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PubMed2006

Synthesis, labeling, and biological evaluation of halogenated 2-quinolinecarboxamides as potential radioligands for the visualization of peripheral benzodiazepine receptors.

The previous exploration of the structure-affinity relationships concerning 4-phenyl-2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands 6 showed as an interesting result the importance of the presence of a chlorine atom in the methylene carbon at position 3 of the quinoline nucleus. The subnanomolar PBR affinity shown by N-benzyl-3-chloromethyl-N-methyl-4-phenyl-2-quinolinecarboxamide (6b) suggested its chlorine atom to be replaced with other halogens in order to optimize the interaction of the quinolinecarboxamide derivatives with PBR and to develop suitable candidates for positron emission tomography (PET) or single photon emission computed tomography (SPECT) studies. The binding studies led to the discovery of fluoromethyl derivative 6a, which showed an IC50 value of 0.11 nM and is, therefore, one of the most potent PBR ligands so far described. Fluoromethyl derivative 6a has been labeled with 11C (t1/2=20.4 min, beta+=99.8%) starting from the corresponding des-methyl precursor (14) using [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF with a 35-40% radiochemical yield (corrected for decay) and 1.5 Ci/micromol of specific radioactivity. Ex vivo rat biodistribution and inhibition (following intravenous pre-administration of PK11195) studies showed that [11C]6a rapidly and specifically accumulated in PBR-rich tissues such as heart, lung, kidney, spleen, and adrenal, and at a lower level in other peripheral organs and in the brain. The images obtained in mouse with small animal YAP-(S)PET essentially confirmed the result of the ex vivo biodistribution experiments. The biological data suggest that [11C]6a is a promising radioligand for peripheral benzodiazepine receptor PET imaging in vivo.

Amides↗
PubMed2004

Novel halogenated nitrobenzylthioinosine analogs as es nucleoside transporter inhibitors.

Nucleoside transporter inhibitors have potential therapeutic applications as anticancer, antiviral, cardioprotective, and neuroprotective agents. We have synthesized and flow cytometrically evaluated the binding affinity of a series of novel halogenated nitrobenzylthioinosine analogs at the human es nucleoside transporter. Structure-activity relationships indicate the importance of hydrophobicity and electron withdrawing capacity of substituents at the para-position of the 6-position benzyl substituent. All of the compounds showed high binding affinity as shown by their ability to displace the fluorescent es transporter ligand, SAENTA-X8-fluorescein. Compound 16 (6-S-(para-iodobenzyl)-6-thioinosine) was the most tightly bound within the series with a K(i) of 3.88 nM (NBMPR exhibited a K(i) of 0.70 nM). This compound has higher affinity than the widely used nonnucleoside, nucleoside transport inhibitor, dipyridamole (K(i) = 8.79 nM), and may serve as a new lead compound.

Flow Cytometry↗
PubMed2004

Fluorescence quenching of parallel-stranded DNA bound ethidium bromide: the effect of 7-deaza-2'-deoxyisoguanosine and 7-halogenated derivatives.

Parallel stranded (ps) duplexes were constructed by incorporating 7-deaza-2'-deoxyisoguanosine (1a) or its 7-halogenated analogs 1b,c in place of 2'-deoxyisoguanosine. UV and Tm analyses prove the high affinity of ethidium bromide (EB) to these modified duplexes. Steady-state fluorescence measurement shows that the fluorescence is quenched when EB is bound to ps duplexes containing compounds 1a-c. The quenching effect depends on the 7-substituent of the nucleobase.

Base Pairing↗
PubMed2004

Vapour pressures, aqueous solubilities, Henry's Law constants, and octanol/water partition coefficients of a series of mixed halogenated dimethyl bipyrroles.

