Radionuclides for radiopharmaceuticals can be produced in cyclotrons or nuclear reactors. Each of these production modes has serious issues, such as high target costs, production of long-lived wastes ...and contaminants, expensive separation. For this reason, new methods are under consideration for the production of highly pure radionuclides. The ISOL (Isotope Separation On-Line) method is the major technique for the production of radioactive ion beams for nuclear physics applications. The SPES-ISOLPHARM project at INFN-LNL (Istituto Nazionale di Fisica Nucleare-Laboratori Nazionali di Legnaro) is a feasibility study for the production of medical isotopes exploiting the ISOL method. The ongoing activities concerning a recent experiment focused on
111
Ag, a study performed in collaboration with Padova and Trento Universities, is presented.
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•Theory of pH-static titrations for metal + ligand complexation kinetics was given.•pH static titrations represent a kinetic method alternative to spectrophotometry.•The kinetics of ...Sr2++DOTA reaction at various pH and temperatures was studied.•Other used methods for kinetic measurements can give wrong results.
The theory of pH-static (or pH-stat) titrations in kinetic measurements of metal ion + ligand complex formation was resumed, and equations required to fit the experimental data were derived. This method was applied to study the kinetics of Sr2++DOTA reaction (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). pH-static titrations were performed at various pH (from 4.00 to 6.00) and temperatures (5, 15, and 25 °C) and at a constant ionic strength of (Na)Cl 0.15 mol/L. The complex formation involved either a rapidly formed intermediate species which then gave the final complex, or the direct metal + ligand reaction. The corresponding equilibrium constant βos and kinetic constants kos (first order) and k (second order) were obtained. Both k and kos increased by increasing pH and temperature. Kinetic data were recorded by pH-static titrations also for Ni2++DOTA reaction, and other kinetic results were obtained by using a more commonly employed method, proposed by Kasprzyk and Wilkins S. P. Kasprzyk and R. G. Wilkins, Inorg. Chem., 1982, 21, 3349, which however appears to be theoretically incorrect. The comparison between the kinetic results for Sr2++DOTA and Ni2++DOTA reactions obtained by pH-static titrations, by the Kasprzyk/Wilkins method, and by the well-established spectrophotometric method (literature data), indicated that the Kasprzyk/Wilkins method should be used with caution as sometimes its systematic errors can be statistically relevant with respect to the typical precision of kinetic data.
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•The granulation process depends on the rheological properties of the wet mass.•A mixer torque rheometer represents a valuable tool for the process development.•The use of a mixer ...torque rheometer was used to assess optimal amount of binder.•The maximum torque developed by the wet mass was used to predict the growth regime.
Although high-shear wet granulation is widely used, the knowledge of this operation is not yet fully clarified and the process design is particularly difficult.
The evolution of this process depends on strength and plasticity of the wet masses, consequently the purpose of this study was to develop a rheological method able to predict the granule growth. To pursue this goal, the torque evolution over the time of three different wet powder formulations was recorded in a mixer torque rheometer (MTR3, Caleva, UK). The torque profiles were then analyzed to find a characteristic torque value that could be correlated to the strength and the deformability of the wet granules. The first selected formulation was composed of 100% (w/w) of microcrystalline cellulose (MCC100), the second consisted in a mixture 1:1 of sucrose and microcrystalline cellulose (SUCR50) and the third contained 5% (w/w) of xanthan gum and 95% (w/w) of microcrystalline cellulose (XG5).
Granulation experiments (material exchange experiments and extended granulation experiments) were performed using different experimental conditions (different amount of liquid binder and impeller speed) to identify the growth mechanism of three formulations studied. Results have shown that the maximum torque peak (Tpk) developed by the wet masses over the time can be successfully used to predict the granule growth mechanisms. In particular, for formulations that developed relatively high Tpk values (>0.2Nm/g), consolidation and growth of the granules were difficult, and an induction growth mechanism could be observed (formulation XG5). If Tpk values lower than 0.2Nm/g, the deformability of the wet mass was high, and the growth regime corresponded to the steady growth (formulations MCC100 and SUCR50).
In addition, experiments have shown that the higher the Tpk values, the faster the growth kinetic. In conclusion the rheological characterization of the wet masses demonstrated to be useful to predict granule growth behaviour in high shear wet granulation and the developed method could represent a valuable tool in the process design and development.
