Accessing the Physical State and Molecular Mobility of Naproxen Confined to Nanoporous Silica Matrixes

Abstract

The pharmaceutical drug naproxen was loaded in three different silica hosts with pore diameters of 2.4 (MCM), 3.2 (MCM), and 5.9 nm (SBA), respectively: nap MCM_2.4 nm , nap MCM_3.2 nm , and nap SBA_5.9 nm . To access the guest physical state in the prepared composites, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and attenuated total reflectance Fourier transform infrared spectroscopy were used. The different techniques provided complementary information on a molecular population that was revealed to be distributed among different environments, namely the pore core, the inner pore wall, and the outer surface. It was found that naproxen is semicrystalline in the higher pore size matrix being able to crystallize inside pores; after melting it undergoes full amorphization. In the case of the lower pore size matrix, naproxen crystallizes outside pores due to an excess of filling while most of the remaining fraction is incorporated inside the pores as amorphous. Crystallinity in these two composites was observed by the emergence of the Bragg peaks in the XRD analysis, whereas for nap MCM_3.2 nm only the amorphous halo was detected. The latter only exhibits the step due to the glass transition by DSC remaining stable as amorphous at least for 12 months. The glass transition in the three composites is abnormally broad, shifting to higher temperatures as the pore size decreases, coherent with the slowing down of molecular mobility as probed by dielectric relaxation spectroscopy. For nap SBA_5.9 nm the dielectric response was deconvoluted in two processes: a hindered surface (S-) process due to molecules interacting with the inner pore wall and a faster α-relaxation associated with the dynamic glass transition due to molecules relaxing in the pore core, which seems a manifestation of true confinement effects. The drug incorporation inside a nanoporous matrix, mainly in 3.2 nm pores, was revealed to be a suitable strategy to stabilize the highly crystallizable drug naproxen in the amorphous/supercooled state and to control its release from the silica matrix, allowing full delivery after 90 min in basic media.

Nanocrystallization of Rare Tolbutamide Form V in Mesoporous MCM-41 Silica

“…This phenomenon is frequently observed for drug-silica composites and was discussed by Cordeiro et al for naproxen confined within MCM-41 and SBA-15 silica hosts. 48 The detailed study of mobility of TB confined in porous silicas will be presented in a separate publication.…”

How Molecular Mobility, Physical State, and Drug Distribution Influence the Naproxen Release Profile from Different Mesoporous Silica Matrices

“…The observed profile acts as an indication of a molecular population distribution also found for similar drug incorporated matrices. 8 It goes from a less thermal-resistant naproxen's population, attributed to bulk-like molecules, to a highly hindered and hard to decompose one due to naproxen molecules interacting with pore walls.…”

“…Infrared spectroscopy can also give some insight in guest− host interactions. Meanwhile, in the MCM-41-based composites, these occur mainly via hydrogen bonds, 8 as discussed above in terms of CO vibrations; in the case of the PMO Bph material, the interaction may involve aromatic groups as π−π coupling. However, the spectral comparison between unloaded PMO Bph , the respective composite, and the native drug in the wavenumber region associated with CC stretching vibrations in the aromatic groups (1500−1900 cm −1 shown in Figure S1a) in the Supporting Information) only shows a 2 cm −1 shift from 1603 (pristine PMO and native naproxen) to 1605 cm −1 (composite).…”

“…56 While the latter shows distinct and sharp Bragg peaks, the unloaded MCM-41 based matrices only present the halo in the 2θ region between 15 and 30 o , which is characteristic of the amorphous form. 8 The long-range order of the two-dimensional hexagonal symmetry of these matrices give rise to small angle peaks (2θ < 5°). 57 For MCM-41 sil , this indicates that no crystallization occurred during the chemical modification of this matrix.…”

“…Indeed, in the respective following scans, no exothermal peaks due to recrystallization are registered, in opposition to which occurs for the native drug that readily recrystallizes upon cooling. 8 The detection of a glass transition indicates that naproxen is incorporated inside the pores.…”