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



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.


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.


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.


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.


amorphous solid dispersion miscibility fluorescence solid state nuclear magnetic resonance 



Amorphous-amorphous phase separation


Active pharmaceutical ingredient


Amorphous solid dispersion


Cross polarization


Cross polarization magic angle spinning




Differential scanning calorimetry


Hydroxypropyl methyl cellulose








Spray drying


Scanning electron microscopy


Solid state nuclear magnetic resonance


Laboratory frame relaxation time


Rotating frame relaxation time


Glass transition temperature




X-ray diffraction


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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