Accelerator-based techniques with electromagnetic mass separation are considered among the most innovative and promising strategies to produce non-conventional radionuclides for nuclear medicine. ...Such approach was successfully used at CERN, where the dedicated MEDICIS facility was built, and at TRIUMF, where the ISAC radioactive beam facility was used to produce unconventional α-emitters. In such framework, the Legnaro National Laboratories of the Italian Institute of Nuclear Physics (INFN-LNL) proposed the ISOLPHARM project (ISOL technique for radioPHARMaceuticals), which will exploit radionuclides producible with the SPES (Selective Production of Exotic Species) ISOL (Isotope Separation On-Line) facility to develop novel radiopharmaceuticals. The ISOL technique utilizes the irradiation with a primary beam of particles/nuclei of a production target where radionuclides are produced. A radioactive ion beam is subsequently extracted from the production target unit, and transported up to an analyzing magnet, where non-isobaric contaminants are filtered out. The so-obtained purified radioactive beam is dumped onto an implantation substrate, referred as collection target. Then, the desired nuclides can be chemically harvested from the collected isobars, and the isotopically pure atom collection can be employed to radiolabel high specific activity radiopharmaceuticals. Metallic deposition targets in the form of coated metal foils were mostly used at TRIUMF and CERN. At ISOLPHARM, a different approach is under investigation which foresees the use of soluble cold-pressed collection targets, possibly facilitating the chemical purification process of the collected radionuclides. In this study, the production and characterization of some of the ISOLPHARM collection targets is presented, in particular, soluble salts (NaCl and NaNO3) and organic materials widely used for pharmaceutical tablets production are considered. All such materials proved to be potentially suitable as collection targets, since solid samples were easily produced and resulted compatible with the vacuum conditions required for the ion implantation process. Furthermore, some of the selected substrates were used for proof-of-concept deposition tests with stable silver, to prove their suitability as ISOLPHARM deposition substrates for silver-111, a promising candidate for radiotherapy. Such tests highlighted possible scenarios useful for the development of new alternative materials, as the use of insoluble organic targets.
•ISOL based techniques for the production of medical radionuclides require the use of an implantation target.•Generally, implantation targets are metallic foil, ISOLPHARM at INFN-LNL proposes saline or organic substrates.•NaCl, NaNO3, cellulosic and dextrates substrates were produced by direct compression.•All samples were characterized in terms of density, mechanical strength, disaggregation and vacuum compatibility.•Implantation depth calculations and tests with the deposition of Ag + ions were performed.
Improvements of the oral bioavailability of lipophilic drugs can be obtained using lipidic formulations such as the self-emulsifying drug delivery systems. The high shear wet granulation (HSWG), ...using microemulsions as binder, is a viable process to produce self-emulsifying granules. However only few information are present in the literature on the effect of process variables on the properties of the granules obtained with these binders. Consequently, this article compares the effects of some relevant experimental variables (impeller speed and massing time) on the final technological and pharmaceutical properties of the granules produced using simple water, or alternatively, a microemulsion as binder and containing simvastatin (SV) as model drug. The effects of the variables were determined by evaluating the granule median diameter, their particle size distribution, roundness, disintegration time and dissolution rate of SV. Results clearly demonstrated that the microemulsion-based process was less sensitive to operating conditions than the water-based process. With microemulsion the nucleation process and growth regimes were more difficult to control, resulting in products with broader PSDs. At the same operating conditions microemulsion-based granules were more brittle but rounder and showed smaller median diameter compared to water-based granules. The dissolution rate of simvastatin was not significantly affected by the operating conditions.
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•Wet granulation process in high shear mixer is a useful technique to produce SEDDS.•Granules containing microemulsion can be used to increase dissolution of simvastatin.•Properties of microemulsion based granules are insensitive to operating conditions.•Microemulsion based granules are more plastic and rounder than water based granules.
Radiopharmaceuticals represent a fundamental tool for nuclear medicine procedures, both for diagnostic and therapeutic purposes. The present work aims to explore the Isotope Separation On-Line (ISOL) ...technique for the production of carrier-free radionuclides for nuclear medicine at SPES, a nuclear physics facility under construction at INFN-LNL. Stable ion beams of strontium, yttrium and iodine were produced using the SPES test bench (Front-End) to simulate the production of 89Sr, 90Y, 125I and 131I and collected with good efficiency on suitable targets.
•The use of ISOL method for radionuclides production is proposed.•ISOL method allows to produce carrier-free radionuclides for nuclear medicine.•Tests with stable ion beams were produced as a proof of concept.•Sodium Chloride is suitable as material for targets for Sr and Y beams.•Activated Carbon can be compacted with PVA to have a solid target for I2 beams.
