LAQV-REQUIMTE/CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa , 2829-516 Caparica, Portugal.
Faculdade de Ciências Farmacêuticas, Universidade de São Paulo , Av. Prof. Lineu Prestes, 580, Butanta, 05508-000 São Paulo, Brasil.
Mol Pharm. 2017 Sep 5;14(9):3164-3177. doi: 10.1021/acs.molpharmaceut.7b00386. Epub 2017 Aug 24.
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.
易结晶的治疗成分和食品添加剂薄荷醇的无定形化成功地通过将纯薄荷醇包埋在 3.2nm 和 5.9nm 孔径的介孔硅基质中实现。通过热分析检测到玻璃化转变，确认了薄荷醇的无定形化。各自的玻璃化转变温度 T=-54.3°C，与通过薄荷醇：氟比洛芬治疗深共晶溶剂（THEDESs）确定的 T 值组成依赖性预测的温度非常吻合。未观察到纯薄荷醇负载到硅载体中的非等温结晶，这可以表明薄荷醇作为完全无定形/过冷材料存在于硅基质的孔内。通过介电弛豫光谱研究了薄荷醇的迁移率，该方法允许在两种孔径下识别出两个弛豫过程：一个与类似纯薄荷醇分子的迁移率相关的较快过程（α过程），以及一个由于吸附在内部孔壁上的薄荷醇分子的迁移受限而导致的较慢的主导过程（S 过程）。在较高（5.9nm）孔径的基质中，控制α 过程的分子群体分数更大，尽管在这两种情况下，S 过程比α 过程更为强烈。从弛豫时间对 100s 的温度依赖性，为每个α（T）和 S（T）分子群体估算介电玻璃化转变温度。虽然 T 与从假设薄荷醇：氟比洛芬 THEDES 理想行为的 Fox 方程线性化获得的值更吻合，但由于吸附群体在孔内占主导地位，T 更接近复合材料的热分析确定的值。然而，5.9nm 孔径基质中具有更高迁移率的块状分子的较大分数似乎决定了初始时相对 3.2nm 复合材料更快的药物释放。然而，后者抑制了孔内结晶，因为其尺寸小于薄荷醇成核的临界尺寸。这表明这些复合材料适用于药物释放曲线可以通过调节主体孔径来控制的药物输送系统。
