Duloxetine Hydrochloride(doo lox' e teen hye'' droe klor' ide).C18H19NOS ·HCl 333.882-Thiophenepropanamine, N-methyl--(1-naphthalenyloxy)-, hydrochloride, (S)-; (+)-(S)-N-Methyl--(1-naphthyloxy)-2-thiophenepropylamine hydrochloride[136434-34-9].DEFINITIONDuloxetine Hydrochloride contains NLT 97.0% and NMT 102.0% of C18H19NOS ·HCl, calculated on the dried basis.IDENTIFICATIONChange to read:• A. Infrared Absorption 197K (ERR 1-Jul-2012)• B. The retention time of the major peak in the Sample solution correspondsto that of the duloxetine S-isomer from the System suitability solution in the test for Limit of Duloxetine Related Compound A.Change to read:• C. Identification Tests —General, Chloride 191Sample solution: 5 mg/mL in methanolAcceptance criteria: Meets the requirements (ERR 1-Jul-2012)ASSAY• ProcedureProtect solutions of duloxetine from light.Buffer: 2.9 g/L of phosphoric acid in water. Adjust with sodium hydroxide solution to a pH of 2.5. To each L of this solution add 10.3 g of sodium 1-hexanesulfonate monohydrate, and dissolve.Mobile phase: Acetonitrile, n-propanol, and Buffer (13:17:70)Diluent: Acetonitrile and water (25:75)ClickSystem suitability solution: 0.2 mg/mL of USP Duloxetine Hydrochloride RS in Mobile phase. Heat the solution to at least 40for a minimum of 1 h.[Note —The resulting solution contains duloxetine impurity B, duloxetine impurity C, duloxetine impurity D, duloxetine impurity E, and duloxetine related compound F. ] Standard solution: 0.1 mg/mL of USP Duloxetine Hydrochloride RS in DiluentSample solution: 0.1 mg/mL of Duloxetine Hydrochloride in DiluentChromatographic system(See Chromatography 621, System Suitability .)Mode: LCDetector: UV 230 nmColumn: 4.6-mm × 15-cm; 3.5-µm packing L7Column temperature: 40 ± 3Flow rate: 1 mL/minInjection size: 10 µLRun time: 2 times the retention time of duloxetineSystem suitabilitySample: System suitability solution[Note —See Table 1 for relative retention times. ]Suitability requirements Resolution: NLT 1.5 between duloxetine and duloxetine relatedcompound F peaksTailing factor: NMT 1.5 for the duloxetine peakRelative standard deviation: NMT 1.0% for the duloxetine peakAnalysisSamples: Standard solution and Sample solutionCalculate the percentage of duloxetine hydrochloride (C18H19NOS ·HCl) in the portion of sample taken:Result = (rU/rS) × (CS/CU) × 100Acceptance criteria: 97.0%–102.0% on the dried basisIMPURITIES• Heavy Metals, Method II 231: NMT 10 ppm• Residue On Ignition281: NMT 0.2% rU =peak response from the SamplesolutionrS =peak response from the StandardsolutionCS =concentration of USP DuloxetineHydrochloride RS in the Standardsolution (mg/mL)CU =concentration of DuloxetineHydrochloride in the Sample solution(mg/mL)• Organic ImpuritiesProtect solutions of duloxetine from light.Buffer, Mobile phase, Diluent, and System suitability solution: Proceed as directed in the Assay.Sensitivity solution: 0.2 µg/mL of USP Duloxetine Hydrochloride RS in DiluentSample solution: 0.2 mg/mL of Duloxetine Hydrochloride in DiluentChromatographic system: Proceed as directed in the AssayRun time: 2.4 times the retention time of duloxetineSystem suitabilitySamples: System suitability solution and Sensitivity solution[Note —See Table 1 for relative retention times. ]Suitability requirementsResolution: NLT 1.5 between duloxetine impurity C and duloxetineimpurity D; NLT 1.5 between duloxetine and duloxetine relatedcompound F, System suitability solutionTailing factor: NMT 1.5 for the duloxetine peak, System suitabilitysolutionRelative standard deviation: NMT 1.0% for the duloxetine peak, System suitability solutionSignal-to-noise ratio: NLT 20 for the duloxetine peak, Sensitivity solution AnalysisSample: Sample solutionCalculate the percentage of any individual impurity in the portion ofDuloxetine Hydrochloride taken:Result = (rU/rT) × (1/F) × 100Acceptance criteria: See Table 1. Table 1 rU =peak response of each impurity fromthe Sample solutionrT =sum of the responses of all the peaksfrom the Sample solutionF =relative response factor (see Table 1)Name Relative Retention TmeRelative Response Factor AcceptanceCriteriaNMT (%)Duloxetine impurity B a ,g 0.150.36—Duloxetine impurity C b ,g0.43 1.0—Duloxetine impurity D c ,g0.48 1.8—Duloxetine impurity E d ,g0.74 1.0—Duloxetine 1.0——• Limit of Duloxetine Related Compound AMobile phase: Hexane and isopropyl alcohol (83:17). To 1 L of this mixture add 2 mL of diethylamine.System suitability solution: 0.1 mg/mL each of USP DuloxetineHydrochloride RS and USP Duloxetine Related Compound A RS inMobile phase. Sonication may be used to aid in dissolution.Sensitivity solution: 0.1 µg/mL of USP Duloxetine Hydrochloride RS in Mobile phaseSample solution: 0.1 mg/mL of Duloxetine Hydrochloride in Mobile phase.Sonication may be used to aid in dissolution.Chromatographic system (See Chromatography 621, System Suitability .)Mode: LCDetector: UV 230 nmColumn: 4.6-mm × 25-cm; 5-µm packing L40Column temperature: 40Flow rate: 1 mL/minInjection size: 10 µLRun time: 2 times the retention time of duloxetineSystem suitabilitySamples: Sensitivity solution and System suitability solution[Note —The relative retention times for duloxetine and duloxetine related compound A are 1.0 and 1.3, respectively. ]Suitability requirementsResolution: NLT 3.5 between duloxetine and duloxetine relatedcompound A, System suitability solutionTailing: Between 0.8 and 1.5 each for duloxetine and duloxetine related compound A peaks, System suitability solutionRelative standard deviation: NMT 5.0% for the duloxetine peak, System suitability solutionSignal-to-noise ratio: NLT 3, Sensitivity solutionAnalysisDuloxetine related compound F e 1.1 1.00.5Duloxetine impurity G f ,g 1.40.51—Any individual unspecified impurity — 1.00.1Total impurities——0.6a 3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol.b 4-[3-(Methylamino)-1-(thiophen-2-yl)propyl]naphthalen-1-ol.c Naphthalen-1-ol.d 1-(3-(Methylamino)-1-(thiophen-2-yl)propyl)naphthalen-2-ol.e (S)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-3-yl)propan-1-amine.f 1-Fluoronaphthalene.g Controlled at Any individual unspecified impurity level.Sample: Sample solutionCalculate the percentage of duloxetine related compound A in the portion of Duloxetine Hydrochloride taken:Result = (rU/rT) × 100Acceptance criteria: NMT 0.5%SPECIFIC TESTS• Loss On Drying 731: Dry at 105 for 3 h: it loses NMT 0.5% of its weight. ADDITIONAL REQUIREMENTS• Packaging And Storage: Protect from light. Store at room temperature. • USP Reference Standards 11:USP Duloxetine Hydrochloride RSUSP Duloxetine Related Compound A RS(R)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine hydrochloride.C18H19NOS ·HCl 333.88Auxiliary Information — Please check for your question in the FAQs before contactingUSP. USP36–NF31 Page 3354Pharmacopeial Forum: Volume No. 37(4)Chromatographic Column —DULOXETINE HYDROCHLORIDEChromatographic columns text is not derived from, and not part of, USP 36 or NF 31.rU =peak response for duloxetine relatedcompound A from the SamplesolutionrT =sum of the responses of duloxetineand duloxetine related compound Apeaks from the Sample solutionTopic/Question Contact Expert CommitteeMonograph Heather R. Joyce, Ph.D. Associate Scientific Liaison1-301-918-8442(SM42010) Monographs - SmallMolecules 4Reference Standards RS Technical Services1-301-816-8129rstech@。