CN1658938A

CN1658938A - Multicolumn selectivity inversion generator for production of high purity actinium for use in therapeutic nuclear medicine

Info

Publication number: CN1658938A
Application number: CN038137259A
Authority: CN
Inventors: P·E·霍尔维茨; A·H·邦德
Original assignee: PG Research Foundation Inc
Current assignee: PG Research Foundation Inc
Priority date: 2002-04-12
Filing date: 2003-04-10
Publication date: 2005-08-24
Anticipated expiration: 2023-04-10
Also published as: CA2482294A1; EP1499412A4; CN1327926C; AU2003230886B2; CA2482294C; WO2003086569A1; EP1499412B1; EP1499412A1; ZA200408384B; AU2003230886A1

Abstract

Disclosed is a process for producing a solution of a daughter radionuclide that is substantially free of impurities by contacting an aqueous parent-daughter radionuclide solution with a first separation medium, eg. Chromatographic column. The product solution of the desired daughter radionuclide is then contacted with a second separation medium to produce a pure daughter radionuclide solution.

Description

The reverse selectivity generator of polystyle for preparing ultrapure radionuclide

The cross reference of related application

The application requires the priority of following provisional application: the No.60/372327 that on April 12nd, 2002 submitted; The No.10/159003 that on May 31st, 2002 submitted; The No.10/351717 that the No.10/261031 that on September 30th, 2002 submitted and on January 27th, 2003 submit.

Background technology

Acceptant use radioactive substance in diagnostic medicine because these program safeties, minimumly infect, price is feasible, and can provide by the unavailable exclusive structural and/or function information of other method to the clinician.The practicality of nuclear medicine is indicated by singly carrying out 1,300 ten thousand diagnostic programs every year in the U.S., has 1 to accept the nuclear medicine disposal in the patient of hospital admission corresponding to 4.(see, Adelstein et al.Eds., Isotopes for Medicine and the Life Science;National Academy Press, Washington, DC (1999); Wagneret al., " Expert Panel:Forecast Future Demand for Medical Isotopes, " Department of Energy, Office of Nuclear Energy, Science, andTechnology (1999); Bond et al., Ind.Eng.Chem.Res. (2002) 393130-3134.) all be to be used for the diagnostic imaging purpose wherein more than 90% program, and use technetium-99m ( ^99mTc) as radionuclide. ^99mTc have concurrently be convenient to prepare and acquisition and suitable nucleatr decay mode, decay can and the exclusive combined characteristic of chemical reactivity aspect.These characteristics make ^99mTc can locate agent coupling mutually with biology, can be to numerous disease and in fact human anatomical each position imaging.(see Bremer, Radiochim.Acta (1987) 41:73-81; Steigman et al., The Chemistry of Technetium in Medicine,National Academy Press:Washington, D.C., (1992); Schwochau, Angew.Chem.Int.Ed.Eng. (1994) 33:2258-2267.)

Medical radionuclide as ^99mThe life cycle of Tc is shown in Fig. 1, promptly obtains beginning and through the Clinical Processing of radiochemical nucleogenesis and radiopharmaceutic purifying and sterilization from raw material.Under discussion with technetium-99m as special case because most of nuclear medicine method is all utilized this radionuclide, and new technology of preparing is also compared with this successful pattern usually.Required " daughter " ^99mTc be by uranium-235 in nuclear reactor, fission formed " parent " molybdenum-99 ( ⁹⁹Mo) β ^-(or negatron) decay and form.(see Bremer, Radiochim.Acta (1987) 41:73-81; Schwochau, Angew.Chem.Int.Ed.Eng. (1994) 33:2258-2267; Boyd, Radiochim.Acta (1987) 41:59-63; And Ali et al., Radiochim.Acta (1987) 41:65-72.)

Molybdenum-99 during " chemical treatment " with its nucleosynthesis precursor and separation of by-products, by Fig. 1 should " chemical treatment " be the final step of " radiochemistry ".Should " radiochemistry " run into the strict regulations of much less aspect pure, do not impose requirement (as aseptic and non-pyrogen) biologically at chemical purity and radioactive nucleus.When finishing " chemical treatment " that comprises the generator preparation, should ⁹⁹Mo/ ^99mTc is to becoming " radiopharmaceutical " (pressing Fig. 1), and to stand chemical purity, radioactive nucleus is pure, aseptic and the strictness of nonthermal source aspect control.

Chemical purity is very important to safety and effective medical procedures, because before use, this radionuclide will be located the agent coupling with biology usually.This coupling reaction depends on the Coordinative Chemistry principle, wherein radionuclide is chelated to covalency to be connected on the biological ligand of locating in the agent.In chemical pure sample, the existence of type impurity ion can be disturbed this coupling reaction.If it is abundant ^99mTc for example is not coupled in the given biology location agent, then can be owing to photon density and/or because the video that background rising acquisition is difficult to determine in the body that the specific distribution in the stagnation of the blood or surrounding tissue causes in target position place deficiency.

The regulation that radioactive nucleus is pure is derived to patient and introduces the radioimpurity radioactive impurity of long-life or high energy and the danger followed, if particularly more dangerous under the situation that the biology location and the body eliminating characteristic of this radioimpurity radioactive impurity are not known.Radioactive nucleus impurity has biggest threat to patient's health, and this chaff interference is to give the required main key point of taking clinical quality control method of radiation harmful and the possibility lethal dose for preventing to patient.

Except that to the pure control of the chemical purity of " radiopharmaceutical " and radioactive nucleus, Fig. 1 also shows the requirement that will formulate the biology aspect.Radiopharmaceutic vivo medicine-feeding stipulates that clearly radiopharmaceutical should be aseptic and nonthermal source, and this requirement is that the medical matters professional is familiar with.

^99mTc has good nuclear properties and chemical characteristic concurrently, and this radionuclide that preparation is satisfied the radiopharmaceutical standard is favourable on economical and easy.In a word, these factors are extremely important to the success of nuclear medicine.

From ⁹⁹Separate among the Mo ^99mTc based on chemical fundamentals be aluminium oxide (Al ₂O ₃) in normal saline solution to molybdate-99 ( ⁹⁹MoO ₄ ^2-) high-affinity and to pertechnetate-99m ( ^99mTcO ₄ ^1-) low affine closing property.Fig. 2 illustrates general ^99mThe Tc generator or " ^99mThe Tc cow wherein should ⁹⁹MoO ₄ ^2-Parent is at Al ₂O ₃Be what not move on the adsorbent, and by up physiological saline stream wash can be easily with ^99mTcO ₄ ^1-Separate and enter vacuum tank.(see Bremer, Radiochim.Acta (1987) 41:73-81; Schwochau, Angew.Chem.Int.Ed.Eng. (1994) 33:2258-2267; Boyd, Radiochim.Acta (1982) 30:123--145; And Molinski, Int.J.Appl.Radiat.Isot. (1982) 33:811-819.)

What above-mentioned " general generator " provided that patients uses has the pure and mild radioactive nucleus of appropriate chemical pure ^99mTcO ₄ ^1-, and its advantage is easy to use, volume compact and makes main radiation hazard (promptly ⁹⁹MoO ₄ ^2-) be fixed on solid Al ₂O ₃Security on the carrier.This latter's advantage has alleviated the restriction that this generator transports to the nuclear pharmacy, and has simplified NMT personnel's artificial treatment.

Because ^99mTc is showing status and shown in Figure 2 general in nuclear medicine ^99mThe valid function of Tc generator, the program of this radionuclide generator and design have become the industrial standard of nuclear medicine.But the method for this class generator is not that all radionuclides all generally are suitable for, particularly to the parent source of low-activity specific activity or to be used for the treatment of those radionuclides of nuclear medicine inapplicable.Parent radionuclide to the low-activity specific activity, promptly the parent radioisotope of trace is as existing with the isotopic mixture of one or more a large amount of on-radiation parents, it uses the difficulty of general generator technology to come from needs a large amount of parent isotopes is distributed on the carrier of large volume, so that can not surpass the capacity of adsorbent.Big chromatographic column is unpractical to nuclear medicine application, because required daughter activity nucleic will reclaim with the eluant, eluent of large volume, this just is not suitable for clinical practice under the situation of no secondary concentration.Useful radionuclide in the treatment nuclear medicine is technical circuitous to unique difficulty at general generator, and is necessary further to be discussed.

In disease treatment, use the existing long-term practice of radiation, the treatment of main dependence external radiation bundle has now been proposed a kind of implementing method that more can aim at.For example adopt the sealed thing of imbedding that contains palladium-103 or iodine-125 that prostate cancer is done the short distance treatment; Being coupled to based on samarium-153 or rhenium-188 in the biology location agent of bisphosphonates is at the transfer in the remissive treatment of osteocarcinoma pain; Utilize radionuclide to be coupled on peptide, protein or the antibody of selectivity to the Huaihe River disease location with radioimmunoassay treatment (RIT), this radioactive decay provides the cytotoxin effect in its vicinity.A kind of cytotoxin dosage with radiation of radioimmunoassay treatment representative is supplied with the disease cell and the tool of the tissue that do not impair one's health simultaneously method optionally.(see Whitlock, Ind.Eng.Chem.Rev. (2000) 39:3135-3139; Hassfjell et al., Chem.Rev. (2001) 101:2019-2036; Imam, J.Radiation Oncology Biol.Phys. (2001) 51:271-278; And McDevitt et al.Science (2001) 294:1537-1540.) in addition, recently come from the information explosion about disease cause and function of the Human Genome Project, estimate can with RIT as treatment little lymphatic metastasis cancer (as lymthoma and leukaemia) and from the fritter tumour to the main method of piece tumour.

The half-life that is suitable for the optional radionuclide of RIT is generally 30 minutes to several days, and it has the Coordinative Chemistry that can be attached in the biological location agent and higher linear energy transfer (LET).LET is defined as the energy loss of charged particle unit length range in material, (see Choppin et al., J. Nuclear Chemistry:Theory and ApplicationPergamon Press:Oxford, 1980) and the LET of alpha particle obviously greater than the LET of beta particle.

For example average energy is that the alpha particle of 5-9MeV has just consumed its energy usually in the tissue of 50-90 μ m, and this range is equivalent to the diameter of several cells.Energy is about the β of the low LET of 0.5-2.5MeV ^1-The stroke of-particle in tissue reaches 10000 μ m, this β ^1-The low LET of emission needs nearly just can make the probability of cell killing reach 99.99% 100000 times in the cell surface decay.But to single alpha particle, when this independent alpha particle passed through nucleus, its quite high LET can make the probability of cell death reach 20-40%.(seeing Hassfjell et al., Chem.Rev. (2001) 101:2019-2036)

Unfortunately, make radiation α and β ^1-Nucleic become the LET of the possible cytotoxic agent that the cancer vermachen treats, also cause the difficulty of many uniquenesses at preparation and these radionuclides that are used for medical science of purifying.Wherein Zui Da difficulty is the radiation degradation that carrier material can take place when being used for the radionuclide of high LET with the generator method commonly used shown in Fig. 2.(see Hassfjell et al., Chem.Rev. (2001) 101:2019-2036; Gansow et al., In Radionuclide Generator:New Systems for Nuclear Medicine Application,Knapp etal., Eds., American Chemistry Society:Washington, DC (1984) pp215-227; Knapp et al., Eds., Radionuclide Generator:New Systems For Nuclear Medicine ApplicationAmerican Chemistry Society:Washington, DC (1984) Vol.241; Dietz et al., Appl.Radiat.Isot. (1992) 43:1093-1101; Mirzadeh et al., J.Radioanal.Nucl.Chem. (1996) 203:471--488; Lambrecht et al., Radiochim.Acta (1997) 77:103-123; And Wu et al., Radiochim.Acta (1997) 79:141-144.)

