Preparation of stable nitrendipine nanocystal suspension using a modified anti-solvent precipitation method

摘要

Objects: The aim of this study was to investigate the effect of stabilizer and crystal size on the nanosuspension stability, dissolution rate and solubility of water insoluble drug. Nitrendipine was used as a poor water soluble model drug. Methods: Nanocrystal suspensions of nitrendipine were produced by modified anti-solvent precipitation method. Firstly, nitrendipine was dissolved in the mixed solvent of PEG200 and acetone to form an organic solution. Then, the drug solution was quickly injected into water phase under a magnetic stirring and the ultrasonication was performed to produce dispersed drug crystals. To prevent the crystals growing up, some stabilizer was introduced in water phase and the effect of kind of stabilizer and concentration on the crystal size was investigated. As well as the drug concentration in organic phase, time of ultrasonication and temperature on the particle size and stability were investigated. The particle size, Zeta potential and morphology of nanocrystals were characterized by the laser diffractometry, Zeta potential analyzer and scanning electron microscope (SEM), respectively. X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used to analyze the crystalline change of nanocrystals. Dissolution experiments of nitrendipine nanosuspension and raw crystals were performed according to Ch.P.2005 Ed Apparatus III (paddle) method. The solubility of nanocrystals with different mean particle size was determined by HPLC method.Results and discussions: It was well known that the crystal size was largely affected by various operating condition during precipitation process. It was found that the stabilizer should be introduced in water phase to prevent crystal growth and to be advantageous to form crystal nucleus. Some materials were introduced into water phase to control the crystal size. Among them, PVA was selected as a good stabilizer and efficiently arrested crystal growth. Following precipitation, ultrasonic treatment remarkably enhanced stability of nitrendipine nanosuspension. The influences on the crystal size of nitrendipine were investigated systematically. In this modified anti-solvent precipitation, the mean particle size could be well controlled, from 137nm to 2.86μm by adjusting the operation parameters, such as the drug content and PVA concentration. Higher concentration of nitrendipine in organic phase, higher concentration of PVA was required to　achieve smaller particle size. In addition, particle size decreased with the increase of ultrasonic power. The process time of ultrasonication also had an effect on the particle size. The mean particle size was decreased with increasing time of ultrasonication within 15min. However, nanosuspension was not stable when the ultrasonication was applied for 5 min. The temperature of precipitation also affected the average particle size, the lower the temperature, the smaller the crystals. The morphology of crystals under ultrasonic treatment was diverse. With SEM photo observation, plate-like crystals with different shape were obtained after ultrasonication (see Fig.1). X-ray powder diffraction confirmed that no crystalline change was found in the various crystals produced in different condition. However, the differences in the relative intensities of their peaks might be attributed to the differences in crystallinity. All DSC scans of each sample were showed a single sharp endothermic peak ascribing melting of nitrendipine, which also indicated that no substantially crystalline change was found. However, the melting point of crystals obtained with and without ultrasonic treatment was lower than that of original crystals, this might be explained by the size reduction of crystals. The dissolution profiles of nanosized and raw nitrendipine crystals are shown in Fig.2-a. When water containing 0.1mol/L hydrochloric acid and 0.1% SDS was used as dissolution medium, the original crystals did not achieve complete dissolution d