Excipients: Their Role in Rational Formulation Design - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 88

products, so that component 1 in Equation (1) usually refers to water.
Although some uncertainty exists about the value, the glass transition
temperature of water has traditionally been taken as 135 K. 96 Recently,
however, and based on different methods of measurement, this value has
been challenged, and 165 K has been suggested. 97 This value brings
water more in line with other hydrogen-bonded network-forming sys-
tems. The value of the Gordon-Taylor equation, as shown, is limited,
because water is invariably one of the components, and most pharma-
ceutical formulations therefore contain at least three components, in-
cluding water. Equation (1) can, however, be expanded to make it
applicable to any number of components, 78 although the procedure
would require the knowledge of physical properties, including specific
heat data of every component in the mixture; such information rarely
exists. In practice, the application of the Gordon-Taylor equation can
be extended, although in an approximate form to multicomponent
mixtures; the procedure only requires data of their individual T g . 98
Since the T g of water is very low, as is also its molecular weight, even
trace ( o 1% w/w) amounts of water will produce a marked effect on the
glass transition of a mixture.
7.4 Effects of Excipients on Product Attributes
The influence exerted by excipients both on the process parameters and on
the physical properties of the dried product needs to be clearly under-
stood. Since the excipient is frequently the major component of a phar-
maceutical mixture to be freeze-dried, it significantly increases the total
solids content and hence the bulk density of the dried product, rendering
it more stable against mechanical disruption. At the most basic level, a
crystallising excipient will act in this manner without, however, affecting
the chemical stability of any labile mixture components. An amorphous
excipient, on the other hand, reduces the quantity of ice produced and
thus the degree of freeze-concentration. In practice, this will shorten
primary drying times but will, in turn, increase secondary drying times.
As regards the role played by excipients in determining the glass
transitions of the freeze-concentrate and the final dried product, they
may increase T g , thus allowing the implementation of shorter cycles by
raising the maximum safe temperature for ice sublimation. In addition,
any excipient that increases T g of the final dried product will thereby
raise the product's maximum safe storage temperature. This is of
particular importance for the production of shelf-stable products. Some
excipients, particularly those of a PHC type, also stabilise proteins in