Ipratropium Pressurised Inhalation

Anticholinergic (antimuscarinic) bronchodilator.

Ipratropium Pressurised Inhalation is a solution or suspension of Ipratropium Bromide in a suitable liquid in a suitable pressurised container.

The pressurised inhalation complies with the requirements stated under Preparations for Inhalations and with the following requirements.

85.0 to 115.0% of the amount stated to be delivered by actuation of the valve.

A. In the test for Related substances, the principal spot in the chromatogram obtained with solution (2) corresponds to that in the chromatogram obtained with solution (6).

B. In the Assay, 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).

Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.

(1) Punch a small hole in the ferrule of each of three cooled containers, allow the propellant to evaporate for about 1 minute and transfer the contents of the containers, through the punched holes, to a beaker. Stir, using a magnetic stirrer, for about 10 minutes, add 3.5 mL of 0.01m hydrochloric acid and continue stirring for about 1 hour, until the propellant has completely evaporated, filter, add 10 mL of chloroform to the filtrate and shake vigorously for 1 minute. Allow the phases to separate and use the upper layer.

(2) Dilute 1 volume of solution (1) to 50 volumes with 0.01m hydrochloric acid.

(3) Dilute 1 volume of solution (2) to 4 volumes with 0.01m hydrochloric acid.

(4) Dilute 2 volumes of solution (3) to 5 volumes with 0.01m hydrochloric acid.

(5) 0.008% w/v of 8s-isopropyl-3β-hydroxytropanium bromide BPCRS in 0.01m hydrochloric acid.

(6) 0.008% w/v of ipratropium bromide BPCRS in 0.01m hydrochloric acid.

(a) Use a high performance silica gel precoated plate (Merck silica gel 60 HPTLC plates are suitable).

(b) Use the mobile phase as described below.

(c) Apply 5 µL of each solution.

(d) Develop the plate to 6 cm above the line of application.

(e) After removal of the plate, dry it in a current of warm air for about 30 minutes. Spray the plate with a mixture of 1 volume of potassium iodobismuthate solution, 2 volumes of glacial acetic acid and 10 volumes of water, allow to dry briefly, spray with a 5% w/v solution of sodium nitrite and immediately examine the plate.

5 volumes of water, 8 volumes of anhydrous formic acid, 28 volumes of methanol and 70 volumes of dichloromethane.

In the chromatogram obtained with solution (1):

any spot corresponding to 8s-isopropyl-3β-hydroxytropanium bromide is not more intense than the spot in the chromatogram obtained with solution (2) (2%);

any other secondary spot is not more intense than the spot in the chromatogram obtained with solution (3) (0.5%);

not more than two such spots are more intense than the spot in the chromatogram obtained with solution (4) (0.2%).

Carry out the test for aerodynamic assessment of fine particles, Appendix XII C7, but determining the content of active ingredient as described below. Use Apparatus A with 7 mL of 0.001m hydrochloric acid in the upper impingement chamber and 40 mL of a mixture of equal volumes of 0.001m hydrochloric acid and methanol in the lower impingement chamber. Use the same solvent mixture to wash the coupling tube, E, and transfer the combined solution and washings in the lower impingement chamber to a 100 mL graduated flask, rinsing the chamber with the solvent mixture and dilute the combined solution to 100 mL with the solvent mixture.

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Use the diluted solution from the lower impingement chamber.

(2) 0.00007% w/v of ipratropium bromide BPCRS in a mixture of equal volumes of 0.001m hydrochloric acid and methanol.

(a) Use a stainless steel column (12.5 cm × 4 mm) packed with octylsilyl silica gel for chromatography (Lichrospher RP8 select B is suitable).

(b) Use isocratic elution and the mobile phase described below.

(c) Use a flow rate of 2 mL per minute.

(d) Use an ambient column temperature.

(e) Use a detection wavelength of 210 nm.

(f) Inject 20 µL of each solution.

345 volumes of acetonitrile and 750 volumes of 0.012m sodium heptanesulfonate previously adjusted to pH 3.2 with 0.05m orthophosphoric acid.

The test is not valid unless, in the chromatogram obtained with solution (1):

the symmetry factor of the peak due to ipratropium bromide is less than 3.0;

the signal-to-noise ratio of the peak is at least 3.0.

Calculate the amount of ipratropium bromide, C₂₀H₃₀BrNO₃,H₂O, delivered to the lower impingement chamber per actuation of the valve using the declared content of C₂₀H₃₀BrNO₃,H₂O in ipratropium bromide BPCRS. Not less than 25% of the average amount of ipratropium bromide delivered per actuation of the valve, calculated as the average of the three results determined in the Assay, is deposited in the lower impingement chamber.

Determine the content of active ingredient delivered by the first 10 successive combined actuations of the valve after priming. Carry out the procedure for content of active ingredient delivered by actuation of the valve described under Pressurised Inhalations, Preparations for Inhalation, beginning at the words 'Remove the pressurised container from the actuator…' and ending at the words '… to the volume specified in the monograph' using 20 mL of a mixture of equal volumes of 0.001m hydrochloric acid and methanol in the vessel. Use the same solvent mixture to wash the pressurised container and to dilute the combined solution and washings obtained from the set of 10 combined actuations to 50 mL (solution A). Determine the amount of active ingredient in the 10 combined actuations using the following method of analysis.

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Use solution A.

(2) 0.00040% w/v of ipratropium bromide BPCRS in a mixture of equal volumes of 0.001m hydrochloric acid and methanol.

The chromatographic conditions described under Deposition of the emitted dose may be used. In the chromatogram obtained with solution (1) long-running peaks due to excipients may appear.

The test is not valid unless in the chromatogram obtained with solution (1) the symmetry factor for the peak due to ipratropium bromide is less than 3.0.

Calculate the average content of C₂₀H₃₀BrNO₃,H₂O delivered by a single actuation of the valve using the declared content of C₂₀H₃₀BrNO₃,H₂O in ipratropium bromide BPCRS.

Determine the content of active ingredient a second and a third time by repeating the procedure on the middle 10 and the last 10 successive combined actuations of the valve, as estimated from the number of deliveries available from the container as stated on the label. For each of the three determinations the average content of C₂₀H₃₀BrNO₃,H₂O delivered by a single actuation of the valve is within the limits stated under Content of ipratropium bromide.

In addition to the impurities shown in the monograph for Ipratropium Bromide the degradation impurities limited by the requirements of this monograph include:

A. 8s-isopropyl-3β-hydroxytropanium bromide.