NZ716837B2 - Method for the quantification of 227ac in 223ra compositions - Google Patents

Abstract

method for the quantification of 227Ac in a 223Ra composition comprising passing the composition through a first solid phase extraction column A, wherein said column comprises a thorium specific resin, passing the eluate of column A through a second solid phase extraction column B, wherein said column comprises an actinium specific resin and recovering the 227Ac absorbed onto the resin in column B and determining the amount thereof. lumn comprises an actinium specific resin and recovering the 227Ac absorbed onto the resin in column B and determining the amount thereof.

Description

(12) Granted patent specificaon (19) NZ (11) 716837 (13) B2 (47) Publicaon date: 2021.12.24 (54) METHOD FOR THE QUANTIFICATION OF 227AC IN 223RA COMPOSITIONS (51) Internaonal Patent Classificaon(s): B01D 15/08 B01D 15/18 B01D 59/26 A61K 51/00 C01F 13/00 C22B 60/00 G21G 4/08 G21G 4/10 G01N 30/60 (22) Filing date: (73) Owner(s): 2014.08.13 BAYER AS (23) Complete specificaon filing date: (74) Contact: 2014.08.13 DAVIES COLLISON CAVE PTY LTD (30) Internaonal Priority Data: (72) Inventor(s): GB 1314718.6 2013.08.16 HJELLUM, Gro Elisabeth (86) Internaonal Applicaon No.: (87) Internaonal Publicaon number: WO/2015/022074 (57) Abstract: A method for the quanficaon of 227Ac in a 223Ra composion sing passing the composion through a first solid phase on column A, wherein said column comprises a thorium specific resin, passing the eluate of column A through a second solid phase extracon column B, wherein said column ses an acnium specific resin and ring the 227Ac absorbed onto the resin in column B and determining the amount thereof. 716837 B2 METHOD FOR THE QUANTIFICATION OF 227AC IN 223RA COMPOSITIONS Field of the Invention The present invention relates to a novel method for quantifying levels of 227Ac in 223Ra compositions, in particular a method which involves solid phase tion followed by quantification via the in-growth of the 227Th daughter via γspectrometry.

The invention further relates to the use of the method of the invention in determining the level of 227Ac in a 223Ra composition and to an apparatus for use in the method of the invention. ound A substantial percentage of cancer patients is effected by skeletal metastases.

As many as 85% of patients with advanced lung, prostate and breast carcinoma p bony metastates t 1993, Nielsen et al, 1991). They are ated with a decline in health and quality of life, ultimately leading to death, often within a few years.

When tumors or ases cannot be removed by surgery, the conventional approach is to apply external beam radiotherapy and chemotherapy. Both suffer from a lack of selectivity for tumor cells and tumor tissue. As a consequence, treatment most often cannot be applied at curative levels due to toxicity to healthy tissue.

Bone-seeking ȕ-emitters like 89Sr and 153Sm complexed with ethylene-diaminetetramethylene-phosphonate ) have been used as al radiotherapy agents in the pain palliation of painful bone metastases especially in prostate cancer. The altered skeletal metabolic activity around many bone metastases results in a local increase in bone formation and uptake of calcium, which is used to construct the hydroxyapatite bone mineral. Bone-seeking radionuclides target this bone adjacent to the tumor deposits. Calcium mimetics, such as strontium 89Sr, belong to the alkaline earth group of ts in the periodic table. They can be administered as an intravenous radioactive salt that will be incorporated into the newly formed hydroxyapatite in bone metastases. Other radionuclides, such as 153Sm, require a carrier molecule to achieve selective uptake to the bone, for example, EDTMP. By selectively targeting areas of high metabolic activity in bone, a high eutic index is possible.

