Preparation Of Ultrafine Antibiotics By High Gravity Precipitatioin And Investigation Of Their Properties

Pharmaceuticals micronization,. a cutting-edge technology with significant application and medicine prospects, can boost solubility and bioavailability of pharmaceuticals and is regarded as a platform technology for pharmaceuticals formulation.Cephradine, one of the first generation cephalosporins, is widely used in clinic for its activity against both gram-positive and gram-negative microorganisms. In this dissertation, a novel preparation method of cephradine, which combined reactive precipitation with liquid anti-solvent precipitation under high gravity environment, was developed to prepare ultrafine cephradine (UC) with narrow particle size distribution. The morphology and the crystal structure of the UC were characterized by Scanning Electron Microscopy (SEM) and X-ray diffraction (XRD). The dissolution rate of the UC powder and the dissolution rate of the capsule and the troche of the UC were studied. The application of injection and suspension and anti-bacteria performance of UC were also investigated. Compared with the commercial cephradine, the as-prepared UC showed a significant decrease in particle size with a narrow uniform particle size distribution. The width of as-prepared UC was about200-400nm and the mean particle size was about300nm. The specific surface area of the UC was increased to10.87m2/g from2.95m2/g. From the XRD pattern, no crystal structure variation of the UC could be found compared with the original one, but the crystallinity of UC powder was reduced. The dissolution rate of the UC powder is higher than the commercial cephradine when the stirring speed was200rpm. But the dissolution rate of the capsule and the troche of the UC did not show obvious advantages. The UC for injection also showed a shorter dissolving time than that of commercial one. When the amount of L-arginine as solutizer was reduced29%, the mixture of the UC with L-arginine could still dissolve in1minute. The reduction in the amount of L-arginine would result in lower cost of the cephradine for injection and reduce the side effect of L-arginine. Furthermore, the sedimentation experiment showed that the UC suspension could keep good stability, indicating that the UC injection and suspension may find wide applications. At the same time, the UC also exhibited strong and stable anti-bacteria ability.Cefuroxime axetil, the prodrug of cefuroxime, and one of the second generation cephalosporins, is widely used in clinic for its activity against both gram-positive and gram-negative microorganisms. But the crystalline cefuroxime axetil has low bioavailability because of insolubility in water. It is indicated that amorphous cefuroxime axetil has high bioactivity and all the commercial cefuroxime axetil was the amorphous form.In this dissertation, ultrafine amorphous cefuroxime axetil (UACA) was prepared by antisolvent recrystallization under higy gravity environment. The optimum solvent-antisolvent system was determined according to the experiments results of various solvent systems. The factors affecting the particle size of UACA, including the concentration of the solution, the volume ratio of solvent to the antisolvent and the stirring speed were investigated. The as-prepared UACA was characterized by SEM, XRD, BET etc., and the dissolution rate of nanosized cefuroxime axetil was measured.The experimental results illustrated that the as-prepared product is amorphous cefuroxime axetil with the particle size less than500nm. The particle size of UACA reduced and the yield increased with the increase of the concentration of the cefuroxime axetil. Whereas the changes of the volume ratio of solvent to antisolvent and stirring speed were in favor of reducing the particle size of the products and obtained uniform particle size distribution. The dissolution rate of as-prepared UACA was remarkably higher than any other commercial products including crystalline cefuroxime axetil and spray dried ones. Therefore, the UACA should be absorbed more in the gastro-intestinal tract and exhibit a higher bioavailability following oral administration.On the basis of the lab and pilot research, a40t/y UACA production line by high gravity method was built up and put into operation. This production line was also briefed in this dissertation in BETA Inc., North China Pharmaceutical Company.