阅读说明：本技术 一种基于电子加速器生产99Mo的钼锝处理和分离方法 (molybdenum-technetium treatment and separation method for producing 99Mo based on electron accelerator ) 是由 张圈世 张宇皓 王武尚 于 2019-08-20 设计创作，主要内容包括：本发明属于医用放射性诊断核素领域,具体涉及一种基于电子加速器生产~(99)Mo的钼锝处理和分离方法,解决了采用目前商用钼锝发生器或钼锝分离技术分离利用加速器生产的~(99)Mo时,需要大体积的发生器、大体积的Al_2O_3及大体积的淋洗液造成的成本高,操作困难等技术问题。包括以下步骤：首先将照射后的~(100)Mo样品盘取出,并利用双氧水对~(100)Mo样品盘进行溶解,获得钼过氧化物溶液；然后将钼过氧化物转化为钼酸盐；然后,利用初级捕获树脂初次吸附~(99m)Tc；然后将~(99m)Tc从初级捕获树脂中剥离出来；最后用三氧化二铝柱二次吸附步骤五获得的~(99m)Tc,获得纯化的~(99m)Tc。可以应用在利用电子加速器生产~(99)Mo的方法中,也可以应用在~(99)Mo比活度低的分离过程中。(the invention belongs to the field of medical radiodiagnostic nuclides, and particularly relates to a molybdenum-technetium treatment and separation method for producing 99Mo based on an electron accelerator, which solves the technical problems of high cost, difficult operation and the like caused by the need of a large-volume generator, a large-volume Al2O3 and a large-volume leacheate when the 99Mo produced by the accelerator is separated by adopting the conventional commercial molybdenum-technetium generator or molybdenum-technetium separation technology. The method comprises the following steps: firstly, taking out the irradiated 100Mo sample disc, and dissolving the 100Mo sample disc by using hydrogen peroxide to obtain a molybdenum peroxide solution; then converting the molybdenum peroxide into molybdate; then, primary adsorption of 99mTc is carried out using a primary capture resin; then the 99mTc is stripped from the primary capture resin; and finally, adsorbing the 99mTc obtained in the fifth step for the second time by using an aluminum oxide column to obtain the purified 99 mTc. The method can be applied to a method for producing 99Mo by using an electron accelerator, and can also be applied to a separation process with low specific activity of 99 Mo.)

1. A molybdenum-technetium processing and separating method for producing 99Mo based on an electron accelerator is characterized by comprising the following steps:

step one, manufacturing a 100Mo sample disc;

step two, dissolving the irradiated 100Mo sample disc;

Placing the 100Mo sample disc manufactured in the step one in a device for producing 99Mo based on an accelerator for irradiation, taking out the irradiated 100Mo sample disc, and dissolving the 100Mo sample disc by using hydrogen peroxide to obtain a molybdenum peroxide solution;

step three, converting the molybdenum peroxide into molybdate;

Adding KOH or NaOH aqueous solution into the molybdenum peroxide solution obtained in the step two to convert the molybdenum peroxide into molybdate;

Step four, primary adsorption of 99 mTc;

passing the solution of the third step through a primary capture resin to adsorb 99mTc in the solution; the primary capture resin is a capture resin or a chemical matrix resin;

Step five, stripping 99 mTc;

first washing the primary capture resin adsorbed with 99mTc with a hydroxide solution and combining the eluate with the mother liquor; washing the primary capture resin adsorbed with 99mTc with acetic acid/sodium acetate buffer solution and normal saline in sequence, collecting eluate containing 99mTc, and stripping 99mTc from the primary capture resin;

Step six, adsorbing 99mTc for the second time;

And (4) secondarily adsorbing the 99mTc obtained in the fifth step by using an aluminum oxide column, and then eluting by using normal saline to obtain purified 99 mTc.

2. the molybdenum-technetium treatment and separation method for 99Mo production based on an electron accelerator according to claim 1, characterized in that: the concentration of 100Mo powder in the 100Mo sample disc in step one was greater than 99.9%.

