(776d) Study & Control Flow Properties of Ibuprofen from Batch & Continuous Crystallization

Ibuprofen is a common analgesic drug active and always exhibits poor flow properties. It’s difficult to flow and prone to punch-sticking during pharmaceutical tabletting processes. It's well-known that particle size and shape have a significant effect on powder flow properties, which are also important subjects of crystallization study. Ibuprofen is reported to crystallize as plates from polar solvents or needles from nonpolar solvents. Both plate and needle shape are believed to be bad for flow properties. In this study, several batches of ibuprofen crystals have been prepared by delicate control of crystallization process, covering common size distribution from several microns to nearly 1mm. In some batches, plates have been thickened to tabular crystals and needles to rods in delicate controlled crystallization processes. Particle size was analyzed by Malvern and SEM. The aspect ratio of crystals was calculated based on SEM images and microscope images. Overall flow properties of ibuprofen were systematically studied and compared with FT4 powder rheometer for the first time, including shear cell test, stability and variable flow rate (VFR) test, aeration, permeability, compressibility and wall friction. D[3, 2] was suggested to characterize the effect of size and correlate quite well with most flow properties. Some flow properties increased with D[3, 2], such as Basic Flow Energy and compressibility. Most flow properties show a small change in a big size range and will change obviously only when D[3, 2] is above a critical size, such as cohesive energy in dynamic test, aeration, wall friction and permeability. Some other properties are more influenced by shape than size, such as bulk density and flowability, and can be correlated with aspect ratio very well. Free-flow ibuprofen was obtained for plates and rods with D[3,2] above 100 microns. Plates and rods show better flow properties than tabular crystals, probably because tabular crystals are partly aggregated. Aggregation causes mechanical interlocking between particles and impede powder flow. It's believed that problem about flow properties could be solved by the control of crystal size and shape in crystallization. The investigation on the impact of particle size and shape on flow properties will undoubtedly provide a good guidance for crystallization study.