The radiation degradation of carrier material can cause: (a) reduce chemical purity (Tathagata can be stain daughter solution from the radiolysis product of carrier matrix); (b) infringement radioactive nucleus pure (the parent radionuclide can be discharged in the eluent as carrier material: be called " penetrating "); (c) yield (can force the parent radionuclide to enter the stagnant area of carrier as α-recoil, make its decay constant be difficult to enter in the desorb eluent) of reduction daughter activity nucleic; (d) reduce post stream than (fragmentation as carrier matrix produces particle, the pressure drop of passing post with increase); (e) unstable performance (as the yield of product purity instability, non-reproducibility, flowed fluctuation etc.).

The medical radionuclide generator is usually with the adsorbent of three kinds of base class, be used for common method shown in Figure 2: (a) organic adsorbent (as based on the ion exchange resin of the copolymer of polystyrene-divinylbenzene, be suitable for the polypropylene ester carrier of extraction-chromatography etc.), (b) inorganic adsorbent is (as Al ₂O ₃, inorganic gel etc.) and (c) mixed adsorbent (as contain the organic chelated and ion exchange functional groups of surface grafting the inorganic structure thing, be used for the silica supports of extraction-chromatography etc.).

Advised that with various organic adsorbents particularly Chang Yong cationic ion-exchange resin and anion exchange resin are used for the nuclear medicine generator and (see Molinski et al., Int.J.Appl.Radiat.Isot. (1982) 33:811-819.; Gansow et al., In Radionuclide generator: New Systems for Nuclear Medicine Application,Knapp et al., Eds., American Chemistry Society:Washington, DC (1984) pp215-227; Mirzadeh et al., J.Radioanal.Nucl.Chem. (1996) 203:471-488; And Lambrecht et al., Radiochim.Acta (1997) 77:103-123), this is because the chemo-selective of its verified mistake (is seen Diamond et al., In Ion Exchange, Marinsky Ed., Marcel Dekker, New York (1966) Vol.1, p.277; AndMassart, " Nuclear Science Series; Radiochemistry Techniques:Cation-Exchange Techniques in Radiochemistry; " NAS-NS 3113, National Academy of Science (1971)) and the widely property obtained of this class material.Unfortunately, based on organic ion exchange resin when using the program of generator commonly used on using regular meeting lost efficacy or limited by some, and can only under the radiation level of using always far below the mankind, use usually.

For example, be suitable for α-radiation body ²¹²Use cationic ion-exchange resin in the generator of Bi, but " dust cycle " of this material in the 10-20mCi generator is limited to about two weeks (useful life that is generator is by chemistry and mechanical degradation) based on AMBERLITE XAD-4.It is said the radiation degradation of this chromosorb cause flow descend, ²¹²Reduction of Bi yield and Radium-224 ( ²²⁴Ra) parent penetrates.(seeing Mirzadeh et al., J.Radioanal.Nucl.Chem. (1996) 203:471-488.) is same, use organic cation exchanger resin ²¹³The Bi generator is α-radiation of 2-3mCi at radioactive level ²²⁵Under the Ac parent situation, its shelf life is limited to (sees Mirzadeh et al., J.Radioanal.Nucl.Chem. (1996) 203:471-488 in an about week; And Lambrecht et al., Radiochim.Acta (1997) 77:103-123.)

With the approval recently of U.S. food and drug administration based on Yttrium-90 ( ⁹⁰Y) RIT can generally be used for the mankind, and this can continue to occur more effective generator technology to this radionuclide.By Strontium-90 ( ⁹⁰Sr) β of parent radionuclide ^1-Decay forms Yttrium-90, and therefore meaning comprises that Sr (II) and Y (III) (suppose it is chemical pure ⁹⁰The Sr material liquid) two components are separated.Though proposed various preparations ⁹⁰The method of Y (is seen Dietz et al., Appl.Radiat.Isot. (1992) 43:1093-1101; Horwitz et al., U.S. Patent No. 5368736 (1994); AndEhrhardt et al., U.S. Patent No. 5154897 (1992)) but because the radiolysis of solution medium and carrier matrix, every kind of technology all can circuitous difficulty to preparation Curie level level.Generator based on solvent extraction and ion-exchange is right ⁹⁰The unworthiness of Y propose big ring main body/object chemistry as from ⁹⁰Separate among the Sr ⁹⁰Carried out brief review in the document on the basis of Y.(see Dietz et al., Appl.Radiat.Isot. (1992) 43:1093-1101; And Ehrhardt et al., U.S. Patent No. 5154897 (1992))

In these reports, at the crown ether that contains oleophylic is optionally on the chromosorb, in 3M HNO to Sr (II) ₃In from ⁹⁰Separate among the Y ⁹⁰Sr.This extraction-chromatography material is right ⁶⁰The γ radiation of Co shows stable especially, though the delay of Sr (II) has some declines.Unfortunately, exist the air pocket that causes by radiolysis that the chromatographic performance of this generator commonly used is had adverse influence.Therefore after each processing operation, want desorb ⁹⁰Sr is to reduce the radiolysis degraded to carrier as far as possible; But, when reusing, will become more and more difficult for reaching effective desorb.

The use of inorganic material in the generator of radionuclide is subjected to based on Al ₂O ₃Commonly used ^99mThe very big influence of Tc generator technology.(see Bremer, Radiochim.Acta (1987) 41:73-81; Schwochau, Angew.Chem.Int.Ed.Eng. (1994) 33:2258-2267; Boyd, Radiochim.Acta (1987) 41:59--63; Boyd, Radiochim.Acta (1982) 30:123-145; Molinski, Int.J.Appl.Radiat.Isot. (1982) 33:811-819; Benjamins et al., U.S. Patent No. 3785990 (1974); Panek-Finda et al., U.S. Patent No. 3970583 (1976); Matthews et al., U.S. Patent No. 4206358 (1980); Benjamins et al., U.S. Patent No. 4387303 (1983); Weisner et al., U.S. Patent No. 4472299 (1984); Monze et al., Radiochim.Acta (1987) 41:97-101; Forrest, U.S. Patent No. 4783305 (1988); Quint et al., U.S. Patent No. 4833329 (1989); Vanderheyden etal., U.S. Patent No. 4990787 (1991); Evers et al., U.S. Patent No. 5109160 (1992); Ehrhardt et al., U.S. Patent No. 5382388 (1995); And Knapp etal., U.S. Patent No. 5729821 (1998) .) though inorganic adsorbent is demonstrating improvement aspect radiolysis stability, this inorganic material is normal to be shown the ion selectivity of going on business, slow distributed power and is difficult to determine the form of the good chromatographic performance of demonstration.

Use ^99mThe example of Tc generator, need carry out two components separate (promptly the physiological saline first from ⁹⁹MoO ₄ ^2-The middle separation ^99mTcO ₄ ^1-), to this Al ₂O ₃Be very suitable.But for more complicated geneticrelation, can occur between parent that can be in given decay chain and the daughter some very different chemical species (as ²²⁴Ra and ²¹²The gas of Bi, quadrivalent cation and bivalent cation), it is difficult finding out the single inorganic adsorbent that can be detained all other radionuclides except that required daughter activity nucleic.

Rhenium-188 ( ¹⁸⁸Re) as control the malignant boil nucleic prevent ISR at postangioplasty, alleviate osteocarcinoma pain and with some RIT program of the similar property of Coordinative Chemistry of the light congeners Tc of broad research in receive publicity.Rhenium-188 be by tungsten-188 ( ¹⁸⁸W) β ^1-Decay forms, ¹⁸⁸W in the high flux nuclear reactor by enrichment ¹⁸⁶The bineutron of W is captured and is prepared. ¹⁸⁸The poor efficiency of the nucleosynthesis of W produces the parent of low radiation domestic animal specific activity; It is trace ¹⁸⁸W is present in a large amount of ¹⁸⁶W is with in the bit table.This a large amount of tungstate radicle (WO ₄ ^2-) require big pillar, so that Al ₂O ₃To WO ₄ ^2-Capacity can not be exceeded.Big chromatographic column is created in the large volume solution ¹⁸⁸The Re daughter, and drafted various secondary concentration programs and tackle this shortcoming.(see Knapp et al., Eds., American Chemistry Society:Washington, DC (1984) pp215-227; Knappet al., Eds., Radionuclide generator:New Systems for Nuclear Medicine ApplicationAmerican Chemistry Society:Washington, DC (1984) Vol.241; Mirzadeh et al., J.Radioanal.Nucl.Chem. (1996) 203:471-488; Lambrecht et al., Radiochim.Acta (1997) 77:103-123; Knapp et al., U.S. Patent No. 5729821 (1998); Knapp et al., U.S. Patent No. 5186913 (1993); And Knapp et al., U.S. Patent No. 5275802 (1994) .)

When generator method commonly used is used for ¹⁸⁸During Re, the shortcoming that another of appearance seldom discussed is, after generator finishes its dust cycle, this isotope enrichment ¹⁸⁶W needs from numerous Al ₂O ₃Extract on the matrix.Isotope enrichment ¹⁸⁶The recovery of W is cheap preparation and uses with the neutron irradiation that is used for thereafter ¹⁸⁸The key factor of Re, but at large volume Al ₂O ₃On a large amount of isotope enrichments ¹⁸⁶The distribution overslaugh of W target material cost reasonably handle

¹⁸⁸Re " gel generator " is will overcome based on inorganic Al ₂O ₃ ¹⁸⁸The difficulty that the Re generator is faced should ¹⁸⁸Re " gel generator " is based on the wolframic acid zirconium acyl (ZrO (WO that forms slightly solubility ₄)) gel.(seeing Ehrhardt et al., U.S. Patent No. 5382388 (1995) and Ehrhardtet al., U.S. Patent No. 4859431 (1989) .) this principle with based on Al ₂O ₃Generator compared some advantages, but still have the shortcoming that is occurred when common generator method is applied to the radiotherapy nucleic.

Though with based on Al ₂O ₃Generator compare this ZrO (WO ₄) the gel generator is right ¹⁸⁸Re can use less pillar, but for carrying out thereafter again valuable isotope enrichment that irradiation will carry out ¹⁸⁶The recovery of W is still complicated.Other factor also comprises unsettled chromatographic characterization and flow, because the ZrO (WO to precipitating ₄) solid is difficult to determine its granular size or form.

Here the inevitable radiation degradation of the inorganic material of being touched upon is particularly for the radionuclide of high LET.The radiation α's that some are early stage ²¹²The Bi generator (is seen Gansow et al., In Radionuclide Generator:New Systems for Nuclear Medicine Application,Knapp et al., Eds., American Chemistry Society:Washington, DC (1984) pp215-227; And Mirzadeh, S.Generator-Produced Alpha-Emitters.Appl.Radiat.Isot. (1998) 49:345-349) once used the inorganic titanate fork-like farm tool used in ancient China to be detained long-life thorium-228 parent, and from this parent wash-out ²²⁴The Ra daughter then makes this daughter be adsorbed on common cation-exchanger resin.Through after a while, this titanate column material is destroyed in radiation degradation, produces fine grained and under high pressure implements to separate to force.

