Isoproterenol Sulfate Inhalation Aerosol
» Isoproterenol Sulfate Inhalation Aerosol is a suspension of microfine Isoproterenol Sulfate in fluorochlorohydrocarbon propellants in a pressurized container. It contains not less than 90.0 percent and not more than 110.0 percent of the labeled amount of isoproterenol sulfate [(C11H17NO3)2·H2SO4].
Packaging and storage—
Preserve in small, nonreactive, light-resistant aerosol containers equipped with metered-dose valves and provided with oral inhalation actuators.
USP Reference standards 
11
—
11—
USP Isoproterenol Hydrochloride RS 
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Identification—
A:
Place 10 mL of water in a small beaker, and deliver 10 sprays from the Aerosol under the surface of the water, actuating the valve by pressing the tip against the bottom of the beaker. Filter, and to 5 mL of the filtrate add 1 drop of dilute hydrochloric acid (1 in 120). Add 0.50 mL of 0.10 N iodine, allow to stand for 5 minutes, and add 1.0 mL of 0.10 N sodium thiosulfate: a red-brown color is produced.
B:
A portion of the filtrate obtained in Identification test A responds to the tests for Sulfate 191.
191.
Microbial enumeration tests 61 and Tests for specified microorganisms 62—
It meets the requirements of the tests for absence of Staphylococcus aureus and Pseudomonas aeruginosa.
61 and Tests for specified microorganisms 62—
It meets the requirements of the tests for absence of Staphylococcus aureus and Pseudomonas aeruginosa.
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.
601.
Procedure for dose uniformity—
Ferro-citrate solution
and Buffer solution—Prepare as directed under Epinephrine Assay 391.
391.
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 4 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 for 5 minutes. Use the clear supernatant as directed in the 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 and 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 (C11H17NO3)2·H2SO4 contained in the minimum dose taken by the formula:
(260.30 / 247.72)(20CN)(AU / AS)
in which 260.30 is one-half of the molecular weight of isoproterenol sulfate (anhydrous), and 247.72 is the molecular weight of isoproterenol hydrochloride; 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 recommended dose; and AU and AS are the absorbances of the solutions from the Assay preparation and the Standard preparation, respectively.
Particle size—
Prime the valve of the Aerosol by alternately shaking and firing it several times through its oral inhalation actuator, and then actuate one measured spray onto a clean, dry microscope slide held 5 cm from the end of the actuator, perpendicular to the direction of the spray. Carefully rinse the slide with about 2 mL of carbon tetrachloride, and allow to dry. Examine the slide under a microscope, equipped with a calibrated ocular micrometer, using 450 × magnification. Focus on the particles of 25 fields of view near the center of the test specimen pattern, and note the size of the great majority of individual particles: they are less than 5 µm in diameter. Record the number and size of all individual crystalline particles (not agglomerates) more than 10 µm in length measured along the longest axis: not more than 10 such particles are observed.
Assay—
Ferro-citrate solution
and Buffer solution—Prepare as directed under Epinephrine Assay 391.
391.
Standard preparation—
Transfer about 50 mg of USP Isoproterenol Hydrochloride RS, accurately weighed, to a 100-mL volumetric flask, add a freshly prepared solution of sodium bisulfite (1 in 500) to volume, and mix. Transfer 10.0 mL of this solution to a second 100-mL volumetric flask, dilute with the sodium bisulfite solution to volume, and mix. The concentration of USP Isoproterenol Hydrochloride RS in the Standard preparation is about 50 µg per mL.
