Carisoprodol, Aspirin, and Codeine Phosphate Tablets

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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1 DEFINITION

Carisoprodol, Aspirin, and Codeine Phosphate Tablets contain NLT 90.0% and NMT 110.0% of the labeled amounts of carisoprodol (C₁₂H₂₄N₂O₄), aspirin (C₉H₈O₄), and codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄· 1⁄2H₂O).

2 IDENTIFICATION

A. The retention times of the aspirin, carisoprodol, and codeine phosphate peaks of the Sample solutions correspond to those of the Standard

solutions obtained as directed in the Assay for Aspirin and Carisoprodol and the Assay for Codeine Phosphate.

3 ASSAY

Aspirin and Carisoprodol

Buffer: Combine 5 mL of glacial acetic acid and 500 mL of water, and pass the mixture through a membrane filter of 0.5-μm or finer pore size.

Use the filtrate.

Mobile phase: Methanol and Buffer (64:36)

Diluent: Acetonitrile, glacial acetic acid, and water (40:1:59)

Standard solution A: USP Reference Standards in Diluent as listed below and prepared as follows. Transfer 80 mg of USP Aspirin RS and 80J mg of USP Carisoprodol RS to a 25-mL volumetric flask. Add 15 mL of Diluent, swirl for 5 min, and sonicate for 25–30 s. Dilute with Diluent to volume.

Aspirin: 3.2 mg/mL of USP Aspirin RS

Carisoprodol: 3.2J mg/mL of USP Carisoprodol RS, where J is the ratio of the labeled amount, in mg, of carisoprodol to the labeled amount of aspirin

Standard solution B: 0.016 mg/mL of USP Salicylic Acid RS in Diluent

System suitability solution: 0.5 mg/mL of salicylic acid in Standard solution A

Sample solution: Nominally 3.25 mg/mL of aspirin from NLT 20 Tablets prepared as follows. Finely powder NLT 20 Tablets. Transfer a portion of powder, equivalent to 325 mg of aspirin, to a 100-mL volumetric flask. Add 50 mL of Diluent, and swirl for 5 min. Sonicate for 25–30 s, shake by mechanical means for 30 min, and dilute with Diluent to volume. Pass a portion of this solution through a membrane filter of 0.5- μm or finer pore size, and use the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector

Aspirin and carisoprodol: Refractive index

Salicylic acid: UV 313 nm

Column: 4.6-mm × 25-cm; packing L7

Temperatures

Refractive index detector: 30 ± 1°

Column: 30 ± 1°

Flow rate: 1 mL/min

Injection volume: 50 μL

System suitability

Samples: Standard solution A, Standard solution B, and System suitability solution

[Note—The relative retention times for aspirin, salicylic acid, and carisoprodol are about 0.6, 0.7, and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.2 between the solvent and aspirin peaks; NLT 1.5 between aspirin and salicylic acid, System suitability solution using the refractive index detector

Relative standard deviation: NMT 2.0% for Standard solution A using the refractive index detector; NMT 5.0% for Standard solution B at 313 nm

Analysis

Samples: Standard solution A and Sample solution

Calculate the percentages of the labeled amounts of aspirin (C₉H₈O₄) and carisoprodol (C₁₂H₂₄N₂O₄) in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of aspirin or carisoprodol from the Sample solution

r_S = peak response of aspirin or carisoprodol from Standard solution A

C_S = concentration of USP Aspirin RS or USP Carisoprodol RS in the Standard solution A (mg/mL)

C_U = nominal concentration of aspirin or carisoprodol in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0% of the labeled amounts of aspirin (C₉H₈O₄) and carisoprodol (C₁₂H₂₄N₂O₄) Codeine Phosphate

Solution A: 3.7 g/L of Docusate sodium in methanol

Solution B: 2 g/L of ammonium nitrate in water

Mobile phase: Solution A and Solution B (60:40) adjusted with glacial acetic acid to a pH of 3.3 ± 0.05

Diluent: Methanol and 0.01 N sulfuric acid (50:50)

System suitability solution: 0.16 mg/mL of USP Codeine Phosphate RS and 0.12 mg/mL of USP Codeine N-Oxide RS in Diluent

Standard solution: USP Reference Standards in Diluent as listed below. Swirl for 5 min, and sonicate for 25–30 s.

