monograph of aminophylline

(Ph Eur monograph 0300)








C16H24N10O4 420.4 317-34-0
Action and use
Xanthine bronchodilator.
Preparations
Aminophylline Injection
Aminophylline Tablets
Ph Eur
DEFINITION
Theophylline-ethylenediamine contains not less than 84.0 per cent and not more than the equivalent of 87.4 per cent of theophylline (C7H8N4O2; M r 180.2) and not less than 13.5 per cent and not more than the equivalent of 15.0 per cent of ethylenediamine (C2H8N2; M r 60.1), both calculated with reference to the anhydrous substance.
CHARACTERS
A white or slightly yellowish powder, sometimes granular, freely soluble in water (the solution becomes cloudy through absorption of carbon dioxide), practically insoluble in ethanol.
IDENTIFICATION
First identification B, C, E.
Second identification A, C, D, E, F.
Dissolve 1.0 g in 10 ml of water R and add 2 ml of dilute hydrochloric acid R dropwise with shaking. Filter. Use the precipitate for identification tests A, B, D and F and the filtrate for identification test C.
A. The precipitate, washed with water R and dried at 100°C to 105°C, melts (2.2.14) at 270°C to 274°C.
B. Examine the precipitate, washed with water R and dried at 100°C to 105°C, by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with theophylline CRS.
C. To the filtrate add 0.2 ml of benzoyl chloride R, make alkaline with dilute sodium hydroxide solution R and shake vigorously. Filter the precipitate, wash with 10 ml of water R, dissolve in 5 ml of hot alcohol R and add 5 ml of water R. A precipitate is formed, which when washed and dried at 100°C to 105°C, melts (2.2.14) at 248°C to 252°C.
D. Heat about 10 mg of the precipitate with 1.0 ml of a 360 g/l solution of potassium hydroxide R in a water-bath at 90°C for 3 min, then add 1.0 ml of diazotised sulphanilic acid solution R. A red colour slowly develops. Carry out a blank test.
E. It complies with the test for water (see Tests).
F. The precipitate gives the reaction of xanthines (2.3.1).
TESTS
Appearance of solution
Dissolve 0.5 g with gentle warming in 10 ml of carbon dioxide-free water R. The solution is not more opalescent than reference suspension II (2.2.1) and not more intensely coloured than reference solution GY6 (2.2.2, Method II).
Related substances
Examine by thin-layer chromatography (2.2.27), using as the coating substance a suitable silica gel with a fluorescent indicator having an optimal intensity at 254 nm.
Test solution Dissolve 0.2 g of the substance to be examined in 2 ml of water R with heating and dilute to 10 ml with methanol R.
Reference solution Dilute 0.5 ml of the test solution to 100 ml with methanol R.
Apply to the plate 10 ml of each solution. Develop over a path of 15 cm using a mixture of 10 volumes of concentrated ammonia R, 30 volumes of acetone R, 30 volumes of chloroform R and 40 volumes of butanol R. Allow the plate to dry in air and examine in ultraviolet light at 254 nm. Any spot in the chromatogram obtained with the test solution, apart from the principal spot, is not more intense than the spot in the chromatogram obtained with the reference solution (0.5 per cent).
Heavy metals (2.4.8)
1.0 g complies with limit test C for heavy metals (20 ppm). Prepare the standard using 2 ml of lead standard solution (10 ppm Pb) R.
Water (2.5.12)
Not more than 1.5 per cent, determined on 2.00 g dissolved in 20 ml of anhydrous pyridine R, by the semi-micro determination of water.
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.
ASSAY
Ethylenediamine
Dissolve 0.250 g in 30 ml of water R. Add 0.1 ml of bromocresol green solution R. Titrate with 0.1 M hydrochloric acid until a green colour is obtained.
1 ml of 0.1 M hydrochloric acid is equivalent to 3.005 mg of C2H8N2.
Theophylline
Heat 0.200 g to constant mass in an oven at 135°C. Dissolve the residue with heating in 100 ml of water R, allow to cool, add 20 ml of 0.1 M silver nitrate and shake. Add 1 ml of bromothymol blue solution R1 . Titrate with 0.1 M sodium hydroxide .
1 ml of 0.1 M sodium hydroxide is equivalent to 18.02 mg of C7H8N4O2.
STORAGE
Store in airtight container , protected from light.
Ph Eur