Tramadol Hydrochloride and Acetaminophen 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

Tramadol Hydrochloride and Acetaminophen Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂·HCl) and acetaminophen (C₈H₉NO₂).

2 IDENTIFICATION

A. The retention times of the Tramadol sample solution and the Acetaminophen sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Procedure

Mobile phase: Tetrahydrofuran, triethylamine, water, and trifluoroacetic acid (8:0.1:92:0.1). The apparent pH of the final solvent mixture should be between 2.2 and 2.4.

Diluent: Methanol and water (1:9)

Standard solution: 0.065 mg/mL of USP Acetaminophen RS and 0.075 mg/mL of USP Tramadol Hydrochloride RS in Diluent. Sonication may be used to aid dissolution.

Sample stock solution: Weigh NLT 20 Tablets, and determine the average Tablet weight. Grind the Tablets into a fine powder, and transfer an amount equivalent to one Tablet to a 50-mL volumetric flask. Add 30 mL of Diluent with continuous shaking to disperse the powder. Sonicate for 15 min with intermittent shaking, and shake the flask on a mechanical shaker for 30 min. Dilute with Diluent to volume, and mix well. Centrifuge the suspension, and use the supernatant for subsequent dilutions.

Tramadol sample solution: Nominally 75 µg/mL of tramadol hydrochloride in Diluent from the Sample stock solution

Acetaminophen sample solution: Nominally 65 µg/mL of acetaminophen in Diluent from the Sample stock solution

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 216 nm for tramadol hydrochloride and UV 249 nm for acetaminophen
• Column: 4.6-mm × 15-cm; 5-µm packing L11
• Column temperature: 50°
• Flow rate: 1 mL/min
• Injection volume: 20 µL
• Run time: 4 times the retention time of acetaminophen

System suitability

• Sample: Standard solution
• Suitability requirements
• Resolution: NLT 10.0 between acetaminophen and tramadol
• Tailing factor: NMT 2.0 for each analyte
• Relative standard deviation: NMT 2.0% for each analyte

Analysis

Samples: Standard solution, Tramadol sample solution, and Acetaminophen sample solution

Calculate the percentage of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂·HCl) in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of tramadol from the Tramadol sample solution

rₛ = peak response of tramadol from the Standard solution

Cₛ = concentration of USP Tramadol Hydrochloride RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of tramadol hydrochloride in the Tramadol sample solution (mg/mL)

Calculate the percentage of the labeled amount of acetaminophen (C₈H₉NO₂) in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of acetaminophen from the Acetaminophen sample solution

rₛ = peak response of acetaminophen from the Standard solution

Cₛ = concentration of USP Acetaminophen RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of acetaminophen in the Acetaminophen sample solution (mg/mL)

Acceptance criteria

• Tramadol hydrochloride: 90.0%–110.0% of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂·HCl)
• Acetaminophen: 90.0%–110.0% of the labeled amount of acetaminophen (C₈H₉NO₂)

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉

4.1.1 Test 1

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Buffer solution: 6.8 mg/mL of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 2.50.

Mobile phase: Acetonitrile and Buffer solution (1:4)

Standard solution: 0.36 mg/mL of USP Acetaminophen RS and 0.04 mg/mL of USP Tramadol Hydrochloride RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 272 nm
• Column: 4.6-mm × 15-cm; 5-µm packing L7
• Column temperature: 25°
• Flow rate: 1 mL/min
• Injection volume: 25 µL
• Run time: 2 times the retention time of tramadol

System suitability

• Sample: Standard solution
• [Note-The relative retention times for acetaminophen and tramadol are about 0.5 and 1.0, respectively.]
• Suitability requirements
• Resolution: NLT 5.0 between the acetaminophen and tramadol peaks
• Relative standard deviation: NMT 2.0% for both the acetaminophen and tramadol peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of acetaminophen (C₈H₉NO₂) and tramadol hydrochloride (C₁₆H₂₅NO₂·HCl) dissolved:

Result = (rᵤ/rₛ) × Cₛ × V × (1/L) × 100

rᵤ = peak response of acetaminophen or tramadol from the Sample solution

rₛ = peak response of acetaminophen or tramadol from the Standard solution

Cₛ = concentration of USP Acetaminophen RS or USP Tramadol Hydrochloride RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim for acetaminophen or tramadol hydrochloride (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of acetaminophen (C₈H₉NO₂) and tramadol hydrochloride (C₁₆H₂₅NO₂·HCl) is dissolved.

4.1.2 Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 2: 50 rpm

Time: 20 min

Buffer solution, Mobile phase, Standard solution, Sample solution, Chromatographic system, System suitability, and Analysis: Proceed as directed in Dissolution Test 1.

Tolerances: NLT 80% (Q) of the labeled amount of acetaminophen (C₈H₉NO₂) and tramadol hydrochloride (C₁₆H₂₅NO₂·HCl) is dissolved.

4.2 Uniformity of Dosage Units 〈905〉

Meet the requirements

5 IMPURITIES

5.1 4-Aminophenol in Acetaminophen-Containing Drug Products 〈227〉

Meet the requirements

5.2 Organic Impurities

Mobile phase, Diluent, and Sample stock solution: Proceed as directed in the Assay.

Standard solution: 0.75 µg/mL each of USP Tramadol Hydrochloride RS and USP Tramadol Related Compound A RS in Diluent

Sample solution: Pass a suitable volume of Sample stock solution through a nylon membrane filter of 0.45-µm pore size. Use the filtrate after discarding the first 4 mL of filtrate.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: 216 nm
• Column: 4.6-mm × 15-cm; 5-µm packing L11
• Column temperature: 50°
• Flow rate: 1 mL/min
• Injection volume: 30 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Resolution: NLT 2.0 between tramadol related compound A and tramadol hydrochloride
• Relative standard deviation: NMT 6.0% for tramadol hydrochloride

Analysis

Samples: Diluent, Standard solution, and Sample solution. Disregard the peaks due to the Diluent.

Calculate the percentage of each degradation product in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of each degradation product from the Sample solution

rₛ = peak response of tramadol from the Standard solution

Cₛ = concentration of USP Tramadol Hydrochloride RS in the Standard solution (µg/mL)

Cᵤ = nominal concentration of tramadol hydrochloride in the Sample solution (µg/mL)

Acceptance criteria: See Table 1.

Table 1

ᵃ 3-{(1RS,2RS)-2-[(Dimethylamino)methyl]-1-hydroxycyclohexyl}phenol.

6 ADDITIONAL REQUIREMENTS

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

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

USP Reference Standards 〈11〉

USP Acetaminophen RS

USP 4-Aminophenol RS

4-Amino-1-hydroxybenzene.

C₆H₇NO 109.13

USP Tramadol Hydrochloride RS

(±)-cis-2-[(Dimethylamino)methyl]-1-(m-methoxyphenyl)cyclohexanol hydrochloride.

C₁₆H₂₅NO₂·HCl 299.84

USP Tramadol Related Compound A RS

RS,SR-1-(3-Methoxyphenyl)-2-(dimethylaminomethyl)cyclohexanol hydrochloride.