Introduction

In cancer discovery research, radiolabeled monoclonal antibodies directed against tumor-associated antigens have been developed as promising vectors to visualize or to treat tumors, mostly owing to their high affinity and specificity [1], [2]. Since antibodies have a long biological half-life, it takes a long time (in the order of days) to clear the antibodies from plasma. The half-life of radionuclides that are used to radiolabel antibodies should be sufficiently long (>12h) to allow clearance of the radiolabeled antibody from plasma prior to acquire high signal-to-noise ratio tumor PET images. The use of long lived radionuclides (e.g. 64Cu,124I, 89Zr) will however result in prolonged exposure to radiation and a high absorbed radiation dose. Fluorine-18 (F-18) is the most frequently used radionuclide for positron-emission tomography (PET) [3]–[5] radioisotopes due to its favorable physical properties (e.g. half-life of 109.8 min) [6].
Application of shortlived F-18 for in vivo visualization of antibodies can be achieved by pretargeting approaches based on high yield in vivo click reaction using e.g. 18F-labeledtrans -cyclooctene (TCO) or tetrazine derivatives [7]. This reaction strategy has been used for both in vitro and in vivo applications [5], [8], [9].
Trans -cyclooctene has a high reactivity due to the release of high strain energy upon the click reaction providing a well-defined chiral structure which makes it interesting for stereocontrolled synthesis. Therefore, radiolabeled TCOs are good candidates for bio-orthogonal chemistry [10].
There are many routes to synthesize a trans- cyclooctene. A common and elegant way is the photoisomerization of cis totrans -cyclooctene [11]. Yet, the photoisomeri­zation is not irreversible and thus removal of the trans -isomer from the equilibrium cis and trans mixture is required to shift the equilibrium. Fox et al. have proposed an elegant procedure for the photochemical synthesis of TCO [12]. In this method, TCO was produced via photoisomerisation of cis- cyclooctene by exposure to UV light (254 nm) in a batch vessel. The reaction mixture was continuously passed through a bed of silver nitrate impregnated on silica gel. Subsequently, the TCO is selectively retained by silver nitrate and the remaining cis -cyclooctene-containing solution is recycled to the photochemistry batch vessel. This is a very unique method yet the total yield was 66% and the total reaction time was relatively long, i.e. 12 hrs.
Recently, the sustainable production of active pharmaceuticals and excipients in a has received a lot of attention [13]. Novel bioprocesses, continuous-flow processing, process integration and intensification and green chemistry are the main assets of sustainable processes. Flow chemistry, especially micro-flow technology, is a high potential platform in terms of equipment size reduction, energy efficiency , and reduced solvent usage to achieve process intensification and thereby performing more sustainable processes in fine chemistry [14], [15].
More specifically, for photochemical reactions, microreactors have several advantages compared to batch processes such as improved photon transport, energy efficiency and better mixing [16]–[18]. The constricted diameter of the microreactors (shorter photon diffusion pathway) allows better use of the irradiated light efficiently reducing the total exposure time, which leads to shorter reaction time and possibly reduced byproduct formation [19], [20].
Beyond microfabricated channels, and microcapillaries, mini-scale packed-bed reactors allow to form micro-flow in their void spaces. Indeed, enhanced reaction rates, higher conversions and selectivities were found as well and can be attributed to the reduced mass-transfer limitations [21], [22]. This, in combination with the high surface-to-volume ratio, makes the packed-bed reactor suited for performing biphasic reactions in multiple-repeated reentrance-flow mode or for heteroge­neous catalytic reactions [23]. Adsorption (and desorption) is an essential step in heterogeneous catalysis. Hernández Carucci et al. proposed a model based on the competitive adsorption of ethylene and molecular oxygen over a silver surface of microchannels at 260 °C as part of a precise kinetic model for the ethylene oxide formation [24].
Accordingly, it stands to reason that sole adsorption processes (without catalysis) might be intensified in micro-flow. Microspheres have been reported and termed as adsorption ‘microreactors’ and indeed use the same transfer intensification by size reduction [25]. Rutin-Cr(III) loaded alginate microspheres were designed to reduce Cr(VI) to Cr(III) through adsorption and recover it. Yet, true micro(channel)reactors and micro-flow packed bed reactors have been hardly applied for adsorption so far.
Recently, we reported on the combination of a nucleophilic substitution to the thermal-Claisen rearrangement and also to photo-Claisen rearrangement in micro-flow [26], [27]. The motivation was to integrate two processes and to address the resulted challenging issues towards orthogonality. Also, here, we would like to design and integrate two processes, photoreaction and adsorption, yet with more in depth theoretical study for each process.
Therefore, the aim of this study is to develop a photo micro-flow process for the photochemical isomerization of cis -cyclooctene to TCO and its subsequent in-flow separation to isolate isomerically pure TCO derivatives. Such a compact integration of small devices fed with minute volumes provides opportunities for synergism between reaction and separation, which is a means of process intensification and was termed process-design intensification [28] as one arms of novel process windows [29]–[31].
More specifically, we focus in this work on the experimental procedures (batch as well as flow) for the photoisomerisation, and the design and operation of the adsorption column. Furthermore, the theoretical concepts behind these operations are explained and relevant models for both sections are developed. Finally, the results of the experiments and theoretical modeling are presented and discussed.