Separation of Clinical Grade 188Re from 188W Using Polymer Embedded Nanocrystalline Titania

Currently, ¹⁸⁸Re is obtained from ¹⁸⁸W/¹⁸⁸Re chromatographic generator containing alumina which has a limited capacity (~80 mg Wg^?1) for ¹⁸⁸W. This results in high bolus volumes of ¹⁸⁸Re, which often needs to be concentrated before radiolabeling. We have demonstrated the feasibility of using polymer embedded nano crystalline titania (TiP), a novel high capacity sorbent material (~300 mg Wg^?1), for developing a ¹⁸⁸W/¹⁸⁸Re chromatographic generator. A TiP based chromatographic ¹⁸⁸W/¹⁸⁸Re generator was developed in which ¹⁸⁸Re could be eluted with 0.9% saline solution. About 90% of the ¹⁸⁸Re could be recovered in the first 4–5 mL of total activity with more than 80% yield. The purity of ¹⁸⁸Re is adequate for clinical applications.     

An improved tungsten-188/rhenium-188 gel generator based on zirconium tungstate

An improved¹⁸⁸W-¹⁸⁸Re gel generator based on Zr tungstate is described. The influence of synthesis parameters and pre-treatment conditions on¹⁸⁸Re elution yields and the¹⁸⁸W breakthrough was studied with 0.15M aqueous solution of NaCl at pH 5.3 to 7.3 as well as with some organic solvents. An elution efficiency of 80% was achieved during 3 month of explotation with 0.15M NaCl at pH=6.3. The¹⁸⁸W breakthrough was 10^–4 to 10^–3%. The¹⁸⁸W breakthrough may be decreased to 10^–6% when converted into tandem generator with an alumina column. However,¹⁸⁸Re yields are reduced by 8–12% with a tandem generator.     

188W-188Re gel generators based on metal tungstates

Gel generators based on Zn, Co, Ni, Mn and Pb tungstates were prepared as potential supports for the development of¹⁸⁸Re radiopharmaceuticals. Factors which affected either the elution efficiency of¹⁸⁸Re or the breakthrough of¹⁸⁸W were examined.¹⁸⁸Re was produced as perrenate when the generators were eluted with saline (0.15M NaCl) and different organic solvents. The elution yield of¹⁸⁸Re decreased for the various gel supports as: Zn (75%), Co (60%), Ni (37%), Mn (24%), Pb (15%). When a tandem system comprised of a chromatographic alumina column was utilized in combination with the gel generator the¹⁸⁸W breakthrough was controlled to of the order of 10^–6%.     

188Rhenium-glucoheptonate: A radiopharmaceutical for intravascular radiation therapy

The preparation of ¹⁸⁸Re-glucoheptonate (GH) is described using ¹⁸⁸Re, which was obtained from an alumina based ¹⁸⁸W/¹⁸⁸Re generator. The dependence of the radiolabeling yields of ¹⁸⁸Re-GH on reducing agent concentration, GH concentration, pH, temperature and incubation time was examined. In the case of optimum conditions the yield of ¹⁸⁸Re-GH was ~99%. The ITLC technique was employed to monitor the different species formed. A biodistribution study of ¹⁸⁸Re-GH was carried out in rats and compared to the biological behavior of ^99mTc-GH.     

