DESC:Priority Claim:

[0001] This application claims priority from the provisional application numbered 202441009040 filed with Indian Patent Office, Chennai on 10th February 2024 entitled “A process for optimization of larger scale recycling of 18O-Water”, the entirety of which is expressly incorporated herein by reference.
Preamble to the description
[0002] The following specification describes the invention and the manner in which it is to be performed:
Description of the invention
Technical field of the invention
[0003] The present invention relates to a process for optimization of large-scale recycling of 18O-Water. More particularly, the present invention relates to a process for large scale recycling of 18O-Water using a vacuum-assisted fractional distillation procedures followed by using various chemical treatments to remove radiometallic impurities, inorganic ionic impurities and organic impurities for production of Fluorine-18 based radiotracers.
Background of the invention
[0004] Fluorine-18 a fluorine radioisotope, which is an important source of positrons. Fluorine-18 is one of the several isotopes of fluorine that is routinely used in radiolabeling of biomolecules for Positron Emission Tomography (PET) due to its positron emitting property and favorable half-life of 109.8 minutes.
[0005] PET is a nuclear medicine imaging technique that is widely used in early detection and treatment follow up of many diseases, including cancer. PET requires positron-emitting isotope labeled biomolecules, which are synthesized prior to performing imaging studies. PET detects pairs of gamma rays emitted indirectly through an annihilation reaction by a positron-emitting radionuclide, such as 18F, which has been injected into the body through a biologically active molecule as a carrier.
[0006] Fluorine-18 is usually produced by proton bombardment of enriched 18O-water through 18O(p,n)18F nuclear reaction. 18O-Water is one of the most expensive starting materials owing to its very low natural abundance of 0.2% and consequently, extremely difficult enrichment process.
[0007] Due to the high consumption of 18O-Water in PET centers, the necessity to purify the enriched water from impurities in order to be reused in 18FDG production has been a high priority task. It is well known that good manufacturing practices (GMP) guidelines impose the use of well-established and validated method to purify and recycle the enriched water.
[0008] However, there is a scarcity and the requirement of 18O-Water as only a limited number of manufacturers, and any reduction in productivity with any of the manufacturers leads to a shortage of this material thus increasing the demand.
[0009] In order to overcome this, a process is required to recycle 18O-Water. It is noted that the 18O-Water recovered at the end of production reduces in enrichment by more than 5-10% and hence are usable. However, 18O-Water recovered is not usable as it is and requires removal of several organic, inorganic and radiometal impurities, which otherwise may create several complications during reusage. However, direct usage is not a possibility since several organic and inorganic contaminants make their way into the recovered 18O Water during the complete radiolabeling procedure leading to issues that primarily include high pressure in the target and poor radiochemical yield.
[0010] The high target pressure is primarily caused by the presence of the organic contaminants such as ethanol, acetonitrile etc. and inorganic contaminants alongside organic contaminants cause reduced radiochemical yield and sometimes, reduced specific activity.
[0011] Further, the recovered 18O Water is also contaminated by radiometals that originate from the target body as well as the target windows during irradiation of 18O Water. The radiometals have the potential to get trapped in the columns used for separation of [18F]Fluoride from 18O Water and as a result, have the capability in interfering in the radiosynthesis process. I
[0012] In order to make the recovered 18O Water reusable, these contaminants need to be removed by a carefully crafted recycling procedure The reactions between [18F]-?uoride and different substrates permit the synthesis of many PET radiopharmaceuticals and, in particular, of [18 F]-FDG (2-deoxy-2-[18F]-?uoro-D-glucose), a most important radiotracer for oncological applications. The high cost of virgin enriched water has stimulated research into new methods to reuse it.
[0013] However, due to the presence of many organic and inorganic impurities in solution after the first irradiation, which appear to influence the production yield, a purification process is necessary.
[0014] The most common purification method consists of simple distillation with the possible addition of strong oxidizing agents such as potassium permanganate. However, these reagents have to be removed from the water during the treatment. Currently, this method has been replaced by distillation followed by photochemical degradation using UV radiation, electrolysis or ozonolysis.
[0015] The Patent Application No. PCT/RU2016/000925 entitled “A method for obtaining oxygen-18 enriched water and an installation for obtaining said water” discloses the production of oxygen-18 for positron-emission tomography. Oxygen-18 enriched water is obtained using a water fractionation method, under vacuum conditions, in packed columns. The production installation consists of columns of the pre-concentration unit, which operate in an open (non-depleting) arrangement, drawing off the 1st sort, and final concentration columns which increase the oxygen-18 concentration and deplete the oxygen-16. The installation is fed with water, in which the naturally occurring level of oxygen-18 is maintained by chemical isotopic exchange with carbon dioxide gas, which eliminates the possibility of deuterium build-up in the product or semi-finished products. The installation, according to the invention, makes it possible to obtain oxygen-18 enriched water, with a 95% degree of enrichment and a normalized isotopic deuterium composition, with a high level of efficiency and a low level of process losses.
