Orphenadrine Citrate, Aspirin, and Caffeine 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

Orphenadrine Citrate, Aspirin, and Caffeine Tablets contain NLT 90.0% and NMT 110.0% each of orphenadrine citrate (C₁₈H₂₃NO · C₆H₈O₇), aspirin (C₉H₈O₄), and caffeine (C₈H₁₀N₄O₂).

2 IDENTIFICATION

A. The retention times of the orphenadrine, aspirin, and caffeine peaks in the chromatogram of the Sample solution correspond to those of the orphenadrine, aspirin, and caffeine peaks in the chromatogram of the Standard solution, as obtained in the Orphenadrine Citrate and Aspirin and Caffeine tests in the Assay.

3 ASSAY

3.1 Orphenadrine Citrate

Buffer: 6.8 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 3.6. To each L of this solution add 5.8 g of sodium dodecyl sulfate, and dissolve.

Mobile phase: Acetonitrile and Buffer (50:50)

Diluent: Methanol and glacial acetic acid (92:8)

Standard solution: 0.1 mg/mL of USP Orphenadrine Citrate RS prepared as follows. Transfer the weighed amount of standard to a suitable volumetric f;ask with the aid of methanol. Add glacial acetic acid to fill 8% of final volume and methanol to fill 75% of final volume. Sonicate with occasional shaking for NLT 15 min. Allow the solution to equilibrate to room temperature. Dilute with methanol to volume. Filter a portion through a suitable filter of 0.45-μm pore size, discarding at least the first 3 mL of the filtrate.

Sample stock solution: Nominally 0.5 mg/mL of orphenadrine citrate from Tablets (NLT 5), prepared as follows. To the volumetric flask containing the Tablets, add glacial acetic acid to fill 8% of final volume and methanol to fill 75% of final volume. Sonicate with occasional hand shaking for NLT 15 min. Shake mechanically for NLT 15 min. Allow the solution to equilibrate to room temperature. Dilute with methanol to volume. [Note—This solution also contains 7.7 mg/mL of aspirin and 0.6 mg/mL of caffeine.]

Sample solution: Nominally 0.1 mg/mL of orphenadrine citrate by diluting a suitable portion of the Sample stock solution with Diluent. Filter a portion through a suitable filter of 0.45-μm pore size, discarding at least the first 3 mL of the filtrate. [Note—This solution also contains 1.5 mg/mL of aspirin and 0.1 mg/mL of caffeine.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 257 nm

Column: 3.9-mm × 30-cm; 10-μm packing L1

Flow rate: 2 mL/min

Injection volume: 15 μL

Run time: 1.5 times the retention time of orphenadrine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of orphenadrine citrate (C₁₈H₂₃NO · C₆H₈O₇) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Orphenadrine Citrate RS in the Standard solution (mg/mL)

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

Acceptance criteria: 90.0%–110.0%

3.2 Aspirin and Caffeine

Buffer: Dissolve 0.8 g/L of hexanesulfonic acid sodium salt in water. Adjust with glacial acetic acid to a pH of 3.0.

Mobile phase: Methanol and Buffer (40:60)

Diluent: Methanol and glacial acetic acid (92:8)

Standard solution: 1.5 mg/mL of USP Aspirin RS and 0.1 mg/mL of USP Caffeine RS prepared as follows. Transfer the weighed amount of standards to a suitable volumetric flask with the aid of methanol. Add glacial acetic acid to fill 8% of final volume and methanol to fill 75% of final volume. Sonicate with occasional hand shaking for NLT 15 min. Allow the solution to equilibrate to room temperature. Dilute with methanol to volume. Filter a portion through a suitable filter of 0.45-μm pore size, discarding at least the first 3 mL of the filtrate.

Sample stock solution: Nominally 7.7 mg/mL of aspirin from Tablets (NLT 5), prepared as follows. To the volumetric flask containing the Tablets, add glacial acetic acid to fill 8% of final volume and methanol to fill 75% of final volume. Sonicate with occasional hand shaking for NLT 15 min. Allow the solution to equilibrate to room temperature. Dilute with methanol to volume. [Note—This solution also contains 0.6 mg/mL of caffeine and 0.5 mg/mL of orphenadrine citrate.]

Sample solution: Nominally 1.5 mg/mL of aspirin by diluting a suitable portion of the Sample stock solution with Diluent. Filter a portion through a suitable filter of 0.45-μm pore size, discarding at least the first 3 mL of the fi8ltrate. [Note—This Sample solution also contains 0.1 mg/mL of caffeine and 0.1 mg/mL of orphenadrine citrate.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 3.9-mm × 30-cm; 10-μm packing L1

Flow rate: 1.2 mL/min

Injection volume: 15 μL

Run time: 3 times the retention time of aspirin

System suitability

[Note - The relative retention time for caffeine and for aspirin is 0.70 and 1.0, respectively.]

