Controlling Supramolecular Structures of Drugs by Light.

Controlling physicochemical properties of light-unresponsive drugs, by light, prima facie, a paradox approach. We expanded light control by ion pairing light-unresponsive salicylate or ibuprofen to photoswitchable azobenzene counterions, thereby reversibly controlling supramolecular structures, hence the drugs' physicochemical and kinetic properties. The resulting ion pairs photoliquefied into room-temperature ionic liquids under ultraviolet light. Aqueous solutions showed trans-cis-dependent supramolecular structures under a light with wormlike aggregates decomposing into small micelles and vice versa. Light control allowed for permeation through membranes of cis-ibuprofen ion pairs within 12 h in contrast to the trans ion pairs requiring 72 h. In conclusion, azobenzene ion-pairing expands light control of physicochemical and kinetic properties to otherwise light-unresponsive drugs.

Application of pulsed laser ablation (PLA) for the size reduction of non-steroidal anti-inflammatory drugs (NSAIDs).

We studied the application of pulsed laser ablation (PLA) for particle size reduction in non-steroidal anti-inflammatory drugs (NSAIDs). Grinding of the poorly water-soluble NSAID crystallites can considerably increase their solubility and bioavailability, thereby the necessary doses can be reduced significantly. We used tablets of ibuprofen, niflumic acid and meloxicam as targets. Nanosecond laser pulses were applied at various wavelengths (KrF excimer laser, λ = 248 nm, FWHM = 18 ns and Nd:YAG laser, λ1 = 532 nm/λ2 = 1064 nm, FWHM = 6 ns) and at various fluences. FTIR and Raman spectra showed that the chemical compositions of the drugs had not changed during ablation at 532 nm and 1064 nm laser wavelengths. The size distribution of the ablated products was established using two types of particle size analyzers (SMPS and OPC) having complementary measuring ranges. The mean size of the drug crystallites decreased from the initial 30-80 µm to the submicron to nanometer range. For a better understanding of the ablation mechanism we made several investigations (SEM, Ellipsometry, Fast photography) and some model calculations. We have established that PLA offers a chemical-free and simple method for the size reduction of poorly water-soluble drugs and a possible new way for pharmaceutical drug preformulation for nasal administration.

Micro-TiO2 coated glass surfaces safely abate drugs in surface water.

The ingredients of Pharmaceuticals and Personal Care Products (PPCPs) persist in water and conventional treatment plants are not able to remove them efficiently. Sonochemical treatment is insufficient to mineralize organics such as ibuprofen into CO2 and H2O. TiO2 degrades ibuprofen (IBP) under UV light; however, it does not reach a high grade of conversion. Here, we investigated the mineralization of ibuprofen to CO2 by TiO2 UV-C photocatalysis. We replaced nano-sized P25 (the standard catalyst) with a micro-sized commercial sample of TiO2 to preclude the use of nanoparticles which are dangerous for human health and because typical filtration systems are expensive and inefficient. We deposited micro-TiO2 on glass Raschig rings to ensure an easy recovery and reuse of the photocatalyst and we studied its performance both with a batch and a continuous reactor. Micro-TiO2 mineralized 100% of IBP in 24 h. TiO2-coated glass Raschig rings degraded 87% of IBP in 6 h of UV-C irradiation in a continuous reactor, with a mineralization of 25%. Electronspray ionization mass spectrometer (ESI-MS, positive mode) analyses identified 13 different byproducts and we hypothised a degradration pathway for IBP degradation.

Comparative study of the toxicity between three non-steroidal anti-inflammatory drugs and their UV/Na2S2O8 degradation products on Cyprinus carpio.

The efficiency of advanced oxidation processes (AOPs) for disposing of non-steroidal anti-inflammatory drugs (NSAIDs) has been widely studied, but the environmental fates and effects of the NSAIDs and their degradation products (DPs) are poorly understood. In this study, the efficiency of ultraviolet light/Na2S2O8 (UV/PS) in degrading three NSAIDs-diclofenac, naproxen, and ibuprofen-and the toxicity of their DPs on Cyprinus carpio (C. carpio) was investigated. Results showed that the three NSAIDs can be completely removed (removal rate > 99.9%) by UV/PS, while the mineralization rate of the NSAIDs was only 28%. When C. carpio were exposed to 0.1 µM NSAIDs, 10 µM persulfate (PS), and 0.1 µM DPs of the NSAIDs for 96 h, respectively, the toxicity effects are as the NSAID DPs > PS > NSAIDs. Research results into the time-dependent effect of NSAID DPs on C. carpio demonstrated that obvious toxicity effects were observed in the first 48 hours, and the toxicity effects strengthened over time. NSAID DPs may have more severe toxicity effects than NSAIDs on C. carpio; therefore, the operating conditions of UV/PS must be optimized to eliminate the ecotoxicity of DPs.

