Packaging and storage—
Preserve in small, nonreactive, light-resistant aerosol containers equipped with metered-dose valves and provided with oral inhalation actuators.
Identification—
A:
Place 10 mL of water in a small beaker, and deliver 10 sprays from the Inhalation Aerosol under the surface of the water, actuating the valve by pressing the stem tip against the bottom of the beaker. Filter, place 5 mL of the filtrate in a test tube, and retain the remainder of the solution for
Identification test
B. Add 1 drop of 0.2 N sulfuric acid and 0.5 mL of 0.1 N iodine, allow to stand for 5 minutes, and add 1 mL of 0.1 N sodium thiosulfate: a salmon-pink color is produced.
B:
Dilute the remainder of the filtrate obtained in
Identification test
A with an equal volume of water. Add a few drops of 6 N ammonium hydroxide, filter, acidify the filtrate with nitric acid, and divide into two equal portions. To each portion add a few drops of
silver nitrate TS: white precipitates are formed. To one portion add a slight excess of nitric acid: the white precipitate remains. To the other portion add a slight excess of 6 N ammonium hydroxide, and shake: the precipitate dissolves.
Alcohol content 
611
—
Weigh accurately a filled Inhalation Aerosol container, and record the weight. Place the container in a dry ice-alcohol bath, and cool for 60 minutes. Remove the container from the bath, and carefully remove the valve with wire cutters, taking precautions to save all pieces of the valve and cap. With the aid of three 5-mL portions of water, transfer the contents of the container to a beaker previously chilled in the bath. Dry the rinsed empty container and all of its parts in an oven at 105
for 2 hours, cool, and weigh. Calculate the weight of the container contents. Add a few boiling chips to the beaker, and carefully stir to help evaporate the propellant. After the bulk of the propellant has evaporated, transfer the contents of the beaker, with the aid of several mL of water, to a glass-stoppered graduated cylinder, measure the volume, and determine the alcohol content of the
Test solution thus prepared by the gas-liquid chromatographic procedure, methyl ethyl ketone being used as the internal standard. Calculate the alcohol content of the Inhalation Aerosol taken by the formula:
SV / W,
in which
S is the percentage of alcohol (w/v) in the
Test solution; V is the volume, in mL, of the
Test solution; and
W is the weight, in g, of the container contents: between 28.5% and 38.5% (w/w) of C
2H
5OH is found.
Dose uniformity over the entire contents:
meets the requirements for
Metered-Dose Inhalers under
Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers 601.
PROCEDURE FOR DOSE UNIFORMITY—
Standard preparation—
Dissolve an accurately weighed quantity of
USP Isoproterenol Hydrochloride RS in a freshly prepared sodium bisulfite solution (1 in 500), and dilute quantitatively and stepwise with the same sodium bisulfite solution as necessary to obtain a solution having a known concentration of about 6 µg per mL.
Test preparation—
Discharge the minimum recommended dose into the sampling apparatus and detach the inhaler as directed. Rinse the apparatus (filter and interior) with four 5.0-mL portions of a freshly prepared sodium bisulfite solution (1 in 500), and transfer the resulting solutions quantitatively to a 50-mL centrifuge tube. Add 10 mL of chloroform, insert the stopper, shake vigorously for 1 minute, and centrifuge. Use the clear supernatant as directed for Procedure.
Procedure—
Into three separate flasks, transfer the
Test preparation, 20.0 mL of the
Standard preparation, and 20.0 mL of water to provide the blank. To each flask add 100 µL of
Ferro-citrate solution followed by 1.0 mL of
Buffer solution, and mix. Concomitantly determine the absorbances with a suitable spectrophotometer, in 5-cm cells, of the solutions from the
Test preparation and the
Standard preparation, at the wavelength of maximum absorbance at about 530 nm, against the blank. Calculate the quantity, in µg, of C
11H
17NO
3·HCl contained in the minimum dose taken by the formula:
20CN (AU / AS),
in which
C is the concentration, in µg per mL, of
USP Isoproterenol Hydrochloride RS in the
Standard preparation; N is the number of sprays discharged to obtain the minimum dose; and
AU and
AS are the absorbances of the solutions from the
Test preparation and the
Standard preparation, respectively.
Assay—
Ferro-citrate Solution, Buffer Solution, and Standard preparation—
Prepare as directed under Unit spray content.
Assay preparation—
Fit the Inhalation Aerosol container with its inhalation actuator, and prime the unit by firing it 10 times. Remove the actuator, and accurately weigh the container with its remaining contents. Invert the container, place the valve stem tip against the bottom of a 100-mL beaker containing 20 mL of chloroform, and deliver under the surface of the chloroform a number of sprays equivalent to about 500 µg of isoproterenol hydrochloride. Raise the unit above the contents of the beaker, and wash the valve stem with about 2 mL of chloroform. Collect the washings in the beaker. Allow the valve stem to dry, and again accurately weigh the Inhalation Aerosol container with its remaining contents. Record the weight of the expelled specimen. Transfer the contents of the beaker to a centrifuge tube with the aid of two 3-mL portions of chloroform, add 10.0 mL of freshly prepared sodium bisulfite solution (1 in 500), and shake vigorously for 1 minute. Centrifuge, and use the clear supernatant as directed for Procedure.
Procedure—
Into three separate test tubes, pipet 5 mL each of the
Assay preparation,
Standard preparation, and water to provide the blank, respectively. To each tube add 100 µL of
Ferro-citrate Solution, followed by 1.0 mL of
Buffer Solution, and mix. Determine the absorbances of the
Assay preparation and the
Standard preparation at the wavelength of maximum absorbance at about 530 nm, against the blank. Calculate the percentage (w/w) of C
11H
17NO
3·HCl in the portion of Inhalation Aerosol taken by the formula:
0.001(C / W)(AU / AS),
in which
C is the concentration, in µg per mL, of
USP Isoproterenol Hydrochloride RS in the
Standard preparation; W is the weight, in g, of Inhalation Aerosol taken; and
AU and
AS are the absorbances of the solutions from the
Assay preparation and the
Standard preparation, respectively.