Sample: Standard solution

Suitability requirements

Resolution: NLT 1.5 between caffeine and aspirin peaks

Relative standard deviation: NMT 2.0% each for both the caffeine and aspirin peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of aspirin (C₉H₈O₄) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

Calculate the percentage of the labeled amount of caffeine (C₈H₁₀N₄O₂) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

Acceptance criteria: 90.0%–110.0% each of aspirin and caffeine

4 PERFORMANCE TESTS

Dissolution 〈711〉

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Times: 45 min for aspirin and caffeine; 60 min for orphenadrine

Separate dissolution baths must be run for the different time points.

4.1 Orphenadrine citrate

Buffer: 6.8 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 3.6. To each L of this solution add 5.8 g of sodium dodecyl sulfate, and dissolve.

Mobile phase: Acetonitrile and Buffer (50:50)

Standard solution: (L/900) mg/mL of USP Orphenadrine Citrate RS in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 257 nm

Column: 3.9-mm × 30-cm; 10-μm packing L1

Flow rate: 2 mL/min

Injection volume: 100 μL

Run time: 1.2 times the retention time of orphenadrine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 3.0%

Calculate the percentage (Q) of the labeled amount of orphenadrine citrate (C₁₈H₂₃NO · C₆H₈O₇) dissolved:

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

r_U = peak response for orphenadrine from the Sample solution

r_S = peak response for orphenadrine from the Standard solution

C_S = concentration of USP Orphenadrine Citrate RS in the Standard solution (mg/mL)

L = label claim for orphenadrine (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 75% (Q) of the labeled amount of orphenadrine is dissolved in 60 min.

4.2 Aspirin and caffeine

Buffer: 0.8 g/L of hexanesulfonic acid sodium salt in water

Mobile phase: Methanol and Buffer (40:60). Adjust with glacial acetic acid to a pH of 3.0.

Standard stock solution: 1.0 mg/mL of USP Aspirin RS, 0.1 mg/mL of USP Caffeine RS, and 0.1 mg/mL of USP Salicylic Acid RS prepared as follows. Transfer the weighed amount of standards to a suitable volumetric flask with the aid of methanol. Add glacial acetic acid to fill 8% of final volume and methanol to fill 75% of final volume. Sonicate with occasional shaking for NLT 15 min. Allow the solution to equilibrate to room temperature. Dilute with methanol to volume.

Standard solution: Dilute a suitable volume of the Standard stock solution with methanol to obtain a final concentration of about 0.25 mg/mL of USP Aspirin RS and 0.025 mg/mL each of USP Caffeine RS and USP Salicylic Acid RS.

Sample solution: At the time specified, withdraw the solution under test and pass through a suitable filter. If necessary, dilute the filtrate with methanol to obtain a final concentration similar to that of the Standard solution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 3.9-mm × 30-cm; 10-μm packing L1

Flow rate: 1.2 mL/min

Injection volume: 15 μL

Run time: 2 times the retention time of aspirin

System suitability

[Note - The relative retention times for caffeine, aspirin, and salicylic acid are 0.70, 1.0, and 1.3, respectively.]

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 3.0% for both the caffeine and aspirin peaks

Calculate the percentage (Q) of the labeled amount of aspirin (C₉H₈O₄) or caffeine (C₈H₁₀N₄O₂) dissolved:

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

r_U = peak response for aspirin or caffeine from the Sample solution

r_S = peak response for aspirin or caffeine from the Standard solution

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

L = label claim for aspirin or caffeine (mg/Tablet)

D = dilution factor, if applicable

V = volume of Medium, 900 mL

Calculate the percentage of salicylic acid (C₉H₈O₄), relative to the labeled amount of aspirin, dissolved:

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

r_U = peak response for salicylic acid from the Sample solution

r_S = peak response for salicylic acid from the Standard solution

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

L = label claim for aspirin (mg/Tablet)

D = dilution factor

M_r1= molecular weight of aspirin, 180.16

M_r2 = molecular weight of salicylic acid, 138.12

V = volume of Medium, 900 mL

The percentage of salicylic acid dissolved should be added to the percentage of aspirin dissolved.