188Rhenium-EDTMP: A potential therapeutic bone agent

Bone seeking radiopharmaceuticals such as ethylenediaminetetramethylene phosphonate (EDTMP) complexes of ¹⁵³Sm and ¹⁶⁶Ho are receiving considerable attention for therapeutic treatment of bone metastases. Rhenium-188 has both beta-particle emissions for a therapeutic effect and gamma-emissions for imaging and it is available from an in-house generator system similar to the current ^99mTc generator, which makes it convenient for clinical use. The preparation of ¹⁸⁸Re-EDTMP is described using ¹⁸⁸Re, which was obtained from the alumina-based ¹⁸⁸W/¹⁸⁸Re generator. Dependence of the radiolabeling yield of ¹⁸⁸Re-EDTMP on reducing agent concentration, EDTMP concentration, incubation time, pH and addition of carrier was examined. In the case of optimum conditions, the radiolabeling yields of ¹⁸⁸Re-EDTMP were ~98% for carrier-free as well as carrier-added ¹⁸⁸Re. The addition of ascorbic acid plays an important role in the stability of carrier-free as well as carrier-added ¹⁸⁸Re-EDTMP preparations. The biodistribution of carrier-free and carrier-added ¹⁸⁸Re-EDTMP compounds in rats was also studied. The results show that ¹⁸⁸Re (carrier-added)-EDTMP is a potential bone pain palliation radiopharmaceutical due to its high skeletal uptake, rapid blood clearance and relatively low soft tissue absorption.     

Production of carrier free <Superscript>188</Superscript>Re radioisotope generator based on aluminum tungstate matrix

Improved radionuclide generator include a substantially insoluble salt of a radioactive parent which may be directly packed in column for subsequent elution of the daughter radionuclide. An improved ¹⁸⁸Re generator was prepared by reacting a radioactive tungsten (¹⁸⁸W) as parent radionuclide incorporated with aluminum chloride to obtain an insoluble radioactive aluminum tungstate matrix. The investigated matrix was characterized on the basis of the chemical composition, IR, thermal analysis and mechanical stabilities. The factors affecting the elution performance were studied such as influence of pH, molar ratio and drying temperature. From the obtained data, the molar ratio W:Al was 1.5:1 at pH = 4, the matrix dried at 105 °C for 2 h. Chromatographic and multichannel analysis has been currently used to investigate the radiochemical and radionuclidic purity respectively on eluted ¹⁸⁸Re. An elution yield more than 80%, with radiochemical purity <98% and radionuclidic purity <99% with a ¹⁸⁸W break through >10⁻⁴% of the column. The Al⁺³ and W contents value were about 2 and 3 μg/mL eluate. The obtained data approved the stability of the prepared generator and its suitability for medical application.     

Production of carrier-free 188Re in the past ten years in Taiwan

Twenty clinical scale alumina-based ¹⁸⁸W/¹⁸⁸Re generators and carrier-free ¹⁸⁸Re has been produced at the Institute of Nuclear Energy Research (INER-Taiwan) for over ten years. 2845.6 GBq (76.9 Ci) of ¹⁸⁸Re-perrhenate solution has been eluted from generators during the past ten years. We have used the harvesting ¹⁸⁸Re solution for labeling radiopharmaceuticals, such as ¹⁸⁸Re-HEDP, ¹⁸⁸Re-MDP, ¹⁸⁸Re-microsphere, ¹⁸⁸Re-lipiodol, and ¹⁸⁸Re-sulfur colloid, etc. The average eluting yield of ¹⁸⁸Re is 78.6±5.8% that was investigated at 1115 harvesting times from 20 generators. Each generator can be used more than six months but the Millipore needs to be changed every two months for smooth harvesting and high yield of ¹⁸⁸Re solution.     

Formulation of a freeze-dried kit for 188Re-MAG3 and its quality control

The synthesis of ¹⁸⁸Re-MAG₃ is described using ¹⁸⁸Re, which was obtained from the alumina based ¹⁸⁸W/¹⁸⁸Re generator. Dependence of the radiolabeling yields of ¹⁸⁸Re-MAG₃ on reducing agent concentration, Bz-MAG₃ concentration, pH, temperature and incubation time was examined. In the case of optimum conditions the yield of ¹⁸⁸Re-MAG₃ was 98%. TLC and HPLC techniques were employed to monitor the different species formed. Biodistribution study of ¹⁸⁸Re-MAG₃ was carried out in rats and compared with behavior of ^99mTc-MAG₃.     