Mixed adsorbent can be divided into extraction-chromatography material and engineering inorganic ion exchange material.The application of most of disclosed composite material is to use ripe extraction chromatography (to see Dietzet al., in Metal Ion Separation and Preconcentration; Progess and Opportunities;Bond et al., Eds., American Chemistry Society:Washington, DC (1999) Vol.716, pp234-250), and the preparation of engineering inorganic material and use are nearest things.Extraction chromatography uses the solvent extraction agent that is physical absorption on the inertia chromatography matrix can overcome the ion selectivity and the slow distributed power of the difference of inorganic material.(see Dietz et al., in Metal Ion Separation and Preconcentration; Progess and Opportunities;Bond et al., Eds., American Chemistry Society:Washington, DC (1999) Vol.716, pp234-250.)

When inert base is amorphous inorganic material such as silica, improved the radiolysis stability of extraction-chromatography carrier, the result of this excellence is reflected by sustainable maintenance flow in the dust cycle of generator.The radiolysis stability of this but " improvement " is slippery because the Essential Chemistry reaction that separates as parent/daughter still comprise to the radiation degradation sensitivity the molecule of organic framework.Equally, will be incorporated in the engineering inorganic ion exchange material that will improve ion selectivity the sixth of the twelve Earthly Branches based on organic chelating moiety, but this functional group still will stand the influence of radiolysis.

In preparation ²¹³Adopt mixed adsorbent to deliver among the Bi as the preliminary report of the carrier of generator commonly used.(see Lambrecht et al., Radiochim.Acta (1997) 77:103-123; Wu et al., Radiochim.Acta (1997) 79:141-144; And Horwitzet al., U.S. Patent No. 5854968 (1998) .) research of beginning is by the absorption of organic cation-exchanger resin ²²⁵Obvious degradation just takes place in Ra, this resin at short notice, and produces ²¹³Productive rate decline, radionuclide purity variation and the underproof slow post flow of Bi.(see Mirzadeh et al., J.Radioanal.Nucl.Chem. (1996) 203:471-488; Lambrecht et al., Radiochim.Acta (1997) 77:103-123.) initial improvement be concentrate on ²¹³The parent of Bi ²²⁵Ac is adsorbed on the Dipex  resin, and this resin is a kind of carrier based on the inertia silica dioxide gel that absorbs the diphosphonic acid diesters of chelating on it with physics.(seeing Horwitz et al., React.Funct.Polymers (1997) 33:25-36.) this silica matrix has higher radiolysis stability than previously used organic cation-exchanger resin; But be loaded with parent ²²⁵The narrow chromatographic band found around of Ac has radiolysis damage (i.e. decolouring), causes parent at last ²²⁵Ac penetrates.(see Lambrecht et al., Radiochim.Acta (1997) 77:103-123; Wuet al., Radiochim.Acta (1997) 79:141-144.)

Further improvement in this generator is by with parent ²²⁵The radioactivity of Ac is dispersed on the chromosorb of larger volume reducing radiation density, and this will be by means of will ²²⁵Ac loads on the Dipex  resin and realizes with batch mode rather than with narrow chromatographic band.(seeing Wuet al., Radiochim.Acta (1997) 79:141-144.) unfortunately, this batch loading process is reluctant, and the radiation degradation in order to the diphosphonic acid diesters that increases the chelating that separates validity still takes place this Dipex  resin.

Although generator commonly used shown in Figure 2 has industrial superiority, when adopting the high-caliber high LET radioactivity be suitable for treating nuclear medicine, can be subjected to because the above-mentioned major limitation that the mounting medium radiation degradation is brought.These restrictions seriousness and the final reliability of taking into account patient safety just need other generator technology of development, particularly to the generator technology of the radionuclide that is suitable for treating usefulness.

A kind of desirable generator technology should provide the simplification and the convenience of operation, and has reliable generation to have the contemplated productive rate of the pure required daughter activity nucleic of high chemical purity and radioactive nucleus.When being used for diagnostic radionuclide,, can be satisfied with these criterions usually though should on purity and productive rate, find fluctuation by generator commonly used.(seeing Boyd, Radiochim.Acta (1982) 30:123-145and Molinski, Int.J.Appl.Radiat.Isot. (1982) 33:811-819.)

But generator commonly used is unsuitable for comprising that low specific activity parent is (as above-mentioned ¹⁸⁸W/ ¹⁸⁸The Re generator) system and containing is applicable to the system of the high LET radionuclide in the treatment nuclear medicine.For safety and reliably preparation have the pure useful radionuclide in treatment of high chemical pure and radioactive nucleus, need a kind of new scheme in the radionuclide generator technology.The variation of basic principle that decision is suitable for the generator technology of nuclear medicine and particularly therapeutic nucleic is by the fragile health of the carelessness management entail dangers to patient of the long-life parent of high LET therapeutic radiation nucleic and might causes that the dead this fact is supported.Because generator countermeasure commonly used shown in Figure 2 is to rely on the long term storage of parent radionuclide on solid carrier, this carrier constantly stands high LET irradiation, can not guarantee that the chemical pure and the radioactive nucleus of daughter radionuclide in the dust cycle of about 14-60 days generator is pure.

To the additional support of the basic variation of radionuclide generator technology, from normal existing work as biotechnology in the clinical labororatory and the quick growth of blood screening automations in a large number.As radionuclide generator technology used in nuclear pharmacology now backward aspect the routine work automation.At the field of nuclear medicine,, the ever-increasing federal law of protecting patient health and business competition/profit aspect trends towards automation about now also promoting industry.The liquid delivery system of introducing computer-control in nuclear pharmacology might change the generator based on vacuum tank among Fig. 2.Manual minimizing has also reduced the irradiation dose to the NMT personnel as far as possible, has reduced the unfavorable factor that is caused by mistake simultaneously.

The illeffects of above-mentioned radiation degradation is a big difficulty to developing new therapeutic radiation nuclide generator.If any damage to the carrier material of the generator of routine all jeopardizes separative efficiency, may cause parent to radiate penetrating of ashamed nucleic and to patient's administration then can produce fatal irradiation dose.This catastrophic event in theory can fork-like farm tool used in ancient China prevents in the nuclear pharmaceuticals operation by the high quality control measure is incorporated into, but the predictable generator behavior of any shortage safety all is responsibilities of nuclear pharmacology, hospital and its partner separately.What describe below the invention provides another kind of radiation domestic animal nuclide generator technology, its can prepare reliably be bordering on the high chemical pure of having of theoretical yield and radioactive nucleus pure at medically useful radionuclide.

Summary of the invention

The present invention's imagination provides a kind of method that is used to prepare the solution of required daughter activity nucleic free from foreign meter substantially.This method comprises to be made parent-daughter activity nucleic aqueous solution of containing required daughter activity nucleic and required daughter activity nucleic is had high-affinity and parent and other daughter activity nucleic are had the contacted step of first separating medium of low compatibility.When this parent and required daughter activity nucleic exist, has different ionic charges or different charge density or both are all different in this solution.Make this contact keep time enough so that required daughter activity nucleic has the separating medium of required daughter and the solution of the required daughter activity nucleic that contains low concentration (comparing with initial parent-daughter activity nucleic solution) by first separating medium institute bonding to form load.

The solution that will contain the required daughter activity nucleic of low concentration is removed from load has the separating medium of required daughter.This required daughter activity nucleic of desorb is arranged the separating medium of required daughter to form the solution of required daughter activity nucleic from load.Make the solution of this required daughter activity nucleic and the parent radioactive nucleus is have high-affinity and have second separating medium of low compatibility to contact required daughter activity nucleic.In preferred embodiments, before second separating medium (guard column) is gone up elution, solution is not made Chemical Regulation.If make this contact keep time enough so that exist the parent radionuclide by this parent radionuclide of the second separating medium bonding to form the solution of pure basically required daughter activity nucleic.Though this solution can normally reclaim the solution of this pure basically daughter activity nucleic without this radionuclide is attached on the suitable reagent of medical science.

The present invention has some benefits and advantage.

A benefit is that this method need not use air or gas to be separated from each other some solution, and this just provides chromatographic run performance preferably and total preferably chemical pure and radioactive nucleus pure again.

An advantage of contemplated method is that this separating medium has long service life, because the radionuclide of high linear energy transfer is difficult for causing the radiation degradation of medium at the time less that contacts with this medium.

Another benefit of the present invention is to obtain highly purified radionuclide.

Another advantage of the present invention is to select for use commercially available separating medium right in bigger scope, and easily prepares suitable elute soln to obtain being suitable for the different radionuclides of medical science and analytical applications.

The high separating efficiency that an also benefit of the present invention is this separating medium can make the daughter activity nucleic that will reclaim be in the elute soln of small size.

An also advantage of the present invention is the chemical integrity that keeps separating medium, and it provides more foreseeable separating property, reduces the contamination possibility of parent radionuclide to the daughter radionuclide.

The benefit and the advantage that also have are conspicuous from following description to those skilled in the art.

Brief description

Fig. 1 is from Bond et al., and the modification figure of Ind.Eng.Chem.Res. (2000) 39:3130-3134 is illustrated in preparation medically key step and its corresponding purity and management expectancy of suitable radionuclide.

Fig. 2 utilizes ^99mThe diagram of the generator method commonly used that the employing upstream is washed during Tc.

Fig. 3 is the reverse selectivity generator of polystyle of the present invention general principle figure, and wherein PSC represents main splitter, and GC represents guard column.

Fig. 4 is ²³²U decays into ²⁰⁸The radioactive decay figure of Pb focuses in development ²¹²Major impurity in the reverse selectivity generator of the middle polystyle of Bi (can disturb required radionuclide ²¹²Nucleic radium and lead that the medical science of Bi is used).

Fig. 5 is Ba (II) (square point) on TOPO resin master splitter and the dry weight distribution ratio D of Bi (III) (round dot) _WGraph of a relation with the molar concentration of [HCl].

Fig. 6 is every milliliter and flows out the count per minute of liquid and the graph of a relation of the column volume of the outflow liquid that flows through post, this outflow liquid flows through this post during upload (0.75-4.75 BV), drip washing program (4.75-8.75 BV) and desorb program (8.75-12.25BV) under 25 (± 2) ℃, this post is to adopt the TOPO resin to separate Ba (II) (square point) and Bi (III) (round dot), this resin with 0.20M HCl as pre-equilibration, absorption and eluent solution, with the 1.0M NaOAc in 0.20M NaCl as stripping workshop.The dotted line of level shows background count.After proofreading and correct, leakage in 8.75-12.25 BV scope, do not find ¹³³Ba (II).

Fig. 7 is the D of the Bi (III) on sulfonic acid cation-exchanger resin guard column _WValue and [Cl ^1-] the graph of a relation of molar concentration, its used solution is that the pH value is that 1.0M sodium acetate/sodium chloride solution (square point) of 6.5 knows that the pH value is 1.9 0.0122M HCl (round dot).

Fig. 8 is every milliliter and flows out the count per minute of liquid and the graph of a relation of the column volume of the outflow liquid that flows through post, this outflow liquid flows through this post during upload (1-12 BV), drip washing program (12-24.5 BV) and desorb program (24.5-37 BV) under 25 (± 2) ℃, this post is to adopt Dipex ^Resin separates Ba (II) (square point) and Bi (III) (round dot), and this resin is with 1.0M HNO ₃As pre-equilibration, upload and eluent solution, with 2.0M HCl as stripping workshop.The dotted line of level shows background count.After by 30 BV ¹³³The counting of Ba (II) reaches background level.

