Amantadine 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

Amantadine Hydrochloride Tablets contain NLT 95.0% and NMT 105.0% of the labeled amount of amantadine hydrochloride (C₁₀H₁₇N·HCl).

2 IDENTIFICATION

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

Sample: Transfer an amount equivalent to 200 mg of amantadine hydrochloride from finely powdered Tablets (NLT 10) to a suitable beaker.

Add 20 mL of 0.1 N hydrochloric acid solution, sonicate for about 5 min, and filter. Transfer the filtrate to a separatory funnel, add 1 mL of 5 N sodium hydroxide solution, and shake. Add 5 mL of methylene chloride to the solution, shake, and allow the two layers to separate for about 20 min. Pass the lower layer through sodium sulfate anhydrous, then rinse the sodium sulfate with 2 mL of methylene chloride.

Evaporate the filtrate under nitrogen and use the dried residue.

Acceptance criteria: Meet the requirements

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

3 ASSAY

3.1 Procedure

Diluent: Methanol and water (40:60)

Internal standard solution: 0.5 mg/mL of naphthalene in toluene

Standard stock solution: 4 mg/mL of USP Amantadine Hydrochloride RS prepared as follows. Transfer a suitable amount of USP Amantadine

Hydrochloride RS to a suitable volumetric flask. Add 40% of the flask volume of Diluent and sonicate for about 5 min. Dilute with Diluent to volume.

Standard solution: Transfer 1 mL of the Standard stock solution and 5 mL of 5 N sodium hydroxide solution to a separatory funnel. Add 5 mL of the Internal standard solution and shake for about 10 min. Allow the two layers to separate, then collect 4 mL of the clear upper layer and add 500 mg of sodium sulfate anhydrous to remove traces of water. Allow the sodium sulfate to precipitate and use the clear solution for analysis.

Sample stock solution: Nominally 4 mg/mL of amantadine hydrochloride from Tablets prepared as follows. Transfer a number of Tablets (NLT 10) to a suitable volumetric flask and add 80% of the flask volume of Diluent. Sonicate for about 30 min with intermittent shaking.

Dilute with Diluent to volume. Centrifuge a portion and use the supernatant. [Note-The use of a centrifuge speed of 3000 rpm for 10 min may be suitable.]

Sample solution: Transfer 1 mL of the Sample stock solution and 5 mL of 5 N sodium hydroxide solution to a separatory funnel. Add 5 mL of the Internal standard solution and shake for about 10 min. Allow the two layers to separate, then collect 4 mL of the clear upper layer and add 500 mg of sodium sulfate anhydrous to remove traces of water. Allow the sodium sulfate to precipitate and use the clear solution for analysis.

3.2 Chromatographic system

Mode: GC

Detector: Flame ionization

Column: 0.32-mm × 30-m fused silica capillary; coated with a 1-μm film of phase G27

Temperatures

Injector: 280°

Detector: 300°

Column: See Table 1.

Table 1

Carrier gas: Nitrogen

Flow rate: 2 mL/min

Injection volume: 2 μL

Injection type: Split, split ratio 80:1

3.3 System suitability

Sample: Standard solution

[Note-The relative retention times for naphthalene and amantadine are 0.94 and 1.0, respectively.]

3.4 Suitability requirements

Resolution: NLT 5.0 between naphthalene and amantadine

Tailing factor: NMT 1.2

Relative standard deviation: NMT 2.0% for the peak response ratio of amantadine to naphthalene

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amantadine hydrochloride (C₁₀H₁₇N·HCl) in the portion of Tablets taken:

Result =  (R_u/R_s) × (C_s/C_u) × 100

R_u = peak area ratio of amantadine to naphthalene from the Sample solution

R_s = peak area ratio of amantadine to naphthalene from the Standard solution

C_s = concentration of USP Amantadine Hydrochloride RS in the Standard solution (mg/mL)

C_u = nominal concentration of amantadine hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 95.0%–105.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

4.1 Test 1

Medium: Water; 500 mL deaerated

Apparatus 2: 50 rpm; with suitable sinkers

Time: 60 min

Internal standard solution: 0.12 mg/mL of naphthalene in toluene. Sonicate to dissolve if necessary.

