Solid phase transition of CS-891 enantiotropes during grinding

Area of Science:

• Solid-state chemistry
• Pharmaceutical sciences
• Crystallography

Background:

• N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17beta-carboxamide (CS-891) is an orally effective testosterone 5-reductase inhibitor.
• Understanding the physical properties and solid-state behavior of CS-891 is crucial for its pharmaceutical development.

Purpose of the Study:

• To investigate the physical properties of CS-891, including its polymorphic forms and solid-state transitions.
• To examine the effect of grinding temperature on the transformation between crystalline and amorphous states of CS-891.

Main Methods:

• Differential scanning calorimetry (DSC)
• Powder X-ray diffraction (PXRD) at elevated temperatures
• Single crystal X-ray crystallography
• Grinding experiments

Main Results:

• CS-891 exists as two enantiotropic crystalline forms: a low-temperature stable Form A and a high-temperature stable Form B.
• A reversible solid-state transition occurs between Form A and Form B at approximately 58°C.
• Grinding Form A below the transition temperature resulted in an amorphous form.
• Grinding Form A above the transition temperature produced an amorphous form, with some conversion back to Form B.
• The amorphous form in equilibrium with Form B exhibited greater physical stability than the amorphous form generated by grinding below the transition temperature.

Conclusions:

• CS-891 exhibits enantiotropic polymorphism with a transition temperature around 58°C.
• Grinding conditions significantly impact the solid-state form and physical stability of CS-891.
• The physical stability of the amorphous form is dependent on its formation conditions and equilibrium with crystalline phases.