Stabilizing Unstable Amorphous Menthol through Inclusion in Mesoporous Silica Hosts

Teresa Cordeiro, Carmem Castineira, Davide Mendes, Florence Danède, Joao Sotomayor, Isabel M. Fonseca, Marco Gomes Da Silva, Alexandre Paiva, Susana Barreiros, M. Margarida Cardoso, Maria T. Viciosa, Natália T. Correia, Madalena Dionisio

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31 Citations (Scopus)


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, Tg = -54.3 °C, is in good agreement with the one predicted by the composition dependence of the Tg 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 (Tg,dielc(α)) and S (Tg,dielc(S)) molecular population from the temperature dependence of the relaxation times to 100 s. While Tg,dielc(α) agrees better with the value obtained from the linearization of the Fox equation assuming ideal behavior of the menthol:flurbiprofen THEDES, Tg,dielc(S) 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.

Original languageEnglish
Pages (from-to)3164-3177
Number of pages14
JournalMolecular Pharmaceutics
Issue number9
Publication statusPublished - 5 Sept 2017


  • amorphous state
  • drug release
  • flurbiprofen
  • menthol
  • mesoporous silica matrixes
  • molecular mobility


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