Basic physical-chemical properties of five bromine and chlorine containing mixed halogenated dimethyl bipyrroles (HDBPs) were determined using established methods. Subcooled liquid vapour pressures (P(o)(L,25)), aqueous solubilities (S(w,25)), and octanol/water partition coefficients (K(ow)) were determined using the gas chromatography-retention time, generator column, and slow-stirring methods, respectively. Henry's Law constants (H25) were estimated using experimentally-derived P(o)(L) and S(w,25) data. Values of all four properties were generally similar to those reported for other polyhalogenated aromatic compounds [P(o)(L,25) = (7.55-191) x 10(-6) Pa; S(w,25) = (1.0-1.9) x 10(-5) g/l; log K(ow) = 6.4-6.7; H25 = 0.0020-0.14 Pa m3/mol]. The effect of replacing a chlorine with a bromine atom significantly decreased P(o)(L,25) (log P(o)(L,25) = -0.4197 (# bromine atoms) - 2.643, p<0.01) and H25 (log H25 = -0.508 (# bromine atoms) + 0.394, p<0.02). There were no significant effects of bromine/chlorine substitution on S(w,25) or K(ow). A simple Level I equilibrium partitioning model predicted the environmental behaviour of HDBPs to be similar to a tetrabrominated diphenyl ether. Only slight differences in behaviour amongst HDBP congeners were predicted since substitution of a bromine for a chlorine (Cl/Br substitution) atom had less effect than H/Cl or H/Br substitution on P(o)(L,25), S(w,25), H25, and K(ow).

Bromine Compounds↗
PubMed2006

Monobromo and higher brominated congeners of the marine halogenated natural product 2,3,3',4,4',5,5'-heptachloro-1'-methyl-1,2'-bipyrrole (Q1).

The marine halogenated natural product 2,3,3',4,4',5,5'-heptachloro-1'-methyl-1,2'-bipyrrole (Q1) is widely distributed in the environment. In this study, we screened samples which have previously been found to contain remarkably high residues of Q1 (blubber of marine mammals from Australia, samples from Antarctica, human milk from the Faroe Island) for the additional presence of mixed chlorinated and brominated congeners. Using GC/ECNI-MS, all samples tested were positive and many contained four out of five possible bromohexachloro congeners (BrCl6-MBPs), five out of 14 possible dibromopentachloro congeners (Br2Cl5-MBPs), five of 21 possible tribromotetrachloro-congeners (Br3Cl4-MBPs), as well as several higher brominated congeners. About 20 heptahalo congeners of Q1 are described for the first time in the scientific literature. Isomers eluted within about one minute, respectively. Hence it is possible, that the peak clusters identified may be composed of more, co-eluting congeners. Similarities in the GC/ECNI-MS mass spectra with polychlorinated biphenyls (PCBs) were addressed. We also suggest an acronym system similar to that in use for polychlorinated biphenyls that may simplify the use of this substance class in scientific papers. In the samples from Australia, BrCl6-MBPs and Br2Cl5-MBPs amounted for 7-27.5% and 0.4-4.2% of Q1, respectively whereas Br3Cl4-MBPs and higher brominated MBPs were found in the range of <1% of Q1 or less.

Gas Chromatography-Mass Spectrometry↗
PubMed2004

Purge-and-trap capillary gas chromatography with atomic emission detection for volatile halogenated organic compounds determination in waters and beverages.

A method for the simultaneous determination of 10 volatile halogenated organic compounds (VHOCs), including four trihalomethanes (THMs), in waters and beverages was developed. The analytes were stripped from the aqueous sample by a flow of helium, preconcentrated in a capillary trap and thermally desorbed using a purge-and-trap (PT) system. This was followed by capillary gas chromatography with microwave-induced plasma atomic emission spectrometry (GC-AED). For element-specific detection, three wavelengths were monitored, corresponding to chlorine (479 nm), bromine (478 nm) and iodine (193 nm). Each chromatographic run took 21 min, including the purge time. After careful choice of the experimental conditions, the performance of the system was evaluated. Calibration curves were obtained by plotting peak area versus concentration and the correlation coefficients for linear calibration were at least 0.9987. Detection limits, calculated for 5 ml sample volume, ranged from 0.05 microg l(-1) for chloroform to 0.5 microg l(-1) for tetrachloromethane. The method was successfully applied to the quantitative analysis of water samples of different origin and also of several beer and juice samples. The tap water samples analyzed contain variable concentrations of the four trihalomethanes, ranging from 1.0 to 66.5 microg l(-1), depending of the compound. Whereas chloroform, bromodichloromethane and bromoform were found in some of the juice samples, only chloroform was detected in the beer samples. The method is reliable and can be used for routine monitoring in water and beverages.

