新型抗精神分裂症药DT-195处方前研究

Preformulation study on novel antischizophrenic drug DT-195

目的对新型抗精神分裂症药DT-195进行处方前研究,为制剂研究提供理论依据。方法采用扫描电子显微镜、X射线粉末衍射、差示扫描量热分析等方法,表征DT-195的外观、晶型等特征,并考察DT-195在不同溶液中的溶解性;建立处方前研究用HPLC方法,并测定DT-195的表观油水分配系数以及在高、低离子浓度不同pH条件下的平衡溶解度。结果DT-195为类白色结晶性粉末,微溶于水,在10~280μg/ml浓度范围内与峰面积线性关系良好(r=0.9997),在酸性条件下较稳定,在碱性条件下易降解。油水分配系数为0.23,其溶解度随pH值和离子浓度的增大而减小。结论研究建立的DT-195含量测定及有关物质检查的HPLC方法准确可靠,灵敏度高、专属性强、与降解产物分离度良好。处方前研究表明,DT-195为难溶性药物,改善其口服制剂的溶解度,将会有利于提高其体内生物利用度。

ObjectiveTo perform a preformulation study for the novel antischizophrenic drug DT-195,so as to provide infomation for its formulation development.Methods The scanning electron microscopy,X-ray powder diffraction,and the differential scanning calorimetry were used to characterize the appearance and crystalline form of DT-195,and the solubility was tested for DT-195 in different solutions. An HPLC method was established for the preformulation determination of DT-195. The apparent oil/water(O/W)partition coefficient of DT-195 and the equilibrium solubility of the drug under different p H conditions with high and low ion concentrations were determined using the established HPLC method.ResultsDT-195 was an off-white crystalline powder,slightly soluble in water,with a good linearity with the peak area within the concentration range of 10-280 μg/ml(r=0.9997)in the HPLC analysis. DT-195 was stable under acidic conditions and easily degradable under alkaline conditions. The apparent O/W partition coefficient of DT-195 was 0.23. The solubility of DT-195 in solution decreased with the increase in the solution p H value or ion concentration.ConclusionThe established HPLC method is reliable for the determination of DT-195 and related substances with the high sensitivity,good specificity and the good separation of DT-195 and related substances. The present results have shown that DT-195 is a poorly soluble drug,and thus the improvement of DT-195 solubility in oral preparations will enhance the bioavailability in vivo.