The combined toxicity of UV/chlorinated products from binary ibuprofen (IBP) and tyrosine (Tyr) on Escherichia coli: Emphasis on their occurrence and underlying mechanism.

In this study, the combined toxicity of UV/chlorinated products on Escherichia coli (E. coli) was investigated when ibuprofen (IBP) and tyrosine (Tyr) were used as two precursors. The median-effect equation and combined index (CI)-isobologram equation were used to evaluate the combined toxicity of UV/chlorinated products. Results revealed that the UV/chlorinated products originated from binary Tyr and IBP showed a synergism in toxicity on Escherichia coli at low concentration level while it turned into a clear antagonism effect above a fa value of 0.2 in the toxicity trial. The combined toxic effects on E. coli were determined by both the potential toxicity mode of specific disinfection byproducts (DBPs) and the complicated interaction caused by Tyr and IBP. The addition of IBP decreased the yield of N-DBPs generated from Tyr, which dominated the effect of combined toxicity. Even though the antagonism predominated in toxicity effect on E. coli, the synergistic toxicity at low dose levels should be getting attention, which was more close to the natural concentration of N-DBPs in waters.

UV direct photolysis of sulfamethoxazole and ibuprofen: An experimental and modelling study.

Photodegradation characteristics of pharmaceuticals and personal care products (PPCPs) during UV irradiation are of practical and scientific importance in selecting operational parameters during water treatment processes. In this study, the molar extinction coefficient (ε), quantum yield (φ), and degradation kinetics of neutral/anionic forms of sulfamethoxazole (SMX) and ibuprofen (IBU) were compared by varying solution pH. The degradation kinetics of the target compounds were observed to reversely correlate to the energy gap between highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) values of the target compounds. Then, a kinetic model for predicting the direct photolytic rates at different solution pH was established based on ε and φ of neutral/anionic species. The root mean squared errors for the modeled values suggest that the model exhibits good predictive power. Finally, in order to evaluate the electrical energy consumption during the UV direct photolysis process, the electrical energy per order (EE/O) was assessed. The experimental and modelling results are important to elucidate the mechanism of degradation of target PPCPs under UV irradiation and allow for the selection of optimal conditions in water treatment processes.

Effect of halide ions on the photodegradation of ibuprofen in aqueous environments.

Typically contained within ambient surface waters and certain industrial wastewaters, are plentiful halide ions, which possess varying degrees of photosensitivity. The effects of halide ions on the photodegradation of ibuprofen (IBP) were investigated under UV irradiation using a 500 W mercury lamp as a light source. Studies of the mechanism of halide ions were inclusive of both their light shielding effects and quenching experiments. The results indicated that chloride ion has a slight inhibition against IBP photodegradation under neutral condition, and significant inhibition is observed with bromide ions and iodide ions. In addition to the observed increased rate of IBP photodegradation in conjunction with elevated pH in solution, the inhibitory effect of halide ions was different. When the pH value of the IBP solution was 5, chloride ions were seen to facilitate the photodegradation of IBP. Halide ions can inhibit IBP photodegradation by means of a light attenuation effect. All of the halide ions significantly facilitated the generation of 1O2.

Photocatalytic degradation and removal mechanism of ibuprofen via monoclinic BiVO4 under simulated solar light.

Characterized as by X-ray diffraction, scanning electron microscopy and UV-vis diffuse reflectance spectra techniques, BiVO4 photocatalyst was hydrothermally synthesized. The photocatalytic degradation mechanisms of ibuprofen (IBP) were evaluated in aqueous media via BiVO4. Results demonstrated that the prepared photocatalyst corresponded to phase-pure monoclinic scheelite BiVO4. The synthesized BiVO4 showed superior photocatalytic properties under the irradiation of visible-light. The photocatalytic degradation rate of IBP decreased with an increase in the initial IBP concentration. The degradation process followed first-order kinetics model. At an IBP concentration of 10 mg L(-1), while a BiVO4 concentration of 5.0 g L(-1) with pH value of 4.5, the rate of IBP degradation was obtained as 90% after 25 min. The photocatalytic degradation of IBP was primarily accomplished via the generation of superoxide radical (O2(•-)) and hydroxyl radicals ((•)OH). During the process of degradation, part of the (•)OH was converted from the O2(•-). The direct oxidation of holes (h(+)) made a minimal contribution to the degradation of IBP.

Cu2O loaded titanate nanotube arrays for simultaneously photoelectrochemical ibuprofen oxidation and hydrogen generation.

