Mesoporous Silica:  A novel drug delivery platform for stable AMORPHOUS FORMULATIONS

 

Ken K. Qian and Terrence J. Udovic

 

An overwhelming number of drug candidates emerging from discovery are poorly soluble in water.  This problem, which made the cover story of Chemical & Engineering News in 2010, is one of the most difficult challenges the pharmaceutical industry is facing today.  To overcome this obstacle, amorphization of crystalline drugs stands at the forefront among the various strategies.  An amorphous drug has higher solubility in comparison to its crystalline counterpart, the implication of which is exceedingly valuable in pharmaceutical formulation and product development.  However, stability, both physical and chemical, remains an unresolved issue.  Thermodynamically, an amorphous solid is at a higher free-energy state than its corresponding crystalline phase.  Dynamically, molecules in a glassy state often have greater mobilities than those in crystal lattices.  The very properties that make them attractive for solubility enhancement also make them susceptible to re-crystallization and/or chemical degradation.

 

Our approach to stable amorphous formulations is to confine drugs in mesoporous silica (SiO2), which have mean pore diameters between 2 nm and 50 nm, and large surface areas.  Because of the reduced dimensionality and large interfacial effects, matter in nano-porous materials exhibits properties that are drastically different from the corresponding bulk phases.  In this report, we used ibuprofen and lidocaine as two model compounds, representing acidic and basic classes of molecules, respectively.  Using neutron and X-ray scattering, we elucidated the molecular interactions and structural arrangements of the confined species.  More importantly, we proposed a mechanism that is responsible for the inhibition of nucleation and crystal growth of drugs.  These scientific insights are essential to the development of a stable amorphous product.