JP2012223711A - Mo ADSORBING AGENT, METHOD FOR PRODUCING THE SAME, AND 99Mo-99mTc GENERATOR - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a Mo adsorbing agent which is produced by using a safe dispersing solvent without using tetrahydrofran to improve the efficiency of an alkoxylation reaction and which has high Mo adsorptivity, excellent stability and an improved capacity for elutingTc.SOLUTION: This method for producing the Mo adsorbing agent comprises: an alkoxylation step being a first step of adding butyl ether being the dispersing solvent to a mixture of zirconium halide being a raw material with alcohol and reacting them with one another to produce an alkoxylated product; a hydrolysis/dehydration condensation step being a second step of adding water and butyl ether to the alkoxylated product and subjecting the water-/butyl ether-added alkoxylated product to hydrolysis/dehydration condensation to produce a precursory product; and a third step of subjecting the precursory product to polymerization, condensation, solvent removal and heat treatment. The produced Mo adsorbing agent has a skeletal structure of -O-Zr-Cl and ≥160 mg(Cl)/g chlorine content.

Description

The present invention relates to a Mo adsorbent, a method for producing the same, and a ⁹⁹ Mo- ^99m Tc generator.

^99m Tc is administered to the human body as a so-called radiopharmaceutical bonded to various compounds, and is used for nuclear medicine diagnosis such as cancer.

^{Conventionally, 99m} Mo as a way to retrieve the ^99m Tc, the ⁹⁹ Mo a column filled with Mo adsorbent adsorbed with _MoO ^{4 2-form,} only ^99m Tc by milking process by flowing saline ^99m TcO ₄ ^- of A generator system that elutes in form has been used.

Patent Document 1 includes a first step of reacting at least one of a zirconium halide and a halogenated zirconium oxide with an alcohol having 1 to 6 carbon atoms in a solvent or without a solvent, and further, hydrolysis or water. ⁹⁹ Mo- ^99m comprising the second step of coordination and the third step of heating the precursor thus obtained in an oxidizing or non-oxidizing atmosphere containing moisture to crosslink it, thereby making it insoluble in water. A method for producing a Mo adsorbent for a Tc generator is described.

In this document, ZrCl ₄ is suitable as a zirconium halide used in the first step, and methanol, ethanol, isopropyl alcohol, butanol, ethylene glycol, glycerin, porvinyl as 1 to 6 alcohols are used. It is described that alcohol or the like can be a raw material.

Japanese Patent No. 2857349

Conventionally, tetrahydrofuran (THF) is used as a dispersion solvent in the first step, but tetrahydrofuran has a problem that it is biotoxic and unsuitable for the synthesis of medical materials. And the use of this tetrahydrofuran has poor alkoxylation reaction efficiency, and the produced Mo adsorbent has poor Mo adsorption ability, lacks stability, and has a large residual amount of organic substances used in the synthesis reaction. ^99m Tc elution There is a problem that ability is low.

  In addition, the conventional synthesis process for producing the Mo adsorbent consists of three steps: a first step (alkoxylation reaction step), a second step (polymerization treatment / solvent removal step), and a third step (heat treatment step). Since the reaction vessel is transferred separately for each process, there is a problem that the raw material and the reaction intermediate (precursor) are lost or the synthesis time is long.

In view of this point, the present invention does not use tedrahydrofuran as a dispersion solvent, and uses a safe solvent. By using this solvent, the alkoxylation reaction efficiency is improved, and the Mo adsorbent produced thereby However, the object is to have a high Mo adsorption capacity and good stability and to improve the ^99m Tc elution capacity.

The present invention relates to a Mo adsorbent having a skeleton structure of —O—Zr—Cl, capable of adsorbing ⁹⁹ Mo, which is a radioisotope, together with Mo, and eluting ^99m TcO ₄ ^— produced from ⁹⁹ Mo. A manufacturing method comprising:
A first step alkoxylation step of adding a butyl ether as a dispersion solvent to a zirconium halide and an alcohol as a raw material and reacting them to produce an alkoxylation product;
A hydrolysis / dehydration condensation step of the second step in which water and further butyl ether are added to the reaction-generated alkoxylation product, followed by hydrolysis and dehydration condensation to produce a precursor product;
The resulting precursor product is polymerized and concentrated, and the heat treatment solvent is removed to obtain a skeleton structure of -O-Zr-Cl,
A third step of polymerization / solvent removal and a heat treatment step to produce a reaction product having a chlorine content of 160 mg (Cl) / g or more,
The continuous production method of Mo adsorbent characterized by comprising.