A p-n junction Cu2O doped TiO2 nanotube arrays (Cu2O/TNAs) were synthesized by square wave voltammetry electrochemical (SWVE) deposition method and employed as the working anode. The crystalline, optical properties, surface morphology, and structure of the Cu2O/TNAs were characterized by XRD, UV-vis absorbance edges, SEM, and XPS. Results showed that the Cu2O/TNAs were dominated by anatase phase after sintering at 450 °C with significant visible light response. XPS finding confirmed XRD results that the copper element in Cu2O/TNAs was Cu (I) instead of Cu (II). SEM images illustrated the diameter and the length of supported TiO2 nanotubes was approximately 100 nm and 2.75-4.34 µm, respectively. After Cu2O doping, the nano-tubular structure of TiO2 nanotube kept its integrity with no significant morphological change, which was beneficial for PEC applications. The photocurrent of Cu2O/TNAs was 1.45 times larger than that of TNAs, implying that Cu2O doping significantly enhanced electron mobility by reducing the recombination of electron-hole pairs. In addition, electrochemical impedance spectroscopy (EIS) measurements revealed that the recombination of photogenerated electron-hole pairs was inhibited as the bias potential was applied. Results of Bode plot further demonstrated that the electron lifetime τel of Cu2O/TNAs-20 (30.79 ms), under 0.5 V bias potential, was about 2.23 times higher than that of pure TNAs (13.82 ms). Results of electron spin resonance (ESR) analyses demonstrate that the hydroxyl radicals (OH) are responsible for the PEC decomposition of Ibuprofen.

Visible-light driven degradation of ibuprofen using abundant metal-loaded BiVO4 photocatalysts.

An efficient method for the degradation of ibuprofen as an aqueous contaminant was developed under visible-light irradiation with as-prepared bismuth vanadate (BiVO4) catalysts. The metal-loaded catalysts Cu-BiVO4 and Ag-BiVO4 were synthesized using a hydrothermal process and then a wet-impregnation method. All of the materials were fully characterized by X-ray diffraction, scanning electron microscopy, UV-vis diffuse reflectance spectroscopy, X-ray photoelectron spectroscopy and BET surface area. The results indicated that all of the prepared samples had monoclinic scheelite structures. In the metal-loaded catalysts, silver existed as a mixture of Ag and Ag2O on the surface of the catalysts. However, copper existed as Cu2O and CuO. Additionally, the band gap values of BiVO4, Ag-BiVO4, and Cu-BiVO4 were 2.38, 2.31, and 2.30eV, respectively. Compared to the BiVO4 catalyst, the metal-loaded BiVO4 catalysts showed superior photocatalytic properties for the degradation of ibuprofen.

Enzymatic resolution of ibuprofen in an organic solvent under ultrasound irradiation.

Ultrasound has been successfully adopted to improve the biocatalytic properties of APE1547 (a novel esterase from the archaeon Aeropyrum pernix K1) in the resolution of ibuprofen. After optimizing the conditions (ultrasound power, 200 W; temperature, 35 °C), the best biocatalytic performance of APE1547 (enzyme activity, 5.39 µmol/H/mg; E value, 130.8) was obtained. Compared with the conventional reaction in an orbital shaker, the enzyme activity was significantly enhanced about 90-fold, and the enantioselectivity was enhanced about fourfold after an ultrasound. The results of scanning electron microscopy clearly indicated that the activation effect of ultrasound on APE1547 originated mainly in the morphological change of the enzyme powder. Both lower particle size and conformational change of APE1547 under ultrasound might be helpful to enhance the enantioselectivity. In addition, APE1547 kept its best performance under the low-power ultrasound for at least five reaction cycles.

Photolysis and photocatalysis of ibuprofen in aqueous medium: characterization of by-products via liquid chromatography coupled to high-resolution mass spectrometry and assessment of their toxicities against Artemia salina.

The degradation of the pharmaceutical compound ibuprofen (IBP) in aqueous solution induced by direct photolysis (UV-A and UV-C radiation) and photocatalysis (TiO2 /UV-A and TiO2 /UV-C systems) was evaluated. Initially, we observed that whereas photocatalysis (both systems) and direct photolysis with UV-C radiation were able to cause an almost complete removal of IBP, the mineralization rates achieved for all the photodegradation processes were much smaller (the highest value being obtained for the TiO2 /UV-C system: 37.7%), even after an exposure time as long as 120 min. Chemical structures for the by-products formed under these oxidative conditions (11 of them were detected) were proposed based on the data from liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) analyses. Taking into account these results, an unprecedented route for the photodegradation of IBP could thus be proposed. Moreover, a fortunate result was achieved herein: tests against Artemia salina showed that the degradation products had no higher ecotoxicities than IBP, which possibly indicates that the photocatalytic (TiO2 /UV-A and TiO2 /UV-C systems) and photolytic (UV-C radiation) processes can be conveniently employed to deplete IBP in aqueous media.

Hydroxyl radical induced degradation of ibuprofen.

