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Doxepin Hydrochloride
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C19H21NO·HCl 315.84

1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N- dimethyl-, hydrochloride.
N,N-Dimethyldibenz[b,e]oxepin-D11(6H),-propylamine hydrochloride [1229-29-4; 4698-39-9 ((E)-isomer); 25127-31-5 ((Z)-isomer)].
» Doxepin Hydrochloride, an (E) and (Z) geometric isomer mixture, contains the equivalent of not less than 98.0 percent and not more than 102.0 percent of doxepin (C19H21NO·HCl), calculated on the dried basis. It contains not less than 13.6 percent and not more than 18.1 percent of the (Z)-isomer, and not less than 81.4 percent and not more than 88.2 percent of the (E)-isomer.
Packaging and storage— Preserve in well-closed containers.
Identification—
B: Ultraviolet Absorption 197U—
Solution: 50 µg per mL.
Medium: alcohol.
Absorptivities at 296 nm, calculated on the dried basis, do not differ by more than 3.0%.
Melting range, Class I 741: between 185 and 191.
Loss on drying 731— Dry it in vacuum at 60 for 3 hours: it loses not more than 0.5% of its weight.
Residue on ignition 281: not more than 0.2%.
Heavy metals, Method II 231: 0.002%.
Organic volatile impurities, Method I 467: meets the requirements.
Chloride content— Dissolve about 100 mg, accurately weighed, in a mixture of 100 mL of water and 100 mL of alcohol. Titrate with 0.05 N silver nitrate VS, determining the endpoint potentiometrically using a silver-silver sulfide sensing electrode and a double-junction reference electrode containing potassium nitrate filling solution in the outer jacket and a standard filling solution in the inner jacket. Each mL of 0.05 N silver nitrate is equivalent to 1.773 mg of chloride. Not less than 10.9% and not more than 11.6% of chloride is found.
Residual solvents 467: meets the requirements.
(Official January 1, 2007)
Assay—
Mobile phase— Prepare a mixture of 0.2 M monobasic sodium phosphate buffer and methanol (7:3), adjust with 2 N phosphoric acid to a pH of 2.5, filter, and degas. Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard preparation— Dissolve an accurately weighed quantity of USP Doxepin Hydrochloride RS in Mobile phase, and dilute quantitatively and stepwise with Mobile phase to obtain a solution having a known concentration of about 100 µg per mL.
Assay preparation— Transfer about 50 mg of Doxepin Hydrochloride, accurately weighed, to a 100-mL volumetric flask. Add about 70 mL of Mobile phase, and sonicate to dissolve. Dilute with Mobile phase to volume, and mix. Pipet 10.0 mL of this solution into a 50-mL volumetric flask, and dilute with Mobile phase to volume.
Chromatographic system— The liquid chromatograph is equipped with a 254-nm detector and a 4-mm × 12.5-cm column, heated to 50, that contains packing L7. The flow rate is about 1 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed under Procedure: the resolution between the (E)- and (Z)-isomers is not less than 1.5, the tailing factor for each analyte peak is not more than 2.0, and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of C19H21NO·HCl in the portion of Doxepin Hydrochloride taken by the formula:
0.5C[(rU(Z) + rU(E)) / (rS(Z) + rS(E))],
in which C is the concentration, in µg per mL, of USP Doxepin Hydrochloride RS in the Standard preparation, and rU(Z) and rU(E) are the respective peak responses of the (Z)- and (E)-isomers obtained from the Assay preparation, and rS(Z) and rS(E) are the respective peak responses of the (Z)- and (E)-isomers obtained from the Standard preparation. Calculate the percentage of the (Z)-isomer in the Assay preparation taken by the formula:
(rU(Z) / rS(Z))(WS / WT)(PZ),
in which WS is the weight, in mg, of USP Doxepin Hydrochloride RS in the Standard preparation, WT is the weight, in mg, in the portion of Doxepin Hydrochloride taken, and PZ is the labeled percentage of (Z)-isomer in USP Doxepin Hydrochloride RS. Similarly calculate the percentage of (E)-isomer in the Assay preparation taken by the formula:
(rU(E) / rS(E))(WS / WT)(PE),
in which PE is the labeled percentage of (E)-isomer in USP Doxepin Hydrochloride RS.
Auxiliary Information— Staff Liaison : Ravi Ravichandran, Ph.D., Senior Scientist
Expert Committee : (MDPP05) Monograph Development-Psychiatrics and Psychoactives
USP29–NF24 Page 758
Pharmacopeial Forum : Volume No. 27(4) Page 2730
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