Limit of related compound C—
Mobile phase—
Prepare a mixture of
n-hexane, absolute alcohol, water, and trifluoroacetic acid (900:100:2:2). Make adjustments if necessary (see
System Suitability under
Chromatography 
621
).
Diluent:
a mixture of absolute alcohol and n-hexane (1:1).
Standard solution—
Dissolve an accurately weighed quantity of
USP Paroxetine Related Compound C RS, and dilute quantitatively, and stepwise if necessary, with
Diluent to obtain a solution having a known concentration of about 1 mg per mL.
Test solution—
Transfer about 125 mg of Paroxetine Hydrochloride, accurately weighed, to a 25-mL volumetric flask, dissolve in and dilute with Diluent to volume, and mix.
System suitability solution—
Dilute known volumes of the
Test solution and the
Standard solution with
Diluent to obtain a solution having known concentrations of about 0.1 mg per mL each of Paroxetine Hydrochloride and of
USP Paroxetine Related Compound C RS.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 295-nm detector and a 4.6-mm × 25-cm column that contains packing L51. The flow rate is about 1.0 mL per minute, and the column temperature is maintained at 30
. Chromatograph the
System suitability solution, and record the peak responses as directed for
Procedure: the relative retention times for paroxetine and paroxetine related compound C are 1.0 and about 0.6, respectively; the resolution,
R, between paroxetine and paroxetine related compound C is not less than 2.0; and the tailing factor for paroxetine related compound C is not greater than 2.5. Chromatograph the
Standard solution, and record the peak responses as directed for
Procedure: the relative standard deviation for replicate injections is not more than 2.0% for the paroxetine related compound C.
Procedure—
Separately inject equal volumes (about 5 µL) of the
Standard solution and the
Test solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the percentage of paroxetine related compound C in the portion of Paroxetine Hydrochloride taken by the formula:
2500(C/W)(ri / rS)
in which
C is the concentration, in mg per mL, of
USP Paroxetine Related Compound C RS in the
Standard solution; W is the weight, in mg, of Paroxetine Hydrochloride, on the anhydrous basis, used to prepare the
Test solution; and
ri and
rS are the peak areas for paroxetine related compound C in the
Test solution and the
Standard solution, respectively: not more than 0.1% of paroxetine related compound C is found.
Change to read:
Limit of 1-methyl-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine—
Solution A—
Dissolve about 30 g of sodium perchlorate in about 900 mL of water. Add 3.5 mL of phosphoric acid and 2.4 mL of triethylamine. Dilute with water to volume, and mix. Adjust with phosphoric acid or triethylamine to a pH of 2.0. Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Solution B:
acetonitrile, filtered and degassed.
Diluent:
a mixture of water and acetonitrile (4:1).
Mobile phase—
Use variable mixtures of
Solution A and
Solution B as directed for
Chromatographic system. Make adjustments to either solution as necessary (see
System Suitability under
Chromatography 621).
Standard solution—
Dissolve an accurately weighed quantity of USP Paroxetine Hydrochloride Related Compound E RS, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 42 ng per mL of 1-methyl-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine.
Test solution—
Transfer about 420 mg of Paroxetine Hydrochloride, accurately weighed, to a 10-mL volumetric flask, dissolve in about 7 mL of Diluent with sonication. Dilute with Diluent to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 242-nm detector and a 4.0-mm × 25-cm column that contains packing L1. The column temperature is maintained at 30
. The flow rate is about 1.5 mL per minute. The chromatograph is programmed as follows.
Time
(minutes) |
Solution A
(%) |
Solution B
(%) |
 Elution |
| 0 |
85 |
15 |
equilibration |
| 0–20 |
85®80 |
15®20 |
linear gradient |
| 20–27 |
80®55 |
20®45 |
linear gradient |
| 27–36 |
55 |
45 |
isocratic |
| 36–38 |
55®85 |
45®15 |
linear gradient |
| 38–45 |
85 |
15 |
re-equilibration |
Chromatograph the
Standard solution, and record the peak responses as directed for
Procedure: the relative retention times are 0.6 for 1-methyl-4-(
p-fluorophenyl)-1,2,3,6-tetrahydropyridine and 1.0 for paroxetine; and the relative standard deviation for replicate injections is not more than 15.0% for the 1-methyl-4-(
p-fluorophenyl)-1,2,3,6-tetrahydropyridine peak.
