Venlafaxine Hydrochloride Extended-Release Capsules
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- DEFINITION
- IDENTIFICATION
- ASSAY
- PERFORMANCE TESTS
- DISSOLUTION (711)
- Test 1
- Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2
- Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3
- Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4
- Test 5: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5
- Test 6: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6
- Test 7: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7
- Test 8: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 8
- Test 9: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 9
- Test 10: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 10
- Test 11: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 11
- Test 12: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 12
- UNIFORMITY OF DOSAGE UNITS (905)
- IMPURITIES
- ADDITIONAL REQUIREMENTS
This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition
Issued and maintained by the United States Pharmacopeial Convention (USP)
1 DEFINITION
Venlafaxine Hydrochloride Extended-Release Capsules contain an amount of Venlafaxine Hydrochloride equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of venlafaxine (C17H27NO2).
2 IDENTIFICATION
A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Ultraviolet-Visible Spectroscopy: 197U
Wavelength range: 250-310 nm
Acceptance criteria: Meet the requirements
B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
3 ASSAY
PROCEDURE
Mobile phase: Acetonitrile, triethylamine, and water (250:4:750), Adjust with phosphoric acid to a pH of 3.5.
Standard solution: 0.25 mg/mL of USP Venlafaxine Hydrochloride RS in Mobile phase
Sample stock solution: Nominally 1.0 mg/mL of venlafaxine (from the contents of NLT 10 Capsules) prepared as follows. Transfer a weighed quantity of Capsule contents to a suitable volumetric flask. Add 8% of the flask volume of acetonitrile, and shake for 40 min. Add 50% of flask volume of Mobile phase, and shake for an additional 20 min. Dilute with Mobile phase to volume. Pass a portion through a suitable filter of 0.45-µm pore size.
Sample solution: 0.25 mg/mL of venlafaxine (using the filtrate from the Sample stock solution) in Mobile phase
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 226 nm
Column: 4.6-mm x 25-cm; 5-µm packing L1
Flow rate: 1 mL/min
Injection volume: 10 µL
Run time: 1.5 times the retention time of venlafaxine
Suitability requirements
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 1.5%
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) in the portion of Capsules taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
rU = peak response from the Sample solution
rS = peak response from the Standard solution s
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
CU = nominal concentration of venlafaxine in the Sample solution (mg/mL)
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Acceptance criteria: 90.0%-110.0%
4 PERFORMANCE TESTS
Change to read:
4.1 DISSOLUTION (711)
4.1.1 Test 1
Medium: Water; 900 mL
Apparatus 1: 100 rpm
Times: 3, 6, 16, and 24 h
Mobile phase: Acetonitrile, triethylamine, and water (450:4:550). Adjust with phosphoric acid to a pH of 3.5.
Standard stock solution: 0.1 mg/mL of USP Venlafaxine Hydrochloride RS in water
Standard solution: 0.05 mg/mL of USP Venlafaxine Hydrochloride RS in acetonitrile, from the Standard stock solution
Sample stock solution: Pass a portion of the solution under test through a suitable filter.
Sample solution: Sample stock solution and acetonitrile (50:50)
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 274 nm
Column: 4.6-mm x 25-cm; 5-µm packing L1
Flow rate: 1 mL/min
Injection volume: 60 µL
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.5
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration, Ci of venlafaxine (C17H27NO2) in Medium (mg/mL) after time point i:
Result = (rU/rS) x CS x D x (Mr1/Mr2)
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of the USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
D = dilution factor for the Sample solution, 2
Mr1 = molecular weight of venlafaxine, 277,40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point i:
Result1 = C1 x V x (1/L) x 100
Result2 = {[C2 x (V - VS)] + (C1 x VS)} x (1/L) x 100
Result3 = ({C3 x [V - (2 x VS)]} + [(C2 + C1) x VS]) x (1/L) x 100
Result4 = {[C4 x (V- (3 x VS))] + [(C3 + C2 + C1) x VS]} x (1/L) x 100
Ci = 1 concentration of venlafaxine in Medium in the portion of sample withdrawn at time pointi (mg/mL)
V = volume of Medium, 900 mL
VS = volume of the Sample solution withdrawn from the Medium (mL)
L = label claim (mg/Capsule)
Tolerances: See Table 1.
