Method for determining actinide 227 in actinide 225

Abstract

The invention relates to a method for determining actinide 227 (Ac-227) by means of an indirectly produced Ra-225 / Ac-225 parent / daughter. Assay of Ac-227 or decay daughters thereof may be used as a "pre-release" quality control test for total Ac-227 content. The method includes extracting actinide isotopes from purified Ra-225 to produce a feedstock A. The raw material A is stood to allow the Ac-227 to decay to Th-227. And adding a thorium tracer to the raw material A. And the Th-227 and the thorium tracer agent are separated in a chemical manner. And installing the thorium isotope to an alpha counting disc. The alpha disks are counted using an alpha spectrum counting device to determine the number of Th-227 and tracer recovery%. The amount of Ac-227 is measured by using the count.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 64 / 435,881, filed in the U.S. Patent and Trademark Office on December 29, 2022, and U.S. Patent Application No. 18 / 397,165, filed on December 27, 2023. The disclosures of which are incorporated herein by reference in their entireties. Technical Field

[0003] The present invention relates to a method for determining actinium-227 (Ac-227) in actinium-225 (Ac-225), and more particularly to a method for determining Ac-227 in Ac-225 via an indirectly generated Ra-225 / Ac-225 parent / daughter. Background Art

[0004] Actinium-225 (Ac-225) is an isotope of actinium and emits Actinides are of particular interest from the perspective of therapeutic active pharmaceutical ingredients (APIs). Ac-225 is produced by separation from legacy materials (uranium) or by proton bombardment of thorium (Th). Proton bombardment of Th-232 produces a variety of radionuclides, including Ra-225, Ac-225, and Ac-227.

[0005] There are two known methods for obtaining Ac-225 from this radiation (direct and indirect). In the direct method, all actinium is separated from the remaining radionuclides. This concentrates both Ac-225 and Ac-227 together (chemically inseparable) and produces an Ac-225 product that is significantly contaminated with Ac-227 and is less desirable.

[0006] In the indirect method, the parent isotope of Ac-225, which is radium-225, is isolated and purified. Although this indirect method produces lower amounts of Ac-225, it has a much lower concentration of Ac-227 and is therefore safer for patients.

[0007] Figure 1 is a graphic representation of the known Ra-225 / Ac-225 decay scheme. Figure 2 is a diagram of the known decay scheme of Ac-227.

[0008] However, there are drawbacks to obtaining the level of Ac-227 impurity in Ac-225 using known methods. For example, due to interference from the many decay products of Ac-225, Ac-227 measurements are performed months after the Ra-225 / Ac-225 batch is produced. This post-release quality control (QC) measurement, while accurate, is not desirable, particularly due to patient safety concerns, as Ac-227 is highly toxic. Emitter.

[0009] Furthermore, it would be preferable if the Ac-227 impurity were to be quantified by a technique with ion counting technology, such as inductively coupled plasma mass spectrometry (ICP-MS). However, the mass range 211-229 lacks ICP-MS standards with naturally occurring elements, and therefore makes quantifying Ac-227 in any manner other than semi-quantitative mode challenging.

[0010] Therefore, there is a need for an alternative method for determining actinium-227 (Ac-227) in actinium-225 (Ac-225) that overcomes the disadvantages of the known methods. The method of the present invention overcomes these disadvantages. Summary of the Invention

[0011] The method of the present invention is used to determine actinium-227 (Ac-227) via the indirectly generated Ra-225 / Ac-225 parent / daughter. The determination of Ac-227 or its decay daughters 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 the drug product specifications, with approved results prior to batch release and / or patient use.

[0012] Since thorium can be chemically separated from radium and actinium and other radionuclides, the measurement of Th-227 (one of the daughter products of Ac-227) is possible. Therefore, according to the method of the present invention, the measurement of Ac-227 in Ac-225 solution is based on the decay of Ac-227 to Th-227.

[0013] An advantage of the present invention is that it provides the value of Ac-227 in an Ac-225 batch at the time of release of the Ac-225 batch, thereby giving confidence in the API in terms of patient safety. This is an improvement over post-release testing and can potentially identify problems after patients have used the API.

