*3.1. Dissolution Reactor Assembly*

The two dissolution reactors have been assembled, respectively, on the E&Z Modular-Lab and the Trasis' AllinOne modules in a hot cell. All the parts were installed without particular difficulties on the commercial modules, and the slots available on the mounting rods allowed to align the vial with the target holder's baseplate with the required precision. Connection of the reactor with the cassette is made easy thanks to the compatibility of the vial with the PEEK head.

Figure 5 shows the developed systems implemented on the tested commercial modules, hosted inside the hot cell. In the dissolution process, after target placement, the reactor vial can be positioned on top of the coin target by controlling the movement of the syringe actuator. The pressure applied by the stepper motor adequately seals, by means of the O-ring, the vial during the chemical attack. Once the dissolution is completed, the solution can be pumped through the outlet channel connected to the top of the vial to the subsequent radiochemistry steps. All the operations can be remotely controlled with the respective modules' software, and the system allows for the incorporation of the purification and radiolabelling steps within a single cassette manifold. Furthermore, the proposed reactor offers an intrinsic flexibility in processing targets having different thicknesses of the deposited target pellet.

**Figure 5.** Pictures of the solid target dissolution system mounted on: (**a**) an E&Z module; (**b**) a TRASIS AllinOne module. **Figure 5.** Pictures of the solid target dissolution system mounted on: (**a**) an E&Z module; (**b**) a TRASIS AllinOne module.

#### *3.2. Operational Testing 3.2. Operational Testing*

the deposited target pellet.

All the devices successfully passed the preliminary leakage tests without losses, thus proving to have enough rigidity to prevent possible release of radioactive liquid. All the devices successfully passed the preliminary leakage tests without losses, thus proving to have enough rigidity to prevent possible release of radioactive liquid.

respective modules' software, and the system allows for the incorporation of the purification and radiolabelling steps within a single cassette manifold. Furthermore, the proposed reactor offers an intrinsic flexibility in processing targets having different thicknesses of

Following the automated transportation of the irradiated target from the cyclotron target station to the hot cell docking station, the target is transferred to the dissolution unit of the automatic system with tongs or telemanipulators. The target can be easily accommodated on the reactor heater baseplate with the target material pointing upwards in alignment with the bottom of the vial. The sealing of the vial on the target by the O-ring, during the chemical attack, allows for the selective dissolution of the target material minimizing the contact of the solution with the backing and avoiding liquid leakage. Liquid leakage never occurred during our dissolution tests. The dissolution of the irradiated target can be activated or hastened by heating the conductive baseplate. The use of a transparent glass vial allowed for the monitoring of the process, as was useful in the case of non-well-established procedures, like with the dissolution of Cr and Mo, whereas with Y target it was possible to use PEEK vial since the procedure was well-known. Following the automated transportation of the irradiated target from the cyclotron target station to the hot cell docking station, the target is transferred to the dissolution unit of the automatic system with tongs or telemanipulators. The target can be easily accommodated on the reactor heater baseplate with the target material pointing upwards in alignment with the bottom of the vial. The sealing of the vial on the target by the O-ring, during the chemical attack, allows for the selective dissolution of the target material minimizing the contact of the solution with the backing and avoiding liquid leakage. Liquid leakage never occurred during our dissolution tests. The dissolution of the irradiated target can be activated or hastened by heating the conductive baseplate. The use of a transparent glass vial allowed for the monitoring of the process, as was useful in the case of non-wellestablished procedures, like with the dissolution of Cr and Mo, whereas with Y target it was possible to use PEEK vial since the procedure was well-known.

Average weights of the target/backing ensembles and of the backing after target material dissolution are listed in Table 3. The amount of dissolved weight corresponds to the amount of the original target material. Therefore, in all three cases, all the target material was efficiently dissolved and removed from the backing in a reproducible manner. Average weights of the target/backing ensembles and of the backing after target material dissolution are listed in Table 3. The amount of dissolved weight corresponds to the amount of the original target material. Therefore, in all three cases, all the target material was efficiently dissolved and removed from the backing in a reproducible manner.

**Table 3.** Mean weight with standard deviation before and after dissolution of the tested targets. Accuracy interval of ±10<sup>−</sup><sup>4</sup> **Table 3.** Mean weight with standard deviation before and after dissolution of the tested targets. Accuracy interval of <sup>±</sup>10−<sup>4</sup> g.