However, the ȕ-particles are characterized by low-linear energy transfer (LET) typically in the range of 0.2-1.0 keV/μm and a modest relative biological effectiveness (RBE). The use of highly energetic ȕ-particles is restricted by the radiation burden and cell damage to surrounding healthy tissue and ally by the ssion of blood cells in the red bone marrow. Hence, there is an unmet need for more effective bone-targeted treatments that improve y of life and survival whilst maintaining a favorable safety profile.

The use of ting radionuclides has a major advantage in radiotherapy of cancer. Compared to the low LET values of ȕ-emitters, Į-emitters have a mean LET value of 80-100 keV/μm. 223Ra has shown particular promise. For example, adin® (223RaCl2) has completed a global phase-III clinical trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Data shows that Alpharadin prolongs patient overall survival time while offering a well tolerated safety profile (Brady et al, Cancer J., 2013, 19, 71-78). 223Ra, like 89Sr, is a calcium mimic and also an alkaline earth element and can be administered as an intravenous radioactive salt. Due to the high LET-values of Į-particles and, uently, their short path-length in human tissue (< 100 μm), a highly cytotoxic radiation-dose can be delivered to targeted cancer cells, while damage to the surrounding healthy tissue is limited.

Quality control is an ial part of pharmaceutical manufacture, to ensure the drugs sent to the market are safe and eutically active formulations have a mance which is consistent and table. The term quality control refers to the sum of all procedures undertaken on each batch to ensure e.g. the identity, activity and purity.

Radionuclidic purity is defined as the percentage of a contaminating radionuclide relative to the wanted radionuclide e.g. 227Ac relative to 223Ra with t to activity in Bq. The primary reason for seeking radionuclidic purity in a radiopharmaceutical is to avoid unwanted administration of radiation to the patient.

It is therefore extremely important to ly control the levels of radionuclidic impurities in radiopharmaceuticals. Radionuclidic impurities may originate from several sources. For example, when a parent-daughter uclide generator system is used to produce the radionuclide of interest, the parent nuclides are defined as impurities in the product. Actions must be taken during production to ensure that the parent nuclides are separated from the e of interest and, before release of the finished product for human use, it has to be med that the radioactivity of the radionuclidic impurities are below the limit specified for the product.

Production of 223Ra for pharmaceutical use is typically based on a radionuclide tor where the mother nuclide 227Ac (t ½ = 21.77 years) is adsorbed on a column material. The daughter radionuclides are 227Th (t ½ = 18.68 days) and 223Ra (t 223Ra is separated by column elution. 227Ac and its ½ = 11.43 days). daughter nuclide 227Th must be strongly retained under conditions were 223Ra can be eluted. 227Ac and 227Th do not have the same bone seeking properties as 223Ra and are regarded as impurities. Even very low amounts of these nuclides cannot be accepted in the pharmaceutical product. The acceptance criterion for adin has been set to not more than 0.004% for 227Ac and not more than 0.5% for 227Th relative to 223Ra with respect to ty in Bq. Similar criteria would be expected for other 223Ra products. Prior to formal release of the product to patients, each produced batch of radiopharmaceutical (e.g. adin) must be tested to show that it meets the acceptance criteria ately defined identity, strength, quality and purity). Due to the inherently short half-life of 223Ra, the radiopharmaceutical may be released before completion of all tests (e.g. sterility testing). This naturally has the disadvantage that ts could be exposed to a formulation which does not meet all the quality control criteria.

A quantitative determination of 227Ac is difficult as 227Ac decays almost entirely by on of a low-energy ȕ-particle (Eȕ,max = 0.0448 MeV), which is virtually undetectable in the presence of all the energetic Į- and ȕ-emitters of the 227Ac chain (see Figure 1). 227Ac also decays by Į-emission in 1.38% of its disintegrations. However, direct Į-spectrometric determination of 227Ac is complicated by interferences from the Į-emissions of its rapidly growing decay products. Freshly purified 227Ac emits no analytically useful Ȗ-radiation.

