Upon dissolution, amorphous solid dispersions (ASDs) of poorly water-soluble compounds can generate supersaturated solutions consisting of bound and free drug species that are in dynamic equilibrium with each other. Only free drug is available for absorption. Drug species bound to bile micelles, polymer excipients, and amorphous and crystalline precipitate can reduce the drug solute’s activity to permeate, but they can also serve as reservoirs to replenish free drug in solution lost to absorption. However, with multiple processes of dissolution, absorption, and speciation occurring simultaneously, it may become challenging to understand which processes lead to an increase or decrease in drug solution concentration. Closed, nonsink dissolution testing methods used routinely, in the absence of drug removal, allow only for static equilibrium to exist and obscure the impact of each drug species on absorption. An artificial gut simulator (AGS) introduced recently consists of a hollow fiber-based absorption module and allows mass transfer of the drug from the dissolution media at a physiological rate after tuning the operating parameters. In the present work, ASDs of varying drug loadings were prepared with a BCS-II model compound, ketoconazole (KTZ), and hypromellose acetate succinate (HPMCAS) polymer. Simultaneous dissolution and absorption testing of the ASDs was conducted with the AGS, and simple analytical techniques were utilized to elucidate the impact of bound drug species on absorption. In all cases, a lower amount of crystalline precipitate was formed in the presence of absorption relative to the nonsink dissolution “control”. However, formation of HPMCAS-bound drug species and crystalline precipitate significantly reduced KTZ absorption. Moreover, at high drug loading, inclusion of an absorption module was shown to enhance ASD dissolution. The rank ordering of the ASDs with respect to dissolution was significantly different when nonsink dissolution versus AGS was used, and this discrepancy could be mechanistically elucidated by understanding drug dissolution and speciation in the presence of absorption.

中文翻译：

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人工肠道/吸收模拟器：了解吸收对非晶固体分散体体外溶解、形态形成和沉淀的影响

溶解后，水溶性差的化合物的无定形固体分散体（ASD）可以生成由彼此处于动态平衡的结合药物种类和游离药物种类组成的过饱和溶液。只有游离药物才能被吸收。与胆汁胶束、聚合物赋形剂以及无定形和结晶沉淀物结合的药物种类可以降低药物溶质的渗透活性，但它们也可以作为储存库来补充溶液中因吸收而损失的游离药物。然而，由于溶解、吸收和形态形成的多个过程同时发生，了解哪些过程导致药物溶液浓度增加或减少可能变得具有挑战性。常规使用的封闭式、非下沉溶出测试方法，在没有药物去除的情况下，仅允许存在静态平衡，并且掩盖了每种药物种类对吸收的影响。最近推出的人工肠道模拟器（AGS）由基于中空纤维的吸收模块组成，在调整操作参数后允许药物以生理速率从溶出介质中进行传质。在目前的工作中，使用 BCS-II 模型化合物、酮康唑 (KTZ) 和醋酸羟丙甲纤维素琥珀酸酯 (HPMCAS) 聚合物制备了不同载药量的 ASD。使用 AGS 对 ASD 同时进行溶出度和吸收测试，并利用简单的分析技术来阐明结合的药物种类对吸收的影响。在所有情况下，相对于非下沉溶解“对照”，在存在吸收的情况下形成的结晶沉淀物的量较少。然而，HPMCAS 结合药物种类和结晶沉淀的形成显着降低了 KTZ 的吸收。此外，在高载药量下，吸收模块的加入可以增强 ASD 的溶出。当使用非下沉溶出与 AGS 时，ASD 相对于溶出的排序显着不同，并且可以通过了解吸收存在下的药物溶出和形态形成来机械地阐明这种差异。