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[Display omitted] This study aimed to investigate the amorphous stabilization of BCS Class II drugs using mesoporous silica as a carrier to produce amorphous solid dispersions. Ibuprofen, fenofibrate, and budesonide were selected as model drugs to evaluate the impact of molecular weight and partition coefficient on the solid state of drug-loaded mesoporous silica (MS) particles. The model drugs were loaded into three grades of MS, SYLYSIA SY730, SYLYSIA SY430, and SYLYSIA SY350, with pore diameters of 2.5 nm, 17 nm, and 21 nm, respectively, at 1:1, 2:1, and 3:1, carrier to drug ratios, and three different loading concentrations using solvent immersion and spray drying techniques. Differential scanning calorimetry (DSC) thermograms of SY430 and SY350 samples exhibited melting point depressions indicating constricted crystallization inside the pores, whereas SY730 samples with melting points matching the pure API may be a result of surface crystallization. Powder x-ray diffraction (PXRD) diffractograms showed all crystalline samples matched the diffraction patterns of the pure API indicating no polymorphic transitions and all 3:1 ratio samples exhibited amorphous halo profiles. Response surface regression analysis and Classification and Regression Tree (CART) analysis suggest carrier to drug ratios, followed by molecular weight, have the most significant impact on the crystallinity of a drug loaded into MS particles. [ABSTRACT FROM AUTHOR]

[Display omitted] Fenofibrate has shown therapeutic effects on diabetic retinopathy. However, fenofibrate can be rapidly cleared from the eye after a single intravitreal injection. Here, we aim to develop fenofibrate loaded PLGA microparticles (Feno-MP) with high drug loading and sustained in vitro release up to 6 months suitable for intravitreal injection. First, orthogonal array experimental design was applied for formulation optimization. The selected formulation parameters were used to formulate Feno-MP using homogenization method and direct membrane emulsification method. Both methods generated Feno-MP with high drug loading and sustained in vitro drug release more than 140 days. Unlike the polydisperse Feno-MP prepared using homogenization method, membrane emulsification method generated Feno-MP with uniform size distribution. By controlling the membrane pore size, 1.5 µm, 8 µm and 16 µm Feno-MP were formulated and we found that larger Feno-MP demonstrated higher drug loading, more sustained drug release in vitro with less burst drug release than the smaller Feno-MP. In conclusion, we developed Feno-MP with high drug loading and sustained release profile, and elucidated that changing the particle size could have notable impacts on drug loading and release kinetics. Formulating Feno-MP with uniform size distribution by membrane emulsification method would benefit the batch-to-batch repeatability. [ABSTRACT FROM AUTHOR]

The purpose of this study was to improve solubility and oral bioavailability of fenofibrate via solid dispersion (SD) using a supercritical anti-solvent (SAS) process with amphipathic polymers P407 and TPGS. Solid dispersion techniques have been widely used to enhance the solubility and dissolution profiles of poorly soluble drugs. Fenofibrate is classified as a Biopharmaceutics Classification System class II compound because of its low solubility and high gastrointestinal permeability. Two copolymers were selected based on solubility and dissolution tests. Their physicochemical properties were compared with those prepared by conventional solvent evaporation (CSE). The SD formulations containing fenofibrate were successfully prepared using the SAS and CSE methods. The dissolution rate (%) of fenofibrate at 60 min was significantly improved compared with the solution of raw fenofibrate (19.5% ± 3.7%) by 95.1% ± 2.5% and 93.7% ± 4.1% using the SAS and the CSE process, respectively. This approximately four-fold increase in dissolution rate indicates that oral bioavailability can be enhanced. In addition, pharmacokinetic study was analyzed using the area under the curve (AUC) and C max values of SAS-SD and CSE-SD in rats. The AUC was 2.1 times higher and C max was 1.9 times higher in SAS-SD, indicating higher concentrations of fenofibrate in the blood. In a pharmacodynamic study to evaluate the efficacy of the drug in hyperlipidemic rat models, SAS-SD showed strong lipid-lowering effects including cholesterol (1.9-fold) and triglycerides (3.3-fold), than CSE-SD. Taken together, these results suggested that SAS-SD has excellent potential as a formulation for the poorly soluble drug fenofibrate. [ABSTRACT FROM AUTHOR]

[Display omitted] Amorphous solid dispersions (ASD) represent a viable formulation strategy to improve dissolution and bioavailability of poorly soluble drugs. Our study aimed to evaluate the feasibility and potential role of hydrogenated phospholipid (HPL) as a matrix material and solubilizing additive for binary (alone) or ternary (in combination with polymers) solid dispersions, using fenofibrate (FEN) as the model drug. FEN, incorporated within ASDs by melting or freeze-drying (up to 20% m/m), stayed amorphous during short-term stability studies. The solubility enhancing potential of HPL depended on the dissolution medium. In terms of enhancing in vitro permeation, solid dispersions with HPL were found equally or slightly more potent as compared to the polymer-based ASD. For studied ASD, in vitro permeation was found substantially enhanced as compared to a suspension of crystalline FEN and at least equal compared to marketed formulations under comparable conditions (literature data). Additionally, while the permeation of neat FEN and FEN in binary solid dispersions was affected by the dissolution medium (i.e., the "prandial state"), for ternary solid dispersions the permeation was independent of the "prandial state" (FaSSIF = FeSSIF). This suggests that ternary solid dispersions containing both polymer and HPL may represent a viable formulation strategy to mitigate fenofibrate's food effect. [ABSTRACT FROM AUTHOR]