Table 1
| Time Point, i | Time (h) | Amount Dissolved |
| 1 | 3 | NMT 40% |
| 2 | 6 | 35%–60% |
| 3 | 16 | 60%–85% |
| 4 | 24 | NLT 75% |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved 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 it meets USP Dissolution Test 2
Medium: Water, 900 mL
Apparatus 1: 100 rpm
Times: 2, 4, 8, 12, and 20 h
Capsule correction solution: Dissolve 6 empty Capsule shells in 900 mL of water.
Blank: Dilute 150 mL of Capsule correction solution with water to 900 mL..
Standard solution: (L/900) mg/mL of USP Venlafaxine Hydrochloride RS, where L is the label claim, in mg/Capsule, prepared as follows. To a weighed amount of the Standard equivalent to the sample claim, add Capsule correction solution to fill 17% of final flask volume. Dilute with water to volume.
Sample solution: Pass a portion of the solution under test through a suitable filter.
Instrumental conditions
Mode: UV
Detector: 274 nm
Analysis
Samples: Standard solution and Sample solution
[NOTE-If necessary, the volume of Medium may be corrected for volumes removed from any previous sample time points.] Calculate the concentration, Ci of venlafaxine (C17H27NO2) in Medium (mg/mL) after time point i:
Result = (AU/AS) x CS x (Mr1/Mr2)
AU = absorbance from the Sample solution
AS = absorbance from the Standard solution S
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point i:
Result1 = C1 x V x (1/L) x 100
Result2 = {[C2 x (V - VS)] + (C1 x VS)} x (1/L) x 100
Result3 = {(C3 x [V - (2 x VS))] + [(C2 + C1) x VS]} x (1/L) x 100
Resulti = {[Ci x (V - ([i-1] x VS))] + [(Ci-1 + Ci-2 +.....+ C1) x VS]} x (1/L) x 100
Ci = concentration of venlafaxine in Medium in the portion of sample withdrawn at time point i (mg/mL)
V = volume of Medium, 900 mL
VS = volume of the Sample solution withdrawn from the Medium (mL)
L = label claim (mg/Capsule)
Tolerances: See Table 2.
Table 2
| Time Point, i | Time (h) | Amount Dissolved |
| 1 | 2 | 10%–30% |
| 2 | 4 | 33%–53% |
| 3 | 8 | 58%–78% |
| 4 | 12 | 68%–88% |
| 5 | 20 | NLT 80% |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved 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 it meets USP Dissolution Test 3
Medium: 0.1 N bydrochloric acid: 900 mL
Apparatus 1: 100 rpm
Times: 4, 8, and 16 h
Buffer: Dissolve 1.4 g of monobasic potassium phosphate in 1 L of water. Add 5 mL of triethylamine, and adjust with phosphoric acid to a pH of 3.0.
Mobile phase: Acetonitrile and Buffer (35:65)
Standard stock solution: 0.9 mg/mL of USP Venlafaxine Hydrochloride RS in Medium
Standard solution: (L/750) mg/mL of USP Venlafaxine Hydrochloride RS in Medium from the Standard stock solution, where L is the label claim, in mg/Capsule. Pass a portion through a suitable filter of 0.45-µm pore size.
Sample solution: At the end of the specified time interval, withdraw a known volume of the solution from the dissolution vessel, and replace with an equal volume of fresh Medium. 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 225 nm
Column: 4.6-mm x 25-cm; 5-µm packing L1
Flow rate: 1 mL/min
Column temperature: 30°
Injection volume: 10 µL
Run time: 2 times the retention time of venlafaxine
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration, Ci of venlafaxine (C17H27NO2) in Medium (mg/mL) after time point i:
Result = (rU/rS) × CS × (Mr1/Mr2)
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point i:
Result1 = C1 x V x (1/L) x 100
Result2 = [(C2 x V)+ (C1 x VS)] x (1/L) x 100
Result3 = {(C3 x V) + [(C2 + C1) x VS]} x (1/L) x 100
Ci = concentration of venlafaxine in Medium in the portion of sample withdrawn at time pointi (mg/mL)
V = volume of Medium, 900 mL
VS = volume of the Sample solution withdrawn from the vessel and replaced with Medium (mL)
L = label claim (mg/Capsule)
Tolerances: See Table 3.
