Preparation For Ultrafine Particle Of Megestrol Acetate In Subcritical Water

Sub-critical water is in a state between atmospheric liquid water and supercritical water. As the decreasing polarity of sub-critical water as its temperature goes up, the drugs which are less polar or non-polar could dissolve in it obviously. Compared with traditional method of preparing pharmaceutical particles, there are more advantages in sub-critical water such as nontoxic, mild, environment-friendly. Generally, no or little residual organic solvents exist in the process. Megestrol Acetate (MA), as a progesterone drug which is insoluble in water at room temperature, is mainly used for the treatment of breast cancer and uterine endometrial carcinoma. In this paper, the sub-critical water technology and anti-solvent crystallization method is combined to obtain ultrafine MA particles with uniform morphology.For the first time, a set of devices for researching the solubility of MA in subcritical water was established. At the range of100～180℃, the detailed solubility data was obtained. In addition, the effect of pressure on solubility was also considered. When temperature increases, the dissolve rate of MA in subcrical water is accelerated. However, there is barely no change in solubility at different pressure. Based on the solubility data, two models were established: dielectric constant model and temperature model. By simulating the solubility data at the range of130～180℃, the maximums of average error were5.19%,2.36%, respectively. At a specified pressure (5MPa) and stirring rate (1000r/min), a series of experiment were carried out to gain and improve the morphology of MA. In these experiments, the effects of volume ratio of subcritical water and deionized water, their temperature, surfactant were taken into accout. The difference of temperature between subcritical water and deionized water is more liable to the formation of an over-saturated solution, also to smaller particles. When volume ratio of deionized water and subcritical water increases, the size of ultrafine particle is further reduced and its distribution is more uniform. The use of surfactant could effectively diminish the agglomeration of the particles. Finally, the optimum experimental condition is as follows:the temperature of deionized water and subcritical water temperature is0℃and170℃, the volume ratio of them is13.6; The concentration of polyvinylpyrrolidone (PVP) is0.1wt%. Under this condition, the particle size prepared is in the range of100-200nm.The particles of MA prepared and its raw material were both characterized by scanning electron microscope (SEM), Fourier trans-form-infrared spectroscopy (FT-IR) and dissolution test. The result of SEM and dissolution test indicated that MA nanoparticle is amorphous and exhibited a higher dissolution rate than raw MA. The image of FT-IR showed that chemical structure of MA does not change.