Terbutaline Sulfate Inhalation Aerosol »Terbutaline Sulfate Inhalation Aerosol is a suspension of microfine Terbutaline Sulfate in suitable propellants in a pressurized container.It contains not less than 90.0percent and not more than 110.0percent of the labeled amount of (C12H19NO3)2·H2SO4. Packaging and storage— Preserve in small,nonreactive,light-resistant aerosol containers equipped with metered-dose valves and provided with oral inhalation actuators.Store at controlled room temperature. USP Reference standards á11ñ USP Terbutaline Sulfate RS. Identification— Chill 10filled containers to about -75in a dry ice-acetone mixture for 15to 20minutes.Carefully remove the top of each container with a tube cutter,allow to stand for 15minutes,and pour the contents into a 100-mLbeaker.Pour about 5mLof the combined contents into a 100-mLbeaker containing 50mLof chloroform,shake,and filter through a medium-porosity sintered-glass funnel.Wash the residue with five 10-mLportions of chloroform.Allow the residue to dry by drawing air through the funnel:the IRabsorption spectrum of a potassium bromide dispersion of the residue so obtained exhibits maxima only at the same wavelengths as that of a similar preparation of USP Terbutaline Sulfate RS. Water,Method Iá921ñ Transfer the contents of a weighed container to the titration vessel by attaching the valve stem to an inlet tube.Weigh the empty container,and determine the weight of the specimen taken.The Watercontent,determined by Method Iá921ñ,is not more than 0.02%. Delivered dose uniformity over the entire contents: meets the requirements for Metered-Dose Inhalersunder Aerosols,Nasal Sprays,Metered-Dose Inhalers,and Dry Powder Inhalers á601ñ. PROCEDURE FOR DOSE UNIFORMITY4-Aminoantipyrine solution— On the day of use,prepare a solution of 4-aminoantipyrine in water having a concentration of 20mg per mL. Potassium ferricyanide solution— On the day of use,prepare a solution of potassium ferricyanide in water having a concentration of 80mg per mL. Standard preparation— Dissolve an accurately weighed quantity of USP Terbutaline Sulfate RSin water,and dilute quantitatively and stepwise with water to obtain a solution having a known concentration of about 20µg of terbutaline sulfate 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 4.0-mLportions of 0.01Nsulfuric acid,and quantitatively transfer the resulting solutions to a 50-mLcentrifuge tube.Wash the apparatus (filter and interior)with 10mLof chloroform,and add the washing to the solution in the centrifuge tube.Wash the apparatus (filter and interior)with 4.0mLof 0.01Nsulfuric acid,and quantitatively transfer the resulting liquid to the same centrifuge tube.Shake vigorously for 1minute,and centrifuge for 10minutes.Use the clear aqueous phase as the Test preparation. Procedure— Pipet 2mLof the Test preparation,2mLof the Standard preparation,and 2mLof water to serve as a reagent blank,into separate 1-cm stoppered cells.To each cell add 0.5mLof 4-Aminoantipyrine solution,and mix.Add 0.5mLof Potassium ferricyanide solutionto each cell,and mix.Thirty seconds,accurately timed,after the addition of the Potassium ferricyanide solution,determine the absorbances of the solutions against the blank,at the wavelength of maximum absorbance at about 550nm.Calculate the quantity,in µg,of (C12H19NO3)2·H2SO4contained in the minimum dose taken by the formula: 10CN(AU/AS), in which Cis the concentration,in µg per mL,of USP Terbutaline Sulfate 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,corrected for the absorbances of the reagent blank solution. Particle size— Prime the valve of Aerosol container by alternately shaking and firing it several times,and actuate one measured spray onto a clean,dry microscope slide held 5cm from the end of the oral inhalation actuator,perpendicular to the direction of the spray.Carefully rinse the slide with about 2mLof carbon tetrachloride,and allow to dry.Prepare four additional slides in the same manner from four additional containers.Examine each slide under a microscope equipped with a calibrated ocular micrometer,using 450×magnification.Focus on the particles of 5fields of view on each slide,near the center of the test specimen pattern,and note the size of the majority of individual particles.They are less than 5µm along the longest axis.Record the number and size of all individual crystalline particles (not agglomerates)more than 10µm in length,measured along the longest axis:not more than 10such particles are observed. Assay— Mobile phase— Prepare a solution containing 750mLof water,140mLof methanol,110mLof tetrahydrofuran,and 1.08g of sodium 1-octanesulfonate.Filter and degas.Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ). System suitability solution— Dissolve suitable quantities of USP Terbutaline Sulfate RSand 3,5-dihydroxy-w-tert-butylaminoacetophenone sulfate in water to obtain a solution containing about 50and 20µg per mL,respectively. Standard preparation— Dissolve an accurately weighed quantity of USP Terbutaline Sulfate RSin water to obtain a solution having a known concentration of about 0.3mg per mL. Assay preparation— Accurately weigh not less than three containers,and separately perform the following procedure for each of the units.Chill in a dry ice-acetone mixture to about -75for 15to 20minutes.Quickly and carefully remove the top of the container with a tube cutter.Allow the propellants to evaporate at room temperature for 10to 15minutes.[NOTE—Avoid complete evaporation of the propellants.]Quantitatively transfer the suspension to a 500-mLseparatory funnel with the aid of chloroform.Wash all parts of the container alternately with several small portions of chloroform followed by small portions of 0.01Nsulfuric acid.Transfer the washings to the separatory funnel,and adjust the phase volumes to about 100mLeach with chloroform and 0.01Nsulfuric acid,respectively.Dry the container and all of its parts at 105for 1hour.Cool to room temperature,and weigh.Shake the separatory funnel for 1minute,allow the phases to separate,and discard the chloroform layer.Filter the acidic aqueous phase through filter paper into a 250-mLvolumetric flask.Wash the separatory funnel with two 10-mLportions of water,and transfer the washings to the volumetric flask.Dilute with water to volume,mix,and filter,discarding the first 2mLof the filtrate. Chromatographic system (see Chromatography á621ñ)—The liquid chromatograph is equipped with a 280-nm detector and a 6.2-mm ×8-cm column that contains 3-µm packing L7and is maintained at 40,and fitted with a 0.5-µm pre-column.The flow rate is about 1.5mLper minute.Chromatograph the System suitability solution,and record the peak responses as directed for Procedure:the relative retention times are about 0.83and 1.0for terbutaline and 3,5-dihydroxy-w-tert-butylaminoacetophenone,respectively;and the resolution,R,between terbutaline sulfate and 3,5-dihydroxy-w-tert-butylaminoacetophenone is not less than 1.6.Chromatograph the Standard preparation,and record the peak responses as directed in the Procedure:the relative standard deviation for replicate injections is not more than 2.0%. Procedure— Separately inject equal volumes (about 20µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in mg,of (C12H19NO3)2·H2SO4in each container taken by the formula: 250C(rU/rS), in which Cis the concentration,in mg per mL,of USP Terbutaline Sulfate RSin the Standard preparation,and rUand rSare the peak responses obtained from the Assay preparationand Standard preparation,respectively. Auxiliary Information— Staff Liaison:Kahkashan Zaidi,Ph.D.,Senior Scientific Associate Expert Committee:(AER)Aerosols USP28–NF23Page 1869 Phone Number:1-301-816-8269