利巴韦林的多晶型研究及药动学评价

 目的 研究利巴韦林多晶型状态，建立不同晶型物质状态的有效制备技术及晶型检测方法，评价不同晶型状态的利巴韦林药代动力学特点。方法 通过晶型筛查技术，发现利巴韦林存在4种晶型物质状态（晶A型、晶B型、晶C型、晶D型），制备获得了4种晶型纯品，采用单晶X射线衍射技术（SXRD）、粉末X射线衍射技术（PXRD）、差示扫描量热技术（DSC）、红外光谱分析技术（IR）与熔点技术（MP）对利巴韦林4种晶型物质状态进行了表征；SD大鼠灌胃给予不同晶型利巴韦林固体后，采用液质联用技术检测不同时间大鼠血药浓度变化、比较不同晶型的生物利用度。结果 利巴韦林药物存在多晶型现象，其中晶C型和晶D型为首次发现并报道；研究证明粉末X射线衍射技术法、差示扫描量热技术法、红外光谱分析技术法、熔点技术法均可实现对不同晶型物质状态的表征和鉴别；发现使用利巴韦林不同晶型物质作为药物原料会对药物临床治疗作用产生影响。结论 发现了利巴韦林新晶型物质状态，获得对晶型物质的有效鉴别分析方法；通过生物学实验证明晶型物质状态会对药物临床作用产生影响。

Polymorphism and Pharmacokinetic Research of Ribavirin

OBJECTIVE To establish the preparation method and detection technology of ribavirin polymorphism， and to estimate the bioavailability differences among the ribavirin polymorphs. METHODS Through polymorphism screening， ribavirin crystals of the form A， B， C， D were obtained. The crystal forms of ribavirin were characterized by different analysis methods， such as single crystal X-ray diffraction method (SXRD)， powder X-ray diffraction method (PXRD)， differential scanning calorimetry method (DCS)， infrared spectrum method (IR) and melting point method (MP)； solid ribavirin in different forms were orally administered to rats， and an HPLC-MS method was established to determine the plasma levels of ribavirin， and the bioavailability was analyzed. RESULTS Of the four polymorphs of ribavirin， form C and form D were reported for the first time. The four polymorphic forms all could be identified by PXRD， DSC， IR and MP. The ρ_max and AUC_0-t of form A were superior to those of the other forms. CONCLUSION Characteristic data for ribavirin polymorphism are obtained； and form A of ribavirin is a suitable medicinal crystal. This study has provided the basis for choice of medicinal crystal and the improvement of quality standards.