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  • Preparation of Amorphous Solid Dispersions by Cryomilling: Chemical and Physical Concerns Related to Active Pharmaceutical Ingredients and Carriers.

Preparation of Amorphous Solid Dispersions by Cryomilling: Chemical and Physical Concerns Related to Active Pharmaceutical Ingredients and Carriers.

Molecular pharmaceutics (2020-01-22)
Timothy Pas, Alessandra Bergonzi, Emiel Michiels, Frederic Rousseau, Joost Schymkowitz, Robin Koekoekx, Christian Clasen, Bjorn Vergauwen, Guy Van den Mooter
ABSTRACT

In this work, a chemical (and physical) evaluation of cryogenic milling to manufacture amorphous solid dispersions (ASDs) is provided to support novel mechanistic insights in the cryomilling process. Cryogenic milling devices are considered as reactors in which both physical transitions (reduction in crystallite size, polymorphic transformations, accumulation of crystallite defects, and partial or complete amorphization) and chemical reactions (chemical decomposition, etc.) can be mechanically triggered. In-depth characterization of active pharmaceutical ingredient (API) (content determination) and polymer (viscosity, molecular weight, dynamic vapor sorption, Fourier transform infrared spectroscopy, dynamic light scattering, and ANS and thioflavin T staining) chemical decomposition demonstrated APIs to be more prone to chemical degradation in case of presence of a polymer. A significant reduction of the polymer chain length was observed and in case of BSA denaturation/aggregation. Hence, mechanochemical activation process(es) for amorphization and ASD manufacturing cannot be regarded as a mild technique, as generally put forward, and one needs to be aware of chemical degradation of both APIs and polymers.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phosphorus pentoxide, ReagentPlus®, 99%