Method for measuring actinium-227 in actinium-225

Abstract

A method for measuring actinium-227 (Ac-227) via indirectly generated Ra-225 / Ac-225 parent / daughter nuclides. Measurement of Ac-227 or its decay products can be used as a "pre-release" quality control test for total Ac-227 content.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority in the United States Patent and Trademark Office to U.S. Provisional Patent Application No. 64 / 435,881, filed December 29, 2022, and U.S. Patent Application No. 18 / 397,165, filed December 27, 2023, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The present invention relates to a method for measuring actinium-227 (Ac-227) in actinium-225 (Ac-225), and more particularly to a method for measuring Ac-227 in Ac-225 via indirectly generated Ra-225 / Ac-225 parent / daughter nuclides. [Background technology]

[0003] Actinium-225 (Ac-225), an isotope of actinium, is an alpha-emitting actinide of great interest from the perspective of therapeutic active pharmaceutical ingredients (APIs). Ac-225 can be produced by isolation from legacy materials (uranium) or by proton irradiation of thorium (Th). Proton irradiation of Th-232 produces multiple radionuclides, including Ra-225, Ac-225, and Ac-227.

[0004] There are two known methods for obtaining Ac-225 from this irradiation: direct and indirect. In the direct method, all actinium is isolated from other radionuclides. This method concentrates both Ac-225 and Ac-227 together (they are chemically inseparable), resulting in a less desirable Ac-225 product that is heavily contaminated with Ac-227.

[0005] The indirect method involves isolating and purifying the parent isotope of radium-225, Ac-225. This indirect method produces smaller amounts of Ac-225, but with much lower concentrations of Ac-227, and is therefore safer for patients.

[0006] Figure 1 is a diagram of a known Ra-225 / Ac-225 decay scheme, and Figure 2 is a diagram of a known Ac-227 decay scheme.

[0007] However, known methods for obtaining the impurity level of Ac-227 in Ac-225 have drawbacks. For example, measurements of Ac-227 are performed several months after the Ra-225 / Ac-225 batch is made due to interference from many decay products of Ac-225. This post-"release" quality control (QC) measurement, while accurate, is undesirable, especially from patient safety perspectives, because Ac-227 is a highly toxic alpha emitter.

[0008] Additionally, it would be preferable to quantify the Ac-227 impurity using an ion counting technique such as inductively coupled plasma mass spectrometry (ICP-MS). However, the mass range 211-229 lacks ICP-MS standards containing naturally occurring elements, making quantification of Ac-227 difficult in anything other than semi-quantitative mode.

[0009] Therefore, there is a need for an alternative method for measuring actinium-227 (Ac-227) in actinium-225 (Ac-225) that overcomes the shortcomings of known methods. The method of the present invention overcomes these shortcomings. Summary of the Invention

[0010] The method of the present invention is used to measure actinium-227 (Ac-227) via indirectly generated Ra-225 / Ac-225 parent / daughter nuclides. Measurement of Ac-227 or its decay daughter nuclides can be used as a pre-release quality control test for total Ac-227 content. Pre-release generally refers to a quality control procedure performed against pharmaceutical product specifications, with results approved prior to batch release and / or patient use.

[0011] Measurement of Th-227, one of the daughter nuclides of Ac-227, is possible because thorium can be chemically separated from radium and actinium as well as other radionuclides. Therefore, according to the method of the present invention, measurement of Ac-227 in Ac-225 solution is based on the decay of Ac-227 to Th-227.

[0012] An advantage of the present invention is that it provides confidence in the API from a patient safety perspective by providing values ​​of Ac-227 in a batch of Ac-225 at the time of release of the batch, an improvement over post-release testing and the potential for discovering problems after patient use of the API.

[0013] Considering the consequences of using Ac-225 in patients when high Ac-227 loads are found after release and use, its commercial value is considerable. This would also be beneficial for the commercial production of Ac-225 from Ra-225 stock over its entire lifespan (Ra-225 stock is "milked" for Ac-225 multiple times).

[0014] Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

[0015] The present invention will become more fully understood from the detailed description and the accompanying drawings, which are not necessarily to scale. [Brief explanation of the drawings]

[0016] [Figure 1] 1 is a diagram of a known Ra-225 / Ac-225 decay scheme.

