Strategies for formulating and delivering poorly water-soluble drugs

Abstract

Water solubility is a key parameter in drug formulation since it highly influences drug pharmacokinetics and pharmacodynamics. In the past decades, the challenge with poorly water soluble drugs has been growing continuously. As a matter of fact, poorly soluble compounds represent 40% of the top 200 oral drugs marketed in the US, 33% of drugs listed in the US Pharmacopeia, 75% of compounds under development and 90% of new chemical entities. The present article presents and discusses the pharmaceutical strategies available to overcome poor water solubility in light of final drug product examples. First, chemical modifications based on the adjustment of the pH and the design of prodrugs are presented and discussed. Physical modifications based on modified solid states of the drug, small drug particles, cosolvents, surfactants, lipids and cyclodextrins are discussed in a second part. Finally, the option of modifying the route of administration is briefly presented.

Introduction

The water solubility of drugs strongly influences their pharmacokinetics and pharmacodynamics and is a key parameter for formulators. Drug solubilization is based on the breaking of some drug–drug and water–water interactions for the creation of new drug–water interactions. The strength of such interactions determines the solubility of a drug in water. Water solubility is one of the main parameters of the biopharmaceutical classification system (BCS) of drugs, as illustrated in Fig. 1A [1]. Moreover, “Lipinski's rule of 5” considers the solubility of drug candidates in view of the rejection of inappropriate candidates at early stages of the drug discovery process [2].

In the past decades, the challenges linked to poor water solubility have been continuously growing. The surge of combinatorial chemistry and high throughput miniaturized screening methods for drug discovery have resulted in an increase in molecular weight and lipophilicity of drug candidates [3], [4], [5]. In addition, the push towards increasing the potency of drugs often resulted in an increase in their lipophilicity (leading to stronger interactions with their receptors). Currently, poorly soluble compounds represent approximately 40% of the top 200 oral drugs marketed in the US and Europe, as shown in Fig. 1B [6]. In addition, they represent 90% of new chemical entities, 75% of compounds under development and 33% of drugs listed in the US Pharmacopeia [2], [3], [6], [7], [8], [9], [10], [11].

Interestingly, a variety of pharmaceutical strategies have been designed to address the formulation and delivery challenges presented by poorly soluble drugs, these are reviewed and discussed in the present article.