Preparation Of Macrolides Nanosuspensions And The Modeling Research For The Formation Mechanism Of Nano/Micro Particles

Nanomedicine is of great significance in the field of medicine and human health. With the advantages of improved solubility and bioavailability, nanosuspensions are considered to be a promising drug delivery strategy and are recognized as one of the best method deal with dissolution and absorption problem for poorly water-soluble drugs. Nanosuspensions can be prepared by media milling or high-pressure homogenization method. Both of the methods have been commercialized, however, these methods need high-energy input and usually result in the contamination of pharmaceutical, besides, the broad particle size distribution and difficulty to control surface properties are the common problems that exist in the prepare methods mentioned above.Liquid phase crystallization is an effective technology for the formation of nanoparticle. The nucleation and crystal growth in crystallization process are multi-phasic and multi-composition process of heat and mass transfer. Due to the mutual interaction of solute-solvent and solvent-solvent, the growth morphology of nanoparticle is quite diverse. In the industrial crystallization process, the prediction of crystal morphology has remarkable economic meaning and value. The crystal morphology has a pronounce influence on the purity, flowability and dissolubility of the product. A favourable crystal habit will facilitate the process of separation, washing, packaging, transportation, storage and even improve the yield of product in some degree. With respect to pharmaceuticals, crystal habit has a sharp effect on the preparation, disintegration and bioavailability. However, compared with the relatively mature research achievements in crystal preparation, the formation mechanism research is not enough, many research remain in phenomenon observe and qualitative analysis level.This study firstly conducted the technical study for the preparation of macrolides nanosuspensions by liquid phase crystallization method. Then, based on molecular simulation method, the exploratory research on the formation mechanism of macrolides particles in liquid phase crystallization process was proceed. The main contents of this article are as follows:1. This study provided an alternative method for the preparation of azithromycin nanosuspensions of poorly water-soluble drugs through liquid phase crystallization. Preparation process optimization was carried out in this study and amorphous AZI nanoparticles were obtained by the freeze-drying of nanosuspensions. The prepared nanoparticles can transform to nanosuspensions when dispersed in water. The as-prepared nanoparticles have such characteristics as small particle diameter, large surface area, increased saturation solubility, rapidly dissolution rate and excellent stability during storage. The method is preferable lies on its cost effective, easy to operate and it does not have any pollution to the environment. The prepared azithromycin nanosuspensions are biocompatible and expected to be given directly by oral or parenteral administration. All of above illustrate the opportunity to prepare nanususpensions of poorly soluble drug with significant improvement of in vitro dissolution rate, and thus possibly improved oral bioavailability.2. Modeling study of the formation mechanism of macrolides particles in liquid phase crystallization process was carried out. The crystal morphology of macrolide pharmaceuticals was predicted by the building of interface layer model. In order to investigate the interaction of solute-solvent and solvent-solvent, the crystal layer and solvent layer were eatablished by molecular simulation software. The interaction between different crystal layer and solvent layer was estimated by molecular mechanics and molecular dynamic method. The modified attach energy could be calculated and be related with the growth rate of crystal surface. Finally, the crystal habit considering the solvent effect was obtained. The calculated results indicated an identical morphology between simulated crystal habit and experimental habit.