[0017] [Figure 2] FIG. 1 is a diagram of a known Ac-227 decay scheme. DETAILED DESCRIPTION OF THE INVENTION

[0018] The following description of the embodiments of the present invention is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses. The following description is provided herein by way of example merely for the purpose of providing an enabling disclosure of the invention, but is not intended to limit the scope or content of the invention.

[0019] The method of the present invention is a timely pre-release method for determining the impurity of actinium-227 (Ac-227) in actinium-225 (Ac-225) from indirect Ra-225.

[0020] Ra-225 is first highly purified from any actinium isotopes (and other interfering radionuclides). After purification, the entire Ra-225 stock can be sampled to allow for lower levels of Ac-227 / Th-227 detection / quantification. At the end of Ra-225 purification, no additional Ac-227 is produced, so the Ra-225 stock is sampled immediately after purification (for future Th-227 measurements). The desired Ac-225 "grows-in" from the Ra-225 over a period of seven days (nominally) before extraction of the Ac-225. The Ac-227 method involves several chemical separation steps.

[0021] Thus, the methods of the present invention generally involve providing a purified Ra-225 stock and sampling the purified Ra-225 stock to determine the Ac-225 and / or Ac-228 content by alpha or gamma spectroscopy. In the purified Ra-225 stock, impurities have been removed and the remaining Ac-227 impurity is not significantly altered by the 14-day half-life of Ra-225, since Ac-227 has a half-life of 23 years.

[0022] The method further includes extracting all actinium isotopes from the Ra-225 stock. The first actinium extracted Ac-225 / 227 / 228 is referred to herein as "Stock A." The extracted actinium-225 or -228 values ​​(mCi or μCi) and the actinium-225 or -228 values ​​(mCi or μCi) in the original Ra-225 stock are used to calculate the efficiency fraction A: (Actinium extracted) / (Actinium in original Ra-225 stock) = Efficiency Fraction A

[0023] for example,

[0024] (Ac-225 mCi extracted / Ac-225 mCi in original Ra-225 stock) = fraction recovered

[0025] Recovered fraction x 100 = recovery rate by alpha spectroscopy

[0026] The method further comprises allowing Stock A to stand for at least 5 days to allow the Ac-227 to decay to Th-227, which accumulates over this period and the percentage saturation factor is calculated using the following formula:

[0027] (1-e (-Ln2×時間 / 半減期) ) = saturation factor

[0028] 1-e (-0.69315×5d / 18.7日 ) = 0.17 fraction

[0029] Recovered fraction 0.17 x 100 = 17% saturation factor percentage (5 days)

[0030] Note that 18.7 days is the half-life of Th-227.

[0031] The settling time can be varied to yield different saturation values.

[0032] The method further includes adding a Th-230 tracer to Stock A, which allows for subsequent calculation of thorium recovery by adding a known amount of tracer. Thorium tracers that may be used include, but are not limited to, Th-228, Th-229, Th-230, Th-231, Th-232, Th-234, and combinations thereof.

[0033] The method further includes chemically isolating (i.e., by chromatography) the thorium (227 and 230) from all other impurities, including actinium.

[0034] The method further includes mounting the thorium isotope on an alpha counting disk using an alpha spectroscopy preparation method.

[0035] The method further includes counting the alpha discs using alpha spectroscopy counting equipment to determine the amount of Th-227 and % Th-230 recovery as follows: Recovered Th-230 / added Th-230 = efficiency fraction B

[0036] The method further comprises determining the amount of Ac-227 in Stock A by using the count in a calculation as follows:

number

[0037] *Note: Approximately 20% counting efficiency (combination: geometry / scattering)

[0038] In one embodiment of the present invention, the method for measuring Ac-227 in Ac-225 comprises:

[0039] Prepare a refined Ra-225 stock,

[0040] Obtaining Ra-225 and Ac-225 (or Ac-228) activity in purified Ra-225 stocks (e.g., Ra-225 by sampling and liquid scintillation (LS) / low energy gamma (LEG) or Ac-225 (or Ac-228) by sampling the whole stock by LEG, alpha, or gamma spectroscopy; note that Ra-225 values ​​may not be required for this calculation) and

[0041] An Ac-225 / 228 extraction was performed to make Stock A, and spectroscopy (by alpha spectroscopy) was performed (referred to herein as "Stock A").