DESCRIPTION OF THE PREFERRED

From the solution that contains parent and required daughter activity nucleic, separate among the present invention of parent and required daughter activity nucleic using here overview to be called the reverse process for selective of polystyle, the problem that is caused by radiation degradation when using high LET radionuclide has been found answer.Term " parent radionuclide " here often uses with odd number, can contain and contain just like from the known a plurality of parent radionuclides of radioactive decay figure usually so that understand the contemplated solution that contains parent and required daughter activity nucleic, also contain the one or more daughter nuclides that comprise required daughter nuclide and daughter nuclide thereof.

Contemplated method is preferably used a plurality of separation chromatography posts.The separating medium filler of these posts has different selectivity to parent with required daughter activity nucleic, and the generator method commonly used among these selectivity and Fig. 2 similar to separate used usually selectivity be reverse.Promptly with contacted first splitter of the aqueous solution that contains parent and required daughter to required daughter selectivity greater than selectivity to parent and other daughter that may exist, otherwise, the separating medium of at least a contact thereafter to the selectivity of this parent greater than selectivity to required daughter activity nucleic.Should point out, can use multiple second separating medium in first separation, when being suitable for the medium of specific use, these media are independently or same guard column.

The major advantage that the solution of radioactive parent and daughter is stored is to have reduced the radiation degradation of the chromatographic isolation material of decision product purity as far as possible, because the damage of main radiolysis has given solution matrix such as water, rather than gives separating medium.

By using high chromatogram flow (as the automatic fluid induction system) to reduce radioactive solution and, further to have kept the integrality of separating medium as far as possible to daughter radionuclide time of contact between the separating medium selectively.Keep the chemical integrity of separating medium to be equivalent to better to estimate separating property and to reduce the possibility that the parent radionuclide stains the daughter product.In addition, be to have purpose to extract required daughter activity nucleic rather than stream is washed generator commonly used when needing, thus do not need the inorganic adsorbent of anti-radiolysis, and can use the optionally various chromatography separation medias of bigger solute.

For further reducing the possibility that the parent radionuclide stains, the downstream introducing another kind of separating medium is optionally separating medium to parent required daughter being optionally.Introduce second splitter and can increase the degree of safety of guaranteeing long-life radionuclide of danger not to be supplied with patient.The example of this serial connection column device is shown in Fig. 3.Use this method segregative exemplary required daughter ion/parent ion group to comprise Y ³⁺/ Sr ²⁺TcO ₄ ^1-/ MoO ₄ ^2-PdCl ₄ ^2-/ Rh ³⁺In ³⁺/ Cd ²⁺I ^1-/ Sb ³⁺ReO ₄ ^1-/ WO ₄ ^2-Tl ¹⁺/ Pb ²⁺Sc ³⁺/ TiO ²⁺Or Ti ⁴⁺Bi ³⁺/ Ra ²⁺, Pb ²⁺Bi ³⁺/ Ac ³⁺, Ra ²⁺At ^1-/ Bi ³⁺And Ra ²⁺/ Ac ³⁺, Th ⁴⁺

Shown in the top of Fig. 3, parent and required daughter activity nucleic can be in accepting the aqueous solution matrix of main dose of radiation rather than on the separating medium of decision Chemical Decomposition efficient, near or reach the radioactivity equilibrium attitude.When needs, make the solution that contains parent and required daughter activity nucleic be optionally to the daughter radionuclide that the chromatographic column of first separating medium (main splitter) contacts (uploading) with containing, and one or more parents and any other " daughter " are flowed out as the daughter of required daughter activity nucleic.When this required daughter activity nucleic and one or more parent radionuclides are present in this solution more below or difference arranged on 2: (i) ionic charge or (ii) charge density.

Therefore, when parent and daughter activity nucleic be present in the contacted solution of first separating medium in the time, one of this parent and daughter activity nucleic can be+divalent cation and another be+3 valency cations, or one can be+divalent cation and another be for-1 valency anion etc.Usually in whole separation process, this parent and daughter activity nucleic are all kept this difference on electric charge, but this is optional.For example, at TcO ₄ ^1-Want and MoO ₄ ^2-Separate or ReO ₄ ^1-Want and WO ₄ ^2-Under the situation of separating, these anion are kept its electric charge in whole separation.On the other hand, bismuth and actinium have+3 valence charges usually, but bismuth as with the complex compound such as the BiCl of chlorion ₄ ^1-Anionic solution complex compound preferably separates with actinium, because actinium does not form this complex compound under same condition, and still keeps Ac ³⁺Cation.

Though a large amount of Chemical Decompositions can be by the clean ionic charge difference of two or more analytes as the basis of separating, many other separation are to rely on the more fine distinction of Coordinative Chemistry and/or solution particular state as the means of effectively separating.Generally speaking, between two ions difference aspect preferred property of coordination and/or solution particular state can be aptly owing to the dominant different charge density of electrostatic interaction wherein.

Charge density is defined as the total electrical charge monatomic or per unit volume that multi-atomic ion occupied.The notion of charge density be to firmly/decisive factor of soft acid/alkali theory.According to this theory, the ion that is defined as " firmly " is not too polarizable, has big charge density absolute value usually (as Li ⁺, Al ³⁺, F ^-, and O ^2-), and those ions that are defined as " soft " have lower charge density, and easier to be polarized (as Hg ²⁺, Bi ³⁺, I ^1-, TcO ₄ ^1-Deng).

Only, be not enough to illustrate many separation of carrying out the customary analyte that similar electric charge is arranged that separates usually based on the charge density difference of those analytes based on the explanation of ionic charge difference; Ce for example ³⁺And Lu ³⁺Separation or F ^1-And I ^1-Separation.To Ce ³⁺/ Lu ³⁺Separate, its cation has identical charges, but the contraction of known lanthanide series makes the lanthanide ion radius produce well-regulated reducing, and the ion volume that the charge density that causes lanthanide series series is had a net increase of reduces.The having a net increase of of charge density can cause the different of the difference of different, solution particular state of hydration number (main electron shell and secondary electron shell) and Coordinative Chemistry, its each or combination all can be used as the basis of separation.

In another example, the charge density of halide anion reduces downwards along this family, more disperses because its ionic radius (and volume) increases and electric charge becomes.This difference on charge density can be used for separating, because decision ion-ligand is different with the interactional electrostatic interaction of ion-solvent, it is provided for the chemical form that is suitable for of given separation.

The charge density notion is not limited to monatomic ion, and is easy to expand to the polyatom form; NH for example ₄ ¹⁺/ N (CH ₂CH ₃) ¹⁺And TcO ₄ ^1-/ IO ₃ ^1-In each example, this ion has same electric charge, but each ion occupies different volumes, changes the particular state of charge density and change ionic interaction characteristic and solution with this, as is reflected in parameter such as hydration free energy, total hydration number, complexing and forms in the constant etc.

The outflow liquid that contains parent and more a small amount of required daughter activity nucleic that will come out from main splitter (parent of the required daughter of dilution-daughter solution or the solution of less required daughter activity nuclide concentration is arranged) is removed from first separating medium that is adsorbed with required daughter (separation).This solution can discard, but preferably is collected in the container, and makes its convergence radioactivity equilibrium attitude once more, so that obtains the more required daughter of volume.In wash-out daughter (desorb) before, the main splitter that contains the daughter activity nucleic is carried out drip washing, from the space, to remove any remaining impurity that may exist.

For making this multicolumn separator method optimum and effective, can utilize understanding to the solution particular state of daughter radionuclide and its radionuclide parent, select the material of second separating medium of stripping workshop and second chromatographic column (guard column).In desirable practice; contain daughter is the post of main separating medium optionally through a kind of solution stripping; this solution can make required daughter activity nucleic wash-out; and need not this solution medium is carried out any Chemical Regulation and directly by guard column, any parent and interference body is trapped on this second post.

The reverse selectivity method of polystyle is stored and used to the solution of radioactive source material; be that required daughter activity nucleic is at first through selective extraction; with through containing the guard column of second separating medium; further purge remaining parent ion the maximum radiolysis that reduces of mounting medium is damaged, and prepare highly purified required daughter activity nucleic reliably with nearly theoretical yield.In the typical case uses; main splitter is high-affinity to required daughter activity nucleic; parent and its daughter activity nucleic of any tool are low compatibility, and guard column contains parent is high-affinity and required daughter activity nucleic is second separating medium of low compatibility.

This pairing with condition that multiple separating medium contacts under the gross decontamination coefficient from required daughter activity nucleic that provides to parent be about 10 ⁴-10 ¹⁰Or it is higher.The DF that every used post provides respectively under the condition of contact is about 10 ²-10 ⁵Or it is higher.The DF of given step multiply by the DF of next step, or when with exponential representation, with the DF exponential quantity addition of every step.About 10 ¹⁰The DF value be the maximum approximately DF value that can use typical laboratory putting equipment easily to measure.

Coefficient of purification (DF) is pressed the following formula definition:

To the system that is in the radioactivity equilibrium attitude (as ²²⁴Ra and comprising ²¹²The daughter of Bi and its daughter), this denominator is about 1.This means the DF value can be by the desorb peak of analyzing in the chromatogram and with impurity (promptly ²²⁴The Ra parent) it (is required that radioactivity is removed this analyte ²¹²Bi daughter activity nucleic) maximum cpm/ml is similar to and asks for.

In addition, this DF can be by the dry weight distribution ratio (D of analyte and impurity _W) calculate.Suppose that " inflow " is radioactivity equilibrium attitude (denominator that makes DF is 1), the then D of analyte/impurity _WThe ratio of value is:

After making an appointment, be simplified to:

A wherein _o, A _f, V, m _R, and the % solid define elsewhere.These radioactive ratios are proportional to the molar concentration of quoting elsewhere in the DF definition.

Basic difference between contemplated polystyle reverse selectivity generator technology and method in common shown in Figure 2 is aspect three at least: the medium for storing of (1) parent radionuclide is solution rather than solid carrier, when (2) needing from the solution that contains the parent radionuclide the required daughter activity nucleic of selective extraction and (3) second separating mediums prevent that the parent radionuclide from leaving generating apparatus.

When the reverse selectivity generator of polystyle among use Fig. 3 extracts a spot of daughter (being a small amount of component), except that the radiolysis damage that can as far as possible reduce, also can adopt little chromatographic column to chromosorb.Therefore required daughter activity nucleic can be little liquor capacity recovery, and this solution is convenient to be diluted to the dosage that is suitable for clinical use.Common 90% daughter activity nucleic can be transferred in about 5 bed volumes less than first separating medium of this first post.

Contemplated separation method carries out usually at ambient temperature.Utilize gravity flow to pass through pillar, but preferably this is separated in to be higher than under the atmospheric pressure and carry out, as can by hand syringe or electric pump implementing.As adopt syringe to be implemented in less than also being preferred under the atmospheric pressure (flowing) as vacuum aided.

Normally utilizing the time of staying that this solution passes post under any pressure time of contact between solution and the separating medium.Though be several hours to several days the time of contact that therefore given solution is mixed with separating medium and keep being reached, because the absorption of separating medium is enough fast usually; Be that bonding and phase transfer are enough fast, so that arranged the time of contact that is enough to reach required separation by the contact of flowing through the separating medium particle and being provided.

Represented importance of the present invention in oppositely optionally total notion that main splitter extracts between this required daughter activity nucleic and guard column delay parent and other chaff interference.Seem similar notion use diagnostic ⁶⁴Briefly proposed (to see Zinn in the Cu radionuclide, U.S. Patent No. 5409677 (1995)), but the diagnostic radionuclide that the reverse selectivity generator of polystyle being used for property treatment nucleic and height ratio are put, formerly do not test or estimated, and the ioni valence of parent and daughter activity nucleic is identical in this article, promptly+and the copper ion and the zinc ion of divalent.This Cu ²⁺And Zn ²⁺Charge density also be identical basically.