The tungsten-188/rhenium-188 generator: Effective coordination of tungsten-188 production between the HFIR and BR2 reactors

The rapidly increasing therapeutic applications of ¹⁸⁸Re in nuclear medicine, oncology and interventional cardiology require routine production of large, multi-Curie levels of the ¹⁸⁸W parent. The capability and effective coordination of back-up production sites is important to insure that high level ¹⁸⁸W/¹⁸⁸Re generators are continually available. We have coordinated ¹⁸⁸W production at the High Flux Isotope Reactor (HFIR - Oak Ridge, US) with production at the BR2 Reactor (Mol, Belgium) characterized by peak thermal neutron fluxes of 2.51·0¹⁵ (HFIR) and 1·10¹⁵ (BR2) neutrons/cm²·sec, respectively. The long 69-day physical half-life permits receipt of ¹⁸⁸W from BR2 within 0.25 T _1/2's, even after the 12-day post irradiation cooling required for ¹⁸⁷W decay (T _1/2 = 24 hours). Since ¹⁸⁸W production by double neutron capture of enriched ¹⁸⁶W is a function of the square of the thermal neutron flux, HFIR production (4-5 Ci ¹⁸⁸W/g ¹⁸⁶W/cycle) is higher than at the BR2 (1.0-1.1 Ci/g ¹⁸⁶W/cycle). However, the specific activity (SA) of BR2-produced ¹⁸⁸W is still about 0.8-0.9 Ci/g after processing at ORNL following shipment from Belgium. This SA is sufficiently high to permit fabrication of 1 Ci generators suitable for clinical use, since simple post elution concentration of the saline bolus (30-50 ml) obtained from the generator can provide samples with high specific volume (1 ml volume). The time periods from reactor push in Mol and completion of processing, fabrication and shipment of generators from Oak Ridge have been 19-21 days. Six campaigns have been successfully completed since 1998, with processed levels of ¹⁸⁸W in Oak Ridge from 8-26 Curies/campaign. ¹⁸⁸W has been provided to MAP Medical technologies Oy (Tikkakoski, Finland) for fabrication and distribution of generators for use at IAEA-supported research projects in developing countries. We have thus established and demonstrated an effective collaboration between the Studiecentrum voor Kernenergie-Centre d'Etude de l'Energie Nucléaire (SCK·CEN) and ORNL for back-up production of ¹⁸⁸W. This collaboration continues to be especially helpful during periods when interruption of HFIR operation is necessary for maintenance and upgrades.     

Studies of gel metal-oxide composite samples as filling materials for W-188/Re-188 generator column

Studies of zirconium tungstate gels for production of ¹⁸⁸W/¹⁸⁸Re generators using tungsten of natural isotopic abundance irradiated in a moderate flux nuclear reactor have been carried out. Composites of WO₃–ZrO₂ have been synthesized by Complex Sol–Gel Process developed in INCT and other techniques. Different proportions of metal oxides and temperature were applied. Elution profiles of columns filled with gel samples irradiated in nuclear reactor have been studied using as an eluent 0.9% NaCl solution. Purity of ¹⁸⁸Re fraction and efficiency of elution were determined. Ageing effect on elution efficiency was also examined. It was found that the best elution performance showed zirconium tungstate gel prepared in 110 °C or 500 °C in which molar ratio of metal oxides was 1:2.     

Practicality of Tetragonal Nano-Zirconia as a Prospective Sorbent in the Preparation of 99Mo/99mTc Generator for Biomedical Applications