[0014] If a high Ac-227 burden is found after release and use, the commercial value is considerable, given the consequences of using Ac-225 in patients. This is also valuable for any commercial production of Ac-225 from Ra-225 feedstock (which is "milked" many times to obtain Ac-225).

[0015] 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 the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The present invention will become more fully understood from the detailed description and accompanying drawings, which are not necessarily drawn to scale, in which:

[0017] Figure 1 is a graphic representation of the known Ra-225 / Ac-225 decay scheme.

[0018] Figure 2 is a diagram of the known decay scheme of Ac-227. DETAILED DESCRIPTION

[0019] The following description of embodiments of the present invention is merely exemplary in nature and is in no way intended to limit the present invention, its application, or use. For the purpose of providing a feasible disclosure of the present invention, the following description is provided herein only by way of example, but does not limit the scope or substance of the present invention.

[0020] The method of the present invention is a timely pre-release method for the determination of actinium-227 (Ac-227) impurities in actinium-225 (Ac-225) from indirect Ra-225.

[0021] Ra-225 is initially purified to a high degree from any actinium isotopes (and other interfering radionuclides). The entire Ra-225 feedstock is sampled after purification to provide detection / quantification of lower levels of Ac-227 / Th-227. At the end of the Ra-225 purification, since no additional Ac-227 is produced, the Ra-225 feedstock is sampled immediately after purification (for future Th-227 determination). The desired Ac-225 "grows-in" from the Ra-225 for (nominally) 7 days before Ac-225 is extracted. The Ac-227 process includes several chemical separation steps.

[0022] Thus, the methods of the present invention generally comprise providing a purified Ra-225 feedstock and sampling the purified Ra-225 feedstock to be purified by or The amount of Ac-225 and / or Ac-228 is determined spectroscopically. In the purified Ra-225 raw material, the impurities have been removed, and since the half-life of Ac-227 is 23 years, any remaining Ac-227 impurity is not significantly altered relative to the 14-day half-life of Ra-225.

[0023] The method further includes extracting all actinium isotopes from the Ra-225 feedstock. The first actinium extraction Ac-225 / 227 / 228 is referred to herein as "feedstock A." The value of the extracted actinium-225 or -228 (mCi or μCi) and the value of the actinium-225 or -228 (mCi or μCi) in the original Ra-225 feedstock are used to calculate an efficiency fraction A:

[0024]

[0025] For example:

[0026]

[0027]

[0028] The method further includes allowing feedstock A to stand for at least 5 days to allow Ac-227 to decay into Th-227. Th-227 will accumulate over this period of time, and the saturation factor percentage is calculated using the following equation:

[0029]

[0030]

[0031]

[0032] .

[0033] The rest time can be varied to produce different saturation values.

[0034] The method further includes adding a Th-230 tracer to feedstock A. This allows for subsequent calculation of thorium recovery by adding a known amount of the tracer. Possible thorium tracers include, but are not limited to, Th-228, Th-229, Th-230, Th-231, Th-232, Th-234, and combinations thereof.

[0035] The method further includes chemically separating (ie, chromatography) the thorium (227 and 230) from all other impurities including actinium.

[0036] The method further comprises using Spectral preparation method to install thorium isotopes into On the counting plate.

[0037] The method further comprises using Spectral counting equipment The plates were counted to determine the Th-227 quantity and Th-230 recovery % as follows:

[0038]

[0039] The method further includes determining the amount of Ac-227 in the feedstock A by using the counts in a calculation as shown below:

[0040]

[0041]

[0042] In aspects of the present invention, the method for determining Ac-227 in Ac-225 comprises:

[0043] Provide purified Ra-225 raw materials,

[0044] Obtaining Ra-225 and Ac-225 (or Ac-228) activity in purified Ra-225 stock (e.g., by sampling and Liquid Scintillation (LS) / low energy (LEG) Ra-225 or LEG whole stock, by sampling or spectrum of Ac-225 (or Ac-228, note: this calculation may not require the Ra-225 value).