Therefore right ⁶⁴The example that Cu quoted as proof only relies on and uses motionless ligand with complexing ⁶⁴Cu, and from a large amount of zinc isotopes with its separation.Preferably with form not clear anion-exchanger resin from ⁶⁴Second removal zinc in the Cu product, this is need carry out when the complex coordination body shows poor selectivity in initial separation.In addition, need big bed volume, and ⁶⁴The Cu product is transferred in the strong acid solution greater than 20mL, and this solution exists ⁶⁴Cu need carry out secondary concentration and neutralization before being attached in the biology location agent that is used for medical procedures.Advised ⁶⁴The separation system of Cu is not discussed the uniformity of the ionic charge of ion to be separated, does not discuss in radionuclide generator that height ratio is put or the application in the high LET radiation yet, and the two is unique difficulty of design radionuclide generator.

When the radiation degradation of shorter mention carrier material when (as to diagnostic radioactive nucleus), the reverse selectivity generator of polystyle shown in Figure 3 also can provide many advantages.For example the target irradiation in accelerator and reactor often need use the target material of isotope enrichment to reach the required parent radionuclide of maximum preparation.This nucleosynthesis reaction may be not effective, only can prepare low than the parent of putting.By using reverse selectivity generator of polystyle and extraction daughter composition in a small amount only, the target ion of a large amount of isotope enrichments is retained in the solution, and can easier recovery to be used for the irradiation in future.It is also important that the daughter activity nucleic is recovered in the little volume solution; This has just had this possibility when using pillar and the reverse selectivity generator of polystyle principle.

This method is usually designed under no air and operates, and therefore can reach chromatographic performance preferably.The existence of space air pocket can cause solution pass not stream through or around the passage of medium grain; This solution is worn the passage that does not contact with separating medium or rather.The air or the gas that particularly pass separating medium can cause the channel that generation can not contact fully between solution and the separating medium.Like this just will be in contemplated method used post be designed for carrying with the device of treat liquid.

Be that when filtering, air or gas need not to filter sterilization through aseptic air filter to this another advantage of lacking the device of air or weak breath body.Compare the parts of in contemplated method, being adopted with the employing air with the parts of liquid combination like this and can have more uncomplicated design.

The benefit of this generator technology is a far reaching, and the versatility of basic principle shown in Figure 3 means, can adopt the various radionuclides of the reverse selectivity generator of polystyle notion purifying.Following table 1 provides a row system to imaging or the useful radionuclide of treatment nuclear medicine, also lists the chromatographic material that exemplary solution condition and the reverse selectivity generator of employing polystyle carry out purifying.The a series of radionuclides mentioned in table 1 and separation condition are not restriction, but the parent/daughter that has very different solution chemistries, ionic charge and charge density as example explanation to be how to separate and purifying to be used for nuclear medicine application.Because constantly can get separating medium newly and the interest of other radionuclide also increased, so the reverse selectivity generator of polystyle can be easy to adapt to high chemical pure and the pure radionuclide of high radioactive nucleus that provides a kind of method easily to be used for preparing reliably to be used for diagnostic or therapeutic nuclear medicine.

Table 1

The main method feedstock solution stripping workshop that nucleic produces

The main separation ^bMain splitter ^cGuard column

(solute/chaff interference)

^aMedical radionuclide such as nuclear medicine circle are defined.〔Bond?et.Al.，Ind.Eng.Chem.Res.(2000)39：3130-3134〕。

^bNormal some preparation methods that exist, those methods of being quoted as proof are methods that nuclear medicine adopts usually.

^cWidely used separation method comprises: the AIX=anion-exchange chromatography; The CIX=cation-exchange chromatography; The EXC=extraction-chromatography; The acid organophosphor extractant-EXC of AOPE-EXC=; Neutral organic extractant-the EXC of NE-EXC=; Neutral organic extractant-the EXC of MF-NE-EXC=polyfunctional group; ABEC=water-based two-phase extraction-chromatography.

^dInhibitor comprises carboxylate, polyaminocarboxylate, some inorganic anions, chelating agent etc.

^ePhys.Saline Solution=physiological saline.

The method and apparatus of imagination can utilize one or more separating mediums.As know, to the separating medium that adopts of given separation be by the radionuclide decision that will separate.Preferred separating medium solid-phase resin normally granular or that have identical size and form also can use sheet, textile-like or fibrous separating medium certainly.

A kind of preferred solid phase separation media is H ⁺The Bio-Rad of type ^The 50W-X8 cationic ion-exchange resin, it can be from Bio-Rad Laboratory, Inc., of Hercules, CA company is obtained by commercially available.Other highly acidic cation exchange media that is suitable for comprises the Bio-Rad of ion exchange resin ^AGMP-50 and Dowex ^The Amberlite of 50W series and ion exchange resin ^IR series, it can be from Sigma Chemistry Co., St.Louis, MO. company is obtained by commercially available.The Bio-Rad of anion exchange resin such as ion exchange resin ^AGMP-1 and Dowex ^1 series also can be used as separating medium.

The another kind of resin that can be used in this process is the SDEB styrene diethylenebenzene polymeric matrix, and it comprises with the sulfonic acid of chemical bonding on it, phosphonic acids and/or together with-di 2 ethylhexyl phosphonic acid functional group.This can be from being positioned at 8205S.Cass Avenue together with-di 2 ethylhexyl phosphonic acid resin, Darien, IL, Eichrom Technologies, Inc. company is Diphonix with the trade mark ^The resin city fetches to be entangled.In this process, Diphonix ^Resin is with H ⁺Type uses.Diphonix ^The characteristic of resin and characteristics U.S. Patent No.5539003, U.S. Patent No.5 449462 and the U.S. Patent No.5281631 of being described in more.

Be adsorbed on composition to exchange composition and be the TEVA of the mixture on the insoluble carrier of water of inert with quaternary ammonium salt, particularly trioctylphosphine and tridecyl ammonio methacrylate ^TMResin has high selectivity to the ion of tetravalence attitude.For example in salpeter solution+thorium of 4 valencys is attached to TEVA ^TMOn the resin, and actinium (Ac) and radium (Ra) ion (its valence state be respectively+3 and+2) are not extracted when contacting with this resin under similarity condition basically.TEVA ^TMResin can be from EichromTechnologies, and Inc. company obtains with commercially available.

In contemplated method, this second separating medium (Ion Exchange Medium) contains disulfonic acid (DPA) ligand and functional group.Some replacement disulfonic acid types that contain DPA are known in the prior art, and can here use.A kind of exemplary disulfonic acid ligand has following molecular formula:

C ^R1R ²(PO ³R ²) ₂

Wherein R is selected from hydrogen (hydride), C ₁-C ₈Alkyl, cation and its mixture;

R ¹Be hydrogen or C ₁-C ₂Alkyl; And R ²Be hydrogen or be attached to key on the polymer.

Work as R ²When being the key that is attached on the polymer, this phosphorous functional group is that the dry weight with the copolymer of the about 10mmol/g of 1.0-exists, and the value of mmol/g is based on wherein R ¹It is the polymer of hydrogen.The exemplary exchange medium that contains the disulfonic acid ligand will be discussed below.

A kind of such exchange media is called Dipex ^Resin, it is a kind of extraction-chromatography material that contains the first di 2 ethylhexyl phosphonic acid that belongs to two esterifications as the liquid di 2 ethylhexyl phosphonic acid extractant of two-2-ethylhexyl first bisphosphonates.This extractant is adsorbed on matrix such as the Amberchrom that mobile phase is inertia ^On-CG71 (can be, Montgomeryville, PA company obtains) or the hydrophobic silica from TosoHaas.In this extractant, R ¹And R ²Be that H and a R are that 2-(ethyl)-hexyl and another R are H.

Dipex ^Resin has shown to trivalent lanthanide series, various trivalent actinides, tetravalence actinides, hexavalent actinide and preceding actinides ²²⁵The Tricationic of Ac has high compatibility, to radium and ²²⁵Some decay constant of Ac has lower compatibility.Even also demonstrate these compatibilities in the presence of complex anion such as fluorine ion, oxalate and the phosphate radical having.

Preferred Dipex ^The active component of resin is the liquid di 2 ethylhexyl phosphonic acid of following general formula:

Wherein R is C ₆-C ₁₈Alkyl or aryl, preferably by the ester that the 2-ethyl-the 1-hexyl derives, preferred compound is P, P '-two-2-(ethyl) hexyl first di 2 ethylhexyl phosphonic acid.

The active component of bisphosphonates can be mixed with lower boiling organic solvent such as methyl alcohol, ethanol, acetone, diethyl ether, methyl ethyl ketone, hexane or toluene, and coats known inert carrier such as glass grain, polypropylene grain, polyester grain or the silica gel that is used for chromatographic column in the prior art.Also can use acrylic resin and aromatic polymer resin such as AMBERLITE ^, it can be from Rohm and Haas company, Philadelphia, and PA obtains with commercially available.

Dipex ^The characteristic of resin and feature are described in more detail in Horwitz et.al., U.S. Patent No. 5651883 and Horwitz et.al., U.S. Patent No. 5851401.Dipex ^Resin can be from Eichrom Technologies, and Inc. company obtains.

Another ion exchange resin that is suitable for is Diphosil ^TMResin.Be similar to other DPA resin, Diphosil ^TMThe di 2 ethylhexyl phosphonic acid ligand that resin contains a plurality of paired replacements those as providing by vinylidene diphosphonic acid.This ligand is to be chemically bonded on the organic matrix that is grafted on the silica dioxide granule.Diphosil ^TMResin can be from Eichrom Technologies, and Inc. company obtains.

Another resin that is suitable for has with grafting and is added to side group-CR on the preformed water-insoluble copolymer again ¹(PO ₃R ₂) ₂Promptly this phosphonate group forms the back adding at copolymer pellet.To these polymer, R is hydrogen (hydride), C ₁-C ₈Alkyl, cation or its mixture, R ¹Be hydrogen or C ₁-C ₈Alkyl.To the contemplated side group-CR of this group resin ¹(PO ₃R ₂) ₂Following molecular formula is arranged.This particle also

The side aromatic sulphonic acid ester group that contains the about 5mmol/g dry weight of 0-.

Usually contain two C as the contemplated methylene biphosphonic acid esters that at first forms ₁-C ₈The di alkyl phosphonic acid ester group.The exemplary C of these known esters of being mentioned here ₁-C ₈Alkyl and other C ₁-C ₈Alkyl comprises methyl, ethyl, propyl group, isopropyl, butyl, tert-butyl, amyl group, cyclopenta, hexyl, cyclohexyl, 4-methylcyclopentyl, heptyl, octyl group, ring octyl group, 3-ethyl suberyl etc.Isopropyl is preferred R base, R ¹Most preferably be hydrogen.

After the formation, this alkyl ester group is thought use through hydrolysis, and R is hydrogen (proton), Ca in above-mentioned molecular formula ²⁺Ion or alkali metal ion such as lithium, sodium or potassium ion.

