Oral Solution Containing at Least Three of the Following— Acetaminophen and Salts of Chlorpheniramine, Dextromethorphan, and Pseudoephedrine

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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Oral Solution Containing at Least Three of the Following—

Acetaminophen and Salts of Chlorpheniramine, Dextromethorphan,

and Pseudoephedrine

Oral Solution Containing at Least Three of the Following—Acetaminophen and Salts of Chlorpheniramine, Dextromethorphan, and Pseudoephedrine contains not less than 90.0 percent and not more than 110.0 percent 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 o￾cial title. It is not intended that the name described herein be recognized as the o￾cial 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.]

1 Packaging and storage—

Preserve in tight containers, and store at controlled room temperature.

USP Reference standards 〈11〉—

USP Acetaminophen RS

USP Chlorpheniramine Maleate RS

USP Dextromethorphan Hydrobromide RS

USP Pseudoephedrine Hydrochloride RS

USP Pseudoephedrine Sulfate RS

2 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.

3 Identification—

A: If pseudoephedrine hydrochloride or pseudoephedrine sulfate is claimed in the labeling to be present, the retention time of the major peak for pseudoephedrine in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay for pseudoephedrine hydrochloride or the Assay for pseudoephedrine sulfate.

B: If acetaminophen is claimed in the labeling to be present, the retention time of the major peak for acetaminophen in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay for acetaminophen.

C: If chlorpheniramine maleate is claimed in the labeling to be present, the retention time of the major peak for chlorpheniramine in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay for chlorpheniramine maleate.

D: If dextromethorphan hydrobromide is claimed in the labeling to be present, the retention time of the major peak for dextromethorphan in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay for dextromethorphan hydrobromide.

Uniformity of dosage units 〈905〉—

for oral solution packaged in single-unit containers: meets the requirements.

Deliverable volume 〈698〉—

for oral solution packaged in multiple-unit containers: meets the requirements.

pH 〈791〉: between 3.7 and 7.5.

Alcohol Determination, Method II 〈611〉 (if present): between 90.0% and 110.0% of the labeled amount of C₂H₅OH.

Microbial enumeration tests 〈61〉 and Absence of specified microorganisms 〈62〉—

The total bacterial count does not exceed 100 cfu per g, the total combined molds and yeasts count does not exceed 10 cfu per g, and it meets the requirements of the tests for absence of Salmonella species and Escherichia coli.

Assay for pseudoephedrine hydrochloride

(where pseudoephedrine hydrochloride is the salt form used, if present in the formulation)—

4 Mobile phase—

Prepare a ￾ltered and degassed mixture of methanol and water (60:40) containing 0.34 g of monobasic potassium phosphate, 0.15 g of triethylamine hydrochloride, 0.25 g of sodium lauryl sulfate, and 0.1 mL of phosphoric acid in each 100 mL of solution. Make adjustments if necessary (see System Suitability under Chromatography 〈621〉).

Standard preparation—

Dissolve an accurately weighed quantity of USP Pseudoephedrine Hydrochloride RS in water to obtain a solution having a known concentration of about 1.5 mg per mL. Transfer 1.0 mL of this solution to a 10-mL volumetric ￾ask, add 8.0 mL of Mobile phase, dilute with water to volume, and mix.

Chlorpheniramine standard preparation—

Prepare as directed for Standard preparation in the Assay for chlorpheniramine maleate.

Dextromethorphan standard preparation—

Prepare as directed for Standard preparation in the Assay for dextromethorphan hydrobromide.

System suitability solution 1

(for Oral Solution that contains either all the four ingredients or a combination of three containing chlorpheniramine salt)—

Mix equal volumes of the Standard preparation and the Chlorpheniramine standard preparation.

System suitability solution 2

(for Oral Solution that contains no chlorpheniramine salt)—

Mix equal volumes of the Standard preparation and the Dextromethorphan standard preparation.

Assay preparation—

Transfer an accurately measured volume of the Oral Solution, equivalent to 15 mg of pseudoephedrine hydrochloride, to a 100-mL volumetric ￾ask, add 80.0 mL of Mobile phase, dilute with water to volume, and mix.

Chromatographic system

(See Chromatography 〈621〉.)

The liquid chromatograph is equipped with a 214-nm detector and a 4.6-mm × 15-cm column that contains packing L11. The ￾ow rate is about 2 mL per 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 10 µL of System suitability solution 1 or 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 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the pseudoephedrine peaks. Calculate the quantity, in mg, of pseudoephedrine hydrochloride (C₁₀H₁₅NO · HCl) in each mL of the Oral Solution taken by the formula:

100(C/V)(rᵤ/rₛ)

in which C is the concentration, in mg per mL, of USP Pseudoephedrine Hydrochloride RS in the Standard preparation; V is the volume, in mL, of the Oral Solution taken; and rᵤ and rₛ are the pseudoephedrine peak responses obtained from the Assay preparation and the Standard preparation, respectively.

