Tramadol Hydrochloride Extended-Release 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 Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl).

2 IDENTIFICATION

2.1 A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

Change to read:

2.2 B. Spectroscopic Identification Tests 〈197〉, Ultraviolet-Visible Spectroscopy: 197U

Sample solution: Use the Sample solution from the Assay.

Analysis: Using separate 1-cm cells, record the UV spectrum of the Sample solution and Standard solution.

Acceptance criteria: The UV absorption spectrum of the Sample solution exhibits maxima and minima at the same wavelength as that of a similar solution of the Standard solution.

3 ASSAY

3.1 Procedure

Mobile phase: Tetrahydrofuran, trifluoroacetic acid, triethylamine, and water (10:0.1:0.1:90). [Note-Maintain at a pH range of 2.2–2.4.]

Standard stock solution: 1 mg/mL of USP Tramadol Hydrochloride RS prepared by dissolving in 20% of the flask volume of methanol. Sonicate if necessary, and dilute with water to volume.

Standard solution: 0.13 mg/mL of USP Tramadol Hydrochloride RS in Mobile phase, from the Standard stock solution

Sample solution: Nominally 0.13 mg/mL of tramadol hydrochloride in Mobile phase. Prepare by dissolving 10 Tablets in 20% of the flask volume of methanol, in a water bath for 60 min, at about 60° with intermittent shaking. Sonicate for 10 min. Add 40% of the flask volume of water, and sonicate for 30 min. If all Tablets are not fully disintegrated, then continue to sonicate until disintegration is completed. Shake the flask vigorously for 10 min using a mechanical shaker, and dilute with water to volume. Centrifuge a portion of the solution, pass through a suitable nylon filter, and collect the filtrate after discarding the first 2 mL. Pipet 5.0 mL of the filtrate into a 200-mL volumetric flask, and dilute with Mobile phase to volume.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 216 nm
• Column: 4.6-mm × 15-cm; 5-µm packing L11
• Column temperature: 40°
• Flow rate: 1 mL/min
• Injection volume: 10 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Column efficiency: NLT 2000 theoretical plates
• Tailing factor: NMT 2.0
• Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and 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 from the Sample solution

rₛ = peak response 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 Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

4.1 Dissolution 〈711〉

4.1.1 Test 1

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 1: 75 rpm

Times: 2, 4, 8, 10, and 16 h

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

Sample solution: Withdraw 10 mL of the solution under test, and pass through a suitable filter of 0.45-µm pore size, discarding the first 4 mL of the filtrate. Replace the volume withdrawn with the same volume of Medium preheated at 37.0 ± 0.5°.

Instrumental conditions

• Mode: UV
• Analytical wavelength: 271 nm
• Cell: 5 mm
• Blank: Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (Cᵢ), in mg/mL, of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) in the sample withdrawn from the vessel at each time point (i):

Resultᵢ = (Aᵤ/Aₛ) × Cₛ

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

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

Calculate the percentage of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × Vₛ)] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₅ = {(C₅ × V) + [(C₄ + C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

Cᵢ = concentration of tramadol hydrochloride in the portion of the sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) released at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

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

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 1: 75 rpm

Times: 2, 4, 8, 10, and 16 h

Standard stock solution: 5 mg/mL of USP Tramadol Hydrochloride RS in Medium. Sonicate if necessary.

Standard solution: Dilute the Standard stock solution with Medium to obtain a concentration of USP Tramadol Hydrochloride RS (see Table 2).

Table 2

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

Instrumental conditions

• Mode: UV
• Analytical wavelength: 271 nm
• Cell
• For Tablets labeled to contain 100 mg: 1 cm
• For Tablets labeled to contain 200 and 300 mg: 0.5 cm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) dissolved at each time point (i):

Result_i = (Aᵤ/Aₛ) × Cₛ × V × (1/L) × 100

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) released at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

4.1.3 Test 3 If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 3.

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 1: 75 rpm

Times: 2, 4, 8, and 16 h

Buffer: Trifluoroacetic acid and water (2:1000)

Mobile phase: Acetonitrile and Buffer (30:70)

Standard stock solution: 0.55 mg/mL of USP Tramadol Hydrochloride RS in water

Standard solution: (L/900) mg/mL of USP Tramadol Hydrochloride RS in Medium from the Standard stock solution, where L is the label claim of tramadol hydrochloride, in mg/Tablet. Pass the solution through a suitable filter of 0.45-µm pore size. Discard the first 5 mL of filtrate.

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Replace the portion of solution withdrawn with an equal volume of Medium. Discard the first 5 mL of filtrate.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 270 nm
• Column: 4.6-mm × 25-cm; 5-µm packing L1
• Temperatures
• Autosampler: 10°
• Column: 25°
• Flow rate: 1.0 mL/min
• Injection volume: 20 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Column efficiency: NLT 2000 theoretical plates
• Tailing factor: NMT 2.0
• Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (Cᵢ), in mg/mL, of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) in the sample withdrawn from the vessel at each time point (i):

Resultᵢ = (rᵤ/rₛ) × Cₛ

rᵤ = peak response of tramadol from the Sample solution

rₛ = peak response of tramadol from the Standard solution

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

Calculate the percentage of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × Vₛ)] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

Cᵢ = concentration of tramadol hydrochloride in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See Table 4.

Table 4

The percentages of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) released at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

4.1.4 Test 4 If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 4.

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 1: 75 rpm

Times: 2, 4, 8, 10, and 16 h

Buffer: Dissolve 6.8 g of monobasic potassium phosphate in 1 L of water and adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Acetonitrile and Buffer (20:80)

Standard solution: 0.22 mg/mL of USP Tramadol Hydrochloride RS in Medium. Sonication may be necessary for complete dissolution.

