Institute of Physics, University of Silesia in Katowice, ul. 75 Pułku Piechoty 1, 41-500 Chorzow, Poland.
Silesian Center for Education and Interdisciplinary Research, ul. 75 Pułku Piechoty 1a, 41-500 Chorzow, Poland.
Int J Mol Sci. 2022 Aug 29;23(17):9794. doi: 10.3390/ijms23179794.
In this paper, we thoroughly investigated the physical stability of the anti-inflammatory drug etoricoxib, which has been reported earlier to be resistant to recrystallization in its glassy and supercooled states at ambient pressure. Our unique application of the standard refractometry technique showed that the supercooled liquid of the drug was able to recrystallize during isothermal experiments in atmospheric conditions. This enabled us to determine the crystallization onset timescale and nucleation energy barrier of etoricoxib for the first time. As the physical instability of etoricoxib requires working out an efficient method for improving the drug's resistance to recrystallization to maintain its amorphous form utility in potential pharmaceutical applications, we focused on finding a solution to this problem, and successfully achieved this purpose by preparing binary mixtures of etoricoxib with octaacetylmaltose. Our detailed thermal, refractometry, and molecular dynamics studies of the binary compositions near the glass transition revealed a peculiar behavior of the glass transition temperatures when changing the acetylated disaccharide concentration in the mixtures. Consequently, the anti-plasticization effect on the enhancement of physical stability could be excluded, and a key role for specific interactions in the improved resistance to recrystallization was expected. Invoking our previous results obtained for etoricoxib, the chemically similar drug celecoxib, and octaacetylmaltose, we formulated a hypothesis about the molecular mechanisms that may cause an impediment to crystal nuclei formation in the amorphous mixtures of etoricoxib with octaacetylmaltose. The most plausible scenario may rely on the formation of hydrogen-bonded heterodimers of the drug and excipient molecules, and the related drop in the population of the etoricoxib homodimers, which disables the nucleation. Nevertheless, this hypothesis requires further investigation. Additionally, we tested some widely discussed correlations between molecular mobility and crystallization properties, which turned out to be only partially satisfied for the examined mixtures. Our findings constitute not only a warning against manufacturing the amorphous form of pure etoricoxib, but also evidence for a promising outcome for the pharmaceutical application of the amorphous compositions with octaacetylmaltose.
本文深入研究了抗炎药物依托考昔的物理稳定性，此前已有报道称，在常压下，依托考昔的玻璃态和过冷态下不易再结晶。我们应用标准折射技术的独特方法表明，在大气条件下的等温实验中，药物的过冷液体能够再结晶。这使我们首次能够确定依托考昔的结晶起始时间尺度和成核能垒。由于依托考昔的物理不稳定性需要找到一种有效的方法来提高其抗再结晶能力，以保持其在潜在药物应用中的无定形形式的效用，因此我们专注于解决这个问题，并通过制备依托考昔与八乙酰麦芽糖的二元混合物成功实现了这一目标。我们对玻璃化转变附近的二元组成进行了详细的热学、折射和分子动力学研究，发现当混合物中乙酰化二糖的浓度发生变化时，玻璃化转变温度会出现异常行为。因此，可以排除抗塑化效应对增强物理稳定性的影响，并且预计特定相互作用在提高抗再结晶能力方面发挥关键作用。根据我们之前对依托考昔、化学类似物塞来昔布和八乙酰麦芽糖的研究结果，我们提出了一个关于分子机制的假设，这些机制可能会阻碍依托考昔与八乙酰麦芽糖的无定形混合物中晶体核的形成。最合理的情况可能依赖于药物和赋形剂分子形成氢键异二聚体，以及相关的依托考昔同二聚体的数量减少，从而使成核受阻。然而，这一假设需要进一步研究。此外，我们还测试了一些广泛讨论的分子迁移率与结晶性质之间的相关性，结果表明这些相关性仅部分适用于所研究的混合物。我们的研究结果不仅对制造纯依托考昔的无定形形式提出了警告，而且还为含有八乙酰麦芽糖的无定形组合物在药物应用方面提供了有希望的结果。