Beverages↗
PubMed2005

Comparative study of aqueous and non-aqueous capillary electrophoresis in the separation of halogenated phenolic and bisphenolic compounds in water samples.

Capillary zone electrophoresis methods, based on either aqueous and non-aqueous solutions as running buffers and UV spectrophotometric detection, have been developed and optimized for the separation of several halogenated phenolic and bisphenolic compounds, suspected or proved to exhibit hormonal disrupting effects. Both aqueous capillary electrophoresis (CE) and non-aqueous capillary electrophoresis (NACE) methods were suitable for the analysis of compounds under study. The separation of the analytes from other 25 potentially interfering phenolic derivatives was achieved with NACE method. Large-volume sample stacking using the electroosmotic flow pump (LVSEP) was assayed as on-column preconcentration technique for sensitivity enhancement. LVSEP-CE and LVSEP-NACE improved peak heights by 5-26 and 16-330 folds, respectively. To evaluate their applicability, the capillary electrophoresis methods developed were applied to the analysis of water samples, using solid-phase extraction as sample pre-treatment process.

Electrophoresis, Capillary↗
PubMed2005

Improved analysis of volatile halogenated hydrocarbons in water by purge-and-trap with gas chromatography and mass spectrometric detection.

An analytical system composed of a purge-and-trap injection system coupled to gas chromatography with mass spectrometric detection (PTI-GC-MS) specific for the analysis of volatile chlorinated hydrocarbons (VCHCs) (chloroform; 1,1,1-trichloroethane; tetrachloromethane; 1,1,2-trichloroethylene; tetrachloroethylene) and trihalomethanes (THMs) (chloroform; bromodichloromethane; dibromochloromethane; bromoform) in water was optimised. Samples were purged and trapped in a cold trap (-100 degrees C) fed with liquid nitrogen (cryo-concentration). In order to make this method suitable also for only slightly contaminated waters, some modifications were made to PTI sample introduction, in order to avoid any air intake into the system. PTI, GC and MS conditions were optimised for halogenated compound analysis and limits of detection (LOD) were evaluated. The proposed method allows analysis of samples whose concentrations range from microg/L to ng/L. It is, therefore, applicable to drinking waters, in analyses required by law, and to slightly contaminated aqueous matrices, such as those found in remote areas, in environmental monitoring. Moreover, by changing cold trap temperature, even sparkling mineral waters can be analysed, thus avoiding CO2 interference during the cryo-concentration phase. Our method has been successfully used on real samples: tap water, mineral water and Antarctic snow.

Gas Chromatography-Mass Spectrometry↗
PubMed2006

Simultaneous determination of bisphenol A and its halogenated derivatives in river water by combination of isotope imprinting and liquid chromatography-mass spectrometry.

A restricted access media-molecularly imprinted polymer (RAM-MIP) for [2H16]bisphenol A (BPA-d16) was prepared by a multi-step swelling and polymerization method using 4-vinylpyridine as a functional monomer and ethylene glycol dimethacrylate as a cross-linker, followed by hydrophilic surface modification using glycerol dimethacrylate and glycerol monomethacrylate as hydrophilic monomers. The obtained RAM-MIP showed excellent molecular recognition abilities for BPA and BPA-d6 as well as BPA-d16 used as the template molecule, and good ones for tetrachlorobisphenol A (Cl4-BPA) and tetrabromobisphenol A (Br4-BPA). Next, the RAM-MIP was utilized for selective on-line pretreatment and enrichment of BPA, Cl4-BPA and Br4-BPA in a river water sample, followed by their separation and determination by LC-MS. The calibration graphs of BPA, Cl4-BPA and Br4-BPA, constructed using BPA-d6 as an internal standard, showed good linearity in the range of 12.5-200 pg/mL (r > 0.999) with a 2-mL injection of a river water sample. The inter-day precision data for the assay of BPA, Cl4-BPA and Br4-BPA at 25 pg/mL were 1.08, 3.67 and 1.58%, respectively. Furthermore, this method was successfully applied for the simultaneous determination of BPA and its halogenated derivatives in river water.

