Influence of process parameters on the effectiveness of photooxidative treatment of pharmaceuticals.

In this study, UV-C/H2O2 and UV-C/[Formula: see text] processes as photooxidative Advanced oxidation processes were applied for the treatment of seven pharmaceuticals, either already included in the Directive 2013/39/EU "watch list" (17α- ethynylestradiol, 17ß-estradiol) or with potential to be added in the near future due to environmental properties and increasing consumption (azithromycin, carbamazepine, dexamethasone, erythromycin and oxytetracycline). The influence of process parameters (pH, oxidant concentration and type) on the pharmaceuticals degradation was studied through employed response surface modelling approach. It was established that degradation obeys first-order kinetic regime regardless structural differences and over entire range of studied process parameters. The results revealed that the effectiveness of UV-C/H2O2 process is highly dependent on both initial pH and oxidant concentration. It was found that UV-C/[Formula: see text] process, exhibiting several times faster degradation of studied pharmaceuticals, is less sensitive to pH changes providing practical benefit to its utilization. The influence of water matrix on degradation kinetics of studied pharmaceuticals was studied through natural organic matter effects on single component and mixture systems.

Photostability Issues in Pharmaceutical Dosage Forms and Photostabilization.

Photodegradation is one of the major pathways of the degradation of drugs. Some therapeutic agents and excipients are highly sensitive to light and undergo significant degradation, challenging the quality and the stability of the final product. The adequate knowledge of photodegradation mechanisms and kinetics of photosensitive therapeutic entities or excipients is a pivotal aspect in the product development phase. Hence, various pharmaceutical regulatory agencies, across the world, mandated the industries to assess the photodegradation of pharmaceutical products from manufacturing stage till storage, as per the guidelines given in the International Conference on Harmonization (ICH). Recently, numerous formulation and/or manufacturing strategies has been investigated for preventing the photodegradation and enhancing the photostability of photolabile components in the pharmaceutical dosage forms. The primary focus of this review is to discuss various photodegradation mechanisms, rate kinetics, and the factors that influence the rate of photodegradation. We also discuss light-induced degradation of photosensitive lipids and polymers. We conclude with a brief note on different approaches to improve the photostability of photosensitive products.

A new efficient method of generating photoaffinity beads for drug target identification.

Affinity purification is one of the most prevalent methods for the target identification of small molecules. Preparation of an appropriate chemical for immobilization, however, is a tedious and time-consuming process. A decade ago, a photoreaction method for generating affinity beads was reported, where compounds are mixed with agarose beads carrying a photoreactive group (aryldiazirine) and then irradiated with ultraviolet light under dry conditions to form covalent attachment. Although the method has proven useful for identifying drug targets, the beads suffer from inefficient ligand incorporation and tend to shrink and aggregate, which can cause nonspecific binding and low reproducibility. We therefore decided to craft affinity beads free from these shortcomings without compromising the ease of preparation. We herein report a modified method; first, a compound of interest is mixed with a crosslinker having an activated ester and a photoreactive moiety on each end. This mixture is then dried in a glass tube and irradiated with ultraviolet light. Finally, the conjugates are dissolved and reacted with agarose beads with a primary amine. This protocol enabled us to immobilize compounds more efficiently (approximately 500-fold per bead compared to the original method) and generated beads without physical deterioration. We herein demonstrated that the new FK506-immobilized beads specifically isolated more FKBP12 than the original beads, thereby proving our method to be applicable to target identification experiments.

Adsorption and photocatalytic degradation of pharmaceuticals and pesticides by carbon doped-TiO2 coated on zeolites under solar light irradiation.