In the present invention, the Mo adsorption produced by the continuous production method is
Mo adsorption amount is 230-240 mg (Mo) / g, and
^99m Tc elution rate is 90-93%
A method for continuously producing a Mo adsorbent characterized by exhibiting the following properties:

In the present invention, the residual organic matter content is 0.05 to 0.2%, and the material hardness is 500 to 800 gw / cm ^2.
A continuous production method of an Mo adsorbent is provided, characterized in that a reaction product exhibiting the following properties is produced.

  In the present invention, the alkoxylation step of the first step can be controlled in the internal pressure and temperature, and is performed in a gas flow rotary reaction type reactor, and the hydrolysis and dehydration condensation steps of the second step are performed. The Mo adsorbent is characterized in that it is made in the reactor continuously in the first step, and the polymerization / solvent removal and heat treatment steps in the third step are made in the reactor continuously in the second step. A continuous production method is provided.

The present invention also provides a Mo adsorbent characterized in that the Mo adsorbent produced by the continuous production method has a chlorine content of 160 mg (Cl) / g or more.

The present invention also includes a column containing Mo adsorbent produced by the continuous production method and having a chlorine content of 160 mg (Cl) / g or more, wherein the Mo adsorbent contains ⁹⁹ Mo. There is provided a ⁹⁹ Mo- ^99m Tc generator characterized by having means for adsorbing and generating ^99m Tc from ⁹⁹ Mo, and milking means for eluting ^99m Tc in the form of ^99m TcO ₄ ⁻ .

In the present invention, since butyl ether is added as a dispersion solvent to the halide of zirconium, there is no problem in the synthesis of medical materials, the alkoxidation reaction efficiency is improved, and the chlorine content is 160 mg (Cl) g or more. to be able to, Mo adsorbent produced has a high Mo adsorption capacity, have been Mo adsorbed produced is a high Mo adsorption capacity, yet stable, small residual amounts of organic matter, ^99m Tc The elution ability can be improved.

Further, according to the present invention, the internal pressure and temperature can be controlled as described above, and the processes of the first step, the second step, and the third step are continuously performed using a gas flow rotary reaction type reactor. since as can be performed, it is possible to mass production, also ^99m TcO ₄ as a medical material efficiently by reducing the synthesis time ^- can generate elution capability.

The synthetic | combination flowchart of PZC-BE which is an Example of this invention. The figure which shows the synthesis | combining method of PZC-BE. The synthetic | combination flowchart of conventional Mo adsorbent PZC. The figure which shows the synthesis | combining method of PZC. The figure which shows the Mo adsorption amount performance of PZC-BE and PZC. PZC-BE and shows the ^99m Tc elution rate performance of PZC. The figure which shows the material hardness (material strength) performance of PZC-BE and PZC. The figure which shows the performance of FIGS. 5-7 collectively. ^The figure which shows the basic composition of ^99m Tc generator. PZC-BE (or PZC) by ^{Mo (99} Mo) diagram illustrating the principle of adsorption and ^99m Tc elution.

  Embodiments of the present invention will be described below with reference to the drawings.

  A Mo adsorbent production apparatus is used for the implementation of the present invention. The Mo adsorbent manufacturing apparatus includes a reactor capable of pressure and temperature control and gas flow rotation, and a Mo adsorbent generating unit configured in the reactor.

  FIG. 1 shows a continuous production method of Mo adsorbent which is an embodiment of the present invention.

  In FIG. 1, a reactor capable of controlling pressure and temperature and rotating a gas flow is used for continuous production of Mo adsorbent.

In this reactor, the alkoxylation process in the first step, the hydrolysis in the second step, the dehydration condensation step, the polymerization in the third step, the solvent removal, and the heat treatment step are successively formed.
An example of a synthesis flow for continuously producing the Mo adsorbent by these steps is as follows.

In the alkoxylation step, ZrCl ₄ as a zirconium halide and isopropyl alcohol (IPA) as an alcohol are placed in a flask (SI), and an apparatus set (S2) is performed.

The zirconium halide and halogenated zirconium oxide used in the first step of this production method are preferably chlorides, and particularly ZrCl ₄ is preferred. As the other starting material alcohol, for example, monohydric alcohol such as methanol, ethanol, isopropyl alcohol and butanol, dihydric alcohol such as ethylene glycol, polyhydric alcohol such as glycerin and polyvinyl alcohol, and the like can be used. Benzyl alcohol, phenol and the like can also be used as a raw material for the Mo adsorbent. N ₂ gas is bubbled as an atmospheric gas, and butyl ether (BE) is added as a dispersion solvent.