Benzhydryl Compounds↗
PubMed2002

Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism.

Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate beta-lyases to pyruvate, ammonia, and an alpha-chloroenethiolate (with DCVC) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate beta-lyases are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction.

Animals↗
PubMed1997

Halogenated aromatic hydrocarbon-mediated porphyrin accumulation and induction of cytochrome P4501A in chicken embryo hepatocytes.

Concentration-dependent induction of cytochrome P4501A (CYP1A) and intracellular porphyrin accumulation were observed following treatment of chicken embryo hepatocyte (CEH) cultures with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 3,3',4,4'-tetrachlorobiphenyl (PCB 77, IUPAC nomenclature), 2,3',4,4',5-pentachlorobiphenyl (PCB 118), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169), and a commercial mixture of PCBs (Aroclor 1254). For these halogenated aromatic hydrocarbons (HAHs), or mixture, maximal CYP1A activity [measured as ethoxyresorufin-O-deethylase (EROD) activity] and immunodetectable protein were observed at concentrations just prior to, or coincident with, the concentrations at which porphyrin accumulation became evident. Both immunodetectable CYP1A protein and catalytic activity decreased at high concentrations of these compounds, but the rate and extent of decrease of immunodetectable CYP1A protein varied. Time-course studies with PCB 77 indicated a decrease in potency and an increase in maximal CYP1A induction between 24 and 48 hr of exposure which may indicate in vitro metabolism of this HAH. Intracellular accumulation of total porphyrins without CYP1A induction, was observed for 2,2',5,5'-tetrachlorobiphenyl (PCB 52), 2,2',6,6'-tetrachlorobiphenyl (PCB 54), 2,2',3,5',6-pentachlorobiphenyl (PCB 95), 2,2',4,5,5'-pentachlorobiphenyl (PCB 101), 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136), and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153). Overall, these results are consistent with a role for CYP1A induction and/or Ah receptor activation in porphyrin accumulation mediated by HAHs with a planar configuration, whereas those that are not planar may mediate porphyrin accumulation by a mechanism not involving induction of CYP1A.

Animals↗
PubMed1997

Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the Meyer-Overton hypothesis of general anesthetic potency.

The membrane localization and properties of two halogenated cyclobutanes were examined using 2H and 19F NMR. The common predictors of potency indicate that these two compounds will have anesthetic activity; however, 1,2-dichlorohexafluorocyclobutane (c(CCIFCCIFCF2CF2)) is not an effective anesthetic, whereas 1-chloro-1,2,2-trifluorocyclobutane (c(CCIFCF2CH2CH2)) is an effective general anesthetic. Using 2H NMR, the effect of these compounds on the acyl chain packing in palmitoyl (d31) oleoylphosphatidylcholine membranes was examined. The addition of the anesthetic c(CCIFCF2CH2CH2) results in small increases in the segmental order near the headgroup, whereas segments deeper in the bilayer show decreases in order. These results are consistent with those obtained previously for halothane, isoflurane, and enflurane. On the addition of the nonanesthetic c(CCIFCCIFCF2CF2), the segmental order in vitually unchanged, except for a slightly changed order near the segents 10-12 of the palmitoyl chains. These results, and the 19F chemical shifts, indicate that the anesthetic c(CCIFCF2CH2CH2) exhibits a preference for the membrane interface, as do the other general anesthetics, whereas the nonanesthetic c(CCIFCIFCF2CF2) resides within the membrane hydrocarbon core. The compound c(CCIFCCIFCF2CF2) and other nonanesthetic halocarbons have lower molecular dipole moments compared to effective anesthetic halocarbons, which may account for their altered distribution within the membrane. These data strongly suggest that preferential localization of a halocarbon within the membrane interface is a predictor of anesthetic potency. Furthermore, the data indicate that the properties and forces in the membrane interface deserve consideration as mediators of anesthetic activity.

Anesthetics↗
PubMed2003

Identification and confirmation of traces of chlorinated fatty acids in fish downstream of bleached kraft pulp mills by gas chromatography with halogen-specific detection.