To evaluate the performance of zeolite-supported carbon-doped TiO(2) composite catalysts toward target pollutants under solar light irradiation, the adsorption and photocatalytic degradation of 18 pharmaceuticals and pesticides with distinguishing features (molecular size and volume, and photolysis) were investigated using mordenite zeolites with SiO(2)/Al(2)O(3) ratios of 18 and 240. Different quantities of carbon-doped TiO(2) were coated on the zeolites, and then the finished composite catalysts were tested in demineralized, surface, and hospital wastewater samples, respectively. The composite photocatalysts were characterized by X-ray diffraction, field emission scanning electron microscopy, and surface area and porosity analyses. Results showed that a dispersed layer of carbon-doped TiO(2) is formed on the zeolite surface; this layer blocks the micropores of zeolites and reduces their surface area. However, these reductions did not significantly affect adsorption onto the zeolites. Our results demonstrated that zeolite-supported carbon-doped TiO(2) systems can effectively degrade 18 pharmaceuticals and pesticides in demineralized water under natural and simulated solar light irradiation. In surface and hospital wastewaters, zeolite-supported carbon-doped TiO(2) systems present excellent anti-interference capability against radical scavengers and competitive organics for pollutants removal, and higher pollutants adsorption on zeolites evidently enhances the removal rate of target pollutants in surface and hospital wastewater samples with a complicated matrix.

Degradation of pharmaceuticals and metabolite in synthetic human urine by UV, UV/H2O2, and UV/PDS.

To minimize environmental pharmaceutical micropollutants, treatment of human urine could be an efficient approach due to the high pharmaceutical concentration and toxic potential excreted in urine. This study investigated the degradation kinetics and mechanisms of sulfamethoxazole (SMX), trimethoprim (TMP) and N4-acetyl-sulfamethoxazole (acetyl-SMX) in synthetic fresh and hydrolyzed human urines by low-pressure UV, and UV combined with H2O2 and peroxydisulfate (PDS). The objective was to compare the two advanced oxidation processes (AOPs) and assess the impact of urine matrices. All three compounds reacted quickly in the AOPs, exhibiting rate constants of (6.09-8.53) × 10(9) M(-1)·s(-1) with hydroxyl radical, and (2.35-16.1) × 10(9) M(-1)·s(-1) with sulfate radical. In fresh urine matrix, the pharmaceuticals' indirect photolysis was significantly suppressed by the scavenging effect of urine citrate and urea. In hydrolyzed urine matrix, the indirect photolysis was strongly affected by inorganic urine constituents. Chloride had no apparent impact on UV/H2O2, but significantly raised the hydroxyl radical concentration in UV/PDS. Carbonate species reacted with hydroxyl or sulfate radical to generate carbonate radical, which degraded SMX and TMP, primarily due to the presence of aromatic amino group(s) (k = 2.68 × 10(8) and 3.45 × 10(7) M(-1)·s(-1)) but reacted slowly with acetyl-SMX. Ammonia reacted with hydroxyl or sulfate radical to generate reactive nitrogen species that could react appreciably only with SMX. Kinetic simulation of radical concentrations, along with products analysis, helped elucidate the major reactive species in the pharmaceuticals' degradation. Overall, the AOPs' performance was higher in the hydrolyzed urine than fresh urine matrix with UV/PDS better than UV/H2O2, and varied significantly depending on pharmaceutical's structure.

Enhanced ozonation of selected pharmaceutical compounds by sonolysis.

In search of new options to achieve removal of pharmaceuticals in the environment, combined ultrasound and ozonation has become a focus of intense investigation for wastewater treatment. In this study, three pharmaceuticals were selected as model compounds for degradation experiments: diclofenac (DCF), sulfamethoxazole (SMX) and carbamazepine (CBZ). Comparison of the degradation rates for both ozonation and combined ultrasound/ozonation treatments was performed on single synthetic solutions as well as on a mixture of the selected pharmaceuticals, under different experimental conditions. For single synthetic solutions, the efficiency removal for ozonation reached 73%, 51% and 59% after 40 min for DCF, SMX and CBZ, respectively. Comparable results were obtained for pharmaceuticals in mixture. However, the combined ultrasound/ozone treatment was found to increase degradation efficiencies for both DCF and SMX single solutions up to 94% and 61%, respectively, whereas lower removal yields, up to 56%, was noted for CBZ. Likewise, when the combined treatment was applied to the mixture, relatively low removal efficiencies was found for CBZ (44%) and 90% degradation yield was achieved for DCF.

