Martínez Luz María, Videa Marcelo, Sosa Nahida González, Ramírez José Héctor, Castro Samuel
School of Engineering and Sciences, Tecnologico de Monterrey, Campus Monterrey Av. Eugenio Garza Sada 2501 Sur. Monterrey N.L., México 64849, Mexico.
Department of Chemistry and Nanotechnology, Tecnologico de Monterrey, Campus Monterrey Av. Eugenio Garza Sada 2501 Sur. Monterrey N.L., México 64849, Mexico.
Molecules. 2016 Dec 14;21(12):1712. doi: 10.3390/molecules21121712.
The amorphous state is of particular interest in the pharmaceutical industry due to the higher solubility that amorphous active pharmaceutical ingredients show compared to their respective crystalline forms. Due to their thermodynamic instability, drugs in the amorphous state tend to recrystallize; in order to avoid crystallization, it has been a common strategy to add a second component to hinder the crystalline state and form a thermally stable co-amorphous system, that is to say, an amorphous binary system which retains its amorphous structure. The second component can be a small molecule excipient (such as a sugar or an aminoacid) or a second drug, with the advantage that a second active pharmaceutical ingredient could be used for complementary or combined therapeutic purposes. In most cases, the compositions studied are limited to 1:1, 2:1 and 1:2 molar ratios, leaving a gap of information about phase transitions and stability on the amorphous state in a wider range of compositions. In the present work, a study of novel co-amorphous formulations in which the selection of the active pharmaceutical ingredients was made according to the therapeutic effect is presented. Resistance against crystallization and behavior of glass transition temperature ( T g were studied through calorimetric measurements as a function of composition and shelf time. It was found that binary formulations with T g temperatures higher than those of pure components presented long-term thermal stability. In addition, significant increments of T g values, of as much as 15 ∘ C, were detected as a result of glass relaxation at room temperature during storage time; this behavior of glass transition has not been previously reported for co-amorphous drugs. Based on these results, it can be concluded that monitoring behavior of T g and relaxation processes during the first weeks of storage leads to a more objective evaluation of the thermomechanical stability of an amorphous formulation.
无定形状态在制药行业中备受关注，因为与各自的结晶形式相比，无定形活性药物成分具有更高的溶解度。由于其热力学不稳定性，无定形状态的药物往往会重结晶；为了避免结晶，一种常见的策略是添加第二种成分来阻碍结晶状态并形成热稳定的共无定形体系，也就是说，一种保留其无定形结构的无定形二元体系。第二种成分可以是小分子赋形剂（如糖或氨基酸）或第二种药物，其优点是第二种活性药物成分可用于补充或联合治疗目的。在大多数情况下，所研究的组合物限于1:1、2:1和1:2的摩尔比，在更广泛的组合物范围内留下了关于无定形状态下相变和稳定性的信息空白。在本工作中，展示了一项关于新型共无定形制剂的研究，其中活性药物成分的选择是根据治疗效果进行的。通过量热测量研究了抗结晶性和玻璃化转变温度（Tg）随组成和储存时间的变化行为。发现Tg温度高于纯组分的二元制剂具有长期热稳定性。此外，在储存期间室温下的玻璃松弛导致Tg值显著增加，高达15℃；这种玻璃化转变行为此前尚未在共无定形药物中报道。基于这些结果，可以得出结论，在储存的最初几周监测Tg行为和松弛过程可以更客观地评估无定形制剂的热机械稳定性。
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