[0045] Ac-225 / 228 extraction was performed to prepare raw material A and spectroscopic analysis (by spectroscopy) (referred to herein as "raw material A"),

[0046] Compare the Ac-225 / 228 before and after extraction to obtain the Ac-225 recovery percentage (referred to herein as "efficiency A," e.g., 90%),

[0047] Allow feedstock A to begin to saturate (e.g., 10%-23% saturation for Th-227),

[0048] If there is no Th tracer initially (Th-230 or Th-232 if freshly purified), add it to the feedstock A,

[0049] Mix and / or separate Th from Ac mixture using chromatography (e.g., AG1x8 @ 8N HNO3), (note Th-230 is at 4.6 MeV, which is significantly different from Th-227 at about 6 MeV (48%), making them distinguishable and measurable).

[0050] Th is stripped from the column (Th purification can be repeated if necessary) and evaporated to dryness,

[0051] Th was returned to solution with 1 mL of 1N HNO3.

[0052] A 0.5 mL aliquot was added to the SS planchet, evaporated and an additional 0.5 mL was added to rinse the beaker.

[0053] Optionally, flame seal the SS template,

[0054] pass Spectroscopic counting of SS templates (for Th-227 and Th-230) (The recovery of Th-230 is the Th recovery efficiency "B")

[0055] Note the counting efficiency (combined geometry / scatter) of approximately 20%.

[0056] Prophetic Embodiments

[0057] Typically, The limit of detection (LOD) of counts is about 50 counts / 180 minutes. Therefore, the LOD in this case is ,

[0058] Therefore, if the extracted Ac-225 raw material is 2 mCi 7 days after the production of raw material A, then Nominal LOD Ac-227 / Ac-225. This is the worst-case LOD value for Ra-225 feedstock, which can be reduced by longer counting times, higher Ac-225 activity, and Th-227 saturation.

[0059] Therefore, it will be readily understood by those skilled in the art that the present invention is easy to be widely used and applied. Without departing from the main content or scope of the present invention, many embodiments of the present invention and changes and many variations, modifications and equivalent arrangements except those described herein will be clear from the present invention and its foregoing description or reasonably suggested by the present invention and its foregoing description. Therefore, although the present invention has been described in detail in conjunction with its preferred embodiments, it should be understood that this disclosure is merely illustrative and exemplary of the present invention, and is only for the complete and feasible disclosure of the present invention. The foregoing disclosure is not intended to or should not be construed as limiting the present invention or otherwise excluding any such other embodiments, changes, variations, modifications and equivalent arrangements.

Claims

1. A method for determining Ac-227 in Ac-225, the method comprising: Ac-227 in Ac-225 is measured by the indirectly generated Ra-225 / Ac-225 parent / daughter.

2. A method for determining Ac-227 in Ac-225, the method comprising: Provide purified Ra-225 raw materials, Sampling the purified Ra-225 raw material to determine the Ac-225 and / or Ac-228 content; Extracting actinium isotopes from Ra-225 raw material to produce raw material A; Allowing feedstock A to decay into Th-227 by allowing Ac-227 to decay; Adding a thorium tracer to raw material A; Chemically separating Th-227 and thorium tracers from other impurities, including actinium; Install the thorium isotope into On the counting plate; use Spectral counting equipment for the The plates were counted to determine the amount of Th-227 and the tracer recovery rate; and The amount of Ac-227 in the raw material A was determined by using the counting.

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 determining Ac-227 in Ac-225, the method comprising: Provide purified Ra-225 raw materials, Sampling the purified Ra-225 raw material to determine the Ac-225 and / or Ac-228 content; Extracting actinium isotopes from Ra-225 raw material to produce raw material A; Allowing feedstock A to decay into Th-227 by allowing Ac-227 to decay; Add Th-230 tracer to raw material A; Chemically separating Th-227 and Th-230 from other impurities including actinium; Install the thorium isotope into On the counting plate; use Spectral counting equipment for the Disc counts to determine Th-227 quantity and Th-230 recovery; and The amount of Ac-227 in the raw material A was determined by using the counting.

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