Table 3
| Time Point, i | Time (h) | Amount Dissolved |
| 1 | 4 | 35%–55% |
| 2 | 8 | 65%–90% |
| 3 | 16 | NLT 85% |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved 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 it meets USP Dissolution Test 4
Medium: Water: 900 mL
Apparatus 1: 100 rpm
Times: 2, 4, 8, 12, and 20 h
Solution A: Dilute 10 mL of phosphoric acid with water to 100 mL.
Buffer: 11.4 g/L of ammonium dihydrogen phosphate in water
Mobile phase: Acetonitrile and Buffer (35:65). Adjust with Solution A to a pH of 4.4.
Standard stock solution: 0.24 mg/mL of USP Venlafaxine Hydrochloride RS in Medium. Sonication may be used to aid in dissolution.
Standard solution: See Table 4 for the concentration of USP Venlafaxine Hydrochloride RS in Medium from the Standard stock solution.
Using a glass syringe, pass a portion through a suitable filter of 0.45-µm pore size.
Table 4
| Label Claim (L) | Standard Solution (mg/mL) |
| 37.5 | 0.05 |
| 75 | 0.1 |
| 150 | 0.1 |
Sample solution: At the end of the specified time interval, withdraw a known volume of the solution from the dissolution vessel, and replace with an equal volume of fresh Medium. For Capsules that are labeled to contain 150 mg of venlafaxine, dilute this solution with an equal volume of Medium. Using a glass syringe, 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 225 nm
Column: 4.6-mm x 25-cm; 5-µm packing L7
Flow rate: 1.2 mL/min
Injection volume: 20 µL
Run time: 2 times the retention time of venlafaxine
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration, Ci of venlafaxine (C17H27NO2) in Medium (mg/mL) after time point i
Result = (rU/rS) × CS × D ×(Mr1/Mr2)
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
D = dilution factor for the Sample solution, 2 for Capsules labeled to contain 150 mg of venlafaxine; 1 for Capsules labeled to contain 37.5 or 75 mg of venlafaxine
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point i:
Result1 = C1 x V x (1/L) x 100
Result2 = [(C2 x V)+ (C1 x VS)] x (1/L) x 100
Result3 = {(C3 x V) + [(C2 + C1) x VS]} x (1/L) x 100
Result4 = {[C4 x V] + [(C3 + C2 + C1) x VS]} x (1/L) x 100
Result5 = {[C5 × V] + [(C4 + C3 + C2 + C1) × VS]} × (1/L) × 100
Ci = concentration of venlafaxine in Mediurn in the portion of sample withdrawn at time point / (mg/mL)
V = volume of Medium, 900 mL
VS = volume of the Sample solution withdrawn from the vessel and replaced with Medium (mL)
L = label claim (mg/Capsule)
Tolerances: See Table 5.
Table 5
| Time Point, i | Time (h) | Amount Dissolved |
| 1 | 2 | 10%–30% |
| 2 | 4 | 35%–55% |
| 3 | 8 | 60%–80% |
| 4 | 12 | NLT 70% |
| 5 | 20 | NLT 85% |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved 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 it meets USP Dissolution Test 5
Medium: Water: 900 mL
Apparatus 1: 100 rpm
Times: 2, 5, 8, and 20 h
Buffer: 11.4 g/L of monobasic ammonium phosphate in water. Adjust with dilute phosphoric acid (1 in 10) or dilute ammonia solution (1 in 10) to a pH of 4.4.
