Magnesium-Molybate Compounds as Matrix for 99Mo/99mTc Generators

This work reports the preparation of a 99mTc generator based on conversion of 99Mo produced by neutron irradiation, into insoluble magnesium 99Mo-molybdates compounds as matrix. The effect of magnesium salt types and concentration, Mg:Mo molar ratios, pH of molybdate solutions, eluate volume as well as the addition order of molybdate and magnesium solutions' influences on the final 99mTc were evaluated. Polymetalates and polymolybdates salts either crystallized or amorphous were obtained depending on the magnesium salt and Mg:Mo molar ratio used in matrix preparation. 99Mo/99mTc generator production based on magnesium-99Mo molybdate compounds allow reduction of preparation time and eliminates the use of specialized installations. The best generator performances were attained using matrices prepared from 0.1 mol/L MgCl2·6H2O solutions, ammonium molybdate solutions at pH 7 and at a Mg:Mo molar ratio of 1:1.


Introduction
Technetium-99m ( 99m Tc) is used for more than two thirds of nuclear imaging techniques because of its short 6.02 h half-life, simple decay scheme (a single 141 KeV photon), minimum whole-body dose, versatile chemistry, and availability from the 99 Mo/ 99m Tc generator [1][2]. This system is based on OPEN ACCESS adsorption of 99 Mo on an alumina column where 99m Tc formed from decay of the 99 Mo is periodically eluted from the column using physiological saline, as sodium pertechnetate (Na 99m TcO 4 ) while 99 MoO 4 2− remains attached to alumina. The limited loading capacity of alumina for molybdenum (2 mg Mo/g alumina) forces the use of a uranium fission product with a high specific activity, 99 Mo (10 5 Ci/g Mo) [3], thus requiring sophisticated separation processing infrastructure and disposal of large amounts of radioactive wastes [4][5]. To avoid this, alternative methods of 99 Mo/ 99m Tc generator production have been investigated using low and medium specific activity 99 Mo, produced from (n,γ) nuclear reaction with natural Mo (activation method) and directly converted into insoluble substrates that can be eluted in a column. 99 Mo/ 99m Tc generator based on heteropolyanions such as zirconium molybdate, titanium molybdate, molybdocerates, etc., [6][7][8][9][10][11][12] have been developed by some laboratories around the world. This is due to the molybdates' matrix capacity to incorporate up to 30% in weight of 99 Mo [13] compared to 0.2% in traditional alumina based generators. Although these generators has opened a way of making column type 99m Tc generator even using low and medium specific activity 99 Mo, the handling problems (precipitation, filtration drying, fragmentation, etc.) still exist because these 99 Mo-molybdates are mostly synthesized from 99 Mo, requiring sophisticated remote handling facilities and at least 6 h processing time [12,14]. To simplify the production process of these systems, we propose preparing 99 Mo/ 99m Tc generators based on magnesium 99 Mo-molybdate compounds by synthesizing magnesium molybdate compounds, followed by irradiation. This approach has three advantages: (1) it eliminates the use of specialized installations for molybdates synthesis; (2) it reduces 99 Mo/ 99m Tc generator preparation time and (3) it minimizes radiological contributions at 99m Tc eluats due to the only radioisotope produced for the manganesium ( 24 Mg) during magnesium molybdate compound irradiation which has a short half life: 9.46 min.
Systematic studies on 99 Mo/ 99m Tc generators based on magnesium 99 Mo-molybdate compounds were performed. The effect of six parameters on the 99 Mo/ 99m Tc generator performance were evaluated: magnesium concentration and salt type, Mg:Mo molar ratios, molybdates solutions and precipitated pH, and addition order of molybdate and magnesium solutions. The physical-chemical properties of magnesium molybdate compounds were also determined to relate their properties with generator performance. Table 1 shows the performances of the 99 Mo/ 99m Tc generators based on magnesium 99 Mo-molybdate compounds prepared in this research. Results are divided into three series, in line with the type of magnesium salts used in the generator preparation: magnesium chloride hexahydrate (series A), magnesium nitrate hexahydrate (series B) and magnesium sulfate hexahydrate (series C). The generator performances were compared with those advised by the Pharmacopoeia for the 99m Tc eluates used with medical purposes: 99 Mo breakthrough less than 0.015%, a minimum percentage of 95% for the radiochemical purity, a chemical purity less than 10 ppm for aluminium and pH values between 4.5 and 7.5 [15]. 99 Mo breakthrough percentages of less than 0.015% were only obtained in the matrices prepared from: (a) 0.5 mol/L MgCl 2 6H 2 O (series A) and b) 1 mol/L MgNO 3 6H 2 O solutions (series B) using ammonium molybdate solutions at pH of 7 and a Mg:Mo molar ratio of 1:2 ( Figure 1). However, 99m Tc elution efficiencies of theses generators were less than 48%, except for the matrix B7. On the other hand, the highest elution efficiencies (>70%) were obtained in the generators prepared from 0.1 mol/L Mg(NO 3 ) 2 6H 2 O solutions, at a Mg:Mo molar ratio of 0.2:1 and ammonium molybdate solutions at pH values between 4.5 and 10, however under these conditions, 99 Mo breakthrough of the eluates were more than 0.7%, apart from the matrix B7. 99m Tc eluates of the matrices prepared preferably with Mg:Mo molar ratio of 2:1 presented radiochemical purity of more than 95% and, in general, those made from MgCl 2 6H 2 O solutions which satisfy the eluate pH values fixed by the Pharmacopoeia: between 4.5 and 7.5, while the eluate pH values obtained from the matrices formed with MgSO 4 6H 2 O were the more acid, between 1 and 3. The average elution volume of all the generators studied ranged between 2 and 3.5 mL and all 99m Tc eluates had an Al content of less than 10 ppm. It is important to note that a high 99 Mo breakthrough percentage in the eluates entails the presence of Mg 2+ in solution.