Codeine phosphate: 0.16 mg/mL of USP Codeine Phosphate RS

Aspirin: 0.16J mg/mL of USP Aspirin RS, where J is the ratio of the labeled amount, in mg, of aspirin to that of codeine phosphate

Sample solution: Nominally 0.16 mg/mL of codeine phosphate prepared as follows. Finely powder NLT 20 Tablets. Transfer an amount of powder equivalent to 16 mg of codeine phosphate to a 100-mL volumetric flask. Add 50 mL of Diluent, sonicate for 30 min, shake by mechanical means for 30 min, and dilute with Diluent to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 3.9-mm × 30-cm; packing L1

Flow rate: 1.5 mL/min

Injection volume: 50 μL

System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for codeine N-oxide and codeine phosphate are 0.9 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.2 between codeine phosphate and codeine N-oxide, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄· 1⁄2H₂O) in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × (M_r1 /M_r2 ) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Codeine Phosphate RS in the Standard solution (mg/mL)

C_U = nominal concentration of the Sample solution (mg/mL)

M_r1 = molecular weight of codeine phosphate hemihydrate, 406.37

M_r2 = molecular weight of anhydrous codeine phosphate, 397.37

Acceptance criteria: 90.0%–110.0% of the labeled amount of codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄· 1⁄2H₂O)

4 PERFORMANCE TESTS

Dissolution 〈711〉

Medium: Water; 900 mL

Apparatus 2: 75 rpm

Time: 45 min

Procedure for aspirin and carisoprodol

Buffer: Glacial acetic acid in water (1 in 50)

Mobile phase: Methanol and Buffer (51:49)

Standard solution: USP Reference Standards as listed below and prepared as follows. Transfer 90 mg of USP Aspirin RS and 90J mg of

USP Carisoprodol RS to a 250-mL volumetric flask. Add 5 mL of acetonitrile, previously passed through a membrane filter of 0.5-μm or finer pore size, and swirl to dissolve. Dilute with water to volume.

Aspirin: 0.36 mg/mL of USP Aspirin RS

Carisoprodol: 0.36J mg/mL of USP Carisoprodol RS, where J is the ratio of the labeled amount, in mg, of carisoprodol to the labeled amount of aspirin

System suitability solution: 0.36 mg/mL of salicylic acid in the Standard solution

Sample solution: Pass a portion of the solution under test through a suitable filter, and use the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: Refractive index

Column: 3.9-mm × 30-cm; packing L1

Temperatures

Detector: 30 ± 1°

Column: 30 ± 1°

Flow rate: 2 mL/min

Injection volume: 300 μL

System suitability

Samples: Standard solution and System suitability solution

[Note—The relative retention times for aspirin and carisoprodol are 0.4 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.5 between aspirin and salicylic acid; NLT 1.5 between carisoprodol and salicylic acid, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amounts of aspirin (C₉H₈O₄) and carisoprodol (C₁₂H₂₄N₂O₄) dissolved:

Result = (r_U/r_S) x C_S × V × (1/L) × 100

r_U = peak response of aspirin or carisoprodol from the Sample solution

r_S = peak response of aspirin or carisoprodol from the Standard solution

C_S = concentration of USP Aspirin RS or USP Carisoprodol RS in the Standard solution (mg/mL)

V = volume of the Medium, 900 mL

L = label claim of aspirin or carisoprodol (mg/Tablet)

Procedure for codeine phosphate

Buffer: 4.0 g/L of docusate sodium and 1.5 g/L of ammonium nitrate in water

Mobile phase: Acetonitrile and Buffer (45:55)

Standard solution: 0.018 mg/mL of USP Codeine Phosphate RS in water

Sample solution: Pass a portion of the solution under test through a suitable filter, and use the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 3.9-mm × 30-cm; packing L1

Flow rate: 2 mL/min

Injection volume: 50 μL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄· 1⁄2H₂O) dissolved:

Result = (r_U/r_S ) × C_S × (M_r1 /M_r2) × V × (1/L) × 100

r_U = peak response of the Sample solution

r_S = peak response of the Standard solution

C_S = concentration of USP Codeine Phosphate RS in the Standard solution (mg/mL)

M_r1 = molecular weight of codeine phosphate hemihydrate, 406.37

M_r2 = molecular weight of anhydrous codeine phosphate, 397.37

V = volume of the Medium, 900 mL

L = label claim of codeine phosphate (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amounts of aspirin (C₉H₈O₄), carisoprodol (C₁₂H₂₄N₂O₄) and codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄· 1⁄2H₂O)) are dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements for Content Uniformity with respect to aspirin, carisoprodol, and codeine phosphate

5 IMPURITIES

Organic Impurities

Limit of free salicylic acid

Mobile phase, Diluent, Standard solution B, System suitability solution, Sample solution, Chromatographic system, and System suitability: Proceed as directed in the Assay for Aspirin and Carisoprodol.

Analysis

Samples: Standard solution B and Sample solution

Calculate the percentage of free salicylic acid in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of salicylic acid from the Sample solution

r_S = peak response of salicylic acid from Standard solution B

C_S = concentration of USP Salicylic Acid RS in Standard solution B (mg/mL)

C_U = nominal concentration of aspirin in the Sample solution (mg/mL)

Acceptance criteria: NMT 3.0% of free salicylic acid

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers.

USP Reference Standards 〈11〉

USP Aspirin RS

USP Carisoprodol RS

USP Codeine N-Oxide RS

7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol N-oxide.

C₁₈H₂₁NO₄ 315.37

USP Codeine Phosphate RS

USP Salicylic Acid RS