Effect of Polymer Size and Cosolutes on Phase Separation of Poly(Vinylpyrrolidone) (PVP) and Dextran in Frozen Solutions

Effects of Solute Miscibility on the Micro- and Macroscopic Structural Integrity of Freeze-Dried Solids

“…Thermal analysis of frozen solutions showed different miscibilities of PVP and dextran depending on their molecular size and concentration ratios. [18][19][20][21] The large PVP and dextran molecules were freeze-concentrated into different phases that contain specific ratios of a major solute and a minor counterpart component, as has been reported previously in aqueous two-layer systems. 21,24 The absence of apparent clouding before ice formation and the two T 0 g s also observed in freezing a lower concentration initial solution (10 mg/ mL each) indicated that the increased solute concentrations due to ice growth, rather than the lower Figure 5.…”

“…different solute miscibility in the freeze-concentrated phases surrounding ice crystals. 21,22 Single transitions that shifted between T 0 g of the component solutes (dextran 1060 and PVP 10,000 or dextran 35,000) indicated their freeze-concentration into the same nonice-phase (A). Two transitions at temperatures close to the T 0 g of the individual polymers indicated freezing-induced separation of PVP 29,000 and dextran 35,000 into different concentrated phases predominant in one of the polymers (B).…”

“…The polymer mixture also showed the two T 0 g s in freezing from more dilute aqueous solutions (10 mg/mL each, data not shown). 21 Single T 0 g transitions observed in some frozen solutions containing predominantly one of the polymers (PVP 29,000 or dextran 35,000, !90%, w/w) suggested their miscibility in the freeze-concentrated phase and/or an inapparent transition of the minor phase. Aqueous two-layer formation of the PVP 29,000 and dextran 35,000 mixture solutions was observed at above certain polymer concentrations, dependent on the temperature (120 mg/mL each at room temperature, 80 mg/mL each at À108C).…”

“…Some polymers (e.g., large poly(vinyl pyrrolidone) (PVP) and dextran) that are miscible in their lower concentration aqueous solutions separate into multiple freeze-concentrated phases predominant in one of the polymers, showing different transitions (T 0 g s) for the individual phases in the thermal analysis. [18][19][20][21][22] Thermodynamically unfavorable interactions between the polymer molecules that cause aqueous two-layer formation in their higher concentration solutions, as well as the excess concentrations caused by ice growth, induce the multiple freeze-concentrated phases. 19,23,24 The polymer miscibilities also depend on various factors including monomer structure, molecular size, concentration ratio, and cosolute compositions.…”

Lyophilization Process Design and Development Using QbD Principles

“…During freezing, stability problems may arise due to pH changes resulting from crystallization of certain buffer components (Gomez et al 2001), cryoconcentration, ice-liquid interface (Bhatnagar et al 2007(Bhatnagar et al , 2008, phase separation (Izutsu et al 2005;Padilla and Pikal 2010), and cold denaturation (Tang and Pikal 2005). Formulations used for freeze-drying exhibit super-cooling tendencies and thermal events such as eutectic or glass transitions (Pikal 1990).…”