Establishment and intra-/inter-laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation.

A reactive oxygen species (ROS) assay was previously developed for photosafety evaluation of pharmaceuticals, and the present multi-center study aimed to establish and validate a standard protocol for ROS assay. In three participating laboratories, two standards and 42 coded chemicals, including 23 phototoxins and 19 nonphototoxic drugs/chemicals, were assessed by the ROS assay according to the standardized protocol. Most phototoxins tended to generate singlet oxygen and/or superoxide under UV-vis exposure, but nonphototoxic chemicals were less photoreactive. In the ROS assay on quinine (200 µm), a typical phototoxic drug, the intra- and inter-day precisions (coefficient of variation; CV) were found to be 1.5-7.4% and 1.7-9.3%, respectively. The inter-laboratory CV for quinine averaged 15.4% for singlet oxygen and 17.0% for superoxide. The ROS assay on 42 coded chemicals (200 µm) provided no false negative predictions upon previously defined criteria as compared with the in vitro/in vivo phototoxicity, although several false positives appeared. Outcomes from the validation study were indicative of satisfactory transferability, intra- and inter-laboratory variability, and predictive capacity of the ROS assay.

Oxidation of aqueous pharmaceuticals by pulsed corona discharge.

Oxidation of aromatic compounds of phenolic (paracetamol, beta-oestradiol and salicylic acid) and carboxylic (indomethacin and ibuprofen) structure used in pharmaceutics was studied. Aqueous solutions were treated with pulsed corona discharge (PCD) as a means for advanced oxidation. Pulse repetition frequency, delivered energy dose and oxidation media were the main parameters studied for their influence on the process energy efficiency. The PCD treatment appeared to be effective in oxidation of the target compounds: complete degradation of pollutant together with partial mineralization was achieved at moderate energy consumption; oxidation proceeds faster in alkaline media. Low-molecular carboxylic acids were identified as ultimate oxidation by-products formed in the reaction.

The photodegradation of metronidazole in the presence of coexisting pharmaceuticals.

The objective of this study was to investigate if coexisting compounds could affect the fate of pharmaceuticals in surface water under solar irradiation. The degradation of metronidazole (MET) in the presence of different coexisting pharmaceuticals was investigated in batch experiments with exposure to sunlight. Tinidazole, which has a similar structure to MET, was employed as an analogue. The results indicated that the presence of an analogue with a similar photosensitive group to MET could inhibit the photodegradation of MET. In addition, the effect of coexisting pharmaceuticals with different absorption spectra on the degradation of MET was investigated. The results showed that the effect depended on the degree of overlapping absorption spectra between MET and the coexisting pharmaceuticals. The relationship between the degree of the influence and the ultraviolet absorption spectra of coexisting pharmaceuticals found in this study could give guidance in assessing the fate of pharmaceuticals in environmental water.

Degradation of some typical pharmaceuticals and personal care products with copper-plating iron doped Cu2O under visible light irradiation.

A mixture of five commonly used pharmaceuticals and personal care products (PPCPs) was degraded using a new combined catalyst under visible light irradiation. Scanning electron microscopy and X-ray diffraction analysis revealed that the combined catalyst was composed of copper-plating iron doped Cu2O (FeCu/Cu2O). Compared with the Fe/C inner micro-circuit, the electric currents flowing between Cu and Fe increase the speed of anodic Fe dissolution. Moreover, due to the photochemical properties, Cu2O can accelerate the PPCPs degradation processes under the irradiation of visible light. In addition, shaking increased the dissolved oxygen concentration in the solution, which not only preconditioned the photo-catalysis reaction, but also set the stage for Fe reduction. According to the experimental results, we propose the possible reaction mechanism of the reaction.