3. The molybdenum-technetium treatment and separation method for 99Mo production based on an electron accelerator according to claim 2, wherein the first step is specifically:

Step 1.1), grinding 100Mo powder;

step 1.2), placing the ground 100Mo powder in a film sleeve of a compression disc;

Step 1.3), sleeving a compression disc membrane in a hydraulic press, and pressing a disc;

step 1.4), sintering for 0.4-0.6 min under the pressure of 25kn/cm 2-250 kn/cm2, and then sintering for 5-6 hours at 1200-2000 ℃ in an inert atmosphere to obtain the 100Mo sample disc.

4. the molybdenum-technetium processing and separating method for 99Mo based on electron accelerator according to claim 3, characterized in that: the junction temperature in step 1.4) was 1700 ℃.

5. the molybdenum-technetium treatment and separation method for producing 99Mo based on an electron accelerator according to claim 1, wherein the parameters for dissolving the 100Mo sample disk with hydrogen peroxide in the second step are as follows:

The hydrogen peroxide concentration is as follows: 30 percent;

the initial dissolution temperature was: 70 ℃;

The addition speed is as follows: 40ml/g is added at a rate of 1ml/min, wherein 40ml/g means 40ml of hydrogen peroxide is added per 1g of 100Mo sample trays.

6. The molybdenum-technetium processing and separating method for producing 99Mo based on an electron accelerator as claimed in claim 1, wherein in step four, after the initial adsorption, the mother liquor is left to stand for a certain time, and then the mother liquor is passed through the primary capture resin again, and the process from step four to step six is repeated until the mother liquor contains a small amount of 99 Mo.

7. the molybdenum-technetium treatment and separation method for 99Mo production based on an electron accelerator according to claim 1, characterized in that: the selection principle of the alumina column in the sixth step is as follows: the alumina columns have selective adsorption on the existing parent species Mo (Vi) and do not adsorb on 99 mTc.

8. the molybdenum-technetium treatment and separation method for 99Mo production based on an electron accelerator according to claim 1, characterized in that: the KOH or NaOH aqueous solution is deionized water aqueous solution.

9. The molybdenum-technetium processing and separating method for 99Mo production based on an electron accelerator according to claim 2, wherein the sixth step is specifically:

Step 6.1), washing the alumina column by using a glucose acid liquor buffer solution;

step 6.2), performing secondary adsorption on 99mTc by using the aluminum oxide column treated in the step 6.1), and then eluting by using normal saline.

Technical Field

The invention belongs to the field of medical radioactive diagnosis nuclide, and particularly relates to a molybdenum-technetium treatment and separation method for producing 99Mo based on an electron accelerator.

Background

for over fifty years, the radioisotope 99mTc has become the most commonly used radiopharmaceutical in nuclear medicine imaging diagnostic procedures due to its unique properties. The 99 mTc-containing medicine is suitable for various human organs, such as cardiac and cerebral vascular diseases, such as myocardial thrombosis, atrial thrombosis, atherosclerosis, etc., tumors, such as prostate cancer, lung cancer, breast cancer, head and neck cancer, etc., and functional diseases, such as Parkinson's disease, kidney, liver and gall bladder, bone and arthritis imaging, etc. Of the 35 in vivo radiopharmaceuticals approved for production in our country, 99mTc radiopharmaceuticals account for 16, and account for the vast majority, about 75%, of all imaging drug markets.

nearly forty million doses of 99mTc are administered annually worldwide (human). However, 99mTc is mainly derived from a molybdenum-technetium generator (99Mo-99mTc, hereinafter referred to as cow), and 99Mo is used to generate 99 mTc. The annual demand for 99Mo is up to 250 ten thousand Curie. At present, 99Mo is mainly produced by fission of a reactor 235U. There are nine world 99Mo production piles, six major processing plants, all built in the fifth and sixty years of the last century, where two reactors have stopped producing in 2015 and 2018, and the rest will be shut down in 2030.

