Doxepin 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)

DOWNLOAD PDF HERE

1 DEFINITION

Doxepin Hydrochloride Capsules contain an amount of Doxepin Hydrochloride equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of doxepin (C₁₉H₂₁NO).

2 IDENTIFICATION

A. The retention times of the major peaks for the (E)- and (Z)-isomers of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

B. The UV spectra of the major peaks for the (E)- and (Z)-isomers of doxepin in the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

PROCEDURE

Solution A: 27.6 g/L of monobasic sodium phosphate in water

Mobile phase: Methanol and Solution A (30:70). Adjust with diluted phosphoric acid to a pH of 2.5.

Standard solution: 0.11 mg/mL of USP Doxepin Hydrochloride RS (equivalent to 0.1 mg/mL of doxepin) in Mobile phase

Sample stock solution: Nominally 0.57 mg/mL of doxepin hydrochloride (equivalent to 0.5 mg/mL of doxepin) from the contents of NLT 20 Capsules in Mobile phase, prepared as follows. Remove, as completely as possible, the contents of NLT 20 Capsules. Mix the combined contents, and transfer a suitable quantity of the powder, equivalent to 50 mg of doxepin, to a 100-mL volumetric flask. Add 70 mL of Mobile phase, and shake by mechanical means for 30 min. Dilute with Mobile phase to volume, and filter. Use the filtrate.

Sample solution: Nominally 0.1 mg/mL of doxepin from Sample stock solution in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm. For Identification B, use a diode array detector in the range of 200-400 nm.

Column: 4-mm x 12.5-cm; 5-µm packing LZ

Column temperature: 50°

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 2 times the retention time of the first peak of doxepin

System suitability

Sample: Standard solution

[NOTE-The relative retention times for the (E)- and (Z)-isomers are 1.0 and 1.1, respectively.]

Suitability requirements

Resolution: NLT 1.5 between the (E)- and (Z)-isomers

Tailing factor: NMT 2.0 each for the (E)- and (Z)-isomers

Relative standard deviation: NMT 2.0% each for the (E)- and (Z)-isomers

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of doxepin (C₁₉H₂₁NO) in the portion of Capsules taken:

Result = [(r_U(Z) + r_U(E) )/(r_S(Z) + r_S(E) )] × (C_S /C_U ) × (M_r1 /M_r2 ) × 100

r_U(Z) = peak response of the (Z)-isomer from the Sample solution

r_U(E) = peak response of the (E)-isomer from the Sample solution

r_S(Z) = peak response of the (Z)-isomer from the Standard solution

r_S(E) = peak response of the (E)-isomer from the Standard solution

C_S = concentration of doxepin hydrochloride in the Standard solution (mg/mL)

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

M_r1 = molecular weight of doxepin, 279.38

M_r2 = molecular weight of doxepin hydrochloride, 315.84

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1

Medium: Water; 900 mL

Apparatus 1: 50 rpm

Time: 30 min

Standard solution: USP Doxepin Hydrochloride RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable lter. Dilute with Medium, if necessary, to the same

concentration as the Standard solution.

Instrumental conditions

Mode: UV

Analytical wavelength: 292 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of doxepin (C₁₉H₂₁NO) in the portion of Capsules taken:

Result = (A_u /A_s ) × C_s × D × (M_r1 /M_r2 ) × V × (1/L) × 100

A_u = absorbance of the Sample solution

A_s = absorbance of the Standard solution

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

D = dilution factor of the Sample solution, if necessary

M_r1 = molecular weight of doxepin, 279.38

M_r2 = molecular weight of doxepin hydrochloride, 315.84

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of doxepin (C₁₉H₂₁NO) is dissolved.

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

Medium: 0.15% w/v pepsin (1:10000 with Albumin substrate) in water, 900 mL. [NOTE-The Medium may appear hazy.]

Apparatus 1: 50 rpm

Time: 30 min

Dilute phosphoric acid: Transfer 6.5 mL of phosphoric acid to a 100-mL volumetric flask and dilute with water to volume.

Buffer: 1.42 g/L of anhydrous dibasic sodium phosphate in water, adjust with dilute phosphoric acid to a pH of 7.7

Mobile phase: Acetonitrile and Buffer (60:40)

Standard stock solution: 0.63 mg/mL of USP Doxepin Hydrochloride RS (equivalent to 0.6 mg/mL of doxepin) prepared as follows. Transfer a suitable quantity of USP Doxepin Hydrochloride RS to an appropriate volumetric flask. Add 70% of the flask volume of Medium. Sonicate for about 5 min and dilute with Medium to volume.

