Solid state of a new PDE-5 inhibitor DA-8159: characterization, dissolution, transformation

Area of Science:

• Pharmaceutical Sciences
• Solid-State Chemistry

Background:

• Understanding drug polymorphism is crucial for formulation development and bioavailability.
• DA-8159 is a novel phosphodiesterase type 5 (PDE-5) inhibitor.

Purpose of the Study:

• To prepare and characterize different polymorphic forms of DA-8159.
• To evaluate the solubility and stability of these forms.

Main Methods:

• Differential Scanning Calorimetry (DSC) for thermal analysis.
• Powder X-ray Diffractometry (PXRD) for structural identification.
• Thermogravimetric Analysis (TG) to assess solvates/hydrates.
• Dissolution studies in simulated intestinal fluid.
• Stability studies under varying relative humidity (R.H.).

Main Results:

• Two distinct crystal forms (Form 1, Form 2) and one amorphous form of DA-8159 were successfully isolated and characterized.
• TG confirmed the absence of solvates or hydrates in the crystal forms.
• PXRD patterns differentiated the two crystal forms.
• Solubility order was: amorphous form > Form 1 > Form 2.
• Form 1 transformed into the more stable Form 2 upon storage.
• The amorphous form converted to Form 2 at 52% and 95% R.H., but remained stable at 0% R.H.

Conclusions:

• DA-8159 exhibits polymorphism with varying solubility and stability.
• The amorphous form offers higher solubility but is less stable, converting to crystalline Form 2.
• Form 2 represents the most stable polymorphic form, crucial for drug product development.