to solve the problem of 99Mo supply, some accelerator-based methods and techniques for producing 99Mo have emerged. For example, patent CN 105453187B proposes the use of the photonuclear reaction 100Mo (γ, n)99Mo to produce 99Mo by converting the electron beam of a 40MeV high energy electron accelerator into bremsstrahlung radiation to bombard a 100Mo target. Industrial production of 100Mo is possible because it has a wide "giant dipole resonance" (GDR) of the photonuclear reaction at a photon energy of about 15MeV, which results in a large reaction cross-section between 100Mo and 99 Mo. Patent CN 108696980 a bombards 100Mo with 40-80MeV protons of a proton cyclotron to produce 99Mo by a (p, pn) reaction. But the range of this energetic proton in 100Mo is short and the target cannot be too thick. Meanwhile, the direct production of 99Mo at 100Mo using proton beams often results in the production of other Tc isotopes from other stable Mo isotopes that may be present in the concentrated 100Mo target. In contrast, the radiation length of high energy bremsstrahlung in the range of 10 to 30MeV in 100Mo is about 10mm, which is significantly longer than the radiation length of protons of the same energy. Therefore, the effective target thickness for photoneutron reactions is also greater compared to proton reactions. In addition, the small number of reaction channels of bremsstrahlung and Mo limits the production of unwanted isotopes, and photoneutron reactions of bremsstrahlung with other Mo isotopes present in a 100Mo target typically produce stable Mo, non-radioactive impurities.

medical applications have severe limitations on the amount of other radioisotopes that may be present with 99Tc, and therefore 99Tc production using an electron accelerator appears to be more preferred because the risk of producing other Tc isotopes is significantly lower. However, compared with the 99Mo produced by the 235U fission of the reactor, the 99Mo yield obtained by the methods is low because the nuclear reaction section of the methods and the technologies for producing the 99Mo based on the accelerator is far smaller than that of the 235U fission of the reactor, and the specific activity of the 99Mo is low because of the existence of the molybdenum carrier, and the typical specific activity is 1 to 2 orders of magnitude lower than that of the 99Mo produced by the 235U fission of the reactor.

the current conventional commercial molybdenum-technetium generator (99Mo-99mTc, hereinafter referred to as cow) is based on fission of reactor 235U to produce 99Mo, and their separation principle is basically the same. As disclosed in patent CN1234290A, 99Mo fuel solution produced by reactor and satisfying certain conditions is loaded into an alumina (hereinafter referred to as Al2O3) separation column, and since Al2O3 has strong affinity and adsorption capacity for the parent nuclide 99Mo, it hardly absorbs the parent nuclide 99 mTc. After the mother-child balance is carried out for a certain time, the daughter nuclide 99mTc accumulates a certain amount, and the Al2O3 separation column is leached by normal saline, so that the qualified 99mTc can be obtained like 'milk dropping'. And keeping 99Mo in the Al2O3 separation column continuously for the next time of 'milk feeding'. As mentioned above, the specific activity of 99Mo produced by the accelerator is 1-2 orders of magnitude lower than that of 99Mo produced by fission of 235U reactor, and a huge amount of carriers 100Mo are also provided, so if a current commercial molybdenum-technetium generator or molybdenum-technetium separation technology is used, not only a large Al2O3 volume is required, the generator volume is also large, the size of leacheate is also large, great challenges and difficulties are encountered in practical application, more importantly, the specific activity of 99mTc in the leacheate after leaching is relatively low, and the like, and a plurality of problems exist in clinical application.

disclosure of Invention

the invention aims to provide a molybdenum-technetium treatment and separation method for producing 99Mo based on an electron accelerator, which aims to solve the technical problems of high cost, difficult operation and the like caused by the need of a large-volume generator, a large-volume Al2O3 and a large-volume leacheate when the current commercial molybdenum-technetium generator or molybdenum-technetium separation technology is adopted to separate the 99Mo produced by the accelerator.

The technical scheme of the invention is to provide a molybdenum-technetium treatment and separation method for producing 99Mo based on an electron accelerator, which comprises the following steps:

step one, manufacturing a 100Mo sample disc;

step two, dissolving the irradiated 100Mo sample disc;

placing the 100Mo sample disc manufactured in the step one in a device for producing 99Mo based on an accelerator for irradiation, taking out the irradiated 100Mo sample disc, and dissolving the 100Mo sample disc by using hydrogen peroxide to obtain a molybdenum peroxide solution;

Step three, converting the molybdenum peroxide into molybdate;

Adding KOH or NaOH aqueous solution into the molybdenum peroxide solution obtained in the step two to convert the molybdenum peroxide into molybdate;

