Do We Still Need Chemistry for Water-Soluble Prodrugs? What Biocatalysis Already Does, and What It Does Not

Poor aqueous solubility limits roughly 40% of marketed oral drugs and up to ~90% of development candidates. One established remedy is the prodrug strategy: the covalent attachment of a bioreversible promoiety that regenerates the parent drug in vivo. The same conjugation can move a molecule in either direction along the hydrophilic–lipophilic axis: lipophilization raises membrane and oil solubility for permeation-limited or topical uses, whereas hydrophilization raises aqueous solubility. This review addresses hydrophilization and asks whether enzymatic (biocatalytic) synthesis can replace conventional chemistry in building water-soluble prodrugs. We examine, class by class of hydrophilic promoiety (polyol and sugar esters, glycosides, amino acid esters, poly(ethylene glycol), and ionizable phosphates), the biocatalytic toolbox (lipases, acyltransferases, glycosidases, and glycosyltransferases), the molecular determinants of its selectivity, the pharmacokinetic consequences of hydrophilization, and the translation of these reactions to process, benchmarking each against the corresponding chemical route. A three-part test emerges: enzymes suffice, and frequently surpass chemistry, wherever an accessible hydroxyl or carboxyl must be functionalized regioselectively on a promoiety bearing no competing group and a moderate solubility gain is required. This is the regime of polyols, most sugars, and glycosides, with drug-conjugate aqueous-solubility increases of roughly 4-fold to 5500-fold; chemistry remains necessary for ionizable phosphates, amino acid esters, and PEG carriers. Two gaps limit translation: the field’s central ‘green’ claim is asserted far more often than it is measured (E-factor, PMI, life-cycle assessment), and in vivo pharmacokinetic data for enzymatically synthesized hydrophilizing prodrugs remain almost absent. We provide a decision flowchart that assigns each bond of a synthesis to biocatalysis or to chemistry, and reporting guidelines for the seven quantities that make a published E-factor recoverable.