Standard solution: (L/800) mg/mL of USP Doxepin Hydrochloride RS (equivalent to [L/900] mg/mL of doxepin) from Standard stock solution, where L is the label claim in mg/Capsule, prepared as follows. Transfer a portion of Standard stock solution to an appropriate volumetric flask and dilute with Medium to volume. Pass the resulting solution through a suitable filter discarding the first few milliliters.

Sample solution: Pass a portion of the solution under test through a suitable filter discarding the first few milliliters.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 15-cm; 3.5-µm packing L1

Column temperature: 40°

Flow rate: 1.2 mL/min

Injection volume: 10 µL

Run time: NLT 1.5 times the retention time of doxepin

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.5%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of doxepin (C₁₉H₂₁NO) dissolved:

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

r_u = peak response of doxepin from the Sample solution

r_s = peak response of doxepin from the Standard solution

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

V = volume of Medium, 900 mL

M_r1 = molecular weight of doxepin, 279.38

M_r2 = molecular weight of doxepin hydrochloride, 315.84

L = label claim for doxepin (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of doxepin (C₁₉H₂₁NO) is dissolved.

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

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

Apparatus 1: 100 rpm

Time: 30 min

Buffer: 27.6 g/L of sodium phosphate monobasic in water. Adjust with phosphoric acid to a pH of 2.5.

Mobile phase: Methanol and Buffer (50:50). Adjust with phosphoric acid to a pH of 2.5, if necessary.

Standard solution: 0.023 mg/mL of USP Doxepin Hydrochloride RS in Medium. Sonicate, 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 few milliliters. If necessary, dilute with Medium to a concentration similar to that of the Standard solution.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 15-cm; 3.5-µm packing LZ

Column temperature: 50°

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 1.5 times the retention time of the (Z)-isomer

System suitability

Sample: Standard solution

[NOTE-The relative retention times of (E)- and (Z)-isomers are 1.00 and 1.08, respectively.]

Suitability requirements

Resolution: NLT 1.5 between the (E)-and (Z)-isomers

Tailing factor: NMT 2.0 each for the (E)- and (Z)-isomers

Relative standard deviation: NMT 2.0% for sum of the (E)- and (Z)-isomers

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of doxepin (C₁₉H₂₁NO) dissolved:

Result = [(r_U(E) + r_U(Z) )/(r_S(E) + r_S(Z) )] × C_S × D × V × (M_r1 /M_r1 ) × (1/L) × 100

r_U(E) = peak response of the (E)-isomer from the Sample solution

r_U(Z) = peak response of the (Z)-isomer from the Sample solution

r_S(E) = peak response of the (E)-isomer from the Standard solution

r_S(Z) = peak response of the (Z)-isomer from the Standard solution

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

D = dilution factor of the Sample solution

V = volume of Medium, 500 mL

M_r1 = molecular weight of doxepin, 279.38

M_r2 = molecular weight of doxepin hydrochloride, 315.84

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of doxepin (C₁₉H₂₁NO) is dissolved.

Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.

Medium: 0.1 N hydrochloric acid; 500 mL

Apparatus 2: 75 rpm, with suitable sinkers

Time: 30 min

Standard stock solution: 1.12 mg/mL of USP Doxepin Hydrochloride RS in water. Sonicate to dissolve.

Standard solution

[NOTE-The Standard solution may be stable for 17 h at room temperature.]

For Capsules labeled to contain 10 mg: 0.0224 mg/mL of USP Doxepin Hydrochloride RS from Standard stock solution in Medium

For Capsules labeled to contain 25, 50, 75, and 100 mg: 0.056 mg/mL of USP Doxepin Hydrochloride RS from Standard stock solution in Medium

Sample stock solution: Pass a portion of the solution under test through a suitable filter of 0.22-µm pore size, discarding the first 5 mL of filtrate.

Sample solution

[NOTE-The Sample solution may be stable for 17 h at room temperature.]

For Capsules labeled to contain 10 and 25 mg: Use Sample stock solution.

For Capsules labeled to contain 50 mg: Transfer 5.0 mL of Sample stock solution to a 10-mL volumetric flask and dilute with Medium to volume.

For Capsules labeled to contain 75 mg: Transfer 3.0 mL of Sample stock solution to to a 10-mL volumetric flask and dilute with Medium to volume.

For Capsules labeled to contain 100 mg: Transfer 6.0 mL of Sample stock solution to a 25-ml volumetric flask and dilute with Medium to

volume.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy (857).)