Methyl esters of threo-9,10-dichlorooctadecanoic, threo-7,8-dichlorohexadecanoic, and threo-5,6-dichlorotetradecanoic acids, present in transesterified extracts of filets, gonad, intestinal fat and carcass of white sucker (Catostomus commersoni) sampled in receiving waters of bleached kraft pulp mill effluents, were identified by gas chromatography with halogen-specific detection (XSD). Identification was based on (1) a comparison of the retention times of a sample peak with a prospective reference standard on two stationary phases of very different polarities by spiking, and (2) elution behavior of configurational and positional isomers of dichloro fatty acid methyl esters.

Animals↗
PubMed2003

Evaluation of modulators and electron-capture detectors for comprehensive two-dimensional GC of halogenated organic compounds.

Different cryogenic and a heated GC x GC modulator(s) were evaluated and compared for the analysis of high-boiling halogenated compounds. The cryogenic modulators investigated were: (i) the longitudinally modulated cryogenic system; (ii) the liquid-nitrogen-cooled jet modulator (KT2001); (iii) a dual-jet CO2 modulator (made in-house); (iv) a semi-rotating cryogenic modulator (made in-house) and (v) a CO2 loop modulator (KT2003); the heated modulator was the slotted heater system (sweeper). Each modulator was optimised with respect to analyte peak widths at half height in the second-dimension. n-Alkanes, chlorinated alkanes, polychlorinated biphenyls (PCBs) and fluorinated polycyclic aromatic hydrocarbons (F-PAHs) were used as test analytes. The flow rate of the coolant was found to be an important parameter, i.e. the flow rate of the gaseous nitrogen in the KT2001, and of the liquid CO2 in the other cryogenic modulators. For the slotted heater the stroke velocity and pause time were important parameters. This modulator had a limited application range in terms of temperature due to a necessary 100 degrees C difference between sweeper and oven temperature. All cryogenic modulators were found to be suitable for the GC x GC analysis of high-boiling compounds, but the CO2 modulators are to be preferred to the KT2001 due to a wider application range and slightly narrower peaks. As regards the performance of three commercially available electron-capture detectors (ECDs), the aim was to obtain narrow peak widths in GC x GC, i.e. to avoid band broadening caused by the cell volume. The most important parameters were the flow rate of the make-up gas and the detector temperature which both should be as high as possible. Comparison of analyte peak widths obtained with ECD mode and flame ionisation detection (FID) showed that all ECDs exhibited band broadening compared to the FID. The narrowest peaks were obtained with the Agilent micro-ECD, which has a cell volume of only 150 microl.

Chromatography, Gas↗
PubMed2004

Persistent halogenated compounds in black guillemots (Cepphus grylle) from Greenland--levels, compound patterns and spatial trends.

Twenty-seven black guillemot eggs and 39 livers were analysed for polychlorinated biphenyls (PCBs), chlorinated pesticides including chlordane-related compounds and toxaphene, and polybrominated diphenylethers (PBDEs). The samples were collected at Qeqertarsuaq (Godhavn, West Greenland) and Ittoqqortoormiit (Scoresbysund, East Greenland). The concentrations of halogenated organic compounds in samples from East Greenland were somewhat higher than the corresponding concentrations from West Greenland. Differences in compound patterns were found between West and East Greenland, with higher percentages of the heavier PCB molecules, p,p(')-DDE and alpha-HCH in the samples from Ittoqqortoormiit. Similarly, different levels and different compositions were observed for eggs and livers. The eggs had generally higher concentrations of all compounds as well as higher percentages of CHB-50, CHB-62 and alpha-HCH than liver samples from the same area. Dividing the liver samples into age groups revealed increasing concentrations with age.

Animals↗
PubMed2003

Adsorption of halogenated aromatic pollutants by a protein released from Bacillus pumilus.

