Chemistry Reference
In-Depth Information
Figure 1.15.
Rates of nucleation and crystal growth as a function of temperature in relationship
to
T
gα
and
T
gβ
(reproduced with permission from Ref. 29. Copyright 1997, Elsevier).
a reduction in molecular mobility for inhibiting crystallization over long storage times
should require
T
g
T
to be somewhere in the range of 100
-
50 K.
1.6 SUPERSATURATION OF API IN AQUEOUS MEDIA
FROM THE AMORPHOUS STATE
The major purpose of using the amorphous form of an API in solid dosage forms is to
take advantage of the greater apparent solubility from the amorphous state relative to that
from the crystal because of the lack of a well-ordered crystal lattice with attractive
intermolecular energy that ordinarily tends to reduce solubility in the crystal. Three
questions have to be addressed when taking this approach for enhancing API solubility:
(i) Can the amorphous solid be maintained in the amorphous state over the time of
storage before use? (ii) What level of improvement in solubility in aqueous media can be
expected for the amorphous form relative to the crystal? (iii) Can the desired super-
saturated concentration of dissolved API from the amorphous form be maintained over
the time period required to ensure acceptable oral bioavailability? In the previous
sections of this chapter, we have outlined a number of principles that allow the
rst
question to be addressed. Here, we wish to examine the underlying principles that can be
applied to address questions 2 and 3.
From a thermodynamic perspective, we would expect the relative solubility of a
molecule in the amorphous and crystalline states at any temperature
T
to be directly
determined by the free energy difference between the amorphous and crystalline forms,
as illustrated in Figure 1.2. This free energy difference, designated as
G
A
=
C
T
Δ
, can be
