(Ph. Eur. monograph 2124)
C22H23ClN2O2 382.9 79794-75-5
Action and use
Histamine H1 receptor antagonist; antihistamine.
Preparation
Loratadine Tablets
DEFINITION
Ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate.
Content
98.5 per cent to 101.5 per cent (dried substance).
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Practically insoluble in water, freely soluble in acetone and in methanol.
It shows polymorphism (5.9).
IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
Comparison: loratadine CRS.
If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in acetone R, evaporate to dryness and record new spectra using the
residues.
TESTS
Appearance of solution
The solution is clear (2.2.1) and not more intensely coloured than reference solution BY5 (2.2.2, Method II).
Dissolve 1.0 g in methanol R and dilute to 20.0 mL with the same solvent.
Impurity H
Gas chromatography (2.2.28).
Internal standard solution: Dissolve 25 mg of isoamyl benzoate R in methylene chloride R and dilute to 100 mL with the same solvent. Dilute 5.0 mL of this solution to 50 mL with methylene chloride R.
Test solution: Dissolve 25.0 mg of the substance to be examined in methylene chloride R, add 1.0 mL of reference solution (a) and 1.0 mL of the internal standard solution and dilute to 5.0 mL with methylene
chloride R.
Reference solution (a): Dissolve 25.0 mg of loratadine impurity H CRS in methylene chloride R and dilute to 100.0 mL with the same solvent. Dilute 5.0 mL of this solution to 50.0 mL with methylene chloride R.
Reference solution (b): To 1.0 mL of reference solution (a) add 1.0 mL of the internal standard solution and dilute to 5.0 mL with methylene chloride R.
Column:
— material: fused silica;
— size: l = 25 m, Ø = 0.32 mm;
— stationary phase: methylpolysiloxane R (film thickness 0.52 μm).
Carrier gas: helium for chromatography R.
Flow rate: 1.0 mL/min.
Split ratio: 1:30.
Temperature:
| Time (min) |
Temperature (°C) |
|
| Column | 0 – 1 | 80 |
| 1 – 23 | 80 → 300 | |
| 23 – 33 | 300 | |
| Injection port | 260 | |
| Detector | 300 |
Detection: Flame ionisation.
Injection: 1 μL of the test solution and reference solution (b).
Relative retention: With reference to loratadine (retention time = about 32 min): impurity H = about 0.33; isoamyl benzoate = about 0.37.
System suitability: Reference solution (b):
— resolution: minimum 2.0 between the peaks due to impurity H and isoamyl benzoate;
— signal-to-noise ratio: minimum 10 for the peak due to impurity H.
Limit:
— impurity H: calculate the ratio (R) of the area of the peak due to impurity H to the area of the peak
due to isoamyl benzoate from the chromatogram obtained with reference solution (b); from the chromatogram obtained with the test solution, calculate the ratio of the area of the peak due to impurity H to the area of the peak due to isoamyl benzoate: this ratio is not greater than twice R (0.1 per
cent).
Related substances
Liquid chromatography (2.2.29).
Test solution: Dissolve 25.0 mg of the substance to be examined in the mobile phase and dilute to 25.0 mL
with the mobile phase.
Reference solution (a): Dissolve 5 mg of loratadine impurity F CRS in the mobile phase and dilute to 25 mL with the mobile phase. Dilute 1 mL of this solution to 10 mL with the mobile phase.
Reference solution (b): Dissolve 5 mg of loratadine for system suitability CRS (containing impurities A
and E) in the mobile phase, add 0.5 mL of reference solution (a) and dilute to 5 mL with the mobile phase.
Reference solution (c): Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase.
Column:
— size: l = 0.25 m, Ø = 4.6 mm;
— stationary phase: spherical end-capped octadecylsilyl silica gel for chromatography R (5 μm) with very low silanol activity;
— temperature: 40 °C.
Mobile phase: Mix 30 volumes of methanol R, 35 volumes of a 6.8 g/L solution of potassium dihydrogen phosphate R previously adjusted to pH 2.80 ± 0.05 with phosphoric acid R and 40 volumes of acetonitrile R.
Flow rate: 1.5 mL/min.
Detection: Spectrophotometer at 220 nm.
Injection: 20 μL of the test solution and reference solutions (b) and (c).
Run time: 5 times the retention time of loratadine.
Identification of impurities: Use the chromatogram supplied with loratadine for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peaks due to impurities A and E.
Relative retention: With reference to loratadine (retention time = about 12 min): impurity D = about 0.2;
impurity B = about 0.4; impurity F = about 0.9; impurity E = about 1.1; impurity A = about 2.4; impurity C = about 2.7.
System suitability: Reference solution (b):
— peak-to-valley ratio: minimum 2.5, where Hp = height above the baseline of the peak due to impurity E and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to loratadine.
Limits:
— correction factors: for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor: impurity A = 1.7; impurity F = 1.6; impurity E = 1.9;
— impurity F: not more than twice the area of the principal peak in the chromatogram obtained with
reference solution (c) (0.2 per cent);
— impurities A, B, C, D, E: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.1 per cent);
— unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.10 per cent);
— total: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.5 per cent);
— disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.05 per cent).
Sulfates (2.4.13)
Maximum 150 ppm.
Ignite 1.33 g at 800 ± 25 °C and take up the residue with 20 mL of distilled water R. Filter, if necessary, through paper free from sulfates. Repeat the filtration with new paper filters until the filtrate is no longer
turbid.
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 0.300 g in 50 mL of glacial acetic acid 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 38.29 mg of C22H23ClN2O2.
IMPURITIES
Specified impurities A, B, C, D, E, F, H.
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) G.
A. ethyl 4-[(11RS)-8-chloro-11-hydroxy-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]piperidine-1-carboxylate,
B. 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one,
C. ethyl 4-(4,8-dichloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-
carboxylate,
D. 8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,
E. ethyl 4-[(11RS)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-3,6-dihydropyridine-
1(2H)-carboxylate,
F. ethyl 4-[(11RS)-8-chloro-11-fluoro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]piperidine-1-carboxylate,
G. 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,
H. ethyl 4-oxopiperidine-1-carboxylate.