Mixer agglomeration, in particular high shear wet granulation, is a unit operation typically used in the pharmaceutical industry to improve the flowability, the compressibility, the dosing accuracy ...during tableting or the content uniformity of a blend. Thanks to its advantages (production of spherical and dense granules, reduction of production time), this technique can be potentially successful also in the food industry as for example in the production of dietary supplements. In this work four thickening agents (povidone, maltodextrin, k-carrageenan and xanthan gum) have been tested to study their effects on the granule growth behavior and on some technologically relevant granule properties (size, shape, strength and flowability). Experiments highlighted the full feasibility of the process and the possibility of using these agents to get products with satisfactory technological properties. The dependence of product properties on the formulation variables (water and binder amount) has been analyzed according to a multivariate approach and a robust predictive tool for the granule size has been developed. Furthermore it was observed that a reduced amount of binding liquid (water) can be used in the presence of strongly thickening binders with a reduction up to 25%. This would decrease drying time and energy requirement and be beneficial especially in the food and food supply industry where products have generally lower added value than in the pharmaceutical one and reducing production costs is critical.
•High shear granulation was successfully performed using alternative thickening agents.•It was possible to predict granule size through experimental design techniques.•Agents with high thickening power reduced water required for granulating up to 25%.
In this investigation, the preparation of solid self-emulsifying drug delivery systems (solid-SEDDS) by means of a wet granulation process was optimized in a lab-scale high shear mixer in order to ...improve the dissolution rate of piroxicam, a poorly water-soluble model drug. With this aim, the classic liquid granulation binder was replaced with an oil-in-water microemulsion, loaded with the drug.
The microemulsion formulations were first selected on the basis of phase diagrams and their physicochemical properties, such as viscosity and droplet size. The best microemulsions were then used to prepare solid-SEDDS while maintaining the composition of the solid carrier and the operating conditions of the lab-scale high shear mixer used in this study.
These pellets demonstrated an emulsifying capability and their piroxicam release was significantly enhanced with respect to pure drug. Since their dissolution was a function of pellet size fraction, in the subsequent step the yield of the best performing fraction was further increased by modifying experimental conditions for pellet production (impeller speed and amount of povidone). In this way, the 400μm pellet size fraction of the selected formulation was produced with a percentage yield of 42.5 by wt., with satisfactory technological properties and unchanged drug dissolution performance.
In this paper, solid self-emulsifying drug delivery systems have been produced by means of a wet granulation process using an emulsion as a binder in order to increase oral bioavailability of piroxicam. The process has been optimized by setting the amount of povidone and the impeller speed during massing time. Display omitted
► Self-emulsifying pellets were prepared and optimized in high shear mixer. ► The pellets demonstrated emulsifying capability. ► Solid-SEDDS significantly improved the piroxicam dissolution rate.
Stability, defined as the reproducible behavior of a device upon its storage, is an important issue in pharmaceutical formulation. Silica xerogels obtained through the sol-gel route are relatively ...new as matrices for the controlled release of drugs. In some cases, it was observed that their behavior changes upon storage, so that they cannot always be defined as "stable". This occurs especially when gel processing is performed at mild temperatures, a procedure that may have to be used to prevent degradation of the embedded drug. This work investigated the use of inorganic catalysts as potential xerogel stability inducers when gel curing by heating is not applicable. Three compounds known to accelerate sol-gel polymerization, namely ammonia, sodium fluoride and sodium carbonate, were introduced during the polymerization of low-temperature processed inorganic and organically modified gels, and the effect of each compound on xerogel stability and drug release was monitored. The use of carbonate leads to formulations with good retention properties, as opposed to ammonia and NaF, which lead to poorly retentive xerogels in accordance with their known ability to increase porosity. Ammonia was shown to be a poor stability promoter independently of gel composition, as opposed to fluoride and carbonate, which both displayed stabilizing properties in a dose-dependent manner. No correlation was found between xerogel stability and drug release properties. An attempt was also made to correlate stability data with polymerization rates and wet gel syneresis time evolution with the purpose of identifying one or more synthesis parameters that could act as stability predictors for pre-formulation studies. No correlation was found between stability and syneresis data. A similar trend in the curve of gel time vs. catalyst concentration was observed for the two stabilizing catalysts, which was different for the non-stabilizing ammonia. It was concluded that the trend of this curve could potentially provide an indicator of catalyst stabilizing efficacy.
The use of surfactants in suppository formulations has been suggested to improve availability of poorly soluble drugs. In the present study, different kinds of surfactants have been investigated to ...clarify the influence on piroxicam release from suppositories formulated with both lipophilic and hydrophilic bases. Two hydrophilic glucose-derivate surfactants, and a polyoxylglyceride amphiphilic surfactant, all with high HLB values, were investigated for their use in improving drug availability. The two glucose derivate surfactants reduced drug availability from both lipophilic suppositories and hydrophilic formulations, according to longer disintegration times and drug micellization. The more complex surfactant, a lauroyl macrogolglyceride, showed an increase in piroxicam availability from lipophilic suppositories at the higher tested concentrations (15% and 20%). Otherwise, when used in hydrophilic formulations, it was less effective in promoting drug release and even reduced drug availability.
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