Stabilizing Unstable Amorphous Menthol through Inclusion in Mesoporous Silica Hosts

Abstract

The amorphization of the readily crystallizable therapeutic ingredient and food additive, menthol, was successfully achieved by inclusion of neat menthol in mesoporous silica matrixes of 3.2 and 5.9 nm size pores. Menthol amorphization was confirmed by the calorimetric detection of a glass transition. The respective glass transition temperature, T = -54.3 °C, is in good agreement with the one predicted by the composition dependence of the T values determined for menthol:flurbiprofen therapeutic deep eutectic solvents (THEDESs). Nonisothermal crystallization was never observed for neat menthol loaded into silica hosts, which can indicate that menthol rests as a full amorphous/supercooled material inside the pores of the silica matrixes. Menthol mobility was probed by dielectric relaxation spectroscopy, which allowed to identify two relaxation processes in both pore sizes: a faster one associated with mobility of neat-like menthol molecules (α-process), and a slower, dominant one due to the hindered mobility of menthol molecules adsorbed at the inner pore walls (S-process). The fraction of molecular population governing the α-process is greater in the higher (5.9 nm) pore size matrix, although in both cases the S-process is more intense than the α-process. A dielectric glass transition temperature was estimated for each α (T) and S (T) molecular population from the temperature dependence of the relaxation times to 100 s. While T agrees better with the value obtained from the linearization of the Fox equation assuming ideal behavior of the menthol:flurbiprofen THEDES, T is close to the value determined by calorimetry for the silica composites due to a dominance of the adsorbed population inside the pores. Nevertheless, the greater fraction of more mobile bulk-like molecules in the 5.9 nm pore size matrix seems to determine the faster drug release at initial times relative to the 3.2 nm composite. However, the latter inhibits crystallization inside pores since its dimensions are inferior to menthol critical size for nucleation. This points to a suitability of these composites as drug delivery systems in which the drug release profile can be controlled by tuning the host pore size.

Establishing the Transitory Existence of Amorphous Phases in Crystallization Pathways by the CLASSIC NMR Technique

“…Given the low melting points of l ‐menthol (42.9 °C; α polymorph) and dl ‐menthol (33.8 °C; α polymorph), the molten phases are readily prepared and cooling under appropriate conditions may be anticipated to lead to glass formation. However, definitive evidence (from DSC data) for the formation of an amorphous phase of pure menthol has been reported only for crystallization of menthol confined inside mesoporous silica host materials, with no evidence for the formation of an amorphous phase in crystallization of l ‐menthol or dl ‐menthol from bulk (non‐confined) molten phases, in agreement with previous literature…”

Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies

“…Furthermore, a new type of molecular mobility, the S-type, was observed. S-type refers to mobility of a hindered molecule that is nano-confined within a single pore, and is much slower than standard molecular mobility events [44]. Based on these findings as well as those of our study (Figure 4; Figure 5), mesoporous silica may be a suitable way forward to stabilizing GFA-I glass formers under accelerated conditions.…”

“…Similar to the work by Mehta and colleagues, Brás et al focused on good glass formers (GFA-III). Additional work demonstrated that a reduction in molecular mobility leads to successful stabilization of the very poor glass former menthol (GFA-I), which has a glass transition temperature of −54.3 °C [44]. This stabilization was related to a decrease in molecular mobility of both α (free transitional mobility in space) and the aforementioned Johari–Goldstein β relaxations.…”

Insights into the Nature of Eutectic and Deep Eutectic Mixtures

“…Duarte et al [36] proposed a DES composed of menthol and three different APIs: ibuprofen, BA, and phenylacetic acid, and demonstrated their efficiency in the enhancement of the solubility, permeability and thus, bioavailability of APIs by changing the physical state of the pure components. From another perspective, menthol:flurbiprofen was suggested as a DES to avoid menthol crystallization and allow the estimation of its glass transition temperature [37]. Later, Dietz et al [38] selectively separated furfural and hydroxymethylfurfural from an aqueous solution using supported so-called DES (decanoic acid and thymol or menthol, and thymol and lidocaine) liquid membranes.…”