EUROPEAN PHARMACOPOEIA 10.

1 Diprophylline

Relative density (2.2.5) : 1.100 to 1.104. 01/2017:0486

Refractive index (2.2.6) : 1.478 to 1.480. corrected 10.1
Freezing point (2.2.18) : minimum 18.3 °C.
Absorbance (2.2.25). Purge with nitrogen R for 15 min. The
absorbance, measured using water R as the compensation
liquid, is not more than 0.30 at 275 nm and not more than 0.20 DIPROPHYLLINE
at both 285 nm and 295 nm. The substance to be examined
shows no absorption maximum between 270 nm and 350 nm.
Related substances. Gas chromatography (2.2.28): use the
Diprophyllinum
normalisation procedure.
Test solution. The substance to be examined.
Reference solution (a). Dissolve 50 mg of the substance to
be examined and 50 mg of dimethyl sulfone R (impurity A)
in methylene chloride R and dilute to 100 mL with the same
solvent.
Reference solution (b). Dilute 1.0 mL of the test solution to
10.0 mL with methylene chloride R. Dilute 0.5 mL of this C10H14N4O4 Mr 254.2
solution to 100.0 mL with methylene chloride R. [479-18-5]
Column :
DEFINITION
– material : fused silica ;
7-[(2RS)-2,3-Dihydroxypropyl]-1,3-dimethyl-3,7-dihydro-
– size : l = 30 m, Ø = 0.25 mm ; 1H-purine-2,6-dione.
– stationary phase : methylpolysiloxane R (5 μm). Content : 98.5 per cent to 101.0 per cent (dried substance).
Carrier gas : helium for chromatography R.
CHARACTERS
Flow rate : 1.5 mL/min.
Split ratio : 1:100. Appearance : white or almost white, crystalline powder.
Temperature : Solubility : freely soluble in water, slightly soluble in ethanol
(96 per cent).
Time Temperature
(min) (°C) IDENTIFICATION
Column 0-6 70 Infrared absorption spectrophotometry (2.2.24).
6 - 24 70 → 250 Comparison : diprophylline CRS.
Injection port 280 TESTS
Detector 280 Solution S. Dissolve 2.5 g in carbon dioxide-free water R and
dilute to 50 mL with the same solvent.
Detection : flame ionisation. Appearance of solution. Solution S is clear (2.2.1) and
Injection : 0.4 μL. colourless (2.2.2, Method II).
Relative retention with reference to dimethyl sulfoxide Acidity or alkalinity. To 10 mL of solution S add 0.25 mL
(retention time = about 5.4 min): impurity A = about 1.2. of bromothymol blue solution R1. The solution is yellow or
System suitability : reference solution (a) : green. Not more than 0.4 mL of 0.01 M sodium hydroxide is
– resolution : minimum 5.0 between the peaks due to dimethyl required to change the colour of the indicator to blue.
sulfoxide and impurity A. Related substances. Liquid chromatography (2.2.29).
Limits : Test solution. Dissolve 50 mg of the substance to be examined
– unspecified impurities : for each impurity, maximum in water R and dilute to 50.0 mL with the same solvent.
0.10 per cent ; Reference solution (a). Dilute 1.0 mL of the test solution to
– total : maximum 0.15 per cent ; 100.0 mL with water R. Dilute 1.0 mL of this solution to
– reporting threshold : 0.05 per cent (reference solution (b)). 10.0 mL with water R.
Reference solution (b). Dissolve 5 mg of etofylline CRS
Water (2.5.32) : maximum 0.2 per cent, determined on 1.00 g.
(impurity C) in water R and dilute to 50 mL with the same
STORAGE solvent. Dilute 0.5 mL of the solution to 20 mL with the test
solution.
In an airtight, glass container, protected from light.
Column :
IMPURITIES – size : l = 0.15 m, Ø = 4.6 mm ;
Other detectable impurities (the following substances would, – stationary phase : end-capped octadecylsilyl silica gel for
if present at a sufficient level, be detected by one or other of chromatography with embedded polar groups R (3 μm) ;
the tests in the monograph. They are limited by the general
– temperature : 30 °C.
acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical Mobile phase : methanol R, water for chromatography R
use (2034). It is therefore not necessary to identify these (10:90 V/V).
impurities for demonstration of compliance. See also 5.10. Flow rate : 0.7 mL/min.
Control of impurities in substances for pharmaceutical use) : A. Detection : spectrophotometer at 272 nm.
Injection : 10 μL.
Run time : 3 times the retention time of diprophylline.
Relative retention with reference to diprophylline (retention
A. (methanesulfonyl)methane (dimethyl sulfone). time = about 18 min): impurity C = about 1.1.

