Action and use
Beta2-adrenoceptor agonist; bronchodilator.
DEFINITION
Salmeterol Pressurised Inhalation, Suspension is a suspension of Salmeterol Xinafoate 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 salmeterol, C25H37NO4
85.0 to 115.0% of the stated delivered dose (ex-actuator).
IDENTIFICATION
A. Cool the contents of the pressurised container, remove the valve assembly and allow the propellant to evaporate. The infrared absorption spectrumof the residue, Appendix II A, is concordant with the reference spectrum of Salmeterol Xinafoate (RS 499).
B. In the Uniformity of delivered dose, the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the principal peak in the chromatogram obtained with solution (2).
TESTS
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.
(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 methanol to produce a solution containing the equivalent of 0.000021% w/v of salmeterol.
(2) 0.0000375% w/v of salmeterol xinafoate EPCRS in methanol.
(3) 0.0000375% w/v of salmeterol xinafoate for system suitability EPCRS in methanol.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (3.0 mm × 5.0 cm) packed with octadecylsilyl silica gel for chromatography (5μm) (Hypersil ODS C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a fluorimetric detector with an excitation wavelength of 225 nm and an emission wavelength of 305 nm.
(f) Inject 100 μL of each solution.
MOBILE PHASE
1 volume of 0.0025M sodium dodecyl sulfate containing 1% v/v glacial acetic acid and 10 volumes of methanol.
When the chromatograms are recorded under the prescribed conditions the relative retention of impurity F with reference to salmeterol (retention time about 2.6 minutes) is about 1.1.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the peak-to-valley ratio is at least 3, where Hp is the height above the baseline of the peak due to impurity E and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to salmeterol.
DETERMINATION OF CONTENT
Calculate the content of salmeterol, C25H37NO4, per delivered dose using the declared content of C36H45NO7 in salmeterol xinafoate EPCRS. Each mg of C36H45NO7 is equivalent to 0.6880 mg of C25H37NO4. Repeat the procedure as described under Pressurised Metered-dose Preparations for Inhalation, Uniformity of delivered dose.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
Solution A A mixture of equal volumes of acetonitrile and water.
(1) Prepare the sample in an appropriate manner and dissolve the sample in sufficient solution A to produce a solution containing the equivalent of 0.02% w/v of salmeterol.
(2) Dilute 1 volume of solution (1) to 100 volumes with solution A.
(3) 0.054% w/v of salmeterol xinafoate for system suitability EPCRS in solution A.
(4) Dilute 1 volume of solution (2) to 10 volumes with solution A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl amorphous organosilica polymer (5μm) (X Terra MS-C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 30°.
(e) Use a detection wavelength of 225 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
Solution B: Dilute 1 volume of 1M potassium dihydrogen phosphate, previously adjusted to pH 2.5 with orthophosphoric acid, to 100 volumes with water.
Mobile phase A: 0.005M sodium dodecyl sulfate in a mixture of equal volumes of solution B and acetonitrile.
Mobile phase B: 0.005M sodium dodecyl sulfate in a mixture of 2 volumes of solution B and 8 volumes of acetonitrile.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-5 | 100 | 0 | isocratic |
| 5-20 | 100→0 | 0→100 | linear gradient |
| 20-25 | 0 | 100 | isocratic |
| 25-26 | 0→100 | 100→0 | linear gradient |
| 26-31 | 100 | 0 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to salmeterol (retention time about 12 minutes) are: xinafoic acid, about 0.1; impurity A, about 0.4; impurity B, about 0.7; impurity C, about 0.85; impurity D, about 0.93; impurity E, about 0.96; impurity F, about 1.2 and impurity G, about 2.0.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between salmeterol and impurity E is at least 1.5.
LIMITS
Identify any peak corresponding to impurity D in the chromatogram obtained with solution (1), using the chromatogram obtained with solution (3), and multiply the area of this peak by a correction factor of 0.7.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to salmeterol impurity G is not greater than twice the area of the principal peak in the chromatogram obtained with solution (4) (0.2%);
the area of any other secondary peak is not greater than 0.8 times the area of the principal peak in the chromatogram obtained with solution (2) (0.8%);
the sum of the areas of all impurities 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%).
ASSAY
Use the average of the individual results determined 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, B, C, D, E, F and G listed under Salmeterol Xinafoate.
