36 - Preparation of Water-Soluble Compounds by Covalent Attachment of Solubilizing Moieties

Abstract

The strategy described in this chapter aims to convert a water-insoluble drug into a water-soluble one by covalently attaching an appropriate solubilizing side chain. The solubilizing chain can be reversibly or irreversibly grafted to the parent molecule. Reversible linkages are usually provided by esters, peptides, or glucosides. Irreversible attachment of side chains is achieved by O- and N-alkylation and creation of C–C bonds. The grafted side chains can be basic, acidic, or neutral. First of all, a careful examination of the parent molecule must be undertaken to identify the parts of the molecule that present adequate chemical reactivity and are suitable as attachment points for the solubilizing chain. Functions such as OH, SH, NH, acidic CH, or CO2H are reactive sites that furnish nucleophilic or basic entities. Conversely, aromatic double bonds are sensitive to electrophilic attack, whereas carbonyl groups and conjugated carbon–carbon double bonds are sensitive to nucleophilic attack. The second criterion that has to be considered is of a biological nature: The solubilizing chain can only be grafted to those parts of the molecule that are not involved in the drug–receptor interaction. The size of the solubilizing chain is one of the selection parameters. The chains can be strictly limited to the minimum and simply represent functional groups, or they can be made from larger residues containing several atoms. The nature of the side chains is the second selection parameter. It has to be decided if they can be ionizable or non ionizable.