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Pharmaceutical Research

, Volume 34, Issue 7, pp 1364–1377 | Cite as

Insights into Nano- and Micron-Scale Phase Separation in Amorphous Solid Dispersions Using Fluorescence-Based Techniques in Combination with Solid State Nuclear Magnetic Resonance Spectroscopy

  • Hitesh S. Purohit
  • James D. Ormes
  • Sugandha Saboo
  • Yongchao Su
  • Matthew S. Lamm
  • Amanda K. P. Mann
  • Lynne S. TaylorEmail author
Research Paper

Abstract

Purpose

Miscibility between the drug and the polymer in an amorphous solid dispersion (ASD) is considered to be one of the most important factors impacting the solid state stability and dissolution performance of the active pharmaceutical ingredient (API). The research described herein utilizes emerging fluorescence-based methodologies to probe (im)miscibility of itraconazole (ITZ)-hydroxypropyl methylcellulose (HPMC) ASDs.

Methods

The ASDs were prepared by solvent evaporation with varying evaporation rates and were characterized by steady-state fluorescence spectroscopy, confocal imaging, differential scanning calorimetry (DSC), and solid state nuclear magnetic resonance (ssNMR) spectroscopy.

Results

The size of the phase separated domains for the ITZ-HPMC ASDs was affected by the solvent evaporation rate. Smaller domains (<10 nm) were observed in spray-dried ASDs, whereas larger domains (>30 nm) were found in ASDs prepared using slower evaporation rates. Confocal imaging provided visual confirmation of phase separation along with chemical specificity, achieved by selectively staining drug-rich and polymer-rich phases. ssNMR confirmed the results of fluorescence-based techniques and provided information on the size of phase separated domains.

Conclusions

The fluorescence-based methodologies proved to be sensitive and rapid in detecting phase separation, even at the nanoscale, in the ITZ-HPMC ASDs. Fluorescence-based methods thus show promise for miscibility evaluation of spray-dried ASDs.

KEY WORDS

amorphous solid dispersion miscibility fluorescence solid state nuclear magnetic resonance 

Abbreviations

AAPS

Amorphous-amorphous phase separation

API

Active pharmaceutical ingredient

ASD

Amorphous solid dispersion

CP

Cross polarization

CP-MAS

Cross polarization magic angle spinning

DCM

Dichloromethane

DSC

Differential scanning calorimetry

HPMC

Hydroxypropyl methyl cellulose

ITZ

Itraconazole

MeOH

Methanol

R6G

Rhodamine-6-G

SD

Spray drying

SEM

Scanning electron microscopy

ssNMR

Solid state nuclear magnetic resonance

T1

Laboratory frame relaxation time

T1rho

Rotating frame relaxation time

Tg

Glass transition temperature

TMS

Tetramethylsilane

XRD

X-ray diffraction

Notes

Acknowledgments and Disclosures

Financial support to HSP from Migliaccio/Pfizer graduate fellowship is greatly acknowledged. The authors would like to thank the New Technology Review and Licensing Committee (NTRLC) at Merck & Co., Inc., Kenilworth, NJ, USA, for financial support. The authors would also like to thank Drs. Ellen C. Minnihan, Wei Xu, Anthony Leone, Timothy Rhodes, Andrew Latham and Christopher J. Welch for helpful discussions.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Hitesh S. Purohit
    • 1
  • James D. Ormes
    • 2
  • Sugandha Saboo
    • 1
  • Yongchao Su
    • 3
  • Matthew S. Lamm
    • 2
  • Amanda K. P. Mann
    • 4
  • Lynne S. Taylor
    • 1
    Email author
  1. 1.Department of Industrial and Physical Pharmacy, College of PharmacyPurdue University,IndianaUSA
  2. 2.Preformulation, MRL,Merck & Co., Inc.RahwayUSA
  3. 3.Preformulation, MRL,Merck & Co., Inc.West PointUSA
  4. 4.Analytical Sciences, MRL,Merck & Co., Inc.RahwayUSA

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