Phenylpropanolamine Hydrochloride

(Ph. Eur. monograph 0683)

C₉H₁₄ClNO 187.7 154-41-6

Action and use

Adrenoceptor agonist.

DEFINITION

(1RS,2SR)-2-Amino-1-phenylpropan-1-ol hydrochloride.

Content

99.0 per cent to 101.5 per cent (dried substance).

CHARACTERS

Appearance

White or almost white, crystalline powder.

Solubility

Freely soluble in water and in ethanol (96 per cent), practically insoluble in methylene chloride.

IDENTIFICATION

First identification: B, D.

Second identification: A, C, D.

A. Melting point (2.2.14): 194 °C to 197 °C.

B. Infrared absorption spectrophotometry (2.2.24).

Comparison: phenylpropanolamine hydrochloride CRS.

C. Thin-layer chromatography (2.2.27).

Test solution: Dissolve 20 mg of the substance to be examined in ethanol (96 per cent) R and dilute to 10 mL with the same solvent.

Reference solution: Dissolve 10 mg of phenylpropanolamine hydrochloride CRS in ethanol (96 per cent) R and dilute to 5 mL with the same solvent.

Plate: TLC silica gel G plate R.

Pretreatment: Spray with a 20 g/L solution of disodium tetraborate R, using 8 mL for a plate 100 mm x 200 mm and dry in a stream of cold air for 30 min.

Mobile phase: concentrated ammonia R, ethanol (96 per cent) R, butanol R (6:24:70 V/V/V).

Application: 10 μL as bands of 10 mm by 3 mm.

Development: Over 1/2 of the plate.

Drying: In a current of warm air.

Detection: Allow to cool, then spray with a 2 g/L solution of ninhydrin R in ethanol (96 per cent) R and heat at 110 °C for 15 min.

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. It gives reaction (a) of chlorides (2.3.1).

TESTS

Solution S

Dissolve 1.25 g in water R and dilute to 25 mL with the same solvent.

Appearance of solution

Solution S is clear (2.2.1) and colourless (2.2.2, Method II).

Acidity or alkalinity

To 10 mL of solution S add 0.1 mL of methyl red solution R and 0.2 mL of 0.01 M sodium hydroxide. The solution is yellow.

Add 0.4 mL of 0.01 M hydrochloric acid. The solution is red.

Liquid chromatography (2.2.29).

Buffer solution: Dissolve 3.4 g of potassium dihydrogen phosphate R in 500 mL of water for chromatography R and adjust to pH 2.5 with phosphoric acid R.

Test solution: Dissolve 25.0 mg of the substance to be examined in methanol R and dilute to 25.0 mL with the same solvent.

Reference solution (a): Dilute 1.0 mL of the test solution to 100.0 mL with methanol R. Dilute 1.0 mL of this solution to 10.0 mL with methanol R.

Reference solution (b): Dissolve 5 mg of cathine hydrochloride R (1S,2S-enantiomer of impurity A) in methanol R and dilute to 50 mL with the same solvent. Dilute 1 mL of the solution to 10 mL with methanol R. Dilute 1 mL of this solution to 10 mL with the test solution.

Column:

— size: l = 0.075 m, Ø = 3.0 mm;

— stationary phase: octadecylsilyl silica gel for chromatography R (1.8 μm);

— temperature: 40 °C.

Mobile phase:

— mobile phase A: acetonitrile R1, buffer solution (2:98 V/V);

— mobile phase B: water for chromatography R, acetonitrile R1 (30:70 V/V);

Time (min)	Mobile phase A (per cent V/V)	Mobile phase B (per cent V/V)
0 – 6	100	0
6 – 14	100 → 48	0 → 52
14 – 18	48	52

Flow rate: 0.56 mL/min.

Detection: Spectrophotometer at 206 nm.

Injection: 1 μL.

Identification of impurities: Use the chromatogram obtained with reference solution (b) to identify the peak due to impurity A.

Relative retention: With reference to phenylpropanolamine (retention time = about 3 min): impurity A = about 1.2.

System suitability: Reference solution (b):

— peak-to-valley ratio: minimum 2.0, where Hp = height above the baseline of the peak due to impurity A and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to
phenylpropanolamine.

Calculation of percentage contents:

— for each impurity, use the concentration of phenylpropanolamine hydrochloride in reference solution (a).

Limits:

— unspecified impurities: for each impurity, maximum 0.10 per cent;

— total: maximum 0.2 per cent;

— reporting threshold: 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 0.150 g in a mixture of 5.0 mL of 0.01 M hydrochloric acid and 50 mL of ethanol (96 per cent) R. Carry out a potentiometric titration (2.2.20), using 0.1 M sodium hydroxide. Read the volume added between the 2 points of inflexion.

1 mL of 0.1 M sodium hydroxide is equivalent to 18.77 mg of C₉H₁₄ClNO.

IMPURITIES

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) A, B, C, D, E.