Systematic Investigation on Particle and Pore Size Effects of Mesoporous Silica on Molecular Mobility and Physical Stability of Overloaded Amorphous Acetaminophen.

Polymeric excipients are generally used for physical stabilization of amorphous drugs. However, a more strategic design of amorphous formulations is needed to reduce the amount of excipients, for which the use of mesoporous materials can be a promising option. In this study, mesoporous silica (MS) with various particle and pore sizes were added to amorphous acetaminophen (AAP) at various mixing ratios to systematically clarify their stabilization mechanisms. In particular, how the presence of MS affects the stability, at mixing ratios where AAP is present in excess relative to the pore volume, was focused. Six types of MS, with pore and particle sizes ranging from 2.5 to 21 nm and from 3 to 9 μm, respectively, were used in the study. Differential scanning calorimetry (DSC) analysis suggested the presence of three molecular fractions of amorphous AAP with different molecular mobilities: free, intermediate, and rigid fractions. The free fraction behaved similarly to pure AAP, whereas the intermediate fraction appeared to be relatively more stable. The rigid fraction had limited molecular mobility and was expected to strongly interact with the MS surface. AAP molecules mainly existed as the free fraction in the presence of 10% MS, regardless of the MS type. The free fraction disappeared to allow domination by the intermediate fraction with 50% MS having 17 or 21 nm pores, whereas a significant amount of the free fraction remained with MS having 2.5 nm pores. Broadband dielectric spectroscopy (BDS) analysis revealed that the addition of MS both increased and decreased the molecular mobility of amorphous AAP. The presence of all types of 10% MS slightly accelerated the γ-relaxation of amorphous AAP without affecting the α-relaxation. The addition of 50% MS with 17 or 21 nm pores slowed down the a-relaxation time of amorphous AAP, whereas the effect was marginal for MS with 2.5 nm pores. Isothermal crystallization of amorphous AAP at 60 °C was accelerated in the presence of MS with 2.5 nm pores at mixing ratios of both 10 and 50%. In contrast, 50% MS with 17 or 21 nm pores exhibited a strong stabilization effect. The accelerated crystallization in the presence of MS with 2.5 nm pores was explained by an increase in local molecular mobility. Mixtures with MS with 17 or 21 nm pores exhibited higher stability, which was explained by the large portion of the intermediate fraction with slower motion relative to that of pure AAP. The intermediate fraction was assumed to move inside and outside the pores, and the ease of molecular exchange was explained by the size of the pores and characteristic length of the cooperatively rearranging region of amorphous AAP. These observations provide guidance for the selection of MS materials for the stabilization of large amounts of pharmaceutical glasses and the scientific significance of the molecular dynamics of glasses in the presence of porous materials.