Strategies in the design of solution-stable, water-soluble prodrugs I: A physical-organic approach to pro-moiety selection for 21-esters of corticosteroids

Article abstract of DOI:10.1002/jps.2600740402

The ideal water-soluble prodrug should exhibit sufficient aqueous solution stability to allow long-term storage of its solutions (i.e., 2 years at room temperature) and yet should be converted rapidly in vivo to the active parent drug - two severe and seemingly conflicting demands which limit the utility of many common solubilizing pro-moieties. For example, succinate esters, which are commonly utilized as water-soluble prodrugs, are unstable in solution and may undergo slow and incomplete bioconversion in vivo. In this study, the solution stability problems associated with 21-esters of corticosteroids are reviewed. It is concluded that the most important reaction limiting shelf life is ester hydrolysis. From a consideration of the influence of molecular structure on ester reactivity, a strategy for the design of solution-stable, water-soluble prodrugs of corticosteroids has been developed. Two key requirements for dilute solution are (a) high solubility at the pH of optimum stability and (b) appropriate design of the pH-rate profile. Several 21-esters of methylprednisolone have been synthesized, and the rates of their aqueous solution hydrolysis have been determined to test the strategy. Compounds exhibiting estimated shelf lives in dilute solution of >2 years at 25°C have been identified.