Preparation Of Ketoconazole Water Dispersible Soft Granules

Fusion method was used to prepare ketoconazole water dispersible soft granules in order to produce a new drug which could improve bioavailability effectively. Then, the preparation process, phase identification methods and quality indexes were investigated systematically. Finally, the MIC was determinated. The main results were as follows:1. Through orthogonal designs and screening of excipients, we determined the optim- ization proportion, of which poloxamer188 accounted for 8%, the lauryl sodium sulfate for 0. 8%, sodium ascorbate 0.8%, ketoconazole 8%, and ratio of the polyethyleneglycol and sucrose was 1:10; Technological parameters of granulation were established by fusion method as follows: rate of agitation 1200 r/min, heating temperature 80℃, agitation time 3 min, cooling time 3 min. Yeild of ketoconazole water dispersible soft granules was 86.3%.2. The observation results of scanning electron microscope indicated that ketoconazole water dispersible soft granules were composed of many particles by certain special mode, which come into being plenty of cavities look like dome structure, so the surface of ketocona- -zole water dispersible soft granules was either convex or concave, but the surface of solid dispersion looked smooth. Infrared spectrum analysis indicated that there were some combined forces between ketoconazole and excipients, maybe like hydrogen bond in molecu- lars or between moleculars and so on. The forces between ketoconazole and excipients is between solid dispersion and physical mixture, which was in the intermediate state. X-ray powder diffraction analysis results indicated that parts modification of ketoconazole had changed and then transformed amorphous phase. The crystallinity of three mixtures respectiv- ely were: physical mixture being 56.67%, solid dispersion being 50.39%, water dispersible soft granules being 51.28%, The crystallinity of water dispersible soft granules was between them of solid dispersion and physical mixture. Ultraviolet spectral analysis showed that the chemical structure of ketoconazole hadn't changed except some simple secondary bonds and physical action during preparation.3. Quality testing results indicated that appearance and granularity ketoconazole water dispersible soft granules with uniform appearance and granularity had good decentralized uniformity, their bulk density and fluidity both accord with qulified standards; Ultravioiet spectrophotometry was used to determine its content, which had good stability and good recovery of 97.27 percent, labelled content of ketoconazole was 99.52 percent; Under fixed conditions of formulation and craftwork; The avarege time of dissolution determined by rotating basket method was less than 9 min when the dissolution of granules reached 90 percent in vitro; Accelerated stability experiment indicated that ketoconazole water dispersibl- e soft granules had good stability; Long period stability experements showed that the content of ketoconazole had a little change, but the chemical structure hadn't changed yet and didn't affect drug effect; Classical fixed temperature heating stability experiment was used to estimate the effective period, and the effective period was 1.6 years; Research of moisture absorption showed that critical relative humidity of ketoconazole water dispersible soft granules was 68.3 percent.4. Minimal inhibitory concentrations(MIC) of ketoconazole water dispersible soft gran- ules for three fungi were respectively: Candida albicans(C. albicans) 1.25～2.5μg/mL, Candida parapsilosis(C.parapsilosis) 0.074～0.16μg/mL, Torulopsis pintolopesii(T. pintol- opesii) 0.31～0.62μg/mL.Conclusion: ketoconazole water dispersible soft granules is compound fusion grunules, which is between solid dispersion and physical mixture; The granules has the feature of fast dissolution and accords with the stated quality standards; and its antibacterial effects in vitro is similar with the other anti-fungal drugs.