Procedure—
Separately inject equal volumes (about 75 µL) of the
Standard solution and the
Test solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the percentage of 1-methyl-4-(
p-fluorophenyl)-1,2,3,6-tetrahydropyridine in the portion of Paroxetine Hydrochloride taken by the formula:
1000(CI/W)(ri / rS)
in which
C is the concentration, in mg per mL, of USP Paroxetine Hydrochloride Related Compound E RS in the
Standard solution; I is the fraction, by weight, of 1-methyl-4-(
p-fluorophenyl)-1,2,3,6-tetrahydropyridine in USP Paroxetine Hydrochloride Related Compound E RS;
W is the weight, in mg, of Paroxetine Hydrochloride, on the anhydrous basis, used to prepare the
Test solution; and
ri and
rS are the peak areas for 1-methyl-4-(
p-fluorophenyl)-1,2,3,6-tetrahydropyridine obtained from the
Test solution and the
Standard solution, respectively: not more than 0.0001% of 1-methyl-4-(
p-fluorophenyl)-1,2,3,6-tetrahydropyridine is found.
USP29
Change to read:
Chromatographic purity—
[NOTE—Perform all related impurities methods unless the manufacturer has assurance, based on knowledge of the manufacturing process, that one of the tests is not relevant to their material.
]
TEST 1—
Solution A—
Prepare a filtered and degassed mixture of water, tetrahydrofuran, and trifluoroacetic acid (180:20:1).
Solution B—
Prepare a filtered and degassed mixture of acetonitrile, tetrahydrofuran, and trifluoroacetic acid (180:20:1).
Mobile phase—
Use variable mixtures of
Solution A and
Solution B as directed for
Chromatographic system. Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Diluent:
a mixture of water and tetrahydrofuran (9:1).
Standard solution—
Dissolve an accurately weighed quantity of
USP Paroxetine Hydrochloride RS, and dilute quantitatively, and stepwise if necessary, with
Diluent to obtain a solution having a known concentration of about 1 µg per mL.
System suitability solution—
Dissolve, by sonication if necessary, a suitable quantity of USP Paroxetine Hydrochloride for System Suitability RS in
Diluent to obtain a solution having a known concentration of about 1 mg per mL.
USP29
Test solution—
Transfer about 25 mg of Paroxetine Hydrochloride, accurately weighed, to a 25-mL volumetric flask, dissolve in 20 mL of Diluent, sonicate, dilute with Diluent to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 285-nm detector and a 4.6-mm × 25-cm column that contains packing L7. The flow rate is about 1 mL per minute. The column temperature is maintained at 40
. The chromatograph is programmed as follows.
Time
(minutes) |
Solution A
(%) |
Solution B
(%) |
Elution |
| 0 |
80 |
20 |
equilibration |
| 0–30 |
80 |
20 |
isocratic |
| 30–50 |
80®20 |
20®80 |
linear gradient |
| 50–60 |
20 |
80 |
isocratic |
| 60–70 |
20®80 |
80®20 |
linear gradient |
Chromatograph the
System suitability solution, and record the peak responses as directed for
Procedure: the relative retention times are about
0.66 for paroxetine related compound A, 0.73 for paroxetine related compound B, and 1.0 for paroxetine;
USP29 the resolution,
R, between paroxetine related compound A and paroxetine related compound B is not less than 2.0; the tailing factor of the paroxetine related compound A peak is between 0.8 and 2.0; and the relative standard deviation for replicate injections is not more than 2.0% for paroxetine related compound A.
Procedure—
Separately inject equal volumes (about 20 µL) of the
Standard solution, the
Test solution, and the
Diluent into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the percentage of each impurity in the portion of Paroxetine Hydrochloride taken by the formula:
2500(C/W)(rU / rS)
in which
C is the concentration, in mg per mL, of
USP Paroxetine Hydrochloride RS in the
Standard solution; W is the weight, in mg, of Paroxetine Hydrochloride, on the anhydrous basis, used to prepare the
Test solution; rU is the peak area of each impurity in the
Test solution, excluding the peaks obtained from the chromatogram of the
Diluent; and
rS is the peak area of paroxetine obtained from the
Standard solution: not more than 0.3% of any peak at a retention time of paroxetine related compound B is found; not more than 0.1% of any other individual impurity is found; and not more than 1.0% of total impurities is found.
TEST 2—
Phosphate buffer—
Dissolve 3.4 g of monobasic potassium phosphate and 3.4 g of tetrabutylammonium hydrogen sulfate in 1.0 L of water.
Solution A—
Prepare a filtered and degassed mixture of Phosphate buffer and acetonitrile (98:2).
Solution B—
Prepare a filtered and degassed mixture of Phosphate buffer and acetonitrile (6:4).
Mobile phase—
Use variable mixtures of
Solution A and
Solution B as directed for
Chromatographic system. Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Diluent:
a mixture of Phosphate buffer and acetonitrile (9:1).
