Preparation And Characterisation Of Hydrophobic Drug Sub-Micro Particles By High-Gravity Antisolvent Precipitation Method

Sub-micro or nano-pharmaceutical particles possess some superior properties, such as high solubility, high bioavailability, low side-effect and a capability of target delivering and permeating the barrier of bio-membrane. Hence, there is a great interest in the study of sub-micro or nano-pharmaceutical particle preparation.In this study, the preparation of hydrophobic drugs sub-micro particles, Cefuroxime Axetil (CFA) and Simvastatin (SST), were investigated, and then the Cefuroxime Axetil (CFA) and Simvastatin (SST) sub-micro particles were successfully prepared by High-gravity antisolvent precipitation method (HGAP)For CFA particles, the influence of operation parameters, such as, stirring speed, solvent/anti-solvent (S/AS) volumetric ratio, drug concentration and temperature, were tested and optimized initially. In order to obtain uniform CFA nano-particles, high-gravity technology was incorporated with anti-solvent precipitation to establish a novel technology:high-gravity anti-solvent precipitation (HGAP). Amorphous CFA particles (-300nm) prepared by HGAP had a narrow particle size distribution, larger specific surface area and higher solubility compared to commercial spray-dried CFA. The scaling up of HGAP technology was displayed in a GMP-compliance CFA production line which has an annual capacity of40tons (Beta Co. Ltd., North China pharmaceutical Group Corporation).Next, in the study of SST sub-micro particles preparation, the influence of the operation parameters, such as, types of solvents, anti-solvent and surfactant, stirring speed, solvent/anti-solvent (S/AS) volumetric ratio, drug concentration, surfactant concentration and temperature, were optimized. Sub-micro SST particles (～1αm) prepared by HGAP possessed a large specific surface area and high solubility while retaining the molecular structure of the SST raw material.In addition, the thermodynamics properties of SST crystallization system was studied with the aim to obtain desired SST particles through the control of the crystallisation process to obtain desired SST particles. The effect of surfactant, SST concentration, temperature and S/AS volumetric ratio on the crystallization process had also been investigated. The results indicated that these parameters had significant effects on the metastable region and crystallisation induction time. Besides, the type and concentration of surfactant also played an important role in controlling the shape and size of SST particles.In addition, the effect of secondary ageing process on SST particles had also been studied. During the ageing process of SST particles, two processes occurred—Ostwald ripening and fragmentation. Reaction temperature and stirring speed influenced the competition between the two processes hence affecting the final particle shape and size. At a relatively low temperature, fragmentation process was predominant under high stirring speed, resulting in uniform small particles.The HGAP technique offered a direct and continuous process to bulk produce sub-micron drug particles using simple re-precipitation process. The effect of various experimental parameters investigated herein can also be referenced in the preparation of other sub-micron pharmaceutical particles.