Amitriptyline 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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C₂₀H₂₃N·HCI 313.87(ERR 1-Jun-2021)

1-Propanamine, 3-(10,11-dihydro-5H-dibenzo[a,d)cyclohepten-5-ylidene)-N,N-dimethyl-,hydrochloride;

10,11-Dihydro-N,N-dimethyl-5H-dibenzo[a,d]cycloheptene-Δ⁵, γ-propylamine hydrochloride CAS RN^®: 549-18-8.

1 DEFINITION

Amitriptyline Hydrochloride contains NLT 98.0% and NMT 102.0% of amitriptyline hydrochloride (C₂₀H₂₃N·HCI), calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197A or 197K

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 (191), Chemical Identification Tests, Chloride: Meets the requirements

3 ASSAY

3.1 PROCEDURE

Buffer: 1.4 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)

System suitability stock solution A: 1 mg/mL of USP Amitriptyline Related Compound A RS in methanol

System suitability stock solution B: 0.4 mg/mL of USP Amitriptyline Hydrochloride RS, 0.6 mg/mL each of USP Amitriptyline Related Compound B RS, USP Cyclobenzaprine Hydrochloride RS, and USP Nortriptyline Hydrochloride RS in Mobile phase

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

System suitability solution: 0.5 µg/mL of USP Amitriptyline Related Compound A RS, 1 µg/mL of USP Amitriptyline Hydrochloride RS, and 1.5 µg/mL each of USP Amitriptyline Related Compound B RS, USP Cyclobenzaprine Hydrochloride RS, and USP Nortriptyline Hydrochloride RS from suitable volumes of System suitability stock solution A and System suitability stock solution B in Mobile phase

Sample solution: 0.2 mg/mL of Amitriptyline Hydrochloride in Mobile phase

3.2 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

3.3 System suitability

Samples: Standard solution and System suitability solution

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

Suitability requirements

Resolution: NLT 1.5 between amitriptyline related compound B and nortriptyline, System suitability solution

Relative standard deviation: NMT 0.73% for amitriptyline, Standard solution

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of amitriptyline hydrochloride (C₂₀H₂₃N·HCI) in the portion of Amitriptyline Hydrochloride 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 = concentration of Amitriptyline Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 98.0%-102.0% on the dried basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.1%

4.2 ORGANIC IMPURITIES

Buffer, Mobile phase, and Chromatographic system: Proceed as directed in the Assay.

Sensitivity solution: 0.5 µg/mL of USP Amitriptyline Hydrochloride RS in Mobile phase

Standard solution: Use the System suitability solution, prepared as directed in the Assay.

Sample solution: 1000 µg/mL of Amitriptyline Hydrochloride in Mobile phase

System suitability

Samples: Sensitivity solution and Standard solution

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

Suitability requirements

Resolution: NLT 1.5 between amitriptyline related compound B and nortriptyline, Standard solution

Relative standard deviation: NMT 5.0% each for amitriptyline related compound A, amitriptyline related compound B, nortriptyline, cyclobenzaprine, and amitriptyline, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentages of amitriptyline related compound A, amitriptyline related compound B, and nortriptyline hydrochloride in the portion of Amitriptyline Hydrochloride 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 = concentration of Amitriptyline Hydrochloride in the Sample solution (µg/mL)

Calculate the percentage of cyclobenzaprine in the portion of Amitriptyline Hydrochloride taken:

Result = (r_U/r_S) x (C_S/C_U) x (M_r1/M_r2) x 100

r_U = peak response of cyclobenzaprine from the Sample solution

r_S = peak response of cyclobenzaprine from the Standard solution

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

C_U = concentration of Amitriptyline Hydrochloride in the Sample solution (µg/mL)

M_r1 = molecular weight of cyclobenzaprine, 275.39

M_r2 = molecular weight of cyclobenzaprine hydrochloride, 311.85

Calculate the percentage of each unspecified impurity in the portion of Amitriptyline Hydrochloride taken:

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

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

r_S = peak response of USP Amitriptyline Hydrochloride RS from the Standard solution

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

C_U = concentration of Amitriptyline Hydrochloride in the Sample solution (µg/mL)

Acceptance criteria: See Table 1. Do not include any peak with a relative retention time less than 0.22. The reporting threshold is 0.05%.

Table 1

5 SPECIFIC TESTS

5.1 PH (791)

Sample: 10 mg/mL in water

Acceptance criteria: 5.0-6.0

5.2 LOSS ON DRYING (731)

Analysis: Dry at a pressure not exceeding 5 mm of mercury at 60° to constant weight.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in well-closed containers.

Change to read:

6.2 USP REFERENCE STANDARDS (11)

USP Amitriptydine 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(ERR 1-Jun-2021)

USP Cyclobenzaprine Hydrochloride RS

USP Nortriptyline Hydrochloride RS