Influence of Drying TIME and Temperature on Zirconium-Based Material (ZBM) Properties for 99Mo/99mTc Generator Development

Zirconium-based material (ZBM) has an important role in producing Technetium-99m (99mTc) due to its high adsorption capacity to Molybdenum-99 (99Mo). The adsorption capacity of the ZBM depends on the specific surface area which is influenced by several parameters in the synthesis process. This study aims to investigate the influence of drying time and temperature on the structure and specific surface area of the ZBM. Synthesis of the ZBM was carried out using zirconium chloride, 2-propanol, water and tetrahydrofuran at 75 °C, 90 °C and 120 °C and for 3 hr, 5 hr and 7 hr, respectively. Functional group and specific surface area of the ZBM was analyzed by FTIR and BET method, respectively. At the variation of drying time, the functional group pattern showed by FTIR spectra was not significantly different. The O-H group of the ZBM increased as the drying temperature decreases. At 75 and 90°C, the specific surface area increased as the function of time was increased but was decreased at 120°C. The highest surface area of the synthesized ZBM had a poor performance as a 99Mo/99mTc generator material, whereas the eluate met the required standard.


Development of new material for
Mo)/ Technetium-99m ( 99m Tc) generator is very important due to the shortage of fission 99 Mo in the future, which encourages the world to use non-fission 99 Mo (Mahesh and Madsen 2017). The shortage is caused by several issues including the safety issue regarding the uranium usage, the high activity of radioactive waste and the aging of the main research reactors supplying fission 99 Mo in the world (Cutler and Schwarz 2014;Dash, Knapp, and Pillai 2013;M. R. A. Pillai, Dash, and Knapp 2013). Non-fission 99 Mo is obtained from natural Molybdenum (MoO 3 ) irradiated by either cyclotron or research reactor (M. R. a Pillai, Dash, and Knapp 2015;Selivanova et al. 2016;Amin et al. 2014). The advantages of nonfission 99 Mo compared to fission 99 Mo are the easy handling of the waste, the low radioactivity waste, and the simple post-irradiation method. On the other hand, the drawback is the low specific activity compared to fission 99 Mo (Blaauw et al. 2017;Marlina et al. 2017 Saptiama et al. 2016;Munir et al. 2017;Indra Saptiama et al. 2014). The ZBM is an inorganic polymer of zirconium which contains chlorine on its surface and synthesized from zirconium chloride (ZrCl 4 ) as the main starting material. The ZBM has enough hardness and radiation resistance during 99 Mo adsorption and Technetium-99m ( 99m Tc) elution (Indra Saptiama et al. 2014). So et al. (2007) developed poly zirconium compound (PZC), which has a similar function, properties and synthesis route with the ZBM. This material has an adsorption capacity to molybdenum up to 240 mg/g PZC and 99m Tc yield up to 98.8%. A tandem column of PZC and alumina was applied in generator system to reduce the 99 Mo breakthrough. The ZBM has been developed by sol-gel process using tetraethyl ortho silicate (TEOS) coating to increase its hardness as well as using sodium hypochlorite to increase the 99m Tc yield (Awaludin et al. 2015;Marlina et al. 2016). The resulting 99m Tc had been tested for methylene diphosphonate (MDP) radiopharmaceuticals kit (I Saptiama et al. 2016). Further development of the ZBM was carried out to increase the adsorption capacity to molybdenum and 99m Tc yield. Zhao et al. reported, generally, a specific surface area has an important role to increase the adsorption capacity of an adsorbent material due to the availability of surface sites (Zhao et al. 2016). The surface area of a material produced by the sol-gel process is influenced by the characteristic of the reagents and solvent, the molar ratio of the reactants, the use of a modifying agent, pH, and the drying condition (Danks, Hall, and Schnepp 2016). The reagents composition in the ZBM synthesis has been well established, though the influence of temperature and drying time is not clearly understood yet. These parameters might play an important role as well. The study aims to determine the influence of drying time and temperature on the properties of the ZBM for 99 Mo/ 99m Tc generator development. The material which has the highest surface area was chosen and evaluated its adsorption capacity, 99m Tc yield, and the other generator parameters.

Material
All chemicals were used as received without any further purification. Zirconium chloride (ZrCl 4 ), 2-propanol, tetrahydrofuran (THF), NaOH, and HCl were purchased from Merck. Purified water was obtained from IPHA Laboratory.

Method
The ZBM synthesis procedure was conducted by the modification procedure similar to PZC as described previously (I Saptiama et al. 2016;Awaludin et al. 2015). A zirconium (IV) chloride (ZrCl 4 ) was added to the mixture of THF and 2-propanol followed by another addition of water and THF. The solution was then stirred at room temperature for 24 hr, and heated. The temperature was varied at 75 °C, 90 °C, and 120 °C, whereas the time was varied at 3 hr, 5 hr and 7 hr. The functional groups of the resulted ZBM were analyzed using Fourier Transform Infrared (FTIR) using Alpha FTIR Spectrometer Bruker at 4000-400 cm -1 . Its specific surface area was tested by BET method using Quadrasorb SI -QuantachromeQuadrawin.
A 99 Mo adsorption capacity and 99m Tc elution test of the selected ZBM variation were conducted by the procedure described by Saptiama et al (2016).