Previous studies of the biosorption of halogenated aromatic pollutants (HAPs) have focused on the sorption of these compounds by cell bodies. However, in this study we investigated the adsorption of HAPs by biocompounds released from a bacterium, Bacillus pumilus. When B. pumilus was exposed to high temperature, it released a protein and carbohydrates, exclusively. After determining experimental conditions using 1,2,3,4-tetrachlorinated dibenzofuran (1,2,3,4-TCDF), the adsorption characteristics of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), chlorinated benzenes, and chlorinated naphthalenes were investigated. These HAPs were adsorbed considerably not only by cells but also by the released protein. In general, highly chlorinated congeners were adsorbed to a greater extent on the protein than lowly chlorinated ones, and the amount adsorbed differed between isomers. The present results are consistent with adsorption occurring via a passive physico-chemical mechanism. Finally, the importance of biocompounds released or excreted from microorganisms for the removal of HAPs is discussed.

Adsorption↗
PubMed1996

Enhancement of chromosome aberrations by the combination of DNA substitution with halogenated deoxyuridine and streptonigrin treatments.

We treated CHO cells with streptonigrin (SN) alone, in combination with BrdUrd or IdUrd substitution, and with or without the addition of caffeine. The cells assessed for chromosome damage by SN were in the G2 period and the magnitude of the damage was expressed as monosubstituted chromatid breaks, bisubstituted chromatid breaks and boundary regions breaks (boundary regions indicate the point of exchange of mono- and bisubstituted chromatids). We found that the combination of BrdUrd or IdUrd substitution with SN treatments produced a remarkable increase in the frequency of breaks over the frequencies observed with the halogenated compound only. The effect was more evident with IdUrd than with BrdUrd, and more dramatic in bisubstituted than in monosubstituted chromatids. The frequency of boundary breaks in cells treated with BrdUrd plus SN was similar to the frequency of breaks in monosubstituted chromatids treated similarly. Conversely, the damage in boundary regions was almost similar to that in bisubstituted chromatids in cells challenged with IdUrd plus SN. The addition of caffeine to BrdUrd-substituted chromosomes gave rise to a marked enhancement of breakages with a gradient of chromatid damage that was: bisubstituted > monosubstituted > boundary regions. A further increase of chromatin breaks maintaining the gradient indicated above was obtained when the cells were treated with BrdUrd plus SN plus caffeine. We propose that BrdUrd and IdUrd substitution alone or in combination with caffeine treatments and with SN in its capacity to bind DNA, give rise to different chromatin structures capable of modulating the DNA damage induced along the chromatin fibril by the active oxygen species liberated by SN-DNA complexes.

Animals↗
PubMed2002

Sustained release of etanidazole from spray dried microspheres prepared by non-halogenated solvents.

Etanidazole, a kind of radiosensitizer, was encapsulated in the spray-dried microspheres using biodegradable polymer PLGA 65:35 as the carrier for controlled release applications. Two non-halogenated solvents, e.g., ethyl acetate (EA) and ethanol, were tested to modify the properties of microspheres prepared by the commonly used solvent dichloromethane (DCM) alone. Their effects on the release behavior, morphology, particle size, and encapsulation efficiency of etanidazole-loaded microspheres were determined, and results were compared with DCM. The particle formation process via spray drying technique was also analyzed in order to understand the results obtained. It was found that larger percentage of EA (in the solvent mixture consisting of DCM and EA) in the fabrication of PLGA 65:35 microspheres decreases the initial burst, release rate and prolongs the release duration of etanidazole. In contrast to the spherical and porous microspheres prepared by DCM, the microspheres prepared by the solvent EA are all nonporous with a doughnut like surface structure due to its comparatively rapid phase transition (phase inversion) but slow solvent evaporation rate (longer time required to solidify). Increasing the polymer concentration (e.g., 4%, w/v) can bring about much more spherical microspheres by spray drying. Although ethanol, as a co-solvent, can dissolve a higher amount of etanidazole and lead to a higher drug encapsulation efficiency, the addition of ethanol in the DCM solvent can significantly increase the initial burst and the release rate of the microspheres due to the inhomogeneous drug distribution and structure of microspheres caused by phase separation. This study shows that ethyl acetate is an excellent low-toxic solvent that can be used in the spray drying technique for decreasing the initial burst, prolonging the release duration of a highly water-soluble drug like etanidazole. The use of EA provides a promising way to develop a sustained release system for etanidazole and other highly water-soluble drugs.

Acetates↗