Standard solution—
Dissolve an accurately weighed quantity of
USP Paroxetine Hydrochloride RS,
USP Paroxetine Related Compound B RS,
USP Paroxetine Related Compound F RS, and
USP Paroxetine Related Compound G RS in
Diluent, and dilute quantitatively, and stepwise if necessary, with
Diluent to obtain a solution having known concentrations of about 4 µg per mL, 10 µg per mL, 10 µg per mL, and 4 µg per mL, respectively.
Test solution—
Transfer about 25 mg of Paroxetine Hydrochloride, accurately weighed, to a 50-mL volumetric flask, dissolve in and dilute with Diluent to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 210-nm detector and a 3.9-mm × 15-cm column that contains packing L1. The flow rate is about 1.0 mL per minute. The chromatograph is programmed as follows.
Time
(minutes) |
Solution A
(%) |
Solution B
(%) |
Elution |
| 0 |
100 |
0 |
equilibration |
| 0–5 |
100 |
0 |
isocratic |
| 5–70 |
100®40 |
0®60 |
linear gradient |
| 70–90 |
40®0 |
60®100 |
linear gradient |
| 90–95 |
0 |
100 |
isocratic |
| 95–95.1 |
0®100 |
100®0 |
linear gradient |
| 95.1–110 |
100 |
0 |
re-equilibration |
Chromatograph the
Identification solution, and record the peak responses as directed for
Procedure: the relative retention times are about 0.91 for paroxetine related compound B, about 0.96 for paroxetine related compound F, 1.0 for paroxetine, and about 1.34 for paroxetine related compound G. Chromatograph the
Standard solution, and record the peak responses as directed for
Procedure: the relative standard deviation for replicate injections is not more than 10.0% for the paroxetine related compound B, paroxetine related compound F, paroxetine hydrochloride, and paroxetine related compound G peaks.
Procedure—
Separately inject equal volumes (about 25 µL) of the
Standard solution and the
Test solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the percentage of paroxetine related compound B, paroxetine related compound F, and paroxetine related compound G in the portion of Paroxetine Hydrochloride taken by the formula:
5000(C/W)(ri / rS)
in which
C is the concentration, in mg per mL, of the appropriate USP Reference Standard in the
Standard solution; W is the weight, in mg, of Paroxetine Hydrochloride, on the anhydrous basis, used to prepare the
Test solution; and
ri and
rS are the peak areas for the corresponding impurity in the
Test solution and the
Standard solution, respectively: not more than 0.5% of paroxetine related compound B is found; not more than 0.2% of paroxetine related compound F is found; and not more than 0.2% of paroxetine related compound G is found. Calculate the percentage of any unknown impurity in the portion of Paroxetine Hydrochloride taken by the formula:
5000(C/W)(ri / rS)
in which
C is the concentration, in mg per mL, of
USP Paroxetine Hydrochloride RS in the
Standard solution; W is the weight, in mg, of Paroxetine Hydrochloride, on the anhydrous basis, used to prepare the
Test solution; ri is the peak area for any unknown impurity in the
Test solution; and
rS is the peak area of paroxetine in the
Standard solution: not more than 0.1% of any single unknown impurity is found, and not more than 1.0% of total impurities is found.
Assay—
Acetate buffer—
Prepare a 0.05 M solution of ammonium acetate in water, adjust with glacial acetic acid to a pH of 4.5, mix, and filter.
Mobile phase—
Prepare a filtered and degassed mixture of
Acetate buffer, acetonitrile, and triethylamine (60:40:1). Adjust with glacial acetic acid to a pH of 5.5. Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Standard preparation—
Dissolve an accurately weighed quantity of
USP Paroxetine Hydrochloride RS in water, and dilute quantitatively, and stepwise if necessary, with water to obtain a solution having a known concentration of about 0.5 mg per mL.
Assay preparation—
Transfer about 50 mg of Paroxetine Hydrochloride, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with water to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 295-nm detector and a 4.6-mm × 25-cm column that contains packing L13. The flow rate is about 1 mL per minute. Chromatograph the
System suitability solution, and record the peak responses as directed for
Procedure: the relative retention times are about 0.9 for paroxetine related compound B and 1.0 for paroxetine; the resolution,
R, between paroxetine related compound B and paroxetine is not less than 2.0; the column efficiency determined from the paroxetine peak is not less than 3000 theoretical plates; the tailing factor for the paroxetine peak is not more than 1.6; and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 10 µL) of the
Standard preparation and the
Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of C
19H
20FNO
3·HCl in the portion of Paroxetine Hydrochloride taken by the formula:
100C(rU / rS)
in which
C is the concentration, in mg per mL, of
USP Paroxetine Hydrochloride RS in the
Standard preparation; and
rU and
rS are the peak responses obtained from the
Assay preparation and the
Standard preparation, respectively.
;)
)-(3S,4R)-4-(p-Fluorophenyl)-3-[(3,4-methylenedioxy)phenoxy]methyl]piperidine hydrochloride