Modified rivaroxaban microparticles for solid state properties improvement based on drug-protein/polymer supramolecular interactions

• Published in: Powder technology 2019-02, Vol.344, p.819-829
• Main Authors: Chen, Ning, Di, Peiwen, Ning, Shangqi, Jiang, Wenjun, Jing, Qiufang, Ren, Guobin, Liu, Yan, Tang, Yun, Xu, Zhongyu, Liu, Guixia, Ren, Fuzheng
• Format: Article
• Language: English
• Subjects: Anticoagulants; Bottom-up; Bovine serum albumin; Calorimetry; Comminution; Crystallization; Differential scanning calorimetry; Dissolution; Fluorescence; Fluorescence spectroscopy; Fourier transforms; Hydrogen bonding; Hydrophobicity; Infrared spectroscopy; Methylcellulose; Microparticles; Microscopy; Molecular docking; Particle size distribution; Polymers; Properties (attributes); Proteins; Rivaroxaban; Serum albumin; Size distribution; Size reduction; Solid state; Spectroscopy; Spectrum analysis; Supramolecular interactions; X ray powder diffraction; X-ray diffraction
• ISSN: 0032-5910; 1873-328X
• DOI: 10.1016/j.powtec.2018.12.085

To tailor the solid state properties of rivaroxaban (RXB), microparticles were prepared using an anti-solvent precipitation technique. A mixture of hydroxypropyl methylcellulose (HPMC) and bovine serum albumin (BSA) was used for modification of the crystallization process. The solid state properties of RXB microparticles were characterized by techniques including scanning electronic microscopy, differential scanning calorimetry and powder X-ray diffraction analysis. The microparticles were found to be small, ranging from 1 to 10 μm diameter with a good size distribution, and existed in a stable crystalline form. The nature of the drug-polymer/protein supramolecular interactions was explored by Fourier transform-infrared spectroscopy and fluorescence spectroscopy. Molecular docking was also conducted to validate the mechanism of the supramolecular interactions. Formation of the RXB-BSA complexes was mainly driven by van der Waals and hydrophobic interactions, which contributed to the particle size reduction. Hydrogen bonding between HPMC and RXB was responsible for polymorph control during crystallization. The results suggest that drug-polymer/protein supramolecular interactions play a vital role in modification of the solid state properties of poorly water soluble drugs. [Display omitted] •Rivaroxaban microparticles were prepared by anti-solvent precipitation.•Bovine serum albumin inhibited the crystal growth of rivaroxaban.•Hydroxypropyl methylcellulose promoted the exclusive growth of stable crystal form of rivaroxaban.•The microparticles showed improved solid state properties.