- British Pharmacopoeia Volume III
- Formulated Preparations: Specific Monographs
Salbutamol Powder for Inhalation |
Salbutamol Powder for Inhalation consists of Salbutamol Sulfate in microfine powder either alone or admixed with Lactose. It may be presented either as pre-metered units for use in a designated powder inhaler or as a powder reservoir within a metered-dose powder inhaler.
The powder for inhalation complies with the requirements stated under Preparations for Inhalation and with the following requirements.
Salbutamol pre-metered unit powder inhalers consist of Salbutamol Sulfate in microfine powder either alone or admixed with Lactose in a suitable container for use within a suitable device.
Complies with the requirements for Uniformity of delivered dose stated under Preparations for Inhalation using the method described in the European Pharmacopoeia or other methodology where justified and authorised.
95.0 to 105.0% of the stated amount per pre-metered unit.
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Dissolve a quantity of the powder for inhalation containing the equivalent of 1 mg of salbutamol in 10 mL of water.
(2) 0.010% w/v of salbutamol sulfate BPCRS in water.
(a) Use as the coating substance silica gel G (Merck plates are suitable).
(b) The mobile phase is a mixture of 4 volumes of 13.5m ammonia, 16 volumes of water, 30 volumes of propan-2-ol and 50 volumes of ethyl acetate.
(c) Application volume of 5 µL for each solution.
(d) Develop to 15 cm.
(e) Remove the plate, allow it to dry in air, spray with a 0.1% w/v solution of 3-methylbenzothiazolin-2-one hydrazone hydrochloride in methanol (90%) and dry in air for 10 minutes. Spray the plate with a 2% w/v solution of potassium hexacyanoferrate(iii) in a mixture of 1 volume of 18m ammonia and 3 volumes of water and spray again with the 0.1% w/v solution of 3-methylbenzothiazolin-2-one hydrazone hydrochloride in methanol (90%).
The spot in the chromatogram obtained with solution (1) corresponds to that in the chromatogram obtained with solution (2).
B. In the test for Related substances, the principal peak in the chromatogram obtained with solution (2) has the same retention time as the principal peak in the chromatogram obtained with solution (3).
C. Dissolve 0.25 g in 5 mL of water. Add 5 mL of 6m ammonia and heat in a water bath at 80° for 10 minutes. An orange-red colour is produced.
D. Dissolve about 45 mg in 5 mL of water. The resulting solution yields reaction A characteristic of sulfates, Appendix VI.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Dissolve a quantity of the powder for inhalation in sufficient mobile phase to produce a solution containing 0.020% w/v of Salbutamol Sulfate and filter.
(2) Dilute 1 volume of solution (1) to 100 volumes with the mobile phase, dilute 3 volumes to 10 volumes with the mobile phase.
(3) 0.00004% w/v of salbutamol sulfate BPCRS in the mobile phase.
(4) 0.00016% w/v of salbutamol impurity F EPCRS in the mobile phase.
(5) 0.00004% w/v of each of salbutamol sulfate BPCRS and salbutamol impurity B BPCRS in the mobile phase.
(6) Dilute 1 volume of solution (1) to 100 volumes with the mobile phase, dilute 1 volumes to 20 volumes with the mobile phase.
(a) Stainless steel column (15 cm × 3.9 mm) packed with spherical end-capped octylsilyl silica gel for chromatography (5 µm) (Symmetry C8 is suitable),
(b) Isocratic elution using the mobile phase described below.
(c) Flow rate of 1 mL per minute.
(d) Ambient column temperature.
(e) Detection wavelength of 220 nm.
(f) Injection volume of 20 µL for each solution.
A mixture of 22 volumes of acetonitrile R1 and 78 volumes of a solution containing 0.287% w/v of sodium heptanesulfonate and 0.25% w/v of potassium dihydrogen orthophosphate adjusted to pH 3.7 with 2m orthosphosphoric acid.
Allow the chromatography to proceed for 25 times the retention time of the principal peak.
The test is not valid unless, in the chromatogram obtained with solution (5), the resolution factor between the two principal peaks is at least 3.0. The retention time of the peak due to Salbutamol is about 2 minutes.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to salbutamol impurity F is not greater than the area of the peak in the chromatogram obtained with solution (4) (0.8%);
the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.3%);
disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (6) (0.05%).
The total related substances are not greater than 2.0%.
Complies with the requirements stated under Powders for Inhalation using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Collect single doses of the preparation being examined using the procedure described under Powders for Inhalation, Uniformity of delivered dose and dissolve the collected dose in sufficient mobile phase to produce a solution containing the equivalent of 0.00009% w/v of salbutamol.
(2) 0.0001% w/v of salbutamol sulfate BPCRS in the mobile phase.
The chromatographic conditions described under Related substances may be used with the exception of run time.
