Doxepin 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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1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N- dimethyl-, hydrochloride;

N,N-Dimethyldibenz[b,e]oxepin-Δ^11-

11-(6H)-γ-propylamine hydrochloride CAS RN^®: 1229-29-4; UNII: 3U9A0FE9N5.

(E)-isomer CAS RN^_®: 4698-39-9; UNII: CU61C5RH24.

(Z)-isomer CAS RN^®: 25127-31-5; UNII: XI27WMG8QK.

1 DEFINITION

Doxepin Hydrochloride, an (E) and (Z) geometric isomer mixture, contains the equivalent of NLT 98.0% and NMT 102.0% of doxepin hydrochloride (C₁₉H₂₁NO · HCl), calculated on the dried basis. It contains NLT 13.6% and NMT 18.1% of the (Z)-isomer, and NLT 81.4% and NMT 88.2% of the (E)-isomer.

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K or 197A (USP 1-May-2021)

Change to read:

B. The retention times of the major peaks for the (E)- and (Z)-isomers of the Sample solution correspond to those (USP 1-May-2021) of the Standard solution, as obtained in the Assay.

Change to read:

C. IDENTIFICATION TESTS GENERAL (191), Chemical Identification Tests. Chloride

Diluent: Alcohol and water (50:50)

Sample solution: 10 mg/mL of Doxepin Hydrochloride in Diluent

Acceptance criteria: Meets the requirements of the test for amine hydrochlorides (USP 1-May-2021)

3 ASSAY

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PROCEDURE

Solution A: 27.6 g/L of monobasic sodium phosphate in water (USP 1-May-2021)

Mobile phase: Methanol and Solution A (30:70) (USP 1-May-2021) Adjust with diluted phosphoric acid (USP 1-May-2021) to a pH of 2.5.

Standard solution: 0.1 mg/mL of USP Doxepin Hydrochloride RS in Mobile phase

Sample solution: 0.1 mg/mL of Doxepin Hydrochloride in Mobile phase. Sonication may be used to aid in dissolution.

Chromatographic system

(See Chromatography (621) System Suitability)

Mode: LC

Detector: UV 254 nm

Column: 4-mm x 12.5-cm 5-µm (USP 1-May-2021) Packing L7

Column temperature: 50°

Flow rate: 1 mL/min

Injection volume: 20 µl

Run time: NLT 2 times the retention time of the (E)-isomer (USP 1-May-2021)

System suitability

Sample: Standard solution

[Note: The relative retention times for the (E) and (2) isomera are 1.0 and 1.1, respectively) (USP 1-Mar-2021)

Suitability requirements

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

Tailing factor: NMT 2.0 each for (USP 1-May-2021) the (E)- and (Z)-isomers

Relative standard deviation: NMT 2.0% each for the (E)- and (Z)-isomers (USP 1-May-2021)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of doxepin hydrochloride (C₁₉H₂₁NO · HCl) in the portion of Doxepin Hydrochloride taken:

Result = [(r_U(Z) + r_U(E) )/(r_S(Z) + r_{​​​​​​​S(E)} ] × (C_S /C_U ) × 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 USP Doxepin Hydrochloride RS in the Standard solution (mg/mL)

C_U​​​​​​​ = concentration of Doxepin Hydrochloride in the Sample solution (mg/mL)

Calculate the percentage of the (Z)-isoner of doxepin hydrochloride (C₁₉H₂₁NO · HCl) in the portion of Doxepin Hydrochloride taken: 

Result = (r_U(Z)/(r_{​​​​​​​S(Z)}) × (C_S /C_U ) × 100

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

r_{​​​​​​​U(E)} = peak response of the (Z)-isomer from the Standard solution

r_{​​​​​​​S(Z)} = concentration of the (Z)-isomer in the Standard solution (mg/mL) based on the labeled percentage of the (Z)-isomer in USP Doxepin Hydrochloride RS

r_{​​​​​​​S(E)} = concentration of Doxepin Hydrochloride in the Sample solution (mg/mL)

