Pfizer Inc. Cambridge, Massachusetts, United States
Purpose: Mesoporous silica has received increasing attention for (1) stabilizing API in the amorphous phase and (2) yielding enhancement of apparent solubility relative to crystalline forms. Numerous poorly water-soluble API’s have shown promise with mesoporous silica, however, the underlying factors determining API supersaturation are not well understood. In this research, molecular descriptors are being investigated to help elucidate the properties which are most important for solubility enhancement and supersaturation by mesoporous silica Methods: Organic solvent (THF) evaporation method was used for co-loading an API and precipitation inhibitor (HPMCAS-L) on mesoporous silica at 30% (w/w) active loading. The resultant co-loaded silica formulations were dried under vacuum and stored at -20°C until characterization. Polarized light microscopy (PLM) and Powder X-Ray Diffraction (PXRD) were used to characterize solid state of loaded silica formulations. Potency and chemical stability were evaluated using HPLC-UV. A ‘fit-for-purpose’ non-sink gastric to intestinal (GB-IB) precipitation method was developed to evaluate supersaturation of loaded silica formulations relative to the crystalline form. In GB-IB, sample was suspended in gastric media for 30min followed by 1:2 dilution in the simulated intestinal media and potency was evaluated at pre-determined time points for up to 120min. Results: Of the 12 model compounds tested, 8 demonstrated supersaturation by mesoporous silica over the crystalline reference. An investigation of the molecular descriptors of these 12 compounds indicated that hydrogen bond acceptor/donor count (HBA & HBD) and ratio of melting point/ glass transition temperature (Tm/Tg) may be correlated with a material’s ability to be stabilized by silica carrier. It is highly likely to form a stable and solubility-enabling formulation with mesoporous silica if the compound has cumulative number of HBA and HBD ≥5 with moderate Tm/Tg (1.35 to 1.5). Conclusion: Through 12 compounds, a preliminary chemical map and calibration set was developed for mesoporous silica technology. Future works aims at challenging the predictability of this model by using a series of test compounds and in vivo PK comparison of silica dispersion drugs verses crystalline APIs.
