Development of separation technology for the removal of radium-223 from targeted thorium conjugate formulations. Part I: purification of decayed thorium-227 on cation exchange columns

Targeted thorium conjugates (TTCs) are being explored as a potential future platform for specific tumor targeting pharmaceuticals. In TTCs, the alpha emitting radionuclide thorium-227 (²²⁷Th) with a half-life of 18.697 d is labeled to targeting moieties, such as monoclonal antibodies (mAbs). The amount of daughter nuclide radium-223 (²²³Ra, t_1/2?=_?11.435 d) will increase during manufacture and distribution, and so a technology for purification is required to assure an acceptable level of ²²³Ra is administrated to the patient. Since ²²³Ra is the only progeny of ²²⁷Th with a long half-life (days), the progenies of ²²³Ra will have a very limited stay in the formulation once ²²³Ra is removed. The focus in this study has, therefore, been on the removal of ²²³Ra. In this study, the sorption and separation of ²²³Ra (radium(II)) and ²²⁷Th (thorium(IV)) on cation exchange columns has been evaluated as a purification method of decayed ²²⁷Th (i.e. prior to radiolabelling of a mAb and formation of TTC). The goal is to minimize the sorption of ²²⁷Th and maximize the sorption of ²²³Ra. Statistical experimental design with formulation and process parameters, including buffered formulations comprising citrate and acetate, at various concentrations and pH, presence of free radical scavenger and chelator, and resin amount have been evaluated for impact on the purification process. The studies have been interpreted by the aid of multivariate data analysis. The correlations between design of experimental variables and sorption are summarized by regression models. The predictive accuracy of radionuclide sorption was given by standard deviation and 95% confidence intervals originating from statistical cross validation. Experimental results and statistical models for citrate-buffered formulations verified reproducible and acceptable sorption levels of ²²³Ra and ²²⁷Th under selected conditions. For acetate-buffered formulations, prediction of ²²⁷Th sorption was influenced by complex variable relationships and hence a risk of obtaining irreproducibility. Fine-tuned variable levels showed, however, variable combinations predicting high sorption of ²²³Ra (>90%) and low sorption of ²²⁷Th (<3%) also for the acetate-buffered formulations. The optimal separation conditions should be decided based on tuning the variables levels for ²²³Ra in the citrate-buffered formulations, while for acetate, the optimal separation should be based on tuning variable levels for ²²⁷Th sorption. The ionic strength of the formulation also seemed to affect the radionuclide sorption. Labeling of an antibody-chelator conjugate with purified ²²⁷Th (i.e. preparation of TTC) was successful in the selected citrate-buffered formulations tested.     

Development of separation technology for the removal of radium-223 from targeted thorium conjugate formulations. Part II: purification of targeted thorium conjugates on cation exchange columns

Tumor targeting pharmaceuticals will play a crucial role in future pharma pipelines. The targeted thorium conjugate (TTC) therapeutic platform could provide real benefit to patients, whereby targeting moieties like monoclonal antibodies are radiolabelled with the alpha-emitting radionuclide thorium-227 (²²⁷Th, t_1/2?=?18.7?days). A potential problem could be the accumulation of the long-lived daughter nuclide radium-223 (²²³Ra, t_1/2?=?11.4?days) in the drug product during manufacturing and distribution. Therefore, the level of ²²³Ra must be standardized before administration to the patient. The focus in this study has been the removal of ²²³Ra, as the other progenies will have a very limited stay in the formulation. In this study, the purification of TTCs labeled with decayed ²²⁷Th has been explored. Columns packed with a strong cation exchange resin have been used to sequester ²²³Ra. The separation of TTC from ²²³Ra has been evaluated as influenced by both formulation and process parameters with a design of experiments (DOE) study; including citrate or acetate buffer, pH, buffer concentration, presence or absence of pABA?+?EDTA, resin amount and sodium chloride concentration. The aim was to achieve a separation with high sorption of ²²³Ra and accompanying low TTC sorption. The results were analyzed by multivariate analysis. Four regression models of TTC and ²²³Ra sorption from citrate and acetate buffered formulations were developed. The predictive accuracy of sorption in the four statistical models was given by standard deviations and confidence intervals. The TTC sorption in citrate and acetate buffered formulations was affected by the identical variables and the variation in TTC sorption was comparable for the two models. However, the DOE variables had a significantly stronger impact on the ²²³Ra sorption in citrate buffered formulations than the ²²³Ra sorption in acetate buffer. An optimal separation with a TTC sorption below 25% and ²²³Ra sorption above 90% can be achieved in both citrate and acetate buffered formulations. Stability studies of radiochemical purity (RCP) indicated that the measured ²²⁷Th values may be partly due to free ²²⁷Th and not TTC, but the results indicate that TTC stability may be controlled by optimizing formulation parameters. Hence, the sorption data and the regression models presented must be reviewed and further explored with regard to what is known about the stability of the TTC in the different buffered formulations.     