RESULT AND DISCUSSION
The PZC spectra were used as a reference for the FTIR analysis of the ZBM due to their structural similarity. The overlapping spectra between the PZC and the synthesized ZBM are shown in Figure 1. These show that the structure of the ZBM, represented by the treatment of 75°C, 3 hr, has similar spectra with the PZC. The PZC and the ZBM have an identical function as a material for 99 Mo/ 99m Tc generator system as well as the starting material. Awaludin et al. (2015) developed the ZBM synthesis process from PZC with several modifications.  (So et al. 2007).
The presence of H 3 O + and Zr-OH in the ZBM was caused by the hydrolysis of Zr-Cl (Le 2014;So et al. 2007). Zr-Cl bond was not observed in FTIR spectra, however, its presence was observed by So et al. (2017) using thermal analysis and Awaludin et al. (2015) using X-ray. The presence of H 2 O was from both moisture content and water crystal. The water crystal was from the reagent during the synthesis process, which was trapped in the ZBM, whereas the presence of moisture content was caused by the hygroscopicity of the ZBM (So et al. 2007). Figure 2 illustrates the infrared spectra of the ZBM at 3600 -2000 cm -1 and 2000 -1000 cm -1 . The figure shows that the spectra of various drying temperature the ZBM are similar in its pattern. The similarity of the spectra indicates that the structural bonds in variations of the ZBM are similar, without significant differences as a function of temperature. On the other hand, the spectra as a variety of drying time were similar in its pattern and overlapping each other. The ZBM spectra were not influenced by the drying time. Figure 2 shows that the lower the temperature, the higher the peak intensity. At the lowest temperature, the drying process was not completed and retained the amount of water in the ZBM. On the other hand, at the highest temperature, the retained water concentration was the lowest, because the evaporation was more effective.
The specific surface areas of the ZBM at 3 levels of temperature and time are presented in Table 1, while the data distribution is presented in Figure 3.   The specific surface area at the temperature of 75 °C and 90 °C increased as the drying time increases. This was caused by the aging process of gel in the sol-gel process. Iswar et al. 2017 reported the identical phenomenon on the silica sol-gel process. The aging process strengthens the gel network which can withstand the material shrinkage during the drying process. The phenomenon explained by Iswar et al (2017) might also happen in the sol-gel process of the ZBM. The aging process was conducted at room temperature, but it was continued at 75 °C and 90 °C due to the presence of excess water in the mixture. The similar phenomenon at 75 °C and 90°C was occurred because both temperatures were below the boiling point of water. Hence, the presence of water was retained.
On the other hand, at the temperature of 120°C, specific surface area decreased as the function of drying time. The aging process at this temperature was not occurred because of the absence of excess water in the mixture. This temperature was higher than a boiling point of the water so the solvent was completely evaporated. Without the aging process, the gel network was not adequate to withstand the shrinkage. The drying step in the sol-gel process at ambient pressure drying (APD) usually causes the shrinkage of the synthesized material. The shrinkage in silica sol-gel process can be used to explain the phenomenon in the ZBM. The factor which encourages the shrinkage during the APD process was the polar OH groups on the material surface. The OH group causes the capillary and tension effect which pull the surface material during the APD step. The shrinkage was also caused by the generating of a new crosslink among near surfaces (Seraji, Seifi, and Bahramian 2015;Seraji et al. 2017).
The proposed illustration of the drying process is shown in figure 4. Figure 4 illustrates the material structure growth from the initial process to final drying. At 75 °C and 90 C, the aging process was occurred in presence of water, therefore a strong material structure was formed, and a shrinkage possibility was reduced. These resulting surface areas that getting higher by time increasing at 75 °C and 90C, as shown in table 1. On the other hand, as shown in figure 4, the aging process at 120 C was not occurred due to the absence of water, therefore it increased the shrinkage. As the result, the surface areas was getting lower by time increasing as shown in table 1.
The prediction of the polymerization mechanism of the ZBM can be constructed by general sol-gel reaction scheme presented by C. Jeffrey and George W (1990). As shown in figure  5, the reactions produce water, however, the presence of a solvent, such as water, is prerequisite for the reaction. The aging process requires a solvent to bring the monomer to the existing polymer and strengthen the network as shown in figure 6. Without a solvent, the strengthening process was not occurred.
The undesirable shrinkage in the drying process can be avoided by supercritical drying. However, either a high temperature-pressure drying or freeze-drying process is difficult to be applied in the ZBM synthesis due to its susceptibility to high temperature and the presence of acid vapour from the material. In the attempt to reduce the shrinkage of the ZBM, solvent modification, as reported by Omranpour and Motahari, might be applied (Omranpour and Motahari 2013).
An evaluation of the highest surface area the ZBM as an adsorbent for 99 Mo/ 99m Tc generator is presented in Table 2.     Awaludin et al. 2015). However, the NaOCl residue in 99m Tc eluate inhibits a radiolabeling reaction of 99m Tc and radiopharmaceutical kit. NaOCl reduces the function of stannous chloride (SnCl 2 ) in the kit. The 99m Tc elution profile is presented in figure 4. The 99m Tc elution profile as shown in figure 7 was good for 99 Mo/ 99m Tc generator system. The high yield in the first elution reduces the eluate volume.
The radiochemical purity and aluminium breakthrough are the quality parameter of 99m Tc eluate. Table 2 shows that these parameter quality meet the required standard of European Pharmacopeia. Tc elution profile.

CONCLUSION
The drying time and temperature have a significant influence on the specific surface area of the ZBM. The highest surface area the ZBM as the best-resulted material has a poor performance as a 99 Mo/ 99m Tc generator material. Hence, there is a need to investigate another parameter, such as atmosphere, heat distribution and reagent composition, for a 99 Mo/ 99m Tc generator development. The eluate of generator met the required quality based on USP/NF and Ph.Eur.