Crystalline Fenofibrate Research Articles

Melt-extruded formulations of fenofibrate with various grades of hydrogenated phospholipid exhibit promising in-vitro biopharmaceutical behavior

In the current study, it was demonstrated that three commercially available grades of hydrogenated phospholipids (HPL) differing in their content of phosphatidylcholine may be used as components for hot melt-extruded binary (HPL as sole excipient) or ternary (in combination with copovidone) solid dispersions of fenofibrate (FEN) at mass fractions between 0.5 and 20% (ternary) or 80% (binary). X-ray powder diffraction indicated complete conversion of crystalline fenofibrate into the amorphous state by hot melt extrusion for all ternary blends. In contrast, both the binary blends (HPL- and copovidone-based) contained minor remaining crystallites. Irrespectively, all solid dispersions induced during dissolution studies a supersaturated state of FEN, where the ternary ASDs showed enhanced and more complete release of FEN as compared to the binary blends and, even more pronounced, in comparison to the marketed micronized and nano-milled formulations. In terms of the cumulated amount permeated, there were marginal differences between the various formulations when combined dissolution/permeation was done using FeSSIF as donor medium; with FaSSIF as donor medium, the binary HPL-ASD containing the grade with the highest phosphatidylcholine fraction performed best in terms of permeation, even significantly better than the marketed nano-crystal formulation. Otherwise, no significant differences were seen between the various grades of HPL when FEN dissolution and permeation were analyzed for ternary solid dispersions. In conclusion, the in-vitro biopharmaceutical behaviour of hydrogenated phospholipid-containing blends manufactured by hot melt extrusion appears promising. They can be a viable formulation option for poorly water-soluble and lipophilic drug compounds like FEN.

Quantitative Measures of Crystalline Fenofibrate in Amorphous Solid Dispersion Formulations by X-Ray Microscopy

In the pharmaceutical industry, amorphous solid dispersion can be utilized to enhance the solubility, hence bioavailability, of poorly solubility active pharmaceutical ingredients owing to the higher free energy of the amorphous state. Measuring the concentration, size and spatial distribution of crystalline API particles that may be present in amorphous solid dispersions (ASD) is critical to understanding product performance and developing improved formulations. In this study X-Ray Microscopy (XRM) was used to nondestructively measure these attributes in ASDs. Model tablets of amorphous fenofibrate in a copovidone matrix spiked with known concentrations of crystalline fenofibrate were examined by XRM to measure the concentration, size and distribution of crystalline particles in the tablets. Data collection and analysis conditions were evaluated and reported. XRM images showed contrast between the crystalline API and the amorphous matrix of the tablet. Image analysis using basic thresholding provided quantitative and distribution data of the crystallinity present. Crystals as small as 10 μm were detected and practical quantitation limits of 0.2% (w/w of total tablet) crystallinity were demonstrated. The aspects of manual data thresholding were tested for operator influence and threshold selection and found to be robust. This technique was demonstrated to provide quantitative measures of crystallinity below standard X-Ray Powder Diffraction (XRPD) techniques, provide three-dimensional information regarding size, shape and distribution of API crystals and can be performed nondestructively.

Immediate-released pelletized solid dispersion containing fenofibrate: Formulation, in vitro characterization, and bioequivalence studies in experimental beagle dogs.

There have been many strategies to increase solubility, dissolution rates, and oral bioavailability of fenofibrate such as micronization, nanonization, solid dispersion, and emulsion so far. To our knowledge, only first three technologies have been applied in producing marketed products, and no combination of solid dispersion and pellet has been found even in laboratory-based reports. Therefore, the aim of this study was to develop novel solid dispersion-based pellets via an one-step process directly from fenofibrate powder using layering method. Developed fenofibrate pellets were in vitro characterized on size distribution, dissolution rates, sensory evaluation and stability. In addition, the transformation from crystalline fenofibrate to amorphous fenofibrate, and intermolecular interactions of fenofibrate in solid dispersion were confirmed using physico-chemical methods. The dissolution rate of pellets containing fenofibrate was significantly higher than that of the reference, Lipanthyl® 160 mg tablets at early stage, satisfying the criteria in USP 38. The pellets, then, were packed in hard capsules for bioequivalence studies in experimental beagle dogs using a validated HPLC assay. Final findings of the present study should be beneficial for further development of new fenofibrate formulations containing solid dispersion-based pellets which were bioequivalent to Lipanthyl® 160 mg tablets.