In this way, reagent addition (S3) is formed. In the presence of butyl ale, the raw materials are mixed and heated to 50 ° for reaction treatment (S4). The time required for the reaction process is assumed to be 1.5 hours. By this reaction treatment, an alkoxylation product is generated as shown in FIG.
After the 50 ° treatment, the process shifts to the second step without transferring the reaction product train to another reaction vessel following the alkoxylation step. In the second step, water (H ₂ O) is added, butyl ether (BE) is further added, and a reagent is added (S5) (reagent addition). Thus, a reagent is made to react with the alkoxy product produced | generated at the 1st process (S6). This reaction is continued for 1 hour while maintaining the temperature at 50 ° C.

  By this step, a hydrolysis / dehydration condensation step is formed, and a precursor product is generated as shown in FIG.

Next, the third step is performed in the same reactor. In the third step, N ₂ gas is introduced and polymerization is performed by concentration (S7) by gradually raising and maintaining the temperature to 50 to 130 ° C. This 50-130 ° C. treatment is continued for 3.5 hours. Next, the pressure is reduced and heat treatment (S8) is performed. This heat treatment is a heat treatment at a temperature of 160 ° C. This 160 ° C. treatment is continued for 1 hour, and then pulverized and sized (S9). This cooling and pulverization process is continued for 1 hour. By these treatments, polymerization, solvent removal, and heat treatment steps are formed, and PZC-BE as a Mo adsorbent is generated as shown in FIG.

  From the first step to the third step, the synthesis time is 8 hours, and 500 g to 3,000 g of Mo adsorbent (PZC-BE) is generated by batch processing.

  The conventional PZC synthesis flow for comparison of synthesis conditions is shown in FIGS. The steps shown in FIGS. 3 and 4 are as follows.

[First step: alkoxylation reaction]
ZrCl ₄ + 2CH ₃ CH (OH) CH ₃ − → ZrCl ₂ (OC ₃ H ₇ ) ₂ + 2HCl (1)
Since the above involves a violent reaction, conventional products use THF (tetrahydrofuran C ₄ H ₈ O) as a solvent to relax the reaction and disperse the raw materials (zirconium chloride ZrCl _4, isopropyl alcohol CH ₃ CH (OH) CH ₃ ). is doing. This THF is not directly related to the synthesis reaction shown in (1) above. Since THF contains p-cresol and hydroquinone (boiling point of 200 ° C. or more) as stabilizers, there is a difficulty that non-volatile substances and thermal decomposition products remain in the solvent removal and heat treatment in the second to third steps in the subsequent stage. there were.

[Second step: Hydrolysis treatment / Dehydration condensation step]
ZrCl ₂ (OC ₃ H ₇ ) ₂ + 2H ₂ O → ZrCl ₂ (OC ₃ H ₇ ) OH + C ₃ H ₇ OH (2)
The alkoxy product (ZrCl ₂ (OC ₃ H ₇ ) ₂ ) produced in the first step is reacted with water to hydrolyze the alkoxy group (OC ₃ H ₇ ), and the produced alcohol and unreacted water are removed by heating. While dehydrating and condensing.

[Third step: heat treatment step]
_{ZrCl 2 (OC 3 H 7)} OH → [-ZrClx-O-] _{n + C 3 H 7 OH +} H 2 O (HCl) ... (3)
The intermediate product in the second step is usually heated at about 150 to 160 ° C. to crosslink the precursor and increase the molecular weight. Mo adsorption agent (PZC) is synthesize | combined by the above process.
In the Mo adsorbent synthesis process of the embodiment of the present invention, the first step (alkoxylation reaction step), the second step (hydrolysis / dehydration condensation step) and the third step (polymerization treatment / solvent removal step) of the conventional synthesis process. And the heat treatment step) are continuously performed in one container. Further, BE (dibutyl ether) is used in place of tetrahydrofuran (THF), which is a dispersion solvent in the conventional first step, to improve the alkoxylation reaction efficiency.

  The Mo adsorbent having a skeleton structure of -O-Zr-Cl is generated by the first step, the second step, and the third step described above.

This Mo adsorbent includes those represented by the following general formula.

  This example is characterized in that the chlorine content can be 160 mg (Cl) / g or more by improving the alkoxylation reaction efficiency.

  5 to 8 show a performance comparison between this example PZC-BE and the conventional Mo adsorbent PZC.

  FIG. 5 shows the Mo adsorption amount of both Mo adsorbents.

  As described above, the following effects are configured by increasing the chlorine content.

  Conventionally, the Mo adsorption amount of the Mo adsorbent PZC lacked stability in the range of 160 to 220 mg (Mo) / g, whereas in this example PZC-BE, the Mo adsorption amount was 230 to 240 mg (Mo). The amount of Mo adsorption is high and stable as compared to the conventional Mo adsorbent (PZC).

