Doxepin Hydrochloride
;)
1-Propanamine,3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-,hydrochloride.
N,N-Dimethyldibenz[b,e]oxepin-D11(6H),g-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 98.0percent and not more than 102.0percent of doxepin (C19H21NO·HCl),calculated on the dried basis.It contains not less than 13.6percent and not more than 18.1percent of the (Z)-isomer,and not less than 81.4percent and not more than 88.2percent of the (E)-isomer.
Packaging and storage—
Preserve in well-closed containers.
Identification—
A:
Infrared Absorption á197Kñ.
B:
Ultraviolet Absorption á197Uñ—
Solution:
50µg per mL.
Medium:
alcohol.
Absorptivities at 296nm,calculated on the dried basis,do not differ by more than 3.0%.
Loss on drying á731ñ—
Dry it in vacuum at 60
for 3hours:it loses not more than 0.5%of its weight.
for 3hours:it loses not more than 0.5%of its weight.
Residue on ignition á281ñ:
not more than 0.2%.
Heavy metals,Method IIá231ñ:
0.002%.
Organic volatile impurities,Method Iá467ñ:
meets the requirements.
Chloride content—
Dissolve about 100mg,accurately weighed,in a mixture of 100mLof water and 100mLof alcohol.Titrate with 0.05Nsilver 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 mLof 0.05Nsilver nitrate is equivalent to 1.773mg of chloride.Not less than 10.9%and not more than 11.6%of chloride is found.
Assay—
Mobile phase—
Prepare a mixture of 0.2Mmonobasic sodium phosphate buffer and methanol (7:3),adjust with 2Nphosphoric acid to a pHof 2.5,filter,and degas.Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Standard preparation—
Dissolve an accurately weighed quantity of USP Doxepin Hydrochloride RSin Mobile phase,and dilute quantitatively and stepwise with Mobile phaseto obtain a solution having a known concentration of about 100µg per mL.
Assay preparation—
Transfer about 50mg of Doxepin Hydrochloride,accurately weighed,to a 100-mLvolumetric flask.Add about 70mLof Mobile phase,and sonicate to dissolve.Dilute with Mobile phaseto volume,and mix.Pipet 10.0mLof this solution into a 50-mLvolumetric flask,and dilute with Mobile phaseto 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 1mLper 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%.
,that contains packing L7.The flow rate is about 1mLper 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 20µL)of the Standard preparationand the Assay preparationinto 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 Cis the concentration,in µg per mL,of USP Doxepin Hydrochloride RSin 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 preparationtaken by the formula:
(rU(Z)/rS(Z))(WS/WT)(PZ),
in which WSis the weight,in mg,of USP Doxepin Hydrochloride RSin the Standard preparation,WTis the weight,in mg,in the portion of Doxepin Hydrochloride taken,and PZis the labeled percentage of (Z)-isomer in USP Doxepin Hydrochloride RS.Similarly calculate the percentage of (E)-isomer in the Assay preparationtaken by the formula:
(rU(E)/rS(E))(WS/WT)(PE),
in which PEis the labeled percentage of (E)-isomer in USP Doxepin Hydrochloride RS.
Auxiliary Information—
Staff Liaison:Salvador C.Salado,M.S.,Scientist and Latin American Liaison
Expert Committee:(PA3)Pharmaceutical Analysis 3
USP28–NF23Page 693
Pharmacopeial Forum:Volume No.27(4)Page 2730
Phone Number:1-301-816-8165