Preferably this insoluble copolymer contains the ethylene benzyl halide of the reaction of at least 2 moles of %, and this percentage is more preferably about 10-95 mole %.As previously discussed, the monoene of one or more reactions belongs to unsaturated monomer and exists with about 2-85 mole %, and the above-mentioned monoene that this monomer preferably includes at least 5 moles of % belongs to unsaturated fragrant monomer such as styrene, ethyl styrene, vinyltoluene (methyl styrene) and vinyl-dimethyl benzene.

The insoluble copolymer that is suitable for also comprises the crosslinking agent of reaction.The crosslinking agent that is suitable for this reaction also is various.The exemplary crosslinking agent that is suitable for is selected from divinylbenzene, trimethylolpropane triacrylate or trimethyl acrylic ester, erythrite tetraacrylate or tetramethyl acrylate, 3,4-dihydroxy-1,5-hexadiene and 2,4-dimethyl-1,5-hexadiene.Divinylbenzene is particularly preferred.

It is required insoluble that the amount of crosslinking agent of reaction will be enough to reach.Usually the cross-linked dosage of the reaction that exists is at least 0.3 mole of %.The cross-linked dosage of the preferred reaction that exists is about 2-20 mole %.

The particle of these imaginations is nucleophilic reagent such as CR ¹(PO ₃R ₂) ₂ ^-Multistep reaction product with matrix can be obtained by known method.Therefore, CR ¹(PO ₃R ₂) ₂(its R is alkyl preferably) at first with sodium metal or potassium metal, sodium hydride or organo-lithium compound for example butyl lithium or any reagent reacting that produces the bisphosphonates carbanion.The carbanion and substrate reaction that should form then, this matrix are one or more aforesaid insoluble cross-linked copolymers of vinyl aliphatic series, acrylic acid or aromatic compounds and polyvinyl aliphatic series, acrylic acid or aromatic compounds, as divinylbenzene.This copolymer contains the halide derivative of the reaction of the vinyl-arene of at least 2 moles of % such as vinyl benzyl chlorination thing base, the single ethene aromatic hydrocarbon of preferred 10-95 mole %, the about 85 moles of % of about 2-such as polyethylene aliphatic series and/or aromatics crosslinking agent such as the divinylbenzene of styrene and at least 0.3 mole of %, preferred 2-20 mole %.

Contain its amount and should be about 1.0mmol/g dry weight mutually, the copolymer of the methylenediphosphonate tetraalkyl ester group of the grafting of preferred 2-7mmol/g dry weight preferably reacts with sulfonating agent such as chlorosulfonic acid, the concentrated sulfuric acid or sulfur trioxide, so that highly acid side virtue sulfo group is introduced in its structure.The existence of sulfonation side group provides the hydrophily advantage to particle, and causes cation complexing speed to increase greatly, with leaf the selectivity that is observed is not had adverse effect.

Sulfonating agent and the reaction that contains the graft copolymer of methylene biphosphonic perester radical are by halogenated hydrocarbons such as carrene in the resin product that is reclaimed when ester-formin usually, and ethlyene dichloride, chloroform or 1,1,1 carry out during-trichloroethanes swelling.This sulfonating reaction can be at pact-25-about 50 ℃, and preferably about 10-uses down and carries out at the last chlorosulfonic acid of going back the 0.5-20.0 weight % in the halogenated hydrocarbon solvent for about 30 ℃.This reaction is to make pre-swelling zero (not swelling) contact 0.25-20 hour to about 2 hours resin with above-mentioned sulfonation solution to carry out.

After finishing sulfonating reaction, particle is separated with liquid reaction medium by filter, centrifugal, decant etc.This second final resin product is through fully washing with dioxanes, water, 1M NaOH, water, 1M HCl and water, then through the air drying.

This sulfonating reaction and in water, handle and also make phosphonic acids C ₁-C ₈The alkyl hydrolysis of ester group.Under the situation that sulfonation is not carried out, the hydrolysis of sulphonic acid ester can be undertaken by reacting under refluxing as concentrated hydrochloric acid with acid.

These contemplated particles contain the aromatic units directly linked on the polymeric matrix or the methylene biphosphonic acidic group on the acrylic or methacrylic acid unit and sulfonic group as the side functional group.The resin of imagination shows compatibility to various divalence, trivalent and polyvalent cation in wide pH value scope.Less than 1 time, this resin can change into from the ion-exchange mechanism that cation is removed because the difunctional mechanism of the ion-exchange/coordination of phosphinylidyne oxonium ion in the pH value.Then sulfonic group work make matrix more hydrophily with fast near metal ion; Therefore this methylene biphosphonic acidic group has determined high selectivity.The further details of this resins can be referring to Trochimczuk et.al., U.S. Patent No. 5618851.

The another kind of separating medium that is described in the particularly suitable in the U.S. Patent No. 5110474 is called the Sr resin, and it can be by Eichrom Technologies, and Inc. company obtains.In brief, this Sr resin comprises the inert plastic matrix that is dispersed with the crown ether extraction agent solution that is dissolved in the liquid diluent on it.

This diluent is an organic compound, and this compound has (i) higher boiling; Promptly about 170-200 ℃, the (ii) limited solubility in water or do not dissolve, the (iii) water of the solvable 0.5-6M of terminating an agreement and (iv) be the soluble material of a kind of wherein crown ether.This class diluent comprises alcohols, ketone, carboxylic acids and ester class.The alcohols that is suitable for comprises most preferred 1-octanol, though 1-enanthol and 1-decyl alcohol also are suitable.It is preferably sad that this carboxylic acids also comprises except that enanthic acid and caproic acid.Exemplary ketone comprises methyl-n-butyl ketone and 4-methyl-2 pentanone, and ester comprises butyl acetate and pentyl acetate.

Big acyclic polyether can be any dicyclohexyl crown ether such as dicyclohexyl-1 8-hat-6, dicyclohexyl-21-hat-7 or dicyclohexyl-24-hat-8.Preferred crown ether has molecular formula: 4,4 ' (5 ') [(R, R ') dicyclohexyl]-18-hat-6, wherein R and R ' are the straight or branched alkyl that is selected from H and contains the 1-12 carbon atom.The example comprises methyl, propyl group, isobutyl group, the tert-butyl group, hexyl and heptyl.Preferred ether comprises that dicyclohexyl-18-hat 6 (DCH18C6) and two-methylcyclohexyl-18-are preced with-6 (DmeCH18C6).Most preferred ether is two-4, and 4 ' (5 ')-[(tert-butyl group) cyclohexyl]-18-is preced with-6 (Dt-BuCH18C6).

Crown ether amount in diluent can be by specific crown ether variation.For example the most preferred tert-butyl group form (Dt-BuCH18C6) that concentration is about 0.1-0.5M in diluent is satisfied, and its about 0.2M is most preferred.When fruit was used the H form, its concentration can change between the about 0.5M of about 0.25-.

Preferred Sr resin utilizes inert plastic matrix, and this matrix is based on the resin such as the Amberlite of nonionic acrylic acid ester polymer ^XAD-7 (60-70 weight %) is coated with on it just like the crown ether layer that is dissolved in the Dt-BuCH18C6 (20-25 weight %) in the n-octyl alcohol (5-20 weight %), and its extractant load is 40 weight %.(see Horwitz et.al., Sovent Extr.IonExch., 10 (2): 313-16 (1992).〕

Also find, can be from Eichrom Technologies, the Pb resin that Inc. company obtains, promptly a kind of associated resin also can be used for purifying and gathering ²¹²Pb is with preparation ²¹²Bi.Pb resin and Sr resin have similar characteristic, and not existing together is the alcohol of using higher molecular weight in preparation Pb resin; It is isodecanol.(see Horwitz et.al., Anal.Chim.Acta, 292:263-73 (1994).) having found thereafter can be from desorb on the Pb resin ²¹²Bi, and found ²¹²Pb is detained by force by the Sr resin.

Also can be from Eichrom Technologies, the improved Sr resin that Inc. obtains even have more selectivity.This separating medium is called super Pb (Sr) ^TMSelective resin, it comprises free flowing granule, its distribution ratio (D between n-octyl alcohol and 1M nitric acid _Hat=[hat _OrganicBe preced with]/[ _Water]) greater than about 10 ³, be generally about 10 ³-Yue 10 ⁶, about 5-50 weight %'s is two-4,4 ' (5 ')-[C ₃-C ₈Alkyl-cyclohexyl] 18-hat-6 is dispersed in inert porous carrier such as fluoropolymer resin (as Amberchrom as Dt-BuCH18C6 ^-CG71) or on the silica dioxide granule.This separating medium diluent free, particularly do not contain this diluent promptly (i) in water insoluble or limited (slightly) solubility and (ii) solubilized be present in the diluent of the big water gaging in the Sr resin.See U.S. Patent No. 6511603B1.

The preferred washing and the stripping workshop that use also are used for selecting based on required the making of parent and daughter activity nucleic and product.The reader can consult Horwitz et.al., U.S. Patent No. 5854968 and Dietz et.al., in the U.S. Patent No. 5863439 to the illustrative discussion of this separating medium.

Another separating medium is useful especially to the chaotropic anion in the fractionate aqueous solutions.This separating medium can be by Eichrom Technologies, and Inc. company is with trade mark ABEC ^Obtain, and this separating medium comprise have a plurality of covalent bondings-X-(CH ₂CH ₂O) _n-CH ₂CH ₂The R base, wherein X is O, S, NH or N-(CH ₂CH ₂O) _m-R ₃, wherein m be mean value be 0-about 225 with number, n is that mean value is the number of about 15-about 225, R ³Be hydrogen, C ₁-C ₂Alkyl, 2-hydroxyethyl or CH ₂CH ₂R, R be selected from-OH, molecular weight reach-(CH ₂CH ₂O) _nAbout 1/10 C of-part ₁-C ₁₀Hydrocarbyl ether, carboxylate, sulphonic acid ester, phosphonate ester and-NR ¹R ²Base, wherein R ¹And R ²Each independently is hydrogen, C ₂-C ₃Hydroxyl Anhui base or C ₁-C ₆Alkyl or-NR ¹R ², form the 6-unit cyclammonium that has 0-1 oxygen atom or 0-1 additional nitrogen atom in the ring altogether.This separating particles has granule surface area greater than the CH of about 8000-less than certain percentage of about 1000000 ₂O/mm ²

Exemplary chaotropic anion comprises, simple anion such as Br ^1-And I ^1-With anionic radical such as TcO ₄ ^1-, ReO ₄ ^1-, or IO ₃ ^1-Chaotropic anion also can be the complex compound of metal cation and halide or accurate halide anions.With the attainable useful especially separation of this separating medium is from also containing the parent radionuclide ⁹⁹MoO ₄ ^2-Separate in the aqueous solution of ion ^99mTcO ₄ ^1-Relate to ABEC ^The further details of separating medium and its use are seen U.S. Patent No. 5603834, No.5707525 and No.5888397.

Exemplary chelating resin comprises that those are by the available Chelex of being called of Bio-Rad Laboratories ^TmThe material of resin, it comprises a plurality of iminodiacetic acid ligands, and similar ligand can with 4% granular agar reaction, this granular agar can be from Sigma Chemical, Co., St.Louis, MO obtains.

In the method for optimizing that utilizes the separating medium grain, this carrier grain that contains separating medium is inserted in the post.When solution passed through this, solution can flow through, pass through and around this grain, fully contact with separating medium.

Embodiment

All acid is the trace metal level, and all other chemical reagent are the ACS SILVER REAGENT and receive promptly and use. ²⁰⁷Bi and ¹³³The Ba radioactive tracer before use each through twice of evaporate to dryness and be dissolved in 0.50M HNO in red fuming nitric acid (RFNA) ₃In.Whole employing standard radiometric analysis programs, all counting rates are all through background correction.

