Loratadine

 

C22H23ClN2O2                                                                                              Mol. Wt. 382.9

Loratadine is ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene) piperidine-1-carboxylate.

Loratadine contains not less than 98.5 per cent and not more than 101.5 per cent of C22H23ClN2O2 , calculated on the dried basis.

Category. H₁ receptor antagonist; antihistamine.

Dose. 10 mg orally once a day.

Description. A white or almost white, crystalline powder.

Identification

 Determine by infrared absorption spectrophotometry (2.4.6). Compare the spectrum with that obtained with loratadine RS or with the reference spectrum of loratadine.

Tests

Appearance of solution. A 5.0 per cent w/v solution in methanol is clear (2.4.1), and not more intensely coloured than reference solution YS6 (2.4.1).

Impurity H. Determine by gas chromatography (2.4.13).

Internal standard solution. A 0.025 per cent v/v solution of isoamyl benzoate in methylene chloride. Dilute 5.0 ml of this solution to 50 ml with same solvent.

Test solution. Dissolve 25 mg of the substance under examination in methylene chloride 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.

Reference solution (a). A 0.0025 per cent w/v solution of loratadine impurity H RS (ethyl 4-oxopiperidine-1-carboxylate) in methylene chloride.

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.

Chromatographic system

     –   a fused silica capillary column 25 m x 0.32 mm, packed with poly(dimethyl) siloxane (film thickness 
0.52 µm),

     –   temperature:

            column                  time                        temperature

                                           (min.)                               (º)

                                         0                                 80

                                      0®1                              80

                                      1®23                           80®300

                                      23®33                         300

                                               

     –   inlet port 260° and detector at 300°,

     –   split ratio. 1:30,

     –   flame ionization detector,

     –   flow rate: 1.0 ml per minute, using helium/nitrogen as the carrier gas,

    –    injection volume: 1 µl.

Name                                                                        Relative

                                                                              retention time

impurity H1                                                                                                   0.33

isoamyl benzoate                                                                                  0.37

loratidine                                                                         1

1 ethyl 4-oxopiperidine-1-carboxylate,

Inject reference solution (b) and the test solution.

Inject reference solution (b). The test is not valid unless the resolution between the peaks due to impurity H and isoamyl benzoate is not less than 2.0, the signal to noise ratio is not less than 10 for the impurity H peak.

Calculate the ratio of the area of the peak due to impurity H to the area of the peak due to isoamyl 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 more than twice (0.1 per cent).

Related substances. Determine by liquid chromatography (2.4.14).

Test solution. Dissolve 25 mg of the substance under examination in the mobile phase and dilute to 25.0 ml with the mobile phase.

Reference solution(a). A 0.002 per cent w/v solution of loratadine impurity F RS in the mobile phase.

Reference solution (b). Dissolve 5 mg of loratadine for system suitability RS containing impurity A and impurity E in the mobile phase, add 0.5 ml of reference solution (a) and dilute to 5.0 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.

Chromatographic system

     –   a stainless steel column 25 cm x 4.6 mm, packed with end-capped octadecylsilane bonded to porous silica (5 µm),

    –    column temperature: 40°,

     –   mobile phase: a mixture of  30 volumes of methanol, 35 volumes of a  buffer solution prepared by dissolving 6.8 g of potassium dihydrogen orthophosphate in 1000 ml of water, adjusted to pH 2.8 with orthophosphoric acid and 40 volumes of acetonitrile,

     –   flow rate: 1.5 ml per minute,

     –   spectrophotometer set at 220 nm,

     –   injection volume: 20 µl.

Name                                                                          Relative                 Correction

                                                                                  retention time              factor

impurity D¹                                                                                           0.2                              ---                     

impurity B2                                                                                           0.4                              ---

impurity F3                                                                                           0.9                              1.6

impurity E4                                                                                           1.1                              1.9

impurity A5                                                                                           2.4                             1.7

impurity C6                                                                                                    2.7                                                     --- 

1 8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

2 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridine-11-one,

3 ethyl 4-[(11RS)-8-chloro-11-fluoro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]piperidine-1-carboxylate,

4 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,

5 ethyl 4-[(11RS)-8-chloro-11-hydroxy-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]piperidine-1-carboxylate,

6 ethyl 4-(4,8-dichloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridine-11-ylidene)piperidine-1-carboxylate.

Use the chromatogram supplied with loratadine for system sutability RS and the chromatogram obtained with reference solution (b) to identify the peaks due to impurity A and E.

Inject reference solution (b). The test is not valid unless the peak–to–valley ratio is not less than 2.5, where Hp is the height above the baseline of the peak due to impurity E and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to loratadine.                                                                         

Inject reference solution (c) and the test solution. In the chromatogram obtained with the test solution, the area of peak due to impurity F is not more than twice the area of the principal peak in the chromatogram obtained with reference solution (c) (0.2 per cent), the area of peak due to impurityes A,B,C,D and E are not more than the area of the principal peak in the chromatogram obtained with reference solution  (c) (0.1 per cent). The area of any other secondary peak is not more than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.1 per cent) and the sum of the areas of all the secondary peaks is not more than 5 times the area of the peak in the chromatogram obtained with the reference solution (c) (0.5 per cent). Ignore any peaks with an area 0.5 times the area of the principal peak in the chromatogram obtained with the reference solution (c) (0.05 per cent).

Sulphated ash (2.3.18). Not more than 0.1 per cent, determined on 1.0 g. 

Loss on drying (2.4.19). Not more than 0.5 per cent, determined on1.0 g by drying in an oven at 105°.

Sulphates (2.3.17). Ignite 1.33 g at 800± 25°and take up the residue with 20.0 ml of distilled water. Filter, if necessary, through paper free from sulphates. Repeat the filtration with new paper filters until the filtrate is no longer turbid (150 ppm).

Assay. Weigh accurately about 0.3 g and dissolve in 50.0 ml of anhydrous glacial acetic acid and titrate with 0.1 M perchloric acid, determining the end point potentiometrically (2.4.25). Carry out a blank titration.

1 ml of 0.1 M perchloric acid is equivalent to 0.03829 g of C22H23ClN2O2.