The feasibility of using tetragonal nano-zirconia (t-ZrO₂) as an effective sorbent for developing a ⁹⁹Mo/^99mTc chromatographic generator was demonstrated. The structural characteristics of the sorbent matrix were investigated by different analytical techniques such as XRD, BET surface area analysis, FT-IR, TEM etc. The material synthesized was nanocrystalline, in tetragonal phase with an average particle size of ~7 nm and a large surface area of 340 m² g^?1. The equilibrium sorption capacity of t-ZrO₂ is >250 mg Mo g^?1. The present study indicates that ⁹⁹Mo is both strongly and selectively retained by t-ZrO₂ at acidic pH and ^99mTc could be readily eluted from it, using 0.9% NaCl solution. A 9.25 GBq (250 mCi) t-ZrO₂ based chromatographic ⁹⁹Mo/^99mTc generator was developed and its performance was repeatedly evaluated for 10 days. ^99mTc could be eluted with >85% yield having acceptable radionuclidic, radiochemical and chemical purity for clinical applications. The compatibility of the product in the preparation of ^99mTc labeled formulations such as ^99mTc-EC and ^99mTc-DMSA was evaluated and found to be satisfactory.     

Identification of Acepromazine and Its Metabolites in Horse Plasma and Urine by LC–MS/MS and Accurate Mass Measurement

Acepromazine maleate (Sedalin^®) was administered orally to six thoroughbred horses at a dose of 0.15 mg kg⁻¹. Urine and blood samples were collected up to 412 h post-administration. Plasma and urine were hydrolysed; plasma samples were then processed using liquid–liquid extraction and urine samples using solid-phase extraction. A sensitive tandem mass spectrometric method was developed in this study, achieving a lower limit of quantification for acepromazine of 10 pg mL⁻¹ in plasma and 100 pg mL⁻¹ in urine. Acepromazine, hydroxyethylpromazine, hydroxyacepromazine, hydroxyethylpromazine sulphoxide, hydroxyethylhydroxypromazine, dihydroxyacepromazine and dihydroxyhydroxyethylpromazine were detected in the post-administration samples. The parent drug and its metabolites were identified using a combination of UPLC–MS/MS and accurate mass measurement. Separation of the structural isomers hydroxyethylpromazine sulphoxide and hydroxyethylhydroxypromazine was another significant outcome of this work and demonstrated the advantages to be gained from investing in chromatographic method development.

     

Preparation and evaluation of two 188Re-radiopharmaceuticals for endovascular irradiation

Procedures for complexing DTPA with ¹⁸⁸Re from a ready kit and by conventional manipulation were elaborated and the study of the stability and biodistribution of ¹⁸⁸Re perrhenate and ¹⁸⁸Re-DTPA were performed. Best labeling was achieved using DTPA (38 mM) with 2 mg/ml of SnCl₂ ·2H₂O. The radiochemical purity was 95.9±2.9%. The complex was stable for 24 hours when ascorbic acid was used. Greatest uptake of ¹⁸⁸Re-DTPA was by kidneys (19.3±2.1%ID/g) and for ¹⁸⁸Re-perrhenate by stomach (21.3±2.8%ID/g). In conclusion a kit of freeze-dried DTPA was developed. Organ damage is unlikely by virtue of its rapid urinary excretion. This revised version was published online in July 2006 with corrections to the Cover Date.     

Development and Validation of Stability Indicating LC Method to Quantify Captopril in Tablets of Controlled Release

An accurate, simple, reproducible, and sensitive liquid chromatographic method was developed and validated for the captopril determination in controlled release tablets. The analyses were performed at room temperature on a reversed-phase Phenomenex Luna C₁₈ column (250 mm × 4.6 mm). The mobile phase was composed of water:methanol (45:55; v/v) pH 2.5, and it was eluted isocratically at a 1.0 mL min⁻¹ flow rate. The method was validated in terms of specificity, linearity, quantification limit, detection limit, accuracy, precision and robustness. The response was linear in the range 0.3–1.5 mg mL⁻¹ (r ² = 0.9983). The relative standard deviation values for inter-and intra-day precision were 0.77% and 0.50%, respectively. Recoveries ranged between 97.7 and 99.1%. The method was successfully applied for the determination of captopril in the developed formulations.