Table 4 reports the measured activity at the end of dissolution (EOD) and rescaled to end of bombardment (EOB). These measurements can be compared with the theoretical predicted activity calculated at EOB by using the on-line tool ISOTOPIA [38]. The reported values are in agreement with the predicted activity and the gamma-spectrometry analysis. Furthermore, as additional confirmation of complete target dissolution, an additional chemical attack was performed with fresh solvents after dissolved target removal from the reactor in order to detect any residual activity remaining undissolved on the backing. From the following activity measurement, no relevant activity was found in any of the three solutions. values are in agreement with the predicted activity and the gamma-spectrometry analysis. Furthermore, as additional confirmation of complete target dissolution, an additional chemical attack was performed with fresh solvents after dissolved target removal from the reactor in order to detect any residual activity remaining undissolved on the backing. From the following activity measurement, no relevant activity was found in any of the

Table 4 reports the measured activity at the end of dissolution (EOD) and rescaled to end of bombardment (EOB). These measurements can be compared with the theoretical predicted activity calculated at EOB by using the on-line tool ISOTOPIA [38]. The reported

*Molecules* **2021**, *26*, x FOR PEER REVIEW 8 of 11

three solutions.

**Table 4.** Activity measured with dose calibrator at EOD and rescaled to EOB compared to the predicted activity at EOB calculated by using ISOTOPIA tool. **Table 4.** Activity measured with dose calibrator at EOD and rescaled to EOB compared to the pre-


As an example, Figure 6 shows a picture of Au/Cu backing after dissolution of not irradiated natCr target analysed by SEM-EDS. The grooves on the right side of the SEM image correspond to the part where Cr pellet was attached. It is clearly visible that the Cr pellet was completely dissolved. Indeed, the EDS analysis detected traces of Cr (about 30% at.) that could be due to the bonding of Cr pellet to the Au layer. Considering that the SEM-EDS electron beam penetration depth is about 2 µm, the 30% at. of Cr corresponds to about 0.24 mg, approximately 0.1% of the Cr pellet mass, over the 1 cm diameter Cr spot, supporting the data shown in Table 3. As an example, Figure 6 shows a picture of Au/Cu backing after dissolution of not irradiated natCr target analysed by SEM-EDS. The grooves on the right side of the SEM image correspond to the part where Cr pellet was attached. It is clearly visible that the Cr pellet was completely dissolved. Indeed, the EDS analysis detected traces of Cr (about 30% at.) that could be due to the bonding of Cr pellet to the Au layer. Considering that the SEM-EDS electron beam penetration depth is about 2 µm, the 30%at. of Cr corresponds to about 0.24 mg, approximately 0.1% of the Cr pellet mass, over the 1 cm diameter Cr spot, supporting the data shown in Table 3.

**Figure 6.** Left: image of the Au/Cu backing after the dissolution of Cr pellet; Right: SEM image of the Au layer surface at the boundary of the area where Cr was bonded. **Figure 6.** Left: image of the Au/Cu backing after the dissolution of Cr pellet; Right: SEM image of the Au layer surface at the boundary of the area where Cr was bonded.

Below we report a spectrum of the natCr dissolved target (Figure 7). In the spectrum only energy peaks corresponding to manganese and chromium isotopes are identifiable. In all the three performed dissolution studies, no radioactive contaminants coming from the backing material were detected. Minimum detectable activity (MDA) of the most prominent gamma lines for the contaminants 197m/gHg and 93mMo (potentially coming from the activation of Au and Nb backing materials, respectively) calculated from the spectra of the dissolved target solution for 52Mn, 99mTc, and 89Zr are reported in Table 5. Below we report a spectrum of the natCr dissolved target (Figure 7). In the spectrum only energy peaks corresponding to manganese and chromium isotopes are identifiable. In all the three performed dissolution studies, no radioactive contaminants coming from the backing material were detected. Minimum detectable activity (MDA) of the most prominent gamma lines for the contaminants 197m/gHg and 93mMo (potentially coming from the activation of Au and Nb backing materials, respectively) calculated from the spectra of the dissolved target solution for <sup>52</sup>Mn, 99mTc, and <sup>89</sup>Zr are reported in Table 5.

**Figure 7.** γ-spectrum of the dissolved natCr target. **Figure 7.** γ-spectrum of the dissolved natCr target.

**Table 5.** MDA of the most prominent gamma lines for the contaminants 197m/gHg and 93mMo. **Table 5.** MDA of the most prominent gamma lines for the contaminants 197m/gHg and 93mMo.