We present the absorption improvement mechanism of fenofibrate (FFB), a Biopharmaceutics Classification System (BCS) class II drug, from self-microemulsifying drug delivery systems (SMEDDS), centered on improving the diffusion of FFB through the unstirred water layer (UWL). Four SMEDDS formulations containing Labrafac™ lipophile WL 1349 (WL1349) or Labrafil ® M 1944CS (M1944) oils and NIKKOL HCO-40 (HCO40) or NIKKOL HCO-60 (HCO60) surfactants were prepared. Every SMEDDS formulation formed microemulsion droplets of approximately 30 nm. In vitro tests showed that the microemulsion droplets containing M1944 had relatively small FFB solubilization capacities, causing larger amounts of FFB to be dissolved in the bulk water phase, compared to the droplets containing WL1349. The diffusivity of the microemulsion droplets through the mucin solution layer was enhanced when using HCO40 compared to HCO60. The oral absorption in rats was the highest when using the SMEDDS formulation containing M1944 and HCO40. High FFB distribution in the bulk water phase and fast diffusion of microemulsion droplets through the mucus layer contributed to the efficient delivery of FFB molecules through the UWL to the epithelial cells, leading to enhanced FFB absorption. [ABSTRACT FROM AUTHOR]

Amongst other strategies for the formulation of poorly water-soluble drugs, solubilization of these drugs in lipid-based formulations is a promising option. Most screening methods for the identification of a suitable lipid-based formulation fail to elucidate the role interfacial effects play for drug solubility in disperse systems. In a novel screening approach called passive drug loading, different preformed lipid nanocarrier dispersions are incubated with drug powder. Afterwards, undissolved drug is filtered off and the amount of solubilized drug is determined. The aim of this study was to identify parameters for drug solubility in pure lipids as well as for drug loading to the lipid-water interface of lipid nanoparticles. Using passive loading, the solubility of eight poorly water-soluble drugs in seven lipid nanocarriers varying in particle size or lipid matrix was investigated. Drug solubility in the nanocarriers did not follow any apparent trend and different drugs dissolved best in different carriers. Drugs with a melting point below approximately 150 °C displayed distinctly better solubility than higher melting drugs. Additionally, relating the specific lipid nanocarrier surface area to the drug solubility allowed drawing conclusions on the drug localization. Fenofibrate, dibucaine and, less distinctly also clotrimazole, which all melt below 150 °C, were predominantly located in the lipid droplet core of the nanoparticles. In contrast, the five remaining drugs (betamethasone valerate, flufenamic acid, itraconazole, ketoconazole, mefenamic acid) were also located at the lipid-water interface to different, but substantial degrees. The ability to account for drug loading to the lipid-water interface is thus a major advantage of passive loading. [ABSTRACT FROM AUTHOR]

The goal of this work was to compare fenofibrate (FEN)-containing self-micellizing solid dispersion (SmSD) and non-self-micellizing solid dispersion (NsSD) systems. Exploration of underlying mechanisms to improve FEN dissolution/solubility profiles was conducted to understand the enhanced therapeutic potential. SmSD and NsSD of FEN systems (SmSD/FEN and NsSD/FEN) were fabricated using a fuse-quench cooling method. The self-micellizing Soluplus ® cloud point was then determined experimentally and FEN phase solubility was measured in solutions containing self-micellizing Soluplus ® or non-self-micellizing polymers. Physicochemical characteristics of SmSD/FEN and NsSD/FEN were evaluated using microscopic morphology, amorphous state, thermal performance, dissolution and solubility profiles. FEN exhibited an amorphous state in SmSD/FEN but was not completely amorphous in NsSD/FEN. The dissolution and solubility profile of SmSD/FEN achieved about 1.2- to 2-fold improvement over that of NsSD/FEN. Consequently, relatively enhanced hypolipidemic efficacy in vivo was observed in SmSD/FEN vs NsSD/FEN, as measured by serum levels of total cholesterol (TC), total triglycerides (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Compared with non-self-micellizing polymers, self-micellizing Soluplus ® significantly inhibited FEN crystal growth from a supersaturated state. However, no obvious difference in intermolecular interactions was observed between SmSD/FEN and NsSD/FEN systems. Overall, the SmSD approach exhibited as trengthened dissolution effect, enhancing FEN hyperlipidemic disease therapy efficacy. [ABSTRACT FROM AUTHOR]

