Tablets Containing at Least Three of the Following—Acetaminophen and Salts of Chlorpheniramine,Dextromethorphan,and Pseudoephedrine »Tablets Containing at Least Three of the Following—Acetaminophen and Salts of Chlorpheniramine,Dextromethorphan,and Pseudoephedrine contain not less than 90.0percent and not more than 110.0percent of the labeled amounts of acetaminophen (C8H9NO2),chlorpheniramine maleate (C16H19ClN2·C4H4O4),dextromethorphan hydrobromide (C18H25NO·HBr ·H2O),and pseudoephedrine hydrochloride (C10H15NO·HCl)or pseudoephedrine sulfate [(C10H15NO)2·H2SO4]. NOTE—The heading of this monograph does not constitute the official title.It is not intended that the name described herein be recognized as the official title or the common or usual name.The name for each article encompassed by this monograph shall be composed of the names of the active ingredients contained therein,as well as the quantitative amount of each active ingredient,and a statement of the function (or purpose)of the ingredient in the article. Packaging and storage— Preserve in tight containers,and store at controlled room temperature. USP Reference standards á11ñ USP Acetaminophen RS.USP Chlorpheniramine Maleate RS.USP Dextromethorphan Hydrobromide RS.USP Pseudoephedrine Hydrochloride RS.USP Pseudoephedrine Sulfate RS. Labeling— The label for each article encompassed by this monograph bears a name composed of the active ingredients.The label states the name and quantity of each active ingredient and indicates its function (or purpose)in the article. Identification— A: If pseudoephedrine hydrochloride or pseudoephedrine sulfate is claimed in the labeling to be present,the chromatogram of the Assay preparation,obtained as directed in the Assay for pseudoephedrine hydrochlorideor the Assay for pseudoephedrine sulfate,exhibits a major peak for pseudoephedrine,the retention time of which corresponds to that exhibited by the Standard preparation. B: If acetaminophen is claimed in the labeling to be present,the chromatogram of the Assay preparation,obtained as directed in the Assay for acetaminophen,exhibits a major peak for acetaminophen,the retention time of which corresponds to that exhibited by the Standard preparation. C: If chlorpheniramine maleate is claimed in the labeling to be present,the chromatogram of the Assay preparation,obtained as directed in the Assay for chlorpheniramine maleate,exhibits a major peak for chlorpheniramine,the retention time of which corresponds to that exhibited by the Standard preparation. D: If dextromethorphan hydrobromide is claimed in the labeling to be present,the chromatogram of the Assay preparation,obtained as directed in the Assay for dextromethorphan hydrobromide,exhibits a major peak for dextromethorphan,the retention time of which corresponds to that exhibited by the Standard preparation. Dissolution,Procedure for a Pooled Sample á711ñ Medium: water;900mL. Apparatus 2: 50rpm. Time: 45minutes. Test preparation— Mix 9.0mLof a filtered portion of the solution under test with 1.0mLof 1%phosphoric acid solution. Procedure— Determine the amounts of pseudoephedrine hydrochloride or pseudoephedrine sulfate (as appropriate),acetaminophen,chlorpheniramine maleate,and dextromethorphan hydrobromide dissolved,employing the procedures set forth in the Assay for pseudoephedrine hydrochlorideor Assay for pseudoephedrine sulfate,Assay for acetaminophen,Assay for chlorpheniramine maleate,and Assay for dextromethorphan hydrobromide,respectively,making any necessary volumetric adjustments. Tolerances— Not less than 75%(Q)of the labeled amounts of pseudoephedrine hydrochloride (C10H15NO·HCl)or pseudoephedrine sulfate [(C10H15NO)2·H2SO4],acetaminophen (C8H9NO2),chlorpheniramine maleate (C16H19ClN2·C4H4O4),and dextromethorphan hydrobromide (C18H25NO·HBr ·H2O)are dissolved in 45minutes. Uniformity of dosage units á905ñ: meet the requirements. Assay for pseudoephedrine hydrochloride (where pseudoephedrine hydrochloride is the salt form used,if present in the formulation)— Mobile phase— Prepare a filtered and degassed mixture of methanol and water (60:40)containing 0.34g of monobasic potassium phosphate,0.3g of triethylamine hydrochloride,0.15g of sodium lauryl sulfate,and 0.1mLof phosphoric acid in each 100mLof solution.Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ). Standard preparation— Dissolve an accurately weighed quantity of USP Pseudoephedrine Hydrochloride RSin water to obtain a solution having a known concentration of about 3.0mg per mL.Transfer 1.0mLof this solution to a 25-mLvolumetric flask,add 2.5mLof methanol,dilute with 0.1%phosphoric acid to volume,and mix. Chlorpheniramine standard preparation— Prepare as directed for the Standard preparationin the Assay for chlorpheniramine maleate. Dextromethorphan standard preparation— Prepare as directed for the Standard preparationin the Assay for dextromethorphan hydrobromide. System suitability solution 1 (for Tablets that contain either all the four ingredients or a combination of three containing chlorpheniramine salt)—Mix equal volumes of the Standard preparationand the Chlorpheniramine standard preparation. System suitability solution 2 (for Tablets that contain no chlorpheniramine salt)—Mix equal volumes of the Standard preparationand the Dextromethorphan standard preparation. Assay preparation— Weigh and finely powder not fewer than 20Tablets.Transfer an accurately weighed quantity of the powder,equivalent to about 6mg of pseudoephedrine hydrochloride,to a 50-mLvolumetric flask.Add 5mLof methanol,and sonicate to disperse the powder.Dilute with 0.1%phosphoric acid to volume,mix,and filter. Chromatographic system (see Chromatography á621ñ) The liquid chromatograph is equipped with a 214-nm detector and a 4.6-mm ×15-cm column that contains packing L11.The flow rate is about 2mLper minute.Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the tailing factor for the pseudoephedrine peak is not greater than 2.5,and the relative standard deviation for replicate injections is not more than 2.0%.Separately inject about 10µLof System suitability solution 1or System suitability solution 2,as appropriate.The resolution,R,between pseudoephedrine and chlorpheniramine or between pseudoephedrine and dextromethorphan is not less than 2.0. Procedure— Separately inject equal volumes (about 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the pseudoephedrine peaks.Calculate the quantity,in mg,of pseudoephedrine hydrochloride (C10H15NO·HCl)in the portion of Tablets taken by the formula: 50C(rU/rS), in which Cis the concentration,in mg per mL,of USP Pseudoephedrine Hydrochloride RSin the Standard preparation,and rUand rSare the pseudoephedrine peak responses obtained from the Assay preparationand the Standard preparation,respectively. Assay for pseudoephedrine sulfate (where pseudoephedrine sulfate is the salt form used,if present in the formulation)— Mobile phase,Chlorpheniramine standard preparation,Dextromethorphan standard preparation,System suitability solutions,and Chromatographic system— Proceed as directed in the Assay for pseudoephedrine hydrochloride. Standard preparation— Dissolve an accurately weighed quantity of USP Pseudoephedrine Sulfate RSin water to obtain a solution having a known concentration of about 3.0mg per mL.Transfer 2.0mLof this solution to a 25-mLvolumetric flask,add 2.5mLof methanol,dilute with 0.1%phosphoric acid to volume,and mix. Assay preparation— Weigh and finely powder not fewer than 20Tablets.Transfer an accurately weighed quantity of the powder,equivalent to about 12mg of pseudoephedrine sulfate,to a 50-mLvolumetric flask.Add 5mLof methanol,and sonicate to disperse the powder.Dilute with 0.1%phosphoric acid to volume,mix,and filter. Procedure— Proceed as directed for Procedurein the Assay for pseudoephedrine hydrochloride.Calculate the quantity,in mg,of pseudoephedrine sulfate [(C10H15NO)2·H2SO4]in the portion of Tablets taken by the formula: 50C(rU/rS), in which the terms are as defined therein,pseudoephedrine sulfate being substituted for pseudoephedrine hydrochloride. Assay for acetaminophen (if present)— Mobile phase— Prepare a filtered and degassed mixture of water,methanol,and glacial acetic acid (79:20:1).Make adjustments,if necessary (see System Suitabilityunder Chromatography á621ñ). Standard preparation— Transfer about 50mg of USP Acetaminophen RS,accurately weighed,to a 100-mLvolumetric flask.Add 4mLof methanol,and mix until solution is complete.Dilute with 0.1%phosphoric acid to volume,and mix. Assay preparation— Weigh and powder not fewer than 20Tablets.Transfer an accurately weighed portion of the powder,equivalent to about 100mg of acetaminophen,to a 50-mLvolumetric flask.Add about 7.5mLof methanol,and sonicate to disperse the powder.Add 0.5mLof phosphoric acid,dilute with water to volume,mix,and filter.Transfer 25.0mLof the filtered solution to a 100-mLvolumetric flask,dilute with water to volume,and mix. Chromatographic system (see Chromatography á621ñ) The liquid chromatograph is equipped with a 280-nm detector and a 4.6-mm ×15-cm column that contains packing L7.The flow rate is about 1mLper minute.Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the tailing factor for the acetaminophen peak is not greater than 2.0,and the relative standard deviation for replicate injections is not more than 2.0%. Procedure— Separately inject equal volumes (about 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the acetaminophen peaks.Calculate the quantity,in mg,of acetaminophen (C8H9NO2)in the portion of Tablets taken by the formula: 200C(rU/rS), in which Cis the concentration,in mg per mL,of USP Acetaminophen RSin the Standard preparation;and rUand rSare the acetaminophen peak responses obtained from the Assay preparationand the Standard preparation,respectively. Assay for chlorpheniramine maleate (if present)— Mobile phase andChromatographic system— Proceed as directed in the Assay for pseudoephedrine hydrochloride. Standard preparation— Dissolve an accurately weighed quantity of USP Chlorpheniramine Maleate RSin water to obtain a solution having a known concentration of about 0.8mg per mL.Quantitatively dilute a portion of this solution with 0.1%phosphoric acid to obtain a solution having a known concentration of about 8µg per mL. Assay preparation— Weigh and finely powder not fewer than 20Tablets.Transfer an accurately weighed portion of the powder,equivalent to about 2mg of chlorpheniramine maleate,to a 250-mLvolumetric flask.Add 25mLof methanol,and sonicate to disperse the powder.Add 1mLof phosphoric acid,dilute with water to volume,mix,and filter. Procedure— Separately inject equal volumes (about 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the chlorpheniramine peaks.Calculate the quantity,in mg,of chlorpheniramine maleate (C16H19ClN2·C4H4O4)in the portion of Tablets taken by the formula: 250C(rU/rS), in which Cis the concentration,in mg per mL,of USP Chlorpheniramine Maleate RSin the Standard preparation;and rUand rSare the peak responses for chlorpheniramine obtained from the Assay preparationand the Standard preparation,respectively. Assay for dextromethorphan hydrobromide (if present)— Mobile phase andChromatographic system— Proceed as directed in the Assay for pseudoephedrine hydrochloride. Standard preparation— Dissolve an accurately weighed quantity of USP Dextromethorphan Hydrobromide RSin water to obtain a solution having a known concentration of about 0.6mg per mL.Quantitatively dilute a portion of this solution with 0.1%phosphoric acid to obtain a solution having a known concentration of about 0.06mg per mL. Assay preparation— Weigh and finely powder not fewer than 20Tablets.Transfer an accurately weighed portion of the powder,equivalent to about 6mg of dextromethorphan hydrobromide,to a 100-mLvolumetric flask.Add 10mLof methanol,and sonicate to disperse the powder.Add 0.4mLof phosphoric acid,dilute with water to volume,mix,and filter. Procedure— Separately inject equal volumes (about 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the peak responses for the dextromethorphan peaks.Calculate the quantity,in mg,of dextromethorphan hydrobromide (C18H25NO·HBr ·H2O)in the portion of Tablets taken by the formula: (370.33/352.32)(100C)(rU/rS), in which 370.33and 352.32are the molecular weights of dextromethorphan hydrobromide monohydrate and anhydrous dextromethorphan hydrobromide,respectively;Cis the concentration,in mg per mL,of USP Dextromethorphan Hydrobromide RSin the Standard preparation;and rUand rSare the dextromethorphan peak responses obtained from the Assay preparationand the Standard preparation,respectively. Auxiliary Information— Staff Liaison:Clydewyn M.Anthony,Ph.D.,Scientist Expert Committee:(PA2)Pharmaceutical Analysis 2 USP28–NF23Page 32 Pharmacopeial Forum:Volume No.30(1)Page 44 Phone Number:1-301-816-8139