Freeze-Concentration Separates Proteins and Polymer Excipients Into Different Amorphous Phases |
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Authors: | Izutsu Ken-ichi Kojima Shigeo |
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Institution: | (1) National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo, 158-8501, Japan;(2) National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo, 158-8501, Japan |
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Abstract: | Purpose. To study the miscibility of proteins and polymer excipients in frozen solutions and freeze-dried solids as protein formulation models.
Methods. Thermal profiles of frozen solutions and freeze-dried solids containing various proteins (lysozyme, ovalbumin, BSA), nonionic polymers (Ficoll, polyvinylpyrrolidone PVP]), and salts were analyzed by differential scanning calorimetry (DSC). The polymer miscibility was determined from the glass transition temperature of maximally freeze-concentrated solute (Tg ) and the glass transition temperature of freeze-dried solid (Tg).
Results. Frozen Ficoll or PVP 40k solutions showed Tg at –22°C, while protein solutions did not show an apparent Tg . All the protein and nonionic polymer combinations (5% w/w, each) were miscible in frozen solutions and presented single Tg s that rose with increases in the protein ratio. Various salts concentration-dependently lowered the single Tg s of the proteins and Ficoll combinations maintaining the mixed amorphous phase. In contrast, some salts induced the separation of the proteins and PVP combinations into protein-rich and PVP-rich phases among ice crystals. The Tg s of these polymer combinations were jump-shifted to PVP's intrinsic Tg at certain salt concentrations. Freeze-dried solids showed varied polymer miscibilities identical to those in frozen solutions.
Conclusions. Freeze-concentration separates some combinations of proteins and nonionic polymers into different amorphous phases in a frozen solution. Controlling the polymer miscibility is important in designing protein formulations. |
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Keywords: | protein formulation freeze-drying phase separation excipient |
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