Purpose: Pharmaceutical cocrystals represent a suitable strategy to improve some intrinsic properties of active pharmaceutical ingredients (APIs), such as solubility and processability. While solubility studies are commonly performed on pharmaceutical cocrystals, fewer studies investigate cocrystal mechanical properties, which are critical to ensuring successful manufacturing processes. Ibuprofen (IBU) is a small molecule API which can form cocrystals with different coformers, including nicotinamide (NIC) and isonicotinamide (INIC). An increase in dissolution performance, hygroscopicity and tabletability for IBU-NIC cocrystals relative to IBU was previously reported. Fluidized bed dryer granulation may be considered a useful tool for the production of granules containing pharmaceutical crystals. The focus of this study was to investigate the possibility of obtaining IBU-NIC and IBU-INIC cocrystals-in-granules using a one-step manufacturing process, and to evaluate the mechanical proprieties of the prepared granules.
Methods: Using a Mini-Glatt fluidized bed dryer, granules containing IBU cocrystals (1:1 molar ratio) were produced under different conditions related to process variables (inlet temperature and gas pressure, solution feed rate and frequency of filter cleaning cycle) and formulation variables (type of co-former, filler and binder, % API+coformer, binder concentration, solvent volume and composition). A regular two-level factorial design study composed of eleven factors and sixteen runs (Table 1) was used to estimate main effects and interactions. Solid-state characterization was performed using DSC, TGA and PXRD. Laser diffraction was used to evaluate the particle size distribution, and drug loading efficiency was also investigated. The granule porosity was calculated from the bulk density and the true density as measured using a helium pycnometer. Flow properties of the granules were studied in a powder rheometer equipped with a shear stress cell, and powder cohesion, flow function and bulk density were analysed. Mechanical properties were investigated using a single-punch tablet press and tablet hardness tester.
Results: IBU cocrystal granules with different particle size distributions were obtained for eleven runs processed by the one-step manufacturing process. However, five runs in the design showed a failure in the granulation process. The average IBU loading in granules was determined to be between 10% and 20%. The amount of API+coformer used was found to have the most significant effect on granule drug loading, followed by the inlet gas pressure and the inlet temperature, respectively. Excluding the solvent composition and the type of filler used, all the variables in the model were shown to have a significant effect on the value of flow function, especially the binder concentration in the solution and the volume of solvent (low binder concentrations in high volume of solvent produce granules with high flowability). The granule porosity was shown to depend on the amount of API+coformer, and the type of coformer and binder used. Furthermore, the model generated by the design highlighted that the granule size depends on the type of coformer (larger particles using NIC compared to INIC) and the inlet gas pressure used. The yield of the process increased when a high inlet temperature was used at high solution feed rate.
Conclusion: In this work, we have investigated the possibility of producing granules containing IBU cocrystals in a one-step process and have undertaken a design of experiment approach to understand which variables are critical for obtaining a good quality product. Different variables were highlighted as important to produce IBU cocrystals granules presenting good properties, suitable for tablet production. To avoid the formation of sticky particles, caking and over wetting of the powder during the process, the utilization of high inlet temperature (80° C), low amount of API+coformer, high solvent volume and low solution feed rate is strongly suggested by the model. The developed multivariable model enables optimization of the granulation process for IBU cocrystals.
Anne Marie Healy– Head of School, Trinity College Dublin, Dublin 2