     

Identification of Iridoids,Flavonoids and Triterpenes from the Methanolic Extract of Melampyrum bihariense A. Kern. and the Antioxidant Activity of the Extract

Melampyrum bihariense A. Kern. (Scrophulariaceae), a plant species used in traditional medicine for the treatment of rheumatic disorders and skin infections, was investigated with regard to its antioxidant activity and identification of its bioactive chemical constituents. The crude methanolic extract of the aerial parts of M. bihariense was examined by the spectrophotometric DPPH (1,1-diphenyl-2-picrylhydrazyl) and ferric reducing antioxidant power methods. The free radical scavenging capacity (SC₅₀) of the extract was found by the DPPH method to be 27.10 mg mL⁻¹, and the ferric reducing ability equivalent to ascorbic acid at 50 mg mL⁻¹ was 0.709 μg mL⁻¹. The chemical composition of this highly effective in the methanolic extract was analysed, and the main compounds were isolated through solvent–solvent partition, and multiple chromatographic separations, including column chromatography, vacuum liquid chromatography, centrifugal planar chromatography and preparative thin-layer chromatography. The structures were established by one- and two-dimensional NMR and liquid chromatography-mass spectrometry. The iridoids aucubin (1), 8-epi-loganin (2) and mussaenoside (3), the flavones apigenin and luteolin and the triterpene acids ursolic acid and oleanolic acid were identified; components 2, 3, ursolic acid and oleanolic acid for the first time in this species. The present study reveals that M. bihariense exerts antioxidant activity, and the iridoids, flavonoids and triterpene acids may be the main bioactive constituents of its methanolic extract.

     

An On-line Admicellar SPE-HPLC System Using CTAB-Modified Zeolite NaY as Sorbent for Determination of Carbamate Pesticides in Water

Zeolite NaY modified with cetyltrimethylammonium bromide (CTAB) was considered for extraction/preconcentration of carbamate pesticides using an on-line SPE-HPLC system. The simultaneous determination of carbamate pesticides, including aldicarb, carbofuran, carbaryl, isoprocarb, methiocarb and promecarb, was performed by HPLC–UV using a LichroCART RP-18 column with gradient elution of methanol and 0.1 % acetic acid. The sorbent presented admicelles of CTAB on its surfaces and exhibited a sorption capacity of 180–18,600 mg kg⁻¹ sorbent, which could be re-modified for at least five extraction cycles. The quantitative retention of target pesticides on the admicellar sorbent involved hydrophobic and π-cation interaction, while pesticides were eluted from the admicellar SPE column using only 750 μL of methanol. LODs and LOQs of the proposed method were 0.005–140 and 0.02–600 μg L⁻¹, respectively. The analytes were effectively concentrated with the enrichment factors between 5 and 551. The developed on-line admicellar SPE-HPLC system was successfully applied to the determination of carbamate pesticides in ten environmental water samples from different sources. Recoveries of spiked samples at a concentration of 0.1–5 mg L⁻¹ ranged from 77 to 111 %.

     

Porous ZrC-carbon microspheres as potential insoluble target matrices for production of <Superscript>188</Superscript>W/<Superscript>188</Superscript>Re

New microsphere sorbents are reported, which could find application in demanding radiation environments and especially as targets for the production of nuclear medicines by neutron irradiation. An easily-synthesized Zr anionic complex was introduced into quaternary amine-functionalised polystyrene-divinylbenzene-based anion-exchange resins by batch adsorption. Upon carbothermal reduction, the precursors were converted to porous carbon matrices containing particles of ZrC and ZrO₂ polymorphs. The most phase-pure material, ZrAX-1, possessed high surface area, multi-scale porosity and high mechanical strength. Adsorption of Re and W was investigated and its possible deployment as a reusable host for the production of ¹⁸⁸W/¹⁸⁸Re is discussed.     

