Effect of inorganic salts on crystallization of poly(ethylene glycol) in frozen solutions

Effect of inorganic salts on crystallization of poly(ethylene glycol) in frozen solutions
January 2005
Ken-ichi Izutsu and Nobuo Aoyagi, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya, Tokyo 158-8501, Japan
International Journal of Pharmaceutics Volume 288, Issue 1 , 6 January 2005, Pages 101-108
Received 19 July 2004; revised 25 August 2004; accepted 21 September 2004. Available online 11 November 2004.
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Abstract
The effect of inorganic salts on eutectic crystallization of poly(ethylene glycol) (PEG) 1500?20,000 in frozen solution was studied to model the polymer and inorganic salt interaction in freeze-dried formulations. Thermal analysis of an aqueous PEG 3000 solution showed a eutectic PEG crystallization exotherm at approximately -47 ?C and a subsequent PEG crystal melting endotherm at -14.9 ?C. Addition of sodium chloride prevented the PEG crystallization in the freeze-concentrated solution surrounding ice crystals. Higher concentration NaCl was required to retain higher molecular weight PEG in the amorphous state. Various inorganic salts prevented the PEG crystallization to varying degrees depending mainly on the position of the anion in the Hofmeister's lyotropic series. Some salting-in and ?intermediate? salts (NaSCN, NaI, NaBr, NaCl, LiCl, KCl, and RbCl) inhibited the crystallization of PEG 7500 in frozen solutions. On the other hand, salting-out salts (NaH2PO4, Na2HPO4, Na2SO4, and NaF) did not show an apparent effect on the PEG crystallization. Some salting-out salts induced PEG crystallization in PEG and sucrose combination frozen solutions. The varying abilities of salts to prevent the PEG crystallization in frozen solutions strongly suggested that the solutes had different degrees of miscibility in the freeze-concentrates.