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Review/Preview: Prodrug Ionic Liquids – Combining the Prodrug and Ionic Liquid Strategies to Active Pharmaceutical Ingredients

corresponding

O. ANDREEA COJOCARU, JULIA L. SHAMSHINA, ROBIN D. ROGERS*
*Corresponding author
Center for Green Manufacturing and Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487, USA

Abstract

A prodrug is an inactive derivative that is converted to the active drug in vivo through chemical and/or enzymatic transformations. The prodrug pharmaceutical strategy is a common approach used to overcome poor aqueous solubility, limited bioavailability, chemical instability, and/or poor permeability of active pharmaceutical ingredients (APIs). Ionic liquids (ILs) are salts with melting points or glass transition temperatures below 100°C, but in the context of APIs specifically below body temperature. The IL pharmaceutical strategy applied to readily ionisable drugs can be used to overcome disadvantages associated with the solid state of APIs, such as polymorphism or poor solubility/bioavailability. By combining the IL strategy with the prodrug approach, IL forms of APIs can be further expanded to those APIs with non-ionisable or hard to ionise functional groups. Moreover, by making a prodrug into an IL, a second active might be introduced into the resulting salt (a dual functional prodrug IL), such as a transdermal penetration enhancer. This review of the limited published data might also be considered a preview of a new tool for the pharma industry.


INTRODUCTION

Most of the current solid active pharmaceutical ingredients (APIs) used in the pharmaceutical industry can exhibit several drawbacks in performance due to limitations in their physico-chemical properties such as limited solubility, insufficient bioavailability, low stability, etc. Often, these are related to the existence of polymorphic (different crystalline states) (1) and/or pseudo-polymorphic (e.g., hydrate, solvate) forms (2, 3). Another common problem with solid APIs is particle size (4) which is often critical to drug performance.
Based on the chemical structure of the drug molecules (ionisable or non-ionisable), several approaches are now widely used to overcome these problems. Two of the most common ones are: (a) salt formation: th