Performances of 99 Mo/ 99m Tc Generators Based on Magnesium 99 Mo-Molybdate Compounds
The Mo and Mg content in the generators is directly connected with: the Mg:Mo molar ratio, the type and concentration of magnesium salt used during matrix synthesis and matrix washing before irradiation. Thus the highest (75-50%) and lowest (18-7%) Mo percentages, and vice versa for Mg content, were recorded in the washed matrices and those prepared from MgSO 4 6H 2 O solutions at Mg:Mo molar ratio of 2:1 respectively.
Matrix washing caused a decrease of the 99m Tc elution efficiencies and Mg percentage in the matrix, while an increase in magnesium salt concentration (series C) induced a drop in the 99m Tc elution efficiency and acidification of 99m Tc eluates. The addition order of magnesium salt and ammonium molybdate solutions, and ammonium molybdate pH in the matrix process preparation (series B) did not cause meaningful changes in 99 Mo/ 99m Tc generator performance. Tc eluates produced by the generators prepared from MgCl 2 6H 2 O solutions (series A) mostly attained the pH values established by the Pharmacopoeia: between 4.5 and 7.5, while higher acid eluates were obtained in the matrices synthesized from MgSO 4 6H 2 O solutions. When the Mg proportion was higher than Mo in the Mg:Mo molar ratio, 99 Mo breakthrough percentage increased in the 99m Tc eluates and the Mo percentages in the matrix decreased. All 99m Tc eluates of series A were colorless, those prepared from MgNO 3 6H 2 O solutions at pH 10 or adding the ammonium molybdate solutions to magnesium salts (series B) presented a yellow coloration, while some of series C eluates showed a yellow coloring or a blue precipitate, in fact only the 99m Tc eluates obtained from generator prepared with 0.1 mol/L MgSO 4 6H 2 O solutions were colorless.

Characterization of Magnesium Molybdate Compounds
Crystalline phases identified by XRD (see Table 1 and Figure 2a) showed that the type of magnesium salt used in preparing generator matrices determines their chemical composition. In accordance with these data, Mg-Mo compounds prepared from MgCl 2 6H 2 O, Mg(NO 3