Mobile phase: Acetonitrile and Buffer (25.5:74.5)
Standard solution: (L/900) mg/mL of USP Venlafaxine Hydrochloride RS in Medium, where L is the label claim, in mg/Capsule
Sample solution: At the end of the specified time interval, withdraw a known volume of the solution from the dissolution vessel, and replace with an equal volume of fresh Medium. Pass a portion of the withdrawn sample through a suitable filter of 0.45-µm pore size.
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 225 nm
Column: 4.6-mm x 15-cm; 5-µm packing L7
Flow rate: 1 mL/min
Injection volume: 10 µL
Run time: 1.5 times the retention time of venlafaxine
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration, Ci of venlafaxine (C17H27NO2) in Medium (mg/mL) after time point i:
Result = (rU/rS) × CS × (Mr1/Mr2)
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point i:
Result1 = C1 x V x (1/L) x 100
Result2 = [(C2 x V)+ (C1 x VS)] x (1/L) x 100
Result3 = {(C3 x V) + [(C2 + C1) x VS]} x (1/L) x 100
Result4 = {[C4 x V] + [(C3 + C2 + C1) x VS]} x (1/L) x 100
Ci = concentration of venlafaxine in Medium in the portion of sample withdrawn at time point / (mg/mL)
V = volume of Medium, 900 mL
VS = volume of the Sample solution withdrawn from the vessel and replaced with Medium (mL)
L = label claim (mg/Capsule)
Tolerances: See Table 6.
Table 6
| Time Point, i | Time (h) | Amount Dissolved |
| 1 | 2 | NMT 20% |
| 2 | 5 | 35%–55% |
| 3 | 8 | 60%–80% |
| 4 | 20 | NLT 80% |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.
4.1.6 Test 6: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6
Medium: Water: 900 mL, deaerated
Apparatus 1: 100 rpm
Times: 2, 4, 8, 12, and 24 h
Buffer: 10 mL/L of triethylamine in water adjusted with phosphoric acid to a pH of 3.0
Mobile phase: Acetonitrile and Buffer (20:80)
Standard solution: (L/900) mg/mL of venlafaxine from USP Venlafaxine Hydrochloride RS in Medium, where L is the label claim, in mg/Capsule
Sample solution: Centrifuge a portion of the solution under test.
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 226 nm
Column: 4.6-mm x 15-cm; 5-µm packing L1
Flow rate: 2.5 mL/min
Injection volume: 20 µL
Run time: 1.5 times the retention time of venlafaxine
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration, C, of venlafaxine (C17H27NO2) in Medium (mg/mL) after time point /:
Result = (rU/rS) × CS × (Mr1/Mr2)
rU = peak response from the Sample solution
rS = peak response from the Standard solution s
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point i
Result1 = C1 x V x (1/L) x 100
Result2 = {[C2 x (V - VS)] + (C1 x VS)} x (1/L) x 100
Result3 = {(C3 x [V - (2 x VS)]} + [(C2 + C1) x VS]) x (1/L) x 100
Result4 = ({C4 x [V - (3 x VS)] + [(C3 + C2 + C1) x VS]} x (1/L) x 100
Result5 = {[C5 x (V- (4 x VS))] + [(C4 + C3 + C2 + C1) x VS]} x (1/L) x 100
Ci = concentration of venlafaxine in Medium in the portion of sample withdrawn at time point i (mg/mL)
V = volume of Medium, 900 mL
VS = volume of the Sample solution withdrawn from the Medium (mL)
L = label claim (mg/Capsule)
Tolerances: See Table 7.
Table 7
| Time Point, i | Time (h) | Amount Dissolved |
| 1 | 2 | NMT 30% |
| 2 | 4 | 40%–60% |
| 3 | 8 | 60%–80% |
| 4 | 12 | 70%–90% |
| 5 | 20 | NLT 85% |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.
4.1.7 Test 7: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7
Medium: Water: 900 mL
Apparatus 1: 100 rpm
Times: 2, 4, 8, 12, and 20 h
Buffer: 1.7 g/L of dibasic potassium phosphate in water. Adjust with phosphoric acid (1 in 10) to a pH of 7.0.
