Bupropion Hydrochloride Extended-Release Tablets
DEFINITION
Bupropion Hydrochloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of bupropion hydrochloride (C13H18ClNO·HCl).
IDENTIFICATION
• A. Infrared Absorption 
197K
197K
Sample:
Crush 1 Tablet using a mortar and pestle. Prepare an approximate 1% (w/w) dispersion of the sample in potassium bromide.
Acceptance criteria:
The Sample shows strong bands at about 1690, 1560, and 1240 cm
1 and a weaker band at about 740 cm1, similar to the reference preparation.
1 and a weaker band at about 740 cm1, similar to the reference preparation.
• B.
The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
Diluent 1:
Methanol and 0.001 N hydrochloric acid (20:80)
Solution A:
Acetonitrile, trifluoroacetic acid, and water (10:0.04:90)
Solution B:
Acetonitrile, trifluoroacetic acid, and water (95:0.03:5)
Mobile phase:
See Table 1.
Table 1
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 90 | 10 |
| 3.4 | 87 | 13 |
| 10.0 | 15 | 85 |
| 10.1 | 0 | 100 |
| 13.0 | 0 | 100 |
| 13.2 | 90 | 10 |
| 19.0 | 90 | 10 |
System suitability stock solution A:
0.02 mg/mL of USP Bupropion Hydrochloride Related Compound C RS and 0.2 mg/mL of USP Bupropion Hydrochloride Related Compound F RS in methanol
System suitability solution A:
0.0018 mg/mL of USP Bupropion Related Compound C RS and 0.018 mg/mL of USP Bupropion Related Compound F RS from System suitability stock solution A and Diluent 1
System suitability stock solution B:
0.09 mg/mL of m-chlorobenzoic acid in water
System suitability solution B:
0.0018 mg/mL of m-chlorobenzoic acid from System suitability stock solution B and Diluent 1
Standard solution:
0.6 mg/mL of USP Bupropion Hydrochloride RS in Diluent 1
Sample stock solution A:
Transfer a number of Tablets intact or crushed, to a suitable homogenizer vessel containing sufficient methanol to obtain a concentration of 3.0 mg/mL of bupropion hydrochloride. Immediately homogenize the sample for 30 s at 20,000 rpm. Allow extraction for 3 min, and follow by two additional 10-s pulses, each at 20,000 rpm, pausing 3 min between these pulses to ensure complete extraction. Pass a portion of the solution through a nylon filter of 0.45-µm pore size, discarding the first 2–4 mL of the filtrate.
Sample solution A:
Nominally 0.6 mg/mL of Sample stock solution A in 0.001 N hydrochloric acid. Alternatively, the Sample solution can be prepared as follows:
Buffer:
Dissolve 100 g of anhydrous disodium hydrogen phosphate in 1 L of water. Add 50 mL of phosphoric acid, stir or sonicate until dissolved, and mix. Adjust with phosphoric acid to a pH of 3.0.
Diluent 2:
Methanol and Buffer (1:4)
Sample stock solution B:
Weigh and grind NLT 20 Tablets to prepare a solution of nominal concentration of 3 mg/mL. Initially add Diluent 2 (75% of the volume of the flask), stir for 30 min, and sonicate for 15 min, and then dilute to volume. Mix, centrifuge a portion, and use the supernatant.
Sample solution B:
Nominally 0.6 mg/mL of Sample stock solution B in Diluent 2
Chromatographic system
Mode:
LC
Detector:
UV 226 nm
Column:
4.6-mm × 10-cm; 3.5-µm packing L1
Column temperature:
40
Flow rate:
1.5 mL/min
Injection size:
5 µL
System suitability
Samples:
System suitability solution A, System suitability solution B, and Standard solution
Suitability requirements
Resolution:
NLT 1.5 between bupropion hydrochloride related compound C and bupropion hydrochloride related compound F, System suitability solution A
Tailing factor:
NMT 1.9, Standard solution
Relative standard deviation:
NMT 1.5%, Standard solution
Relative response factor:
Between 0.22 and 0.26 for m-chlorobenzoic acid. [Note—Use the responses from System suitability solution B and the Standard solution. ]
Analysis
Samples:
Standard solution and Sample solution A or Sample solution B
Calculate the percentage of the labeled amount of bupropion hydrochloride (C13H18ClNO·HCl) in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of bupropion hydrochloride from Sample solution A or Sample solution B |
| rS | = | = peak response of bupropion hydrochloride from the Standard solution |
| CS | = | = concentration of USP Bupropion Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of bupropion hydrochloride in Sample solution A or Sample solution B (mg/mL) |
Acceptance criteria:
90.0%–110.0%
PERFORMANCE TESTS
• Dissolution 711
711
For products labeled for dosing every 12 h
Test 1
Medium:
Water; 900 mL
Apparatus 2:
50 rpm
Times:
1, 4, and 8 h
Standard solution:
USP Bupropion Hydrochloride RS at a known concentration in Medium
Sample solution:
Pass a portion of the solution under test through a suitable filter, and dilute with Medium, if necessary.
