Nortriptyline 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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C₁₉H₂₁N · HCl         299.84

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

10,11-Dihydro-N-methyl-5H-dibenzo[a,d]cycloheptene-Δ⁵,γ-propylamine hydrochloride CAS RN: 894-71-3; UNII: 00FN6IH15D.

1 DEFINITION

Nortriptyline Hydrochloride contains NLT 97.0% and NMT 101.5% of nortriptyline hydrochloride (C₁₉H₂₁N · HCl), calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 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 of the test for amine hydrochlorides

3 ASSAY

PROCEDURE

Solution A: Phosphoric acid and water (1:10)

Buffer: Dissolve 1.4 1.4 g of dibasic sodium phosphate in 1 L of water, and adjust with Solution A to a pH of 7.7.

Mobile phase: Methanol and Buffer (70:30)

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

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

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 215 nm

Column temperature: 45^o

Flow rate: 1.5 mL/min

Injection volume: 10 µL

Run time: NLT 1.3 times the retention time of nortriptyline

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of nortriptyline hydrochloride (C₁₉H₂₁N · HCl) in the portion of Nortriptyline Hydrochloride taken:

Result = (r_u /r_s ) × (C_s /C_u ) × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

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

C_u = concentration of Nortriptyline Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 97.0%–101.5% on the dried basis

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.1%

ORGANIC IMPURITIES

Solution A: 400 mg/mL of tetrabutylammonium hydroxide in water

Solution B: Phosphoric acid and water (1:7)

Buffer: Dissolve 0.7 g of potassium dihydrogen phosphate in 900 mL water. Add 3.25 mL of Solution A, and adjust with Solution B to a pH of 7.5. Dilute with water to 1 L.

Mobile phase: Methanol and Buffer (75:25). [NOTE-The Mobile phase ratio can be adjusted to 70:30 to meet the system suitability requirements.]

System suitability solution: 2.0 µg/mL each of USP Amitriptyline Related Compound B RS, USP Cyclobenzaprine Related Compound B RS and USP Nortriptyline Hydrochloride RS in Mobile phase

Standard solution: 0.002 mg/mL of USP Nortriptyline Hydrochloride RS in Mobile phase

Sample solution: 2.0 mg/mL of Nortriptyline Hydrochloride in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm x 15-cm; 5-µm packing LZ

Column temperature: 35°. [NOTE-The Column temperature can be adjusted to 45° to meet the system suitability requirements.]

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 3 times the retention time of nortriptyline

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.4 between the amitriptyline related compound B and cyclobenzaprine related compound B peaks; NLT 2.0 between the cyclobenzaprine related compound B and nortriptyline peaks, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of Nortriptyline Hydrochloride taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (1/F) × 100

r_u = peak response of each individual impurity from the Sample solution

r_s = peak response of nortriptyline from the Standard solution

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

C_u = concentration of Nortriptyline Hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1. The reporting threshold is 0.05%.

Table 1

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers.

Change to read:

USP Reference Standards 〈11〉

USP Amitriptyline Related Compound B RS

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

C₂₀H₂₅NO                 295.43 _{(ERR 1-Jul-2021)}

USP Cyclobenzaprine Related Compound B RS

3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine hydrochloride.

C₁₉H₁₉N · HCl           297.81

USP Nortriptyline Hydrochloride RS