Doxepin Capsules

General Notices

Action and use

Monoamine reuptake inhibitor; tricyclic antidepressant.

Definition

Doxepin Capsules contain Doxepin Hydrochloride.

The capsules comply with the requirements stated under Capsules and with the following requirements.

Content of doxepin, C19H21NO

95.0 to 105.0% of the stated amount.

Identification

Wash a quantity of the contents of the capsules containing the equivalent of 100 mg of Doxepin with three 5-mL quantities of petroleum spirit (boiling range, 40° to 60°). Dry in air, extract the residue with three 10-mL quantities of chloroform, evaporate the combined extracts to dryness and dry the residue at 105°. The residue complies with the following tests.

A. The infrared absorption spectrum, Appendix II A, is concordant with the reference spectrum of doxepin hydrochloride (RS 117).
B. Yields reaction A characteristic of chlorides, Appendix VI.

TESTS

Z-Isomer

13.0 to 18.5%, when determined by the following method.

Carry out the method for gas chromatography, Appendix III B, using the following solutions.

(1) Extract a quantity of the mixed contents of 20 capsules containing the equivalent of 25 mg of doxepin with 5 mL of methanol, centrifuge and use the supernatant liquid.
(2) 0.5% w/v of doxepin hydrochloride BPCRS in methanol.
chromatographic conditions
(a) Use a fused silica capillary column (30 m × 0.53 mm) bonded with a film (3 µm) of 6% cyanopropylphenyl siloxane and 94% polydimethylsiloxane (DB-624 is suitable).
(b) Use helium as the carrier gas at 20 mL/min.
(c) Use an oven temperature maintained at 200°.
(d) Use an inlet temperature of 240°.
(e) Use a flame ionisation detector maintained at a temperature of 300°.
(f) Use a split ratio of 1:10.
(g) Inject 1 µL of each solution.

When the chromatograms are recorded under the prescribed conditions the retention of E-doxepin is about 29 minutes.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (2), a peak due to Z-doxepin immediately precedes the principal peak due to E-doxepin and the resolution between the peaks due to Z-doxepin and E-doxepin is at least 2.0.

determination of content

Measure the areas or heights of the peaks due to the Z- and E-isomers in the chromatograms obtained with solutions (1) and (2) and calculate the content of Z-isomer in the substance being examined using the declared content of Z-isomer in doxepin hydrochloride BPCRS.

Related substances (other than the Z-Isomer)

Carry out the method for liquid chromatography, Appendix III D, using the following solutions in solvent A.

Solvent AA mixture of 2 volumes of 2m sodium hydroxide and 1000 volumes of mobile phase.

(1) Dissolve with the aid of ultrasound a quantity of the contents of the capsules containing the equivalent of 100 mg of doxepin in 100 mL of solvent A and filter.
(2) Dilute 1 volume of solution (1) to 100 volumes with solvent A and further dilute 1 volume to 10 volumes with solvent A.
(3) Dissolve the contents of a vial of doxepin impurity standard BPCRS in 25 mL of the mobile phase.
chromatographic conditions
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Phenomenex Luna C18 (2) is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use a column temperature of 30°.
(e) Use a detection wavelength of 215 nm.
(f) Inject 20 µL of each solution.
(g) For solution (1), allow the chromatography to proceed for twice the retention time of the principal peak.
mobile phase

20 volumes of acetonitrile R1, 30 volumes of 0.01m disodium hydrogen orthophosphate, adjusted to pH 7.7 using 0.02m orthophosphoric acid, and 50 volumes of methanol.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (3):

the resolution between the peaks due to impurity A and impurity C is at least 1.5;

the resolution between the peaks due to impurity C and impurity B is at least 1.5.

limits

Identify any peak corresponding to impurity B using the chromatogram obtained with solution (3) and multiply the area of the peak by a correction factor of 1.7.

In the chromatogram obtained with solution (1):

identify any peaks corresponding to impurity A, B and C using the chromatogram obtained with solution (3) and the chromatogram supplied with doxepin impurity standard BPCRS;

the Z-isomer may appear as a shoulder on the peak due to doxepin;

the area of any peak corresponding to impurity A is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);

the area of any peak corresponding to impurity B is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);

the area of any peak corresponding to impurity C is not greater than 5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);

the area of any other peak is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);

the sum of the areas of any other secondary peaks is not greater than 4 times the area of the principal peak in the chromatogram obtained with solution (2) (0.4%);

the sum of the areas of all the peaks is not greater than 10 times the area of the principal peak in the chromatogram obtained with solution (2) (1.0%).

Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (2) (0.1%).

Assay

Weigh and powder the contents of 20 capsules. Carry out the method for liquid chromatography, Appendix III D, using the following solutions in solvent A, as described under Related substances (other than the Z-isomer).

(1) Dissolve with the aid of ultrasound a quantity of the contents of the capsules containing the equivalent of 100 mg of Doxepin in 100 mL of solvent A, filter and dilute 1 volume to 10 volumes with solvent A.
(2) Prepare a solution of doxepin hydrochloride BPCRS containing the equivalent of 0.01% w/v doxepin in solvent A.
(3) Dissolve the contents of a vial of doxepin impurity standard BPCRS in 25 mL of the mobile phase.
chromatographic conditions

The chromatographic conditions described under Related substances (other than the Z-isomer) may be used.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (3):

the resolution between the peaks due to impurity A and impurity C is at least 1.5;

the resolution between the peaks due to impurity B and impurity C is at least 1.5.

determination of content

Calculate the content of C19H21NO in the capsules using the declared content of C19H21NO,HCl in doxepin hydrochloride BPCRS. Each mg of C19H21NO,HCl is equivalent to 0.884g of C19H21NO.

Impurities

The impurities limited by the requirements of this monograph include those listed under Doxepin Hydrochloride.

Labelling

The quantity of active ingredient is stated in terms of the equivalent amount of doxepin.