Use aforementioned general program to prepare the extraction-chromatography material.(see Horwitz et.al., Anal.Chem., 63:522-525 (1991).) sketch it, will be dissolved in the ethanol of about 25mL at the 0.25M three in the n-dodecane (0.78g)-just-octyl group phosphine oxide (TOPO), and with the Amberchrom of 50-100 μ m ^{￡ }-CG71 resin (3.30g) mixes in about 25mL ethanol.This mixture is in about 30 minutes of rotation in rotary evaporator under the room temperature, vacuum distillation ethanol afterwards.The gained solid is called the TOPO resin, and it is corresponding to Amberchrom ^{￡ }Be loaded with 0.25M TOPO/ n-dodecane on the-CG71.Prepare the TOPO resin of modification with similar method, different is that this material is not just containing-the dodecane diluent, and dispersion solvent is methyl alcohol rather than ethanol.This TOPO resin is contained in the Amberchrom of 50-100 μ m ^{￡ }-CG71 uploads and reaches 40% Cyanex ^-923 (just-alkylphosphine oxide mixture) and diamyl (amyl group)-phosphonate ester etc. molar mixture.

Bio-Rad ^The percentage amount of solid of AGMP-50 cationic ion-exchange resin is by changing a part of wet resin in the taring phial over to, and is dried to constant weight measures in 110 ℃ stove.The equal triplicate of each gravimetric analysis, the percentage amount of solid that provides are 48.6 (± 0.3) %.All resins all are stored in the container of closed cover, and long-term not ingress of air is to avoid the change of percentage amount of solid.

All dry weight distribution ratios all are that resin is contacted and measured by radiometric analysis at 25 (± a 2) ℃ following batch (-type) with required solution.This dry weight distribution ratio (D _W) define by following formula:

A wherein _oCounting rate in=the solution before contacting with resin, A _f=with solution after resin contacts in counting rate, the liquor capacity that V=contacts with resin (mL), m _R=wet resin quality (g), this percentage amount of solid is convertible into the dry mass of resin.

The batch (-type) absorption experiment be with μ L amount at 0.50M HNO ₃In ¹³³Ba or ²⁰⁷Bi is added in the related solution of 1.2mL, mixes gently, and takes out 100 μ L and carry out γ counting (A _o).All the other solution of 1mL are added to the wet resin (m of known quantity _R) in, and centrifugal 1 minute.So stirred this mixture (so that this resin just in time is suspended in the solution) gently 30 minutes, and followed centrifugal 1 minute, stirred again 30 minutes.Through 1 minute centrifugal make resin settled after, this solution of sucking-off and the PTFE filter by 0.45 μ m filter to remove the resin particle of any suspension.Get 100 μ L solution and carry out γ counting (A _f).All dry weight distribution ratios all are accurate to two position effective digitals.

Will a certain amount of TRPO resin in 0.20M HCl make pulpous state and insert the 1.2mL capacity disposable Bio-Spin plastics chromatographic column (Bio-Rad Laboratories, Inc.) in so that the bed volume of 0.5mL to be provided.The porous plastics sintered sheets is placed on the top of bed to prevent the disturbance when adding flowing lotion.The 0.20M HCl of this post through flowing through 3.0mL (6 BV) adjusts, and then with being added with trace quantity ¹³³Ba and ²⁰⁷The 0.20M HCl of the 2.0mL of Bi (4 BV) washes with gravity current.This post is with the 0.20M HCl drip washing of 2.0mL (4 BV) then, again with 1.0M sodium acetate (NaOAc) desorb in 0.20M NaCl of 2.0mL (4 BV) ²⁰⁷Bi.The post eluent is collected in the V counter tube shape bottle of taring, all volumes all adopt solution density separately to calculate with gravimetric method.

Dipex with a 20-50 μ m ^Resin { 40% P on Amberchrom-CG71, P '-two (2-ethylhexyl) methyl di 2 ethylhexyl phosphonic acid, Eichrom Technologies, Inc. (seeing Horwitz et.al., React.Funct.Polymers, 33:25-36 (1997)) } is at 1.0M HNO ₃In pack in the conventional plastics chromatographic column with slurries, so that the BV of 0.16mL to be provided.Resin is original position during adopting the porous plastics sinter to remain on chromatographic run, adopts conventional automatic low-pressure chromatography device operation.This post is through flowing through the about 1.0M HNO of 4.0mL (25 BV) ₃Adjust, and then with being added with trace quantity ¹³³Ba and ²⁰⁷The 1.0M HNO of the 2.0mL of Bi (12.5 BV) ₃With the flow is that about 0.25mL/min stream is washed.This post is with the 1.0M HNO of 2.0mL (12.5 BV) then ₃Drip washing is again with the 2.0M HCl desorb of 2.0mL (12.5 BV) ²⁰⁷Bi.The post eluent is collected in the V counter tube shape bottle of the taring heart, all volumes adopt solution density separately to calculate with gravimetric method.

As discussed above, utilize α and the β of the high LET of radiation ^1-Radiation treatment micrometastasis cancer and solid tumor piece are had very big future.(see Whitlock et.al., Ind.Eng.Chem.Res.39:3135-3139 (2000); Hassfjell et.al., Chem.Res 101:2109-2136 (2001); Imam, Int.J.Radiation Oncology Biol.Phys.51:271-278 (2001); And McDevitt et.al., Science 294:1537-1540 (2001).) a kind of candidate α-radiation body of controlling cancer that is proposed to be used in is ²¹²Bi (sees Whitlock et.al., Ind.Eng.Chem.Res.39:3135-3139 (2000); Hassfjell et.al., Chem.Res 101:2109-2136 (2001); And Imam, Int.J.RadiationOncology Biol.Phys.51:271-278 (2001)) it constitute uranium shown in Figure 4-232 ( ²³²U) part of decay chain.

The bismuth-the 212nd that now to use, wash-out from the generator commonly used, longer life in this generator (promptly 3.66 days) ²²⁴The Ra parent is trapped on the cationic ion-exchange resin, ²¹²Bi is through the mixture wash-out of about 1-3M HCl or HCl and HI.(see Mirzadeh et.al., J.dioanal.Nucl.Chem.203:471-488 (1996) and Mirzadeh, Appl.Radiat.Isot.49:345-349 (1998).) radiation degradation of cationic ion-exchange resin makes ²¹²The Acceptable life of Bi generator is restricted to nearly two weeks, and (seeing Mirzadeh et.al., J.Radioanal.Nucl.Chem.203:471-488 (1998)) and the reverse selectivity generator of polystyle can provide purifying ²¹²The advantage of Bi.Cause ²¹²The decay chain of Bi has also proposed on the make experimental basis to the reverse selectivity generator of polystyle notion, and following specific embodiment is at new ²¹²The development of Bi generator.

To the analysis showed that of radioactive half-life shown in Figure 4, t _1/2=3.66 days ²²⁴The solution of Ra is suitable in nuclear pharmaceuticals as the radionuclide source material very much.Employing can extract from this solution the selectively main splitter of Bi (III) ²¹²Bi, and make Ra (II), Po (IV) and Pb (II) wash-out. ²¹²Among the Bi embodiment, the most dangerous radioactive nucleus impurity is the close bone of longer life ²²⁴The Ra parent, and ²¹²Pb (t _1/2=10.64 hours) less stake arranged.

The behavior of Ra (II) can be by the research extrapolation that utilizes its lighter congeners Ba (II), and this chemical similarity is utilized in the following discussion.Fig. 5 is illustrated in Ba (II) on the TOPO resin and the D of Bi (III) _WWith the graph of relation of [HCl], this resin be contain with 20% be uploaded at 50-100 μ m still on the Amberchrom-CG71 just-the extraction-chromatography material of 0.25M three in the dodecane-just-octyl group phosphine oxide (TOPO).

This chart understands that the TOPO resin is used for separating from Ba (II) possibility of Bi (III), is piled outward by its chemical similarity, shows the possibility of separating Bi (III) in 0.04-0.4M HCl scope from Ra (II).It is to be noted from these batch (-type)s contact research, obtain less than 10 D _WValue show given analyte (being that Ba (II) and extrapolation are that Ra (II) all is not detained under the chromatography eluant condition basically).Be used for producing Fig. 5 data with chromatogram mode rather than the DF of Ba (II) (and Ra (II)) that can reach Bi (III) with the operation of intermittent mode greater than 10 ³

Fig. 5 also illustrates the D of Bi (III) _WPlace, two ends in HCl concentration presents decline, and this shows that the buffering stripping workshop greater than 1M HCl concentration or pH=3-10 can be used as effective strippant.Because use radionuclide it is attached in the biological location agent in the body of being advised,,, and can locate agent generation chemical etching to biology because of the highly acid medium has stoped association reaction so nearly physiological pH value is preferred with needing.

Carry out chromatogram research to analyze the desorb validity under low acid concentration, particularly used the validity of sodium acetate (NaOAc) desorb of pH=6.5.The chromatographic isolation that adopts the TOPO resin (closely related with the TOPO resin that contains phosphine oxide) of modification from Bi (III) Ba (II) to be carried out is shown in Fig. 6, and the NaOAc that uses nearly neutral pH principle of desorb Bi (III) from the TOPO resin is confirmed.

Fig. 6 illustrates Ba (II) and uploads the outflow of solution (as D from Fig. 5 with the 0.2M HCl of the first free column volume _WEstimated less than 10), its outflow continues to drop to the background level after the drip washing of the 0.2MHCl of about 2 column volumes.Outflow liquid when uploading detects on a small quantity ²⁰⁷Bi (III), but ²⁰⁷Statistically see it is insignificant less than 2 times of background radiation levels in the Bi detection window.Fail to detect in the stripping workshop of 1.0M NaOAc in being contained in 0.20M NaCl ¹³³Ba (II) can remove Bi (III) greater than 85% with this stripping liquid of nearly 2 column volumes from post.This studies confirm that, adopts to make on TRPO that acid concentration reduces to the available modification of pH=6.5 (1.0M NaOAc) from pH=0.70 (0.2M HCl) and the TOPO resin and effectively separates and desorb Bi (III) from Ba (II).

The chromatogram of Fig. 6 shows that the DF of the Ba that the TRPO resin provides (II) (and Ra (II)) from Bi (III) is about 10 ³, this resin can be used as effective main splitter in the reverse selectivity generator of polystyle.But for guaranteeing high purity product and maximum the minimizing ²²⁴Ra and ²¹²Pb maternal influence patient, once developed guard column so that ²¹²Bi (III) flows out, and is detained ²²⁴Ra (II) and ²¹²Pb (II).

Fig. 7 is illustrated in Bi (III) absorption and (Cl under two different pH values on macropore sulfonic acid cation-exchanger resin ^1-) relation curve.The Cl of about 1M ^1-Concentration forms the anion chloro-complex of Bi (III) (as BiCl ₄ ^1-, BiCl ₅ ^2-, etc.), this complex compound is not detained by cationic ion-exchange resin.As a result, the D of the Bi shown in Fig. 7 (III) _WBe worth very lowly, the anion chloro-complex of this Bi (III) also is little if any the words of being detained under chromatographic condition.(see Massart very greatly in the delay of Ra (II) on sulfonic acid cation-exchanger resin under this pH, " Nuclear Science Series; Radiochemical Techniques:Cation-Exdhange Techniques inRadiochemistry, " NAS-NS 3113; National Academy of Science, (1971)), this shows ²²⁴Ra (II) can not flow out from the cationic ion-exchange resin guard column, can't obviously stain ²¹²Bi (III).

