【摘要】 目的：研究不同温度和湿度对异欧前胡素两种晶型稳定性的影响以及大鼠血浆中两种晶型的药代动力学特性，明确优势药物晶型。方法：采用粉末X射线衍射法分析异欧前胡素两种晶型在不同温度（5、60、80℃，24 h）与湿度（RH25%、45%、65%、75%,1周）条件下的稳定性；将健康雄性SD大鼠随机分为两组，灌胃给予200 mg·kg^-1的CMC-Na混悬液，于给药后0.25、0.5、0.75、1、1.5、2、3、4、6、8和12 h采集血样，通过HPLC测定大鼠血浆中异欧前胡素的含量，并采用Kinetica4.4软件按非房室模型拟合计算药代动力学参数。结果：两种晶型在不同湿度下均稳定；晶型Ⅱ在不同温度下稳定，晶型Ⅰ在60℃下部分转变为晶型Ⅱ，在80℃下则完全转晶；药代动力学参数显示，大鼠血浆中晶型Ⅰ和晶型Ⅱ的达峰时间t_max分别为4.17 h和3.83 h，最大血药浓度C_max分别为1.48μg·m L^-1和0.51μg·mL^-1，药时曲线下面积AUC_{0～12 h}分别为7.94μg·h·mL^-1和2.28μg·h·mL^-1,AUC_0～∞分别为7.97μg·h·mL^-1和2.33μg·h·mL^-1，消除半衰期t_1/2分别为0.95 h和1.77 h。结论：异欧前胡素的晶型Ⅱ为稳定晶型，晶型Ⅰ为亚稳晶型，其制剂过程温度不宜超过60℃；晶型Ⅰ的生物利用度是晶型Ⅱ的348%，表明晶型差异显著影响其体内吸收。更多还原

【Abstract】 Objective: To study the influence of different temperatures and humidity on the stability of isoimperatorin two crystal types and the pharmacokinetics of different polymorph forms in rats plasma after intragastric administration of isoimperatorin Form Ⅰ and Form Ⅱ, so as to provide a guidance for the selection of superiority drug crystal. Methods: The stability of two crystal forms of isoimperatorin under different temperature（5, 60, 80°C for 24 h） and humidity（RH25%, 45%, 65%, 75% for 1 week） conditions was analyzed using powder X-ray diffraction. Healthy male SD rats were randomly divided into two groups and administered a 200 mg·kg^-1 CMC-Na suspension via oral gavage. Blood samples were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 h after administration. The concentration of isoimperatorin in rat plasma was determined by HPLC, and pharmacokinetic parameters were calculated using Kinetica 4.4 software based on a non-compartmental model. Results: Both crystal forms remained stable under different humidity conditions. Form Ⅱ was stable across the tested temperatures, whereas Form Ⅰ partially transformed into Form Ⅱ at 60°C and converted completely at 80°C. The pharmacokinetic parameters revealed the following for Form Ⅰ and Form Ⅱ in rat plasma, respectively: the time to reach peak concentration(t_max) was 4.17 h and 3.83 h; the maximum plasma concentration(C_max) was 1.48 μg·mL^-1 and 0.51 μg·mL^-1; the area under the concentration-time curve from 0 to 12 hours(AUC_{0-12 h}) was 7.94 μg·h·mL^-1 and 2.28 μg·h·mL^-1; the area under the curve from time zero to infinity(AUC_0-∞) was 7.97 μg·h·mL^-1 and 2.33 μg·h·mL^-1; and the elimination half-life(t_1/2) was 0.95 h and 1.77 h. Conclusion: Imperatorin’s crystal form Ⅱ is the stable polymorph, while crystal form Ⅰ is a metastable polymorph. The temperature during the formulation process should not exceed 60°C. The bioavailability of crystal form Ⅰ is 348% that of crystal form Ⅱ, indicating that polymorphic differences significantly affect its in vivo absorption.更多还原