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  • Several authors have been pursuing the aim of finding

    2020-06-01

    Several authors have been pursuing the aim of finding good performing organic solvent compatible adsorbers useful in the context of API purification [[10], [11], [12], [13], 22, 23]. For sulfonate GTIs, scavenging nucleophilic resins [22, rat 4 23] or molecular imprinted polymers (MIPs) [10] have been explored, taking advantage of specific interactions established between the polymers functional groups and the target sulfonate molecules. The amount of adsorber varies between 50 and 200 mg per 1 mL of solution to be treated [10, 22, 23] and generally, when GTI removal is around 100% there is still a considerable API loss in some cases [23]. Therefore, the challenge remains to find a platform suitable to perform in organic solvents, able to remove the highest amount of GTI with the lowest API loss possible. GTIs cover a wide range of compounds from different chemical families including electrophilic reagents such as sulfonates, alkyl halides or epoxides, which are genotoxins that act as DNA alkylating agents. These species alkylate DNA through a nucleophilic attack by the nitrogen or oxygen of the pyrimidine and purine bases present in DNA to the electrophilic carbon of the GTIs [4, [24], [25], [26], [27]]. In order to mimic the process that takes place in vivo, herein we explore the potential of a recent material developed within our group, based on polybenzimidazole (PBI) polymer with an appending rat 4 moiety (PBI-adenine, Fig. 1) for API purification [28]. PBI is a versatile organic solvent compatible polymer that contains heterocyclic amine groups that can be modified with adequate chemical functionalities. In this case, PBI was modified to present as side group a DNA base, namely adenine, originating a new powder porous material suitable to interact with a wide range of DNA alkylating agents. The modification of PBI with adenine had never been attempted in order to mimic what happens in biologic systems, where alkylating GTIs interact with DNA originating DNA-GTI adducts [24], as exemplified in Fig. 1. The synthesis of modified polymer (PBI-adenine) is presented elsewhere [28] and the current study is focused on exploring the capability of this innovative material to remove a broad range of DNA alkylating agents from API organic solvent solutions, identify limitations for the use of PBI-adenine for API degenotoxification and, to define strategies and operation conditions at which PBI-adenine can successfully remove GTIs down to TTC values, with minimal API losses.
    Experimental
    Results and discussion
    Conclusions The potential development of a versatile material able to scavenge a broad range of DNA alkylating agents from organic solvent based solutions was investigated. Adsorption of GTIs from different chemical families, on an adenine modified PBI polymer, was found to be effective (> 80%) at room temperature. Our results show that in a typical industrial scenario, where the GTI is present in low concentration compared to the API, the efficiency and GTI removal rate can be improved with temperature increase. Furthermore, a simple solvent washing step was implemented to recover the API trapped in PBI-adenine polymer without GTI back contamination, exploring the fact that, the GTI is not easily retrieved from the adsorbing platform. Based on these achievements, a strategy is proposed for the efficient removal of a DNA alkylating GTI from an API solution in an organic solvent, leading to GTI to API ratios within the limits imposed by legislation, as low as 0.6 mg GTI/g API with only a 3.5% loss of API for the worst-case scenario considered. From the point of view of an industrial application this is a major advantage, since with one simple washing step it could be possible to recover the API, minimizing its loss, addressing the economic impact for the pharmaceutical companies associated with API losses in time consuming and material demanding elaborated purification strategies.
    Data availability statement