O-H
In this region, ammonium and water displays strong broad N-H and O-H stretching bands between 3500 and 3300 cm −1 and bands at 1405 and 1640 cm −1 respectively [8,[17][18]; while significant differences in intensities and wavenumber values and of each matrix were noted in fingerprint region (1200-400 cm −1 ). All matrices spectra exhibit characteristic absorption bands of Mo-O-Mo vibration at 960, 910 cm −1 and N-H bonds at 1075 and 1220 cm −1 as well as a band at 620 cm −1 possibly originated from Mg vibrations [8,[18][19]. Only the matrix prepared from Mg(NO 3 ) 2 *6H 2 O presented broad bands at around 470 cm −1 attributed to Mg-O bonds [19], and that from MgSO 4 *6H 2 O showed characteristic bands assigned to [SO 4 2− ] (628, 700, 1075, 1130, 1287 cm −1 ) and Mo-O vibrations at 792 and 880 cm −1 whereas that from MgCl 2 *6H 2 O presented peaks 760 and 545 cm −1 assigned to the Mo-O vibrations and possibly to Mg-Cl bonds respectively [8,[18][19]. The X-ray diffraction patters and thermograms of a typical matrix washed and unwashed are shown in Figure 3a and 3b. The diffractograms show that the washed matrix before irradiation is constituted only by MoO 3 and the unwashed one by a mixture of MoO 3 and NH 4 MgCl 3 *6H 2 O. These data match with thermograms of the washed and unwashed matrix which have typical patterns of pure and mixed compounds respectively. Thus, washed matrices before irradiation cause soluble compounds to be removed, mainly those containing ammonium and magnesium in the matrix and conversion of the molybdenum compounds in MoO 3 . It is important to note that this behavior is independent of the type of magnesium salt used in preparing the matrix ( Table 1).
The effect of matrix washing on morphology is shown in Figure 3c. The unwashed matrices present a crystalline phase soaked in an amorphous material, and the washed matrices only have the crystalline phase, constituted by rods of different thicknesses and length.

Discussion
The performance of the 99 Mo/ 99m Tc generators based on magnesium-molybdate compounds depends upon matrix preparation and treatment methods. The latter has to be an insoluble precipitate to avoid 99 Mo leakage, whilst simultaneously allowing 99m Tc release, and have a high Mo content that enables the use of low specific activities of 99 Mo (2.5 Ci/g) in the generator and a good thermal and radiation stability.
In this work, insoluble magnesium molybdate compound precipitation was favored by adjusting pH and irradiation, and not by thermal treatment. Under these experimental conditions, magnesium molybdate compounds obtained were mainly polymetalates salts such as xNH 4 MgCl 3 yMoO 3 , and polymolybdates [NH 4 Mo 5 O 15 (OH)] (see Figure 2 and Table 2). Assuming that compound formation is the result of three steps, firstly the formation of ammonium molybdates according to reaction (1) [19,[28][29]]. X-ray diffraction data (see Table 2 and Figure 2) suggests polymetalates formation such as xNH 4 MgCl 3 yMoO 3 or polymolybdates according to: The Cl − ion usually displaces NO 3 − and SO 4 2− ions [30] when magnesium nitrate and sulfate are employed in preparing magnesium molybdates; for that reason ammonium magnesium chlorides (NH 4 MgCl 3 ) were present in all the series studied (see Table 2 and Figure 2), however mixtures of NH 4 MgCl 3 and (NH 4 ) 2 Mg(SO 4 ) 2 were also identified in matrices prepared from magnesium sulfates. An excess of molybdenum favors polymolybdates and formation of amorphous phases whereas a surplus of magnesium the presence of ammonium magnesium salts and crystalline phases. Thus, the crystallinity degree of the compounds contained in the matrix is closely attached to 99 Mo/ 99m Tc generator performances. For example amorphous matrices presented the best 99m Tc elution efficiencies (series B) while the crystalline (series A) presented lower 99 Mo breakthrough (see Table 1, Figure 1). Assuming that amorphous materials also consist of molybenum oxides or polymolybdates and that the oxides and hydrous oxides of Mo(VI) exhibit cation exchange properties and show little or no anion exchange character even in acid solution [31] and ammonium magnesium salts have no adsorption properties, so the separation mechanism of the 99 Mo and 99m Tc in the generators can be explained by free diffusion of 99m TcO 4 − ion inside the matrix because the 99m TcO 4 − anion produced in the generator is not adsorbed in the matrix and can be removed from the chromatographic column by elution with isotonic saline solution, leaving the 99 Mo inside. In accordance with this argument, a crystalline matrix acts as a molecular sieve preventing 99m Tc mobility and causing generator efficiency decrease. Whereas a flexible random network (amorphous) increases generator efficiency and radiochemical purity because the matrix is more elastic but simultaneously harder and more resistant to mechanical breakdown and more difficult to dissolve. The low 99m Tc eluate radiochemical purities obtained in some generators can be explained by Tc(VII) reduction caused by the presence of insoluble species of polymolybdates, which are strong oxidizing agents [18]. Inorganic materials are susceptible to irradiation-induced amorphization producing particularly volume changes in crystalline or amorphous phases. The main concern with large differential volume changes is that it may affect atomic bonding, local coordination, and the pathways for ion exchange, all of which can impact the release rates of radionuclides [32]. Thus the matrix amorphization caused by its irradiation could be linked to the high 99 Mo breakthrough obtained in generators for which matrices are mainly formed by amorphous compounds such as the series B and C.