[Review of the stabitlity of photosensitive medications]. / Revisión de la estabilidad de los medicamentos fotosensibles.

OBJECTIVES: Identify the photosensitive drugs included in the hospital pharmacotherapeutic guide and search for stability data on the storage, reconstitution, and dilution of these compounds. METHODS: The data were obtained by referencing technical specifications, information provided by drug laboratories, and in some cases, we performed a more extensive bibliographic search (tertiary sources and conference lectures) for each particular medication. We also performed a data search on the PubMed information database (from 2004 to 2009). The drugs were placed in alphabetical order by brand since the stability of each drug when exposed to light does not depend exclusively on the primary active ingredient. Eight columns describe the principal characteristics of the drugs: brand name, active ingredient, laboratory, storage, reconstitution and dilution conditions, observations, and references. RESULTS: The listing was comprised of 139 photosensitive medicines, of the 1,954 included in the pharmacotherapeutical guide (table 1). CONCLUSIONS: The lack of studies published on the stability of photosensitive medications provided the need for an internal review at our hospital. It is important for drug-producing laboratories to perform photo-sensitivity tests on their products, with the results presented in the technical specifications in order to provide more accessible and reliable information. We believe that this should be required by law.

[Radiated drugs, the way of health]. / Médicaments irradiés, sources de santé.

During the inter-war years, the word "radiated" did not only suggest radioactivity, but it was also used to indicate exposure to others radiations, such as ultraviolets. The actinotherapy, a new therapy in vogue, was applied to many pathologies and tried on many substances. "Radiated drugs" result of those experimentations. Their therapeutical characteristics were found during searches on rickets. Our study relates the story of fight against rickets in France, from the use of cod liver oil to the synthesis of Vitamine D.

Use of commercial pharmaceutical drug (Daktarin®) for retrospective/accidental/forensic thermoluminescence dosimetry.

Retrospective/accidental dosimetry seeks for materials that can be used as probes for the dose assessment by means of several methods when there is no dose data available (e.g. from personal dosimeters). In the same respect, researchers also seek materials appropriate for forensic purposes, which would allow to identify the prior presence of radioactive materials at buildings, sites or even vehicles. To this direction, several solid-state drugs, which are ubiquitous, have also been studied as probes for the dose estimation in emergency situations. However, due to their heat-sensitive character, measurements were possible only with OSL. The scope of the present work is to identify a heat-resistant drug (Daktarin) and conduct, for the first time, a detailed study of the thermoluminescence properties of it along with computerized curve deconvolution analysis which would shed light on the traps involved. Results indicate that the glow curve of Daktarin has at least three peaks that can be used for dosimetric purposes, since they exhibit linear dose response for doses up to 20 Gy, do not exhibit any sensitization, have high lifetime and their stability with time is good, since an appreciable signal remains unaffected even 3 months post irradiation. All the above were validated conducting dose recovery tests and successfully calculating the unknown delivered dose for various periods after the irradiation of the samples. The new findings are very supportive and point towards the efficient use of commercial pharmaceuticals as probes for retrospective/accidental/forensic dosimetry using thermoluminescence.

Effects of Glycan Structure on the Stability and Receptor Binding of an IgG4-Fc.

