Izutsu K, Yoshioka S, Kojima S, Randolph T W, Carpenter J F
National Institute of Health Sciences, Tokyo, Japan.
Pharm Res. 1996 Sep;13(9):1393-400. doi: 10.1023/a:1016086319851.
This study examined the effect of third components (low-molecular-weight saccharides and polymers) on the crystallization of poly(ethylene) glycol (PEG) in frozen solutions, focusing on the relationship between their crystallization-inhibiting ability and molecular compatibility.
Effects of sugars and polymers on the crystallization of PEG 3000 in frozen solution were monitored by differential scanning calorimetry (DSC). Pulsed-NMR was employed to monitor the molecular mobility of water and solutes in the frozen solutions. Miscibility between PEG and third components in aqueous solution was estimated from the lowering of cloud point of PEG 20,000. Thermal analysis of frozen solutions containing some non-crystallizing solutes was used to examine the possibility of phase separation in frozen solutions.
Some sugars and polymers inhibited the crystallization of PEG and formed practically stable amorphous phases among ice crystals. The mobility of solute molecules in the amorphous phase increased above the softening temperature of maximally concentrated solutions (Ts), whereas that of water molecules appeared at a lower temperature. Mono- and disaccharides that are relatively less miscible with PEG in solution inhibit PEG crystallization to a lesser degree. Two Ts regions were observed in frozen solutions containing both polyvinylpyrrolidone (PVP) and dextran, at much lower concentrations than those causing aqueous two-phase separation at ambient temperatures.
Ice crystallization raises the concentration of solutes in the remaining solution, which can lead to phase separation in the amorphous phase. Molecular compatibility between components is an important factor determining their propensity to phase separate and crystallize.
本研究考察了第三组分（低分子量糖类和聚合物）对聚乙二醇（PEG）在冷冻溶液中结晶的影响，重点关注它们的结晶抑制能力与分子相容性之间的关系。
通过差示扫描量热法（DSC）监测糖类和聚合物对PEG 3000在冷冻溶液中结晶的影响。采用脉冲核磁共振（NMR）监测冷冻溶液中水和溶质的分子流动性。根据PEG 20,000浊点的降低来估算PEG与第三组分在水溶液中的混溶性。对含有一些非结晶溶质的冷冻溶液进行热分析，以研究冷冻溶液中相分离的可能性。
一些糖类和聚合物抑制了PEG的结晶，并在冰晶之间形成了实际稳定的非晶相。在最大浓度溶液的软化温度（Ts）以上，非晶相中溶质分子的流动性增加，而水分子的流动性出现在较低温度。在溶液中与PEG混溶性相对较差的单糖和二糖对PEG结晶的抑制程度较小。在含有聚乙烯吡咯烷酮（PVP）和葡聚糖的冷冻溶液中观察到两个Ts区域，其浓度远低于在环境温度下导致水相两相分离的浓度。
冰结晶提高了剩余溶液中溶质的浓度，这可能导致非晶相中的相分离。组分之间的分子相容性是决定它们相分离和结晶倾向的重要因素。
