Amitriptyline 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

Amitriptyline Hydrochloride Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of amitriptyline hydrochloride (C₂₀H₂₃N·HCI).

2 IDENTIFICATION

A. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

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

Buffer: 11.04 g of monobasic sodium phosphate in 900 mL of water. Adjust with phosphoric acid to a pH of 2.5 ± 0.5, and dilute to make 1000 mL.

Mobile phase: Acetonitrile and Buffer (42:58)

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

Sample solution: Nominally 0.2 mg/mL of amitriptyline hydrochloride in Mobile phase, prepared as follows. Transfer NLT 20 Tablets to a suitable volumetric flask, add 50% of the flask volume of Mobile phase, and shake the mixture for 1 h or until the Tablets have disintegrated. Dilute with Mobile phase to volume, and filter. Dilute the clear filtrate with Mobile phase to obtain a solution with a nominal concentration of 0.2 mg/mL of amitriptyline hydrochloride.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm. For Identification A, use a diode array detector in the range of 220-400 nm.

Column: 3.9-mm × 30-cm; 10-µm packing L1

Flow rate: 2 mL/min

Injection volume: 20 µL

Run time: NLT 1.5 times the retention time of amitriptyline

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation : NMT 2.0%

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amitriptyline hydrochloride (C₂₀H₂₃N·HCI) in each Tablet taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

4.1 DISSOLUTION (711)

4.1.1 Test 1 (RB 26-May-2023)

Medium: 0.1 N hydrochloric acid: 900 mL

Apparatus 1: 100 rpm

Time: 45 min

Standard solution: (L/900) mg/mL of USP Amitriptyline Hydrochloride RS in Medium, where L is the Tablet label claim in milligrams. Dilute with Medium, if necessary.

Sample solution: Pass a portion of solution under test through a suitable filter. Dilute with Medium, if necessary.

Instrumental conditions

Analytical wavelength: UV 239 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amitriptyline hydrochloride (C₂₀H₂₃N·HCI) dissolved:

Result = (A_U/A_S) × (C_S/C_U) × D × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

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

D = dilution factor, if necessary

Tolerances: NLT 75% (Q) of the labeled amount of amitriptyline hydrochloride (C₂₀H₂₃N·HCI) is dissolved.

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

Medium: 0.1 N hydrochloric acid; 500 mL, deaerated, if necessary

Apparatus 1: 100 rpm

Time: 30 min

Diluted phosphoric acid: Phosphoric acid and water (1:10)

Buffer: Dissolve 0.87 g of potassium phosphate dibasic in 1 L of water. Adjust with Diluted phosphoric acid to a pH of 7.0. Add 1.0 mL of triethylamine. Adjust with Diluted phosphoric acid to a pH of 7.0.

Mobile phase: Acetonitrile and Buffer (35:65)

Standard solution: (L/500) mg/mL of USP Amitriptyline Hydrochloride RS in Medium, where L is the label claim in mg/Tablet. Sonicate to dissolve, if necessary.

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding the first 3 mL of the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 15-cm; 5-µm packing 11

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

Run time: NLT 1.5 times the retention time of amitriptyline

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of amitriptyline hydrochloride (C₂₀H₂₃N·HCI) dissolved:

Result = (r_U/r_S) x C_S x V x (1/L) × 100

r_U = peak response of amitriptyline from the Sample solution

r_S = peak response of amitriptyline from the Standard solution

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

V = volume of the Medium, 500 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of amitriptyline hydrochloride (C₂₀H₂₃N·HCI) is dissolved. (RB 26-May-2023)

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

Buffer: 1.42 g/L of anhydrous dibasic sodium phosphate in water adjusted with 1.5 M phosphoric acid TS to a pH of 7.7

Mobile phase: Methanol and Buffer (70:30)

Diluent: Methanol and water (70:30)

Standard solution: 2 µg/mL each of USP Amitriptyline Hydrochloride RS, USP Amitriptyline Related Compound A RS, USP Amitriptyline Related Compound B RS, and USP Nortriptyline Hydrochloride RS in Diluent

Sample solution: Nominally 1000 µg/mL of amitriptyline hydrochloride in Diluent, prepared as follows. Transfer NLT 10 Tablets to a suitable volumetric flask, add 80% of the flask volume of Diluent, and shake the mixture for 1 h or until the Tablets have disintegrated. Dilute with Diluent to volume. If needed, a portion of this solution can be further diluted with Diluent. Centrifuge a portion of the solution with a nominal concentration of 1000 µg/mL of amitriptyline hydrochloride and use the supernatant. [NOTE-A centrifuge speed of 3000 rpm for about 10 min may be suitable.]

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 215 nm

Column: 4.6-mm × 25-cm; 5-µm packing L7

Column temperature: 45°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

Run time: NLT 1.5 times the retention time of amitriptyline

System suitability

Sample: Standard solution

[NOTE-For relative retention times, see Table 1.]

Suitability requirements

Resolution: NLT 3.0 between amitriptyline related compound B and nortriptyline

Relative standard deviation: NMT 5.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of amitriptyline related compound A, amitriptyline related compound B, and nortriptyline hydrochloride in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of amitriptyline related compound A, amitriptyline related compound B, or nortriptyline from the Sample solution

r_S = peak response of amitriptyline related compound A, amitriptyline related compound B, or nortriptyline from the Standard solution

C_S = concentration of USP Amitriptyline Related Compound A RS, USP Amitriptyline Related Compound B RS, or USP Nortriptyline Hydrochloride RS in the Standard solution (µg/mL)

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

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

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of any other individual degradation product from the Sample solution

r_S = peak response of amitriptyline from the Standard solution

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

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

Acceptance criteria: See Table 1.

Table 1

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in well-closed containers. Store at controlled room temperature.

Add the following:

6.2 LABELING

When more than one Dissolution Test is given, the labeling states the test used only if Test 1 is not used. (RB 26-May-2023)

6.3 USP REFERENCE STANDARDS (11)

USP Amitriptyline Hydrochloride RS

USP Amitriptyline Related Compound A RS

10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-one;

Also known as Dibenzosuberone.

C₁₅H₁₂O 208.26

USP Amitriptyline Related Compound B RS

5-[3-(Dimethylamino)propyl]-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ol;

Also known as Amitriptynol.

C₂₀H₂₅NO 295.43

USP Nortriptyline Hydrochloride RS