Volume V of the series Biotechnology: Pharmaceutical Aspects pp 157-215

Overcoming Poor Aqueous Solubility of Drugs for Oral Delivery

  • Tycho HeimbachAffiliated withDepartment of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development
  • , David FleisherAffiliated withCollege of Pharmacy, The University of Michigan
  • , Amal KaddoumiAffiliated withCollege of Pharmacy, The University of Michigan


It is estimated that 40% of active new chemical entities (NCEs) identified in combinatorial screening programs employed by many pharmaceutical companies are poorly water soluble, i.e., these compounds have an aqueous solubility less than 10 µM (5 µg/mL for a compound with a molecular weight of 500) (Lipinski, 2002, 2004). When these poorly soluble NCEs are further advanced in discovery and ultimately brought into development they are often plagued by incomplete absorption and low, erratic bioavailability. There are a limited number of options available to drug discovery scientists to enhance the solubility of a compound by conventional formulation approaches. These include the identification and selection of stable pharmaceutical salts (Stahl, 2003). However, salt formation requires an ionizable group and, therefore, this is not a viable option for neutral compounds or those with ionization constants that do not fall within the physiological range. Other common approaches are reducing solid particle size by micronization, such as milling or the formation of nanosuspensions (Müller et al., 2001), the use of complexation agents such as cyclodextrins (Rao and Stella, 2003), or the use of solubilizing excipients (Strickley, 2004). While these solubilization techniques often lead to significant improvement in systemic exposure when availability is solubility- or dissolution-rate limited, conventional formulation approaches are not always successful and an alternate strategy is required.