Memantine Hydrochloride Tablets

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 Tablets contain an amount of memantine hydrochloride equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of memantine hydrochloride (C₁₂H₂₁N · HCl).

2 IDENTIFICATION

Change to read:

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

Analytical range: 4000–400 cm–1

Standard: 6.7 mg/mL of USP Memantine Hydrochloride RS in dichloromethane. Shake for 10 min, and pass through a suitable filter.

Evaporate the solvent at room temperature. Collect the residue powder, and dry at 60° for 15 min. Prepare an approximate 1% (w/w) dispersion of the sample in potassium bromide.

Sample: 6.7 mg/mL of memantine hydrochloride in dichloromethane from NLT 20 crushed Tablets. Shake for 10 min, and centrifuge for 10min. Pass the supernatant through a suitable filter. Evaporate the solvent at room temperature. Collect the residue powder, and dry at 60° for 15 min. Prepare an approximate 1% (w/w) dispersion of the sample in potassium bromide.

Acceptance criteria: Fingerprint region of the Standard and Sample spectrum exhibit maxima at the same wave numbers.

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

3 ASSAY

Procedure

Solution A: 200 mg/mL of sodium hydroxide in water

Internal standard solution: 25 μg/mL of USP Amantadine Hydrochloride RS in water

Standard stock solution: 25 μg/mL of USP Memantine Hydrochloride RS prepared as follows. Weigh a suitable quantity of the Standard into a volumetric flask. Add methanol to fill 40% of the final flask volume, and sonicate. Dilute with water to volume.

Standard solution: Pipet 4.0 mL each of the Internal standard solution and the Standard stock solution into a test tube. Add 2 mL of Solution A, and mix on a vortex mixer for 1 min. Add 4.0 mL of toluene, and mix on a vortex mixer for 3 min. Allow the two layers to separate. Inject the toluene layer.

Sample stock solution: Nominally 20 μg/mL of memantine hydrochloride prepared as follows. Transfer a suitable number of Tablets to a volumetric flask to obtain a 0.1 mg/mL memantine hydrochloride solution. Add methanol to fill 40% of the final flask volume, and sonicate for 30 min with intermittent shaking. Add water to fill 40% of the final flask volume, and sonicate for 30 min with intermittent shaking. Dilute with water to volume, and centrifuge a portion for 10 min. Pipet a suitable volume of the clear centrifugate into a volumetric flask, and dilute with water to volume.

Sample solution: Pipet 5.0 mL of the Sample stock solution, 4.0 mL of the Internal standard solution, and 2 mL of Solution A into a test tube, and mix on a vortex mixer for 1 min. Add 4.0 mL of toluene, and mix on a vortex mixer for 5 min. Allow the two layers to separate. Inject the toluene layer.

Blank: To 5.0 mL of 80 μL/mL of methanol in water add 2 mL of Solution A, and mix on a vortex mixer for 1 min. Add 4.0 mL of toluene, and mix on a vortex mixer for 5 min. Allow the two layers to separate. Inject the toluene layer.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 30-m × 0.32-mm; 0.25-μm packing G27

Temperatures

Injection port: 210°

Detector: 300°

Oven: See Table 1.

Table 1

Carrier gas: Helium

Flow rate: 34.8 psi

Injection volume: 4 μL

Injection type: Split ratio, 1:10

System suitability

Sample: Standard solution

[Note—The relative retention times for amantadine and memantine are 0.97 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between amantadine and memantine

Tailing factor: NMT 2.5 for amantadine; NMT 2.0 for memantine

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

Analysis

Samples: Standard solution, Sample solution, and Blank

Calculate the percentage of the labeled amount of memantine hydrochloride (C₁₂H₂₁N · HCl) in the portion of Tablets taken:

Result = (R_U/R_S) × (C_S/C_U) × 100

R_U = peak area ratio of memantine to amantadine from the Sample solution

R_S = peak area ratio of memantine to amantadine from the Standard solution

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

C_U = nominal concentration of memantine hydrochloride in the Sample solution (μg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Dissolution 〈711〉

Medium: 0.1 N hydrochloric acid with sodium chloride (2 g/L of sodium chloride in water), adjusted with hydrochloric acid to a pH of 1.2; 900mL

Apparatus 1: 100 rpm

Time: 30 min

Standard stock solution: (L/900) mg/mL of USP Memantine Hydrochloride RS in Medium, where L is the label claim in mg/Tablet

Internal standard solution: 28 μg/mL of USP Amantadine Hydrochloride RS in Medium

Standard solution

For Tablets labeled to contain 5 mg: Transfer 5 mL of the Standard stock solution to a test tube, add 1 mL of the Internal standard solution and 2 mL of 5 N sodium hydroxide, and mix for 1 min. Add 3 mL of toluene, and mix for 2 min. Use the toluene layer.

For Tablets labeled to contain 10 mg: Transfer 5 mL of the Standard stock solution to a test tube, add 2 mL of the Internal standard solution and 2 mL of 5 N sodium hydroxide, and mix for 1 min. Add 3 mL of toluene, and mix for 2 min. Use the toluene layer.

Sample solution: Pass a portion of the solution under test through a suitable filter.

For Tablets labeled to contain 5 mg: Transfer 5 mL of the filtrate to a test tube, add 1 mL of the Internal standard solution and 2 mL of 5 N sodium hydroxide, and mix for 1 min. Add 3 mL of toluene, and mix for 2 min. Use the toluene layer.

