Influence of Pore Size of Mesoporous Silica on Physical Stability of Overloaded Celecoxib Glass

The stabilization mechanism of mesoporous silica (MS) of two different pore sizes (21 and 2.5 nm) on overloaded celecoxib (CEL) glass was investigated. Differential scanning calorimetry (DSC) measurements revealed the presence of three fractions with different molecular mobilities: free, intermediate, and rigid ones. The free fraction exhibited cold crystallization during DSC heating and was assumed to have almost the same properties as those of the bulk molecules. The rigid fraction did not exhibit either glass transition or cold crystallization behavior, which should be stabilized by interactions with the MS surface. The remaining molecules exhibited glass transition behavior without any tendency toward cold crystallization during heating, which is called the intermediate fraction. The molecular dynamics of each fraction was investigated by using broadband dielectric spectroscopy (BDS). While the intermediate and free fractions exhibited comparable mobility, the rigid fraction demonstrated pore-size-dependent behavior: enhanced and suppressed molecular mobility was observed for the rigid fraction confined in 21 and 2.5 nm-pores, respectively. Isothermal crystallization of CEL glass was investigated using DSC and BDS at 95 °C. The results revealed that the CEL glass mixed with MS with large pores exhibited slower crystallization compared to the CEL glass without MS, whereas accelerated crystallization was observed for the CEL mixed with a small amount of MS of small pores. The pore size of 21 nm was much larger than the cooperatively rearranging region (CRR) of the CEL glass, whereas the pore size of 2.5 nm was comparable to that. When the pore size was larger than that of the CRR, most of the loaded CEL molecules behaved as an intermediate fraction, presumably because the molecules could exchange inside and outside the pore. In contrast, the exchange was not likely to proceed when the pore size was comparable to or smaller than that of the CRR, leaving a large free fraction. This finding provides a deep understanding of the stabilization mechanism of overloaded pharmaceutical glass by using mesoporous materials.