Related compounds—
NOTE—On the basis of the synthetic route, perform either Test 1 or Test 2. Test 2 is recommended if 4,8-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one is a potential related compound.
TEST 1—
Mobile phase and Diluent—
Prepare as directed in the Assay.
Standard stock solution—
Prepare as directed for Standard preparation in the Assay.
Standard solution—
Pipet 5.0 mL of Standard stock solution into a 100-mL volumetric flask, dilute with Diluent to volume, and mix. Dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 0.8 µg per mL.
Test solution—
Use the Assay preparation.
Chromatographic system (see Chromatography 
621
)—
The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm × 15-cm column that contains 5-µm packing L7. The column temperature is maintained between 25
and 35
. The flow rate is about 1 mL per minute. Chromatograph the
Test solution, and record the peak areas as directed for
Procedure: the relative retention times are about 0.79 for 4-(8-chloro-11-fluoro-6,11-dihydro-5
H-benzo[5,6]cyclohepta[1,2-
b]pyridin-11-yl)-1-piperidinecarboxylate ethyl and 1.0 for loratadine. Chromatograph the
Standard solution, and record the peak area of the main peak as directed for
Procedure: the relative standard deviation for replicate injections is not more than 4.0%.
Procedure—
Separately inject equal volumes (about 50 µL) of the
Test solution and the
Standard solution into the chromatograph, record the chromatograms, and measure all the peak areas in the
Test solution and the area of the main peak in the
Standard solution. Calculate the percentage of each impurity in the portion of Loratadine taken by the formula:
10,000(C/F)(ri / rS)/W,
in which
C is the concentration, in mg per mL, of USP Loratadine RS in the
Standard solution; F is the relative response factor for each impurity, if known (
F is 0.25 for 4-(8-chloro-11-fluoro-6,11-dihydro-5
H-benzo[5,6]cyclohepta[1,2-
b]pyridin-11-yl)-1-piperidinecarboxylate ethyl);
ri is the peak area response for each impurity in the
Test solution; rS is the peak area response of loratadine in the
Standard solution; and
W is the quantity, in mg, of Loratadine taken to prepare the
Test solution: not more than 0.2% of 4-(8-chloro-11-fluoro-6,11-dihydro-5
H-benzo[5,6]cyclohepta[1,2-
b]pyridin-11-yl)-1-piperidinecarboxylate ethyl is found; not more than 0.1% of any other individual impurity is found; and not more than 0.3% of total impurities is found.
TEST 2—
Solution A—
Dissolve 0.96 g of 1-pentanesulfonic acid sodium salt in 900 mL of water. Adjust with phosphoric acid solution (1 in 10) to a pH of 3.00 ± 0.05, dilute with water to 1 L, filter, and degas.
Solution B—
Use acetonitrile.
Mobile phase—
Use variable mixtures of
Solution A and
Solution B as directed for
Chromatographic system. Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Standard solution—
Dissolve accurately weighed quantities of USP Loratadine RS,
USP Loratadine Related Compound A RS, and
USP Loratadine Related Compound B RS in methanol, and dilute quantitatively, and stepwise if necessary, with methanol to obtain a solution containing about 0.1 mg of each compound per mL. Transfer 1.0 mL of this solution to a 10-mL volumetric flask, add 2 mL of
Solution A, dilute with methanol to volume, and mix to obtain a solution having a known concentration of about 0.01 mg of each per mL.
Test solution—
Transfer about 100 mg of Loratadine, accurately weighed, to a 10-mL volumetric flask, and dissolve in 2 mL of methanol. Add 2 mL of Solution A, then dilute with methanol to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm × 25-cm column containing 5-µm packing L1. The flow rate is about 1.2 mL per minute. The chromatograph is programmed as follows.