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 270 nm
• Column: 4.6-mm × 5-cm; 3-µm packing L1
• Flow rate: 1.5 mL/min
• Injection volume: 10 µL
• Run time: NLT 6 times the retention time of tramadol

System suitability

• Sample: Standard solution
• Suitability requirements
• Column efficiency: NLT 1000 theoretical plates
• Relative standard deviation: NMT 2%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (Cᵢ), in mg/mL, of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) in the sample withdrawn from the vessel at each time point (i):

Resultᵢ = (rᵤ/rₛ) × Cₛ

rᵤ = peak response of tramadol from the Sample solution

rₛ = peak response of tramadol from the Standard solution

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

Calculate the percentage of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − Vₛ)] + (C₁ × Vₛ)} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × Vₛ)]} + [(C₂ + C₁) × Vₛ]) × (1/L) × 100

Result₄ = ({C₄ × [V − (3 × Vₛ)]} + [(C₃ + C₂ + C₁) × Vₛ]) × (1/L) × 100

Result₅ = ({C₅ × [V − (4 × Vₛ)]} + [(C₄ + C₃ + C₂ + C₁) × Vₛ]) × (1/L) × 100

Cᵢ = concentration of tramadol hydrochloride in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 5.

Table 5

The percentages of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) released at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

4.1.5 Test 5 If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 5.

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 1: 75 rpm

Times: 2, 4, 8, 10, and 16 h

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

Sample solution: Withdraw NLT 8 mL of the solution under test, and pass through a suitable filter of 0.45-µm pore size, discarding the first 4 mL of the filtrate. Replace the volume withdrawn with the same volume of Medium.

Instrumental conditions

• Mode: UV
• Analytical wavelength: 271 nm
• Cell
• For Tablets labeled to contain 100 mg: 1 cm
• For Tablets labeled to contain 200 and 300 mg: 0.5 cm
• Blank: Medium

System suitability

• Sample: Standard solution
• Suitability requirement
• Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (Cᵢ), in mg/mL, of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) in the sample withdrawn from the vessel at each time point (i):

Resultᵢ = (Aᵤ/Aₛ) × Cₛ

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

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

Calculate the percentage of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × Vₛ)] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₅ = {(C₅ × V) + [(C₄ + C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

Cᵢ = concentration of tramadol hydrochloride in the portion of the sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See Table 6.

Table 6

The percentages of the labeled amount of tramadol hydrochloride (C₁₆H₂₅NO₂ · HCl) released at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

4.2 Uniformity of Dosage Units 〈905〉

Meet the requirements

5 IMPURITIES

5.1 Organic Impurities

Mobile phase: Acetonitrile, trifluoroacetic acid, and water (20:0.1:80)

Diluent: Methanol and water (1:4)

System suitability stock solution: 0.05 mg/mL each of USP Tramadol Hydrochloride RS and USP Tramadol Related Compound A RS in Diluent prepared by dissolving in 20% of the flask volume of methanol. Sonicate if necessary, and dilute with water to volume.

System suitability solution: 2.5 µg/mL each of USP Tramadol Hydrochloride RS and USP Tramadol Related Compound A RS in Diluent, from the System suitability stock solution

Standard stock solution: 0.05 mg/mL of USP Tramadol Hydrochloride RS in Diluent prepared by dissolving in 20% of the flask volume of methanol. Sonicate if necessary, and dilute with water to volume.

Standard solution: 2.5 µg/mL of USP Tramadol Hydrochloride RS in Diluent, from the Standard stock solution

Sample solution: Nominally 1.2 mg/mL of tramadol hydrochloride in Diluent. Finely powder NLT 20 Tablets. Transfer a portion of the powder, equivalent to 300 mg of tramadol hydrochloride, to a 250-mL volumetric flask. Add about 50 mL of methanol and heat in a water bath for 20 min at about 60°, with intermittent shaking to disperse the powder. Sonicate for 10 min. Add 100 mL of water, and sonicate with intermittent shaking for 10 min. Shake the flask vigorously for 10 min using a mechanical shaker. Dilute with water to volume, pass through a suitable nylon filter, and collect the filtrate after discarding the first 4 mL of filtrate.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 216 nm
• Column: 2.1-mm × 10-cm; 1.7-µm packing L1
• Column temperature: 50°
• Flow rate: 0.6 mL/min
• Injection volume: 3 µL
• Run time: 6 min

System suitability

• Samples: System suitability solution and Standard solution
• Suitability requirements
• Resolution: NLT 3.0 between tramadol related compound A and tramadol, System suitability solution
• Column efficiency: NLT 5000 theoretical plates, Standard solution
• Capacity factor, k′: NLT 1.5, Standard solution
• Tailing factor: NMT 2.0, Standard solution
• Relative standard deviation: NMT 6.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (1/F) × 100

rᵤ = peak response of each individual impurity from the 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 Sample solution (mg/mL)

F = relative response factor (see Table 7)

Acceptance criteria: See Table 7.

Table 7

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

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

ᶜ 1-(3-Methoxyphenyl)-2-(dimethylaminomethyl) cyclohex-6-ene hydrochloride (identified and reported as an individual unspecified impurity if present).

ᵈ 1-(3-Methoxyphenyl)-2-(dimethylaminomethyl) cyclohex-1-ene hydrochloride (identified and reported as an individual unspecified impurity if present).

6 ADDITIONAL REQUIREMENTS

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

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

USP Reference Standards 〈11〉

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.

C₁₆H₂₅NO₂ · HCl 299.84