The objective of the current study is the formulation development and manufacturing of solid self-emulsifying drug delivery systems (HME S-SEDDS) via a single-step continuous hot-melt extrusion (HME) process. For this study, poorly soluble fenofibrate was selected as a model drug. From the results of pre-formulation studies, Compritol® HD5 ATO, Gelucire® 48/16, and Capmul® GMO-50 were selected as oil, surfactant and co-surfactant respectively for manufacturing of HME S-SEDDS. Neusilin® US2 was selected as a solid carrier. The design of experiments (response surface methodology) was employed to prepare formulations via a continuous HME process. The formulations were evaluated for emulsifying properties, crystallinity, stability, flow properties and drug release characteristics. The prepared HME S-SEDDS showed excellent flow properties, and the resultant emulsions were stable. The globule size of the optimized formulation was 269.6 nm. The DSC and XRD studies revealed the amorphous nature of the formulation and FTIR studies showed no significant interaction between fenofibrate and excipients. The drug release studies showed significant (p < 0.05) improvement in solubility compared to the pure drug (DE 15  = 45.04 for the optimized formulation), as >90% of drug release was observed within 15 min. The stability studies for the optimized formulation were conducted for 3 months at 40 °C/75% RH., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The objective of the present study was to confirm the usefulness of BioGIT data in the evaluation of the impact of dose and/or formulation on early exposure after oral administration of immediate release or enabling products of low solubility active pharmaceutical ingredients (APIs) with a glass of water in the fasted state. BioGIT experiments were performed with four APIs: Compound Α (tablet, three dose levels), Compound E (capsule PiC1, capsule PiC2 and tablet), fenofibrate (Lipidil® capsule and Lipidil 145 ONE® tablet) and Compound F (HP-β-CD aqueous solution and tablet). Based on mean plasma AUC 0-60min values which became available after completion of the BioGIT experiments, mean BioGIT AUC 0-50min values were useful for the evaluation of the impact of dose and/or formulation on early exposure. The log-transformed ratios of mean BioGIT AUC 0-50min values for two doses and/or two formulations estimated in this study and in a recent study for two diclofenac potassium products (Cataflam® tablet and Voltfast® sachet, same dose) vs. the corresponding log-transformed ratios of mean plasma AUC 0-60min values (n = 7 pairs of ratios), were included in a previously established correlation between log-transformed ratios of mean BioGIT AUC 0-50min values and log-transformed ratios of plasma AUC 0-60min values (n = 9 pairs of ratios). The correlation between log-transformed plasma AUC 0-60min ratios vs. log-transformed BioGIT AUC 0-50min ratios was confirmed (n = 16 pairs of ratios, R = 0.90). Compared with the previously established correlation the statistical characteristics were improved. Based on this study, the BioGIT system could be useful as a screening tool for assessing the impact of dose and/or formulation differences on early exposure, after administration of immediate release or enabling drug products of low solubility APIs with a glass of water in the fasted state, on an a priori basis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The purpose of this study was to develop a high drug loading hollow mesoporous silica nanoparticles (HMS) and apply for regulation insoluble drug release. HMS was synthesized using hard template phenolic resin nanoparticles with the aid of cetyltrimethyl ammonium bromide (CTAB), which was simple and inexpensive. To compare the difference between normal mesoporous silica (NMS) and hollow mesoporous silica in drug loading efficiency, drug release behavior and solid state, NMS was also prepared by soft template method. Transmission electron microscopy (TEM), specific surface area analysis, FT-IR and zeta potential were employed to characterize the morphology structure and physicochemical property of these carriers. The insoluble drugs, carvedilol and fenofibrate(Car and Fen), were chosen as the model drug to be loaded into HMS and NMS. We also chose methylene blue (MB) as a basic dye to estimate the adsorption ability of these carriers from macroscopic and microscopic view, and the drug-loaded carriers were systematically studied by differential scanning calorimetry (DSC), X-ray diffraction (XRD) and UV-vis spectrophotometry. What’ more, the in vivo process of HMS was also study by confocal microscopy and in vivo fluorescence imaging. In order to confirm the gastrointestinal safety of HMS, the pathological examination of stomach and intestine also be evaluated. HMS allowed a higher drug loading than NMS and exhibited a relative sustained release curve, while NMS was immediate-release. And the effect of preventing drugs crystallization was weaker than NMS. As for in vivo process, HMS was cleared relatively rapidly from the mouse gastrointestinal and barely uptake by intestinal epithelial cell in this study due to its large particle size. And the damage of HMS to gastrointestinal could be ignored. This study provided a simple method to obtain high drug loading and regulation insoluble drug release, expanded the application of inorganic carriers in drug delivery system and pharmaceutic adjuvant. [ABSTRACT FROM AUTHOR]

The objective of the present study was to develop a one-step process for the production of tablets directly from primary powder by means of injection molding (IM), to create solid-dispersion based tablets. Fenofibrate was used as the model API, a polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol graft co-polymer served as a matrix system. Formulations were injection-molded into tablets using state-of-the-art IM equipment. The resulting tablets were physico-chemically characterized and the drug release kinetics and mechanism were determined. Comparison tablets were produced, either directly from powder or from pre-processed pellets prepared via hot melt extrusion (HME). The content of the model drug in the formulations was 10% (w/w), 20% (w/w) and 30% (w/w), respectively. After 120 min, both powder-based and pellet-based injection-molded tablets exhibited a drug release of 60% independent of the processing route. Content uniformity analysis demonstrated that the model drug was homogeneously distributed. Moreover, analysis of single dose uniformity also revealed geometric drug homogeneity between tablets of one shot. [ABSTRACT FROM AUTHOR]

Low oral bioavailability can be circumvented by the formulation of the poorly water soluble drug in ordered mesoporous silica (OMS-L-7). Fenofibrate is an orally administered, poorly water-soluble active pharmaceutical ingredient (API), used clinically to lower lipid levels. Fenofibrate was loaded into silica using two methods: incipient wetness and supercritical impregnation. This study investigates the impact of loading and the impact of varying supercritical carbon dioxide (scCO 2 ) processing conditions. The objective is to enhance Fenofibrate loading into silica while reducing degree of the drug crystallinity, so as to increase the drug's dissolution rate and its bioavailability. The comparison of both impregnation processes was made in terms of impregnation yields and duration as well as physical characterization of the drug. While incipient wetness method led to a Fenofibrate loading up to 300 mg drug /g silica in 48 h of impregnation, the supercritical impregnation method yielded loading up to 485 mg drug /g silica in 120 min of impregnation duration, at 16 MPa and 308 K, with a low degree of crystallinity (about 1%) comparable to the crystallinity observed via the solvent method. In addition to the enhancement of impregnation efficiency, the supercritical route provides a solvent-free alternative for impregnation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] Cardiovascular diseases (CVDs) remain one of the leading causes of death with an estimated 17.9 million lives lost each year. Circulating high levels of low-density lipoproteins (LDL), are susceptible to various modifications such as oxidation and glycosylation (diabetics). This leads to development of atherosclerosis, which can impair quality of life and death. There is a growing need for detection and subsequent treatment of high LDL cholesterol, which could be achieved through design of a system for detection of LDL with subsequent drug release for disease management. Fenofibrate-loaded solid lipid nanoparticles (SLNs) were synthesized and coated with anti-oxidized LDL antibodies to form anti-LDL SLN. The nanoparticles were delivered via an osmotic pump delivery device implanted on the jugular vein of Large White pigs as an anti-LDL theranostic system, referred to as an Intra-Vascular Implantable Sensor and Drug Delivery Device (IVISDDD), for modulation of systemic LDL cholesterol levels. Modulatory fenofibrate release was observed from the IVISDDD following in vivo analysis in response to anti-LDL SLN-LDL complex uptake and degradation. This notably contributed to a 29.9% reduction in total cholesterol via a 37.4% reduction in LDL levels, and an increase in HDL levels. The observed effect on cholesterol levels indicated that the device could be employed for detection of circulating biomarkers and delivery of lipophilic drugs in CVDs. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop a novel fenofibric acid-loaded controlled release pellet showing enhanced, or equivalent to, bioavailability compared with two commercially available products containing fenofibrate or choline fenofibrate. The effect of solubilizing agents on drug solubility and the impact of fillers on core properties were investigated. Among them, magnesium carbonate most improved drug solubility, and κ-carrageenan provided the best spherical cores. The fenofibric acid-loaded pellet was prepared with magnesium carbonate and κ-carrageenan employing the extrusion/spheronizing technique followed by coating with ethylcellulose. Furthermore, dissolution and pharmacokinetic study in beagle dogs were performed compared to the fenofibrate-loaded commercial tablet (FCT) and choline fenofibrate-loaded commercial mini-tablet (CFCM). This fenofibric acid-loaded pellet showed controlled release of the drug in phosphate buffer (pH 6.8) and 0.025 M sodium laurylsulfate within 4 h. Furthermore, this pellet and CFCM exhibited similar dissolution profiles. Plasma concentrations greater than 1000 ng/ml were maintained from 30 min to 8 h, suggesting a sustained release pattern. Also, the fenofibric acid-loaded pellet gave significantly higher AUC and C max values than FCT, indicating that it improved the bioavailability of fenofibrate due to enhanced solubility and sustained release. In addition, this pellet and CFCM were not significantly different in terms of pharmacokinetic parameters including AUC, C max and T max . Thus, this pellet was bioequivalent to CFCM in beagle dogs. In conclusion, this fenofibric acid-loaded controlled release pellet would be a potential alternative to the choline fenofibrate-loaded commercial product. [ABSTRACT FROM AUTHOR]

