| Oral formulation is the most popular one among various pharmaceutical dosage forms because for the patients oral administration is very convenient and for the manufacturers the production costs of oral formulation are relatively low. The drug absorption in vivo depends on its solubility in the gastrointestinal tract. However, presently, about40%of drugs in the development pipelines and approximately60%of drugs coming directly from synthesis exhibit high lipophilicity and poor aqueous solubility, which make the bioavailability of poorly soluble drugs after oral administration insufficient and far below the therapeutic level. Therefore, how to improve the dissolusion rate of poorly soluble drugs has become a research focus. By adopting fenofibrate and gemfibrozil, the poorly soluble lipid-regulating drugs, as the research objects, ultrafine drug particles were successfully prepared by the anti-solvent re-crystallization process, the solidification from emulsion process and the reactive re-crystallization process, respectively. Accordingly, the obvious reduction of drug particle size led to the increase of the specific surface area, and the corresponding improvement of the in ivtro dissolution rate. Furthermore, the possible formation mechanism of fenofibrate particles n the re-crystallization process was explored. The important factors arrecting he particle size and the related rules were found. The main contents and findings were summarized as follows.1. The anti-solvent re-crystallization process was employed to prepare ultrafine fenofibrate particles. The effects of experimental parameters, such as solvent and anti-solvent systems, volume ratios of solvent to anti-solvent, surfactants and their consumptions, concentrations of fenofibrate solutions, stirring rates and time, on the morphology and size of fenofibrate particles were investigated in detail. The obtained particles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), specific surface area analysis and dissolution test. The experimental results showed that the spherical fenofibrate particles with the mean size less than500nm were obtained in the anti-solvent re-crystallization process when ethanol was used as solvent and de-ionized water as anti-solvent. The slurry was homogeneous, but it was very hard to separate solid and liquid in slurry by filtration and centrifugation. Moreover, the particles grew evidently with the time. Thus, to obtain dried particles with regular morphology and small size, methyl cellulose (MC-M20) were employed to inhibit the growth and agglomeration of particles. Based on the above experimental results, the optimum experimental conditions were obtained:volume ratio of solvent to anti-solvent of1/10, fenofibrate ethanol solution concentration of0.035g/ml, stirring rate of1000rpm, stirring time of 25min, mixing temperature of22℃and MC-M20consumption of3%(based on the weight of drug). The dried particles prepared under the optimized conditions had a size less than5μm and a surface area of6.57m2/g, which was about26times as large as that of raw fenofibrate. The results of in vitro dissolution test indicated that about94.4%of ultrafine fenofibrate was dissolved after120min, which was2times as much as that of raw drug.2. In order to effectively control the particle size, the possible mechanism of fenofibrate nucleation and crystal growth in the anti-solvent re-crystallization process were explored. The impacts of fenofibrate initial concentration on solution supersaturation and solution supersaturation on the mean size of fenofibrate particles were investigated. The growth model of particles at different temperatures and aging time was studied. The experimental results suggested that the solution supersaturation increased with the augment of fenofibrate initial concentration and promoted the growth of drug particles. The relationship of particle mean size and the solution supersaturation could be expressed with the equation as d=367.4+11.22es/0.7287. In addition, the growth of fenofibrate particles accorded with the kinetic mechanism of Ostwald ripening, viz. the fenofbirate particle radius (r) and the cubic root of aging time (t) had a linear relationship, which could be expressed by the equations as follows:r=181.0+16.29/1/3and r=277.1+28.9t1/3when the system temperatures were0-2℃and8-10℃, repectively.3. To aquire a better preparation method, fenofibrate was used as a model drug and the solidification from emulsion process was firstly utilized to prepare ultrafine particles of poorly soluble drugs with low melting point (<100℃). The influences of factors such as emulsifiers and their consumptions, stirring methods and time, volume ratios of cold phase to hot phase on droplet size, emulsion stability and morphology and size of fenofibrate particles were studied. The experimental results showed that fenofibrate melted and self-emulsified in hot de-ionized water with the temperature≥95℃to form stable emulsion with the help of F-127utilized as emulsifier. The hot emulsion was poured into cold de-ionized water (about2℃) under vigorous agitation. The ultrafine fenofibrate particles were obtained and had a mean size less than5μm. The surface area of corresponding dried particles was6.23m2/g, which was24times larger than that of raw fenofibrate and1.6times as large as that of commercial micronized product. The results of in vitro dissolution test showed that the dissolution rate of the as-prepared ultrafine fenofibrate increased to18.9%after2.5min, while only13.0%of commercial micronized product and7.5%of raw fenofibrate dissolved at the same time. After120min, about96.1%of ultrafine fenofibrate was dissolved, which was1.1time as fast as that of commercial micronized product and1.5times faster than that of raw fenofibrate.4. The reactive re-crystallization process was employed to prepare ultrafine particles of gemfibrozil based on the fact that it was an acid poorly soluble drug. The influences of experimental parameters such as reactive systems, concentrations of acid and basic solution, volume ratios of acid solution to basic solution, mixing temperatures and drying methods on the morphology and size of gemfibrozil particles were studied and the optimum conditions were that the reactive system was NaOH-H2SO4system, the concentrations of NaOH and H2SO4were0.15mol/L and0.225mol/L, respectively, the surfactant was MC-M20whose dosage was5%(based on the weight of drug), stirring speed was5000rpm, stirring time was30min, reactive temperature was5℃and the drying method was spray-freeze drying. The ultrafine dried particles of gemfibrozil obtained under these conditions had a mean size of1.25μm and a specific surface area of11.02m2/g, which was6times as large as that of raw drug. XRD patterns and FT-IR spectra showed that the as-obtained ultrafine gemfibrozil was a crystalline powder with the structure and components similar to those of raw product. But the crystallinity of micronized product was obviously lower than that of raw drug. The results of in vitro dissolution test indicated that the dissolution rate of the as-prepared ultrafine gemfibrozil increased to91.2%after120min, while only23.6%of raw drug was dissolved at the same time. |
