Development and characterization of ibuprofen co-crystals granules prepared via fluidized bed granulation in a one-step process – a design of experiment approach

OBJECTIVE: The focus of this study was to investigate the possibility of producing ibuprofen-nicotinamide (IBU-NIC) and ibuprofen-isonicotinamide (IBU-INA) cocrystal-containing granules, using a one-step fluidized bed dryer granulation manufacturing process, and evaluate their mechanical properties. SIGNIFICANCE: Pharmaceutical cocrystals represent a suitable strategy to improve properties of active pharmaceutical ingredients (APIs), such as solubility and processability. Ibuprofen (IBU) is a small molecule API which can form cocrystals with different coformers, including NIC and INA. An improvement in mechanical properties for IBU-NIC cocrystals relative to IBU was previously reported but, to date, the formulation of IBU cocrystals in a solid dosage form has not been investigated. METHODS: cocrystallization and granulation were achieved concurrently by processing in a lab-scale fluidized bed granulator following a design of experiment (DoE) approach using a two-level factorial design with both process and formulation variables. Solid-state, micrometric, dissolution, and mechanical (tabletability) characteristics of granules were assessed post-processing. RESULTS: Granules containing cocrystals were successfully prepared for 11 of 16 DoE runs. Parameters with a significant effect on granule drug loading, flow function, porosity, and size could be identified from the DoE model. Process yield was increased by using a high inlet temperature at high solution feed rate. To avoid the formation of sticky particles, caking and over-wetting of the powder during the process, the utilization of high inlet temperature, low API + coformer:filler ratio, low API concentration in solution and low solution feed rate were suggested by the model. CONCLUSION: The multivariable model developed enables accurate optimization of the granulation process for IBU cocrystals.