The robustness of the polymer strip film platform to successfully deliver a variety of BCS Class II drug nanoparticles without the need for surfactant while retaining positive characteristics such as nanoparticle redispersibility and fast dissolution is demonstrated. Fenofibrate (FNB), griseofulvin (GF), naproxen (NPX), phenylbutazone (PB), and azodicarbonamide (AZD) were considered as model poorly water-soluble drugs. Their aqueous nanosuspensions, produced via wet stirred media milling, were mixed with hydroxypropyl methylcellulose solution containing glycerin as plasticizer, followed by casting and drying to form films. For the purpose of comparison, sodium dodecyl sulfate (SDS) was used as surfactant, but was found to be unnecessary for achieving fast dissolution ( t 80 between 18 and 28 min) for all five drugs. Interestingly, SDS was required for the full recovery of nanoparticles for PB, yet lack of it did not impact the dissolution. Interactions between drug and polymer were investigated with FTIR spectroscopy whereas drug crystallinity within the film was investigated via Raman spectroscopy. Films for all drugs, even for very small samples, exhibited excellent content uniformity (RSD <4%) regardless of use of surfactant. Overall, these results demonstrate the novelty and robustness of the polymer strip film platform for fast release of poorly water-soluble drugs without requiring any surfactants. [ABSTRACT FROM AUTHOR]

Recently, we developed a new approach to rationalize an optimized design for self-emulsifying drug delivery system (SEDDS) by introducing the HLB and the response surface as determinant factors in SEDDS development. The aim of this current paper is to assess the suitability of this HLB-RSM approach to enhance the oral bioavailability of BCS class II compounds using fenofibrate as drug model. Eight SEDDS formulations (I → VIII) were pre-selected regarding their self-emulsification capacity and their effect on increasing in vitro drug release. They were firstly evaluated for their thermodynamic stability and zeta potential. Unstable SEDDS were discarded meanwhile the structural morphology of the stable ones (I, VI and VIII) was characterized using transmission electron microscopy (TEM). A pharmacokinetic study was then undertaken on male BALB/cJRj mices. The in vivo results showed a significant increase of fenofibrate absorption for all the three stable SEDDS formulations compared to the commercialized form, (LIPANTHYL micronized ® ( p < 0.05)). The highest enhancement was recorded for SEDDS I, where AUC and C max values respectively increased by 2 and 4.4 folds. This justifies the fact that HLB-RSM approach could be considered as a promising method for the development of efficient and highly stable SEDDS aiming to increase the poor bioavailability of BCS class II molecules. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a formulation containing fenofibrate and Gelucire ® 50/13 (Gattefossé, France) in order to improve the oral bioavailability of the drug. Particles from gas saturated solutions (PGSS) process was chosen for investigation as a manufacturing process for producing a solid dispersion. The PGSS process was optimized according to the in vitro drug dissolution profile obtained using a biphasic dissolution test. Using a design of experiments approach, the effects of nine experimental parameters were investigated using a PGSS apparatus provided by Separex ® (Champigneulles, France). Within the chosen experimental conditions, the screening results showed that the drug loading level, the autoclave temperature and pressure, the connection temperature and the nozzle diameter had a significant influence on the dissolution profile of fenofibrate. During the optimization step, the three most relevant parameters were optimized using a central composite design, while other factors remained fixed. In this way, we were able to identify the optimal production conditions that would deliver the highest level of fenofibrate in the organic phase at the end of the dissolution test. The closeness between the measured and the predicted optimal dissolution profiles in the organic phase demonstrated the validity of the statistical analyses. [ABSTRACT FROM AUTHOR]

