The glass transition temperatures of amorphous trehalose–water mixtures and the mobility of water: an experimental and in silico study Alexandra Simperler, a Andreas Kornherr, b, * Reenu Chopra, a William Jones, a, * W. D. Samuel Motherwell c and Gerhard Zifferer b a The Pfizer Institute for Pharmaceutical Materials Science, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK b Institute of Physical Chemistry, University of Vienna, Wa ¨ hringer Strasse 42, A-1090 Wien, Austria c Cambridge Crystallographic Database Centre, 12 Union Road, Cambridge CB2 1EZ, UK Received 27 November 2006; received in revised form 6 April 2007; accepted 11 April 2007 Available online 27 April 2007 Abstract—Isothermal–isobaric molecular dynamics simulations are used to calculate the specific volume of models of trehalose and three amorphous trehalose–water mixtures (2.9%, 4.5% and 5.3% (w/w) water, respectively) as a function of temperature. Plots of specific volume versus temperature exhibit a characteristic change in slope when the amorphous systems change from the glassy to the rubbery state and the intersection of the two regression lines provides an estimate of the glass transition temperature T g . A com- parison of the calculated and experimental T g values, as obtained from differential scanning calorimetry, shows that despite the pre- dicted values being systematically higher (about 21–26 K), the trend and the incremental differences between the T g values have been computed correctly: T 5:3% ðw=wÞ g < T 4:5% ðw=wÞ g < T 2:9% ðw=wÞ g < T 0:0% ðw=wÞ g . The mobility of water has been investigated over temperature ranges covering the rubbery and the glassy phases of the trehalose–water mixtures by calculating the diffusion coefficients of water. The temperature dependence of the diffusion coefficient changes in the region of the glass transition and can be used as well to esti- mate T g values. The activation energies for water diffusion were found to be independent of the amount of water in amorphous trehalose. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Amorphous trehalose–water mixtures; Differential scanning calorimetry; Diffusion; Glass transition temperatures; Molecular dynamics simulations 1. Introduction Amorphous carbohydrates are often employed in the pharmaceutical and food industries to effectively encap- sulate, stabilise and ultimately release labile pharmaceu- tically active materials. They possess advantageous properties such as being readily available with high pur- ity, low toxicity, good glass-formers and have high glass transition temperatures (T g ). 1,2 At temperatures below T g , in the so-called glassy state, molecular mobility is sharply reduced. High viscosity of the system slows the relaxation time down dramatically and the amorphous formulation gains physical stability. 1 The higher the T g value of an amorphous formulation the higher the tem- perature to which the physical stability can be extended. Thus, encased in a high T g amorphous carbohydrate, pharmaceutical products may be stored at room temper- ature and shipped without cooling. For example, the disaccharide trehalose (Scheme 1) is widely used for this purpose due to its relatively high glass transition tem- perature and low tendency to crystallise. 1–4 0008-6215/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2007.04.011 * Corresponding authors. Tel.: +43 0 1 4277 52434 (A.K.); tel.: +44 0 1223 336468 (W.J.); e-mail addresses: andreas.kornherr@univie. ac.at; wj10@cam.ac.uk Carbohydrate Research 342 (2007) 1470–1479