The Effect Of Particle Size Reduction On Nimodipine Oral Absorption And Polymorphic Transformation During Preparation

Nimodipine (Nim) is high permeability, low soluble BCS Ⅱ drug, and has stongliver first effect. Thus, the oral bioavailability of Nim is low. In addition to its waterinsolubility, Nim is known to be a compound with polymorphism. Polymorphs areknown to give rise to significant differences in solubility and bioavailability of drugcompound. In this experiment, the technology of particle size reduction was used toimprove in vitro drug release and in vivo absorption. Furthermore, polymorphictransformation during particle size reduction and tablet preparation was investigated.Microprecipitation was carried out by anti-solvent to get nimodipinemicrosuspension (Nim-Ms). Subsequent homogenization was applied to obtainnimodipine nanosuspension (Nim-Ns). The particle size and morphology of Nim-Msand Nim-Ns were investigated by laser particle size analyzer and scanning electronmicroscope (SEM) respectively. The lyophilized nimodipine microcrystals (Nim-Mc)and nimodipine nanocrystals (Nim-Nc) were then analyzed by X-ray powderdetermination (XRPD) and Differential scanning calorimetry (DSC) for polymorphicdetermination. Nimodipine microcrystal-based tablet (Nim-MBT) andnanocrystal-based tablet（Nim-NBT）were prepared and their disintegration anddissolution in five different media as well as crystalline form confirmation wereaccomplished prior to the investigation of oral absorption in rabbits.The average particle size of Nim-Ms and Nim-Ns were8.26±0.05μm and713±160.45nm respectively. The SEM images showed the microparticles byanti-solvent grew as dendritic crystals while the nanoparticles by high pressurehomogenization were uniform rod crystals. During the preparation, microprecipitationwas the only process where polymorphic transformation happened and the crystalform remained unchanged during homogenization and tableting processes. In the fivedissolution media, the disintegration time of Nim-NBT was longer than that ofNim-MBT and the drug releases from Nim-NBT were faster than that from Nim-MBT.The oral bioavailability in term of AUC0-24hof Nim-NBT in rabbits was1.41timesthat of Nim-MBT.Size reduction for Nim could accelerate drug dissolution and improve oralbioavailability. Polymorphic transformation would most probably happen during thegood-solvent involved tablet preparation process.