Cyclopentolate Hydrochloride

(Ph. Eur. monograph 1093)

C₁₇H₂₅NO₃,HCl    327.8    5870-29-1

Anticholinergic.

Cyclopentolate Eye Drops

Ph Eur

2-(Dimethylamino)ethyl (2RS)-(1-hydroxycyclopentyl)(phenyl)acetate hydrochloride.

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

White or almost white, crystalline powder.

Very soluble in water, freely soluble in ethanol (96 per cent).

It shows polymorphism (5.9).

First identification   B, D.

Second identification   A, C, D.

A. Melting point (2.2.14): 135 °C to 141 °C.

B. Infrared absorption spectrophotometry (2.2.24).

Preparation  discs of potassium chloride R.

Comparison   cyclopentolate hydrochloride CRS.

If the spectra obtained show differences, dissolve the substance to be examined and the reference substance separately in ethanol (96 per cent) R, evaporate to dryness and record new spectra using the residues.

C. Thin-layer chromatography (2.2.27).

Test solution  Dissolve 10 mg of the substance to be examined in 5 mL of ethanol (96 per cent) R.

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

Plate  TLC silica gel plate R.

Mobile phase  concentrated ammonia R, water R, butyl acetate R, 2-propanol R (5:15:30:50 V/V/V/V).

Application  10 µL.

Development  Over 2/3 of the plate.

Drying  In air.

Detection  Spray with alcoholic solution of sulfuric acid R and heat at 120 °C for 30 min; examine in ultraviolet light at 365 nm.

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

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

4.5 to 5.5.

Dissolve 0.2 g in carbon dioxide-free water R and dilute to 20 mL with the same solvent.

Liquid chromatography (2.2.29). Prepare the solutions immediately before use.

Test solution   Dissolve 20 mg of the substance to be examined in water R and dilute to 20.0 mL with the same solvent.

Reference solution (a)  Dilute 1.0 mL of the test solution to 100.0 mL with water R. Dilute 5.0 mL of this solution to 10.0 mL with water R.

Reference solution (b)  Dissolve 10 mg of cyclopentolate for system suitability CRS (containing impurity C) in water R and dilute to 10.0 mL with the same solvent.

• — size: l = 0.125 m, Ø = 4.0 mm;

• — stationary phase: spherical end-capped hexylsilyl silica gel for chromatography R (5 µm).

Mobile phase  Dissolve 0.66 g of ammonium phosphate R in water R, adjust to pH 3.0 with phosphoric acid R and dilute to 1000 mL with water R; mix and filter; mix 55 volumes of this solution and 45 volumes of acetonitrile R1.

Flow rate  1.0 mL/min.

Detection  Spectrophotometer at 220 nm.

Injection  20 μl.

Run time  2.5 times the retention time of cyclopentolate.

Identification of impurities  Use the chromatogram supplied with cyclopentolate for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peak due to impurity C.

Relative retention  With reference to cyclopentolate (retention time = about 4 min): impurity C = about 0.9.

System suitability  Reference solution (b):

• — peak-to-valley ratio: minimum 6, where H_p = height above the baseline of the peak due to impurity C and H_v = height above the baseline of the lowest point of the curve separating this peak from the peak due to cyclopentolate.

• — correction factor: for the calculation of content, multiply the peak area of impurity C by 2.0;

• — impurity C: not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5 per cent);

• — unspecified impurities: for each impurity, not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent);

• — total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (1.0 per cent);

• — disregard limit: 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent).

Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C for 4 h.

Maximum 0.1 per cent, determined on 1.0 g.

Dissolve 0.250 g in a mixture of 1.0 mL of 0.1 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 32.79 mg of C₁₇H₂₆ClNO₃.

Specified impurities  C.

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.

A. (2RS)-(1-hydroxycyclopentyl)(phenyl)acetic acid,

B. phenylacetic acid,

C. 2-(dimethylamino)ethyl phenylacetate.

Ph Eur