Edition: BP 2025 (Ph. Eur. 11.6 update)
Action and use
Antiprotozoal (malaria).
Preparations
Quinine Sulfate Oral Suspension
Quinine Sulfate Tablets
DEFINITION
Alkaloid monosulfates, expressed as bis[(R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]oct-2-yl](6-methoxyquinolin-4- yl)methanol] sulfate dihydrate.
Content
99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or almost white, crystalline powder or fine, colourless needles.
Solubility
Slightly soluble in water, sparingly soluble in boiling water and in ethanol (96 per cent).
IDENTIFICATION
A. Thin-layer chromatography (2.2.27).
Test solution Dissolve 0.10 g of the substance to be examined in methanol R and dilute to 10 mL with the same solvent.
Reference solution Dissolve 0.10 g of quinine sulfate CRS in methanol R and dilute to 10 mL with the same solvent.
Plate TLC silica gel G plate R.
Mobile phase diethylamine R, ether R, toluene R (10:24:40 V/V/V). Application 5 µL.
Development Twice over a path of 15 cm; dry in a current of air for 15 min between the 2 developments.
Drying At 105 °C for 30 min and allow to cool.
Detection Spray with iodoplatinate reagent R.
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.
B. Dissolve about 5 mg in 5 mL of water R. Add 0.2 mL of bromine water R and 1 mL of dilute ammonia R2. A green colour develops.
C. Dissolve 0.1 g in 3 mL of dilute sulfuric acid R and dilute to 100 mL with water R. When examined in ultraviolet light at 366 nm, an intense blue fluorescence appears which disappears almost completely on the addition of 1 mL of hydrochloric acid R.
D. Dissolve about 45 mg in 5 mL of dilute hydrochloric acid R. The solution gives reaction (a) of sulfates (2.3.1).
E. pH (see Tests).
TESTS
Solution S
Dissolve 0.500 g in 0.1 M hydrochloric acid and dilute to 25.0 mL with the same acid.
Appearance of solution
Solution S is clear (2.2.1) and not more intensely coloured than reference solution GY6 (2.2.2, Method II).
pH (2.2.3)
5.7 to 6.6 for a 10 g/L suspension in water R.
Specific optical rotation (2.2.7)
-237 to -245 (dried substance), determined on solution S.
Other cinchona alkaloids
Liquid chromatography (2.2.29): use the normalisation procedure.
Test solution Dissolve 20 mg of the substance to be examined in 5 mL of the mobile phase, with gentle heating if necessary, and dilute to 10 mL with the mobile phase.
Reference solution (a) Dissolve 20 mg of quinine sulfate CRS in 5 mL of the mobile phase, with gentle heating if necessary, and dilute to 10 mL with the mobile phase.
Reference solution (b) Dissolve 20 mg of quinidine sulfate CRS (impurity A) in 5 mL of the mobile phase, with gentle heating if necessary, and dilute to 10 mL with the mobile phase.
Reference solution (c) To 1 mL of reference solution (a) add 1 mL of reference solution (b).
Reference solution (d) Dilute 1.0 mL of reference solution (a) to 10.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 50.0 mL with the mobile phase.
Reference solution (e) Dissolve 10 mg of thiourea R in the mobile phase and dilute to 10 mL with the mobile phase.
Column:
— size: l = 0.15-0.25 m, Ø = 4.6 mm;
— stationary phase: octadecylsilyl silica gel for chromatography R (5-10 µm).
Mobile phase Dissolve 6.8 g of potassium dihydrogen phosphate R and 3.0 g of hexylamine R in 700 mL of water R, adjust to pH 2.8 with dilute phosphoric acid R, add 60 mL of acetonitrile R and dilute to 1000 mL with water R.
Flow rate 1.5 mL/min.
Detection Spectrophotometer at 250 nm for reference solution (e) and at 316 nm for the other solutions.
Injection 10 µL.
Run time 2.5 times the retention time of quinine.
Identification of peaks Use the chromatogram obtained with reference solution (a) to identify the peaks due to quinine and impurity C; use the chromatogram obtained with reference solution (b) to identify the peaks due to impurity A and dihydroquinidine; the chromatogram obtained with reference solution (c) shows 4 peaks due to impurity A, quinine, dihydroquinidine and impurity C which are identified by comparison of their retention times with those of the corresponding peaks in the chromatograms obtained with reference solutions (a) and (b).
Relative retention With reference to quinine: impurity C = about 1.4.
Relative retention With reference to impurity A: dihydroquinidine = about 1.5.
System suitability:
— resolution: minimum 3.0 between the peaks due to quinine and impurity A and minimum 2.0 between the peaks due to dihydroquinidine and quinine in the chromatogram obtained with reference solution (c);
— signal-to-noise ratio: minimum 4 for the principal peak in the chromatogram obtained with reference solution (d);
— mass distribution ratio: 3.5 to 4.5 for the peak due to impurity A in the chromatogram obtained with reference solution (b), tR′ being calculated from the peak due to thiourea in the chromatogram obtained with reference solution (e); if necessary, adjust the concentration of acetonitrile in the mobile phase.
Limits:
— impurity C: maximum 10 per cent;
— any impurity eluted before quinine: for each impurity, maximum 5 per cent;
— any other impurity: for each impurity, maximum 2.5 per cent;
— disregard limit: the area of the principal peak in the chromatogram obtained with reference solution (d) (0.2 per cent).
Loss on drying (2.2.32)
3.0 per cent to 5.0 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 0.300 g in a mixture of 10 mL of chloroform R and 20 mL of acetic anhydride R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 24.90 mg of C40H50N4O8S.
STORAGE
Protected from light.
IMPURITIES
A. (S)-[(2R,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]oct-2-yl](6-methoxyquinolin-4-yl)methanol (quinidine),
B. (R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]oct-2-yl](quinolin-4-yl)methanol (cinchonidine),
C. (R)-[(2S,4S,5R)-5-ethyl-1-azabicyclo[2.2.2]oct-2-yl](6-methoxyquinolin-4-yl)methanol (dihydroquinine).
