BP 2025 (Ph. Eur. 11.6 update)
C24H30N2O4 410.5 521-78-8
Action and use
Monoamine reuptake inhibitor; tricyclic antidepressant.
Preparation
Trimipramine Tablets
DEFINITION
(2RS)-3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine hydrogen (2Z)-but-2-enedioate.
Content
98.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Slightly soluble in water and in ethanol (96 per cent).
IDENTIFICATION
A. Melting point (2.2.14): 140 °C to 144 °C.
B. Infrared absorption spectrophotometry (2.2.24).
Comparison trimipramine maleate CRS.
TESTS
Related substances
Liquid chromatography (2.2.29). Carry out the test protected from light.
Buffer solution pH 7.7 2.64 g/L solution of ammonium phosphate R in water for chromatography R; adjust to pH 7.7 with phosphoric acid R.
Test solution Dissolve 50 mg of the substance to be examined in the mobile phase and dilute to 100 mL with the mobile phase.
Reference solution (a) Dissolve 5 mg of the substance to be examined and 5 mg of iminodibenzyl R (impurity F) in the mobile phase and dilute to 10 mL with the mobile phase.
Reference solution (b) Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase.
Reference solution (c) Dissolve the contents of a vial of trimipramine for peak identification CRS (containing impurities A, B, C, D and E) in 1 mL of acetonitrile R1.
Column:
— size: l = 0.125 m, Ø = 4.0 mm;
— stationary phase: end-capped octadecylsilyl silica gel for chromatography R (5 μm).
Mobile phase acetonitrile R1, buffer solution pH 7.7 (38:62 V/V).
Flow rate 1.5 mL/min.
Detection Spectrophotometer at 210 nm.
Injection 20 μL.
Run time 3 times the retention time of trimipramine.
Identification of impurities Use the chromatogram supplied with trimipramine for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peaks due to impurities A, B, C, D and E; doubling of the peak due to impurity E may be observed.
Relative retention With reference to trimipramine (retention time = about 27 min): impurity A = about 0.1; impurity B = about 0.3; impurity C = about 0.4; impurity D = about 0.5; impurity F = about 1.4; impurity E = about 1.5.
System suitability:
— resolution: minimum 3.5 between the peaks due to trimipramine and impurity F in the chromatogram obtained with reference solution (a);
— the chromatogram obtained with reference solution (c) is similar to the chromatogram supplied with trimipramine for peak identification CRS.
Limits:
— correction factor: for the calculation of content, multiply the peak area of impurity F by 0.5;
— impurity E: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.3 per cent);
— impurity F: not more than 2 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent);
— impurities A, B, C, D: for each impurity, not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.15 per cent);
— unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);
— total: not more than 10 times the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 per cent);
— disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.350 g in 50 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 41.05 mg of C24H30N2O4.
STORAGE
Protected from light.
IMPURITIES
Specified impurities A, B, C, D, E, F.
Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use) G.
A. (2RS)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine N-oxide,
B. (2RS)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,2-dimethylpropan-1-amine,
C. (2RS)-3-(5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine,
D. imipramine,
E. mixture of the stereoisomers of N-[3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-methylpropyl]-N,N′,N′,2- tetramethylpropane-1,3-diamine,
F. 10,11-dihydro-5H-dibenzo[b,f]azepine,
G. 2-methyl-10,11-dihydro-5H-dibenzo[b,f]azepine.
