(Ph. Eur. 11.6 update)
Action and use
Selective serotonin reuptake inhibitor; antidepressant.
DEFINITION
Escitalopram Oral Drops contains Escitalopram Oxalate in a suitable vehicle.
The oral drops comply with the requirements stated under Oral Liquids and with the following requirements.
Content of escitalopram, C20H21FN2O
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Evaporate a quantity of the oral drops containing the equivalent of 100 mg of escitalopram to reduced volume under a stream of nitrogen and dried in a vacuum desiccator. Dissolve the residue in 20 mL of water and filter. Add 5 mL of 5M sodium hydroxide to the filtrate and extract with three 25-mL quantities of dichloromethane. Dry the combined organic layers over sodium sulfate and evaporate to dryness using a rotary evaporator at a temperature not exceeding 40°. The infrared absorption spectrum of the residue, Appendix II A, is concordant with the spectrum of citalopram hydrobromide BPCRS treated in the same manner.
B. Complies with the test for Impurity K.
TESTS
Escitalopram impurity K (enantiomeric impurity)
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Dilute a volume of the oral drops with sufficient of the mobile phase to produce a solution containing the equivalent of 0.012% w/v of escitalopram and filter.
(2) 0.012% w/v of citalopram hydrobromide BPCRS (containing equal amounts of impurity K and escitalopram) in the mobile phase.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with protein derivative of silica gel for chiral separation R (5μm) (Ultron ES-OVM is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 0.6 mL per minute.
(d) Use a column temperature of 30°.
(e) Use a detection wavelength of 240 nm.
(f) Inject 15 μL of each solution.
(g) Allow the chromatography to run for twice the retention time of escitalopram.
MOBILE PHASE
15 volumes of acetonitrile and 85 volumes of 0.05M phosphate buffer solution pH 7.0.
When the chromatograms are recorded under the prescribed conditions, the relative retention with respect to escitalopram (retention time, about 11 minutes) of impurity K is about 1.2.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (2):
the resolution between the peaks due to escitalopram and impurity K is at least 1.3;
the symmetry factors for the peaks due to escitalopram and impurity K are between 0.8 and 4.0.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak due to impurity K is not greater than 2.0% by normalisation;
disregard any peak with an area less than 0.1% of that of the area of the peak due to impurity K.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Dilute a volume of the oral drops containing the equivalent of 100 mg of escitalopram add sufficient mobile phase A to produce 200 mL.
(2) Dilute 1 volume of solution (1) to 100 volumes with mobile phase A and further dilute 1 volume of this solution to 5 volumes with the same solvent.
(3) 0.05% w/v of escitalopram for system suitability EPCRS (containing impurity D) in mobile phase A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 μm) (Luna C18 is suitable).
(b) Use gradient elution with the flow rate and mobile phase described below.
(c) Use a column temperature of 45°.
(d) Use detection wavelengths of 237 nm and 254 nm.
(e) Inject 20 μL of each solution.
MOBILE PHASE
Solution A 0.34% w/v of potassium dihydrogen orthophosphate adjusted to pH 3.0 with orthophosphoric acid.
Mobile phase A 10 volumes of acetonitrile and 90 volumes of solution A.
Mobile phase B 65 volumes of acetonitrile and 35 volumes of solution A.
| Time (Minutes) | Mobile phase A% | Mobile phase B% | Flow rate (mL/min) | Comment |
| 0-2 | 95 | 5 | 1 | isocratic |
| 2-37 | 95→65 | 5→35 | 1 | linear gragident |
| 37-47 | 65→0 | 35→100 | 1 | linear gragident |
| 47-62 | 0 | 100 | 2 | isocratic |
| 62-64 | 0→95 | 100→5 | 1 | linear gragident |
| 64-67 | 95 | 5 | 1 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to escitalopram (retention time about 38 minutes) are: impurity F, about 0.1; impurity J, about 0.2; impurity G, about 0.5;
impurity A, about 0.6; impurity B+M, about 0.8; impurity C+I+L, about 0.9; impurity D, about 0.95; impurity H, about 1.1.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3) at 237 nm, the peak-to-valley ratio is at least 5.0, where Hp is the height above the baseline of the peak due to impurity D and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to escitalopram.
LIMITS
Calculate the amount of each impurity at both 237 nm and 254 nm using the area of the peak due to escitalopram from solution (2) at 237 nm.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity C, I and L is not greater than 2.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);
the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);
the sum of the areas (at 237 mn) of any secondary peaks is not greater than 5 times the area of the principal peak in the chromatogram obtained with solution (2) (1%).
Disregard any peak with an area less than half the area of the principal peak in the chromatogram obtained with solution (2) at 237 nm (0.1%).
ASSAY
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) To a volume of the oral drops containing the equivalent of 100 mg of escitalopram add sufficient mobile phase to produce 100 mL. Dilute 1 volume of this solution to 20 volumes with the mobile phase.
(2) 0.006% w/v of citalopram hydrobromide BPCRS in the mobile phase.
(3) 0.05% w/v of escitalopram for system suitability EPCRS (containing impurity D) in the mobile phase.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 μm) (Luna C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 45°.
(e) Use a detection wavelength of 237 nm.
(f) Inject 20 μL of each solution.
(g) Allow the chromatography to proceed for 1.5 times the retention time of escitalopram (about 11 minutes).
MOBILE PHASE
Solution A 0.34% w/v of potassium dihydrogen orthophosphate adjusted to pH 3.0 with orthophosphoric acid 30 volumes of acetonitrile and 70 volumes of Solution A.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the peak-to-valley ratio is at least 5.0, where Hp is the height above the baseline of the peak due to impurity D and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to escitalopram.
DETERMINATION OF CONTENT
Calculate the content of C20H21FN2O, in the oral drops from the chromatograms obtained and using the declared content of C20H21FN2O, in citalopram hydrobromide BPCRS.
STORAGE
Escitalopram Oral Drops should be stored below 25°.
LABELLING
The quantity of active ingredient is stated in terms of the equivalent amount of escitalopram.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Escitalopram Oxalate.