Step four, primary adsorption of 99 mTc;

Passing the solution of the third step through a primary capture resin to adsorb 99mTc in the solution; the primary capture resin is capture resin or chemical matrix resin; the capture resin is aqueous two-phase extraction chromatographic resin formed by covalent bonding of monomethyl polyethylene glycol (PEG) and a polystyrene carrier, and the resin has strong removal capability to high acid salt in a two-phase solution. See Solvent Extraction And Ion Exchange, https:// www.tandfonline.com/loi/lsei 20. The chemical matrix resin is Chemmatrix resin (PCAS Biomatrix, PQ, Canada) produced by PCAS, Canada.

step five, stripping 99 mTc;

first washing the primary capture resin adsorbed with 99mTc with a hydroxide solution and combining the eluate with the mother liquor; washing the primary capture resin adsorbed with 99mTc with acetic acid/sodium acetate buffer solution and normal saline in sequence, collecting eluate containing 99mTc, and stripping 99mTc from the primary capture resin;

Step six, adsorbing 99mTc for the second time;

And (4) secondarily adsorbing the 99mTc obtained in the fifth step by using an aluminum oxide column, and then eluting by using normal saline to obtain purified 99 mTc.

Further, the concentration of 100Mo powder in the 100Mo sample disc in step one was greater than 99.9%.

Further, the first step is specifically as follows:

Step 1.1), grinding 100Mo powder;

step 1.2), placing the ground 100Mo powder in a film sleeve of a compression disc;

Step 1.3), sleeving a compression disc membrane in a hydraulic press, and pressing a disc;

step 1.4), sintering for 0.4-0.6 min under the pressure of 25kn/cm 2-250 kn/cm2, and then sintering for 5-6 hours at 1200-2000 ℃ in an inert atmosphere to obtain the 100Mo sample disc.

further, in order to obtain a higher quality sample plate, the junction temperature in step 1.4) was 1700 ℃.

Further, in order to achieve sufficient dissolution of the sample disc in a short time, parameters for dissolving the 100Mo sample disc with hydrogen peroxide in the second step are as follows:

The hydrogen peroxide concentration is as follows: 30 percent;

the initial dissolution temperature was: 70 ℃;

the addition speed is as follows: 40ml/g is added at a rate of 1ml/min, wherein 40ml/g means 40ml of hydrogen peroxide is added per 1g of 100Mo sample trays.

and step four, after the primary adsorption, standing the mother liquor for several hours, passing the mother liquor through the primary capture resin again, and repeating the processes from the step four to the step six until the mother liquor contains little 99 Mo.

further, the selection principle of the alumina column in the sixth step is as follows: the alumina columns have selective adsorption on the existing parent species Mo (Vi) and do not adsorb on 99 mTc.

further, the aqueous solution of KOH or NaOH is an aqueous solution of deionized water.

Further, in order to control the pH and Al content of the product, the sixth step is specifically:

step 6.1), washing the alumina column by using a glucose acid liquor buffer solution;

step 6.2), performing secondary adsorption on 99mTc by using the aluminum oxide column treated in the step 6.1), and then eluting by using normal saline.

The invention has the beneficial effects that:

1. the invention realizes the separation of 99mTc by two adsorption processes, has simple separation process, does not require a large-volume generator, has low requirements on an adsorption column and leacheate, can be applied to a method for producing 99Mo by utilizing an electron accelerator and can also be applied to the separation process with low specific activity of 99 Mo;

2. According to the method, primary capture resin is selected to carry out primary adsorption on 99mTc, after the 99mTc in 99Mo is subjected to primary concentration, an aluminum oxide adsorption column is used for carrying out conventional adsorption and elution, and the 99mTc with high specific activity can be obtained;

3. According to the invention, a relatively excellent dissolution parameter is obtained by researching the relation between the dissolution rate and the compression density of the sample disc, and under the condition of the dissolution parameter, the sample disc has relatively high dissolution capacity, so that the test time is further shortened, and the test cost is saved.