Preparation of Magnesium 99 Mo-Molybdate Compounds
Magnesium 99 Mo-molybdate compounds were formed from magnesium and molybdate solutions. The molybdate solutions were prepared from MoO 3 natural pellets, previously heated to 650 °C for 1 h and dissolved in 2 mol/L NH 4 OH at a MoO 3 :2NH 4 OH molar ratio [8]. The pH of the formed ammonium molybdates was adjusted by adding 4 mol/L HCl and converted into magnesium molybdate by reacting with magnesium solutions. Magnesium molybdates pH were also adjusted using 4 mol/L HCl. The resulting solids were dried for 2 days using an infrared lamp and crushed in an agate mortar. One portion of magnesium molybdate precipitate was placed on a funnel to be washed using 200 mL of distilled water and the washed and unwashed solids were dried for 1 day at 40 °C in a stove. The dried magnesium molybdate were irradiated for 2 h at a neutron fluence of about 1.61 × 10 13 n cm −2 s −1 in the Triga Mark III Reactor (Mexico). After irradiation, about 1 g of magnesium 99 Mo-molybdate (~4.9 MBq/g) were added into a glass column (12 mm × 70 mm) containing a bed of 1 g acid alumina.
The column was finally washed with 20 mL of saline solution [8,[17][18]. The magnesium molybdate compounds were synthesized in duplicate at different conditions; where parameters such as magnesium salts and concentrations (MgCl 2 6H 2 O, Mg(NO 3 ) 2 6H 2 O, MgSO 4 6H 2 O), Mo:Mg molar ratios, ammonium and magnesium molybdates pH and the addition order of magnesium and molybdenum solutions were evaluated (see Table 2).

Elution of Generators and Eluate Analysis
The generators were eluted with 6 mL of 0.9% NaCl every 24 h for 1 week and the following parameter of the 99m Tc eluates were determined: 99m Tc elution efficiency, 99 Mo breakthrough, 99m Tc elution profile, 99m Tc radiochemical purity, pH eluate and aluminium concentration. The 99m Tc elution efficiency and the 99 Mo breakthrough were calculated from the 99m Tc and 99 Mo activities measured in a CRC-10R Capintec dose calibrator and a GeHp solid state detector (Canberra 7229P) coupled to a PCmultichannel analyzer (ACUSPECT-A, Canberra, Australia). The radiochemical purity of the 99m Tc eluate was determined by paper chromatography using 1 CHR (Whatman®) paper as solid phase and 85% methanol as mobile phase. The 99m TcO 4 − R f was 0.66-0.72. Aluminium and magnesium concentrations in 99m Tc eluates were determined by the aluminon and Eriochrome Black T methods [18,33]. The eluate pH values were determined by pH paper.

Gel Characterization
Magnesium-molibdate compounds were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), infrared spectrometry, thermogravimetry and neutron activation analysis. The X-ray diffraction patterns were obtained on a Siemens D500 diffractometer for 1 h and scanned from 2.5° to 70° with steps of 0.02°. SEM imaging was performed by Philips SL30. Digital images were obtained at 5,000X, 3,000X, 1,000X and 500X magnifications in randomly selected fields. The infrared measurements were taken on a Nicole Mgna-IR ™ spectrometer 550 with the samples pressed in KBr pellets. The thermogravimetric analyses were performed using a Phillips unit at a heating rate of 10°/min under a nitrogen atmosphere [8,18]. Molybdenum and magnesium concentrations were determined by neutron activation. The procedure described in previous works was applied for molybdenum and in the case of magnesium, 50 mg of each magnesium molybdate and MgO, used as reference material, were irradiated in the Triga Mark II reactor at a neutron fluence of about 1.65 × 10 12 n cm −2 s −1 for 15 s. Magnesium was determined by the 843.4 keV γ-ray of 27 Mg by means of a HPGe detector at a counting time of 100 s [13].

Conclusions
The performances of 99m Tc generators are strongly related to the chemical composition of the matrix and consequently their preparation conditions. The magnesium molybdate compounds obtained were mainly salts of polymetalates such as NH 4