Chemistry Reference
In-Depth Information
The crystallization exotherm observed in the DSC can also be used to probe
interactions between the API and the polymer using the reduced crystallization temper-
ature (
T
RC
) and the following equation [7]:
T
RC
T
c
T
g
=
T
m
T
g
;
(3.2)
where
T
c
is the crystallization exotherm temperature,
T
g
is the glass transition tempera-
ture, and
T
m
is the melting endotherm temperature.
The exotherm temperature is measured with three to four different polymer
loadings. If the crystallization exotherm shifts to higher temperature with increased
polymer, then there are interactions between the components indicating a more stable
system. If there is no shift in the exotherm with increased polymer levels, then there is
minimal interaction. A plot of the polymer content versus the reduced crystallization
temperature results in the crystallization parameter based on the slope of the line. This
crystallization parameter can be used to semiquantitatively rank order the polymers
with the higher values indicating better stability. Work with nifedipine showed good
interactions with PVP K25, PVP/VA 64, and Soluplus
,anditwascon
rmed with
other methods for determining interactions with nifedipine or a related compound
felodipine, such as solubility and Flory
Huggins interaction parameters [30], misci-
bility assessment [35], and stability testing [36]. Studies on a new chemical entity
using the reduced crystallization temperature showed good interactions with only one
polymer (PAA). Physical stability studies performed on the API:PAA dispersion at
40
-
C/75% RH for up to 6 months in a closed container with desiccant showed that the
dispersion was physically stable.
°
For early dispersion systems,
binary mixtures of a polymer and the API will be the easiest to investigate. Once
acceptable binary mixtures have been identi
3.2.2.2 Binary Versus Ternary Systems
ed and characterized, other components can
be added to see whether the properties can be improved [37,38]. These components can
include polymers, surfactants, lipids, pH modi
ers, or even small molecules, such as
citric acid or magnesium oxide. The choice of another component will depend on the API
and the property that needs to be modi
ed. A sampling of some of these components is
given in the following section.
Another approach to selecting ternary systems is to include a variety of
polymers and surfactants during the initial screen. Using a plate screen, a larger
number of combinations can be tried. An example of a ternary dispersion screen for
a development compound used six polymers and eight surfactants [15]. An exci-
pient:compound ratio of 10:1 was used for 14 binary mixtures and a polymer
surfactant ratio of 3:1 was used for 48 ternary formulations. Initial dispersions were
evaluated for solubility in the plate as represented in Figure 3.3. Those dispersions
exhibiting acceptable solubility were moved to the next tiers involving dissolution
and
in vivo
testing. An HPMCP:Vitamin E TPGS amorphous solid dispersion was
foundtogivethebest
in vivo
performance resulting in an oral bioavailability similar
to a solution.