Instrumental conditions
Mode:
UV-Vis
Analytical wavelength:
298 nm
Cell:
1.0 cm
Blank:
Medium
Analysis
Samples:
Standard solution and Sample solution
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, pH 1.5 (prepared by transferring 50 mL of concentrated hydrochloric acid to 6000 mL of water, adding 18 g of sodium hydroxide, mixing, and adjusting with either diluted sodium hydroxide or hydrochloric acid to a pH of 1.5 ± 0.05); 900 mL, deaerated
Apparatus 1:
50 rpm
Times:
1, 2, 4, and 6 h
Determine the percentages of the labeled amount of bupropion hydrochloride (C13H18ClNO·HCl) dissolved by using the following method.
Buffer:
3.45 g of monobasic sodium phosphate monohydrate in 996 mL of water. Add 4.0 mL of triethylamine, and adjust with phosphoric acid to a pH of 2.80 ± 0.05.
Mobile phase:
Methanol and Buffer (7:13)
Standard solution:
USP Bupropion Hydrochloride RS in Medium at a known concentration similar to the one expected in the Sample solution
Sample solution:
Use portions of the solution under test, and pass through a nylon filter of 0.45-µm pore size.
Chromatographic system
Mode:
LC
Detector:
UV 298 nm
Column:
4.6-mm × 15-cm; packing L1
Flow rate:
1 mL/min
Injection size:
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
Test 3:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.
Medium, Apparatus 2, Standard solution, Sample solution, Instrumental conditions, and Analysis:
Proceed as directed for Test 1, except the wavelength is about 250 nm, and use wire coil sinkers, if necessary.
Times:
1, 2, 4, and 6 h
Test 5:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.
Medium and Analysis:
Proceed as directed for Test 1.
Times:
1, 3, and 6 h
Instrumental conditions:
Proceed as directed for Test 1, except use a 0.5-cm cell.
Test 7:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7.
Medium, Apparatus 1, and Times:
Proceed as directed for Test 2, including the quantitative chromatographic method, but using as the Mobile phase a mixture of Buffer with methanol (55:45).
Test 9:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 9.
Medium:
0.1 N hydrochloric acid, pH 1.5 (prepared as directed for Test 2); 900 mL
Apparatus 1:
50 rpm
Times:
1, 2, 4, and 8 h
Standard solution:
(L/1000) mg/mL of USP Bupropion Hydrochloride RS in Medium, where L is the Tablet label claim, in mg
Sample solution:
Pass a portion of the solution under test through a suitable filter.
Instrumental conditions:
Proceed as directed for Test 1.
For products labeled for dosing every 24 h
Test 4:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.
Medium:
0.1 N hydrochloric acid; 900 mL, deaerated
Apparatus 1:
75 rpm
Times:
2, 4, 8, and 16 h
Standard solution:
USP Bupropion Hydrochloride RS at a known concentration in Medium
Sample solution:
Pass a portion of the solution under test through a suitable filter, and dilute with Medium, if necessary.
Instrumental conditions
Mode:
UV-Vis
Analytical wavelength:
252 nm
Cell:
1.0 cm
Blank:
Medium
Analysis
Samples:
Standard solution and Sample solution
Test 6:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6.
Medium and Apparatus 1:
Proceed as directed for Test 4.
Times:
1, 2, 4, 8, and 12 h
Standard solution:
USP Bupropion Hydrochloride RS at a known concentration in Medium
Sample solution:
Pass a portion of the solution under test through a suitable filter, and dilute with Medium, if necessary.
Instrumental conditions
Mode:
UV-Vis
Analytical wavelength:
298 nm
Cell:
1.0 cm
Blank:
Medium
Test 8:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 8.