A rapid and sensitive method for separation of Cu2+ ions from industrial wastewater sample and water samples with methacrylamide‐ethylene glycol dimethacrylate: A new synthesis of molecularly imprinted polymer

In this study, new molecularly imprinted polymer particles (MIP) were synthesised to extract Cu²⁺ ions from aqueous solutions using radical polymerisation. MIP was developed using the methacrylamide‐ethylene glycol dimethacrylate (EGDMA) cross linking agent, methacrylamide monomer, and ACV initiator by the radical polymerisation method. A comparison of various cross linking agents in MIP production showed that the best cross linking agents are EGDMA and gallic acid. The template ions were removed by leaching with 0.100 M HCl. The polymer particles were characterised by FTIR spectroscopy, thermogravimetric analysis (TGA) and scanning electron microscopy (SEM). The effect of different parameters such as cross linkers, pH, time, maximum adsorption capacity, and kinetic and isotherm adsorption were investigated. The best conditions were determined (pH = 8.0, t = 10 min, and q _m  = 262.53 mg g⁻¹). The adsorption data were best fitted by Freundlich isotherm and pseudo second order kinetic models, as well. Due to its high adsorption capacity and multi‐layer behaviour, this method is an easy, fast and safe way to extract cations. Removal of Cu²⁺ in certified tap water and rain water was demonstrated and the industrial wastewater sample (Charmshahr, Iran) with which the MIP was developed using Methacrylamide‐ Ethylene Glycol Dimethacrylate (EGDMA) was good enough for Cu²⁺ determination in matrices containing components with similar chemical property such as Co²⁺, Zn²⁺, Fe².     

A scheme for solving strongly coupled chemical reaction equations appearing in the removal of SO2 and NOx from flue gases

The removal of NO_x from mixtures of NO-NO₂-N₂ and NO-NO₂-O₂-H₂O is discussed theoretically in this study, and the removal of ₂SO and xNO is further discussed when a gas system of NO_x-N₂-O₂-H₂O contains CO₂ and SO₂. The involved chemical reaction rate equations in the process of SO₂/NO_x removal are solved numerically using Treanor's method, in which a scheme separating chemical reactions into fast and slow groups has been proposed for improving the numerical stability. Numerical results show that the contribution of ion reactions to xNO removal is negligible, and that high temperature is not beneficial for the NO oxidation. However, high concentration of O₂ is conducive to the NO oxidation. Addition of water facilitates the NO_x removal, and increasing water vapor concentration enhances the NO_x removal efficiency; inclusion of CO₂ and SO₂ into the system favors the NO removal.     

Generalized model for the simulation of food refrigeration. Development and validation of the predictive numerical method

A generalized mathematical model was developed to simulate food refrigeration in air. The model takes into account surface water evaporation. It allows food physical properties to be considered as functions of temperature and/or composition, while providing means for including internal heat generation, composite materials (for instance, flesh and skin) and time-varying external temperature and humidity. Wetted surfaces and packaging can also be accounted for by the model, which can be used for spheres, infinite or finite cylinders, slabs. The numerical method was developed using the Crank-Nicolson scheme, and compared with exact analytical solutions as well as with experimental data on the refrigeration of various foods.