Clomipramine Capsules

General Notices

Action and use

Monoamine reuptake inhibitor; tricyclic antidepressant.

Definition

Clomipramine Capsules contain Clomipramine Hydrochloride.

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

Content of clomipramine hydrochloride, C19H23ClN2,HCl

95.0 to 105.0% of the stated amount.

Identification

Triturate a quantity of the contents of the capsules containing 0.15 g of Clomipramine Hydrochloride with 10 mL of chloroform, filter and evaporate the filtrate to dryness. The infrared absorption spectrum of the residue, Appendix II A, after recrystallisation from hot acetone and drying at 110° for 30 minutes, is concordant with the reference spectrum of clomipramine hydrochloride (RS 069).

TESTS

Related substances

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

(1) Disperse a quantity of the mixed contents of 20 capsules containing 40 mg of Clomipramine Hydrochloride with 15 mL of mobile phase A with the aid of ultrasound for 15 minutes, cool, dilute to 20 mL with the same solvent and filter through a 0.45 µm PTFE filter.
(2) Dilute 1 volume of solution (1) to 100 volumes with mobile phase A.
(3) 0.002% w/v of clomipramine impurity B BPCRS and 0.0004% w/v of each of clomipramine impurity C BPCRS, clomipramine impurity D BPCRS and clomipramine impurity F BPCRS in mobile phase A.
(4) 0.005% w/v of clomipramine hydrochloride BPCRS and 0.0015% w/v of clomipramine impurity C BPCRS in mobile phase A.
chromatographic conditions
(a) Use a stainless steel column (25.0 cm x 4.6 mm) packed with cyanopropylsilyl silica gel for chromatography (5 µm) (Hypersil BDS CN is suitable).
(b) Use gradient elution and the mobile phases described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 30°.
(e) Use a detection wavelength of 254 nm.
(f) Inject 20 µL of each solution.
mobile phase

Mobile phase ADissolve 1.2 g of sodium dihydrogen orthophosphate in 950 mL of water, add 1.1 mL of nonylamine, adjust to pH 3.0 with orthophosphoric acid and add sufficient water to produce 1000 mL (solution A). Mix 75 volumes of solution A with 25 volumes of acetonitrile.

Mobile phase BMix 65 volumes of solution A and 35 volumes of acetonitrile.

The retention times relative to clomipramine are about 0.5, 0.7, 0.9, 1.7, 2.5, 3.4 and 4.3 for impurities A, B, C, D, E, F and G, respectively.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (4), the resolution factor between the peaks due to clomipramine and clomipramine impurity C is at least 3.0.

limits

In the chromatogram obtained with solution (1):

the area of any peak corresponding to clomipramine impurity B is not greater than the area of the corresponding peak in the chromatogram obtained with solution (3) (1%);

the area of any peak corresponding to impurity C or impurity D is not greater than the area of the corresponding peak in the chromatogram obtained with solution (3) (0.2%),

the area of any peak corresponding to impurity F is not greater than the area of the corresponding peak in the chromatogram obtained with solution (3) (0.2%);

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

and the sum of the areas of any such secondary peaks is not greater than 0.2 times the area of the principal peak in the chromatogram obtained with solution (2) (0.2%).

The sum of the impurities is not greater than 1.0%.

Disregard any peak with an area not greater than 0.01 times the area of the principal peak in the chromatogram obtained with solution (2) (0.01%).

Assay

Shake a quantity of the mixed contents of 20 capsules containing 50 mg of Clomipramine Hydrochloride with 200 mL of 0.1m hydrochloric acid for 1 hour, dilute to 250 mL with 0.1m hydrochloric acid and filter. Dilute 15 mL of the filtrate to 100 mL with 0.1m hydrochloric acid and measure the absorbance of the resulting solution at the maximum at 252 nm, Appendix II B. Calculate the content of C19H23ClN2,HCl taking 226 as the value of A(1%, 1 cm) at the maximum at 252 nm.

Impurities

A. N-[3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propyl]-N,N′,N′-trimethylpropane-1,3-diamine,
B. imipramine,
C. 3-(3-chloro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine,
D. R1=R3=Cl, R2=CH2-CH2-CH2-N(CH3)2: 3-(3,7-dichloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine,
E. R1=R2=R3=H: 10,11-dihydro-5H-dibenzo[b,f]azepine (iminodibenzyl),
F. R1=Cl, R2=R3=H: 3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepine,
G. R1=Cl, R2=CH2-CH=CH2, R3=H: 3-chloro-5-(prop-2-enyl)-10,11-dihydro-5H-dibenzo[b,f]azepine.