Tolerances: NLT 70% (Q) of the labeled amounts of aspirin and caffeine is dissolved in 45 min.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

5.1 Limit of 2-Methylbenzhydrol

Buffer: 6.8 g/L of monobasic potassium phosphate in water

Mobile phase: To 1 L of Buffer add 5.8 g of sodium dodecyl sulfate and 1 L of acetonitrile. Adjust with phosphoric acid to a pH of 3.6.

Standard solution: 7.5 μg/mL of USP Methylbenzhydrol RS (ERR 1-Apr-2023) in methanol

Sample solution: Nominally 1.5 mg/mL of orphenadrine citrate in methanol from a portion of finely powdered Tablets (NLT 20 Tablets). [Note - This Sample solution also contains 0.6 mg/mL of caffeine and 0.5 mg/mL of orphenadrine citrate.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 213 nm

Column: 4.6-mm × 150-mm; 5-μm packing L1

Flow rate: 1.2 mL/min

Injection volume: 10 μL

Run time: 2.5 times the retention time of 2-methyl benzhydrol

System suitability

Sample: Standard solution

Suitability requirements:

Tailing factor: NMT 1.5

Relative standard deviation: NMT 5.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of 2-methylbenzhydrol in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Methylbenzhydrol RS (ERR 1-Apr-2023) in the Standard solution (mg/mL)

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

Acceptance criteria: NMT 0.5%

5.2 Organic Impurities

Buffer: 0.8 g/L of sodium 1-hexanesulfonate in water. Adjust with glacial acetic acid to a pH of 3.0.

Mobile phase: Methanol and Buffer (40:60)

Diluent: Methanol and glacial acetic acid (92:8)

System suitability solution: 0.6 mg/mL of USP Salicylic Acid RS, 1.5 mg/mL of USP Aspirin RS, and 0.1 mg/mL of USP Caffeine RS prepared as follows. Transfer the weighed amount of standards to a suitable volumetric flask with the aid of methanol. Add glacial acetic acid to fill 8% of final volume and methanol to fill 75% of final volume. Sonicate with occasional hand shaking for NLT 15 min. Allow the solution to equilibrate to room temperature. Dilute with methanol to volume. Filter a portion through a suitable filter of 0.45-μm pore size, discarding at least the first 3 mL of the filtrate.

Standard solution: 0.04 mg/mL of USP Salicylic Acid RS prepared as follows. Transfer the weighed amount of standard to a suitable volumetric flask with the aid of methanol. Add glacial acetic acid to fill 8% of final volume, and dilute with methanol to volume. Filter a portion through a suitable filter of 0.45-μm pore size, discarding at least the first 3 mL of the filtrate.

Sample stock solution: Nominally 7.7 mg/mL of aspirin from Tablets (NLT 5), prepared as follows. To the volumetric flask containing the

Tablets, add glacial acetic acid to fill 8% of final volume and methanol to fill 75% of final volume. Sonicate with occasional hand shaking for NLT 15 min. Allow the solution to equilibrate to room temperature. Dilute with methanol to volume. [Note—This solution also contains 0.5 mg/mL of orphenadrine citrate and 0.6 mg/mL of caffeine.]

Sample solution: Nominally 1.5 mg/mL of aspirin by diluting a suitable portion of the Sample stock solution with Diluent. Filter a portion through a suitable filter of 0.45-μm pore size, discarding at least the first 3 mL of the filtrate. [Note - This Sample solution also contains 0.1 mg/mL of orphenadrine citrate and 0.1 mg/mL of caffeine.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 3.9-mm × 30-cm; 10-μm packing L1

Flow rate: 1.2 mL/min

Injection volume: 25 μL

Run time: 3 times the retention time of the aspirin peak

System suitability

[Note - Refer to Table 1 for relative retention times.]

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between the caffeine and aspirin peaks and NLT 1.5 between the aspirin and salicylic acid peaks, System suitability solution

Relative standard deviation: NMT 2.0% each for aspirin and caffeine peaks, System suitability solution; NMT 3.0% for salicylic acid, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of salicylic acid in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

Calculate the percentage of other organic impurities in the portion of Tablets taken:

Result = (r_U/r_T) × 100

r_U = sum of the areas of all other organic impurities from the Sample solution

r_T = sum of the areas of all peaks from the Sample solution

Acceptance criteria: See Table 1.

Table 1

^a Does not include salicylic acid and 2-methylbenzhydrol.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature.

Change to read:

USP Reference Standards 〈11〉

USP Aspirin RS

USP Caffeine RS

USP Methylbenzhydrol RS (ERR 1-Apr-2023)

2-Methylbenzhydrol.

C₁₄H₁₄O 198.26

USP Orphenadrine Citrate RS

USP Salicylic Acid RS