(M1430-07-47) Impact of High Pressure on Structure and Thermal Properties of Amorphous Pharmaceuticals and Biopharmaceuticals

Purpose: The purpose of this study is to establish if solid-state compression results in irreversible changes in structural or thermal properties of amorphous small molecular weight drugs and freeze-dried formulations. We hypothesize that application of high pressure can have similar effect on  properties of amorphous materials as thermal annealing, which can improve chemical stability of both proteins and small molecules¹.  Behavior of glasses under pressure has been a subject of various investigations, with reports on solid-state drug/excipient miscibility and amorphous-to-crystalline conversion.²

Methods: Two small molecular weight drugs, two amorphous carbohydrates, and four freeze-dried protein formulations were studied, with both partially deuterated and completely protonated molecules used. The samples were exposed to pressure 3 to 50 kbar at room temperature in two types of presses, and analyzed at ambient pressure by total neutron scattering on SNAP diffractometer (Oak Ridge National Laboratory, USA), differential scanning calorimetry (DSC), X-ray powder diffraction, and thermal gravimetric analysis, as well as Raman spectroscopy (finger print region) and high performance liquid chromatography.

Results: The majority of the samples remained amorphous after compression, with the exception of freeze-dried glucose.  While thermal properties of one compound were not impacted by compression, other samples showed significant  changes in DSC results, including: an increase in the glass transition temperature, Tg; appearance of a second Tg in a freeze-dried sorbitol/albumin formulation (Figure 1, left); change in non-isothermal trehalose crystallization; increase in the melting temperature and decrease in the enthalpy of thermal unfolding of freeze-dried bovine serum albumin. In addition, a significant, more than 20%, decrease in the heat capacity change at the Tg was observed in two materials after 50 kbar compression; such change is consistent with decreased glass fragility. Neutron scattering results showed structural changes in a pharmaceutical compound (Figure 1 right).

Conclusion: Pressure treatment of amorphous pharmaceuticals can result in irreversible changes in their properties, although the type and magnitude of the modifications depends on the type of material. Follow-up studies are planned to differentiate impact of pressure on materials with different conformational flexibility and hydrogen bonding patterns, investigate role of trace amounts of absorbed water, and perform pair distribution function analysis of the neutron scattering data.

References: 1. (a) B. Wang et al, J Pharm Sci 2010, 99, 683-700; (b) S. A. Luthra, et al. J. Pharm. Sci. 2008, 97, 5240-5251; (c) M. J. Pikal, et al., patent EP 1740214 B1. (d) R. D. Reddy, et al. Can. Pat. Appl., CA 2547216 A1, 2007.
2. (a) K. Chmiel, et al. Eur J Pharm Biopharm, 2019, 143, 8-17. (b) M. Rams-Baron et al, Mol Pharm 2015, 12, 3628-3638; (c) N. K. Thakral, et al. Mol Pharm. 2015, 12, 253-263. (d) S. K. Berzin, R. Suryanarayanan. Cryst Growth Des. 2017, 18, 839-848. (c) K. Kawakami, Pharmaceutics 2019, 11, 202.

Acknowledgements: The study was supported by ORNL proposals IPTS-32367.1 and IPTS-32646.1 JK, KW, SC, AH, and ES are AbbVie employees and may own AbbVie stock. AbbVie did not provide financial funds for the study. AbbVie contributed to the design, data collection, analysis, and interpretation of the results, and wrote, reviewed, and approved the abstract.


Examples of DSC of a freeze-dried formulations before and after 50 kbar compression


Examples of total neutron scattering patterns for amorphous small molecular weight drug before and after 50 kbar compression