The purpose of this work was to explore the feasibility of using Soluplus ® in preparing a fenofibrate (FBT) nanosuspension adopting wet media milling technology. HPMC and Soluplus ® were used as stabilizers to prepare FBT/HPMC nanosuspension (F1) and FBT/Soluplus ® nanosuspension (F2), respectively. The nanosuspensions were subjected to evaluations involving particle size, dissolution, preliminary stability and pharmacokinetic behavior. A marked reduction in particle size was achieved by nanosuspensions (from 17.55 μm to 642 nm (F1) and 344 nm (F2)). The nanosuspensions displayed almost complete dissolution while percentages of 30% and 13% were obtained by physical mixtures and coarse FBT separately. Soluplus ® could stabilize the nanosuspension more effectively due to a weaker Ostwald ripening effect resulting from a slower diffusion of micelles formed by Soluplus ® entrapping dissolved FBT than FBT exposed to pure water directly. In the in vivo evaluation, larger AUC 0–72 h and C max , and shorter T max were obtained by the nanosuspensions. Significant differences were observed between the physical mixtures. The phenomenon of double peaks was present in this study. The major factor may be the multiple absorption sites of FBT. The current work indicated that Soluplus ® is well suited for preparation of a nanosuspension with good stability and improved dissolution and bioavailability. [ABSTRACT FROM AUTHOR]

[Display omitted] • Temperature evolution during milling at 3 stirrer speeds and bead loadings–sizes. • Higher power consumption led to faster heat generation and temperature increase. • Relative impact on temperature rise: stirrer speed > bead loading > bead size. • Higher power led to smaller drug particles, but deteriorated thermal desirability. • Optimal milling conditions: 3000 rpm with 50% loading of 200 or 400 µm beads. Although heat is generated during the wet stirred media milling of drug suspensions, leading to notable temperature rise, a comprehensive analysis of heat generation does not exist. Hence, we investigated the impact of stirrer speed, bead loading, and bead size at three levels on the evolution of suspension temperature at the mill outlet during the milling of fenofibrate. The particle sizes and viscosities of the milled suspensions and power were measured. Our results suggest that stirrer speed had the most significant impact on the temperature increase, followed by bead loading and bead size. Both the time when the temperature reached 22 °C and the temperature at 5 min of milling were strongly correlated with the power. Assessing the impacts of the process parameters on the temperature rise, cycle time, power, and median particle size holistically, an optimal milling process was identified: 3000 rpm with 50% loading of 200 or 400 µm beads. A power number correlation was established to calculate power at any milling condition which determines the heat generation rate. Overall, this study indicated the importance of developing a good understanding of heat generation during nanomilling for development of a robust milling process especially for thermally labile drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] The lipolysis-mediated postprandial small intestinal environment is known to influence the solubilisation and subsequent absorption of lipophilic drugs. In a previously performed small-scale clinical study in healthy volunteers, co-administration of the lipase inhibitor orlistat increased jejunal solubilisation and systemic absorption of fenofibrate after intake of the lipid-based formulation Fenogal. In the present study, the jejunal disposition of the locally acting orlistat was assessed and linked to fenofibrate solubilisation. In addition, the effect of orlistat-induced lipolysis inhibition on bile salt concentrations and composition was evaluated. Orlistat was distributed predominantly in the lipid layer, as indicated by a 5- to 14-fold higher AUC 0-320 min in the total jejunal samples as compared to the micellar layers. No effect of orally administered orlistat on bile salt composition or total concentrations (ranging from 1.5 to 24.8 mM and 1.8 to 33.2 mM with and without orlistat co-administration, respectively) could be observed. The intraluminal presence of orlistat in the total jejunal samples correlated with the increased fenofibrate solubilisation in the jejunum (r = 0.9344) and enhanced absorption (r = 0.8184), highlighting the importance of the intraluminal lipid phase in lipophilic drug absorption. [ABSTRACT FROM AUTHOR]

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 ± 100 μm 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. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a sensitive and discriminative in vitro–in silico model able to simulate the in vivo performance of three fenofibrate immediate release formulations containing different surfactants. In addition, the study was designed to investigate the effect of dissolution volume when predicting the oral bioavailability of the formulations. In vitro dissolution studies were carried out using the USP apparatus 2 or a mini paddle assembly, containing 1000 mL or 100 mL fasted state biorelevant medium, respectively. In silico simulations of small intestinal absorption were performed using the GI-Sim absorption model. All simulation runs were performed twice adopting either a total small intestinal volume of 533 mL or 105 mL, in order to examine the implication of free luminal water volumes for the in silico predictions. For the tested formulations, the use of a small biorelevant dissolution volume was critical for in vitro – in silico prediction of drug absorption. Good predictions, demonstrating rank order in vivo–in vitro – in silico correlations for C max , were obtained with in silico predictions utilizing a 105 mL estimate for the human intestinal water content combined with solubility and dissolution data performed in a mini paddle apparatus with 100 mL fasted state simulated media. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this work was to elaborate a novel approach for the development and optimization of self-emulsifying drug delivery system (SEDDS), using response surface methodology and hydrophilic lipophilic balance (HLB). Fenofibrate was selected as drug model. Rapid selection of excipients was operated with reference to their toxicity and capacity to solubilize the drug. A three level Box–Behnken design was used. The independent variables were (X1) surfactants/oil, (X2) cosurfactant/surfactant and (X3) percentage of cosolvent. The high and low levels of these factors were selected with reference to the experimental domain that covers an interval of HLB from 7.8 to 15. This interval of HLB is assumed to lead to oil in water emulsification and to contain the required HLB. The responses were (Y1) droplet size and (Y2) cumulative percentage drug released in 20mn.Various response surface graphs were constructed to understand the effects of different factor level combinations. The optimized SEDDS with predicted drug release 83.6%, and droplet size 137nm was prepared; the experimental values were in close agreement. The required HLB was 9.85. Optimized SEDDS showed significant increase in dissolution rate compared to conventional prepared gelatin capsules. In conclusion, this paper demonstrated the reliability, rapidity, and robustness of the approach. [Copyright &y& Elsevier]