Consequently, many radiometric methods determine 227Ac indirectly by measurements of the Į- and ations of its daughters, in particular by high- tion Ȗ-spectrometry of its daughter 227Th. However, this cannot be determined until 10-12 months after release of the product as is must wait until there are sufficiently measurable levels of 227Th. At this time, the potential amount of 227Ac contamination is in equilibrium with its daughter 227Th. Furthermore, the initial amounts of 223Ra and any 227Th in the product would have decayed completely.

These disadvantages not only lead to inaccuracy of results and sed costs but, more significantly, mean that the result comes too late for the 223Ra pharmaceutical to be withdrawn from release to patients should it be shown to be contaminated with 227Ac at levels which would be considered to jeopardise the efficacy of the treatment or the safety of the patient.

In view of the above, there remains a need to develop a new, reliable, accurate and cost-effective radiochemical method for early determination of the potential contamination of 227Ac in 223Ra pharmaceuticals, such as Alpharadin (RaCl2). In particular, it would be an advantage to produce a method which is able to give a result in a matter of days rather than months. Ultimately, an analysis method which can be ted prior to release of the product and its stration to patients is attractive. The following criteria set out the desirable es of a new quantification method: 1. 227Ac should selectively be separated from the precursors. 2. Recovery of 227Ac > 70 % and precision > 30 % 3. ness i.e. the ical result should remain unaffected by small variations in method ters. 4. Easy to operate in routine production (in terms of time and cost).

. Sample activity should be as low as possible due to cost and radiation exposure to the operators, and/or Document5-29/07/2021 6. Separation and fication should be fulfilled before release of the product i.e. within 2 days after tion of the 223 Ra pharmaceutical (e.g. 223-radium chloride).

The present inventors have surprisingly found that an analytical method employing a tandem column arrangement comprising two different solid phase extraction resins can fulfil some or all of these requirements. In particular, the two columns enable facile separation and isolation of 227 Ac, which can be rapidly quantified. y of the Invention According to a first aspect, the present disclosure provides a method for the quantification of 227 Ac in a 223 Ra composition, said method consisting essentially of: (i) placing a first solid phase extraction column A comprising a dipentyl phosphonate UTEVA resin and a second solid phase extraction column B comprising N, N, N', N' - tetra-n-octyldiglycolamide DGA resin in series, wherein the output of column A is connected to the input of column B; (ii) adding a volume of a 223 Ra composition corresponding to 15 MBq of 223 Ra to an equal volume of nitric acid, at 8 mol/L nitric acid; (iii) transferring the sample from step (ii) to the input of the column A; (iv) passing said sample through both columns A and B (v) washing both columns with 20-100 times the combined volume of the two columns with 4 mol/L nitric acid; (vi) disconnecting column A from column B; (vii) washing column B with 40-200 times its volume with 4 mol/L nitric acid; (viii) washing column B with 40-200 times its volume with 0.05 mol/L nitric acid. (ix) ining the amount of 227 Ac present in the eluate from column B ed in step (viii) by trometry via in-growth and detection of the daughter 227 Th.

Thus, viewed from one aspect, the invention provides a method for the quantification of 227Ac in a 223Ra composition, said method comprising: Document5-29/07/2021 (i) passing said 223Ra composition through a first solid phase tion column A, wherein said column comprises a m specific resin (e.g. dipentyl pentylphosphonate UTEVA resin); (ii) passing the eluate of column A through a second solid phase extraction column B, wherein said column comprises an actinium specific resin (e.g.

N, N, N', N'-tetra-n-octyldiglycolamide DGA resin); (iii) recovering the 227Ac absorbed onto the resin in column B and determining the amount thereof.

