.45.

ᵃ (S)-3-[1-(Dimethylamino)ethyl]phenyl dimethylcarbamate (racemic mixture = compound B)

Enantiomeric Purity

[Note—Protect solutions from light.]

Buffer:

1.78 g dibasic sodium phosphate dihydrate +

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

Mobile phase:

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

System suitability solution:

0.1 mg/mL Rivastigmine Tartrate RS

0.1 µg/mL R-Isomer RS

Standard solution:

0.1 µg/mL Rivastigmine Tartrate R-Isomer RS

Sample solution:

0.0625 mg/mL Rivastigmine in Mobile phase

Sensitivity solution:

0.05 µg/mL R-Isomer RS

Chromatographic system

Mode: LC

Detector: UV 200 nm

Column: 4.0 mm × 10 cm; 5-µm L41

Flow rate: 0.5 mL/min

Injection volume: 20 µL

System suitability

[Note—RRTs for R-isomer and rivastigmine: 0.85, 1.0]

Requirements:

RSD ≤ 10%, Standard solution

S/N ≥ 10, Sensitivity solution

Resolution ≥ 0.8, R-isomer vs rivastigmine

Analysis

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (Mᵤ / Mₛ) × 100

rᵤ = peak of R-isomer, Sample

rₛ = peak of R-isomer, Standard

Cₛ = concentration in Standard (mg/mL)

Cᵤ = concentration in Sample (mg/mL)

Mᵤ = 250.34

Mₛ = 400.42

Acceptance criteria: NMT 0.3% R-enantiomer

5 SPECIFIC TESTS

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

6 ADDITIONAL REQUIREMENTS

Packaging and Storage:

Preserve in tight containers under inert gas, protected from light.

Store at 2°–8°.

USP Reference Standards 〈11〉

USP Rivastigmine RS

USP Rivastigmine Related Compound B RS

Nor impurity (racemic mixture)

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

C₁₃H₂₀N₂O₂ 236.31

USP Rivastigmine Related Compound C RS

Phenol impurity

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

C₁₀H₁₅NO 165.23

USP Rivastigmine Related Compound D RS

Acetylphenol impurity

3-Acetylphenyl ethyl(methyl)carbamate

C₁₂H₁₅NO₂ 221.25

USP Rivastigmine Tartrate RS

USP Rivastigmine Tartrate R-Isomer RS

(R)-3-[1-(Dimethylamino)ethyl]phenyl ethyl(methyl)carbamate tartrate

C₁₄H₂₂N₂O₂ · C₄H₆O₆ 400.42