Polymorphism of Progesterone: A New Approach for the Formation of Form II and the Relative Stabilities of Form I and Form II

In
the present study, a novel technique has been developed for
producing progesterone form II crystals by using shear-assisted sonocrystallization
(SAS) method. Progesterone, a steroid hormone, has been recognized
for more than 70 years as having two polymorphs, a stable form (form
I) and a metastable form (form II). Previous attempts have failed
to produce a single crystal of form II of progesterone without the
presence of a cocrystal additive or template. The technique proposed
in the current study is the first to report the growth of single crystals
of progesterone form II. The produced crystals were characterized
using X-ray diffraction, differential scanning calorimeter, and Fourier
transform infrared spectroscopy. Single crystal X-ray diffraction
was performed for comparing the hydrogen bond geometry of forms I
and II. Solubility and dissolution rates were estimated, providing
insight on the thermodynamics of both forms. Stability studies of
both forms were conducted for 60 days, which confirmed the higher
stability of progesterone form I. Comparing the crystal structure
of form I and form II provides evidence for their relative stabilities.
The SAS technique can be proposed as a novel strategy for polymorphic
transformation of progesterone, which can increase the dissolution
rate, enhance oral bioavailability, and decrease dose-related side
effects.