Assay preparation—
[note—A suitable sampling beaker is one having a small indentation formed in its inside bottom surface having dimensions adequate to accept the aerosol valve stem during actuation, thereby preventing particle entrapment and side-of-stem leakage during the sample delivery. ] Place 20 mL of chloroform in a suitable 100-mL beaker. Prime the valve of the Aerosol by alternately shaking and firing it 10 times through its oral inhalation actuator. Accurately weigh the Aerosol, shake it, and immediately deliver a single spray under the surface of the chloroform, actuating the valve by pressing the tip into the indentation in the bottom of the beaker. Raise the Aerosol above the surface of the chloroform, and shake it gently preparatory to delivering another spray similarly under the surface of the chloroform. Deliver a total of 5 sprays in this manner. Rinse the valve stem and ferrule with about 2 mL of chloroform, collecting the rinsing with the sample in the beaker. Allow the Aerosol to dry, weigh it, and determine the total weight of the 5 sprays. Transfer the solution to a centrifuge tube with the aid of two 3-mL portions of chloroform, and add 10.0 mL of freshly prepared sodium bisulfite solution (1 in 500). Insert the stopper, shake vigorously for 1 minute, centrifuge for 5 minutes, and use the clear supernatant as directed in the Procedure.
Procedure—
Transfer 5.0 mL each of the Standard preparation and the Assay preparation to separate test tubes. To each tube add 100 µL of Ferro-citrate solution and 1.0 mL of Buffer solution, and mix. Concomitantly determine the absorbances of the solutions in 1-cm cells at the wavelength of maximum absorbance at about 530 nm, with a suitable spectrophotometer, using water as the blank. Calculate the quantity, in mg, of (C11H17NO3)2·H2SO4 in each mL of the Aerosol taken by the formula:
. Obtain the specimen equivalent to the same volume as that obtained during the sampling procedure, from the Aerosol by means of a sampling device consisting of a replaceable rubber septum engaged in the plate threads at one end of a threaded fitting, the opposite end of which contains a sharpened tube capable of puncturing the aerosol container, and a rubber gasket around the tube to prevent leakage of the container contents after puncture.* Record the weight of the volume (v) of the Aerosol as w, and calculate the density by the formula w/v.]
(260.30 / 247.72)(0.01Cd / W)(AU / AS)
in which 260.30 is one-half of the molecular weight of isoproterenol sulfate (anhydrous); 247.72 is the molecular weight of isoproterenol hydrochloride; C is the concentration, in µg per mL, of USP Isoproterenol Hydrochloride RS in the Standard preparation; d is the density, in g per mL, of the Aerosol; W is the weight, in g, of the portion of Inhalation Aerosol taken; and AU and AS are the absorbances of the solutions from the Assay preparation and the Standard preparation, respectively. [The density, d, is determined as follows. Weigh a known volume (v) of the Inhalation Aerosol in a suitable, gas-tight, 5-mL syringe equipped with a linear valve. Calibrate the volume of the syringe by filling to the 5-mL mark with dichlorotetrafluoroethane withdrawn from a plastic-coated glass vial sealed with a neoprene multiple-dose rubber stopper and an aluminum seal, using 1.456 g per mL as the density of the calibrating liquid. Maintain the dichlorotetrafluoroethane, the Aerosol assay specimen, and the syringe (protected from becoming wet) in a water bath at 25. Obtain the specimen equivalent to the same volume as that obtained during the sampling procedure, from the Aerosol by means of a sampling device consisting of a replaceable rubber septum engaged in the plate threads at one end of a threaded fitting, the opposite end of which contains a sharpened tube capable of puncturing the aerosol container, and a rubber gasket around the tube to prevent leakage of the container contents after puncture.* Record the weight of the volume (v) of the Aerosol as w, and calculate the density by the formula w/v.]
*
A suitable sampling system is available from Alltech Associates, 2051 Waukegan Rd., Deerfield, IL 60015.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Ravi Ravichandran, Ph.D.
Principal Scientific Liaison 1-301-816-8330 |
(SM42010) Monographs - Small Molecules 4 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
|
| 61 |
Radhakrishna S Tirumalai, Ph.D.
Principal Scientific Liaison 1-301-816-8339 |
(GCM2010) General Chapters - Microbiology |
| 62 |
Radhakrishna S Tirumalai, Ph.D.
Principal Scientific Liaison 1-301-816-8339 |
(GCM2010) General Chapters - Microbiology |
USP35–NF30 Page 3584