Calculate the content of salbutamol, C13H21NO3, per delivered dose using the declared content of C13H21NO3 in salbutamol sulfate BPCRS. Repeat the procedure nine times as described for pre-metered systems under Powders for Inhalation, Uniformity of delivered dose.
Carry out the test for aerodynamic assessment of fine particles, Appendix XII F, using Apparatus A but determining the content of active ingredient as described below. Use 7 mL of water in the upper impingement chamber and 30 mL of water in the lower impingement chamber. Use water to wash the coupling tube, E, and transfer the combined solution and washings in the lower impingement chamber to a 100-mL graduated flask and dilute the combined solution and washings to 100 mL with water. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Use the diluted solution from the lower impingement chamber diluted, if necessary, with the mobile phase to produce a solution expected to contain the equivalent of 0.0003% w/v of salbutamol.
(2) 0.0003% w/v solution of salbutamol sulfate BPCRS in the mobile phase.
The chromatographic conditions described under Related substances may be used with the exception of run time.
Calculate the amount of salbutamol, C13H21NO3, delivered to the lower impingement chamber per actuation of the device using the declared content of C13H21NO3 in salbutamol sulfate BPCRS. Not less than 30% of the average amount of salbutamol delivered per actuation of the device, determined in the Assay, is deposited in the lower impingement chamber.
4.5 to 5.5% w/w, Appendix IX C. Use 250 mg of the contents of the units and using a mixture of 1 volume of formamide and 2 volumes of methanol as the solvent.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Dissolve the mixed contents of 20 units [blister, capsule, etc] in sufficient water to produce a solution containing the equivalent of 0.0001% w/v of salbutamol.
(2) 0.0001% w/v of salbutamol sulfate BPCRS in water.
(3) 0.0001% w/v of salbutamol sulfate BPCRS and 0.0001% w/v of salbutamol impurity B BPCRS in the mobile phase.
The chromatographic conditions described under Related substances may be used.
The test is not valid unless, in the chromatogram obtained with solution (2), the resolution factor between the two principal peaks is at least 3.0.
Calculate the content of salbutamol, C13H21NO3, using the declared content of C13H21NO3 in salbutamol sulfate BPCRS.
The label states the equivalent amount of salbutamol per unit (blister, capsule etc).
When supplied as a powder reservoir within a metered-dose powder inhaler, the powder for inhalation complies with the following requirements.
When supplied as a powder reservoir within a metered-dose powder inhaler, Salbutamol Powder for Inhalation consists of Salbutamol Sulfate in microfine powder either alone or admixed with Lactose in a suitable device.
80.0 to 120.0% of the stated amount per delivered dose.
For powders for inhalation containing salbutamol sulfate
Complies with Identification tests A, B and D stated above.
For powders for inhalation containing salbutamol sulfate admixed with lactose
Complies with Identification tests A, B, C and D stated above.
Complies with the requirements stated above for Pre-metered units.
Complies with the requirements stated under Powders for Inhalation using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Collect single doses of the preparation being examined using the procedure described under Powders for Inhalation, Uniformity of delivered dose and dissolve the collected dose in sufficient water to produce a solution containing the equivalent of 0.0001% w/v of salbutamol.
(2) 0.0001% w/v of salbutamol sulfate BPCRS in the mobile phase.
The chromatographic conditions described under Related substances for Pre-metered units may be used with the exception of run time.
Calculate the content of salbutamol, C13H21NO3, per delivered dose using the declared content of C13H21NO3 in salbutamol sulfate BPCRS. Repeat the procedure nine times as described for reservoir systems under Powders for Inhalation, Uniformity of delivered dose.
For powders for inhalation containing salbutamol sulfate admixed with lactose 4.5 to 5.5% w/w, Appendix IX C. Use 50 mg of the powder for inhalation and use a mixture of 1 volume of formamide and 2 volumes of methanol as the solvent.
Complies with the requirements stated under Deposition of the emitted dose for Pre-metered units.
Where the label states delivered dose, use the average of the 10 individual results obtained in the test for uniformity of delivered dose.
Where the label states metered dose, carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Dissolve a quantity of the powder in sufficient water to produce a solution containing the equivalent of 0.0001% w/v of salbutamol.
(2) 0.0001% w/v of salbutamol sulfate BPCRS in water.
(3) 0.0001% w/v of salbutamol sulfate BPCRS and 0.0001% w/v of salbutamol impurity B BPCRS in the mobile phase.
The chromatographic conditions described under Related substances for Pre-metered units may be used with the exception of run time.
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the two principal peaks is at least 3.0.
Calculate the content of salbutamol, C13H21NO3, using the declared content of C13H21NO3 in salbutamol sulfate BPCRS.
The label states the dose in terms of the equivalent amount of salbutamol.
The impurities limited by the requirements of this monograph include those listed under Salbutamol Sulfate.