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Pharm Res (2012) 29:26842697 DOI 10.1007/s11095-011-0658-4
RESEARCH PAPER
The Effect of Water Plasticization on the Molecular Mobility and Crystallization Tendency of Amorphous Disaccharides
Ville Petteri Heljo & Antti Nordberg & Mikko Tenho & Tommi Virtanen & Kirsi Jouppila & Jarno Salonen & Sirkka Liisa Maunu & Anne Mari Juppo
Received: 29 September 2011 /Accepted: 13 December 2011 /Published online: 28 December 2011 # Springer Science+Business Media, LLC 2011
ABSTRACTPurpose To study how water plasticization affects the molecular mobility and crystallization tendency of freeze-dried trehalose, sucrose, melibiose and cellobiose.
Methods Freeze-dried disaccharides were subjected to different relative humidity atmospheres and their physical stabilities were evaluated. Lyophilizate water sorption tendencies and glass transition temperatures were modeled using Brunauer-Emmett-Teller (BET) and Gordon-Taylor (GT) equations, respectively. Sucrose and cellobiose crystallization tendencies were compared by using the concept of reduced crystallization temperature (RCT), and the molecular mobilities of trehalose and melibiose were compared by measuring their T1H relaxation time constants.
Results Based on the BET and GT models, water sorption tendency and the resulting plasticizing effect were different in sucrose when compared to the other disaccharides. Trehalose and melibiose exhibited generally slower crystallization rates when compared to sucrose and cellobiose. Amorphous melibiose was shown to be particularly stable within the studied water content range, which may have partly been caused by its relatively slow molecular mobility. Conclusions Slow amorphous-to-crystalline transition rate is known to be important for lyoprotecting excipients when formulating a robust drug product. The physical stabilities of amorphous trehalose and melibiose even with relatively high water contents might make their use advantageous in this respect compared to sucrose and cellobiose.
KEY WORDS amorphous . crystallization . disaccharide . mobility. water
INTRODUCTION
Physical stability of the amorphous state is very important for freeze-dried drug products containing protein-structured pharmaceuticals, where excipients in glassy state are used to inhibit protein degradation during processing and storage (1). Crystallization of such an amorphous excipient can lead to structural alterations, aggregation and activity loss in proteins, as the glassy matrix immobilizing the protein and forming hydrogen bonds with its hydrophilic surface is lost (2). This means that uncontrolled crystallization is never a desirable phenomenon in such drug products.
Disaccharides are often employed in commercial freeze-dried formulations as amorphous lyoprotecting excipients (3). However, the protein...