Biotechnology: Pharmaceutical Aspects Volume V, 2007, pp 157-215

Overcoming Poor Aqueous Solubility of Drugs for Oral Delivery

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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.

“Sadly, while this book chapter was in preparation our mentor and research advisor Dr. David Fleisher passed away. At the College of Pharmacy at the University of Michigan, in Ann Arbor, Dr. Fleisher mentored countless undergraduate, graduate and postgraduate students and fellows who now carry on his teachings and strive to propagate his gentle and wise manner of nurturing young minds that need some direction. Dr. Fleisher was a remarkable intellect and an outstanding researcher/contributor in the fundamentals of oral drug delivery, food effects as well as prodrugs and his pioneering efforts have stood the test of time and veracity. Dr. Fleisher’s ability to instinctively empathize with those that needed solace and comfort and perhaps a gentle steering hand to walk the maze of life, particularly in difficult times, endeared him to all that were fortunate to have known him. Dr. Fleisher is missed dearly and will always be in our hearts. He was 61.”