Chemistry Reference
In-Depth Information
inherent crystallization tendency of the compound will be considered
rst, and then
factors that can impact crystallization behavior will be discussed.
5.3 FACTORS IMPACTING THE CRYSTALLIZATION TENDENCY
OF ACTIVE PHARMACEUTICAL COMPOUNDS
It is intuitive that a compound that has a high tendency to crystallize will be more dif
cult
to stabilize in an amorphous formulation than a compound with a correspondingly low
crystallization tendency. Therefore, there has been some effort devoted to understand
which compound properties are most indicative of crystallization tendency. Some of the
factors that are thought to impact crystallization tendency of active pharmaceutical
ingredients (APIs) include the free energy of crystallization, con
gurational entropy,
interfacial free energy between the crystalline phase and the amorphous phase, molecular
mobility, differences in hydrogen bonding patterns between amorphous and crystalline
phases, and preparation method.
5.3.1 Thermodynamic and Structural Considerations
Con
gurational properties are often used to describe the thermodynamics of the
amorphous state relative to the crystalline state. These properties are all a function of
the con
gurational heat capacity (
C
p,conf
), which is the difference in the heat capacity
between the amorphous and crystalline states.
C
p,conf
can be measured experimentally by
performing differential scanning calorimetry (DSC) experiments on both the amorphous
and crystalline materials. The con
gurational entropy (
S
conf
), entropy of fusion (
Δ
S
m
),
con
gurational enthalpy (
H
conf
), and con
gurational free energy (
G
conf
) for a material
can be expressed as
Z
T
m
C
p
;
conf
T
S
conf
T
Δ
S
m
d
T
;
(5.7)
T
Z
T
m
H
conf
T
Δ
H
m
C
p
;
conf
d
T
;
(5.8)
T
G
conf
T
H
conf
T
TS
conf
T
:
(5.9)
Such thermodynamic properties have been measured and attempts made to correlate
these properties with the crystallization tendency. Zhou et al. [17] related the con
gura-
tional properties (
S
conf
,
H
conf
,
G
conf
) and molecular mobility of
five model pharmaceuti-
cal compounds to their crystallization behavior. It was observed that the compounds with
the highest
S
conf
and lowest mobilities exhibited the lowest crystallization tendencies.
The con
flexibility of a molecule;
thus, molecules with high
S
conf
can exist in multiple conformations in the undercooled
gurational entropy (
S
conf
)re
ects the conformational
