The Study On Preparation And In-vitro Dissolution Performance Of Ultrafine Drug Particles

Phenylbutazone(PBZ)is used as a pyrazole ketones non-steroidal anti-inflammatory drugs,and has a poor solubility in water at room temperature,which limited the clinical application and development of the pharmaceutical preparation of PBZ.It's necessary for us to improve the solubility of PBZ and promote its absorption.And preparing ultrafine drug particles is a new method to improve the dissolution rate of poorly soluble drugs.Accordingly,the decreasing of PBZ particle size arouses the increasing of the saturated solubility,and the improvement of the in ivtro dissolution rate.Thus,we will study on the preparation process of ultrafine PBZ particles as the following three aspects in this paper.The method of laser technique was employed to determine the solubility of PBZ in ten mono-solvents(methanol,ethanol,2-propanol,n-butanol,1-pentanol,n-hexanol,acetonitrile,ethyl acetate,acetone,DMF)and two binary solvents mixtures of methanol + acetone and ethanol +acetonitrile.The the modified Apelblat equation,three-parameter van't Hoff equation and the modified Jouyban-Acree equation were used to correlate the experimental data.The fitting results were good.The thermodynamic functions of the dissolution process were also calculated.The anti-solvent re-crystallization process was used to prepare ultrafine PBZ particles.The obtained particles were characterized by thermal analysis(TG-DTG),differential scanning calorimetry(DSC),Fourier transform infrared spectroscopy(FT-IR),X-ray diffraction(XRD)and scanning electron microscopy(SEM).On account of the above experimental results,we got the optimum experimental conditions:solvent to anti-solvent system of methanol-water,feeding way of reverse adding,volume ratio of solvent to anti-solvent of 1:2,solution concentration of 0.05g · mL-1,re-crystallization temperature of 10?,stirring rate of 200rpm.The ultrafine PBZ particles with the mean size of 15?m were obtained.And the particles had uniform distribution and good crystal shapes.According to the Chinese pharmacopoeia,the paddle method was adopted in the dissolution test of PBZ products and PBZ APIs in the dissolution medium of water and pH6.8 phosphate buffer respectively.The effects of ultrafine PBZ particles on dissolve kinetic parameters,including dissolution rate constant k,the apparent activation energy Ea and pre-exponential factor A were studied.The results show that rate constant k increased,and the apparent activation energy Ea and pre-exponential factor A decreased with the decrease of PBZ particle size.The research has greatly improved the solubility and medicinal value of PBZ,also provided basic data for the clinical application and development.