FIG. 6 shows the ^99m Tc elution rate of both Mo adsorbents.

The ^99m Tc elution rate of the conventional Mo adsorbent PZC is 73 to 80%, whereas this example PZC-BE shows a performance of 90 to 93%, which is ^99m Tc elution rate compared to the conventional Mo adsorbent. Is high and stable.

In FIG. 7C, in this example PZC-BE, the measured value of the material hardness, that is, the material strength, is 550 to 860 gw / cm ² .

In FIG. 7 (d), in this example PZC-BE, the measured value of the material hardness, that is, the material strength, is 500 to 870 gw / cm ² .

From these data, this example PZC-BE shows a measured value of material hardness of 500 to 870 gw / cm ² at least. On the other hand, FIG. 7 (a) shows that in the conventional Mo adsorbent PZC, the measured value of the material hardness, that is, the material strength was 208 to 318 gw / cm ² .

In FIG. 7B, the conventional Mo adsorbent PZC (for example, the material shown in Patent Document 1) had a material hardness, that is, a measured value of material strength, of 130 to 245 gw / cm ² .

  As described above, it can be seen that the material hardness of the PZC-BE of the present invention is dramatically higher than that of the conventional PZC, and is a Mo adsorbent that is easy to handle because the material is strong.

  The performance shown in FIGS. 5 to 7 is summarized as shown in FIG.

  The content of chlorine (Cl), which is a reactive group with Mo, is obtained by chemical analysis, and is expressed as Cl content weight (mg) per unit weight of Mo. Conventional Mo adsorbent is 130 to 140 mg (Cl). However, in this example, it was 160 mg (Cl) / g, which shows a stable high value. The amount of chlorine (Cl) per unit weight increases, and the content is stably increased. Moreover, since the chemical bonding force is increased, the material hardness, that is, the material strength is high, the Mo adsorption amount is high, and stable performance is exhibited.

As described above, the continuous production method of the Mo adsorbent according to the present embodiment can control the internal pressure and temperature as an example. A first step alkoxylation step in which an alcoholic solvent and butyl ether are added to a zirconium halide as a raw material and reacted in a gas flow rotary reaction type reactor,
Continuing from the first step, in the reaction, water and further butyl ether are added to the reaction-generated alkoxylation product, followed by hydrolysis and dehydration condensation, and a second step hydrolysis / dehydration condensation step;
Continuing to the second step, the produced precursor product is polymerized and concentrated in the reactor, and heat-treated after removing the solvent, thereby giving a skeleton structure of -O-Zr-Cl,
The chlorine content is 160 mg (Cl) / g or more, the Mo adsorption amount is 230 to 240 mg (Mo) / g ^99m Tc elution rate is 90 to 93%.
A third step of polymerization, solvent removal and heat treatment to produce a reaction product exhibiting the properties of
Consists of

Moreover, Mo adsorbent (PZC-BE) produced by the present invention is
Residual organic matter content is 0.05-0.2%
Material hardness of 500-870 gw / cm ²
The properties are shown. On the other hand, the conventional Mo adsorbent (PZC) has a high residual organic content of 1 to 5% and a low material hardness of 130 to 318 gw / cm ² , in order to obtain high-quality ^99m Tc required for medical diagnosis. There was a problem as a ^99m Tc generator material.

FIG. 9 shows the basic configuration of a ^99m Tc generator.

In FIG. 9, the ^99m Tc generator 50 includes a ⁹⁹ Mo adsorption PZC-BE column 51 and a purification alumina column 52 connected thereto, and the ⁹⁹ Mo adsorption PZC-BE column 51 has a physiological solution containing physiological saline. A saline container 53 is connected. A ^99m Tc solution is placed on the outlet side of the alumina column 52.

^{A 99m} Tc solution container 54 is connected. In this way, the alumina column 52 for purification is connected to the subsequent stage of the ⁹⁹ Mo adsorption PZC-BE column 51, and the basic configuration of the ^99m Tc generator 50 is formed. The basic configuration of the ^99m Tc generator is the same as the conventional one.

In the ^99m Tc generator 50 basic configuration, the ⁹⁹ Mo adsorption PZC-BE column 51 stores the generated Mo adsorbent PZC-BE shown in FIG. The ⁹⁹ Mo adsorption PZC-BE column 51 is supplied with physiological saline from a physiological saline container 53.

FIG. 10 shows the principle of Mo ( ⁹⁹ Mo) adsorption and ^99m Tc elution by Mo adsorbent (PZC-BE). This principle is not different from the conventional one.