Pulse radiolysis experiments were used to characterize the intermediates formed from ibuprofen during electron beam irradiation in a solution of 0.1mmoldm(-3). For end product characterization (60)Co γ-irradiation was used and the samples were evaluated either by taking their UV-vis spectra or by HPLC with UV or MS detection. The reactions of OH resulted in hydroxycyclohexadienyl type radical intermediates. The intermediates produced in further reactions hydroxylated the derivatives of ibuprofen as final products. The hydrated electron attacked the carboxyl group. Ibuprofen degradation is more efficient under oxidative conditions than under reductive conditions. The ecotoxicity of the solution was monitored by Daphnia magna standard microbiotest and Vibrio fischeri luminescent bacteria test. The toxic effect of the aerated ibuprofen solution first increased upon irradiation indicating a higher toxicity of the first degradation products, then decreased with increasing absorbed dose.

Photocatalytic degradation of non-steroidal anti-inflammatory drugs with TiO2 and simulated solar irradiation.

The aim of this work is to evaluate and compare the degradation achieved for three non-steroidal anti-inflammatory drugs (NSAIDs) by heterogeneous TiO2 photocatalytic means in aqueous solution at laboratory scale. The selected pharmaceutical compounds were diclofenac (DCF), naproxen (NPX) and ibuprofen (IBP). These compounds were used in their sodium salt chemical form. Previous experiments (adsorption, photolysis and thermodegradation) were developed to evaluate non-catalytic degradation for each NSAID. Photocatalytic experiments were carried out in a Xe-lamp reactor in order to study the influences of different operational conditions (catalyst load, temperature and dissolved oxygen concentration). These results showed that the optimum amount of TiO2, to achieve maximum degradation, of IBP was 1g/L. In contrast, the maximum degradation for DCF or NPX was observed at a TiO2 loading of 0.1g/L. Temperature had a significant effect only for NPX degradation, achieving almost 99% phototransformation. No significant differences were observed for DCF and IBP at 20, 30 and 40 degrees C. Dissolved oxygen concentration was an important parameter to increase the degradation for NPX and IBP. However, it was observed that its rate of mineralization did not increase. Intermediate metabolites were detected in all cases. Hydroxyl metabolites were the most important residual compounds after the photocatalytic treatment of IBP. The inhibition percentage of bioluminescence from Vibro fischeri--as a toxicity parameter--increased during the irradiation time due to the residual concentration of the hydroxyl metabolites generated. However, after 120 min, in experiments with 40 mg/L of dissolved oxygen, a decrease of the % inhibition was observed. Only photocatalytic treatment of IBP drives to a satisfactory biodegradability index BOD5/COD (between 0.16 and 0.42) and, only in this case, a post-biological treatment could be suggested.

Theoretical study of ibuprofen phototoxicity.

The photochemical properties and degradation of the common nonsteroid anti-inflammatory drug ibuprofen is studied by means of hybrid density functional theory. Computed energies and properties of various species show that the deprotonated form dominates at physiological pH, and that the species will not be able to decarboxylate from a singlet excited state. Instead, decarboxylation will occur, with very high efficiency, provided the deprotonated compound can undergo intersystem crossing from an excited singlet to its excited triplet state. In the triplet state, the C-C bond connecting the carboxyl group is elongated, and the CO2 moiety detaches with a free energy barrier of less than 0.5 kcal/mol. Depending on the local environment, the decarboxylated product can then either be quenched through intersystem crossing (involving the possible formation of singlet oxygen) and protonation, or serve as an efficient source for superoxide anions and the formation of a peroxyl radical that will initiate lipid peroxidation.

["Non-solvent shock agglomeration"--the technology of a new alternative method for determination of ibuprofen. 6. Stability of s(+)-ibuprofen]. / Die "Non-solvent shock agglomeration"--Technologie als neuartige alternative Methode zur Aufarbeitung von Ibuprofen. 6. Mitt.: Stabilitätsuntersuchungen an S(+)-Ibuprofen.

Due to its low melting range approx. 53 degrees C optically pure ibuprofen can be regarded as problematic in a pharmaceutic-technological sense. With regard to the non-solvent shock agglomeration method this means that the process and product temperatures must strictly be kept in the range of 10 K above the melting point of the substance. Higher temperatures can induce degradation of S(+)ibuprofen. During storage under stress conditions (31 degrees C for a period of 18 months) ibuprofen shows extreme stability independent of its optical activity. Racemic ibuprofen is inert to the influence of light; in individual cases optically pure substance containing an increased level of impurities can show slight degradation tendencies. The thermal and photo stability of ibuprofen is independent of the preparation technology. For comparison, conventional, fluid bed granulated, briquetted and from organic solvents especially recrystallised and optically active substances were investigated besides the shock agglomerated substances.