ABSTRACT
In current study, it was investigated if the moisture-mediated polymorphic transition from δ- to ß-mannitol during twin screw granulation (TSG) also took place in high drug loaded formulations and if the specific granule morphology associated with the polymorphic transition could enable tableting of granules comprising 75% paracetamol, a poorly compactable drug. Experiments were performed on an integrated continuous manufacturing line, including a twin screw granulator, fluid bed dryer, mill and tablet press. The polymorphic transition of δ- to ß-mannitol was observed during twin screw granulation and granules exhibited the needle-shaped morphology, typical of this transition. TSG at low liquid-to-solid (L/S) ratios and use of polyvinylpyrrolidone or hydroxypropylmethylcellulose as binders inhibited the polymorphic transition, whereas screw speed, drying time, drying temperature and airflow did not affect the solid state of mannitol in the granules. Without binder and despite the high paracetamol drug load in the formulation, limited breakage and attrition was observed during drying and milling. In contrast to granules manufactured from a formulation containing paracetamol/ß-mannitol which could not be tableted due to extensive capping, granules prepared from a paracetamol/δ-mannitol formulation showed good tabletability. In conclusion, δ-mannitol is a promising TSG excipient, especially for high drug-loaded formulations with poor tabletability.