Mobile phase: Acetonitrile and Buffer (80:20)
Standard solution: (L/900) mg/mL of USP Venlafaxine Hydrochloride RS in Medium, where L is the label claim, in mg/Capsule
Sample solution: At the end of the specified time interval, withdraw a known volume of the solution from the dissolution vessel, and replace with an equal volume of fresh Medium. Pass a portion of the withdrawn sample through a suitable filter of 0.45-µm pore size.
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 227 nm
Column: 4.6-mm x 25-cm; 5-µm packing L1.
Column temperature: 45°
Flow rate: 1.5 mL/min
Injection volume: 10 µL
Run time: 2 times the retention time of venlafaxine
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration, Ci of venlafaxine (C17H27NO2) in Medium (mg/mL) after time point i:
Result = (rU/rS) × CS × (Mr1/Mr2)
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point i:
Result1 = C1 x V x (1/L) x 100
Result2 = [(C2 x V)+ (C1 x VS)] x (1/L) x 100
Result3 = {(C3 x V) + [(C2 + C1) x VS]} x (1/L) x 100
Result4 = {[C4 x V] + [(C3 + C2 + C1) x VS]} x (1/L) x 100
Result5 = {[C5 x V] + [(C4 + C3 + C2 + C1) x VS]} x (1/L) x 100
Ci = concentration of venlafaxine in Medium in the portion of sample withdrawn at time point i (mg/mL)
V = volume of Medium, 900 mL
VS = volume of the Sample solution withdrawn from the vessel and replaced with Medium (mL)
L = label claim (mg/Capsule)
Tolerances: See Table 8.
Table 8
| Time Point, i | Time (h) | Amount Dissolved |
| 1 | 2 | NMT 10% |
| 2 | 4 | NMT 30% |
| 3 | 8 | 40%–70% |
| 4 | 12 | 60%–90% |
| 5 | 20 | NLT 80% |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.
4.1.8 Test 8: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 8
Medium: Water 900 mL
Apparatus 1: 100 гpm
Times: 1, 6, 16, and 24 h
Diluent: Acetonitrile and water (30:70)
Buffer: Dissolve 8.9 g of dibasic sodium phosphate dihydrate and 2.5 g of sodium 1-octanesulfonate in 1 L of water. Adjust with 10% phosphoric acid to a pH of 3.0.
Mobile phase: Acetonitrile and Buffer (32:68)
Standard stock solution: 0.9 mg/mL of USP Venlafaxine Hydrochloride RS prepared as follows. Dissolve the weighed amount of the Standard first in acetonitrile using 20% of flask volume. Sonicate to dissolve, and dilute with Diluent to volume.
Standard solution: (L/900) mg/mL of USP Venlafaxine Hydrochloride RS from Standard stock solution in Diluent, where L is the label claim, in mg/Capsule
Sample solution: At the end of the specified time interval, withdraw a known volume of the solution from the dissolution vessel, and replace with an equal volume of fresh Medium. Pass a portion of the withdrawn sample through a suitable filter of 0.45-µm pore size.
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 226 nm
Column: 4.6-mm x 25-cm; 5-µm packing L1
Flow rate: 1.5 mL/min
Injection volume: 20 µL
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration, Ci of venlafaxine (C17H27NO2) in Medium (mg/mL) after time point i:
Result = (rU/rS) × CS × (Mr1/Mr2)
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point i:
Result1 = C1 x V x (1/L) x 100
Result2 = [(C2 x V)+ (C1 x VS)] x (1/L) x 100
Result3 = {(C3 x V) + [(C2 + C1) x VS]} x (1/L) x 100
Result4 = {[C4 x V] + [(C3 + C2 + C1) x VS]} x (1/L) x 100
Ci = concentration of venlafaxine in Medium in the portion of sample withdrawn at time point / (mg/mL)
V = volume of Medium, 900 mL
VS = volume of the Sample solution withdrawn from the vessel and replaced with Medium (mL)
L = label claim (mg/Capsule)
Tolerances: See Table 9.