Abstract: A new oral sustained drug delivery system (DDS) involving a combination of inorganic mesoporous material (CMK-5) and organic polymer poly dimethyl diallyl ammonium (PDDA) was established to determine its general suitability for use with poorly water soluble drugs. Nimodipine, carvedilol and fenofibrate, three different drugs with acidic or alkaline properties, were selected as model drugs and loaded into carriers. The physicochemical properties of the drug carriers were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen adsorption. The structural body changes of the composites in release medium, with or without additional salts, were also studied using particle sizing systems, nitrogen adsorption and zeta potential measurement in order to investigate the sustained release mechanism of the drugs. The results obtained showed that sustained release of drug from the designed DDS was mainly due to the blockage effect arising from the strong swelling of the coated polymers when in contact with release medium. Additional salts, when they reached a certain level, allowed a dramatic burst release. We believe that our designed sustained DDS provide a new option for water insoluble drugs and can be considered as fundamental for those more sophisticated DDS increasingly required in modern medical treatments. [Copyright &y& Elsevier]

Abstract: The majority of the candidate drug entities exhibit solubility-limiting absorption. Nanocrystal suspensions with particle size in the nanometer scale (nanonization) can increase aqueous solubility and improve oral bioavailability. Regarding the importance of nanosuspension solidification, this study intended to study the critical parameters on redispersed particle size of dried nanocrystals as pretabletting material during spray drying process, such as supporting agents, inlet temperature and feed rate. Fenofibrate with poor water solubility and low melting point was used as a model drug. Nanocrystals of fenofibrate were prepared by a bead-milling method. Five types of hydrophilic excipients in combination with sodium dodecyl sulfate (SDS) were studied as supporting agents during spray drying. The resultant products were characterized by particle size analysis, scanning electron microscopy imaging, differential scanning calorimetry, X-ray powder diffraction and dissolution testing. Spray dried powder with a mean redispersed particle size of 699nm was produced by using mannitol and SDS as supporting agent. Weight ratio (R F/m) of fenofibrate:mannitol and inlet temperature strongly influenced the particle size of the nanocrystals. The optimal inlet temperature and feed rate was optimized as 75°C and 4mLmin−1, respectively. Partially transformation of fenofibrate crystalline to the amorphous form was observed. The dissolution profiles of tablets prepared with the spray dried powder were similar to the commercial nanocrystal formulation Lipidil™ ez, and faster than that of the micronized formulation. The relative bioavailability of the spray-dried formulation was determined to be 89.6% taking Lipidil™ ez as the reference. There were no significant statistic differences of AUC0–72 and C max between the two formulations. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to develop mesoporous carbon loaded with a poorly watersoluble drug to enhance the drug dissolution and improve the oral bioavailability. Mesoporous carbon was synthesized using Pluronic 127 triblock polymer (F127), TEOS and phenolic resins. Fenofibrate (FFB) was chosen as a model drug and loaded onto mesoporous carbon using three different loading methods involving incipient wetness impregnation, and the solvent and melting methods. The effect of the physical state and the specific surface area were investigated using nitrogen adsorption, transmission electron microscopy (TEM), powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). It was found that the physicochemical properties of the drug as well as the drug loading methods had critical effects on the drug release rate. In vitro drug release studies showed that incorporation of FFB in mesoporous carbon greatly enhanced the dissolution rate in comparison with that of the pure crystalline drug. Moreover, the oral bioavailability of the drug from mesoporous carbon was higher than that of FFB commercial capsules. Furthermore, mesoporous carbon produced no irritation of the mucosa of the gastrointestinal tract as shown by gastric mucosa irritation test. [Copyright &y& Elsevier]

Abstract: 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 30s 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. [Copyright &y& Elsevier]

Abstract: Poor water solubility of drugs can complicate their commercialisation because of reduced drug oral bioavailability. Formulation strategies such as increasing the drug surface area are frequently employed in an attempt to increase dissolution rate and hence, improve oral bioavailability. Maximising the drug surface area exposed to the dissolution medium can be achieved by loading drug onto a high surface area carrier like mesoporous silica (SBA-15). The aim of this work was to investigate the impact of altering supercritical carbon dioxide (SC-CO2) processing conditions, in an attempt to enhance drug loading onto SBA-15 and increase the drug''s dissolution rate. Other formulation variables such as the mass ratio of drug to SBA-15 and the procedure for combining the drug and SBA-15 were also investigated. A model drug with poor water solubility, fenofibrate, was selected for this study. High drug loading efficiencies were obtained using SC-CO2, which were influenced by the processing conditions employed. Fenofibrate release rate was enhanced greatly after loading onto mesoporous silica. The results highlighted the potential of this SC-CO2 drug loading approach to improve the oral bioavailability of poorly water soluble drugs. [Copyright &y& Elsevier]

Abstract: Radiolabeling is a valuable option for tracking drug molecules in biodistribution experiments. In the development of innovative drug delivery systems the influence of the pharmaceutical formulation on the drugs’ pharmacokinetics has to be investigated. The hypolipidemic agent fenofibrate is an ideal model drug for testing the performance of drug delivery systems designed for poorly soluble compounds. Herein, we report a de novo synthesis of a fenofibrate derivative, dechloro-4-iodofenofibrate, as well as its conversion into its radioiodinated derivatives containing 125I or 131I. The enzymatic stability of the radiolabeled compounds synthesized was determined in vitro. A scintigraphic imaging study supplemented by biodistribution experiments and analysis of excreted metabolites revealed the stability required for in vivo applications and its similarity to fenofibrate. Therefore a convenient method is presented to synthesize radioiodinated derivatives of fenofibrate. These tracers show excellent in vitro and in vivo properties to study the behavior of lipophilic drugs. [Copyright &y& Elsevier]

