Theoretical investigation of functionalized fullerene nano carrier drug delivery of fluoxetine

In recent years, fullerene nanoparticles have received extensive attention due to their unique physical and chemical properties. Properly modified fullerene nanoparticles have excellent biocompatibility and significant anti-tumor activity and anti-depression, which makes them have broad application prospects in the field of cancer anti-depression. The present study used the density functional theory (DFT) calculations to perform a theoretical examination of the interaction of fluoxetine (F) as medicine with the functionalized fullerene O and NO (F–O and F–NO surface in gas phase physiological media. According to DFT calculations, adsorption energies were ?3396.6350645, ?3540.2952907, ?6778.526894, and ?6952.251487 kJ for F/P complexes (fullerene O and NO (F–O and F–NO surface) respectively, proposing the possibility of the adsorption process of F molecule onto the fullerene surface concerning the energetic perspective. Calculations of electronic parameters aimed at determining the molecule's reactivity. Bandgap of F–O and F–NO were 0.03715, 0.04328 respectively, by this value we can recognize the reactivity of complexes.     

Spectrophotometric Quantitation of Fluoxetine Hydrochloride Using Benzoyl Peroxide and Potassium Iodide

 Fluoxetine hydrochloride reacts with benzoyl peroxide and potassium iodide, after heating for 1 min at 30 °C, to give a blue colour having maximum absorbance at 570 nm. The reaction is selective for fluoxetine with 0.01 mg/mL as visual limit of quantitation and provides a basis for a new spectrophotometric determination. The colour reaction obeys Beer’s law from 0.1 mg/10 mL to 2.0 mg/10 mL of fluoxetine and the relative standard deviation is 0.68%. The qualitative assessment of tolerable amounts of other drugs is also studied. Received September 21, 1998. Revision September 10, 1999.     

Biocatalytic synthesis towards both antipodes of 3-hydroxy-3-phenylpropanitrile a precursor to fluoxetine, atomoxetine and nisoxetine

The bakers’ yeast reduction of 3-oxo-3-phenylpropanenitrile (1) has been difficult to achieve due to a dominant alkylating mechanism. A library of 20 bakers’ yeast reductases, that are overexpressed in Escherichia coli, were screened against (1). Four enzymes were found to reduce this substrate and by varying the enzyme both enantiomers of 3-hydroxy-3-phenylpropanitrile (2) could be prepared with a high enantiomeric excess. In addition, the Escherichia coli whole-cell system can be optimized to nearly eliminate the competing alkylating mechanism. By using this system, a formal biocatalytic synthesis of both antipodes of fluoxetine, atomoxetine and nisoxetine has been demonstrated.     

Chiral selectors for enantioresolution and quantitation of the antidepressant drug fluoxetine in pharmaceutical formulations by (19)F NMR spectroscopic method

¹⁹F NMR spectroscopy was applied to the quantitative determination of fluoxetine enantiomers using different chiral recognition agents in pharmaceutical formulations. Several parameters affecting the enantioresolution including the type and concentration of chiral selector, concentration of fluoxetine and temperature were studied. The chiral selectors investigated are the cyclic oligosaccharides α-, β- and γ-cyclodextrin and a diamino derivative of methylated α-cyclodextrin (DAM-α-CD), linear polysaccharides (maltodextrin with dextrose equivalents of 4.0-7.0, 13.0-17.0 and 16.5-19.5) and the macrocyclic antibiotic vancomycin. Among the chiral selectors used, DAM-α-CD turned out to give the best resolution of the ¹⁹F NMR signals of (R)- and (S)-fluoxetine. The calibration curve was linear for (R)- and (S)-fluoxetine over the range 0.10-1.35 mg mL⁻¹, the detection limits (S/N = 3) being 5.9 and 7.5 μg mL⁻¹ for the pure solutions of (R)- and (S)-fluoxetine, respectively. The recovery studies performed on pharmaceutical samples ranged from about 90 to 110% with relative standard deviations of <8%. The results showed that the proposed method is rapid, precise and accurate. Applying statistical Student's t-test revealed insignificant difference between the real and measured contents at the 95% confidence level.     

CAN-mediated oxidative cleavage of 4-aryl-3,4-dihydroxypiperidines

A CAN-mediated oxidative cleavage of 4-aryl-3,4-dihydroxypiperidines 2Aa-Be to β-amino carbonyl compounds 3Aa-Be and 4Aa-Be in different ratios is described. This facile strategy was also used to synthesize racemic fluoxetine (5).     

Batch and Flow Injection Fluorimetric Determination of Fluoxetine

Abstract

A method for the fluorimetric determination of fluoxetine in continuous and discontinuous systems is reported. The method is based on the hydrolysis of fluoxetine in acid medium. The fluorescent product has a spectrum with excitation and emission maxima at 253 and 306 nm, respectively. The method was applied to the determination of fluoxetine in pharmaceutical products.     

