Epinephrine Bitartrate Inhalation Aerosol
» Epinephrine Bitartrate Inhalation Aerosol is a suspension of microfine Epinephrine Bitartrate in 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 epinephrine bitartrate (C9H13 NO3·C4H6O6).
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—
USP Epinephrine Bitartrate RS Click to View Structure
Identification—
A: Place 10 mL of water in a small beaker, and deliver 3 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 0.5 mL of 0.1 N iodine, allow to stand for 5 minutes, and add 1 mL of 0.1 N sodium thiosulfate: a red-brown color is produced.
B: Actuate the valve of the Aerosol by pressing the tip against a station of a white porcelain spot plate. Cover the spot with 2 or 3 drops of a mixture of 3 volumes of pyridine and 1 volume of acetic anhydride: an emerald-green color is produced.
Delivered 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—
Ferro-citrate solution and Buffer solution— Prepare as directed under Epinephrine Assay 391.
Standard preparation— Dissolve an accurately weighed quantity of USP Epinephrine Bitartrate 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 15 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 C9H13NO3·C4H6O6 contained in the minimum dose taken by the formula:
(20CN)(AU / AS)
in which C is the concentration, in µg per mL, of USP Epinephrine Bitartrate 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 Test preparation and the Standard preparation, respectively.
Particle size— Proceed with Epinephrine Bitartrate Inhalation Aerosol as directed in the test for Particle size under Isoproterenol Sulfate Inhalation Aerosol. It meets the limits of the test.
Assay—
Ferro-citrate solution and Buffer solution— Prepare as directed under Epinephrine Assay 391.
Standard preparation— Prepare as directed under Delivered dose uniformity over the entire contents.
Assay preparation— [note—A suitable specimen beaker is one having a small indentation formed on 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 delivery of the specimen. ] Place 20 mL of chloroform in a suitable 100-mL beaker. Prime the valve of Epinephrine Bitartrate Inhalation 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 3 sprays in this manner. Rinse the valve stem and ferrule with about 2 mL of chloroform, collecting the rinsing with the specimen in the beaker. Allow the Aerosol to dry, weigh it, and determine the total weight of the 3 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 the Assay preparation.
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 C9H13NO3·C4H6O6 in each mL of the Aerosol taken by the formula:
(0.01Cd / W)(AU / AS)
in which C is the concentration, in µg per mL, of USP Epinephrine Bitartrate RS in the Standard preparation, d is the density, in g per mL, of the Aerosol, determined as directed for d in the Procedure in the Assay under Isoproterenol Sulfate Inhalation Aerosol, W is the weight, in g, of the specimen taken, and AU and AS are the absorbances of the solutions from the Assay preparation and the Standard preparation, respectively.
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