For Tablets labeled to contain 10 mg: Transfer 5 mL of the filtrate to a test tube, add 2 mL of the Internal standard solution and 2 mL of 5 N sodium hydroxide, and mix for 1 min. Add 3 mL of toluene, and mix for 2 min. Use the toluene layer.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC, splitless

Detector: Flame ionization

Column: 30-m × 0.32-mm; 0.25-μm packing G27

Flow rate: 34.8 psi

Temperatures

Injection port: 210°

Detector: 300°

Oven: See Table 2.

Table 2

Carrier gas: Helium

Injection volume: 4 μL

System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 2.0 between amantadine and memantine

Tailing factor: NMT 2.0 each for amantadine and memantine

Relative standard deviation: NMT 2.0% for the ratio of memantine to amantadine peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of memantine hydrochloride (C₁₂H₂₁N · HCl) dissolved:

Result = (R_U/R_S) × (C_S/L) × V × 100

R_U = peak area ratio of memantine to amantadine from the Sample solution

R_S = peak area ratio of memantine to amantadine from the Standard solution

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

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 80% (Q) of the labeled amount of memantine hydrochloride (C₁₂H₂₁N · HCl) is dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Limit of Memantine–Lactose Adduct

[Note—Perform this test if lactose is present in the formulation.]

Solution A: 40 mg/mL of sodium hydroxide in water

Buffer: Dissolve 3.3 g of monobasic potassium phosphate and 2.3 g of sodium 1-octane sulfonate in 1 L of water. Adjust with Solution A to a pH of 6.1.

Mobile phase: Acetonitrile, methanol, and Buffer (26:4:70)

Standard solution: 0.2 mg/mL of USP Memantine Hydrochloride RS in Mobile phase

Sample solution: Nominally 10 mg/mL of memantine hydrochloride from NLT 25 crushed Tablets, prepared as follows. Transfer an amount of powder equivalent to 100 mg of memantine hydrochloride to a 20-mL volumetric flask. Add 10 mL of Mobile phase, and sonicate for 30 min.

Centrifuge, and pass a portion of the centrifugate through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: Refractive index

Column: 4.6-mm × 15-cm; 5-μm packing L1

Temperatures

Column: 40°

Detector: 35°

Flow rate: 1.3 mL/min

Injection volume: 50 μL

Run time: 1.3 times the retention time of the memantine peak

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 3.5

Relative standard deviation: NMT 10.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the memantine–lactose adduct in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100

r_U = peak response of the memantine–lactose adduct from the Sample solution

r_S = peak response of memantine from the Standard solution

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

C_U = nominal concentration of memantine hydrochloride in the Sample solution (mg/mL)

F = relative response factor of the memantine–lactose adduct (see Table 3)

Acceptance criteria: See Table 3.

Disregard all peaks other than the memantine–lactose adduct peak.

Table 3

Organic Impurities

Solution A: 1 N sodium hydroxide

System suitability stock solution A: 0.5 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

System suitability stock solution B: Transfer 75 mg of USP Memantine Hydrochloride RS into a suitable container, add 9 mL of 1.0 N sodium hydroxide and 6 mL of n-hexane, and mix for 10 min.

System suitability solution: Pipet 4.0 mL of the n-hexane layer from System suitability stock solution B into a 10-mL volumetric flask. Add 0.5mL of System suitability stock solution A, and dilute with n-hexane to volume.

Standard stock solution: 1.3 mg/mL of USP Memantine Hydrochloride RS in n-hexane prepared as follows. Weigh a suitable quantity of the

Standard into a volumetric flask. Add Solution A to fill 30% of the final flask volume, and mix for 5 min. Add n-hexane to fill 40% of the final flask volume, and shake for 10 min. Transfer the contents of the flask into a separator. Allow the layers to separate, and filter a portion of the top n-hexane layer through anhydrous sodium sulfate. Use the clear solution.

Standard solution: Pipet 2.0 mL of the clear solution from the Standard stock solution into a 100-mL volumetric flask, and dilute with n-hexane to volume.

Sample solution: Nominally 5 mg/mL of memantine hydrochloride in n-hexane from NLT 20 crushed Tablets, prepared as follows. Transfer a weighed amount of powder equivalent to 100 mg of memantine hydrochloride to a suitable volumetric flask. Add Solution A to fill 15% of the final flask volume. Shake to disperse the material, and then shake for 5 min. Sonicate for 5 min with intermittent shaking. Add n-hexane to fill 20% of the final flask volume, and shake for 10 min. Transfer the contents into a separator. Allow the layers to separate, and filter a portion of the top hexane layer through anhydrous sodium sulfate. Use the clear solution.

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°

Oven: See Table 4.

Table 4

Carrier gas: Helium

Flow rate: 4.0 ± 0.2 mL/min

Injection volume: 3 μL

Injection type: Split ratio, 1:20

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 5 for the relative retention times.]

Suitability requirements

Resolution: NLT 2.0 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, Standard solution

Relative standard deviation: NMT 10.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of memantine related compound E or any individual degradation product in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of memantine related compound E or any individual degradation product 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 = nominal concentration of memantine hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: See Table 5.

Table 5

^a Process impurities controlled in the drug substance and are included for identification only. Not reported for the drug product and not included in the total impurities.

^b Excludes memantine–lactose adduct monitored in the test for Limit of Memantine–Lactose Adduct.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature.

USP Reference Standards 〈11〉

USP Amantadine Hydrochloride RS

USP Memantine Hydrochloride RS

USP Memantine Related Compound A RS