A series of well-defined N-glycosylated IgG4-Fc variants were utilized to investigate the effect of glycan structure on their physicochemical properties (conformational stability and photostability) and interactions with an Fc γ receptor IIIA (FcγRIIIA). High mannose (HM, GlcNAc2Man(8+n) [n = 0-4]), Man5 (GlcNAc2Man5), GlcNAc1, and N297Q IgG4-Fc were prepared in good quality. The physical stability of these IgG4-Fc variants was examined with differential scanning calorimetry and intrinsic fluorescence spectroscopy. Photostability was assessed after photoirradiation between 295 and 340 nm (λ max = 305 nm), and HPLC-MS/MS analysis of specific products was performed. The size of glycans at Asn297 affects the yields of light-induced Tyr side-chain fragmentation products, where the yields decreased in the following order: N297Q > GlcNAc1 > Man5 > HM. These yields correlate with the thermal stability of the glycoforms. The HM and Man5 glycoforms display increased affinity for FcγRIIIA by at least 14.7-fold compared with GlcNAc1 IgG4-Fc. The affinities measured for the HM and Man5 IgG4-Fc (0.39-0.52 µM) are similar to those measured for fucosylated IgG1. Dependent on the mechanisms of action of IgG4 therapeutics, such glycoforms may need to be carefully monitored. The nonglycosylated N297Q IgG4-Fc did not present measurable affinity to FcγRIIIA.

Quantitative analysis in medicine using photoacoustic tomography.

Photoacoustic imaging, or photoacoustic tomography, is a 2D or 3D optical imaging method based on localized optical absorption of pulsed laser radiation. By a spatially resolved detection of the following thermoelastic expansion, the local distribution of the absorption can be determined. The technique has been proven to have significant potential for the imaging of human and animal organs and single blood vessels, combining high contrast with good spatial resolution. The contrast is based on the specific optical absorption of certain components in the visible and near-infrared spectral range, for most applications of blood. Generally, the images represent the local distribution of blood in a qualitative or semiquantitative way. Although photoacoustic imaging is capable of revealing absolute and spatially resolved concentrations of endogenous (such as oxyhemoglobin and deoxyhemoglobin) or artificial (such as tumor markers) chromophores, only a very limited number of publications have dealt with this demanding task. In this report, the problems involved and possible solutions are reviewed and summarized.

Implementation of a mathematical model for the photochemical kinetics of a solid form active pharmaceutical ingredient.

We present here the development of a photochemical model used to quantify the risk to photodegradation of a solid drug substance. A key feature of the proposed model development is streamlined estimation of the dependence of the absorption spectra and the quantum yield to the wavelength. A mathematical description of the relationship between the quantum yield and the wavelength enables estimation of photodegradation kinetics under any light anticipated to be encountered in the manufacturing environment. The system studied here consisted of a first order irreversible transformation (A → B(1Φ)) and the formalism strongly suggested the quantum yield was constant over the relevant wavelength range. The predictive power of the model enabled the design of a control strategy to limit the formation of the photo-degradant to very low levels. Also presented are insights obtained from quantum mechanical modeling of the electronic transitions associated with the UV absorption spectra.

Effects of Radiation on Drug Metabolism: A Review.

BACKGROUND: Radiation is the fourth most prevalent type of pollution following the water, air and noise pollution. It can adversely affect normal bodily functions. Radiation alters the protein and mRNA expression of drugmetabolizing enzymes and drug transporters and the pharmacokinetic characteristics of drugs, thereby affecting drug absorption, distribution, metabolism, and excretion. Therefore, it is important to study the pharmacokinetic changes in drugs under radiation. METHODS: To update data on the effects of ionizing radiation and non-ionizing radiation caused by environmental pollution or clinical treatments on the protein and mRNA expression of drug-metabolizing enzymes and drug transporters. Data and information on pharmacokinetic changes in drugs under radiation were analyzed and summarized. RESULTS: The effect of radiation on cytochrome P450 is still a subject of debate. The widespread belief is that higherdose radiation increased the expression of CYP1A1 and CYP1B1 of rat, zebrafish or human, CYP1A2, CYP2B1, and CYP3A1 of rat, and CYP2E1 of mouse or rat, and decreased that of rat's CYP2C11 and CYP2D1. Radiation increased the expression of multidrug resistance protein, multidrug resistance-associated protein, and breast cancer resistance protein. The metabolism of some drugs, as well as the clearance, increased during concurrent chemoradiation therapy, whereas the half-life, mean residence time, and area under the curve decreased. Changes in the expression of cytochrome P450 and drug transporters were consistent with the changes in the pharmacokinetics of some drugs under radiation. CONCLUSION: The findings of this review indicated that radiation caused by environmental pollution or clinical treatments can alter the pharmacokinetic characteristics of drugs. Thus, the pharmacokinetics of drugs should be rechecked and the optimal dose should be re-evaluated after radiation.

