Isoproterenol Hydrochloride Inhalation Aerosol
»Isoproterenol Hydrochloride Inhalation Aerosol is a solution of Isoproterenol Hydrochloride in Alcohol in an inert propellant base.It contains not less than 90.0percent and not more than 115.0percent of the labeled amount of isoproterenol hydrochloride (C11H17NO3·HCl).
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 10mLof water in a small beaker,and deliver 10sprays 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 5mLof the filtrate in a test tube,and retain the remainder of the solution for Identificationtest B.Add 1drop of 0.2Nsulfuric acid and 0.5mLof 0.1Niodine,allow to stand for 5minutes,and add 1mLof 0.1Nsodium thiosulfate:a salmon-pink color is produced.
B: Dilute the remainder of the filtrate obtained in Identificationtest Awith an equal volume of water.Add a few drops of 6Nammonium 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 6Nammonium hydroxide,and shake:the precipitate dissolves.
Alcohol content á611ñ— Weigh accurately a filled Inhalation Aerosol container,and record the weight.Place the container in a dry ice-alcohol bath,and cool for 60minutes.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-mLportions 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 105for 2hours,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 mLof water,to a glass-stoppered graduated cylinder,measure the volume,and determine the alcohol content of the Test solutionthus 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 Sis the percentage of alcohol (w/v)in the Test solution,Vis the volume,in mL,of the Test solution,and Wis the weight,in g,of the container contents:between 28.5%and 38.5%(w/w)of C2H5OHis found.
Dose uniformity over the entire contents: meets the requirements for Metered-Dose Inhalersunder Aerosols,Nasal Sprays,Metered-Dose Inhalers,and Dry Powder Inhalers á601ñ.
PROCEDUREFOR DOSE UNIFORMITY—
Ferro-citrate solution and Buffer solution—Prepare as directed under Epinephrine Assay á391ñ.
Standard preparation— Dissolve an accurately weighed quantity of USP Isoproterenol Hydrochloride RSin a freshly prepared sodium bisulfite solution (1in 500),and dilute quantitatively and stepwise with the same sodium bisulfite solution as necessary to obtain a solution having a known concentration of about 6µg 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-mLportions of a freshly prepared sodium bisulfite solution (1in 500),and transfer the resulting solutions quantitatively to a 50-mLcentrifuge tube.Add 10mLof chloroform,insert the stopper,shake vigorously for 1minute,and centrifuge.Use the clear supernatant as directed in the Procedure.
Procedure— Into three separate flasks,transfer the Test preparation,20.0mLof the Standard preparation,and 20.0mLof water to provide the blank.To each flask add 100µLof Ferro-citrate solutionfollowed by 1.0mLof Buffer solution,and mix.Concomitantly determine the absorbances with a suitable spectrophotometer,in 5-cm cells,of the solutions from the Test preparationand the Standard preparation,at the wavelength of maximum absorbance at about 530nm,against the blank.Calculate the quantity,in µg,of C11H17NO3·HCl contained in the minimum dose taken by the formula:
20CN(AU/AS),
in which Cis the concentration,in µg per mL,of USP Isoproterenol Hydrochloride RSin the Standard preparation;Nis the number of sprays discharged to obtain the minimum dose;and AUand ASare the absorbances of the solutions from the Test preparationand 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 10times.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-mLbeaker containing 20mLof chloroform,and deliver under the surface of the chloroform a number of sprays equivalent to about 500µg of isoproterenol hydrochloride.Raise the unit above the contents of the beaker,and wash the valve stem with about 2mLof 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-mLportions of chloroform,add 10.0mLof freshly prepared sodium bisulfite solution (1in 500),and shake vigorously for 1minute.Centrifuge,and use the clear supernatant as directed in the Procedure.
Procedure— Into three separate test tubes,pipet 5mLeach of the Assay preparation,Standard preparation,and water to provide the blank,respectively.To each tube add 100µLof Ferro-citrate Solution,followed by 1.0mLof Buffer Solution,and mix.Determine the absorbances of the Assay preparationand the Standard preparationat the wavelength of maximum absorbance at about 530nm,against the blank.Calculate the percentage (w/w)of C11H17NO3·HCl in the portion of Inhalation Aerosol taken by the formula:
0.001(C/W)(AU/AS),
in which Cis the concentration,in µg per mL,of USP Isoproterenol Hydrochloride RSin the Standard preparation,Wis the weight,in g,of Inhalation Aerosol taken,and AUand ASare the absorbances of the solutions from the Assay preparationand the Standard preparation,respectively.
Auxiliary Information— Staff Liaison:Kahkashan Zaidi,Ph.D.,Senior Scientific Associate
Expert Committee:(AER)Aerosols
USP28–NF23Page 1078
Phone Number:1-301-816-8269