Be similar to TOPO on main splitter and the extraction of TRPO, neutral organophosphor extractant is from being low-down less than the solution of 1M HCl to the extraction of Pb (II).(see Sekine et.al., Solvent Rxtraction Chemistry, Marcel Dekker, New York (1977).) the cation exchange guard column of Fig. 7 provides additional right ²¹²The purification of Pb (II), this is to be far more than that Pb (II) is at (Cl ^-) not obvious formation anion chloro-complex during less than 1 M.Can make with 0.5M HCl ²¹²Bi (III) flows out and essentially no it is direct from sulfonic acid cation-exchanger resin ²¹²The experimental result report of Pb (II) parent (being that Pb (II) is detained for cationic ion-exchange resin with this understanding) has been supported this observation.(see Hassfjell et.al., Chem.Res 101:2109-2136 (2001); Mirzadeh et.al., J.Radioanal.Nucl.Chem.203:471-488 (1996); And Mirzadeh, Appl.Radiat.Isot.49:345-349 (1998).) data among Fig. 5-7 and combined the showing of data in literature of Pb (II), use based on the reverse selectivity generator of polystyle of the main splitter of neutral organophosphor extractant can with ²¹²Bi is from its parent ²²⁴Ra and ²¹²Effectively separate among the Pb.

Fig. 8 propose to be used for from ²²⁴Ra (II) and ²¹²Separate among the Pb (II) ²¹²Another program of Bi (III) to the TRPO resin master splitter (Fig. 7) of modification.Dipex ^Resin is to upload 40% P a kind of containing on the Amberchrom-CG71 of 20-50 μ m, the extraction-chromatography material of P '-two (2-ethylhexyl) first di 2 ethylhexyl phosphonic acid.(see Horwitz et.al., React.Funct.Polymers, 33:25-36 (1997).) Fig. 8 illustrates Bi (III) from 1.0M HNO ₃In by Dipex ^Resin is detained by force, and Ba (II) is easy to flow out.Upload with the drip washing program in see not have obviously amount from statistics ²⁰⁷Bi (III) is detected, and 1.0M HNO ₃Drip washing behind 5 column volumes, make ¹³³Ba (II) reaches background level.Can remove greater than 93% with the desorb of 2.0M HCl ²⁰⁷Bi (III), in 2 column volumes with very a spot of ¹³³Ba (II).In main splitter, adopt chelating ion exchange Dipex ^Resin can make total DF greater than 10 ³, but still to adopt above-mentioned guard column to reduce with maximum ²²⁴Ra and ²¹²Pb stains ²¹²The possibility of Bi.

Here each patent, application and the article quoted as proof all draw this as a reference.

Reach and can see from the front, under the situation of essence that does not depart from new ideas of the present invention and scope, practicable many modifications and variations.Should understand to illustrated particular be nonrestrictive maybe should be informative.The disclosure content be will with claims come topped all these be included in modification in the claim scope.

Claims

1. method that is used to prepare the solution of required daughter activity nucleic free from foreign meter substantially, it comprises the following steps:

(a) make parent-daughter aqueous solution of containing required daughter activity nucleic and required daughter activity nucleic is high-affinity and contacts with first separating medium that parent and other daughter activity nucleic is low compatibility, when this required daughter and parent radionuclide are present in this solution, it is more below or difference arranged on 2: (i) ionic charge or (ii) charge density, the time of contact that Bao Te is enough so that required daughter activity nucleic by the first law medium bonding, to form that load has the separating medium of required daughter and through the parent-daughter solution of the required daughter of dilution;

(b) from the parent-daughter solution of this separating medium removal through the required daughter of dilution;

(c) the required daughter activity nucleic of separating medium desorb of required daughter is arranged from load, to form the solution of required daughter activity nucleic;

(d) make the solution of required daughter activity nucleic and the parent radionuclide is high-affinity and contacts with second separating medium that this required daughter activity nucleic is low compatibility, Bao Te enough times of contact, so that this parent radionuclide is by the second law medium bonding, with the solution of the required daughter activity nucleic that forms substantially free of impurities.

2. the method for claim 1 is characterized in that, this required daughter have different ionic charges with the parent radioactive nucleus.

3. the method for claim 1 is characterized in that, this required daughter have different charge density with the parent radioactive nucleus.

4. the method for claim 1 is characterized in that, this required daughter and the existing different ionic charge of parent radionuclide have different charge density again.

5. the method for claim 1 is characterized in that, under contact conditions, required daughter activity nucleic is removed parent radionuclide impurity through first separating medium, and its coefficient of purification is more than or equal to 10 ²

6. the method for claim 1 is characterized in that, under contact conditions, required daughter activity nucleic is through the removal parent radionuclide impurity of second separating medium, and its coefficient of purification is more than or equal to 10 ²

7. method that is used to prepare the solution of required daughter activity nucleic free from foreign meter substantially, it comprises the following steps:

(a) provide the parent-daughter activity nucleic aqueous solution that contains required daughter activity nucleic;

(b) make this parent-daughter solution and required daughter activity nucleic is high-affinity, first separating medium that parent and other daughter activity nucleic are low compatibility contacts, so that under contact conditions, required daughter activity nucleic is through first separating medium, and the coefficient of purification of removing parent radionuclide impurity is more than or equal to 10 ²When this required daughter and parent radionuclide are present in this solution, it is more below or difference arranged on 2: (i) ionic charge or (ii) charge density, enough times of contact of Bao Te so that required daughter activity nucleic by the first law medium bonding, to form that load has the separating medium of required daughter and through the parent-daughter solution of the required daughter of dilution;

(c) from the parent-daughter solution of this separating medium removal through the required daughter of dilution;

(d) the required daughter activity nucleic of separating medium desorb of required daughter is arranged from load, to form the solution of required daughter activity nucleic;

(e) make the solution of required daughter activity nucleic and the parent radionuclide is high-affinity and contacts with second separating medium that this required daughter activity nucleic is low compatibility, so that under contact conditions, required daughter activity nucleic is through second separating medium, and the coefficient of purification of removing parent radionuclide impurity is more than or equal to 10 ², Bao Te enough times of contact are so that this parent radionuclide is by the second law medium bonding, with the solution of the required daughter activity nucleic that forms substantially free of impurities.

8. the method for claim 7 is characterized in that, this required daughter activity nucleic is about 10 through the gross decontamination coefficient of both removal parent radionuclide impurity of first and second separating mediums ⁴-Yue 10 ¹⁰

9. the method for claim 7 is characterized in that, this required daughter have different ionic charges with the parent radioactive nucleus.

10. the method for claim 7 is characterized in that, this required daughter have different charge density with the parent radioactive nucleus.

11. the method for claim 7 is characterized in that, this required daughter and the existing different ionic charge of parent radionuclide have different charge density again.

12. the method for claim 7 is characterized in that, this required daughter activity nucleic is selected from ⁹⁰Y, ^99mTc, ¹⁰³Pd, ¹¹¹In, ¹²⁵I, ¹⁸⁸Re, ²⁰¹Tl, ⁴⁷Sc, ²¹²Bi,, ²¹³Bi, ²¹¹At and ²²³Ra.

13. a method that is used to prepare the solution of required daughter activity nucleic free from foreign meter substantially, it comprises the following steps:

(a) provide to contain and be selected from ⁹⁰Y, ^99mTc, ¹⁰³Pd, ¹¹¹In, ¹²⁵I, ¹⁸⁸Re, ²⁰¹Tl, ⁴⁷Sc, ²¹²Bi, ²¹³Bi, ²¹¹At and ²²³The parent of the required daughter activity nucleic of the Ra-daughter activity nucleic aqueous solution;

(b) make this parent-daughter solution and required daughter activity nucleic is high-affinity and contacts with first separating medium that parent and other daughter activity nucleic is low compatibility, so that under contact conditions, required daughter activity nucleic is through first separating medium, and the coefficient of purification of removing parent radionuclide impurity is more than or equal to 10 ²This required daughter has different ionic charges when being present in this solution with the parent radionuclide, enough times of contact of Bao Te so that required daughter activity nucleic by the first law medium bonding, to form that load has the separating medium of required daughter and through the parent-daughter solution of the required daughter of dilution;

(e) make the solution of required daughter activity nucleic and the parent radionuclide is high-affinity and contacts with second separating medium that this required daughter activity nucleic is low compatibility, so that under contact conditions, required daughter activity nucleic is through second separating medium, and the coefficient of purification of removing parent radionuclide impurity is more than or equal to 10 ², enough times of contact of Bao Te so that this parent radionuclide by the second law medium bonding, with the solution of the required daughter activity nucleic that forms substantially free of impurities.

14. the method for claim 13 is characterized in that, this required daughter activity nucleic is about 10 through the gross decontamination coefficient of both removal parent radionuclide impurity of first and second separating mediums ⁴-Yue 10 ¹⁰

15. a method that is used to prepare the solution of required daughter activity nucleic free from foreign meter substantially, it comprises the following steps:

(b) make this parent-daughter solution and required daughter activity nucleic is high-affinity and contacts with first separating medium that parent and other daughter activity nucleic is low compatibility, so that under contact conditions, required daughter activity nucleic is through first separating medium, and the coefficient of purification of removing parent radionuclide impurity is more than or equal to 10 ²This required daughter has different charge density when being present in this solution with the parent radionuclide, enough times of contact of Bao Te so that required daughter activity nucleic by the first law medium bonding, to form that load has the separating medium of required daughter and through the parent-daughter solution of the required daughter of dilution;

(d) the required daughter activity nucleic of separating medium desorb of required daughter is arranged to form the solution of required daughter activity nucleic from load;

(e) make the solution of required daughter activity nucleic and the parent radionuclide is high-affinity and contacts with second separating medium that this required daughter activity nucleic is low compatibility, so that under contact conditions, required daughter activity nucleic is through second separating medium, and the coefficient of purification of removing parent radionuclide impurity is more than or equal to 10 ², enough times of contact of Bao Te so that this parent radionuclide by the second separating medium bonding, with the solution of the required daughter activity nucleic that forms substantially free of impurities.

16. the method for claim 15 is characterized in that, this required daughter activity nucleic is through both removals of first and second separating mediums, and the gross decontamination coefficient that makes parent radionuclide impurity is about 10 ⁴-Yue 10 ¹⁰

17. the method for claim 15 is characterized in that, this required daughter activity nucleic is ²¹²Bi (III).

18. the method for claim 15 is characterized in that, one of this parent radionuclide is ²²⁴Ra (II).

19. a method that is used to prepare the solution of required daughter activity nucleic free from foreign meter substantially, it comprises the following steps:

(b) make this parent-daughter solution and required daughter activity nucleic is high-affinity and contacts with first separating medium that parent and other daughter activity nucleic is low compatibility, so that under contact conditions, required daughter activity nucleic is through first separating medium, and the coefficient of purification of removing parent radionuclide impurity is more than or equal to 10 ²When this required daughter and parent radionuclide are present in this solution, its ionic charge is all different with charge density, enough times of contact of Bao Te so that required daughter activity nucleic by the first law medium bonding, to form that load has the separating medium of required daughter and through the parent-daughter solution of the required daughter of dilution;

20. the method for claim 17 is characterized in that, this required daughter activity nucleic is through both removals of first and second separating mediums, and the gross decontamination coefficient that makes parent radionuclide impurity is about 10 ⁴-Yue 10 ¹⁰