Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark; Pharmaceutical R&D, H. Lundbeck A/S, Valby, Denmark; Pharmaceutical Sciences, Janssen, Beerse, Belgium.
Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
J Pharm Sci. 2021 Jun;110(6):2479-2488. doi: 10.1016/j.xphs.2020.12.039. Epub 2021 Jan 9.
Eleven simulated intestinal fluids (SIF) were designed using a Design of Experiment (DoE) approach. The DoE SIF covered a range of compositions of fasted state human intestinal fluid (FaHIF) with regard to pH, bile salt (BS), and phospholipid (PL). Using the model compound danazol, the apparent crystalline solubility (aCS) and apparent amorphous solubility (aAS), as well as the supersaturation propensity was determined in the DoE SIF media. The aCS of danazol was dependent on the composition of the SIF, with PL as the main factor, and a small effect from BS and an interaction between BS and PL. From the DoE solubility data a model was derived, which could predict aCS in commercially available SIF (FaSSIF-V1 and -V2) and in a range of FaHIF. The aAS of danazol was differently affected by the SIF composition than the aCS; PL was again the main factor influencing the aAS, but interactions between BS and pH, as well as pH and PL were also important. The supersaturation propensities of danazol in the DoE SIF media were affected by the same factors as the aCS. Hence, the supersaturation behaviour and aCS of danazol, were found to be closely related.
采用实验设计（DoE）方法设计了 11 种模拟肠液（SIF）。DoE SIF 涵盖了空腹状态人肠液（FaHIF）的 pH 值、胆汁盐（BS）和磷脂（PL）组成范围。使用模型化合物丹那唑，在 DoE SIF 介质中测定了表观结晶溶解度（aCS）和表观无定形溶解度（aAS）以及过饱和度倾向。丹那唑的 aCS 取决于 SIF 的组成，PL 是主要因素，BS 和 PL 之间存在小的影响和相互作用。从 DoE 溶解度数据中推导出一个模型，该模型可以预测商业上可用的 SIF（FaSSIF-V1 和 -V2）和 FaHIF 范围内的 aCS。丹那唑的 aAS 与 aCS 相比，受 SIF 组成的影响不同；PL 再次是影响 aAS 的主要因素，但 BS 和 pH 之间以及 pH 和 PL 之间的相互作用也很重要。DoE SIF 介质中丹那唑的过饱和度倾向受到与 aCS 相同的因素的影响。因此，丹那唑的过饱和度行为和 aCS 被发现密切相关。