Viewed from another aspect the invention provides a method as hereinbefore described, said method comprising (i) g a first solid phase extraction column A comprising a thorium specific resin (e.g. dipentyl pentylphosphonate UTEVA resin) and a second solid phase extraction column B comprising an actinium specific resin (e.g. N, N, 30 N', N' - tetra-n-octyldiglycolamide DGA resin) in series, preferably wherein the output of column A is connected to the input of column B; (ii) Adding a volume of a 223Ra ition corresponding to a known activity (e.g. 15 MBq) of 223Ra to an equal volume of nitric acid, preferably 8 mol/L nitric acid; (iii) Transferring the sample from step (ii) to the input of the column A; (iv) Passing said sample through both columns A and B (v) Washing both columns with 20-100 times the combined volume of the two columns (e.g. 5-10 ml) nitric acid, ably 4 mol/L nitric acid; (vi) Disconnecting column A from column B; (vii) Washing column B with 40-200 times its volume (e.g. 5-10 ml) nitric acid, preferably 4 mol/L nitric acid; (viii) Washing column B with 40-200 times its volume (e.g. 5-10 ml) nitric acid at a concentration less than that used in step (vii), such as 0.05 mol/L nitric acid. (ix) Determining the amount of 227Ac present in the eluate from column B obtained in step (viii).

Viewed from another aspect the invention provides the use of a method as hereinbefore described in the quantification of 227Ac in a 223Ra composition.

Viewed from another aspect the ion es apparatus for use in a method as hereinbefore described, wherein said apparatus comprises a first solid phase extraction column A, wherein said column comprises a thorium specific resin (e.g. a dipentyl phosphonate UTEVA resin), and a second solid phase extraction column B, wherein said column comprises an actinium specific resin (e.g. a N, N, N', N'-tetra-n-octyldiglycolamide DGA resin).

Definitions The 223Ra composition of the invention will be understood to be any composition which comprises the uclide 223Ra. The composition will typically be a pharmaceutical composition or a precursor to a pharmaceutical solution and will therefore usually n the additional components often found in such compositions, e.g. pharmaceutically acceptable diluents, excipients and carriers. Such components are well known in the art. The 223Ra may be in any form, however the most preferred form is as a salt such as a halide salt, preferably RaCl2 (Alpharadin®), optionally in combination with other Ra salts. It will be iated that in order to be compatible with the method of the invention the 223Ra composition must be in solution, typically an aqueous solution, such as an aqueous acid solution.

The method of the invention employs solid phase extraction. This technique is well known in the art, however a brief outline is provided here for completeness.

Solid-Phase Extraction (SPE) has become widely accepted as a substitute for traditional liquid-liquid extraction (LLE) in many types of separation procedures, and especially for those ing low to ultralow concentrations of analyte. SPE is based on the same principles as solvent extraction, which often involves complexation to form a lipophilic compound of the e followed by transfer of this compound into an organic phase. In SPE the non-aqueous phase is solid instead of liquid as it is in LLE. SPE is generally faster, more efficient and generates less waste than LLE.

SPE comprises three major components; an inert support, a stationary phase and a mobile phase. The inert support usually consists of porous silica or particles of an organic polymer ranging in size from 50 to 150 μm in diameter. The stationary phase, which is on the surface of the inert support, is selected riately depending on the analytes involved. The mobile phase is usually an aqueous acid solution, e.g. nitric or hydrochloric acid.

The method of the invention employs two different stationary phases (resins).

The first resin is a m specific resin, typically an UTEVA Resin (Uranium und TEtraValents Actinides), which is mainly used for the separation of m and tetravalent actinides. The extractant coated on the inert support is selected to specifically bind thorium in a on mixture of radium, m and actinium. This specificity may be under all conditions, or the conditions used in the methods of the ion may be chosen to ensure specificity.