[0016] The Patent Application No. RU2632697C1 entitled “Method of producing water enriched in oxygen-18 and device for its production” discloses a method of producing water enriched in oxygen-18 from natural water by rectifying water in a vacuum includes water pre-enrichment in oxygen-18 in parallel columns operating in an open circuit with the selection of the first kind of intermediate oxygen concentrate-18 and the final enrichment of the intermediate concentrate in the cascade of columns, consisting of columns concentrating in oxygen-18 and exhausting in oxygen-16. At the same time, water circulating in the pre-enrichment columns is used to power the device, the natural oxygen content of 18 is maintained by chemical isotope exchange with carbon dioxide, which in turn maintains the natural content of oxygen-18 by chemical isotope exchange with natural water. The device for producing water enriched in oxygen-18 from natural water includes a preconcentration unit, which is designed in the form of parallel operation in an open circuit without exhaustion with the selection of the first kind of preconcentration rectification columns, a final concentration unit made in the form of oxygen concentrating-18 columns and oxygen-depleted-16 columns, and a preconcentration unit located on the supply line and consisting of columns of chemical isotope exchange in the system water - carbon dioxide.
[0017] The Publication entitled “Optimized Treatment and Recovery of Irradiated [18O]-Water in the Production of [18F]-Fluoride” an efficient treatment and reprocessing procedure giving rise to high chemical quality [18O]-water, thereby maintaining its enrichment grade. The reprocessing is subdivided into two main steps. In the first step, the [18F]-FDG (fluorodeoxyglucose) synthesis preparation was modified to preserve the enrichment grade. Anhydrous acetonitrile is used to dry tubing systems and cartridges in the synthesis module. Applying this procedure, the loss in the enrichment throughout the reprocessing is <1%. The second step involves a fractional distillation in which a major part of the [18O]-water was recycled. Impurities such as solvents, ions, and radioactive nuclides were almost completely separated. Due to the modified synthesis preparation using acetonitrile, the first distillation fraction contains a larger amount of an azeotropic [18O]-water/acetonitrile mixture. This fraction is not further distillable. Contents of the remaining [18O]-water were separated from the azeotropic mixture by using a molecular sieve desiccant. This process represents a fast, easy, and inexpensive method for reprocessing used [18O]-water into new [18O]-water quality for further application.
[0018] The Publication entitled “Convenient recycling and reuse of bombarded [18O]H2O for the production and the application of [18F]F” discloses simple, effective, easy-handling and reliable method of [18O]H2O purification including oxidation and distillation. The obtained recycled [18O]H2O had comparable quality to commercially distributed [18O]water, which was confirmed by a detailed comparison of produced radionuclides and their activities and the application of [18F]F- for the automated synthesis of [18F]fluspidine.
[0019] Tough, there are multiple methods available for purification, the existing methods does not result in complete removal of the impurities. In addition, only very small quantities of 18O-Water is recovered and the procedures are time-consuming thus limiting the usefulness and increasing the cost of recycling and production.
[0020] Hence, there is a need for a process for recycling which removes the impurities completely and also increases the yield of 18O-Water.
Summary of the invention
[0021] The present invention overcomes the drawbacks of the existing technologies by proving a specific process for large scale recycling of 18O-Water using a vacuum-assisted fractional distillation procedure.
[0022] The process of large-scale recycling of 18O-Water using vacuum-assisted fractional distillation comprises the separation of the radioactive impurities in the retort and the non-radioactive 18O-Water, which is recovered as the distillate. The first fraction after distillation the being left over is considered for subsequent usage and the later fraction is used for the next step in the reprocessing. The second fraction of the distillate thus recovered is free from the radiometallic impurities and comprises low quantities of organic impurities. The fraction of the distillate obtained is mixed with activated charcoal solution, which is prepared by dissolving 20 g of activated charcoal in 500 ml 18O-Water. The solution is continuously stirred overnight. The retort mixture undergoes filtration and isolates 18O-Water with very low quantities of organic impurities and is usually less than 50 ppm. Further, the process of the present invention utilizes the powdered activated charcoal than the granulated activated charcoal, which is used in water purification plants as well as domestic water purifiers for the removal of organic contaminants. The powdered activated charcoal is efficient compared to granulated activated charcoal because of very high surface area.
[0023] 18O-Water thus obtained exhibits high conductivity in spite of additional distillation step is introduced. It is challenging to remove carbonates because of their equilibrium with carbon dioxide dissolved in water. Further, 18O-Water obtained is treated with an acid at a concentration of 85% until pH is reduced below 2 and the mixture is refluxed for approximately two hours. The resultant mixture is subjected to fractional vacuum distillation, in which the first distillate is retained for further usage whereas the second distillate is collected as the final purified reusable 18O-Water.
[0024] The process of the present invention utilizes two distillation apparatus. Each apparatus comprises a fractioning column, a vacuum pump and a heater with a magnetic stirrer in addition to the standard setup found in standard chemical laboratories. 18O-Water obtained by said process is free from radiometallic impurities, exhibits a conductivity level of below 1.5 µs/cm and also the quantity of organic impurities is reduced to acceptable levels. The process results in a recovery rate of 65% for the first cycle and the subsequent steps results in recovery rate in a range between 85% and 90%. The process is unique and the usage of acid for the removal of carbonates reduce the conductivity of the final recycled 18O-Water. This step avoids the formation of any metal oxides and metal hydroxides during the bombardment of 18O-Water in the cyclotron.