Abstract: Hot-melt extrusion was applied to improve dissolution behavior of poorly soluble model drug fenofibrate. Blends of polymers were used as carrier: copovidone (COP), polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol copolymer (PVCL–PVAc–PEG) and hypromellose 2910/5 (HPMC). The ratio of fenofibrate to COP remained constantly 1+3 (weighted parts) with varying amounts of PVCL–PVAc–PEG and HPMC. Solid state of fenofibrate was characterized by X-ray diffractometry and differential scanning calorimetry. Dissolution performance was compared to marketed formulations Lipidil and Lipidil-Ter. Stability studies were conducted at 25°C/60%rH. The dissolution rate from extrudates was significantly increased when compared to pure fenofibrate powder or physical mixture of the components. A supersaturation of 7.6–12.1 was reached with the pelletized extrudates. All extrudates were superior to marketed formulations. No recrystallization was observed after 26 weeks of storage for fenofibrate-COP extrudates 1+3 (weighted parts) with or without polymeric additives. Even so, both degree and duration of supersaturation decreased with increasing storage periods with the exception of fenofibrate-HPMC extrudates. Of particular interest is the finding that by adding polymers with differing release characteristics to the drug–carrier mixture, the dissolution performance of hot-melt extruded solid dosage forms can be readily adapted to meet specific requirements. [Copyright &y& Elsevier]

Abstract: The objective of the present study was to formulate a microemulsion system for oral administration to improve the solubility and bioavailability of fenofibrate. Various formulations were prepared using different ratios of oils, surfactants and co-surfactants (S&CoS). Pseudo-ternary phase diagrams were constructed to evaluate the microemulsification existence area. The formulations were characterized by solubility of the drug in the vehicles, mean droplet size, and drug content. The stability was also investigated by store for 3 months under 4°C, 25°C and 40°C and diluted 100 times for 3 days. The optimal formulation consists of 25% Capryol 90, 27.75% Cremophore EL, 9.25% Transcutol P and 38% water (w/w), with a maximum solubility of fenofibrate up to ∼40.96mg/mL. The microemulsion was physicochemical stable and mean droplet size was about 32.5–41.7nm. The pharmacokinetic study was performed in dogs and compared with Lipanthy® capsule. The result showed that microemulsion has significantly increased the C max and AUC compared to that of Lipanthy® capsule (p <0.05). The oral bioavailability of fenofibrate microemulsions (FEN-MEs) in ME-3 and ME-4 were 1.63 and 1.30-fold higher than that of the capsule. Our results indicated that the microemulsions could be used as an effective formulation for enhancing the oral bioavailability of fenofibrate. [Copyright &y& Elsevier]

Abstract: The goal of this study was to investigate the effect of plasma treatment on the wettability and dissolution of fenofibrate compacts. Contact angle measurements and intrinsic dissolution rate studies of untreated and plasma-treated fenofibrate compacts were conducted. The contact angle data clearly show that the wettability of the tablet surface increased with the duration of plasma treatment. Analyses of stability revealed that the surfaces which were plasma-treated for more than 1min regained some degree of hydrophobicity after storage in air. Since their hydrophobic recovery finally reached the level observed with 1min plasma-treated fenofibrate compacts it was deduced that permanent incorporation of hydrophilic groups had already attained saturation upon plasma irradiation for 1min. Dissolution studies revealed the advantages of the hydrophilized surface of plasma-treated fenofibrate compacts. Due to the improved wettability of plasma-treated fenofibrate its intrinsic dissolution rate was vastly increased compared to untreated fenofibrate. This study thus demonstrates the potential of plasma treatment to enhance the wettability and dissolution behavior of poorly water-soluble drugs. [Copyright &y& Elsevier]

Abstract: The performance of four different lipid-based (Tween 80–Captex 200P, Tween 80–Capmul MCM, Tween 80–Caprol 3GO and Tween 80–soybean oil) and one commercially available micronized formulation (Lipanthyl Micronized®) of the lipophilic compound fenofibrate was compared in vitro in various biorelevant media and in vivo in rats. In simulated gastric fluid without pepsin (SGFsp) and fasted state simulated intestinal fluid (FaSSIF), only Tween 80–Captex 200P system resulted in a stable fenofibrate concentration, but no supersaturation was obtained. The other three lipid based systems created fenofibrate supersaturation; however they did not maintain it. In fed state simulated intestinal fluid (FeSSIF), all lipid-based formulations resulted in complete dissolution of fenofibrate during the experiment, which represented a supersaturated state for Tween 80–Capmul MCM and Tween 80–Caprol 3GO systems. In both FaSSIF and FeSSIF, all lipid-based formulations yielded a higher fenofibrate concentration than the micronized formulation. Contrary to the in vitro results, no significant difference in the in vivo performance was observed among the four tested lipid-based formulations both in the fasted and the fed states. The in vivo performance of all lipid-based formulations was better than that of Lipanthyl Micronized®, in the fasted as well as in the fed state. The fact that for the lipid based systems the in vitro differences in pharmaceutical performance were not translated into in vivo differences can be attributed to the continuous excretion of bile in the gastrointestinal tract of rats, causing enhanced solubilizing capacity for lipophilic drugs. This study clearly points to the conflicting situation that might arise during the preclinical phase of the development of lipid based formulations of lipophilic drugs as the performance of such systems is very often evaluated by both in vitro release studies in human biorelevant media as well as in vivo studies in rats. Care must be taken to select a relevant animal model. [Copyright &y& Elsevier]

Abstract: This work investigates the technical feasibility of formulating water-redispersible nanocrystals of a poorly aqueous soluble drug by a continuous and scalable route. By coupling antisolvent precipitation with immediate spray-drying, fenofibrate nanoparticles were precipitated and formulated into a dry powder form containing lactose or mannitol as redispersant, hydroxylpropyl methyl cellulose (HPMC) and sodium dodecyl sulfate (SDS) as stabilizers. Field emission scanning electron microscopy (FESEM) and dynamic laser light scattering (DLLS) showed that nanosized fenofibrate were observed both upon precipitation and after the formulated powder was reconstituted in water. Analyses with powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) showed that the formulated drug remained predominantly in the crystalline state. USP dissolution testing in 0.1N HCl solution with 0.5% (w/w) Tween-80 showed that the nanocrystals could be readily redispersed upon reconstitution and exhibited significantly a higher dissolution rate with 84.2% drug dissolved in 5min as compared to the conventional spray-dried formulation (31.7%) and the physical mixture (9.7%) using micronized fenofibrate. The results suggest the potential of combining static mixing and spray drying for large-scale continuous production of pharmaceutical nanoformulations. [Copyright &y& Elsevier]

