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

Abstract

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.