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Crystallization from Supersaturated Solutions: Role of Lecithin and Composite Simulated Intestinal Fluid

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Abstract

Purpose

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.

Results

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.

Conclusions

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.

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Abbreviations

FaSSIF:

Fasted state simulated intestinal fluid

HIF:

Human intestinal fluid

J amorph :

Flux at amorphous solubility

NIT:

Nucleation induction time

SGC:

Sodium glycocholate

SGCDC:

Sodium glycochenodeoxycholate

SGDC:

Sodium glycodeoxycholate

SGUDC:

Sodium glycoursodeoxycholate

SIF:

Simulated intestinal fluid

SR :

Supersaturation ratio

SR amorph :

Supersaturation ratio at amorphous solubility

STC:

Sodiun taurocholate

STCDC:

Sodium taurochenodeoxycholate

STDC:

Sodium taurodeoxycholate

STUDC:

Sodium tauroursodeoxycholate

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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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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA

    Anura S. Indulkar & Lynne S. Taylor

  2. Drug Product Development, Research and Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois, 60064, USA

    Anura S. Indulkar & Geoff G. Z. Zhang

  3. Science & Technology (S&T), Operations, AbbVie Inc., 1401 Sheridan Road, North Chicago, Illinois, 60064, USA

    Yi Gao & Shweta A. Raina

Authors
  1. Anura S. Indulkar
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  2. Yi Gao
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  3. Shweta A. Raina
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  4. Geoff G. Z. Zhang
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  5. Lynne S. Taylor
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Corresponding authors

Correspondence to Geoff G. Z. Zhang or Lynne S. Taylor.

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Indulkar, A.S., Gao, Y., Raina, S.A. et al. Crystallization from Supersaturated Solutions: Role of Lecithin and Composite Simulated Intestinal Fluid. Pharm Res 35, 158 (2018). https://doi.org/10.1007/s11095-018-2441-2

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  • DOI: https://doi.org/10.1007/s11095-018-2441-2

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