Dissolution properties, solid-state transformation and polymorphic crystallization: progesterone case study.

Area of Science:

• Solid-state chemistry
• Pharmaceutical sciences
• Materials science

Background:

• Progesterone, a poorly soluble steroid hormone, exists in two polymorphic forms (form 1 and form 2).
• Understanding the physical-chemical properties and solid-state behavior of these polymorphs is essential for drug formulation and stability.

Purpose of the Study:

• To characterize the two polymorphs of progesterone (forms 1 and 2).
• To investigate methods for obtaining form 2 and evaluate its solid-state properties.
• To assess the impact of mechanical stress on the polymorphic stability of progesterone.

Main Methods:

• Solid-state characterization using X-ray powder diffraction, hot stage microscopy, spectroscopy (FTIR, Raman, NMR), thermal analysis, and scanning electron microscopy.
• Determination of intrinsic dissolution rates (IDR) for both polymorphs.
• Evaluation of mechanical stress effects on form 2, including grinding and polymorphic quantification via Rietveld analysis of XRD patterns.

Main Results:

• Form 2 was successfully obtained from diluted solutions and melt crystallization; form 1 from concentrated solutions.
• Mechanical stress (grinding) applied to metastable form 2 induced its transformation into stable form 1.
• Grinding form 2 resulted in a 17% conversion to form 1 within 10 days at room temperature (approx. 25°C).

Conclusions:

• The study successfully characterized progesterone polymorphs and identified methods for their preparation.
• Mechanical stress can induce a solid-state transformation from the metastable form 2 to the stable form 1.
• These findings highlight the importance of considering mechanical stress during progesterone processing and formulation to ensure polymorphic stability.