Assay for pseudoephedrine sulfate

(where pseudoephedrine sulfate is the salt form used, if present in the formulation)—

Mobile phase, System suitability solutions, and Chromatographic system—Proceed as directed in the Assay for pseudoephedrine hydrochloride.

Chlorpheniramine standard preparation—Prepare as directed for Standard preparation in the Assay for chlorpheniramine maleate.

Dextromethorphan standard preparation—Prepare as directed for Standard preparation in the Assay for dextromethorphan hydrobromide.

Standard preparation—

Dissolve an accurately weighed quantity of USP Pseudoephedrine Sulfate RS in water to obtain a solution having a known concentration of about 3.0 mg per mL. Transfer 1.0 mL of this solution to a 10-mL volumetric ￾ask, add 4.0 mL of Mobile phase, dilute with water to volume, and mix.

Assay preparation—

Transfer an accurately measured volume of Oral Solution, equivalent to 30 mg of pseudoephedrine sulfate, to a 100-mL volumetric ￾ask, add 80.0 mL of Mobile phase, dilute with water to volume, and mix.

Procedure—

Proceed as directed for Procedure in the Assay for pseudoephedrine hydrochloride. Calculate the quantity, in mg, of pseudoephedrine sulfate [(C₁₀H₁₅NO)₂ · H₂SO₄] in each mL of the Oral Solution taken by the formula:

100(C/V)(rᵤ/rₛ)

Assay for acetaminophen (if present)—

Mobile phase—

Prepare a suitable degassed and ￾ltered mixture of water, methanol, and glacial acetic acid (79:20:1). Make any necessary adjustments (see System Suitability under Chromatography 〈621〉).

Standard preparation—

Transfer about 16.5 mg of USP Acetaminophen RS, accurately weighed, to a 100-mL volumetric ￾ask. Add 2.5 mL of methanol, and mix until solution is complete. Dilute with water to volume, and mix to obtain a solution having a known concentration of about 0.165 mg per mL.

Assay preparation—

Transfer an accurately measured volume of Oral Solution, equivalent to about 33 mg of acetaminophen, to a 200-mL volumetric ￾ask, add 5 mL of methanol, and mix. Dilute with water to volume, and mix.

Chromatographic system

(See Chromatography 〈621〉.)

The liquid chromatograph is equipped with a 280-nm detector and a 4.6-mm × 15-cm column that contains packing L7. The ￾ow rate is about 1 mL per 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 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the acetaminophen peaks. Calculate the quantity, in mg, of acetaminophen (C₈H₉NO₂) in each mL of the Oral Solution taken by the formula:

200(C/V)(rᵤ/rₛ)

Assay for chlorpheniramine maleate (if present)—

Mobile phase and Chromatographic system—Proceed as directed in the Assay for pseudoephedrine hydrochloride.

Standard preparation—

Dissolve an accurately weighed quantity of USP Chlorpheniramine Maleate RS in water to obtain a solution having a known concentration of about 1 mg per mL. Transfer 1.0 mL of this solution to a 100-mL volumetric ￾ask, add 80 mL of Mobile phase, dilute with water to volume, and mix.

Assay preparation—

Transfer an accurately measured volume of Oral Solution, equivalent to about 1 mg of chlorpheniramine maleate, to a 100-mL volumetric ￾ask. Add 80 mL of Mobile phase, dilute with water to volume, and mix.

Procedure—

Separately inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into 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 Oral Solution taken by the formula:

100(C/V)(rᵤ/rₛ)

Assay for dextromethorphan hydrobromide (if present)—

Mobile phase and Chromatographic system—Proceed as directed in the Assay for pseudoephedrine hydrochloride.

Standard preparation—

Dissolve an accurately weighed quantity of USP Dextromethorphan Hydrobromide RS in water to obtain a solution having a known concentration of about 1.5 mg per mL. Transfer 5.0 mL of this solution to a 100-mL volumetric ￾ask, add 80 mL of Mobile phase, dilute with water to volume, and mix.

Assay preparation—

Transfer an accurately measured volume of Oral Solution, equivalent to about 7.5 mg of dextromethorphan hydrobromide, to a 100-mL volumetric ￾ask, add 80 mL of Mobile phase, dilute with water to volume, and mix.

Procedure—

Separately inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the dextromethorphan peaks. Calculate the quantity, in mg, of dextromethorphan hydrobromide (C₁₈H₂₅NO · HBr · H₂O) in each mL of the Oral Solution taken by the formula:

(370.33/352.32)(100C/V)(rᵤ/rₛ)

in which 370.33 and 352.32 are the molecular weights of dextromethorphan hydrobromide monohydrate and anhydrous dextromethorphan hydrobromide, respectively.