Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition

Abstract

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.

Fragility and Tendency to Crystallization for Structurally Related Compounds

“…However, we obtained the same values of m for all compounds despite the fact that they were characterized by completely different degrees of physical stability, which enabled their classification into classes I, II, and III of crystallization tendency. This is an important result because this is another example of the idea that dynamic fragility derived from dielectric measurements of the global molecular dynamics in terms of Equation (2) does not always correctly predict physical stability, even for materials that have remarkably similar molecular structures [ 10 , 43 , 44 ].…”

“…However, recent experimental studies devoted to amorphous materials have indicated some exceptions regarding the suggested correlation between fragility and tendency to crystallize for pure drugs, as well as pharmaceutical compositions [ 10 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Lately, some interesting reports have been published [ 45 , 46 , 47 ] on crystallization kinetics and inter-conformer relaxation dynamics, invoking discussion about the dynamic fragility parameter that does also not reflect the crystallization properties of materials characterized by similar chemical structures.…”

Glass Transition and Related Phenomena

“…Within the scope of amorphous pharmaceuticals, we reported on the physical instability of the anti-inflammatory drug etoricoxib [9], which was earlier unexpected, at least in atmospheric conditions. All previous BDS and DSC investigations suggested a very high resistance of the drug to recrystallization from both the supercooled liquid and glassy states at ambient pressure.…”

“…This Special Issue includes a communication [5] paper and a review [6] devoted to new experimental ideas as well as regular articles [7][8][9] that report the specific molecular properties of materials near the glass transition, which enhance our understanding of molecular mechanisms that may result in contemporary pharmaceutical or other applications. After many years of tests and challenging considerations completed due to the team leader's great research experience in the fields of dielectric and infrared spectroscopies, Kremer et al [5] showed that it is possible to usefully combine those important measurement techniques.…”

“…One of the leading trends in contemporary pharmaceutical sciences, which covers a complex study on amorphous pharmaceuticals, including their efficient formulation and long-term stability, has been also represented [8,9]. It is worth mentioning that many medical applications of pharmaceuticals require the better bioavailability of drugs, which is usually satisfied by disordered materials characterized by a higher water solubility than their crystalline counterparts.…”