| In the field of drug discovery, poorly water soluble drugs take the majority of new candidate drugs. However, those kind of water-insoluble drugs is difficult to be absorbed through the digestive system, which result in the low bioavailability. Decreasing the size of drug particles into the nanoscale range (nanonization) is an available candidate method to overcome the poor water solubility and improve bioavailability significantly. Solvent-antisolvent precipitation process is an effective way to prepare nano-sized drug particles. The use of organic solvent is essential in this method. For this reason, rigorous organic solvent removal is often required, which is expensive and high technique required, subcritical water (SBCW) has a good solubility for both polar and nonpolar substances and it is an effective solvent. The polarity of SBCW is dependent on temperature. Due to tunable polarity, the SBCW as a new type of solvent has attracted extensively attention. In addition, SBCW is an ideal substitute for organic solvent because of. It is widely used for non-toxic, innocuity and no environment pollution. The objectives of this paper were to explore the solubility and establish the mathematic model of prednisolone (PDL); prepare PDL nanoparticles form SBCW with smaller particle size and uniform morphology PDL nanoparticles, the main contents are as follows:First, we researched the effect of residence time on solubility,so that we can the prednisolone solubiluty in SBCW accurately and effectively. The study showed that during100～160℃,25m in was the optimum residence time to dissolve. Among these temperatures, when the temperature is140℃, PDL spend the longest residence time to dissolve. When temperature higher than140℃, balance time began to fall. Under the optimum residence time, we researched that the change of PDL solubility with the temperature and pressure(100-170℃and5-8MPa). PDL solubility increases with the temperature rise. Results showed that the PDL solubility increased with temperature rise, and increased exponentially over150℃. However, the variety of pressure has little impact on PDL solubility. Compared with normal state, prednisone solubility increased hundreds of times in SBCW. Based on the solubility data, the dielectric constant model was the established. This model is closely related to the characteristics of the SBCW and used to predict the solubility of PDL in SBCW at elevated temperatures with an average error of2.5%.Second, SBCW process combining with anti-solvent re-crystallization process is a promising approach to prepare PDL nano particles. The effects of experimental conditions, such as the temperature of SBCW, volume ratios of solvent to anti-solvent, the temperature of anti-solvent, surfactant types and dosage, on the morphology and size of PDL particles were researched detailedly. The optimal experimental conditions are:water used as anti-solvent, SBCW temperature140℃, volume ratio of SBCW to water1/5, PEG as stabilizers, content of stabilizer0.2wt%, anti-solvent temperature0℃. Under the optimal experimental conditions, as-prepared nano particles had a mean size of31nm. Scanning electron microscopy(SEM) was used to represent the configuration of PDL nano particles. Drug properties were investigated by X-ray diffraction(XRD) and Fourier transform infrared spectroscopy (FT-IR). The FT-IR analysis results show that the drugs have the same chemical composition. XRD analysis indicated that the crystallization of the PDL powder produced after SBCW processing had been changed. The reason may be that the PDL has the pseudo-polymorphic characteristic. In dissolution experiments showed that compared with the raw active pharmaceutical, PDL nano particles showed dramatically enhanced dissolution rate. Dissolution rate can reach93.1%within70min, while the dissolution rate of commercial PDL is only34.7%. |
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