FORMULATION AND CHARACTERIZATION OF HPMC AND HPMCAS BASED SOLID DISPERSIONS OF FENOFIBRATE: A COMPARATIVE STUDY

Objective: The aim of the present study was to investigate the effect of novel polymeric carriers and to develop solid dispersion formulation that could improve in vitro profile of Fenofibrate (FB).
 Methods: Spray drying technique was used to fabricate solid dispersions with hydrophilic carriers, mainly hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Solid dispersions in the form of spray-dried powder were characterized with respect to the pure drug and the corresponding physical mixtures by optical microscopy, x-ray diffraction (XRD), fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC). Size and morphology of optimized solid dispersion were performed by scanning electron microscopy (SEM). Furthermore, in vitro dissolution comparisons were carried out between the optimized solid dispersion against the pure drug and the physical mixtures.
 Results: Solubility studies demonstrated that the solubility of FB was not affected by pH change. The transformation of crystalline FB into an amorphous solid dispersion powder has been clearly demonstrated by optical microscopy. The molecular dispersion of drug in the dispersion matrix prepared by spray drying was confirmed in XRD and DSC studies. IR spectroscopy was observed with negligible incompatibility of the drug with polymers. Spherical morphology was observed in SEM with no evidence of FB crystals. The prepared solid dispersions exhibited dissolution improvement as compared to the pure drug and spray dried FB in 0.05 M SLS, with HPMCAS as the superior carrier over HPMC.
 Conclusion: The present study vouches better in vitro profile of FB from spray-dried HPMCAS based solid dispersions.

Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate.

Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed. Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency. The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation.

In Vivo Precipitation of Poorly Soluble Drugs from Lipid-Based Drug Delivery Systems.

Precipitation of poorly water-soluble drugs from lipid-based drug delivery systems (LbDDS) has been studied extensively during in vitro lipolysis but has never been shown in vivo. The aim of this study was therefore to investigate if drug precipitation can occur from LbDDS during transit of the gastrointestinal tract in vivo. Rats were administered 300 μL of either of two LbDDS (LbDDS I and LbDDS II) loaded with danazol or fenofibrate (or paracetamol to assess gastric emptying). The rats were euthanized at various time points after administration of both LbDDS containing either drug, and the contents of the stomach and proximal part of the small intestine were harvested. The contents were analyzed for crystalline drug by X-ray powder diffraction and polarized light microscopy. No drug precipitation was evident in the stomach or the intestine after administration of LbDDS I containing danazol at the tested time points. Fenofibrate precipitation was absent in the stomach initially after administration of LbDDS I, but was evident in the stomach 90 min after dosing. No crystalline fenofibrate was observed in the intestine. Danazol and fenofibrate precipitation was evident in the stomach following administration of LbDDS II containing either drug, but not in the intestine at the tested time point. Drug precipitation from LbDDS was observed in the stomach, but not in the intestine, which is contrary to what in vitro lipolysis data (obtained under human GI conditions) suggests. Thus, precipitation of drugs from LbDDS in vivo in rats is much lower than might be anticipated from in vitro lipolysis data.

A New Low Melting-Point Polymorph of Fenofibrate Prepared via Talc Induced Heterogeneous Nucleation

Fenofibrate is one of the most commonly prescribed hyperlipidemia agents. Despite its high lipophilicity and ultralow aqueous solubility, most commercially available formulations use micronized crystalline fenofibrate form I, which has a low dissolution rate and poor oral bioavailability. Little is known about the crystallization of other polymorphs from supercooled amorphous fenofibrate. This study reports a new fenofibrate polymorph (form III) obtained via a controlled heterogeneous nucleation method using low quantity (1% w/w) of the generally recognized as safe (GRAS) oral pharmaceutical excipient talc. Form III has a low melting point of 50 °C, and crystallization of form I immediately occurs after the melting of form III. The microscopic, thermal, and spectroscopic characterizations of form III confirmed the distinct molecular packing difference between the new form and other known forms. The discovery of this new form will enrich the understanding of the molecular behavior of fenofibrate and bring ...

Characterization of Physicochemical Properties of Spray-dried Solid Dispersions Loaded with Unmodified Crystalline Fenofibrate

Characterization of Physicochemical Properties of Spray-dried Solid Dispersions Loaded with Unmodified Crystalline Fenofibrate

A comparative study on the effects of amphiphilic and hydrophilic polymers on the release profiles of a poorly water-soluble drug

