The State of Water and Its Impact on Pharmaceutical Systems: Lipid-Based Drug Delivery Systems and Amorphous Solids

Physicochemical properties relevant to aqueous pharmaceutical formulations such as drug solubility and stability have clearly been a focal point of research for many decades. As a result, pharmaceutical scientists have access to a large body of knowledge that provides a framework for understanding the properties of drugs in aqueous solution, such as the kinetics and mechanisms of their degradation, solubility as influenced by ionizable substituents and various solution equilibria, etc. However, most drug products are manufactured, stored, and most frequently administered as solid formulations (e.g., tablets, capsules, suppositories, polymer implants, transdermal patches) rather than as aqueous solutions or suspensions. For these nonaqueous systems, the state of current understanding of the equilibria and kinetics that govern performance is less advanced. Recently, interest in various nonaqueous delivery systems has been increasing because, as drug potency has received greater emphasis during the selection of new drug candidates, the lead compounds emerging from these selection processes tend to be more lipophilic and less water soluble. Consequently, a variety of amorphous or lipid-based delivery systems such as self-emulsifying or self-microemulsifying lipid dispersions often administered in soft gelatin capsule form for oral delivery are now being considered for commercialization. Similarly, various types of colloidal or nanoparticle formulations (e.g., nanosuspensions, solid-lipid nanoparticles, liposomes, micelles, polymeric micelles) in which the drug is suspended as a nano-sized particle or incorporated into a lipid particle have become increasingly attractive as possible vehicles for enhancing the bioavailability of orally administered drugs having poor water solubility, controlling drug release, enabling intravenous injection of nearly insoluble compounds, reducing side effects after intravenous administration, and in some cases providing enhanced permeability and retention in tumor tissue for the treatment of cancer.