Table 9
| Time Point, i | Time (h) | Amount Dissolved |
| 1 | 1 | NMT 25% |
| 2 | 6 | 50%–70% |
| 3 | 16 | 70%–95% |
| 4 | 24 | NLT 80% |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.
4.1.9 Test 9: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 9
Medium: Water, 900 mL, degassed
Apparatus 1: 100 rpm
Times: 2, 4, 8, 12, and 20 h
Buffer: Dissolve 3.4 g of monobasic potassium phosphate in 700 mL of water. Add 5 mL of triethylamine. Adjust with phosphoric acid to a pH of 3.0.
Mobile phase: Acetonitrile and Buffer (30:70)
Standard stock solution: 1.6 mg/mL of USP Venlafaxine Hydrochloride RS prepared as follows. Dissolve a weighed amount of the Standard first in methanol using 20% of flask volume. Sonicate to dissolve, and dilute with water to volume.
Standard solution: (L/900) mg/mL of USP Venlafaxine Hydrochloride RS from the Standard stock solution in Medium, where L is the label claim, in mg/Capsule
Sample solution: At the end of the specified time interval, withdraw a known volume of the solution from the dissolution vessel, and replace it with an equal volume of fresh Medium. Pass a portion of the withdrawn sample through a suitable filter of 0.45-µm pore size.
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 275 nm
Column: 4.6-mm x 15-cm; 5-µm packing L1
Flow rate: 1 mL/min
Injection volume: 20 µL
Run time: 2 times the retention time of venlafaxine
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration, Ci of venlafaxine (C17H27NO2) in Medium (mg/mL) after time point (i):
Result = (rU/rS) × CS × (Mr1/Mr2)
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point (i):
Result1 = C1 x V x (1/L) x 100
Result2 = [(C2 x V)+ (C1 x VS)] x (1/L) x 100
Result3 = {(C3 x V) + [(C2 + C1) x VS]} x (1/L) x 100
Result4 = {[C4 x V] + [(C3 + C2 + C1) x VS]} x (1/L) x 100
Result5 = {[C5 x V] + [(C4 + C3 + C2 + C1) x VS]} x (1/L) x 100
Ci = concentration of venlafaxine in Medium in the portion of sample withdrawn at the specified time point / (mg/mL)
V = volume of Medium, 900 mL
VS = volume of the Sample solution withdrawn from the vessel and replaced with Medium (mL)
L = label claim (mg/Capsule)
Tolerances: See Table 10.
Table 10
| Time Point, i | Time (h) | Amount Dissolved |
| 1 | 2 | NMT 25% |
| 2 | 4 | 30%–50% |
| 3 | 8 | 55%–80% |
| 4 | 12 | 65%–90% |
| 5 | 20 | NLT 80% |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.
4.1.10 Test 10: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 10
Medium: Water, 900 mL
Apparatus 1: 100 rpm
Times: 2, 4, and 20 h
Buffer: Add 5 mL of triethylamine to 1000 ml of water and mix. Adjust with phosphoric acid to a pH of 2.5.
Mobile phase: Acetonitrile and Buffer (20:80)
Standard stock solution: 1 mg/mL of USP Venlafaxine Hydrochloride RS in methanol. Sonicate to dissolve, if necessary.
Standard solution: 0.05 mg/mL of USP Venlafaxine Hydrochloride RS from the Standard stock solution in Medium
Sample solution: At the specified times, withdraw a known volume of the solution from the dissolution vessel. Dilute with Medium, if necessary, to a concentration that is similar to that of the Standard solution. Pass a portion of solution through a suitable filter of 0.45-um pore size, discarding the first 5 mL of filtrate, and use the filtrate. Replace the portion removed with the same volume of Medium.
