Formation of delta-mannitol by co-spray drying: enhancing the tabletability of paracetamol/mannitol formulations

δ-mannitol is a metastable polymorph of mannitol, known for its superior tableting properties. However, there is no easy, reproducible and scalable production method for δ-mannitol. It was evaluated whether δ-mannitol could be formed via co-spray drying with an API exhibiting tabletability issues, to improve the API tabletability in a one-step process prior to compaction. Aqueous suspensions with paracetamol and β-mannitol were co-spray dried. Raman spectroscopy was used to identify the mannitol polymorphs. In these formulations, paracetamol was the key factor to allow the formation of δ-mannitol since no traces of the δ-polymorph could be detected after spray drying a pure mannitol feed. The presence of δ-mannitol after co-spray drying was confirmed even for low paracetamol/mannitol ratios (1:99). The δ-mannitol content varied depending on the process drying parameters, predominantly by the airflow. A lower airflow promoted the formation of δ-mannitol, while more α-mannitol was formed when applying a higher airflow. The starting material, β-mannitol, was often no longer detectable by Raman spectroscopy. The tabletability of the spray dried powders clearly improved in association with the δ-mannitol concentration. The co-processed powders showed superior tabletability in comparison with physical mixtures of the starting materials. Harder tablets with a maximal tensile strength of 2.9 MPa at a main compression pressure of 247 MPa were achieved.