Extractants suitable for thorium specific resins include phosphonates, ularly alkyl onates. Dialkyl alkyl phosphonates such as those of the following formula (Formula I) are preferred: P R3 R2 O R1 (I) wherein each of R1-R3 is independently a C3-C8 straight or branched chain alkyl group. Preferably R1-R3 are straight chain alkyl groups. Preferably R1 is a C4-C6 straight chain alkyl group, most preferably n-pentyl. R2 and R3 may be identical or different. Preferably R2 and R3 are identical. Preferably each of R2 and R3 is a straight chain C4-C6 alkyl group, most preferably n-pentyl. A high preferably extractant is dipentyl phosphonate, which has the following structure: The second resin is an actinium specific resin, typically selected to ically bind actinium in a solution mixture of radium and actinium. This specificity may be under all conditions, or conditions used in the methods of the invention may be selected to ensure specificity.

In some embodiments, the conditions may be such that the um specific resin has some degree of affinity for radium as well as actinium and under those ions both radium and actinium may bind to the second resin. It will be appreciated that, under such circumstances, the method of the invention may require a further step in which the conditions are altered such that any radium which has bound to the second resin may be specifically eluted whilst the actinium remains bound to the resin, before the um may be eluted from the second resin.

Preferably, the conditions used in the methods of the invention are chosen such that the second resin does not have any ty for radium and only actinium binds to the second resin. Thus, in a preferable embodiment, the conditions used in the method of the invention are such that the second resin is specific for actinium.

A resin may be considered "specific" for one element over another if that resin will retain at least 90% of the first element under conditions that would elute at least 90% of the second element. This is preferably 95%, more preferably 99%.

Typically, the conditions chosen in the methods of the invention are certain concentrations of mineral acids (e.g. nitric acid) in water.

Extractants suitable for actinium specific resins include diglycolamides, particularly tetra-alkyl diglycolamides of the following formula (Formula II): O O O R3 N N R4 (II) wherein R1-R4 are independently C3-C12 straight or ed chain alkyl groups, ably C5-C10 straight or branched chain alkyl groups. R1-R4 may be identical or different, preferably identical. R1-R4 may all be C8 alkyl . A preferred example is N,N,N’,N’-tetra-n-octyldiglycolamide (DGA Resin, Normal), which has the following structure: wherein the R-groups are straight chain C8 alkyl groups. The ponding resin where the R-groups are branched C8 alkyl groups is also of value.

In the context of the invention, the term "eluate" refers to the solution of solvent and dissolved matter resulting from elution, i.e. the mixture of components which elutes following separation using a solid phase extraction column.

The term "eluent" should be tood to be hangeable with the term "mobile . Both terms are well known in the art and are used to refer to the solvent which is passed through a solid phase extraction column and is used to effect separation.

Detailed Description The method of the invention comprises the following steps (i) passing a 223Ra composition (e.g. one containing 227Ac and 227Th contaminants) through a first solid phase extraction column A, wherein said column comprises a thorium specific resin (e.g. a dipentyl pentylphosphonate UTEVA resin); (ii) passing the eluate of column A through a second solid phase extraction column B, wherein said column comprises an actinium specific resin (e.g. a N, N, N', ra-n-octyldiglycolamide DGA resin); (ii) recovering the 227Ac absorbed onto the resin in column B and determining the amount thereof.

In a preferable embodiment, column A and column B are arranged in series such that the eluate from column A passes directly into column B, i.e. n the output of column A is connected to the input of column B. The most preferable arrangement is for column A to be positioned above column B such that the eluate from column A drains ly into column B.

The method of the invention relies on the surprising finding that by choice of a resin and column configuration, contaminant 227Ac can be purified from a mixture of 223Ra and 227Th to a sufficient degree to allow for accurate measurement of the 227Ac via 227Th in-growth. For example, a UTEVA resin is capable of selectively ing 227Th out of a mixture of 223Ra, 227Ac and 227Th and moreover that a DGA resin is capable of selectively retaining 227Ac from a mixture of 227Ac and 223Ra.

This results in an efficient separation method. An outline of the process is provided in Figure 2.

The 223Ra composition used in the method of the invention comprises 223Ra.