4. In the secondary adsorption process, the glucose acid liquor buffer solution is used for washing the alumina column, the pH value and the Al content in the product solution are adjusted, and the pH value and the Al content of the product are ensured to be in the standard range.

drawings

FIG. 1 is a schematic flow chart of an exemplary method;

FIG. 2 is a correlation between Al and pH content in a product sub-liquid;

Detailed Description

The invention is further described with reference to the following figures and specific embodiments.

the invention is realized by the following steps:

S1, manufacturing a 100Mo sample disc;

The 100Mo sample disks were made from highly concentrated 100Mo powder, which was selected for this example to have a concentration greater than 99.9%. The 100Mo powder is finely ground or conditioned prior to being dispensed and placed into the compression disc die sleeve forming die. And (5) placing the compression disc die sleeve in a hydraulic press to press a disc. Sintering at 25kn/cm 2-250 kn/cm2 for 0.5min, and sintering at 1700 ℃ in a reducing or inert atmosphere (such as argon) for 5 hours. The volume density of molybdenum in the obtained 100Mo plate is 90-95%. High temperature sintering causes the disk to shrink about 4% in diameter and about 3% in thickness. In other embodiments the primary sintering time may be any time period between 0.4min and 0.6min and the sintering time in reducing or inert gas may be any time period between 4 and 6 hours.

s2, dissolving the irradiated 100Mo sample disc by using hydrogen peroxide;

S21, researching the relation between the dissolution rate and the compressed density of the sample disc;

the dissolution rate of the higher compressed density discs is significantly slower than that of the less dense discs. While this behavior is expected, a more detailed study was conducted to investigate the relationship between dissolution rate and compressed density of the sample disc. In the embodiment, the density and the dissolution rate of the polytetrafluoroethylene convoluted disk are utilized to obtain better dissolution parameters, and the dissolution rate of several Polytetrafluoroethylene (PTFE) and non-Polytetrafluoroethylene (PTFE) sintered disks in hydrogen peroxide is between 56 and 94 percent. The dissolution rates for both Polytetrafluoroethylene (PTFE) and non-Polytetrafluoroethylene (PTFE) disks decreased linearly when the compression/packing density reached 88%. In order to dissolve the sintered disc with the packing density of 94%, the H2O2 solution is heated to 90-95 ℃. Sintered disks with a compression/packing density < 94% typically dissolve in less than 3 minutes (-1.1 g) per disk at 30% H2O2 and an onset temperature of 70 ℃. Therefore, the concentration of the hydrogen peroxide is determined to be 30%, and the dissolution rate is higher at the initial dissolution temperature of 70 ℃.

s22, based on the experimental conclusion, dissolving the irradiated 100Mo sample disc by using hydrogen peroxide;

S221, when an electron beam of a high-energy electron accelerator is converted into a 100Mo sample disc through bremsstrahlung bombardment compression sintering by a conversion target, 99Mo is produced through a photonuclear reaction of 100Mo (gamma, n)99Mo and the like or 99Mo is produced through proton bombardment of a proton cyclotron to the 100Mo sintered sample disc, and then the 100Mo sample disc is taken out;

S222, dissolving the 100Mo sample disc by using hydrogen peroxide (namely hydrogen peroxide, hereinafter referred to as H2O 2). In addition to the factors affecting dissolution described in step S21, another important factor affecting dissolution is the initial volume of H2O2, and to prevent splattering, the volume of H2O2 used should be less than 20% of the volume of the beaker or vessel used for dissolution.

according to the experimental result of step S21, the 100Mo sample disk dissolution conditions of 30% H2O2 was selected and added to the 100Mo sample disk dissolution vessel at a rate of about 1ml/min at a rate of about 40ml/g, with a dissolution initiation temperature of typically about 70 ℃. When a Mo sintered sample disk was added to a 30% H2O2 solution, the temperature rose rapidly (-100 ℃) and large amounts of bubbles and gas were generated.

One reason for affecting complete dissolution of the sample disk may be that the surface tension of H2O2 is relatively high, preventing good contact with the 100Mo sample disk surface. Thus, to reduce the surface tension, the temperature of H2O2 can be increased to 95-100 ℃ to dissolve all undissolved residue from the sample pan. When the H2O2 temperature was maintained at 95oC during dissolution, experiments confirmed that this helped to shorten the dissolution time for the higher density 100Mo sample disks to 10-15 minutes per disk. And if the sample tray is still partially undissolved, drying the sample tray, and repeating the above processes for a plurality of times until the sample tray is completely dissolved. Excess H2O2 was destroyed by heating.

