Edition: BP 2025 (Ph. Eur. 11.6 update)
Ipratropium Pressurised Inhalation
Action and use
Anticholinergic (antimuscarinic) bronchodilator.
DEFINITION
Ipratropium Pressurised Inhalation, Solution is a solution of Ipratropium Bromide in a suitable liquid in a pressurised container fitted with a metering dose valve.
The pressurised inhalation complies with the requirements stated under Preparations for Inhalation and with the following requirements.
PRODUCTION
The size of aerosol particles to be inhaled is controlled so that a consistent portion is deposited in the lungs. The fine- particle characteristics of preparations for inhalation are determined using the method described in Appendix XII C7. Preparations for inhalation: Aerodynamic Assessment of Fine Particles. The test and limits should be agreed with the competent authority.
The water content is controlled to ensure the performance of the product as justified and authorised by the competent authority.
Content of ipratropium bromide, C20H30NO3Br,H2O
85.0 to 115.0% of the stated delivered dose (ex-actuator).
IDENTIFICATION
A. In the test for Impurity A, the principal spot in the chromatogram obtained with solution (2) corresponds to that in the chromatogram obtained with solution (4).
B. In the Uniformity of delivered dose, the chromatogram obtained with solution (1) shows a peak with the same retention time as the peak due to ipratropium bromide in the chromatogram obtained with solution (2).
TESTS
Impurity A
Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
Solution A To one volume of potassium iodobismuthate solution, add 2 volumes of glacial acetic acid and 10 volumes of water.
(1) Place three containers into a freezer for about 20 minutes and punch a small hole in the can wall of each frozen container, allow the propellant to evaporate for about 1 minute and open the containers. Evaporate the contents under a stream of nitrogen and dissolve the residues in sufficient 0.01M hydrochloric acid to make a solution expected to contain 0.6% w/v of ipratropium bromide.
(2) Dilute 1 volume of solution (1) to 50 volumes with 0.01M hydrochloric acid.
(3) 0.08% w/v of 8s-isopropyl-3β-hydroxytropanium bromide BPCRS (impurity A) in 0.01M hydrochloric acid.
(4) 0.08% w/v of ipratropium bromide BPCRS in 0.01M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel F254 (Merck silica gel 60 F254 plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 15 μL of each solution.
(d) Develop the plate to 6 cm.
(e) After removal of the plate, dry it in a current of warm air for about 30 minutes. Spray the plate with Solution A, allow to dry briefly, spray with sodium nitrite solution and immediately examine the plate.
MOBILE PHASE
5 volumes of water, 8 volumes of formic acid, 28 volumes of methanol and 70 volumes of dichloromethane.
LIMITS
In the chromatogram obtained with solution (1):
any spot corresponding to impurity A is not more intense than the spot in the chromatogram obtained with solution (2) (2%).
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
Solution A Water, adjusted to pH 2.6 with orthophosphoric acid.
(1) Empty the contents of one container into a 50 mL-volumetric flask, wash the container with 5 mL of solution A and add the washing to the flask. Make up to volume with solution A. Dilute, if necessary, with sufficient solution A to make a solution containing 0.04% w/v of ipratropium bromide.
(2) Dilute 1 volume of solution (1) to 100 volumes with solution A.
(3) 0.0002% w/v of ipratropium bromide impurity D BPCRS and 0.0002% w/v of ipratropium bromide BPCRS in solution A.
(4) Dilute 1 volume of solution (2) to 10 volumes with solution A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with base-deactivated octadecylsilyl silica gel for chromatography (5 μm) (Zorbax SB-C18 is suitable).
(b) Use isocratic elution using the mobile phase described below.
(c) Use a flow rate of 1.3 mL per minute.
(d) Use a column temperature of 45°.
(e) Use a detection wavelength of 210 nm.
(f) Inject 50 μL of each solution.
(g) Allow the chromatography to proceed for six times the retention time of ipratropium bromide.
MOBILE PHASE
185 volumes of acetonitrile R1 and 815 volumes of a 0.16% w/v of sodium butanesulfonate, adjusted to pH 2.6 with orthophosphoric acid.
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to ipratropium bromide (retention time about 4 minutes) are: for impurity C, about 0.7; impurity D, about 3.5 and impurity F, about 5.0.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peak due to ipratropium bromide and the peak due to impurity D, is not less than 4.0.
LIMITS
In the chromatogram obtained with solution (1):
the area of any other secondary peak is not greater than half the area of the corresponding peak in the chromatogram obtained with solution (2) (0.5%);
the sum of the areas of any secondary peaks is not greater than 1.5 times the area of the principal peak in the chromatogram obtained with solution (2) (1.5%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (4) (0.1%).
Uniformity of delivered dose
Complies with the requirements stated under Pressurised Metered-dose Preparations for Inhalation using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
Solution A water, adjusted to pH 2.6 with orthophosphoric acid.
(1) Collect single doses of the preparation being examined using the procedure described under Pressurised Metered- dose Preparations for Inhalation, Uniformity of delivered dose and dissolve the collected dose in sufficient solution A to produce a solution containing the equivalent of 0.0002% w/v of ipratropium bromide.
(2) 0.0002% w/v of ipratropium bromide BPCRS in solution A.
(3) Mix 1 volume of solution (2) with 1 volume of 0.0002% w/v of ipratropium bromide impurity D BPCRS in solution A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with base-deactivated octadecylsilyl silica gel for chromatography (5 μm) (Zorbax SB-C18 is suitable).
(b) Use isocratic elution using the mobile phase described below.
(c) Use a flow rate of 2.0 mL per minute.
(d) Use a column temperature of 35°.
(e) Use a detection wavelength of 210 nm.
(f) Inject 100 μL of each solution.
(g) Allow the chromatography to proceed for 1.6 times the retention time of ipratropium bromide.
MOBILE PHASE
225 volumes of acetonitrile and 775 volumes of a 0.209% w/v solution of sodium heptanesulfonate, and adjusted to pH 2.6 with orthophosphoric acid.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peak due to ipratropium bromide and the peak due to impurity D, is not less than 4.0.
DETERMINATION OF CONTENT
Calculate the content of ipratropium bromide C20H30NO3Br,H2O per delivered dose using the declared content of C20H30NO3Br,H2O in ipratropium bromide BPCRS. Repeat the procedure as described under Pressurised Metered-dose Preparations for Inhalation, Uniformity of Delivered Dose.
ASSAY
Use the average of the individual results obtained in the test for Uniformity of delivered dose.
LABELLING
The label states the content of active ingredient in terms of the equivalent delivered dose.
IMPURITIES
The impurities limited by the requirements of this monograph include impurities A, C, D and F listed under Ipratropium Bromide.
