Memantine Hydrochloride

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

Memantine Hydrochloride contains NLT 98.0% and NMT 102.0% of memantine hydrochloride (C₁₂H₂₁N · HCl), calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

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

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

C. Identification Tests—General, Chloride 〈191〉: Meets the requirements

3 ASSAY

Procedure

Internal standard solution: 4.0 mg/mL of adamantane in n-hexane

Standard solution: 4.0 mg/mL of USP Memantine Hydrochloride RS in Internal standard solution prepared as follows. Transfer 100 mg of USP

Memantine Hydrochloride RS to a 50-mL centrifuge tube. Add 15 mL of 1 N sodium hydroxide, and mix. Add 25 mL of Internal standard solution, and shake for 15 min. Allow the layers to separate, and filter a portion of the top hexane layer through anhydrous sodium sulfate.

Use the clear filtrate.

Sample solution: 4.0 mg/mL of Memantine Hydrochloride in Internal standard solution prepared as follows. Transfer 100 mg of Memantine Hydrochloride to a 50-mL centrifuge tube. Add 15 mL of 1 N sodium hydroxide, and mix. Add 25 mL of Internal standard solution, and shake for 15 min. Allow the layers to separate, and filter a portion of the top hexane layer through anhydrous sodium sulfate. Use the clear filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 50-m × 0.32-mm; 0.52-μm packing G27

Temperatures

Injection port: 220°

Detector: 300°

Column: See Table 1.

Table 1

Carrier gas: Helium

Flow rate: 4.0 ± 0.4 mL/min

Injection volume: 1 μL

Injection type: Split ratio, 1:50

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 each for memantine and adamantane

Relative standard deviation: NMT 2.0% for the ratio of the peak areas of adamantane and memantine

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of memantine hydrochloride (C₁₂H₂₁N · HCl) in the portion of Memantine Hydrochloride taken:

Result = (R_U/R_S) × (C_S/C_U) × 100

R_U = peak response ratio of memantine to the internal standard from the Sample solution

R_S = peak response ratio of memantine to the internal standard from the Standard solution

C_S = concentration of USP Memantine Hydrochloride RS in the Standard solution (mg/mL)

C_U = concentration of Memantine Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the anhydrous basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities

Standard stock solution A: 2.5 mg/mL each of USP Memantine Related Compound A RS, USP Memantine Related Compound B RS, USP Memantine Related Compound C RS, USP Memantine Related Compound D RS, and USP Memantine Related Compound E RS in n-hexane

Standard stock solution B: 2.5 mg/mL of USP Memantine Hydrochloride RS prepared as follows. To the flask containing a weighed amount of USP Memantine Hydrochloride RS, add 5.0 N sodium hydroxide to fill 20% of the final volume and n-hexane to fill 20% of the final volume.

Shake for 10 min, and transfer the contents to a separator. Allow the layers to separate, filter a portion of the top hexane layer, dry the organic layer by swirling with anhydrous sodium sulfate, and allow to stand for a few min to ensure all the remaining water has been removed. Use the clear filtrate.

System suitability solution: 25 μg/mL each of USP Memantine Related Compound A RS, USP Memantine Related Compound B RS, USP Memantine Related Compound C RS, USP Memantine Related Compound D RS, and USP Memantine Related Compound E RS, from Standard stock solution A in Standard stock solution B. The concentration of USP Memantine Hydrochloride RS is 2.5 mg/mL.

Standard solution: 25 μg/mL each of USP Memantine Related Compound A RS, USP Memantine Related Compound B RS, USP Memantine Related Compound C RS, USP Memantine Related Compound D RS, USP Memantine Related Compound E RS, and USP Memantine Hydrochloride RS, from Standard stock solution A and Standard stock solution B, respectively, in n-hexane

Sample solution: 25 mg/mL of Memantine Hydrochloride prepared as follows. Transfer the weighed amount of Memantine Hydrochloride to a suitable volumetric flask. Add 5.0 N sodium hydroxide to fill 30% of the final volume and n-hexane to fill 40% of the final volume. Shake for 10 min, and transfer the contents to a separator. Allow the layers to separate, filter a portion of the top hexane layer, dry the organic layer by swirling with anhydrous sodium sulfate, and allow to stand for a few min to ensure all the remaining water has been removed. Use the clear filtrate.

Chromatographic system: Proceed as directed in the Assay.

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 2 for the relative retention times.]

Suitability requirements

Resolution: NLT 6.0 between memantine and memantine related compound B; NLT 2.0 between memantine related compound B and memantine related compound C, System suitability solution

Tailing factor: NMT 2.0 for memantine, Standard solution

Relative standard deviation: NMT 10.0% for memantine, Standard solution

Analysis

Samples: Standard solution and Sample solution

[Note—Ignore the peaks at the relative retention times 0.11, 0.12, 0.13, 0.18, and 0.26 with respect to the memantine peak, as they correspond to residual solvents.]

Calculate the percentage of each of memantine related compounds A, B, C, D, and E in the portion of Memantine Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of memantine related compounds A, B, C, D, or E from the Sample solution

r_S = peak response of the corresponding USP Memantine Related Compound RS from the Standard solution

C_S = concentration of the corresponding USP Memantine Related Compound RS in the Standard solution (mg/mL)

C_U = concentration of Memantine Hydrochloride in the Sample solution (mg/mL)

Calculate the percentage of any other impurity in the portion of Memantine Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of any other impurity from the Sample solution

r_S = peak response of memantine hydrochloride from the Standard solution

C_S = concentration of USP Memantine Hydrochloride RS in the Standard solution (mg/mL)

C_U = concentration of Memantine Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: See Table 2.

Table 2

5 SPECIFIC TESTS

Water Determination, Method I 〈921〉: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature.

USP Reference Standards 〈11〉

USP Memantine Hydrochloride RS

USP Memantine Related Compound A RS

1,3-Dimethyladamantane.

C₁₂H₂₀ 164.29

USP Memantine Related Compound B RS

3,5-Dimethyladamantane-1-ol.

C₁₂H₂₀O 180.29

USP Memantine Related Compound C RS

1-Chloro-3,5-dimethyladamantane.

C₁₂H₁₉Cl 198.73

USP Memantine Related Compound D RS

1-Bromo-3,5-dimethyladamantane.

C₁₂H₁₉Br 243.18

USP Memantine Related Compound E RS

N-3,5-Dimethyladamantan-1-yl formamide.

C₁₃H21NO 207.31