It will typically also comprise both 227Th and 227Ac contaminants. Thus, all three radionuclides are usually present in the ng e of analytes. As the mixture passes through the first column A, any 227Th present will absorb onto the thorium specific resin (e.g. UTEVA resin), leaving only 223Ra and 227Ac present in the eluate.

As this eluate passes though the second column B, any 227Ac will absorb onto the actinium specific resin (e.g. DGA resin). The 223Ra will typically remain in the mobile phase. In some embodiments, the actinium specific resin may be washed with additional volumes of mobile phase so as to ensure all 223Ra is eluted. Thus the total 227Ac fraction may be obtained and isolated.

Importantly, the 227Ac fraction, which is bound to the actinium specific resin (e.g. DGA resin), will be substantially free, preferably completely free, of 227Th and 223Ra, thereby enabling more facile determination of its quantity via detection of the wth of its er nuclide, 227Th at very low levels. In particular, results will not be skewed by levels of 227Th initially present in the 223Ra composition or masked by interferences due to other, more energetic, decay chains beginning at 227Th or 223Ra. A first isotope may be considered "substantially free" of a second isotope if the second isotope is present at a concentration of less than 1%, preferably less than 0.01%, relative to the concentration of the first e. Correspondingly, "completely free" may be considered to correspond to a concentration of less than 0.001% of the second isotope relative to the first isotope.

The mobile phase (eluent) is lly a solution comprising an acid, such as hydrochloric acid or nitric acid. The most preferable acid is nitric acid. Typically, the concentration of any acid used in the method of the invention will be in the range 0.01 to 10 mol/L, ably 0.02 to 8 mol/L, such as 0.05 to 4 mol/L.

Column A comprises a thorium specific resin, such as a UTEVA resin. The inventors have found that the affinity of an UTEVA resin for 227Th ses with sing nitric acid concentration. This is thought to arise e as the tration of the nitric acid increases so too does the propensity with which the 227Th will form nitrate complexes. It is believed to be these complexes for which the resin has affinity. Column B comprises an actinium specific resin, such as a DGA resin. DGA resin has been found to have particular affinity for 227Ac.

The 223Ra composition used in the methods of the invention typically comprises 223Ra at a concentration in the range 2 to 30 MBq/ml (e.g. 2.4 to 30 MBq/ml), such as 5 to 20 MBq/ml. The composition will y be used in the form of an aqueous acid solution, such as nitric acid. The acid will typically have a concentration in the range 4-10 mol/L, for example, 8 mol/L.

In step (iii) the 227Ac absorbed onto the resin of column B is removed. This may be carried out by a variety of methods but is typically achieved by g the column with an aqueous acid solution of lower concentration than that which was used as eluent in step (ii), such as 0.05 mol/L nitric acid. The volume of aqueous acid solution used to wash the column may be in the range 16 to 400 times the volume of the column (e.g. 2-20 ml), preferably 40-200 times (e.g. 5-10 ml). The eluate obtained from column B after step (iii) contains 227Ac. Preferably this eluate is substantially free of 227Th. For example, the eluate may n 227Th at a molar concentration of less than 5%, preferably less than 1% or less than 0.1% and more preferably less than 0.01% relative to the concentration of 227Ac.

In a highly red embodiment, the method of the invention comprises the ing steps: (i) Place a first solid phase extraction column A comprising a thorium specific resin (e.g. a dipentyl pentylphosphonate UTEVA resin) and a second solid phase tion column B comprising an actinium specific resin (e.g. a N, N, N', N' - tetra-n-octyldiglycolamide DGA resin) in series, preferably wherein the output of column A is connected to the input of column B; (ii) Add a volume of a 223Ra composition corresponding to a known activity (e.g.

