Paroxetine Hydrochloride
(par ox' e teen hye'' droe klor' ide).
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365.83Piperidine, 3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-, hydrochloride, (3S-trans)-.
(
)-(3S,4R)-4-(p-Fluorophenyl)-3-[(3,4-methylenedioxy)phenoxy]methyl]piperidine hydrochloride
[78246-49-8].Hemihydrate 374.83
» Paroxetine Hydrochloride is anhydrous or contains one-half molecule of water of hydration. It contains not less than 98.5 percent and not more than 102.0 percent of C19H20FNO3·HCl, calculated on the anhydrous and solvent-free basis.
Packaging and storage—
Preserve the anhydrous form in tight containers. Preserve the hemihydrate form in well-closed containers. Store at controlled room temperature.
Labeling—
Label it to indicate whether it is the anhydrous or the hemihydrate form. Label it to indicate with which impurity tests the article complies.
USP Reference standards 
11
—
11—
USP Paroxetine Hydrochloride RS 
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USP Paroxetine System Suitability Mixture A RS
Mixture of approximately 1% paroxetine related compound A piperidine, 3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-methoxyphenyl)-, hydrochloride (3 S-trans); and 1% of paroxetine related compound B [piperidine, 3-[(1,3-benzodioxol-5-yloxy)methyl]-4-phenyl)-, hydrochloride (3 S-trans)] in a matrix of paroxetine hydrochloride.
Mixture of approximately 1% paroxetine related compound A piperidine, 3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-methoxyphenyl)-, hydrochloride (3 S-trans); and 1% of paroxetine related compound B [piperidine, 3-[(1,3-benzodioxol-5-yloxy)methyl]-4-phenyl)-, hydrochloride (3 S-trans)] in a matrix of paroxetine hydrochloride.
USP Paroxetine Related Compound B RS
trans-4-Phenyl-3-[(3,4-methylenedioxy)phenoxy]methylpiperidine hydrochloride.
trans-4-Phenyl-3-[(3,4-methylenedioxy)phenoxy]methylpiperidine hydrochloride.
USP Paroxetine Related Compound C RS
(+)-trans-Paroxetine hydrochloride.
(+)-trans-Paroxetine hydrochloride.
USP Paroxetine Related Compound E Mixture RS
Paroxetine hydrochloride spiked with 1-methyl-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine.
Paroxetine hydrochloride spiked with 1-methyl-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine.
USP Paroxetine Related Compound F RS
trans(–)-1-Methyl-3-[1,3-benzodioxol-5-yloxy)methyl]-4-(fluorophenyl)piperidine.
C20H22FNO3 343.39
trans(–)-1-Methyl-3-[1,3-benzodioxol-5-yloxy)methyl]-4-(fluorophenyl)piperidine.
C20H22FNO3 343.39
USP Paroxetine Related Compound G RS
(±)trans-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4¢¢-fluorophenyl-4¢-phenyl)piperidine hydrochloride.
C25H24FNO3 405.46
(±)trans-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4¢¢-fluorophenyl-4¢-phenyl)piperidine hydrochloride.
C25H24FNO3 405.46
Identification—
A:
Infrared Absorption 197M—
197M—
Test specimen—
Dissolve a suitable portion of Paroxetine Hydrochloride in a solution of water in isopropyl alcohol (1 in 10), heat to 70
to dissolve, recrystallize, and dry the residue under vacuum at 50 for 3 hours.
to dissolve, recrystallize, and dry the residue under vacuum at 50 for 3 hours.
Standard specimen:
a similar preparation of USP Paroxetine Hydrochloride RS.
B:
A solution (1 in 100) in a mixture of methanol and water (1:1) meets the requirements of the test for Chloride 191.
191.
Water, Method I 921:
not more than 1.5% for the anhydrous form and between 2.2% and 2.8% for the hemihydrate form.
921:
not more than 1.5% for the anhydrous form and between 2.2% and 2.8% for the hemihydrate form.
Residue on ignition 281:
not more than 0.1%.
281:
not more than 0.1%.
Heavy metals, Method II 231:
0.002%.
231:
0.002%.
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).
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 0.1 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 10.0% for the paroxetine related compound C.
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 10.0% 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:
100(CS / CT)(rU / rS)
in which CS is the concentration, in mg per mL, of USP Paroxetine Related Compound C RS in the Standard solution; CT is the concentration, in mg per mL, of Paroxetine Hydrochloride on the anhydrous basis in the Test solution; and rU 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.
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 1000 mL, and mix. Adjust with phosphoric acid or triethylamine to a pH of 2.0.
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).
621).
Standard solution—
Dissolve an accurately weighed quantity of USP Paroxetine Related Compound E Mixture 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, and 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.
Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the retention time of 1-methyl-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine relative to paroxetine is about 0.6; and the relative standard deviation for three replicate injections is not more than 15.0% for the 1-methyl-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine peak.
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 |
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:
100(CS / CT)(ri / rS)I
in which CS is the concentration, in mg per mL, of USP Paroxetine Related Compound E Mixture RS in the Standard solution; CT is the concentration, in mg per mL, of Paroxetine Hydrochloride on the anhydrous basis in the Test solution; 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; and I is the fraction, by weight, of 1-methyl-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine in USP Paroxetine Related Compound E Mixture RS: not more than 0.0001% of 1-methyl-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine is found.
Chromatographic purity—
[note—On the basis of the synthetic route, perform either Test 1 or Test 2. Test 2 is recommended if paroxetine related compound F or paroxetine related compound G is a potential related compound. ]
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).
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 System Suitability Mixture A RS in Diluent to obtain a solution having a known concentration of about 1 mg per mL.
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.
Chromatograph the System suitability solution, record the peak responses as directed for Procedure, and identify the peaks using the relative retention time values given in Table 1: 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.
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 |
Table 1
| Related Compound | Relative Retention Time |
Limit (%) |
|---|---|---|
| Paroxetine related compound A1 | 0.66 | 0.1 |
| Paroxetine related compound B2 | 0.73 | 0.3 |
| Paroxetine2 | 1.0 | — |
| Any unspecified impurity | — | 0.1 |
| Total impurities | — | 1.0 |
|
1
[Piperidine,3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-methoxyphenyl)-, hydrochloride (3 S-trans).
2
trans-4-Phenyl-3-[(3,4--methylenedioxy)phenoxy]methylpiperidine hydrochloride.
|
||
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:
100(CS / CT)(rU / rS)
in which CS is the concentration, in mg per mL, of USP Paroxetine Hydrochloride RS in the Standard solution; CT is the concentration, in mg per mL, of Paroxetine Hydrochloride on the anhydrous basis in 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.
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).
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.
Identification 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 to obtain a solution having known concentrations of about 2 mg 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.
Chromatograph the Identification solution, record the peak responses as directed for Procedure, and identify the peaks using the relative retention time values given in Table 2. 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.
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 |
Table 2
| Related Compound | Relative Retention Time | Limit (%) |
|---|---|---|
| Paroxetine related compound B1 | 0.91 | 0.5 |
| Paroxetine related compound F2 | 0.96 | 0.2 |
| Paroxetine | 1.0 | — |
| Paroxetine related compound G3 | 1.34 | 0.2 |
| Any unspecified impurity | — | 0.1 |
| Total impurities | — | 1.0 |
|
1
[trans-4-Phenyl-3-[(3,4-methylenedioxy)phenoxy]methylpiperidine hydrochloride.
2
[trans(–)-1-Methyl-3-[1,3-benzodioxol-5-yloxy)methyl]-4-(fluorophenyl)piperidine].
3
(±)trans-3-[(1,3-Benzodioxol-5-yloxy(methyl]-4-(4¢¢-fluorophenyl-4¢-phenyl)piperidine hydrochloride].
|
||
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:
100(CS / CT)(ri / rS)
in which CS is the concentration, in mg per mL, of the appropriate USP Reference Standard in the Standard solution; CT is the concentration, in mg per mL, of Paroxetine Hydrochloride on the anhydrous basis in the Test solution; and ri and rS are the peak areas for the corresponding impurity in the Test solution and the Standard solution, respectively. Calculate the percentage of any unspecified impurity in the portion of Paroxetine Hydrochloride taken by using the formula given above, in which ri is the peak area for any unspecified impurity in the Test solution; and rS is the peak area of paroxetine in the Standard solution.
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 (70:30:1). [note—The Acetate buffer–acetonitrile–triethylamine ratio can be varied between 70:40:1 and 75:25:1 to meet the system suitability requirements. ] Adjust with glacial acetic acid to a pH of 5.5. Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
System suitability solution—
Dissolve suitable quantities of USP Paroxetine Related Compound B RS and USP Paroxetine Hydrochloride RS in water to obtain a solution having known concentrations of about 0.5 mg of each USP Reference Standard per mL.
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 resolution, R, between paroxetine related compound B and paroxetine is not less than 2.0; the tailing factor for the paroxetine peak is not more than 2.0; and the relative standard deviation for replicate injections is not more than 2.0%. [note—For information purposes, the approximate relative retention times are about 0.9 for paroxetine related compound B and 1.0 for paroxetine. ]
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 resolution, R, between paroxetine related compound B and paroxetine is not less than 2.0; the tailing factor for the paroxetine peak is not more than 2.0; and the relative standard deviation for replicate injections is not more than 2.0%. [note—For information purposes, the approximate relative retention times are about 0.9 for paroxetine related compound B and 1.0 for paroxetine. ]
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 percentage of C19H20FNO3·HCl in the portion of Paroxetine Hydrochloride taken by the formula:
100(CS / CU)(rU / rS)
in which CS is the concentration, in mg per mL, of paroxetine hydrochloride in the Standard preparation; CU is the nominal concentration, in mg per mL, of Paroxetine Hydrochloride in the Assay preparation; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Hariram Ramanathan, M.S.
Associate Scientific Liaison 1-301-816-8313 |
(SM42010) Monographs - Small Molecules 4 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4224
Pharmacopeial Forum: Volume No. 33(5) Page 932