Crystallization from Supersaturated Solutions: Role of Lecithin and Composite Simulated Intestinal Fluid
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,
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.
Key wordsbiorelevant media crystallization nucleation simulated intestinal fluids supersaturation
Fasted state simulated intestinal fluid
Human intestinal fluid
Flux at amorphous solubility
Nucleation induction time
Simulated intestinal fluid
Supersaturation ratio at amorphous solubility
Acknowledgements and Disclosures
The authors would like to acknowledge AbbVie Inc. for providing research funding for this project. Purdue University and AbbVie jointly participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Anura S. Indulkar was a graduate student at Purdue University. Lynne S. Taylor is a professor at Purdue University. Lynne S. Taylor has no additional conflicts of interest to report. Anura S. Indulkar, Shweta A. Raina, Yi Gao, and Geoff G. Z. Zhang are employees of AbbVie and may own AbbVie stock.
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