Pharmaceutical Research

, Volume 32, Issue 11, pp 3660–3673 | Cite as

Using Environment-Sensitive Fluorescent Probes to Characterize Liquid-Liquid Phase Separation in Supersaturated Solutions of Poorly Water Soluble Compounds

  • Shweta A. Raina
  • David E. Alonzo
  • Geoff G. Z. Zhang
  • Yi Gao
  • Lynne S. Taylor
Research Paper

Abstract

Purpose

Highly supersaturated aqueous solutions of poorly soluble compounds can undergo liquid-liquid phase separation (LLPS) when the concentration exceeds the “amorphous solubility”. This phenomenon has been widely observed during high throughput screening of new molecular entities as well as during the dissolution of amorphous solid dispersions. In this study, we have evaluated the use of environment-sensitive fluorescence probes to investigate the formation and properties of the non-crystalline drug-rich aggregates formed in aqueous solutions as a result of LLPS.

Methods

Six different environment-sensitive fluorophores were employed to study LLPS in highly supersaturated solutions of several model compounds, all dihydropyridine derivatives.

Results

Each fluoroprobe exhibited a large hypsochromic shift with decreasing environment polarity. Upon drug aggregate formation, the probes partitioned into the drug-rich phase and exhibited changes in emission wavelength and intensity consistent with sensing a lower polarity environment. The LLPS onset concentrations determined using the fluorescence measurements were in good agreement with light scattering measurements as well as theoretically estimated amorphous solubility values.

Conclusions

Environment-sensitive fluorescence probes are useful to help understand the phase behavior of highly supersaturated aqueous solutions, which in turn is important in the context of developing enabling formulations for poorly soluble compounds.

KEY WORDS

Fluorescence Phase separation Supersaturation 

Abbreviations

ASDs

Amorphous solid dispersions

CMC

Critical micelle concentration

DASPEI

2-(4-(dimethylamino)styryl) -N-Ethylpyridinium Iodide

DMSO

Dimethyl sulfoxide

ESIPT

Excited state intermolecular proton transfer

HPMC

Hydroxypropylmethyl cellulose

HPMCAS

Hydroxypropylmethyl cellulose acetate succinate

ICT

Intermolecular charge transfer

IPA

Isopropyl alcohol

LLPS

Liquid-liquid phase separation

PLM

Polarized light microscopy

PRODAN

4-(4-(Diethylamino)styryl) -N-Methylpyridinium Iodide (4-Di-2ASP) 6-Propionyl-2-dimethylaminonaphthalene

PVP

Polyvinylypyrrolidone

TFA

Trifluoroacetic acid

UV

Ultraviolet

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Shweta A. Raina
    • 1
    • 3
  • David E. Alonzo
    • 2
    • 4
  • Geoff G. Z. Zhang
    • 2
  • Yi Gao
    • 2
    • 5
  • Lynne S. Taylor
    • 1
  1. 1.Department of Industrial and Physical Pharmacy, College of PharmacyPurdue UniversityWest LafayetteUSA
  2. 2.Drug Product Development, Research and Development, AbbVie IncNorth ChicagoUSA
  3. 3.Manufacturing Science and Technology, AbbVie IncNorth ChicagoUSA
  4. 4.Formulation & Process Development, Gilead Sciences, IncFoster CityUSA
  5. 5.Analytical Sciences, Manufacturing Science and Technology, AbbVie IncNorth ChicagoUSA

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