In FIG. 10, Mo adsorbent (PZC-BE) is formed from ZrCl ₄ as a raw material and an alcohol solvent. This Mo adsorbent (PZC-BE) has a structure of -O-Zr-O-Zr-Cl. PZC-BE has a skeleton structure of —O—Zr—Cl, and the properties thereof are as described above.

The Mo adsorbent (PZC-BE) is stored in a ⁹⁹ Mo adsorption PZC-BE column 51 shown in FIG. Mo ( ⁹⁹ Mo) O ₄ ²⁻ is introduced into the column 51 together with H ₂ O, and ⁹⁹ Mo is adsorbed by PZC-BE. The adsorbed ⁹⁹ Mo then emits β rays and is converted to ^99m Tc.

^In FIG. 9, ^99m Tc is eluted as ^99m TcO ₄ ^{− with} physiological saline, purified with an alumina column 52, and stored in a ^99m Tc solution container 54. The stored ^99m TcO ₄ ⁻ will be administered to the human body for radiodiagnosis.

  According to this example, since it became possible to continuously proceed the three steps of the Mo adsorbent synthesis process in one container, there is no loss of raw materials and reaction intermediates (precursors), Since it is not necessary to transfer the reaction vessel for each process, the entire first to third processes can be smoothly proceeded, so the synthesis time is reduced to about 1/3 of the conventional (30 to 40 hours) ( 8-10 h). Moreover, the synthesis capacity of the conventional Mo adsorbent was about 50 g per batch. However, as a result of replacing the reaction vessel with a conventional gas flow rotary reactor capable of pressure control from the stationary / batch type, Mo adsorption It was possible to increase the synthesis capacity of the agent to 500 to 3,000 g per batch which is 10 to 60 times the conventional one.

The improved Mo adsorbent synthesized by the present invention has an increased Mo adsorption capacity and is stable, an ^99m Tc elution capacity is increased and stable, and organic impurities in the material can be reduced and the material hardness can be increased. .

50 ... ^99m Tc generator, 51 ... ⁹⁹ Mo adsorption PZC-BE column, 52 ... alumina column, 53 ... physiological saline container, 54 ... ^99m Tc solution container.

Claims (6)

This is a method for producing a Mo adsorbent having a skeleton structure of —O—Zr—Cl, capable of adsorbing ⁹⁹ Mo, which is a radioisotope, together with Mo and eluting ^99m TcO ₄ ^— produced from ⁹⁹ Mo. And
A first step alkoxylation step of adding a butyl ether as a dispersion solvent to a zirconium halide and an alcohol as a raw material and reacting them to produce an alkoxylation product;
A hydrolysis / dehydration condensation step of the second step in which water and further butyl ether are added to the reaction-generated alkoxylation product, followed by hydrolysis and dehydration condensation to produce a precursor product;
The resulting precursor product is polymerized and concentrated, and the solvent is removed and heat-treated to obtain a skeleton structure of -O-Zr-Cl,
A third step of polymerization / solvent removal and a heat treatment step to produce a reaction product having a chlorine content of 160 mg (Cl) / g or more,
A method for continuously producing a Mo adsorbent comprising the steps of: Mo adsorption produced by the continuous production method according to claim 1,
Mo adsorption amount is 230-240 mg (Mo) / g, and
^99m Tc elution rate is 90-93%
A method for continuously producing a Mo adsorbent characterized by exhibiting the following properties: In Claim 1 or 2, residual organic matter content is 0.05 to 0.2% and material hardness is 500 to 800 gw / cm ^2.
A method for continuously producing a Mo adsorbent, characterized in that a reaction product exhibiting a property of   4. The process according to claim 1, wherein the first alkoxylation step is controlled by a gas flow rotary reaction type reactor, the internal pressure and temperature being controllable, and the second step hydrolysis and dehydration. A condensation step is performed in the reactor continuously with the first step, and a polymerization / solvent removal and heat treatment step in the third step is performed in the reactor continuously with the second step. Continuous production method of Mo adsorbent. The Mo adsorbent produced by the continuous production method according to any one of claims 1 to 4 has a chlorine content of 160 mg (Cl) / g or more. A Mo adsorbent produced by the continuous production method according to any one of claims 1 to 4 and containing a Mo adsorbent having a chlorine content of 160 mg (Cl) / g or more, and the Mo adsorbent There adsorbs ^{99 Mo,} 99 have means for generating a ^99m Tc from ^Mo, the _{^{99m Tc 99m TcO 4 - 99 Mo-}} 99m Tc generators, characterized in that it comprises a milking means for eluting in the form of.

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