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 226 nm
Column: 4.6-mm x 15-cm; 5-µm packing L1
Column temperature: 50°
Flow rate: 1.5 mL/min
Injection volume: 10 µL
Run time: NLT 2 times the retention time of venlafaxine
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration (Ci) of venlafaxine (C17H27NO2) in the sample withdrawn from the vessel at each time point (i):
Result = (rU/rS) × CS × D ×(Mr1/Mr2)
rU = peak response of venlafaxine from the Sample solution
rS = peak response of venlafaxine from the Standard solution
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
D = dilution factor of the Sample solution, if applicable
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point (i):
Result1 = C1 x V x (1/L) x 100
Result2 = [(C2 x V)+ (C1 x VS)] x (1/L) x 100
Result3 = {(C3 x V) + [(C2 + C1) x VS]} x (1/L) x 100
Ci = concentration of venlafaxine in the portion of sample withdrawn at time point / (mg/mL)
V = volume of Medium, 900 mL
L = label claim (mg/Capsule)
VS = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)
Tolerances: See Table 11.
Table 11
| Time Point (i) | Time (h) | Amount Dissolved (%) |
| 1 | 2 | NMT 30 |
| 2 | 4 | 37–57 |
| 3 | 20 | NLT 80 |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.
4.1.11 Test 11: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 11
Medium: pH 6.8, 0.05 M phosphate buffer (Dissolve 6.8 g of monobasic potassium phosphate and 0.9 g of sodium hydroxide in 1 L of water. Adjust with dilute phosphoric acid in water or dilute sodium hydroxide in water to a pH of 6.8.); 900 mL.
Apparatus 1: 100 гpm
Times: 2, 8, and 24 h
Mobile phase: Acetonitrile and water (45:55). Add 4 mL of triethylamine to each liter of the mixture. Adjust with phosphoric acid to a pH of 3.5.
Standard stock solution: 0.1 mg/mL of USP Venlafaxine Hydrochloride RS in Medium
Standard solution: 0.05 mg/mL of USP Venlafaxine Hydrochloride RS from Standard stock solution in acetonitrile
Sample solution: At the specified times, withdraw a known volume of the solution from the dissolution vessel. Pass a portion of solution through a suitable filter of 0.45-µm pore size, discarding the first 2 mL of filtrate. Transfer a suitable volume of the filtrate, equal to one-half of the flask volume, to an appropriate volumetric flask. Dilute with acetonitrile to volume.
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 274 nm
Column: 4.6-mm x 25-cm; 5-µm packing L1
Flow rate: 1 mL/min
Injection volume: 60 µL
Run time: NLT 2 times the retention time of venlafaxine
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.5
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration (Ci) of venlafaxine (C17H27NO2) in the sample withdrawn from the vessel at each time point (i):
Result = (rU/rS) × CS × D ×(Mr1/Mr2)
rU = peak response of venlafaxine from the Sample solution
rS = peak response of venlafaxine from the Standard solution
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL) C
D = dilution factor of the Sample solution,
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point (i):
Result1 = C1 x V x (1/L) x 100
Result2 = {[C2 x (V - VS)] + (C1 x VS)} x (1/L) x 100
Result3 = {(C3 x [V - (2 x VS)]} + [(C2 + C1) x VS]) x (1/L) x 100
Ci = concentration of venlafaxine in the portion of sample withdrawn at time pointi (mg/mL)
V = volume of Medium, 900 mL
L = label claim (mg/Capsule)
VS = volume of the Sample solution withdrawn at each time point from the Medium (mL)
Tolerances: See Table 12.
Table 12
| Time Point (i) | Time (h) | Amount Dissolved (%) |
| 1 | 2 | NMT 25 |
| 2 | 8 | 50–70 |
| 3 | 24 | NLT 80 |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.
4.1.12 Test 12: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 12
Medium: Water, 900 mL
Apparatus 1: 100 rpm
Times: 2, 8, and 20 h
Mobile phase: Acetonitrile, water, and triethylamine (25: 75: 0.4). Adjust with phosphoric acid to a pH of 3.5.
Standard solution: 0.05 mg/ml of USP Venlafaxine Hydrochloride RS in Medium. Sonicate to dissolve, if necessary.
