Assessment of granulation technologies for an API with poor physical properties.

Granulation technologies are widely used in solid oral dosage forms to improve the physical properties during manufacture. Wet, dry, and melt granulation techniques were assessed for Compound A, a BCS class II compound. Characterization techniques were used to quantify physical property limitations inherent for Compound A including hygroscopicity, low solubility and bulk density, and poor powder flowability. High shear aqueous wet granulation induced an undesirable water mediated phase transition of the solid form. A formulation and process for dry granulation by roller compaction was developed and scaled to 10 kg batch size. Roll force, and roll gap parameters were assessed. Porosity of compacted ribbons was analyzed by mercury intrusion porosimetry, and particle size distributions of milled ribbons by sieve analysis. A roll force of 15 kN/cm produced granules with higher density and improved flow properties compared to the pre-blend. Fines content (<75 µm) decreased from approximately 90% pre-granulation to 26% post-granulation. Cohesive properties of Compound A limited drug loading (API:excipient ratio) in roller compaction to 0.6:1 or less. Hot melt granulation by extrusion assessed with four polymers. A vast improvement in drug loading of 4:1 was achieved via melt processes using low molecular weight thermo-binders (glyceryl behenate and Polyethylene glycol 4000). Granules produced by melt processing contained less fines compared to wet and dry granulation. Both roller compaction and melt extrusion are viable granulation process alternatives for scale up to overcome the physical property limitations of Compound A.