Focused Microwave-Assisted Extraction and LC Determination of Ketoprofen in the Presence of Preservatives in a Pharmaceutical Cream Formulation

A simple and rapid open-vessel focused microwave-assisted extraction (FMAE) method followed by LC analysis was developed for the determination of ketoprofen lysine salt in the presence of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate preservatives in topical cream. Extraction were performed in acetone/potassium dihydrogenphosphate (25 mM, pH 3.0) (70:30 v/v) by reaching a target temperature of 65 °C in a 10 min linear ramp. The chromatographic separation was performed on a Discovery RP-Amide C16 column (250 × 4.6 mm I.D., 5 μm particle size). The optimal mobile phase consisted of acetonitrile/potassium dihydrogen phosphate 25 mM adjusted to pH 3.0 with phosphoric acid (50:50 v/v). The complete analytical procedure was validated with regard to limit of quantification, linearity, precision and accuracy. The method was linear over the concentration range of 0.08–0.12 mg mL⁻¹; the relative standard deviations of intra- and inter-day assays were 1.9–2.3 and 1.8% respectively. The limit of quantification was 0.54 μg mL⁻¹. The proposed method shows many advantages as short extraction time, little solvent consumption without requiring further sample clean-up steps before liquid chromatographic analysis and is proposed for vast scale screening of cream dosage forms aimed to the detection of counterfeit and substandard drugs.

     

Determination of Three Nonsteroidal Anti-Inflammatory Drugs in Human Plasma by LC Coupled with Chemiluminescence Detection

A simple and sensitive method was developed for the determination of three nonsteroidal anti-inflammatory drugs (NSAIDs)—ibuprofen, naproxen and fenbufen in human plasma. The method involved in column liquid chromatographic separation and chemilumenescence (CL) detection based on the CL reaction of NSAIDs, potassium permanganate (KMnO₄) and sodium sulfite (Na₂SO₃) in sulfuric acid (H₂SO₄) medium. The chromatographic separation was carried out using a reversed-phase C₁₈ column, which allowed the selective determination of the three medicines in the complicated samples. The special features of the CL detector provided lower LOD for determination than that of existing chromatographic alternatives. The results indicated that the linear ranges were 0.01–10.0 μg mL⁻¹ for ibuprofen, 0.001–1.0 μg mL⁻¹ for naproxen, and 0.01–10.0 μg mL⁻¹ for fenbufen. The limits of detection were 0.5 ng mL⁻¹ for ibuprofen, 0.05 ng mL⁻¹ for naproxen and 0.5 ng mL⁻¹ for fenbufen (S/N = 3). All average recoveries were in the range of 90.0–102.3%. Finally, the method had been satisfactorily applied for the determination of ibuprofen, naproxen and fenbufen in human plasma samples.

     

Modified carbon nanotubes as a sorbent for solid-phase extraction of gold,and its determination by graphite furnace atomic absorption spectrometry

A simple, sensitive and accurate method was developed for solid-phase extraction and preconcentration of trace levels of gold in various samples. It is based on the adsorption of gold on modified oxidized multi-walled carbon nanotubes prior to its determination by graphite furnace atomic absorption spectrometry. The type and volume of eluent solution, sample pH value, flow rates of sample and eluent, sorption capacity and breakthrough volume were optimized. Under these conditions, the method showed linearity in the range of 0.2–6.0 ng L⁻¹ with coefficients of determination of >0.99 in the sample. The relative standard deviation for seven replicate determinations of gold (at a level of 0.6 ng L⁻¹) is ±3.8 %, the detection limit is 31 pg L⁻¹ (in the initial solution and at an S/N ratio of 3; for n = 8), and the enrichment factor is 200. The sorption capacity of the modified MWCNTs for gold(III) is 4.15 mg g⁻¹. The procedure was successfully applied to the determination of gold in (spiked) water samples, human hair, human urine and standard reference material with recoveries ranging from 97.0 to 104.2 %.

A sorbent based on modified carbon nanotubes was prepared and used to extract gold ion from various samples prior to its determination by graphite furnace atomic absorption spectrometry