Preparation, Characterization And Pharmacokinetics Of Florfenicol Microcrystal Modified By HPMC

Florfenicol also known as fluoro thiamphenicol, which is a broad spectrum antibacterial agents used in the late eighty’s to the animals. Because it’s very difficult to dissolve in water, the clinical use was limited. The methods to increase the solubility of Florfenicol at present mainly includes synthetic water-soluble prodrug. preparation of Florfenicol soluble powder, prepare its solid dispersions by PEG-6000 and using DMF or other organic solvents as solvent. But there are many problems with these solubilization methods, such as harmful by-product residues, poor effect of solubilization and stimulate body by organic solvents. So find a suitable solubilization method of Florfenicol is very meaningful and necessary.Particle size of the drug is closely related to the stripping properties, according to Noyes-Whitney equation, dissolution rate of materials is proportional to the surface area, and the decrease in particle size can increase the surface area of the material, so it can improve the solubility of the drug. At present, the micronization technologies to increase drug solubility by reduce drug particle size are very popular, mainly includes Top-down and Bottom-up. Top-down mainly refers to crushing materials from big to small by mechanical, and Bottom-up refers to use chemical methods, first dissolving the drug, then crystallize the smaller drug crystal. This experiment adopts the latter method, which can reduce the possibility of destroy drug structure by mechanical energy and reduces the preparation cost.Improved solvent-antisolvent recrystallization method was used in this experiment, and Florfenicol microcrystal with smaller particle size was get by adding stabilizer to inhibit crystal growth in the anti solvent. At the same time, through the single factor and orthogonal experiments, screening the optimum conditions of preparation and the stabilizer. Experiments show that, where the acetone as solvent, water as anti-solvent, solvent anti-solvent ratio is 1:9, HPMC concentration of 4mg/ml as stabilizer, concentration of Florfenicol as 160mg/ml, Florfenicol microcrystal with a maximum saturation solubility(3.13mg/ml) in 37℃ was received, the yield of the microcrystal under the condition was 73.96%.Optical microscope was used in this experiment to observe Elorfenicol and its microcrystals. results show the appearance of its microcrystal turn into spherical from needle-like, and the particle size decreased significantly. Stability experiments showed that Florfenicol microcrystal was stable in the light, high temperature, high humidity conditions. The solubility and dissolution rate expirement of Florfenicol and its microcrystal showed, in the temperature of 37℃, the saturated solubility of Florfenicol microcrystal increased to 3.13mg/ml from 2.12mg/ml, which is the saturated solubility of Florfenicol. The dissolution rate increased significantly compared with Florfenicol. in 5 minites, solubility of Florfenicol microcrystal has reached the 77.15% of the saturation solubility, and that to Florfenicol only 21.93%. DSC and X-ray diffraction demonstrated crystal forms of Florfenicol microcrystal turned into one from two, and through the analysis of X-ray diffraction, crystallinity of Florfenicol microcrystal was decreased, which improved the dissolution properties of it.This experiment investigated the differences of Florfenicol and its microcrystal in bioavailability through the comparison of pharmacokinetic differences of Florfenicol and its microcrystals in rabbits after oral gavage. High performance liquid chromatography method was used to determination of plasma concentration of Florfenicol, DAS2.0 was used to analyze the pharmacokinetic parameters, and SPSS was used to analyze the difference of the pharmacokinetic parameters. The results showed that the two groups of C-T data were fitted to the two compartment model (weight= 1/CC), mainly pharmacokinetic parameters of Florfenicol:AUC(o-t) was 4.20±1.23mg/l*h, Cmax was 1,68±0.33μg/ml, Tmax was 0.75±0.16h, MRT(o-∞) was 3.23±1.21h. And mainly pharmacokinetic parameters of Florfenicol microcrystal: AUC(o-t) was 6.66 ± 1.35 mg/l*h, Cmax was 2.18±0.37 μg/ml, Tmax was 1.42 ± 0.38h, MRT(o-∞) was 2.75 ± 0.42h.The results showed, Cmax and AUC(o-t) of Florfenicol microcrystal were increased significantly, and bioavailability was enhanced too.In conclusion, this study based on the principle of drug recrystallization, Florfenicol microcrystals was successfully prepared by improved solvent anti-solvent recrystallization. This preparation method has the advantages of simple operation, high yield, low requirements, low costs, and it is suitable for industrialized production. Compared with florfenicol, the saturated solubility, dissolution rate and bioavailability of its microcrystal were significantly increased. The experiment results laid the foundation to further popularization and application of Florfenicol microcrystal. and provided a new idea to the better use of florfenicol in animal disease control, also provides a new way of thinking for the veterinary drug micronization technology and research of the drug crystals, has important significance for promoting the development of veterinary drug preparation technology.