Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 100, Issue 10, Pages 4171-4197Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.22618
Keywords
phase diagrams; formulation; stability; protein; monoclonal antibodies; plasmid DNA; vaccines; circular dichroism; fluorescence; calorimetry; light scattering
Funding
- NIH [NIH48811, 5T32AI070089]
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Determining and preserving the higher order structural integrity and conformational stability of proteins, plasmid DNA, and macromolecular complexes such as viruses, virus-like particles, and adjuvanted antigens are often a significant barrier to the successful stabilization and formulation of biopharmaceutical drugs and vaccines. These properties typically must be investigated with multiple lower resolution experimental methods because each technique monitors only a narrow aspect of the overall conformational state of a macromolecular system. This review describes the use of empirical phase diagrams (EPDs) to combine large amounts of data from multiple high-throughput instruments and construct a map of a target macromolecule's physical state as a function of temperature, solvent conditions, and other stress variables. We present a tutorial on the mathematical methodology, an overview of some of the experimental methods typically used, and examples of some of the previous major formulation applications. We also explore novel applications of EPDs including potential new mathematical approaches as well as possible new biopharmaceutical applications such as analytical comparability, chemical stability, and protein dynamics. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100: 4171-4197, 2011
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