Residual Water and Its Estimation

At the completion of primary drying, more than 99% of the original water in the formulated solution would have frozen the remaining water 

A correct definition of dry has already been commented upon because even the most hydrophobic organic substances, e.g. polystyrene, absorb water vapour to some extent. Water has therefore been called Nature s ubiquitous plasticiser . Apart from this softening role, water, being itself a very reactive and versatile molecule, might also have other effects on amorphous solid substrates, some of them unexpected, and most of them deleterious. The role of low water contents ( 1 % w/w) in affecting the behaviour of solid solutions is a subject that deserves further investigation. 

A weakness, common to all Karl Fischer-type methods, lies in the limitation that they measure the total water content of the sample, irrespective of the water distribution within the sample. In solids that are partially crystalline and partially amorphous, the residual water will be concentrated in the amorphous phase, thus depressing its Tg. This can accelerate or even promote the crystallisation of small molecule substances within the amorphous matrix. Take as an example crystalline sucrose that contains 0.5% of amorphous material and 0.17% of residual water. Since all the water is concentrated in the amorphous phase, the real water content will be 20% with a Tg of 9°C. It is also instructive to calculate the number of water molecule layers for differently sized sucrose particles. This is shown in Table 1. If the measured water content were to rise to 0.5%, corresponding to 50% in the amorphous phase, then Tg of the amorphous phase would be depressed to —70°C. It is therefore useful, if not essential, to have a reasonable estimate of the amorphous content of a preparation. Several more or less laborious methods for its determination hnd application, and they are 

Water molecular layers ( cm) Surface area (cm g f Water layers 

From a knowledge of the crystal-melting temperature, I m, the glass temperature can be estimated with some degree of conhdence, at least for many of the excipients commonly used for freeze-dried pharmaceutical preparations, where it has been found empirically that Fg/rm 0.73. Furthermore, for the same preparations, the temperature of zero mobility can be approximated by Fm/2. Also, for many materials, ACgTg x 100 kJ g At T , the viscosity of most glasses is assumed to lie between 

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