Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Principles of encapsulating hydrophobic drugs in PLA/PLGA microparticles.

PLA micro- and nano-particles

The first study on application of Design of Experiments (DoE) in optimizing drug formulation appeared in 1967. Since then the number of literature reports on the use of DoE optimization in development of drug delivery technologies has been piling up steadily. Such systematic techniques find their use in every type of conventional dosage form and modern drug delivery system. The drug delivery devices investigated for optimization using response surface methodology include controlled release compressed matrices, microparticulates, macroparticulates, vesicular systems, floating systems, bioadhesive systems, semisolids, transdermals, and inhalations. The optimized processes mainly include extrusion-spheronization, pelletization, microencapsulation, coating, granulation, and tableting. Part I of this article [Crit Rev Ther Drug Carrier Syst 2005; 22(1):27-106] dealt with the salient steps involved in the DoE optimization methodology using diverse experimental designs. Part II deals with various retrospective literature findings as well as the prospective application of such DoE procedures while optimizing varied drug delivery technologies. A vast account of various DoE reports on optimization of diverse drug delivery system and processes along with the critical graphical analysis of various designs, input, and response variables have been presented here in a categorical form. Such an explicit and updated review on drug delivery optimization has not been published anywhere else in the recent past.

G Nykamp

Papers

Jet milling--a new technique for microparticle preparation.