Nortriptyline Hydrochloride Capsules

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

Nortriptyline Hydrochloride Capsules contain Nortriptyline Hydrochloride _{(USP 1-May-2024)} equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of nortriptyline (C₁₉H₂₁N).

2 IDENTIFICATION

Delete the following:

A. INFRARED ABSORPTION _{(USP 1-May-2024)}

Add the following:

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. _{(USP 1-May-2024)}

Delete the following:

B. IDENTIFICATION TESTS-GENERAL (191), Chemical Identification Tests, Chloride _{(USP 1-May-2024)}

Add the following:

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. _{(USP 1-May-2024)}

3 ASSAY

Change to read:

PROCEDURE

Solution A: Combine 10 mL of phosphoric acid with 100 mL of water.

Buffer: 1.4 g/L of sodium phosphate, dibasic, anhydrous in water. Adjust with Solution A to a pH of 7.7.

Mobile phase: Methanol and Buffer (70:30)

Diluent: Methanol and water (70:30)

System suitability solution: 0.11 mg/mL of USP Nortriptyline Hydrochloride RS (equivalent to 0.1 mg/mL of nortriptyline) and 1 µg/mL of USP Cyclobenzaprine Related Compound B RS in Diluent

Standard solution: 0.11 mg/mL of USP Nortriptyline Hydrochloride RS (equivalent to 0.1 mg/mL of nortriptyline) in Diluent

Sample stock solution: Nominally 1 mg/mL of nortriptyline in Diluent prepared as follows. Weigh and combine the contents of Capsules (NLT 20). Transfer a portion of the composite to a suitable volumetric flask, and add Diluent to 60% of the flask volume. Shake by mechanical means for 15 min, and sonicate for 10 min. Dilute with Diluent to volume.

Sample solution: Nominally 0.1 mg/mL of nortriptyline in Diluent from the Sample stock solution. Pass through a suitable filter of 0.45-µm pore size, discarding NLT 2 mL of filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm. For Identification B, use a diode array detector in the range of 200-400 nm.

Column: 4.6-mm x 25-cm; 5-µm packing L1

Column temperature: 45°

Flow rate: 1.2 mL/min

Injection volume: 20 µL

Run time: NLT 1.9 times the retention time of nortriptyline

System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for cyclobenzaprine related compound B and nortriptyline are 0.9 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2 between cyclobenzaprine related compound B and nortriptyline, System suitability solution

Tailing factor: NMT 2.5, Standard solution

Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of nortriptyline (C₁₉H₂₁N) in the portion of Capsules taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (M_r1 /M_r2 ) × 100

r_u = peak response of nortriptyline 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 = nominal concentration of nortriptyline in the Sample solution (mg/mL)

M_r1 = molecular weight of nortriptyline, 263.38

M_r2 = molecular weight of nortriptyline hydrochloride, 299.84

_{(USP 1-May-2024)}

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

DISSOLUTION (711)

Test 1

Medium: Water, 500 mL

Apparatus 1: 100 rpm

Time: 30 min

Buffer: 1.63 g/L of monobasic potassium phosphate in water. Adjust with 1 N potassium hydroxide VS to a pH of 6.7.

Mobile phase: Acetonitrile, methanol, and Buffer (40:43:17) _{(USP 1-May-2024)}

Standard solution: 0.023 mg/mL of USP Nortriptyline Hydrochloride RS (equivalent to 0.02 mg/mL of nortriptyline) in Medium

Sample stock solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size.

Sample solution: Nominally 0.02 mg/mL of nortriptyline from the Sample stock solution diluted with Medium, if necessary Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 239 nm

Column: 4.6-mm x 25-cm; 10-µm packing L10

Flow rate: 2.5 mL/min

Injection volume: 100 µL

Run time: NLT 2 times the retention time of nortriptyline _{(USP 1-May-2024)}

System suitability

Sample: Standard solution

Suitability requirement

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of nortriptyline (C₁₉H₂₁N) dissolved:

Result = (r_u /r_s ) × C_s × V × D × (M_r1 /M_r2 ) × (1/L) × 100

r_u = peak response of nortriptyline 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)

V = volume of Medium, 500 mL

D = dilution factor for the Sample solution, if necessary

M_r1 = molecular weight of nortriptyline, 263.38

M_r2 = molecular weight of nortriptyline hydrochloride, 299.84

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of nortriptyline (C₁₉H₂₁N) is dissolved

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

Apparatus 1: 20 mesh basket; 100 rpm.

Time: 30 min

Buffer: 3.6 g/L of potassium phosphate dibasic in water. Add 3 mL of butylamine to the solution. Adjust with phosphoric acid to a pH of 6.7.

Mobile phase: Methanol, acetonitrile, and Buffer (30:20:50)

Standard stock solution: 1.14 mg/mL of USP Nortriptyline Hydrochloride RS in Medium. Sonicate to dissolve, if necessary.

Standard solution: (L/500 x 1.14) mg/mL of USP Nortriptyline Hydrochloride RS from the Standard stock solution in Medium, where L is the label claim in mg/Capsules

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding the first 5 mL of filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 215 nm

Column: 4.0-mm x 15-cm; 5-µm packing L7

Column temperature: 45^o

Flow rate: 1.2 mL/min

Injection volume: 5 µL

Run time: NLT 2 times the retention time of nortriptyline

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 nortriptyline (C₁₉H₂₁N) dissolved:

Result = (r_u /r_s ) × C_s × V × (M_r1 /M_r2 ) × (1/L) × 100

r_u = peak response of nortriptyline 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)

V = volume of Medium, 500 mL

M_r1 = molecular weight of nortriptyline, 263.38

M_r2 = molecular weight of nortriptyline hydrochloride, 299.84

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of nortriptyline (C₁₉H₂₁N) is dissolved

UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements

Add the following:

5 IMPURITIES

ORGANIC IMPURITIES

Solution A, Buffer, Mobile phase, Diluent, System suitability solution, and Chromatographic system: Proceed as directed in the Assay.

Sensitivity solution: 1.1 µg/mL of USP Nortriptyline Hydrochloride RS (equivalent to 1 µg/mL of nortriptyline) in Diluent

Standard solution: 2.3 µg/mL of USP Nortriptyline Hydrochloride RS (equivalent to 2 µg/mL of nortriptyline) in Diluent

Sample solution: Use the Sample stock solution from the Assay. Pass through a suitable filter of 0.45-µm pore size, discarding NLT 2 mL of filtrate.

System suitability

Samples: System suitability solution, Sensitivity solution, and Standard solution

[NOTE-The relative retention times for cyclobenzaprine related compound B and nortriptyline are 0.9 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2 between cyclobenzaprine related compound B and nortriptyline, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each degradation product in the portion of Capsules taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (1/F) × (M_r1 /M_r2 ) × 100

r_u = peak response of each degradation product 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 = nominal concentration of nortriptyline in the Sample solution (mg/mL)

F = relative response factor (see Table 1)

M_r1 = molecular weight of nortriptyline, 263.38

M_r2 = molecular weight of nortriptyline hydrochloride, 299.84

Acceptance criteria: See Table 1. The reporting threshold is 0.1%.

Table 1

^a Dibenzosuberone.

6 ADDITIONAL REQUIREMENTS

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

Labeling: When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used.

Change to read:

USP Reference Standards 〈11〉

USP Cyclobenzaprine Related Compound B RS

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

C₁₉H₁₉N · HCl            297.82 _{(USP 1-May-2024)}

USP Nortriptyline Hydrochloride RS