Clomipramine Hydrochloride

(Ph Eur monograph 0889)

 

C19H23ClN2,HCl 351.3 17321-77-6

 

Ph Eur


 

 

Definition

 

3-(3-Chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine hydrochloride.

 

Content

 

99.0 per cent to 101.0 per cent (dried substance).

 

Characters

 

Appearance

 

White or slightly yellow, crystalline powder, slightly hygroscopic.

 

Solubility

 

Freely soluble in water and in methylene chloride, soluble in alcohol.

 

It shows polymorphism.

 

Identification

 

First identification

 

B, E.

 

Second identification

 

A, C, D, E.

 

A.    Melting point (2.2.14): 191C to 195C.

 

B.    Infrared absorption spectrophotometry (2.2.24).

 

Preparation

 

Discs of potassium bromide R. The transmittance at about 2000 cm-1 (5 mm) is at least 65 per cent without compensation.

 

Comparison

 

Clomipramine hydrochloride CRS.

 

C.    Thin-layer chromatography (2.2.27). Prepare the solutions immediately before use and protected from light.

 

Test solution

 

Dissolve 20 mg of the substance to be examined in methanol  R and dilute to 10 ml with the same solvent.

 

Reference solution

 

Dissolve 20 mg of clomipramine hydrochloride CRS in methanol  R and dilute to 10 ml with the same solvent.

 

Plate

 

TLC silica gel G plate R.

 

Mobile phase

 

Concentrated ammonia R, acetone R, ethyl acetate R (5:25:75 V/V/V).

 

Application

 

5 ml.

 

Development

 

Over a path of 15 cm.

 

Drying

 

In air.

 

Detection

 

Spray with a 5 g/l solution of potassium dichromate R in a 20 per cent V/V solution of sulphuric acid R. Examine immediately.

 

Results

 

The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with the reference solution.

 

D.    Dissolve about 5 mg in 2 ml of nitric acid R. An intense blue colour develops.

 

E.    Dissolve about 50 mg in 5 ml of water  R and add 1 ml of dilute ammonia R1. Mix, allow to stand for 5 min and filter. Acidify the filtrate with dilute nitric acid R. The solution gives reaction (a) of chlorides (2.3.1).

 

Tests

 

Solution S

 

Dissolve 2.0 g in carbon dioxide-free water  R and dilute to 20 ml with the same solvent.

 

Appearance of solution

 

Solution S is clear  (2.2.1) and not more intensely coloured than reference solution Y5 (2.2.2, Method I).

 

pH (2.2.3)

 

3.5 to 5.0 for solution S.

 

Related substances

 

Liquid chromatography (2.2.29). Prepare the solutions immediately before use and protected from light.

 

Test solution

 

Dissolve 20.0 mg of the substance to be examined in a mixture of 25 volumes of mobile phase B and 75 volumes of mobile phase A and dilute to 10.0 ml with the same mixture of mobile phases.

 

Reference solution (a)

 

Dissolve 22.6 mg of imipramine hydrochloride CRS, 4.0 mg of clomipramine impurity C CRS, 4.0 mg of clomipramine impurity D CRS and 2.0 mg of clomipramine impurity F CRS in a mixture of 25 volumes of mobile phase B and 75 volumes of mobile phase A and dilute to 100.0 ml with the same mixture of mobile phases. Dilute 1.0 ml of this solution to 10.0 ml with a mixture of 25 volumes of mobile phase B and 75 volumes of mobile phase A.

 

Reference solution (b)

 

Dilute 1.0 ml of the test solution to 100.0 ml with a mixture of 25 volumes of mobile phase B and 75 volumes of mobile phase A.

 

Reference solution (c)

 

Dissolve 10.0 mg of clomipramine hydrochloride CRS and 3.0 mg of clomipramine impurity C CRS in a mixture of 25 volumes of mobile phase B and 75 volumes of mobile phase A and dilute to 20.0 ml with the same mixture of mobile phases. Dilute 1.0 ml of this solution to 10.0 ml with a mixture of 25 volumes of mobile phase B and 75 volumes of mobile phase A.

 

Column:

size: l = 0.25 m, Ø = 4.6 mm,

 

stationary phase: cyanopropylsilyl silica gel for chromatography R (5 mm),

 

temperature: 30C.

 

Mobile phase:

mobile phase A: dissolve 1.2 g of sodium dihydrogen phosphate R in water  R, add 1.1 ml of nonylamine R, adjust to pH 3.0 with phosphoric acid R and dilute to 1000 ml with water  R,

 

mobile phase B: acetonitrile R.

 

Flow rate

 

1.5 ml/min.

 

Detection

 

Spectrophotometer at 254 nm.

 

Injection

 

20 ml.

 

Relative retentions

 

With reference to clomipramine (retention time = about 8 min): impurity A = about 0.5; impurity B = about 0.7; impurity C = about 0.9; impurity D = about 1.7; impurity E = about 2.5; impurity F = about 3.4; impurity G = about 4.3.

 

System suitability

 

Reference solution (c):

 

resolution: minimum 3.0 between the peaks due to clomipramine and to impurity C.

 

Limits:

impurity B: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (a) (1.0 per cent),

 

impurity C or D: for each impurity, not more than the area of the corresponding peak in the chromatogram obtained with reference solution (a) (0.2 per cent),

 

impurity F: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (a) (0.1 per cent),

 

any other impurity: not more than 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent),

 

total of other impurities: not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent),

 

total: not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 per cent),

 

disregard limit: 0.01 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.01 per cent).

 

Heavy metals (2.4.8)

 

Maximum 20 ppm.

 

2.0 g complies with limit test C. Prepare the standard using 4 ml of lead standard solution (10 ppm Pb) R.

 

Loss on drying (2.2.32)

 

Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 100-105C.

 

Sulphated ash (2.4.14)

 

Maximum 0.1 per cent, determined on 1.0 g.

 

Assay

 

Dissolve 0.250 g in 50 ml of alcohol  R and add 5.0 ml of 0.01M hydrochloric acid. Carry out a potentiometric titration (2.2.20), using 0.1M sodium hydroxide. Read the volume added between the 2 points of inflexion.

 

1 ml of 0.1M sodium hydroxide is equivalent to 35.13 mg of C19H24Cl2N2.

 

Storage

 

In an airtight container , protected from light.

 

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.

 

 

 


Ph Eur

 

Action and use

 

Antidepressant.

 

Preparation

 

Clomipramine Capsules