[0025] The process of the present invention is simple and effective in removing the radiometallic impurities, inorganic ionic impurities and organic impurities. The process of the present invention is effective in removal of the said impurities and also the process results in large recycling of 18O-Water.
Brief description of the drawings
[0026] The foregoing and other features of embodiments will become more apparent from the following detailed description of embodiments when read in conjunction with the accompanying drawings. In the drawings, like reference numerals refer to like elements.
[0027] FIG 1 illustrates a process for optimization of large-scale recycling of 18O-Water according to an embodiment of the invention.
Detailed Description of the Invention
[0028] In order to more clearly and concisely describe and point out the subject matter of the claimed invention, the following definitions are provided for specific terms, which are used in the following written description.
[0029] The term “18O-Water” refers to a form of water consisting of two hydrogen atoms covalently bonded to an oxygen-18 atom.
[0030] The present invention discloses a process for optimization of large-scale recycling of 18O-Water using vacuum-assisted fractional distillation procedures.
[0031] FIG 1 illustrates a process for optimization of large-scale recycling of 18O-Water according to an embodiment of the invention. The process (100) of optimization starts with a step (101) of separation of the radioactive impurities in 18O-Water using vacuum-assisted fractional distillation. After separation, the radioactive impurities are left over in the retort and the non-radioactive 18O-Water is recovered as the distillate. The first fraction after distillation the being left over is considered for further usage and the later fraction is used for the next step in the reprocessing. The second fraction of the distillate thus recovered is devoid of any radiometallic impurities and contains low quantities of organic impurities.
[0032] At step (102), fraction of the distillate obtained in step (101) is mixed with activated charcoal solution, which is prepared by dissolving 20g of activated charcoal in 500ml 18O-Water. The solution is continuously stirred overnight. During this step, the retort mixture undergoes filtration and isolates 18O-Water with very low quantities of organic impurities and is usually less than 50 ppm. The process of the present invention utilizes the powdered activated charcoal than the granulated activated charcoal, which is used in water purification plants as well as domestic water purifiers for the removal of organic contaminants. The powdered activated charcoal used in this step is efficient compared to granulated activated charcoal because of very high surface area.
[0033] The 18O-Water thus obtained exhibits high conductivity in spite of additional distillation step is introduced. This is caused by the excess levels of carbonates available in the isolated 18O-Water and the carbonates has entered recovered 18O-Water from the anion exchange column used to trap [18F]F-. It is challenging to remove carbonates because of their equilibrium with carbon dioxide dissolved in water.
[0034] At step (103), 18O-Water obtained from the step (102) is treated with an acid preferably phosphoric acid at a concentration of 85% until pH is reduced below 2 before second distillation. At step (104), the mixture is refluxed for a duration of two hours. At step (105), the resultant mixture is subjected to fractional vacuum distillation. The first distillate obtained after step (105) is retained for further usage whereas the second distillate is collected as the final purified reusable 18O-Water.
[0035] 18O-Water thus obtained by said process is devoid any radiometallic impurities, exhibits a conductivity level of below 1.5 µs/cm and also the quantity of organic impurities are reduced to acceptable levels.
[0036] The recovery rate is 65% for the above cycle. However, the first distillate set aside in each step shall be repeated for the said process and thus the final recovery attained is in a range between 85% and 90%. The loss of enrichment is about 2%, very likely because of the higher water content in activated charcoal.
[0037] The process of the present invention utilizes two distillation apparatus. Each apparatus comprises a fractioning column, a vacuum pump and a heater with a magnetic stirrer in addition to the standard setup found in standard chemical laboratories.
[0038] The process is unique and the usage of acid for the removal of carbonates reduce the conductivity of the final recycled 18O-Water. This step avoids the formation of any metal oxides and metal hydroxides during the bombardment of 18O-Water in the cyclotron.
[0039] The process of the present invention is simple and effective in removing the radiometallic impurities, inorganic ionic impurities and organic impurities. The presence of radiometallic impurities lead to radiation burden in the non-radioactive areas and also have the potential to impact the radiochemical yield during the radiochemical synthesis of F-18-based radiotracers.
[0040] The presence of organic impurities are associated with increased target pressure during the bombardment of 18O-Water in the cyclotron and leads to several additional impurities that finally lead to reduced radiochemical yield during the synthesis of F-18-based radiotracers.
[0041] The presence of any inorganic ionic impurity impacts the final radiochemical yield of F-18-based radiotracers as they compete as nucleophiles with 18F-Fluoride during radiochemical synthesis.
[0042] Finally, the presence of carbonates combine with metallic impurities from the targets during bombardment and form metallic oxides and hydroxides, which has a negative impact during radiochemical synthesis.
[0043] The process of the present invention is effective in removal of the said impurities and also the process results in large recycling of 18O-Water. The process is useful for any production site by avoiding the usage of expensive analytical instruments for quality assessment.
,CLAIMS:We Claim,