Medium:
0.1 N hydrochloric acid; 900 mL
Apparatus 1:
75 rpm
Times:
2, 4, 8, and 16 h
Standard solution
For Tablets labeled to contain 150 mg:
USP Bupropion Hydrochloride RS dissolved in Medium (about 0.167 mg/mL)
For Tablets labeled to contain 300 mg:
USP Bupropion Hydrochloride RS dissolved in Medium (about 0.333 mg/mL)
Sample solution:
Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size.
Instrumental conditions
Mode:
UV-Vis
Analytical wavelength:
298 nm
Blank:
Medium
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
Procedure for content uniformity
Standard solution:
0.33 mg/mL of USP Bupropion Hydrochloride RS in water
Sample solution:
Transfer 1 Tablet to a suitable homogenizer vessel containing a volume of water to obtain a concentration of about 0.33 mg of bupropion hydrochloride per mL. Immediately homogenize the sample using single 30-s pulses each at 5000, 10,000, and 15,000 rpm, and follow by two pulses each at 20,000 rpm. After the homogenate has settled, mix at 5000 rpm for an additional 30 s. Pass a portion of the solution through a nylon filter of 0.45-µm pore size, discarding the first 4 mL of the filtrate.
Analysis:
Proceed as directed for the appropriate Dissolution procedure, using a 0.5-cm cell, and correct for dilution.
IMPURITIES
• Organic Impurities
Solution A, Solution B, Mobile phase, System suitability solution A, System suitability solution B, Standard solution, Sample solution A or Sample solution B, and Chromatographic system:
Proceed as directed in the Assay.
Analysis
Samples:
Standard solution and Sample solution A or Sample solution B
Calculate the percentage of each impurity in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × F × 100
| rU | = | = peak response of each impurity from Sample solution A or Sample solution B |
| rS | = | = peak response of bupropion hydrochloride from the Standard solution |
| CS | = | = concentration of USP Bupropion Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of bupropion hydrochloride in Sample solution A or Sample solution B (mg/mL) |
| F | = | = relative response factor for each impurity (see Table 11 for values) |
Acceptance criteria:
See Table 11.
Table 11
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|
|---|---|---|---|---|
| 100 mg or less |
150 mg or greater |
|||
| 2-Amino-1-(3-chlorophenyl)-1-propanone | 0.38 | 0.80 | 0.3 | 0.3 |
| (3S,5S,6S)-6-(3-Chlorophenyl)-6- hydroxy-5- methyl-3-thiomorpholine carboxylic acid |
0.56 | 0.86 | 1.0 | 1.5 |
| (3S,5R,6R)-6-(3-Chlorophenyl)-6- hydroxy-5- methyl-3-thiomorpholine carboxylic acid |
0.78 | 0.88 | 0.5 | 0.4 |
| Bupropion | 1.0 | — | — | — |
| Bupropion related compound F |
1.71 | 0.55 | 1.2 | 2.3 |
| Bupropion related compound C |
1.75 | 0.59 | 0.3 | 0.3 |
| m-Chlorobenzoic acid | 1.80 | 0.24 | 0.3 | 0.3 |
| 1-(3-Chlorophenyl)-1,2- propanedione |
2.25 | 1.00 | 0.4 | 0.4 |
| Any unspecified impurity | — | 1.00 | 0.2 | 0.2 |
| Total impurities | — | — | 3.2 | 3.3 |
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in well-closed containers.
• 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
11
USP Bupropion Hydrochloride RS 
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USP Bupropion Hydrochloride Related Compound C RS
1-(3-Chlorophenyl)-2-hydroxy-1-propanone.
C9H9O2Cl 184.62
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1-(3-Chlorophenyl)-2-hydroxy-1-propanone.
C9H9O2Cl 184.62
USP Bupropion Hydrochloride Related Compound F RS
1-(3-Chlorophenyl)-1-hydroxy-2-propanone.
C9H9O2Cl 184.62
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1-(3-Chlorophenyl)-1-hydroxy-2-propanone.
C9H9O2Cl 184.62
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Ravi Ravichandran, Ph.D.
Principal Scientific Liaison 1-301-816-8330 |
(SM42010) Monographs - Small Molecules 4 |
| 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 2405
Pharmacopeial Forum: Volume No. 36(4) Page 906