In-Use Photostability Practice and Regulatory Evaluation for Pharmaceutical Products in an Age of Light-Emitting Diode Light Sources.

This article describes how the increased use of energy-efficient solid-state light sources (e.g., light-emitting diode [LED]-based illumination) in hospitals, pharmacies, and at home can help alleviate concerns of photodegradation for pharmaceuticals. LED light sources, unlike fluorescent ones, do not have spurious spectral contributions <400 nm. Because photostability is primarily evaluated in the International Council of Harmonization Q1B tests with older fluorescent bulb standards (International Organization for Standardization 10977), the amount of photodegradation observed can over-predict what happens in reality, as products are increasingly being stored and used in environments fitted with LED bulbs. Because photodegradation is premised on light absorption by a compound of interest (or a photosensitizer), one can use the overlap between the spectral distribution of a light source and the absorption spectra of a given compound to estimate if photodegradation is a possibility. Based on the absorption spectra of a sample of 150 pharmaceutical compounds in development, only 15% would meet the required overlap to be a candidate to undergo direct photodegradation in the presence of LED lights, against a baseline of 55% of compounds that would, when considering regular fluorescent lights. Biological drug products such as peptides and monoclonal antibodies are also expected to benefit from the use of more efficient solid-state lighting.

Simultaneous analysis of FDG, ClDG and Kryptofix 2.2.2 in [18F]FDG preparation by high-performance liquid chromatography with UV detection.

A practical, sensitive and rapid analytical method was established and validated for chemical impurity tests of 2-deoxy-2-fluoro-d-glucose (FDG), 2-deoxy-2-chloro-d-glucose (ClDG) and Kryptofix 2.2.2 (K-222) in [18F]FDG. This method was based on precolumn derivatization with ultraviolet (UV) detection. FDG and ClDG were rapidly derivatized with 1-phenyl-3-methyl-5-pyrazolone in the presence of borate buffer at 40 degrees C, and the labeled derivatives and K-222 were separated by reversed-phase high-performance liquid chromatography and monitored by UV absorbance at 210 nm. After optimization of the conditions, FDG, ClDG and K-222 could be determined within 15 min and showed good performance in terms of sensitivity, linearity and reproducibility. This method could be successfully applied to the quality control test of [18F]FDG produced by a commercially available apparatus.

Cryo-irradiation as a terminal method for the sterilization of drug aqueous solutions.

The aim of this study is to evaluate the specificities of the irradiation of drugs in frozen aqueous solution. The structures of the degradation products were determined to gain insight into the radiolysis mechanisms occurring in frozen aqueous solutions. Metoclopramide hydrochloride and metoprolol tartrate were chosen as models. The frozen solutions were irradiated at dry ice temperature by high energy electrons at various doses. The drug purity (chemical potency) and the radiolysis products were quantified by HPLC-DAD. Characterization of the degradation products was performed by LC-APCI-MS-MS. The structures of the radiolysis products detected in irradiated frozen aqueous solutions were compared to those detected in solid-state and aqueous solutions (previous studies). For both metoclopramide and metoprolol, solute loss upon irradiation of frozen aqueous solutions was negligible. Five radiolysis products present in traces were identified in irradiated metoclopramide frozen solutions. Three of them were previously identified in solid-state irradiated metoclopramide crystals. The two others were formed following reactions with the hydroxyl radical (indirect effect). Only one fragmentation product was observed in irradiated metoprolol frozen solutions. For both drugs, radiosterilization of frozen solutions, even at high doses (25 kGy), was found to be possible.