1. A process for optimization of large-scale recycling of 18O-Water, the process comprises the steps of:
a. separating one or more radioactive impurities in 18O-Water using a vacuum-assisted fractional distillation to recover non-radioactive 18O-Water as a distillate;
b. mixing the distillate with activated charcoal solution to isolate 18O-Water with a low quantity of one or more organic impurities;
c. treating the isolated 18O-Water with phosphoric acid at a concentration of 85% until pH is reduced below 2;
d. subjecting the treated mixture for refluxing for a duration of two hours;
e. subjecting the refluxed mixture to fractional vacuum distillation to separate as first distillate and second distillate; and
f. retaining the first distillate for subsequent cycle and collecting the second distillate as final purified reusable 18O-Water
wherein the process results in removal of the radiometallic impurities, inorganic ionic impurities and organic impurities from 18O-Water.

2. The process as claimed in Claim 1, wherein vacuum-assisted fractional distillation results in separation of the radioactive impurities in the retort and the non-radioactive 18O-Water is recovered as the distillate.

3. The process as claimed in Claim 1, wherein vacuum-assisted fractional distillation is achieved through an apparatus comprises fractioning column, a vacuum pump and a heater with a magnetic stirrer.

4. The process as claimed in Claim 1, wherein activated charcoal solution is prepared using 20 g of activated charcoal in 500 ml 18O-Water with continuous stirring.

5. The process as claimed in Claim 1, wherein activated charcoal used is in powdered form and is efficient compared to granulated activated charcoal because of very high surface area.

6. The process as claimed in Claim 1, wherein treatment with activated charcoal results in isolation of 18O-Water with low quantities of the organic impurities and is usually less than 50 ppm.

7. The process as claimed in Claim 1, wherein 18O-Water obtained by said process exhibits a conductivity level below 1.5 µs/cm.

8. The process as claimed in Claim 1, wherein the recovery rate of 18O-Water achieved is 65% with the first cycle and is enhanced to a range between 85% and 90% with plurality of cycles using the first distillate.

9. The process as claimed in Claim 1, wherein treatment of 18O-Water with phosphoric acid before second distillation for the removal of carbonates reduce the conductivity of the final recycled 18O-Water thus avoiding the formation of one or more metal oxides and metal hydroxides during the bombardment of 18O-Water in the cyclotron.