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Impact of Micellar Surfactant on Supersaturation and Insight into Solubilization Mechanisms in Supersaturated Solutions of Atazanavir

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Abstract

Purpose

The goals of this study were to determine: 1) the impact of surfactants on the “amorphous solubility”; 2) the thermodynamic supersaturation in the presence of surfactant micelles; 3) the mechanism of solute solubilization by surfactant micelles in supersaturated solutions.

Methods

The crystalline and amorphous solubility of atazanavir was determined in the presence of varying concentrations of micellar sodium dodecyl sulfate (SDS). Flux measurements, using a side-by-side diffusion cell, were employed to determine the free and micellar-bound drug concentrations. The solubilization mechanism as a function of atazanavir concentration was probed using fluorescence spectroscopy. Pulsed gradient spin-echo proton nuclear magnetic resonance (PGSE-NMR) spectroscopy was used to determine the change in micelle size with a change in drug concentration.

Results

Changes in the micelle/water partition coefficient, K m/w , as a function of atazanavir concentration led to erroneous estimates of the supersaturation when using concentration ratios. In contrast, determining the free drug concentration using flux measurements enabled improved determination of the thermodynamic supersaturation in the presence of micelles. Fluorescence spectroscopic studies suggested that K m/w changed based on the location of atazanavir solubilization which in turn changed with concentration. Thus, at a concentration equivalent to the crystalline solubility, atazanavir is solubilized by adsorption at the micelle corona, whereas in highly supersaturated solutions it is also solubilized in the micellar core. This difference in solubilization mechanism can lead to a breakdown in the prediction of amorphous solubility in the presence of SDS as well as challenges with determining supersaturation. PGSE-NMR suggested that the size of the SDS micelle is not impacted at the crystalline solubility of the drug but increases when the drug concentration reaches the amorphous solubility, in agreement with the proposed changes in solubilization mechanism.

Conclusions

Micellar solubilization of atazanavir is complex, with the solubilization mechanism changing with differences in the degree of (super)saturation. This can result in erroneous predictions of the amorphous solubility and thermodynamic supersaturation in the presence of solubilizing additives. This in turn hinders understanding of the driving force for phase transformations and membrane transport, which is essential to better understand supersaturating dosage forms.

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Abbreviations

ASD:

Amorphous solid dispersion

ATZ:

Atazanavir

CMC:

Critical micelle concentration

FRET:

Förster resonance energy transfer

GLPS:

Glass liquid phase separation

HPLC:

High performance liquid chromatography

LLPS:

Liquid liquid phase separation

PGSE-NMR:

Pulsed gradient spin-echo proton nuclear magnetic resonance

SDS:

Sodium dodecyl sulfate

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Acknowledgments and Disclosures

We 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 is a graduate student at Purdue University; Lynne S. Taylor is a professor at Purdue University; Huaping Mo is an Associate Director of Purdue Interdepartmental NMR Facility at Purdue University. They all have no additional conflicts of interest to report. 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. Purdue Interdepartmental NMR Facility and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, 47907, USA

    Huaping Mo

  3. Manufacturing Science & Technology (MS&T), Operations, AbbVie Inc., North Chicago, IL, 60064, USA

    Yi Gao & Shweta A. Raina

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

    Geoff G. Z. Zhang

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  1. Anura S. Indulkar
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Correspondence to Geoff G. Z. Zhang or Lynne S. Taylor.

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Indulkar, A.S., Mo, H., Gao, Y. et al. Impact of Micellar Surfactant on Supersaturation and Insight into Solubilization Mechanisms in Supersaturated Solutions of Atazanavir. Pharm Res 34, 1276–1295 (2017). https://doi.org/10.1007/s11095-017-2144-0

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