Determination of fluoxetine and norfluoxetine in rat brain microdialysis samples following intraperitoneal fluoxetine administration

Fluoxetine (FLX) and the N-desmethyl metabolite, norfluoxetine (NFLX) in rat brain microdialysis samples were determined by high-performance liquid chromatography (HPLC) with fluorescence detection using pre-column derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). In vitro experiment showed that the relative recovery of FLX across microdialysis membrane was enhanced by adding β-cyclodextrin (β-CD) or β-CD polymer to microdialysis perfusion fluid. The perfusion fluid containing β-CD polymer, which has polymeric glyceryl linkers attached to the hydroxyl group, gave the better recovery with satisfactory precisions. Using 1% β-CD polymer in Ringer’s solution as the perfusate, in vivo rat brain microdialysis experiment on intraperitoneal administration of FLX (10 mg/kg) to rats was carried out. The fluorescence peaks of FLX and NFLX appeared later than 30 min after the administration of FLX, and then, gradually increased with time. Two hours later, FLX reached a plateau level, but NFLX slowly increased, and at 24-48 h, NFLX levels were higher than FLX levels. These data suggest that long distributions of FLX and the potent metabolite, NFLX, in brain contributed to the long-term drug actions in vivo.     

Automated determination of venlafaxine in human plasma by on‐line SPE‐LC‐MS/MS. Application to a bioequivalence study

A new automated SPE‐LC‐ESI‐MS/MS method was developed and validated to quantify venlafaxine in human plasma using fluoxetine as an internal standard. The analytes were automatically extracted from plasma by C18 SPE cartridges, separated on a C8 RP column and analyzed by MS in the multiple reaction‐monitoring (MRM) mode. The method has a chromatographic run time of 4.0 min and a linear calibration curve over the range of 0.25–200 ng/mL (r >0.997). The between‐run precisions, based on the percent RSD for replicate quality controls (0.75; 80, and 200 ng/mL), were < 8.5% for all concentrations. The between‐run accuracies, based on the percent relative error, were < 4.0%. This method was successfully employed in a bioequivalence study of two venlafaxine capsule formulations (test formulation from Eurofarma (Brazil) and Efexor XR, reference formulation, from Wyeth‐Whitehall, Brazil) in 48 healthy volunteers of both sexes who received a single 150 mg dose of each formulation. More than 3000 samples were analyzed eliminating the analyst's exposure to hazardous organic solvents normally employed in off‐line liquid–liquid extractions. The 90% confidence interval (CI) of the individual ratio geometric mean for Test/Reference was 91.6–103.4% for AUC_{0–48 h} and 102.2–112.6% for C_max. Since both 90% CI for AUC_{0–48 h} and C_max were included in the 80–125% interval proposed by the US Food and Drug Administration (FDA) and the Brazilian National Health Surveillance Agency (ANVISA), the test formulation was considered bioequivalent to Efexor XR according to both the rate and extent of absorption.     

Development and validation method for determination of fluoxetine and its main metabolite norfluoxetine by nonaqueous capillary electrophoresis in human urine

A simple, rapid and sensitive procedure using nonaqueous capillary electrophoresis (NACE) to measure fluoxetine and its main metabolite norfluoxetine has been developed and validated. Optimum separation of fluoxetine and norfluoxetine, by measuring at 230 nm, was obtained on a 60 cm × 75 μm capillary using a nonaqueous solution system of 7:3 methanol-acetonitrile containing 15 mM ammonium acetate, capillary temperature and voltage 25 °C and 25 kV, respectively and hydrodynamic injection. Paroxetine was used as internal standard. Good results were obtained for different aspects including stability of the solutions, linearity, and precision. Detection limits of 10 μg L⁻¹ were obtained for fluoxetine and its metabolite. This method has been used to determine fluoxetine and it main metabolite at clinically relevant levels in human urine. Before NACE determination, the samples were purified and enriched by means of extraction-preconcentration step with a preconditioned C₁₈ cartridge and eluting the compounds with methanol.     

Optimization of alcohol‐assisted dispersive liquid–liquid microextraction by experimental design for the rapid determination of fluoxetine in biological samples

A sensitive and rapid method based on alcohol‐assisted dispersive liquid–liquid microextraction followed by high‐performance liquid chromatography for the determination of fluoxetine in human plasma and urine samples was developed. The effects of six parameters on the extraction recovery were investigated and optimized utilizing Plackett–Burman design and Box–Benken design, respectively. According to the Plackett–Burman design results, the volume of disperser solvent, extraction time, and stirring speed had no effect on the recovery of fluoxetine. The optimized conditions included a mixture of 172 μL of 1‐octanol as extraction solvent and 400 μL of methanol as disperser solvent, pH of 11.3 and 0% w/v of salt in the sample solution. Replicating the experiment in optimized condition for five times, gave the average extraction recoveries equal to 90.15%. The detection limit of fluoxetine in human plasma was obtained 3 ng/mL, and the linearity was in the range of 10–1200 ng/mL. The corresponding values for human urine were 4.2 ng/mL with the linearity range from 10 to 2000 ng/mL. Relative standard deviations for intra and inter day extraction of fluoxetine were less than 7% in five measurements. The developed method was successfully applied for the determination of fluoxetine in human plasma and urine samples.