Chemistry Reference
In-Depth Information
might be required to provide a certain value of
T
Tgmix
, given only the individual
T
g
values.
This can be done very simply by using Equation 1.32 or Equation 1.33 or by estimating
K
in Equation 1.30 or Equation 1.31 and using Equation 1.29. To test for ideality or
nonideality in the amorphous mixture, one can use these estimates of
T
Tgmix
and
experimentally determine
T
Tgmix
. Deviations of experimental results from the expected
plot would indicate that the mixing of components is nonideal; the deviations can be
either negative or positive, meaning that the experimentally determined values of
T
Tgmix
are either greater or less than predicted. Values greater than those predicted for ideality
indicate that the net excess free volume is less than that expected for the weighted sum of
individual component free volumes, or that A:B interactions are greater than the A:A and
B:B interactions. If the deviations are negative, this means that there is greater excess free
volume than expected or stronger A:A and B:B interactions than those between A and B.
Examples of
T
g
versus concentration pro
les for ideal and nonideal mixtures with
positive and negative deviations from ideality in miscible amorphous mixtures have been
reported for pharmaceutical systems [43
-
45].
1.8 FORMATION AND PROPERTIES OF AMORPHOUS
SOLID DISPERSIONS
The focus of the remaining parts of this chapter, and indeed, the rest of this topic, will be
on amorphous solid dispersions, which we will de
ne as single-phase amorphous
mixtures of an API and water-soluble polymer intended to produce enhanced aqueous
dissolution and oral bioavailability [46]. The polymer is used (i) to provide long-term
storage stability of the amorphous API by inhibiting solid-state crystallization and (ii) to
maintain a desirable level of supersaturation in the dissolution medium by preventing
solvent-mediated crystallization over the time period needed for the required
bioavailability. In some cases a surfactant is included in an ASD to further promote
dissolution and/or to facilitate the manufacturing process. Various details of
the processing of amorphous dispersions and the ingredients used on a practical scale
will be discussed throughout this topic. Here, we wish to introduce some general
concepts and issues that build on the principles discussed above. Depending on the
physical and chemical characteristics of the API and polymer, amorphous solid disper-
sions are primarily prepared by either hot melt extrusion (HME) of a mixture of
powdered API and polymer, or by the spray drying of a solution of API and polymer
from a suitable volatile solvent. In HME the dry powder mixture is placed into an
extruder at elevated temperatures that melts or softens the components to facilitate
mixing. The material is continuously extruded, cooled, and chopped into small frag-
ments, often called lentils, which are further milled with other formulation ingredients
into powdered form. Ideally, to facilitate the process of molecular mixing, the crystalline
API should be melted, if it is not prone to chemical decomposition at these elevated
temperatures, and the polymer should have as low a
T
g
as possible to promote softening
at these temperatures. Surfactants, such as those tabulated in Appendix A, are often
added to lower melting and glass transition temperatures. Advantages of the HME
process are that it can be carried out continuously, is solvent-free, and can be scaled up to
