Sonocrystallization approach in crystal habit modification for improving the pharmaceutical properties of Rivaroxaban

Poor pharmaceutical material properties of active pharmaceutical ingredients (APIs) can result in suboptimal manufacturing and therapeutic outcomes. Rivaroxaban (RIV) was explored as a model API due to its poor pharmaceutical properties and challenging industrial processability. In this research, crystal habit modification (CHM) of RIV was explored via solvent evaporation, cooling crystallization, and sonocrystallization methods. RIV (irregular) habit was modified to cuboidal, plate, and fiber via solvent evaporation; however, these were not further explored due to their large crystal sizes (>400 µm), which could pose serious dissolution and dose uniformity issues. Cooling crystallization method yielded plate (RIV_ACT) and blade-shaped (RIV_ACN) crystals with sizes < 200 µm. Further, CHM by sonocrystallization yielded tabular (RIV_SN6) crystals < 10 µm in size, which also exhibit a lower aspect ratio, a lower span value, and a narrower crystal size distribution than RIV_ACT and RIV_ACN. No polymorphic changes in modified habits were observed, as confirmed by PXRD, DSC, and TGA. Powder flowability improved significantly in the RIV_SN6 than in RIV_ACT and RIV_ACN (p < 0.0001) due to its narrow crystal size distribution. Interestingly, the RIV_SN6 showed improved tensile strength (p < 0.05) at a compression force of 300 MPa and exhibited improved wettability due to the exposure of polar functional groups on the modified habits. Furthermore, significant improvements in polar energy (p < 0.05) and ∼1.88 fold of IDR (p < 0.0001) were observed in RIV_SN6 compared to the RIV_ACT and RIV_ACN due to the prominence of polar groups and hydrophilic components on the particular facet.