(W0930-01-01) Are Amorphous Drugs More Compressible Than Their Crystalline Counterparts?

Purpose: Contemporary research on amorphous solids has focused on how they can be used to overcome solubility- and dissolution-related challenges in the development of poorly water-soluble drugs.¹ Yet, little work has been systematically done to understand their mechanical behavior, which is important to successfully manufacture tablets.^2,3 Consequently, the question of how eliminating the long-range order in molecular crystals alters mechanical responses and, in turn, modulates bulk powder compressibility remains unanswered. This work aimed to highlight the inherent differences in mechanical properties between amorphous and crystalline solids at the bulk scale. Specifically, we hypothesized that eliminating the long-range crystalline order causes an increase in material compressibility, potentially simplifying formulation development.

Methods: To test the hypothesis, we chose a set of nine molecules with diverse molecular structures, inter-molecular interaction possibilities, and crystalline arrangements. Crystalline powders were used as received, whereas amorphous powders were prepared by melt-quenching. These powders were compressed using the Styl’One compaction simulator to ~ 1 GPa pressure with a 6 mm round flat-faced tooling. A V-shaped profile with 1 second load and unload times was used. The bulk powder compressibility was compared using a commonly used plasticity parameter, mean yield pressure (P_y) from in-die Heckel analysis.⁴ Statistical analyses, particularly the Mann-Whitney U-test and the interquartile range (IQR) determinations, along with graph plotting were performed using RStudio (version 2023.12.0+369). For the Mann-Whitney U-test, the null hypothesis was that there is no difference between the medians of crystalline and amorphous sample distributions. The inference was drawn at a 5% significance level.

Results: Results show that amorphous solids have an overall lower median P_y than their crystalline counterparts (Figure 1a). However, the amorphization-induced reduction in P_y is drug-dependent (Figure 1b). Further, for these molecules, the data points for amorphous solids are more narrowly distributed (IQR = 7.29 MPa) than their crystalline counterparts (IQR = 39.99 MPa) (Figure 1b). Compared with crystals, these observations for amorphous solids are attributed to an increase in free volume accompanied by a decrease in inter-molecular interaction strengths, particularly the conventional hydrogen bonds. Therefore, our findings underscore the significant impact of eliminating directional intermolecular interactions that lead to packing anisotropy among crystals on mechanical properties. Also, these results highlight a potential strategy for improving the tableting performance of incompressible crystalline solids by amorphization. Overall, since the tabletability of any material depends on the interplay of bonding area and bonding strength among particles,⁵ a higher compressibility (lower P_y) favors tabletability. Thus, using amorphous solids could effectively improve the tabletability of poorly compressible crystalline drugs.

Conclusion: In general, amorphous drugs are more compressible (and plastic) than their crystalline counterparts. Therefore, amorphous solids may be used to overcome the tableting problems of poorly compressible crystalline drugs.

References: 1. Thakore SD, Sirvi A, Joshi VC, et al. Biorelevant dissolution testing and physiologically based absorption modeling to predict in vivo performance of supersaturating drug delivery systems. Int J Pharm. 2021;607:120958.
2. Lamm MS, Simpson A, McNevin M, et al. Probing the effect of drug loading and humidity on the mechanical properties of solid dispersions with nanoindentation: antiplasticization of a polymer by a drug molecule. Mol Pharm. 2012;9(11):3396-3402.
3. Osei-Yeboah F, Sun CC. Effect of Drug Loading and Relative Humidity on the Mechanical Properties and Tableting Performance of Celecoxib–PVP/VA 64 Amorphous Solid Dispersions. Int J Pharm. 2023:123337.
4. Vreeman G, Sun CC. Mean yield pressure from the in-die Heckel analysis is a reliable plasticity parameter. Int J Pharm X. 2021;3:100094.
5. Sun CC. Materials science tetrahedron—A useful tool for pharmaceutical research and development. J Pharm Sci. 2009;98(5):1671-1687.

Acknowledgements: VCJ thanks Dr. Gerrit Vreeman for helpful discussions regarding Py determinations.


Figure 1. A comparison of the mean yield pressure (Py) from in-die Heckel analysis between crystalline and amorphous solids. (a) A box-and-whisker plot highlighting the distribution of all data collected in this study. (b) A ladder plot highlighting the drug-dependent differences. Overall, amorphization reduces the Py, i.e., improves powder compressibility.