In amorphous solids, molecular mobility has been traditionally invoked to explain stability of diverse pharmaceutical systems, and water role has been commonly limited to its plasticizing properties. However, while the molecular mobility-based approach has been credited with formulating a scientific basis for development of amorphous pharmaceuticals and biopharmaceuticals, it has become increasingly clear that this approach allows only a partial description of the underlying fundamental principles. As an implicit recognition of the fact that mobility alone is not sufficient for a comprehensive understanding of stability of amorphous materials, the subjects of amorphous structure (e.g., hydrogen bonding and water clustering patterns) and media properties (e.g., proton transfer and solvent effects) have recently attracted the attention of the pharmaceutical scientists. For example, solution physical chemistry concepts, such as Hammett acidity function and Bunnett’s equations, have been extended to an amorphous pharmaceutical system, to describe water effect in hydrolysis of a model pharmaceutical compound in an amorphous carbohydrate matrix. Furthermore, on-going experimental studies by Raman, FTIR, and THz spectroscopy are supplemented with MD simulations to understand change in water clustering and distribution and H-bonding as a function of water content in various model amorphous systems. The eventual goal of these studies is to connect the experimentally-determined rates of chemical transformations of model systems (peptides and proteins embedded into amorphous matrixes) at variable water contents/activity with the solvent and water structure around the reaction hotspots. Common pharmaceutical degradation processes, such as hydrolysis, deamidation, and oxidation, are being covered in these investigations. Finally, current gaps in our fundamental understanding of water role in stability of amorphous pharmaceuticals are highlighted.
1In collaboration with: Tapiwa Chiura, Shaoxin Feng, Ke Wu (R&D, Abbvie, Irvine, CA, USA), Christian Schoneich (University of Kansas, USA), Alain Hedoux (Lille University, Lille, France), J. Axel Zeitler, (University of Cambridge, UK), and Christopher J Roberts (University of Delaware, USA)
Solid-state chemical degradation of pharmaceuticals: role of water
Lunedì 6 maggio 2024 - Ore 14:45 - Aula Magna
Dott. Evgenyi Shalaev, Development Sciences, R&D, Abbvie, Irvine, CA, USA
Seminario
Stability of solid pharmaceuticals (e.g., tablets and freeze-dried powders) can be compromised by water molecules, which are either introduced via the gas phase from the environment, or left after certain processing operations, such as freeze-drying, spray drying, or wet granulation (so-called “residual water”). The presentation is focused on amorphous states, which represent growing segment of pharmaceutical products (e.g., amorphous solid dispersions and biopharmaceuticals), while crystalline materials are also mentioned.