Sample stock solution: At the times specified, withdraw 10 mL of the solution under test and replace with 10 mL of Medium. Pass the solution under test through a suitable filter of 0.45-µm pore size, discarding the first 3 mL of filtrate.
Sample solution
For Capsules labeled to contain 37.5 mg: Use the filtrate.
For Capsules labeled to contain 75 mg: Dilute the filtrate with Medium (1:2).
For Capsules labeled to contain 150 mg: Dilute the filtrate with Medium (1:4).
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 274 nm
Column: 4.6-mm x 25-cm; 5-µm packing L1
Flow rate: 1 mL/min
Injection volume: 30 µL
Run time: NLT 1.7 times the retention time of venlafaxine
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the concentration (Ci) of venlafaxine (C17H27NO2) in the sample withdrawn from the vessel at each time point (i):
Result = (rU/rS) × CS × D ×(Mr1/Mr2)
rU = peak response of venlafaxine from the Sample solution
rS = peak response of venlafaxine from the Standard solution S
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
D = dilution factor for the Sample solution, 1 for 37.5 mg Capsules, 2 for 75 mg Capsules, or 4 for 150 mg Capsules
Mr1 = molecular weight of venlafaxine, 277.41
Mr2 = molecular weight of venlafaxine hydrochloride, 313.87
Calculate the percentage of the labeled amount of venlafaxine (C17H27NO2) dissolved at each time point (i):
Result1 = C1 x V1 x (1/L) x 100
Result2 = [(C2 x V2)+ (C1 x VS)] x (1/L) x 100
Result3 = {(C3 x V3) + [(C2 + C1) x VS]} x (1/L) x 100
Ci = concentration of venlafaxine in the portion of sample withdrawn at time point/ (mg/mL)
V = volume of Medium, 900 mL
L = label claim (mg/Capsule)
VS = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)
Tolerances: See Table 13.
Table 13
| Time Point (i) | Time (h) | Amount Dissolved (%) |
| 1 | 2 | NMT 30 |
| 2 | 8 | 60–80 |
| 3 | 20 | NLT 80 |
The percentages of the labeled amount of venlafaxine (C17H27NO2) dissolved at the times specified conform to Dissolution (711). Acceptance Table 2▲(RB 1-Sep-2022)
4.2 UNIFORMITY OF DOSAGE UNITS (905)
Meet the requirements
5 IMPURITIES
ORGANIC IMPURITIES
Mobile phase, Standard solution, and Sample solution: Proceed as directed in the Assay.
System suitability solution: 0.25 µg/mL of USP Venlafaxine Related Compound A RS in the Standard solution
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 226 nm
Column: 4.6-mm x 25-cm; 5-µm packing L1
Flow rate: 1 mL/min
Injection volume: 10 µL
Run time: 4 times the retention time of venlafaxine
System suitability
Sample: System suitability solution
[NOTE-The relative retention times for venlafaxine related compound A and venlafaxine are 0.9 and 1.0, respectively.]
Suitability requirements
Resolution: NLT 1.5 between venlafaxine related compound A and venlafaxine
Tailing factor: NMT 2.0 for venlafaxine
Relative standard deviation: NMT 5.0% for venlafaxine
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Capsules taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) ×100
rU = peak response of each individual impurity from the Sample solution
rS = peak response of venlafaxine from the Standard solution
CS = concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
CU = nominal concentration of venlafaxine in the Sample solution (mg/mL)
Mr1 = molecular weight of venlafaxine, 277.40
Mr2 = molecular weight of venlafaxine hydrochloride, 313.86
Acceptance criteria
Individual impurities: NMT 0.2%
Total impurities: NMT 0.5%
6 ADDITIONAL REQUIREMENTS
PACKAGING AND STORAGE: Preserve in well-closed 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 7 is not used.
USP REFERENCE STANDARDS (11)
USP Venlafaxine Hydrochloride RS
USP Venlafaxine Related Compound A RS
1-(1-(4-Methoxyphenyl)-2-(methylamino) ethyl) cyclohexanol hydrochloride.
C16H25NO2 · HCI 299.84
