Preparation of fenofibrate dry emulsion and dry suspension using octenyl succinic anhydride starch as emulsifying agent and solid carrier.

Purpose of this study was to investigate the ability of octenyl succinic anhydride (OSA) starch as emulsifier and solid carrier in dry emulsion (DE) and dry suspension (DS) formulations. Fenofibrate (FF) was loaded at lower and higher than its saturation concentration in oil phase to prepare the DE and DS by spray drying method. The DE and DS were successfully prepared with 36-48% and 46% production yield, respectively. After reconstitution in water, the emulsion with mean droplet size of 1-2 µm was obtained. Solid state characterization revealed the amorphous state of FF and the crystalline state of OSA starch in both DE and DS formulations. Both DE and DS enhanced FF dissolution rate compared to pure material and DS showed the highest dissolution rate. The DE and DS could be compressed to the tablets with acceptable disintegration time and without changeable dissolution profile. Moreover, the dissolution profiles of both DE and DS remained unchanged after 2 months storage at 40 °C.

Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of α-Oxo Acids.

The direct decarboxylative arylation of α-oxo acids has been achieved by synergistic visible-light-mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple α-oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate.

Media milling process optimization for manufacture of drug nanoparticles using design of experiments (DOE).

Design of experiments (DOE), a component of Quality by Design (QbD), is systematic and simultaneous evaluation of process variables to develop a product with predetermined quality attributes. This article presents a case study to understand the effects of process variables in a bead milling process used for manufacture of drug nanoparticles. Experiments were designed and results were computed according to a 3-factor, 3-level face-centered central composite design (CCD). The factors investigated were motor speed, pump speed and bead volume. Responses analyzed for evaluating these effects and interactions were milling time, particle size and process yield. Process validation batches were executed using the optimum process conditions obtained from software Design-Expert® to evaluate both the repeatability and reproducibility of bead milling technique. Milling time was optimized to <5 h to obtain the desired particle size (d90 < 400 nm). The desirability function used to optimize the response variables and observed responses were in agreement with experimental values. These results demonstrated the reliability of selected model for manufacture of drug nanoparticles with predictable quality attributes. The optimization of bead milling process variables by applying DOE resulted in considerable decrease in milling time to achieve the desired particle size. The study indicates the applicability of DOE approach to optimize critical process parameters in the manufacture of drug nanoparticles.

Preparation of concentrated stable fenofibrate suspensions via liquid antisolvent precipitation.

A major challenge in achieving size stability for relatively high concentration of fine particles from poorly water-soluble drug fenofibrate (FNB) is addressed through T-mixing based liquid antisolvent precipitation in the presence of ultrasonication and judicious use of stabilizers. Multiple stabilizers were screened in a batch mode prior to their continuous formation via T-mixing. In both cases, the stable suspensions maintained their size after 2 days of storage at room temperature, with the smallest particle size of d50: ∼1.2 µm was achieved through a combination of HPMC with SDS or PF-68. The influence of processing parameters, such as sonication energy, sonication probe insert depth and solvent/antisolvent flow rate, on the particle size distribution (PSD) in T-mixing were investigated, to identify optimum processing conditions. Optimal operating and formulation conditions also allowed increase in the drug loading from 0.32% to 4% (w/v), while keeping the median size 2.5 µm. Interestingly, the primary particles observed in the SEM were spherical and under 100 nm in diameter, indicating agglomeration. It was shown that the stabilized particles could be centrifuged and did not show size growth upon resuspension, allowing for increase in the drug loading up to 27% (w/v), which is a significant novel outcome.

An air-tolerant approach to the carbonylative Suzuki-Miyaura coupling: applications in isotope labeling.

Carbonylative Suzuki-Miyaura coupling conditions have been developed that proceed without the exclusion of oxygen and in the presence of nondegassed and nondried solvents. By adapting the method to a two-chamber setup, the direct handling of carbon monoxide, produced from stable CO precursors, is avoided. The protocol afforded the desired benzophenones with excellent functional group tolerance and in good yields. Substituting the CO precursor, in the CO-producing chamber, with its carbon-13 labeled version generated the corresponding carbon-13 labeled benzophenones. Finally, the developed system was applied in the synthesis and isotope labeling of two pharmaceuticals, nordazepam and Tricor.

Synthesis of highly water-soluble fibrate derivatives via BGLation.

Three water-soluble fibrates (fenofibrate, bezafibrate and chlofibrate) conjugated with a symmetrically branched glyceryl trimer (BGL003) were synthesized, and an evaluation of the fenofibrate-BGL003 conjugate as a candidate for anti-hyperlipemia drug was carried out using rats. The water-solubility of the fenofibrate-BGL003 conjugate was several thousand times greater than that of the original fenofibrate. The lipid-lowering effects of the fenofibrate-BGL003 conjugate were as strong as those of the same grams of fenofibrate. The actual active species of fenofibrate, fenofibric acid, was detected in rats' blood, but neither the fenofibrate-BGL003 conjugate nor fenofibrate was detected, probably due to enzymatic hydrolysis of the ester bond. The plasma concentration of fenofibric acid derived from the fenofibrate-BGL003 conjugate was five times higher than that derived from fenofibrate 4h after administration.