Standard stock solution: 0.2 mg/mL of USP Amantadine Hydrochloride RS in Medium. Sonicate to dissolve if necessary.

Standard solution: Equivalent to 0.2 mg/mL(RB 1-Jan-2023) of USP Amantadine Hydrochloride RS in upper layer (toluene) (RB 1-Jan-2023) prepared as follows. Transfer 5 mL of the Standard stock solution and 2.5 mL of 5 N sodium hydroxide solution to a separatory funnel. Add 5 mL of the Internal standard solution and shake for about 10 min. Allow the two layers to separate and use the clear upper layer.

Sample solution: Pass a portion of the solution under test through a filter of 0.45-μm pore size, discarding the first 3 mL of filtrate. Transfer 5 mL of the filtered solution under test and 2.5 mL of 5 N sodium hydroxide solution to a separatory funnel. Add 5 mL of the Internal standard solution and shake for about 10 min. Allow the two layers to separate and use the clear upper layer.

4.1.1 Chromatographic system

Mode: GC

Detector: Flame ionization

Column: 0.32-mm × 30-m fused silica capillary; coated with a 1-μm film of phase G27

Temperatures

Injector: 280°

Detector: 300°

Column: See Table 2.

Table 2

Carrier gas: Nitrogen

Flow rate: 1.5 mL/min

Injection volume: 2 μL

Injection type: Split, split ratio 50:1

4.1.2 System suitability

Sample: Standard solution

[Note-The relative retention times for naphthalene and amantadine are 0.94 and 1.0, respectively.]

4.1.3 Suitability requirements

Resolution: NLT 5.0 between naphthalene and amantadine

Relative standard deviation: NMT 5.0% for the peak response ratio of amantadine to naphthalene

4.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amantadine hydrochloride (C₁₀H₁₇N·HCl) dissolved:

Result = (R_u/R_s) × C_s× V × (1/L) × 100

R_u = peak area ratio of amantadine to naphthalene from the Sample solution

R_s = peak area ratio of amantadine to naphthalene from the Standard solution

C_s = concentration of USP Amantadine Hydrochloride RS in the Standard solution (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of amantadine hydrochloride (C₁₀H₁₇N·HCl) is dissolved.

4.2 Test 2

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: Water; 900 mL deaerated

Apparatus 2: 50 rpm

Time: 45 min

Internal standard solution: 0.054 mg/mL of naphthalene in chromatographic solvent hexane

Standard stock solution: 0.1 mg/mL of USP Amantadine Hydrochloride RS in Medium

Standard solution: Equivalent to 0.15 mg/mL of USP Amantadine Hydrochloride RS in upper layer (hexane) prepared as follows. Transfer 30.0 mL of the Standard stock solution and 10 mL of 5 N sodium hydroxide solution to a suitable volumetric flask. Add 20.0 mL of the Internal standard solution and shake for about 60 min. Allow the two layers to separate and use the clear upper layer.

Sample solution: Pass a portion of the solution under test through a suitable folter of 0.7-μm pore size, discarding the first 10 mL of filtrate.

Transfer 15.0 mL of the filtered solution under test and 5 mL of 5 N sodium hydroxide solution to a suitable centrifuge tube. Add 10.0 mL of the Internal standard solution and shake for about 60 min. Allow the two layers to separate and use the clear upper layer.

4.2.1 Chromatographic system

Mode: GC

Detector: Flame ionization

Column: 0.25-mm × 30-m fused silica capillary; coated with a 0.25-μm film of phase G1

Temperatures

Injection port: 250°

Detector: 300°

Column: See Table 3.

Table 3

Carrier gas: Helium

Flow rate: 1.4 mL/min

Injection volume: 3.0 μL

Injection type: Split, split ratio 40:1

4.2.2 System suitability

Sample: Standard solution

[Note-The relative retention times for naphthalene and amantadine are 0.89 and 1.0, respectively.]