#### **4. Discussion**  In this work the realization of a flexible solid target dissolution system to be easily **4. Discussion**

tions safe and clean.

installed on commercial cassette-based synthesis modules is described. The developed system allows for the dissolution of targets characterized by various diameters/thicknesses of the target material attached to the backing, regardless of their manufacturing protocol. The target material can be selectively dissolved and radiochemically processed in order to achieve an injectable radiopharmaceutical product of high purity. Both Cr and Mo targets were processed with the E&Z module by using transparent borosilicate glass vials enabling the visualization inside the vessel during the chemical attack to monitor the reaction. At the same time, dissolution of Y irradiated target was performed with a Trasis module using a PEEK vial since the dissolution procedure was standard and already established. Both vials correctly fitted with the cap and reactor ensuring a proper system operation. This demonstrates the possibility of manufacturing this particular design of open-bottomed vial with different materials (from PEEK to quartz). Moreover, the system properly works also changing the components' material, both vial or reactor block, which can be selected according to the needs of thermal conductivity, resistance, and chemical inertness to the solvents involved in the process. The dissolution system configuration has been tested on both commercial modules In this work the realization of a flexible solid target dissolution system to be easily installed on commercial cassette-based synthesis modules is described. The developed system allows for the dissolution of targets characterized by various diameters/thicknesses of the target material attached to the backing, regardless of their manufacturing protocol. The target material can be selectively dissolved and radiochemically processed in order to achieve an injectable radiopharmaceutical product of high purity. Both Cr and Mo targets were processed with the E&Z module by using transparent borosilicate glass vials enabling the visualization inside the vessel during the chemical attack to monitor the reaction. At the same time, dissolution of Y irradiated target was performed with a Trasis module using a PEEK vial since the dissolution procedure was standard and already established. Both vials correctly fitted with the cap and reactor ensuring a proper system operation. This demonstrates the possibility of manufacturing this particular design of open-bottomed vial with different materials (from PEEK to quartz). Moreover, the system properly works also changing the components' material, both vial or reactor block, which can be selected according to the needs of thermal conductivity, resistance, and chemical inertness to the solvents involved in the process.

considered in this study and was successfully used to perform the dissolution of chromium, molybdenum and yttrium targets used for the 52Mn, 99mTc, and 89Zr production, respectively. The system is versatile, since it can be used with targets made with different manufacturing techniques and may be adapted with different cassette-based commercial automatic modules (e.g., Eckert & Ziegler Modular-Lab and the Trasis' AllinOne). Thanks to this system, the dissolution of the target can be remotely controlled, directly connected, and totally integrated with the separation and purification processes, keeping the opera-The dissolution system configuration has been tested on both commercial modules considered in this study and was successfully used to perform the dissolution of chromium, molybdenum and yttrium targets used for the <sup>52</sup>Mn, 99mTc, and <sup>89</sup>Zr production, respectively. The system is versatile, since it can be used with targets made with different manufacturing techniques and may be adapted with different cassette-based commercial automatic modules (e.g., Eckert & Ziegler Modular-Lab and the Trasis' AllinOne). Thanks to this system, the dissolution of the target can be remotely controlled, directly

connected, and totally integrated with the separation and purification processes, keeping the operations safe and clean.

The use of a unique automated system for dissolution, separation, purification, and labelling will sharply decrease the radiation exposure of operators in handling high radioactive materials and, secondly, will definitely contribute to making the whole process much more reproducible, faster, and traceable, minimizing environmental contamination. That is indeed a key prerequisite for attaining a clinical-grade quality for the recovered radioisotope and radiopharmaceutical.

It is thus possible, for those who already own synthesis modules like E&Z modular-lab or Trasis AllinOne, to simply implement their modules with the component described in this paper to get an integrated solid target dissolution system. These components may also be compatible with commercial modules of other brands, making only small design/structural refinements (e.g., GE, IBA radiopharma solutions, ORA-NEPTIS, SCIN-TOMICS, IPHASE).

**Author Contributions:** Conceptualization, G.S., P.M., J.E., G.G. and E.C.; methodology, G.S., P.M., S.C., J.E. and E.C.; validation, G.S., P.M., J.A. and E.C.; formal analysis, P.M., L.M. and E.C.; investigation, G.S., P.M., S.C., J.A. and E.C.; resources, G.G. and J.E.; writing—original draft preparation, G.S. and P.M.; writing—review and editing, G.S., P.M., S.C., L.M., J.E. and E.C.; visualization, G.S., P.M., S.C., L.M. and E.C.; supervision, P.M., J.E., G.G. and E.C.; project administration, J.E., G.G. and E.C.; funding acquisition, J.E. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Istituto Nazionale di Fisica Nucleare, Italy, in the framework of the "METRICS" CSN5 project.

**Data Availability Statement:** Technical drawings of the reactor components are available from the corresponding author.

**Acknowledgments:** This work was performed in the framework of the ongoing METRICS project (Multimodal pET/mRI imaging with Cyclotron-produced 51/52Mn iSotopes) in collaboration with the Sacro Cuore Don Calabria Hospital Radiopharmacy, within the LARAMED (LAboratory of RAdioisotopes for MEDicine) research program running at LNL-INFN. We thank the LNL mechanical workshop for the manufacturing of the reactor's components.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

**Sample Availability:** Samples are not available from the authors.