Time
(min) |
Solution A
(%) |
Solution B
(%) |
Elution |
| 0 |
75 |
25 |
isocratic |
| 0–20 |
75®50 |
25®50 |
linear gradient |
| 20–30 |
50®40 |
50®60 |
linear gradient |
| 30–35 |
40®30 |
60®70 |
linear gradient |
| 35–45 |
30 |
70 |
isocratic |
| 45–50 |
30®75 |
70®25 |
step gradient |
Chromatograph the
Standard solution, and record the peak responses as directed for
Procedure: the relative retention times and response factors are as follows in the table below.
| Related Compound |
Relative Retention Time
with respect to Loratadine |
Relative Response Factor (F)
with respect to Loratadine |
| Loratadine related compound A |
0.50 |
1.00 |
| Loratadine related compound B |
0.53 |
0.89 |
8-Chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-one |
0.70 |
0.60 |
8-Chloro-6,11-dihydro-11-[N-methyl-4-piperidinyl]11-
hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridine |
0.75 |
0.46 |
| 4,8-Dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one |
1.23 |
0.92 |
8-Chloro-6,11-dihydro-11-[N-ethoxy carbonyl-4-
piperidinyl]-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridine |
1.60 |
0.42 |
4,8-Dichloro-6,11-dihydro-11-[N-ethoxy carbonyl-4-
piperidylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine |
1.83 |
1.08 |
| Loratadine |
1.00 |
1.00 |
The resolution,
R, between loratadine related compound A and loratadine related compound B is not less than 1.5; and the relative standard deviation of the loratadine peak response from replicate injections is not more than 10%.
Procedure—
Inject a volume (about 20 µL) of the
Test solution into the chromatograph, record the chromatogram, and measure the peak responses. Calculate the percentage of each impurity in the portion of Loratadine taken by the formula:
(100/F)(CS / CT)(ri / rS),
in which
CS is the concentration, in mg per mL, of USP Loratadine RS in the
Standard solution; CT is the concentration, in mg per mL of the
Test solution; F is the relative response factor as indicated in the table (
F = 1.0 for unknown impurities);
ri is the peak area response for the individual impurity in the
Test solution; and
rS is the peak response for loratadine in the
Standard solution: not more than 0.1% of loratadine related compound A is found; not more than 0.1% of loratadine related compound B is found; less than 0.1% for each individual unknown impurity is found; and not more than 0.3% of total impurities is found.
Assay—
0.01 M Dibasic potassium phosphate—
Transfer about 1.74 g of anhydrous dibasic potassium phosphate to a 1000-mL volumetric flask, dissolve in and dilute with water to volume, and mix.
0.6 M Dibasic potassium phosphate—
Transfer 105 g of anhydrous dibasic potassium phosphate to a 1000-mL volumetric flask, dissolve in and dilute with water to volume, and mix.
Mobile phase—
Prepare a filtered and degassed mixture of
0.01 M Dibasic potassium phosphate, methanol, and acetonitrile (7:6:6). Adjust with 10% phosphoric acid solution to an apparent pH of 7.2. Make adjustments if necessary (see
System Suitability under
Chromatography 621).
0.05 N Hydrochloric acid—
Transfer 500 mL of water to a 1000-mL volumetric flask, add 83 mL of hydrochloric acid, dilute with water to volume, and mix. Transfer 50 mL of this solution into a 1000-mL volumetric flask, dilute with water to volume, and mix.
Diluent—
Transfer 400 mL of 0.05 N Hydrochloric acid and 80 mL of 0.6 M Dibasic potassium phosphate to a 1000-mL volumetric flask, dilute with a mixture of methanol and acetonitrile (1:1) to volume, and mix.
Standard preparation—
Dissolve an accurately weighed quantity of USP Loratadine RS in Diluent, and dilute quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 0.4 mg per mL.
Assay preparation—
Transfer about 40 mg of Loratadine, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with Diluent to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm ×15-cm column that contains 5-µm packing L7. The flow rate is about 1 mL per minute. The column temperature is maintained between 25
and 35
. Chromatograph the
Standard preparation, and record the peak area responses as directed for
Procedure: the relative standard deviation for replicate injections is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 15 µL) of the
Standard preparation and the
Assay preparation into the chromatograph, record the chromatograms, and measure the areas for the major peaks. Calculate the quantity, in mg, of C
22H
23ClN
2O
2 in the portion of Loratadine taken by the formula:
100C(rU / rS),
in which
C is the concentration, in mg per mL, of
USP Loratadine RS in the
Standard preparation; and
rU and
rS are the peak area responses obtained from the
Assay preparation and the
Standard preparation, respectively.
;)
