Add the following:
Tramadol Hydrochloride Extended-Release Tablets
DEFINITION
Tramadol Hydrochloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of tramadol hydrochloride (C16H25NO2·HCl).
IDENTIFICATION
• A.
The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
• B. Ultraviolet Absorption 
197U
197U
Sample solution:
Use the Sample solution in 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.
ASSAY
• Procedure
Mobile phase:
Tetrahydrofuran, trifluroacetic 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 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:
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.
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
Mode:
LC
Detector:
UV 216 nm
Column:
4.6-mm × 15-cm; 5-µm packing L11
Flow rate:
1 mL/min
Column temperature:
40
Injection size:
10 µL
System suitability
Sample:
Standard solution
Suitability requirements
Theoretical plates:
NLT 2000
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%
PERFORMANCE TESTS
• Dissolution 711
711
Medium:
0.1 N hydrochloric acid; 900 mL
Apparatus 1:
75 rpm
Time:
2, 4, 8, 10, and 16 h
Standard solution:
(L/900) mg/mL of USP Tramadol Hydrochloride RS in Medium, where L is the Tablet label claim in mg
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 pre-heated at 37.0 ± 0.5.
.
Analysis
Wavelength:
UV 271 nm
Path length:
5 mm, flow cell
Blank:
Medium
Samples:
Standard solution and Sample solution
Calculate the percentage of the labeled amount of tramadol hydrochloride (C16H25NO2·HCl) dissolved at each time point.
At 2 h:
Q2 = (AU/AS) × (CS/L) × V × 100
At 4 h:
Q4 = [(AU/AS) × (CS/L) × V × 100] + [Q2 × (VS/V)]
At 8 h:
Q8 = [(AU/AS) × (CS/L) × V × 100] + [Q2 × (VS/V)] + [Q4 × (VS/V)]
At 10 h:
Q10 = [(AU/AS) × (CS/L) × V × 100] + [Q2 × (VS/V)] + [Q4 × (VS/V)] + [Q8 × (VS/V)]
At 16 h:
Q16 = [(AU/AS) × (CS/L) × V × 100] + [Q2 × (VS/V)] + [Q4 × (VS/V)] + [Q8 × (VS/V)] + [Q10 × (VS/V)]
| AU | = | = absorbance from the Sample solution |
| AS | = | = absorbance from the Standard solution |
| CS | = | = concentration of USP Tramadol Hydrochloride RS in the Standard solution (mg/mL) |
| L | = | = label claim (mg/Tablet) |
| V | = | = volume of Medium, 900 mL |
| VS | = | = volume of sample withdrawn (mL) |
Tolerances:
See Table 1.
Table 1
| Time (h) |
Amount Dissolved |
|---|---|
| 2 | NMT 15% |
| 4 | 10%–40% |
| 8 | 50%–85% |
| 10 | 65%–95% |
| 16 | NLT 80% |
The percentages of the labeled amount of tramadol hydrochloride (C16H25NO2·HCl) released at the times specified conform to Acceptance Table 2.
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
IMPURITIES
Organic Impurities
• Procedure
Mobile phase:
Acetonitrile, trifluroacetic 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 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 System suitability stock solution
Standard stock solution:
0.05 mg/mL of USP Tramadol Hydrochloride RS in Diluent 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 Standard stock solution
Sample solution:
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, into 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.
, 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
Mode:
LC
Detector:
UV 216 nm
Column:
2.1-mm × 10-cm; 1.7-µm packing L1
Flow rate:
0.6 mL/min
Column temperature:
50
Injection size:
3 µL
Run time:
6 min
System suitability
Samples:
System suitability solution and Standard solution
Suitability requirements
Theoretical plates:
NLT 5000, Standard solution
Capacity factor:
NLT 1.5, Standard solution
Tailing factor:
NMT 2.0, Standard solution
Resolution:
NLT 3.0 between tramadol related compound A and tramadol, System suitability 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 2) |
Acceptance criteria
Individual unspecified impurities:
See Table 2.
Table 2
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| Desmethyl tramadol (impurity D)a | 0.57 | 1.0 | 0.1 |
| Tramadol related compound Ab | 0.84 | 1.0 | 0.2 |
| Tramadol hydrochloride | 1.00 | — | — |
| 1,6 Olefinc | 2.78 | 3.0 | — |
| 1,2 Olefind | 3.28 | 2.2 | — |
| Individual unspecified impurity | — | 1.0 | 0.1 |
| Total impurities | — | — | 0.5 |
|
a
3-{(1RS,2RS)-2-[(Dimethylamino)methyl]-1-hydroxycyclohexyl}phenol.
b
RS,SR-1-(3-Methoxyphenyl)-2-(dimethylaminomethyl)cyclohexanol.
c
1-(3-Methoxyphenyl)-2-(dimethylaminomethyl) cyclohex-1-ene hydrochloride (identified and reported as an individual unspecified impurity if present).
d
1-(3-Methoxyphenyl)-2-(dimethylaminomethyl) cyclohex-6-ene hydrochloride (identified and reported as an individual unspecified impurity if present).
|
|||
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers, and store at controlled room temperature.
• USP Reference Standards 11
11
USP Tramadol Hydrochloride RS 
(±)-cis-2-[(Dimethylamino)methyl]-1-(m-methoxyphenyl) cyclohexanol hydrochloride.
C16H25NO2·HCl 299.84
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(±)-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.
C16H25NO2·HCl 299.84
RS,SR-1-(3-Methoxyphenyl)-2-(dimethylaminomethyl)cyclohexanol.
C16H25NO2·HCl 299.84
USP35
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Clydewyn M. Anthony, Ph.D.
Senior Scientific Liaison 1-301-816-8139 |
(SM22010) Monographs - Small Molecules 2 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4906
Pharmacopeial Forum: Volume No. 36(6) Page 1578