Calculate the percentage of the (E)-isomer of doxepin hydrochloride (C,H, NO-HCI) in the portion of Doxepin Hydrochloride taken: 

Result = (r_U(E)/(r_{​​​​​​​S(E)}) × (C_S /C_U ) × 100

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

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

C_S = concentration of the (E)-isomer in the Standard solution (mg/ml) based on the labeled percentage of the (E)-isomer in USP Doxepin Hydrochloride RS

C_U = concentration of Doxepin Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria

Doxepin hydrochloride: 98.0%-102.0% on the dried basis

(Z)-Isomer of doxepin hydrochloride: 13.6%-18.1%

(E)-Isomer of doxepin hydrochloride: 81.4%-88.2%

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.2%

Change to read:

ORGANIC IMPURITIES

[NOTE-This procedure is not intended to resolve the (E)- and (Z)-isomers of doxepin hydrochloride. Minor variations in Mobile phase composition could result in a shoulder in the trailing edge of doxepin. In cases where there may be separation, both the (E)- and (Z)-isomers should be used in the appropriate calculation.

Solution A: Transfer 1 mL of phosphoric acid to a 10-ml volumetric flask containing about 5 mL of water. Cool and dilute with water to volume (USP 1-May-2021)

Buffer: 1.42 g/L of dibasic sodium phosphate, adjusted with Solution A to a pH of 7.7

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USP-NF Doxepin Hydrochloride

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

Diluent: To each liter of Mobile phase add 2 mL of 2N sodium hydroxide TS (USP 1-May-2021)

Standard solution: 0.001 mg/mL each of USP Doxepin Hydrochloride RS, USP Doxepin Related Compound A RS, and USP Doxepin Related Compound B RS: and 0.002 mg/mL of USP Doxepin Related Compound C RS in Diluent. Sonication for about 1 min may be used to aid the initial dissolution of the compounds.

*Sensitivity solution: 0.0005 mg/mL each of USP Doxepin Hydrochloride RS, USP Doxepin Related Compound A RS, and USP Doxepin Related Compound B RS: and 0.001 mg/mL of USP Doxepin Related Compound C RS from Standard solution in Diluent (USP 1-May-2021)

Sample solution: 1 mg/mL of Doxepin Hydrochloride in Diluent

Chromatographic system

(See Chromatography (621). System Suitability)

Mode: LC

Detector: UV 215 nm

Column: 4.6-mm x 25-cm, 5-um packing L1

Column temperature: 30"

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: 2.2 times the retention time of doxepin

System suitability

Samples: Standard solution and Sensitivity solution (USP 1-May-2021)

[Nom-See Table 1 for relative retention times. The doxepin related compound C peak will be the largest peak in the Standard solution chromatogram.]

Suitability requirements

Resolution: NLT 1.5 between doxepin related compound A and doxepin related compound C; NLT 1.5 between doxepin related compound

C and doxepin related compound B, Standard solution

Relative standard deviation: NMT 5.0% for doxepin, Standard solution (USP 1-May-2021)

Signal-to-noise ratio: NLT 10 for doxepin, doxepin related compound A, doxepin related compound B, and doxepin related compound C, Sensitivity solution (USP 1-May-2021)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each doxepin related compound in the portion of Doxepin Hydrochloride taken:

Result = (r_U/(r_{​​​​​​​S}) × (C_S /C_U ) × 100

r_U = peak response of doxepin related compound A, B, or C from the Sample solution

r_S = peak response of doxepin related compound A, B, or C from the Standard solution

C_S = concentration of USP Doxepin Related Compound A RS, USP Doxepin Related Compound B RS, or USP Doxepin Related Compound C RS in the Standard solution (mg/mL)

C_U = concentration of Doxepin Hydrochloride in the Sample solution (mg/ml.)

Acceptance criteria: See Table 1. Disregard any peak with a relative retention time less than 0.25. The reporting threshold is 0.05% (USP 1-May-2021)

5 SPECIFIC TESTS

LOSS ON DRYING (731)

Analysis: Dry under vacuum at 60 for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers.