title: Validation and application of a stability-indicating HPLC method for the in vitro determination of gastric and intestinal stability of venlafaxine.
abstract: Gastrointestinal stability of venlafaxine was evaluated in vitro in simulated gastric (SGF) and intestinal (SIF) fluids using a stability indicating HPLC method. The method was validated using a 5 microm Ascentis C18 column (150 mm x 4.6 mm) and mobile phase consisting of 30% acetonitrile in 20 mM potassium phosphate buffer (pH 6.5) delivered isocratically at a flow rate of 1 mL/min with UV detection at 228 nm. Venlafaxine in USP simulated gastric and intestinal fluids (0.4 mg/mL) was incubated at 37 degrees C in a shaking water bath. The gastric stability study samples were assayed at 0, 15, 30 and 60 min intervals while sampling for the intestinal stability study was at 0, 1, 2 and 3 h. System suitability determinations gave R.S.D.s of 0.68, 0.5 and 3.9% for retention factor (k'), peak area and tailing factor, respectively. The method was shown to be accurate, precise, specific, and linear over the analytical range. Intra- and inter-day precision was <5.3%. Forced degradation studies of drug substance in basic media at 70 degrees C as well as in H2O2 for 1 h and ultra-violet photostability studies at 255 and 365 nm for 24 h did not produce any detectable degradation products. Forced degradation studies of drug substance in acidic media at 70 degrees C for 1 h produced the dehydro-venlafaxine degradant. Venlafaxine was stable in SGF (pH approximately 1.2) for the 1-h incubation period and in SIF (pH 6.8) up to 3 h with <1.5% relative difference (RD) between the amount of drug added and that found for all time points. This stability experiment in simulated gastric and intestinal fluids suggests that drug loss in the gastrointestinal tract takes place by membrane permeation rather than a degradation process.
authors.affiliation: Division of Product Quality Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, United States.
authors.forename: Ebenezer B
authors.initials: EB
authors.lastname: Asafu-Adjaye
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Faustino
authors.forename: Mobin A
authors.initials: MA
authors.lastname: Tawakkul
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Anderson
authors.forename: Lawrence X
authors.initials: LX
authors.lastname: Yu
authors.forename: Hyojong
authors.initials: H
authors.lastname: Kwon
authors.forename: Donna A
authors.initials: DA
authors.lastname: Volpe
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000032:analysis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003511:Cyclohexanols / Q000032:analysis* / Q000737:chemistry; D004355:Drug Stability; D041981:Gastrointestinal Tract / Q000737:chemistry*; D006358:Hot Temperature; D006851:Hydrochloric Acid / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000737:chemistry*; D015394:Molecular Structure; D010194:Pancreatin / Q000737:chemistry; D010434:Pepsin A / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D017680:Potassium Compounds / Q000737:chemistry; D015203:Reproducibility of Results; D012972:Sodium Hydroxide / Q000737:chemistry; D013552:Swine; D013997:Time Factors; D000069470:Venlafaxine Hydrochloride; D014867:Water / Q000737:chemistry
chemical_list: D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D010710:Phosphates; D017680:Potassium Compounds; D014867:Water; D012972:Sodium Hydroxide; D000069470:Venlafaxine Hydrochloride; D010194:Pancreatin; C013216:potassium phosphate; D010434:Pepsin A; D006851:Hydrochloric Acid