Excipients: Their Role in Rational Formulation Design - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 87

Table 3 Glass transitions of freeze-dried anhydrous citric acid and its sodium
salts

T g (1C)

11 (T g ¼ 531C) Citric acid

Na citrate 69

Na 2 citrate 115

at pH 2.98 29

at pH 3.4 56

at pH 4.38 66

Data from Lu and Zografi 106 and Auffret (unpublished).

glass transition of trehalose.2H 2 O, i.e. a glass that contained 66 mol%
(9.5% w/w) of water. 74 This led to several misunderstandings until a
solution of trehalose, rigorously freeze-dried, was found to have a T g of
1061C. In order to determine T g as accurately as possible, rigorous
drying is therefore essential.
The combination of pH buffer with lyoprotectant functions can be
utilised with those salts and acids that possess sufficiently high T g values.
Citric acid and its sodium salts present particularly interesting behav-
iour, a further illustration of the remaining mysteries of glasses. The
results are summarised in Table 3.

7.3 Estimation of T g of Complex Mixtures

Several methods, more or less rigorous, exist for the calculation of T g from
quantities accessible by calorimetric measurements. For binary (anhydrous)
sugar systems, comprising glucose, fructose and sucrose, limiting values of
(dT g /dw 2 ) have been reported, based on the measured heat capacity
differences between the glasses and the fluids at T g . 78 It is interesting that
the glass properties of sucrose do not resemble those of an equimolar
mixture of glucose þ fructose. A good working approximation for estimat-
ing glass transitions of binary systems is provided by the Gordon-Taylor
equation, especially where one of the components is present in excess. It
does not require knowledge of heat capacities but is based solely on the
composition and the T g values of the individual components: 95

T g ¼ [w 1 T 1 þ kw 2 T 2 ]/[w 1 þ kw 2 ] (1)
where T 1 and T 2 are the glass transitions of the two components and w 1 ,
w 2 their mass (or mol) fractions; k is an adjustable parameter, the
magnitude of which provides information about any specific interactions
between the two components. Water is universally present, even in dried