S23, converting the molybdenum peroxy species into molybdate by using NaOH or KOH;

The dissolved target solution is transferred to 5N to 8N NaOH or KOH distilled deionized water, preferably NaOH. After addition of the KOH or NaOH solution to the target solution, the molybdenum peroxide is converted to molybdate.

S24, adsorbing 99mTc by using primary capture resin;

As described in the background art, the accelerator has low specific activity for 99Mo production, and the solution obtained after dissolution of the sample disk contains high concentration of Mo and only trace amount of 99mTc, and the separation process thereof is different from the separation process requirements of Mo/Tc generators with high specific activity of 99mTc currently used for commercialization (reactor production of 99 Mo). The chemical separation of 99mTc from 99Mo in the present invention relies on highly selective resins. The method comprises the steps of selecting primary capture resin or chemical matrix resin, and adsorbing 99mTc in a dissolved solution for the first time; this example selects resin as the primary capture resin. The resin is a double aqueous phase extraction chromatographic resin, and has strong removal capability on -high acid salt in a double-phase solution.

the dissolved solution obtained in step S23 is passed through the resin to adsorb 99mTc in the solution, and separated from the mother liquor.

s25, stripping 99mTc from the primary capture resin;

S251, the primary capture resin (PC) having 99mTc adsorbed thereon is washed with a hydroxide. The primary capture resin with adsorbed 99mTc was specifically washed with 10ml of 4m naoh, flowed into the same mother liquor recovery vessel as described above, after which the passage to the mother liquor recovery vessel was closed;

S252, open the channel to the daughter product, rinse with acetic acid/sodium acetate buffer, and strip 99mTc from PC with physiological saline at 2 mL/min.

S26, performing secondary purification on 99mTc by using an aluminum oxide separation column;

The eluted 99mTc is then passed through a second adsorption alumina separation column (secondary capture purge of 99mTc, abbreviated as SC) which selectively adsorbs any parent species mo (vi) which may be present, while hardly adsorbing 99 mTc. The use of SC corresponds to a second purification step of the final 99mTc product from the parent radioisotope. The SC purified 99mTc was eluted with-5 mL physiological saline (2mL/min) in the daughter receiving vessel- -product vial under stripping conditions.

stripping condition experiment: it is also important to control the pH of the product solution because the aluminum content of the product vial is highly pH dependent. There is a certain correlation between Al content and pH value in the product sub-liquid. After the method is changed, a washing step is added, and the glucose acid liquor buffer solution is used for washing the alumina separation column, so that the pH value and the Al content in the product sub-solution are obviously reduced. The 99Mo concentration in all product vials was determined by gamma analysis and aluminum bleed when the pH of the solution in the product vial was below the maximum of the United States Pharmacopeia (USP) specification in the range of 4.5 to 7.5.

as shown in fig. 2, the correlation between Al and pH content in the product sub-liquid in the product solution is shown. The distribution of 99Mo and 99mTc in the whole experimental process was monitored by PC, SC and gamma analysis in the 99mTc product solution and mother liquor after each separation. The Al content in the product solution was determined using ICP-MS. By testing, over 93% of the available 99mTc is continuously recovered in the product solution, a proportion which is higher than that of the current commercial standard 99mTc generators. Meets the requirements of the standard GB13172-2009 of the people's republic of China on the pH value of a molybdenum-technetium generator and the contents of molybdenum and aluminum.

the mother liquor collected by the mother liquor collecting container after the molybdate solution adsorbs 99mTc by the PC resin can be reused after 8 hours, 12 hours or 24 hours, namely, the mother liquor in the collecting container is adsorbed 99mTc by the PC resin again, and the process is repeated. Repeated use after 8 hours gives 50% of the initial amount, after 12 hours 60% of the initial amount and after 24 hours 80% of the initial amount. Preferably, the elution is carried out within 8 hours, the 16-hour equilibrium accumulation is left, and the influence on the elution yield of the next day is less than 10%.