[0042] Comparing Ac-225 / 228 before and after extraction to obtain Ac-225 recovery (referred to herein as "Efficiency A", such as 90%);

[0043] Begin saturating Stock A (e.g., 10%-23% saturation for Th-227) and

[0044] Adding Th tracer (Th-230 or Th-232, if freshly purified) to Stock A if none is initially present;

[0045] Separating Th from Ac mixtures using mixing and / or chromatography (e.g., AG1x8@8N HNO3) (note that the alpha of Th-230 is 4.6 MeV, significantly different from Th-227 (48%) at approximately 6 MeV, making them distinguishable and measurable);

[0046] Stripping the Th from the column (Th purification can be repeated if necessary) and evaporating to dryness;

[0047] Th was returned to a solution containing 1 mL of 1N HNO3;

[0048] Add a 0.5 mL aliquot to a SS planchette, allow to evaporate, and add another 0.5 mL while rinsing the beaker;

[0049] Optionally, frame seal the SS planchette;

[0050] Counting SS planchets by alpha spectroscopy for Th-227 and Th-230 (Th-230 recovery is Th recovery "efficiency B"); Including,

[0051] Note the approximately 20% counting efficiency (combined: geometry / scattering).

[0052] PROPHETIC EXAMPLE

[0053] Typically, the limit of detection (LOD) for alpha counts is approximately 50 counts / 180 min, so the LOD in this case is 50 / (0.2 x 0.17 x 0.9 x 0.9 x 180) = 10.1 Bq.

[0054] Therefore, if the Ac-225 stock extracted 7 days after the preparation of Stock A is 2 mCi, then the concentration is 10.1 Bq / (0.2 × 3.7 × 10 7 Bq / mCi)×100%=1.4×10 -5 %, which is the nominal LOD of Ac-227 / Ac-225. This is the worst case for the LOD value of the Ra-225 stock, and this value can be reduced by longer counting time, more Ac-225 activity, and saturation of Th-227.

[0055] As such, it will be readily apparent to those skilled in the art that the present invention is susceptible to a wide range of utilities and applications. Many embodiments and adaptations of the present invention other than those described herein, as well as numerous variations, modifications, and equivalent arrangements, will be apparent from, or reasonably suggested by, the present invention and the foregoing description thereof, without departing from the content or scope of the present invention. Thus, while the present invention has been described in detail herein with reference to preferred embodiments thereof, it should be understood that this disclosure is merely illustrative and exemplary of the invention and is made solely for the purpose of providing a complete and enabling disclosure of the invention. The foregoing disclosure is not intended, and should not be construed, to limit the present invention or otherwise exclude all such other embodiments, adaptations, variations, modifications, and equivalent arrangements.

Claims

1. A method for measuring Ac-227 in Ac-225, comprising the steps of: Measuring Ac-227 in Ac-225 via indirectly generated parent / daughter nuclides of Ra-225 / Ac-225; A method comprising:

2. A method for measuring Ac-227 in Ac-225, comprising the steps of: Providing a purified Ra-225 stock; sampling the purified Ra-225 stock to determine its Ac-225 and / or Ac-228 content; extracting actinium isotopes from said Ra-225 stock to produce Stock A; allowing Stock A to stand to allow the Ac-227 to decay to Th-227; adding a thorium tracer to Stock A; chemically isolating Th-227 and said thorium tracer from other impurities, including actinium; mounting a thorium isotope on an alpha counting disk; counting the alpha discs using an alpha spectrometer to determine the amount of Th-227 and the percent recovery of the tracer; determining the amount of Ac-227 in Stock A by using said count; A method comprising:

3. 3. The method of claim 2, wherein the thorium tracer is selected from the group consisting of Th-228, Th-229, Th-230, Th-231, Th-232, Th-234, and combinations thereof.

4. A method for measuring Ac-227 in Ac-225, comprising the steps of: Providing a purified Ra-225 stock; sampling the purified Ra-225 stock to determine the content of Ac-225 and / or Ac-228; extracting actinium isotopes from said Ra-225 stock to produce Stock A; allowing Stock A to stand to allow the Ac-227 to decay to Th-227; adding Th-230 tracer to Stock A; chemically isolating Th-227 and Th-230 from other impurities, including actinium; mounting a thorium isotope on an alpha counting disk; counting the alpha discs using an alpha spectrometer to determine the amount of Th-227 and the % recovery of Th-230; determining the amount of Ac-227 in Stock A by using said count; A method comprising:

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