Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
Drug Product Development, Research and Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois, 60064, USA.
Pharm Res. 2018 Jun 18;35(8):158. doi: 10.1007/s11095-018-2441-2.
The overall purpose of this study was to understand the impact of different biorelevant media types on solubility and crystallization from supersaturated solutions of model compounds (atazanavir, ritonavir, tacrolimus and cilnidipine). The first aim was to understand the influence of the lecithin content in FaSSIF. As the human intestinal fluids (HIFs) contain a variety of bile salts in addition to sodium taurocholate (STC), the second aim was to understand the role of these bile salts (in the presence of lecithin) on solubility and crystallization from supersaturated solutions, METHODS: To study the impact of lecithin, media with 3 mM STC concentration but varying lecithin concentration were prepared. To test the impact of different bile salts, a new biorelevant medium (Composite-SIF) with a composition simulating that found in the fasted HIF was prepared. The crystalline and amorphous solubility was determined in these media. Diffusive flux measurements were performed to determine the true supersaturation ratio at the amorphous solubility of the compounds in various media. Nucleation induction times from supersaturated solutions were measured at an initial concentration equal to the amorphous solubility (equivalent supersaturation) of the compound in the given medium.
It was observed that, with an increase in lecithin content at constant STC concentration (3 mM), the amorphous solubility of atazanavir increased and crystallization was accelerated. However, the crystalline solubility remained fairly constant. Solubility values were higher in FaSSIF compared to Composite-SIF. Longer nucleation induction times were observed for atazanavir, ritonavir and tacrolimus in Composite-SIF compared to FaSSIF at equivalent supersaturation ratios.
This study shows that variations in the composition of SIF can lead to differences in the solubility and crystallization tendency of drug molecules, both of which are critical when evaluating supersaturating systems.
本研究的总体目的是了解不同生物相关介质类型对模型化合物（阿扎那韦、利托那韦、他克莫司和西尼地平）过饱和溶液中溶解度和结晶的影响。第一个目的是了解 FaSSIF 中卵磷脂含量的影响。由于人肠液（HIF）除了牛磺胆酸钠（STC）外还含有各种胆汁盐，因此第二个目的是了解这些胆汁盐（存在卵磷脂的情况下）对过饱和溶液中溶解度和结晶的作用。
为了研究卵磷脂的影响，制备了 STC 浓度为 3mM 但卵磷脂浓度不同的介质。为了测试不同胆汁盐的影响，制备了一种新的生物相关介质（Composite-SIF），其组成模拟禁食 HIF 中的发现。在这些介质中测定了结晶和无定形溶解度。扩散通量测量用于确定在各种介质中化合物无定形溶解度下的真实过饱和度比。在初始浓度等于给定介质中化合物无定形溶解度（等效过饱和度）的情况下，从过饱和溶液中测量成核诱导时间。
结果表明，在恒定 STC 浓度（3mM）下增加卵磷脂含量时，阿扎那韦的无定形溶解度增加且结晶加速。然而，结晶溶解度基本保持不变。FaSSIF 中的溶解度值高于 Composite-SIF。在等效过饱和度下，与 FaSSIF 相比，阿扎那韦、利托那韦和他克莫司在 Composite-SIF 中的成核诱导时间更长。
本研究表明，SIF 组成的变化会导致药物分子的溶解度和结晶倾向的差异，这两者在评估过饱和系统时都很关键。