Synthesis and biological evaluation of orally active hypolipidemic agents.

A series of novel fenofibric acid ester prodrugs 1c-1h were synthesized and evaluated with the aim of obtaining potent hypolipidemic agents. Prodrugs 1c and 1d exhibited potent hypochlolesterolemic activity, lowering the mice plasma triglyceride level up to 47% in Swiss albino mice after oral administration of 50 mg/kg/day for 8 days. Fenofibric acid ester prodrugs 1c-1h were found lipophilic like fenofibrate (1b), indicated by partition coefficients measured in octanol-buffer system at pH 7.4. On the basis of in vivo studies, prodrugs 1c and 1d emerged as potent hypolipidemic agents.

In vitro and in vivo evaluation of fenofibrate solid dispersion prepared by hot-melt extrusion.

OBJECTIVE: This article aimed to develop fenofibrate solid dispersion with high bioavailability using hot-melt extrusion and compare the difference of Eudragit E100 and polyvinylpyrrolidone-vinyl acetate copolymer S630 (PVP-VA) in dissolution. METHODS: Solid dispersion with carrier of Eudragit E100 or PVP-VA was prepared by hot-melt extrusion and then characterized by differential scanning calorimetry (DSC), X-ray diffraction, in vitro dissolution test, and in vivo bioavailability study. RESULTS: Fenofibrate exited as noncrystal state in these two kinds of solid dispersions that can be proved by DSC and X-ray diffraction. Eudragit E100 1:2 solid dispersion has the dissolution of 84% and 65% at 60 minutes in 0.1M HCl and water, respectively. Eudragit E100 1:4 solid dispersion has lower dissolution in 0.1M HCl and higher dissolution in water; the values are 73.6% and 87.3%. PVP-VA 1:2 solid dispersion has the dissolution of 60% and 65% at 60 minutes in 0.1M HCl and water, respectively. PVP-VA 1:4 solid dispersion has higher dissolution in 0.1M HCl and lower dissolution in water; the values are 64% and 53%. The different dissolution of fenofibrate from the two polymers is because of their different solubility and gelling tendency. When Eudragit E100 1:4 solid dispersion was administrated to beagle dogs, its relative bioavailability to micronization Lipanthyl capsule was 177.1%. CONCLUSION: Hot-melt extrusion is an excellent method to improve the dissolution and therefore the bioavailability of fenofibrate.

Preparation of fenofibrate nanosuspension and study of its pharmacokinetic behavior in rats.

BACKGROUND: In this study, nanosuspension was prepared to improve the dissolution rate and bioavailability of lipophilic fenofibrate. METHOD: Melt emulsification method combined with high-pressure homogenization was adapted, and mixture of poloxamer188 and PVP K30 were selected as surfactants. This method consumed less energy and was more efficient than traditional homogenization of drug solid particles suspension directly. RESULTS: The dissolution rate of fenofibrate nanosuspension was increased obviously, and the product was evaluated by pharmacokinetic characteristic in rats. The AUC(0-36 h) and C(max) of nanosuspensions were increased when compared with the reference formulations. No significant differences were found between the two nanosuspensions A and B, of which the mean particle sizes were 356 and 194 nm, respectively. Therefore, nanosuspensions may be a suitable delivery system to improve the bioavailability of those drugs with poor water solubility.

[Fenofibrate: chemical development and differences with clofibrate (author's transl)]. / Le fénofibrate: présentation chimique. Différences avec le clofibrate.

Since its discovery by Thorp and Waring in 1962, the clofibrate molecule has undergone various modifications. The all-important phenoxy-2-methyl-2-propionic acid chain was preserved, but it seemed reasonable to try and improve pharmacological activity by substituting for the Cl atom a group with different hydrophobic profile. However, none of the phenylketone derivatives produced had satisfactory antilipaemic properties, except for the benzoyl derivative. Grafting on this derivative a Cl atom in position 4 by an original method based on a vinylogy principle, and esterifying with propanol-2 yielded the most active and best tolerated compound: fenofibrate. Fenofibrate resembles clofibrate in that it has the same phenoxy-2-methyl-2-propionic chain but differs from it by the way electrons are distributed, by its lipophilia and by its supple structure, the mobile carbon links between the two rings allowing for spatial changes and facilitating adaptation to receptors. The strong individuality of the molecule is undoubtedly responsible for the significant pharmacokinetic and pharmacological differences between fenofibrate and clofibrate.