MBq) of 223Ra to an equal volume of nitric acid, preferably 8 mol/L nitric acid; (iii) Transfer the sample from step (ii) to the input of the column A; (iv) Pass said sample through both columns A and B (v) Wash both columns with 20-100 times the combined volume of the two s (e.g. 5-10 ml) nitric acid, preferably 4 mol/L nitric acid; (vi) nect column A from column B; (vii) Wash column B with 40-200 times its volume (e.g. 5-10 ml) nitric acid, preferably 4 mol/L nitric acid; (viii) Wash column B with 40-200 times its volume (e.g. 5-10 ml) nitric acid at a concentration less than that used in step (vii), such as 0.05 mol/L nitric acid. (ix) Determining the amount of 227Ac t in the eluate from column B obtained in step .

Following isolation of the 227Ac from the actinium specific resin (e.g. DGA resin), its amount may be quantified by any known method in the art. Typical percentage recoveries of 227Ac using the method of the invention are in the range 70- 100%, such as 72-98%, preferably 74-97% (e.g. 80 to 97% or 80 to 90%).

Evidently, for an analytical method reproducibility in recovery of 227Ac is as important as the te recovery. The distribution of such recoveries will thus typically have a standard deviation of no more than 20%, preferably no more than %.

Typical methods used to determine the quantity of 227Ac may involve γspectrometry , α-spectrometry and liquid scintillation counting (LSC) with pulseshape mination. The preferred technique is γ-spectrometry, which enables quantification of 227Ac via in-growth and detection of the daughter 227Th. Methods for performing γ-spectrometry are well known in the art.

The activity of 227Ac, which is not directly determinable by Ȗ-ray spectrometry, can be calculated from measurement of the daughter 227Th. As the specification limit for a 223Ra pharmaceutical is 0.004% 227Ac, relative to 223Ra, an activity of 15 MBq 223Ra should give an activity of 600 Bq of 227Ac. The in-growth of 227Th from 227Ac is calculated by Equation 1. 227Th) −ȜTh-227 t Ingrowth(A ⋅= 0 )e-1(A Due to tory requirements for radiopharmaceuticals, the result from radionuclidic purity of a 223Ra pharmaceutical should be available before release of the product. In order to meet these requirements the maximum in-growth period of 227Th from 227Ac should preferably not be more than two days to avoid a prohibitively high loss of 223Ra by decay before administration. The calculated activity after 24 and 48 hours in-growth of 227Th from 600 Bq 227Ac is shown in Table 1.

Table 1. Ingrowth of 227Th from 600 Bq 227Ac Hours after separation Ingrowth 227Th (Bq) 24 21.9 48 42.9 After separation of 227Ac from 227Th and 223Ra, potential traces of 227Th can be left in the sample um detectable value < 1.6 Bq). By counting only one um, the activity of 227Ac can be overestimated. In the present invention, this issue has been addressed by utilizing two consecutive measurements of the 227Th daughter: one counted after 24 hours and one after 48 hours from separation. 227Th ty obtained from analyses after 24 hours is subtracted from 227Th activity obtained after 48 hours assuming that the in-growth of 227Th is almost linear in the period. Correction of decay of potential traces of 227Th (t 1/2 = 18.68 days) between 24 and 48 hours after separation, has not been taken into account. It is considered to be sufficiently te and within the uncertainty of the measurement.

With the 227Th activity at measurement time one (24 h) and 227Th activity at ement time two (48 h), the unknown, but time independent, activity of the long-lived mother 227Ac can be calculated by: (A 227 227Th) −= 227 Δ Th) spectrum2 (A spectrum1(A Th) (2) The activity of 227Ac in the sample at time 0, is based on wth of 227Th.

The equations used are given below. 227227 § 1 · 0 (A Ac) Δ (A Th)⋅= ¨ ¸ (3) © e-1 −ȜTh-227 t ¹ where: A0(227Ac) = the activity of 227Ac in the 223Ra pharmaceutical (Bq) A¨(227Th) = the activity of 227Th produced between measurement time one and measurement time two, e.g. 24 and 48 hours after separation (Bq) λTh-227 = ln