Mode: UV

Analytical wavelength: 292 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of doxepin (C₁₉H₂₁NO) in the portion of Capsules taken:

Result = (A_u /A_s ) × C_s × V × D × (M_r1 /M_r2 ) × (1/L) × 100

A_u = absorbance of the Sample solution

A_s = absorbance of the Standard solution

C_s = concentration of USP Doxepin 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 doxepin, 279.38

M_r2 = molecular weight of doxepin hydrochloride, 315.84

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of doxepin (C₁₉H₂₁NO) is dissolved. _{(RB 1-Mar-2023)}

Uniformity of Dosage Units 〈905〉: Meet the requirements

The following procedure is used where the test for Content Uniformity is required.

Procedure for content uniformity

Diluent: Methanol and 0.05 M monobasic sodium phosphate TS (50:50). Adjust with 2 N sodium hydroxide TS to a pH of 6.7.

Standard solution: 0.11 mg/mL of USP Doxepin Hydrochloride RS (equivalent to 0.1 mg/mL of doxepin) in Diluent. Filter, and use the resulting filtrate.

Sample solutions: Nominally 0.1 mg/mL of doxepin from 1 Capsule prepared as follows. Transfer the contents of 1 Capsule into an appropriate volumetric flask, add 80% of the final flask volume of Diluent, and shake the flask by mechanical means for about 30 min. Dilute with Diluent to volume. If necessary, transfer a suitable quantity of the resulting solution to another appropriate volumetric flask, and dilute with Diluent to volume. Prepare 10 Sample solutions.

Instrumental conditions

Mode: UV

Analytical wavelength: 292 nm

Cell: 0.5 cm

Analysis

Samples: Standard solution and Sample solutions

Determine the amount of active ingredient in each unit of the Sample solution in comparison with the Standard solution.

5 IMPURITIES

ORGANIC IMPURITIES

Solution A: 1.6 g/L of ammonium formate in water

Mobile phase: Acetonitrile and Solution A (45:55)

System suitability solution: 570 µg/mL of USP Doxepin Hydrochloride RS (equivalent to 500 µg/mL of doxepin), 0.5 µg/mL of USP Doxepin Related Compound B RS, and 1 µg/mL of USP Doxepin Related Compound C RS in Mobile phase

Standard solution: 5.7 µg/mL of USP Doxepin Hydrochloride RS (equivalent to 5 µg/mL of doxepin) in Mobile phase

Sensitivity solution: 0.28 µg/mL of USP Doxepin Hydrochloride RS (equivalent to 0.25 µg/mL of doxepin) from Standard solution in Mobile phase

Sample solution: Nominally 500 µg/mL of doxepin from Capsules prepared as follows. Combine the contents of NLT 20 Capsules. Transfer a portion of the contents, equivalent to 50 mg of doxepin, to a 100-mL volumetric flask. Dilute with Mobile phase to volume and stir for 10 min. Pass the resulting solution through a suitable filter of 0.7-um pore size and discard the first 5 mL.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4,6-mm x 25-cm; 5-µm packing 11

Column temperature: 30°

Flow rate: 1.2 mL/min

Injection volume: 20 µL

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

Run time: NLT 6.3 times the retention time of doxepin

System suitability

[NOTE-See Table 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between doxepin related compound B and doxepin related compound C; NLT 1.5 between doxepin related compound C and doxepin, 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 impurity in the portion of Capsules taken:

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

r_u = peak response of each impurity from the Sample solution

r_s = peak response of doxepin from the Standard solution

C_s = concentration of USP Doxepin Hydrochloride RS in the Standard solution (µg/mL)

C_u = nominal concentration of doxepin in the Sample solution (µg/mL)

M_r1 = molecular weight of doxepin, 279.38

M_r2 = molecular weight of doxepin hydrochloride, 315.84

F = relative response factor (see Table 1)

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

Table 1

^a Process impurity included in the table for identication purposes only. Process impurities are controlled in the drug substance, and are not to be reported or included in the total impurities for the drug product.

^b Dibenzo[b,e]oxepin-11(6H)-one.

6 SPECIFIC TESTS

WATER DETERMINATION (921), Method I

Sample: Contents of 1 Capsule

Acceptance criteria: NMT 9.0%

7 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers. Store at controlled room temperature.

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

USP REFERENCE STANDARDS (11)

USP Doxepin Hydrochloride RS

USP Doxepin Related Compound B. RS

11(RS)-(3-(Dimethylamino)propyl)-6,11-dihydrodibenzo[b,e]oxepin-11-ol.

C₁₉H₂₃NO₂                       297.39

USP Doxepin Related Compound C RS

(EZ)-3-(Dibenzo[b,e]oxepin-11(6H)-ylidene)-N-methylpropan-1-amine hydrochloride.

C₁₈H₁₉NO · HCl                301.81