Preparation And Characterization Of Ultrafine Camptothecin By Anti-Solvent Precipitation

Camptothecin(CPT) is a cytotoxic alkaloid isolated from Chinese tree Camptotheca acuminate by American scientist, which has strong anti-tumor activity against a wide range of experimental tumors. The anti-tumor effect of CPT lies in its ability to inhibit the nuclear enzyme topoisomerase I. It is the only inhibitor of topoisomerase I which have been found up to now. There are diversified CPT that was used on clinic to treat various tumors in USA, Japan, Australia, and countries of Europe. Now dosage forms of CPT mainly include injection and suspension injection. For suspension injection, the particle size must be controlled strictly. The particle size must be less than15μm for normal injector, particle size that between15-20μm there must be less than10%.Otherwise, there may be vein embolism. Therefore, the particle size reduction of CPT is a very effective method to improve the efficiency of drug. In this study, ultrafine CPT was successfully prepared by anti-solvent precipitation method in beaker, and then, successfully scaled up in a rotating packed bed (RPB). Also, the reactive precipitation pathway was explored to synthesize ultrafine CPT. Furthermore, the dissolution of CPT and ultrafine CPT was studied. The mail contents and findings are summarized as follows.1. The effects of experimental parameters on particle size and morphology were investigated in beaker, such as the solvent and anti-solvent, the volume ratio of solution to anti-solution, the pH of anti-solvent, temperature, concentration of CPT solution and stirring speed, etc. New solvent and anti-solvent system was discovered, and the optimum condition was obtained:the pH of anti-solvent of B, temperature of C℃, CPT solution concentration of Dmg/ml, stirring speed of Erpm, and the volume ratio of solution to anti-solution A obtained cubic flakes particles with length xμm, the volume ratio of solution to anti-solution a got needle-like particles mean diameter (short axis) of ynm, average aspect ratio of20-35, and with helical twist. The Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) analysis indicated that no chemical decomposition took place during the process, and the crystal structures of the drug were not changed.2. From the results of experiments in beaker, we know that the micro-mixing situation of solvent and anti-solvent is an important factor affecting the particle size of products when ultrafine CPT was prepared by anti-solvent precipitation. It is well-known that well micro-mixing condition can be achieved in continuous RPB. Therefore, the above experiments in beaker were scaled up in a rotating packed bed (RPB); the results indicated that CPT particles prepared by RPB possessed smaller particle size and narrow size distribution.3. The reactive precipitation pathway was explored to synthesize ultrafine CPT. Obtained needle-like particles with length zμm.4. The dissolution of CPT and ultrafine CPT was studied, the results indicated that the dissolving ability of ultrafine CPT has significantly enhanced compared with commercial crude CPT. When the dissolving time is about Lmin, mmg ultrafine CPT was dissolved completely, respectively, the cumulative percentage of commercial crude camptothecin was only n%.