Abstract: The main purpose of this study was to evaluate oral bioavailability of the poorly water-soluble drug fenofibrate when liposomes containing a bile salt were used as oral drug delivery systems. Liposomes composed of soybean phosphotidylcholine (SPC) and sodium deoxycholate (SDC) were prepared by a dry-film dispersing method coupled with sonication and homogenization. Several properties of the liposomes, including particle size, entrapment efficiency and membrane fluidity, were extensively characterized. In vitro release experiments indicated that no more than 20% of total fenofibrate was released from SPC/cholesterol (CL) and SPC/SDC liposomes at 2h, in contrast with near complete release for micronized fenofibrate capsules. Strikingly, in vivo measurements of pharmacokinetics and bioavailability demonstrated higher rates of fenofibrate absorption from both SPC/SDC and SPC/CL liposomes than micronized fenofibrate. The bioavailability of SPC/SDC and SPC/CL liposomes was 5.13- and 3.28-fold higher, respectively, than that of the micronized fenofibrate. The disparity between oral bioavailability and in vitro release for liposomes strongly suggests alternative absorption mechanisms rather than enhanced release. Importantly, SPC/SDC liposomes exhibited a 1.57-fold increase in bioavailability relative to SPC/CL liposomes, indicating that liposomes containing bile salts may be used to enhance oral bioavailability of poorly water-soluble drugs. [Copyright &y& Elsevier]

Abstract: The solidification process from emulsion, which consisted of emulsifier, water and molten drug as oil phase without use of any organic solvent, was firstly employed to prepare ultrafine fenofibrate (FF) powder. The effects of stirring speed and volume ratios of hot emulsion to cold water on the particle size and morphology were discussed as well as the impacts of different emulsifiers on emulsion. The produced ultrafine powder was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, specific surface area analysis and a dissolution test. XRD patterns and FT-IR spectra showed that the ultrafine FF was crystalline powder with the structure and the components similar to those of bulk drug. The product had a mean particle size of about 3μm with a narrow distribution from 1μm to 5μm. The specific surface area reached up to 6.23m2/g, which was about 25 folds as large as that of bulk FF. In the dissolution tests, about 96.1% of ultrafine FF was dissolved after 120min, while there was only 38.1% of bulk drug dissolved, proving that the dissolution property of ultrafine FF was significantly improved when compared to commercial drug. [Copyright &y& Elsevier]

[Display omitted] Amorphous solid dispersion (ASD) is emerging as a useful formulation strategy to increase the bioavailability of active pharmaceutical ingredients with poor solubility. In vitro dissolution testing under non-sink conditions has often been used to evaluate the ability of ASDs to generate and maintain supersaturation to predict the in vivo performance. However, such a single compartment dissolution setup can fail to predict the oral bioavailability, due to an interdependence between precipitation and permeation. Hence, the use of two compartment dissolution-permeation setups is emerging. In this study, three ASDs containing fenofibrate as model drug substance were developed using Soluplus®, and Hypromellose Acetate Succinate in two different grades (high and low), respectively. The aim was to compare the use of a small-scale in vitro non-sink dissolution setup and a small-scale in vitro dissolution-permeation setup to predict the in vivo oral exposure of the ASDs in rats. The maximum concentration (C max) and area under curve (AUC) obtained in the in vitro studies were used to predict the in vivo rank order of the formulations. The results showed that the two in vitro studies resulted in the same rank order based on both C max and AUC. Interestingly, C max resulted in a better in vitro/in vivo correlation than the in vitro AUC, and based on the in vitro C max , the in vivo rank order was predicted. [ABSTRACT FROM AUTHOR]

Abstract: Dissolution rate of a poorly water-soluble drug, fenofibrate, is increased by adsorbing the drug onto silica. The adsorption is achieved by first dissolving the drug in supercritical carbon dioxide and then depressurizing the solution onto silica. Loadings of up to 27.5wt.% drug onto silica are obtained. Since solvents are not used in the loading process, the fenofibrate/silica formulation is free of any residual solvent, and carbon dioxide is freely removed upon depressurization. The formulation is characterized using infrared spectroscopy, ultraviolet spectroscopy, X-ray diffraction, differential scanning calorimetry and scanning electron microscopy. Based on in vitro dissolution study, a significant increase in the dissolution rate (∼80% drug release in 20min) of drug–silica formulation is observed as compared to micronized fenofibrate (∼20% drug release in 20min), which can be attributed to increase in the surface area and decrease in the crystallinity of drug after adsorption onto silica. Two different formulations are compared: (A) amorphous fenofibrate/silica and (B) slightly crystalline fenofibrate/silica. The second formulation is found to be more stable on storage. [Copyright &y& Elsevier]

Abstract: The structure and UV spectra of fenofibrate have been evaluated in gas phase and in solutions using time dependent density functional theory (TDDFT) method at the B3LYP/6-31G(d), B3LYP/6-311G(d,p) and B3LYP/6-311++G(d,p) levels. The solvent effects have been taken into account based on the polarizable continuum model (PCM). The computed results appear that the introduction of dielectric medium has slight effect on the molecular geometry of fenofibrate. There is one allowed excited state presenting the strongest oscillator strength in the UV region, which is associated with the HOMO→LUMO and HOMO-1→LUMO transition both in gas phase and in solutions. The prediction of the λ max in THF, ethanol and DMSO is 285nm, 286nm and 287nm, respectively, which are in a good agreement with experimental data of 284nm, 285nm and 288nm.The results demonstrate that TDDFT-PCM is a useful tool for study of the electronic absorption in solutions. [Copyright &y& Elsevier]