General Notices (1) apply to all monographs and other texts 4399
Donepezil hydrochloride EUROPEAN PHARMACOPOEIA 10.1

System suitability : reference solution (b) :

– peak-to-valley ratio : minimum 5, where Hp = height above
the baseline of the peak due to impurity C and Hv = height
above the baseline of the lowest point of the curve
separating this peak from the peak due to diprophylline.
Limits :
– unspecified impurities : for each impurity, not more than the D. 7-[(2RS)-2-hydroxypropyl]-1,3-dimethyl-3,7-dihydro-1H-
area of the principal peak in the chromatogram obtained purine-2,6-dione (proxyphylline).
with reference solution (a) (0.10 per cent) ;
– total : not more than 3 times the area of the principal peak
in the chromatogram obtained with reference solution (a)
(0.3 per cent) ; 04/2020:2582
– disregard limit : 0.5 times the area of the principal peak in
the chromatogram obtained with reference solution (a)
(0.05 per cent).
Chlorides (2.4.4): maximum 400 ppm.
DONEPEZIL HYDROCHLORIDE
Dilute 2.5 mL of solution S to 15 mL with water R.
Loss on drying (2.2.32): maximum 0.5 per cent, determined Donepezili hydrochloridum
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
In order to avoid overheating in the reaction medium, mix
thoroughly throughout and stop the titration immediately after
the end-point has been reached.
Dissolve 0.200 g in 3.0 mL of anhydrous formic acid R and add C24H30ClNO3 Mr 416.0
50.0 mL of acetic anhydride R. Titrate with 0.1 M perchloric [120011-70-3]
acid, determining the end-point potentiometrically (2.2.20).
DEFINITION
1 mL of 0.1 M perchloric acid is equivalent to 25.42 mg of
C10H14N4O4. (2RS)-2-[(1-Benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-
dihydro-1H-inden-1-one hydrochloride.
STORAGE Content : 98.0 per cent to 102.0 per cent (anhydrous substance).
Protected from light.
CHARACTERS
IMPURITIES Appearance : white or almost white, crystalline powder.
Other detectable impurities (the following substances would, Solubility : very slightly soluble in water, very soluble in
if present at a sufficient level, be detected by one or other of methylene chloride, very slightly soluble in ethanol (96 per
the tests in the monograph. They are limited by the general cent).
acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical use IDENTIFICATION
(2034). It is therefore not necessary to identify these impurities A. Infrared absorption spectrophotometry (2.2.24).
for demonstration of compliance. See also 5.10. Control of Comparison : donepezil hydrochloride CRS.
impurities in substances for pharmaceutical use): A, B, C, D.
B. Water (see Tests).
C. It gives reaction (a) of chlorides (2.3.1).
TESTS
Related substances. Liquid chromatography (2.2.29).
Solvent mixture : mobile phase B, mobile phase A (20:80 V/V).
A. N-methyl-5-(methylamino)-1H-imidazole-4-carboxamide Test solution (a). Dissolve 25.0 mg of the substance to be
(theophyllidine), examined in the solvent mixture and dilute to 25.0 mL with
the solvent mixture.
Test solution (b). Dilute 5.0 mL of test solution (a) to 10.0 mL
with the solvent mixture.
Reference solution (a). Dilute 1.0 mL of test solution (a) to
100.0 mL with the solvent mixture. Dilute 1.0 mL of this
solution to 10.0 mL with the solvent mixture.
B. 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione Reference solution (b). Dissolve 15.0 mg of donepezil
(theophylline), hydrochloride CRS in the solvent mixture and dilute to 30.0 mL
with the solvent mixture.
Reference solution (c). Dissolve 5 mg of donepezil for system
suitability CRS (containing impurities C, D and E) in the
solvent mixture and dilute to 5 mL with the solvent mixture.
Column :
– size : l = 0.15 m, Ø = 4.6 mm ;
C. 7-(2-hydroxyethyl)-1,3-dimethyl-3,7-dihydro-1H-purine- – stationary phase : end-capped phenylhexylsilyl silica gel for
2,6-dione (etofylline), chromatography R (3 μm).

4400 See the information section on general monographs (cover pages)