4.2.3 Suitability requirements

Resolution: NLT 4.0 between naphthalene and amantadine

Tailing factor: NMT 2.0 for amantadine

Relative standard deviation: NMT 2.0% for the peak response ratio of amantadine to naphthalene

4.2.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amantadine hydrochloride (C₁₀H₁₇N·HCl) dissolved:

Result = (R_u/R_s) × C_s× V × D × (1/L) × 100

R_u = peak area ratio of amantadine to naphthalene from the Sample solution

R_s = peak area ratio of amantadine to naphthalene from the Standard solution

C_s = concentration of USP Amantadine Hydrochloride RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

D = dilution factor for the Sample solution, 0.667

L = label claim (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of amantadine hydrochloride (C₁₀H₁₇N·HCl) is dissolved. (RB 1-Jan-2023)

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

5.1 Organic Impurities

Internal standard solution: 0.5 mg/mL of adamantane in toluene

Standard stock solution: 1.6 mg/mL of USP Amantadine Hydrochloride RS prepared as follows. Transfer 50 mg of USP Amantadine

Hydrochloride RS and 20 mL of 5 N sodium hydroxide solution to a suitable container and sonicate for about 15 min with intermittent shaking. Add 10 mL of the Internal standard solution and sonicate for about 15 min with intermittent shaking. Centrifuge the solution.

Transfer 3 mL of the supernatant to a suitable container and add 300 mg of sodium sulfate anhydrous to remove traces of water. Allow the sodium sulfate to precipitate and use the clear solution for preparation of the Standard solution. [Note-The use of a centrifuge speed of 3000 rpm for 10 min may be suitable.]

Standard solution: 0.16 mg/mL of USP Amantadine Hydrochloride RS prepared as follows. Transfer 1 mL of the Standard stock solution to a 10-mL volumetric flask. Dilute with the Internal standard solution to volume.

Sample solution: Nominally 16.7 mg/mL of amantadine hydrochloride from Tablets prepared as follows. Transfer a portion of powder, equivalent to 500 mg of amantadine hydrochloride, from Tablets (NLT 20) and 20 mL of 5 N sodium hydroxide solution to a suitable container. Sonicate for about 15 min with intermittent shaking. Add 10 mL of the Internal standard solution and sonicate for about 15 min with intermittent shaking. Centrifuge the solution. Transfer 3 mL of the supernatant and add 300 mg of sodium sulfate anhydrous to remove traces of water. Allow the sodium sulfate to precipitate and use the clear solution for analysis. [Note-The use of a centrifuge speed of 3000 rpm for 10 min may be suitable.]

5.2 Chromatographic system

Mode: GC

Detector: Flame ionization

Column: 0.53-mm × 30-m fused silica capillary; coated with a 1-μm film of phase G27

Temperatures

Injector: 220°

Detector: 300°

Column: See Table 4.

Table 4 (RB 1-Jan-2023)

Carrier gas: Helium

Flow rate: 4 mL/min

Injection volume: 1 μL

Injection type: Split, split ratio 50:1

5.3 System suitability

Sample: Standard solution

[Note-The relative retention times for adamantane and amantadine are 0.83 and 1.0, respectively.]

5.4 Suitability requirements

Resolution: NLT 20 between adamantane and amantadine

Relative standard deviation: NMT 5.0% for the peak response ratio of amantadine to adamantane

5.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any unspecified degradation product in the portion of Tablets taken:

Result = (R_u/R_s) × (C_s/C_u) × 100

R_u = peak area ratio of each degradation product to adamantane from the Sample solution

R_s = peak area ratio of amantadine to adamantane from the Standard solution

C_s = concentration of USP Amantadine Hydrochloride RS in the Standard solution (mg/mL)

C_u = nominal concentration of amantadine hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: The reporting threshold is 0.10%.

Any unspecified degradation product: NMT 0.2%

Total degradation products: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers, protected from light and moisture. Store at controlled room temperature.

Add the following:

Labeling: When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used. (RB 1-Jan-2023)

USP Reference Standards 〈11〉

USP Amantadine Hydrochloride RS