Interplay between
Thermodynamics and Kinetics on Polymorphic
Appearance in the Solution Crystallization of an Enantiotropic System,
Gestodene
Posted on 2017-08-21 - 17:47
The
development of rational pharmaceutical polymorph control systems
from crystallization requires the experimental manipulation of both
thermodynamic and kinetic factors. Herein, we discuss the interplay
between thermodynamics and kinetics on the formation mechanism responsible
for concomitant polymorphs and their subsequent phase transformations.
The polymorphic system studied is gestodene, which exhibits two enantiotropic
polymorphs, I and II. The thermodynamic stability in ethanol is I
> II above 18.5 °C and I < II below. At low supersaturation
(1.09 to 1.25), plate-like crystals corresponding to form I become
the dominant polymorph at T ≥ 19 °C,
while at T ≤ 17 °C, needle-like solids
corresponding to form II predominate. Solution crystallization at
5 ≤ T ≤ 25 °C and high supersaturation
(1.36 to 1.81) results in concomitant polymorphs of forms I and II.
The assessments of nucleation and growth kinetics indicate that at
lower supersaturations, both nucleation and growth rates of the stable
form are higher than that of the metastable one, while at higher supersaturations,
the reverse occurs. It is therefore concluded that at lower supersaturations
the stable form is favored by both thermodynamics and kinetics and
at higher supersaturations concomitant polymorphism is the result
of a balance between these competing driving forces. A semiempirical
model that displays the influence of initial supersaturation and crystallization
temperature on the relative nucleation rate of the two forms was derived
and could be used to predict the polymorphic form resulting from nucleation
with good accuracy. As the solvent-mediated polymorphic transformation
kinetics between forms I and II is relatively fast at 5, 10, 30, and
35 °C, it can reasonably be expected that one can use a slurrying
procedure to obtain the pure stable form when concomitant polymorphs
appear at conditions of relatively high supersaturations.
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Zhu, Liang; Wang, Li-yu; Sha, Zuo-liang; Wang, Yan-fei; Yang, Li-bin; Zhao, Xiao-yu; et al. (2017). Interplay between
Thermodynamics and Kinetics on Polymorphic
Appearance in the Solution Crystallization of an Enantiotropic System,
Gestodene. ACS Publications. Collection. https://doi.org/10.1021/acs.cgd.7b00335
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AUTHORS (7)
LZ
Liang Zhu
LW
Li-yu Wang
ZS
Zuo-liang Sha
YW
Yan-fei Wang
LY
Li-bin Yang
XZ
Xiao-yu Zhao
WD
Wei Du
KEYWORDS
growth ratespolymorphic formpolymorphic systemnucleation ratepolymorph control systemssupersaturationEnantiotropic Systemenantiotropic polymorphsSolution Crystallizationsolution crystallizationPolymorphic Appearancecrystallization temperaturesolvent-mediated polymorphic transformation kineticsformation mechanismphase transformationsslurrying proceduregrowth kineticsform II