Preparation of stable nitrendipine nanocystal suspension using a modified anti-solvent precipitation method
(0) 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 during the 60 min testing period and only 13% drug was dissolved over 60 min, owing to its large crystal size. While nanosiezed crystals showed significant enhancement in dissolution rate with 90% of drug dissolved over 1 min, although the dissolution test was not performed in sink condition (the solubility of nitrendipine in this dissolution medium was about 14μg/ml). This enhancement in dissolution rate can attribute to the higher surface area of nanocrystals available for dissolution. Although solubility is normally considered a physicochemical constant, small increases in saturation solubility can be accomplished by particle size reduction as illustrated in Fig.2-b. The particle size stability of final nanocrystal suspensions with different particle size is shown in Fig.3, the particle size remained constant at least for three months. Zeta potentials of nanocrystals ranged from -5.5mV to -12.7mV. It is assumed that the Zeta potential is not the dominant factor to stabilize nanocrystals without agglomeration in this nanosuspension system. Ultrasound played an important role in the formation and stabilization of nanocrystals. Due to the fast process of crystallization and the time dependence of the sufficient adsorption, the newly formed crystal nuclei(in nanometer size range) cannot fully covered by the stabilizer, as a result, crystal growth and agglomeration occurred rapidly. Ultrasound would intensify external mass transfer and adsorption rate 1, stabilizer diffused rapidly and covered the surface of the crystals and stabilized the system by providing a static repulsion between the crystals. Ultrasound did not only enhance the mass transfer of adsorption process, but also promoted disruption of agglomerated crystals and large individual crystals. Conclusions: The modified anti-solvent precipitation is very suitable to prepare nitrendipine nanocrystal suspension. The particle size of nanocrystals is highly dependent on processing parameters such as drug concentration in organic phase and stabilizer concentration in aqueous phase. The stability and dissolution rate of nitrendipine nanocrystal suspension was largely enhanced by the introduction of ultrasoniction treatment. Otherwise, small increase in solubility due to particle size reduction also can be observed. In conclusion, modified anti-solvent precipitation method is useful for preparation of stable nitrendipine nanocrystal suspension.
Nitrendipine Nanocryatal Nanosuspension Anti-solvent Ultrasonication Morphology Solubility Dissolution rate
Xia DengNing Quan Peng Piao Hongzhe Cui Fude
Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University,No Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University, N
国际会议
International Symposium on Crystal Engineering and Drug Delivery System 2009(2009晶体工程与药物传送系统国际会议)
天津
英文
246-249
2009-09-05（万方平台首次上网日期，不代表论文的发表时间）