This paper reports the use of two crystalline polymers, an amphiphilic Pluronic® F-127 (PF-127) and a hydrophilic poly(ethylene glycol) (PEG6000) as drug delivery carriers for improving the drug release of a poorly water-soluble drug, fenofibrate (FEN), via micelle formation and formation of a solid dispersion (SD). In 10% PF-127 (aq.), FEN showed an equilibrium solubility of ca. 0.6 mg/mL, due to micelle formation. In contrast, in 10% PEG6000 (aq.), FEN only exhibited an equilibrium solubility of 0.0037 mg/mL. FEN-loaded micelles in PF-127 were prepared by direct dissolution and membrane dialysis. Both methods only yielded a highest drug loading (DL) of 0.5%. SDs of FEN in PF-127 and PEG6000, at DLs of 5–80%, were prepared by solvent evaporation. In-vitro dissolution testing showed that both micelles and SDs significantly improved FEN’s release rate. The SDs of FEN in PF-127 showed significantly faster release than crystalline FEN, when the DL was as high as 50%, whereas SDs of PEG6000 showed similar enhancement in the release rate when the DL was not more than 20%. The DSC thermograms of SDs of PF-127 exhibited a single phase transition peak at ca. 55–57 °C when the DL was not more than 50%, whereas those in PEG6000 exhibited a similar peak at ca. 61–63 °C when the DL was not more than 35%. When the DL exceeded 50% for SDs of PF-127 and 35% for SDs of PEG6000, DSC thermograms showed two melting peaks for the carrier polymer and FEN, respectively. FT-IR studies revealed that PF-127 has a stronger hydrophobic–hydrophobic interaction with FEN than PEG6000. It is likely that both dispersion and micelle formation contributed to the stronger effect of PF-127 on enhancing the release rate of FEN in its SDs.

Continuous and sustainable granulation of nanopharmaceuticals by spray coagulation encapsulation in alginate

Nanopharmaceuticals (NPs) have emerged as an attractive formulation strategy for bioavailability enhancement of poorly soluble drugs. Their oral solid dosage form preparation requires them to undergo granulation before they can be processed into tablets. Existing NP granulation methods (e.g., spray drying, spray granulation), however, are lacking in sustainability due to their high energy expense and low mass efficiency. Herein we developed a one-step continuous NP granulation process via encapsulation by spray coagulation (ESC) in alginate, which transforms the NP immediately upon their preparation, thus removing the need for NP recovery prior to granulation, resulting in a highly sustainable process. Moreover, unlike spray-dried NP granules, the ESC-prepared granules are readily compacted into tablets owed to their larger size, thus further enhancing the overall sustainability of the solid dosage form preparation. Crystalline fenofibrate nanoparticles prepared by confined impinging jet crystallization were used as the model NP. Granules containing 25% NPs by mass with size ≈300±100μm were successfully prepared at >80% yield. The NPs maintain their fast dissolution (relative to native microcrystalline fenofibrate) after granulation. The tableted NP granules, having uniform dosage, exhibit similar drug release profiles as the free granules indicating complete granule disassociation from the tablets.

Solidification of nanostructured lipid carriers (NLCs) onto pellets by fluid-bed coating: Preparation, in vitro characterization and bioavailability in dogs

There are demands to solidify nanoparticle suspensions to overcome problems associated with liquid formulations. In the present study, the liquid nanostructured lipid carriers (NLCs), which were comprised of Precirol ATO 5, Captex100, Tween-80 and fenofibrate as the model drug, was prepared by the melting-emulsification method and converted to solidified NLC pellets by fluid-bed coating technique. To achieve good coating, polyvinylpyrrolidone K17 was used as the coating polymer to entrap the NLCs. Physical characterization indicated good appearance and confirmed nonexistence of crystalline fenofibrate in the solidified NLC pellets. More than 90% NLCs could be released from the solidified NLC pellets within 15min. The reconstituted NLCs had spherical morphology similar to the original NLCs, but had an average particle size of 227.5nm which was significantly larger than 94.1nm of the original ones. However, both solidified NLC pellets and original NLC suspension showed similar in vitro lipolysis profiles and similar pharmacokinetics parameters in beagle dogs. Results indicated that fluid-bed coating could be a useful tool for the solidification of NLC suspension.

Preparation of fenofibrate solid dispersion using electrospray deposition and improvement in oral absorption by instantaneous post-heating of the formulation

A coaxial electrospray technique was applied to a poorly soluble drug, fenofibrate (FEN), to increase its bioavailability. A particulate core-shell solid dispersion was designed using poly(methacrylic acid-co-methyl methacrylate) (Eudragit L-100) as a shell material and poly(vinyl pyrrolidone) K12-17 as a dispersant for FEN in the core phase. Although 58% of FEN remained in the crystalline state in the electrosprayed formulation, the dissolution behavior was significantly improved due to decrease in particle size, decrease in crystallinity, and increase in dispersion efficiency. The formulation was subjected to post-heating at 100 °C for 30 s to transform the remaining crystals into the amorphous state to further improve the dissolution behavior. Oral bioavailability was also on the order of: heated formulation>intact formulation>crystalline FEN. Instantaneous heating significantly improved the performance of the formulation despite its simple procedure, and thus can be a powerful step to be incorporated in the formulation manufacturing process.