## 1 Introduction
Furthermore, the crosslinking is also responsible for the easy to handle component of the most part of the polymers that are commercially available due to their uniform particle size distribution and robust spherical shape [12; 13]. In summary, the solubility parameters will provide sufficient data for choosing the most adequate solvent for each operation. To the contrary of what happens with other polymeric process, those that are involved in SPPS could be associated with \"Fine Chemistry\". Thus, all of the reactions that are taking place (an amide bond formation, removal of a protecting group) are well defined and should imply almost 100% conversion yields and without side-reaction, which could jeopardize the purification of the final product. Thus, an effective SPPS process should require a strict fine-tuning of solid support, solvents, and reactants looking for the full compatibility of them. The present work has been carried out using 2-chlorortriyl chloride (CTC) resin as a model [14]. CTC is a polystyrene (PS) based resin, which is the most common in the industrial environment as well as in research. CTC forms 2-chlorortriyl ester with the first amino acid, which allows for the liberation of the peptide while using as low as 1-2% trifluoroacetic (TFA) at the end of the synthetic process. The cleavage of the peptide from the CTC resin with low concentration of TFA renders the full protected peptide, which is able be used in the synthesis of long peptides through the fragment condensation process. On the other hand, the fully unprotected peptide is obtained when the cleavage is carried out with a higher concentration of TFA (aprox. 90%). Finally, CTC resin is being used as a polymeric protecting group for a rapid and efficient synthesis of unusual protected amino acids by the interchange of protecting groups [15] and for the synthesis of protected dipeptides to be used as the building blocks in more complex SPPS [16]. This last application is fuelled by the convenient commercial price of the CTC resin and, more importantly, for the possibility of being recyclable through a regeneration/activation process. We would like to point out that this study was also carried out on two other PS resins that were tested in our laboratory \"[Aminomethyl (AM), 4-methylbenzhydrylamine (MBHA)]\", and the results were comparable with those for the CTC resin (Supplemental Figure S1A,B). However, here we focused on CTC resin due to its regeneration capability. The similarity among the three PS resins tested basically indicates that the linkers do not play a role in the final morphology of the resin or the way it is being affected to the introduced solvents, and the main role is basically only ascribed to the PS part. It is worth noting that the reaction kinetics in SPPS is diffusion-dependent, where the diffusion of the reactants, reagents, and solvents first takes place inside of the gel type beads, followed by excluding them to accommodate the growing molecule [9; 15; 16; 17; 18; 19; 20]. This means that each bead represents a reaction vessel. Thus, the morphological characteristics of those beads must be analyzed through the whole synthetic process. Otherwise, it will have similar effects to using a broken reaction vessel in a conventional solution synthesis. Figure 1 shows a schematic representation of the different steps existing in a SPPS strategy while using CTC resin. First of all, the native resin should be swollen, followed by the incorporation of the first amino acid, removal of the temporary protecting group, elongation of the peptide, and ending with the final deprotection and cleavage from the resin. Furthermore, the washings are being carried out after each step with an appropriate solvent [2]. When CTC or other resin is used for the synthesis of unprotected peptides, these are usually precipitated in the reaction medium with an ether. Ether washing is also introduced in several protocols for removing impurities from the resin and/or before drying the resin [21].