Pharmaceutical Research

, Volume 34, Issue 5, pp 957–970 | Cite as

Elucidation of Compression-Induced Surface Crystallization in Amorphous Tablets Using Sum Frequency Generation (SFG) Microscopy

  • Pei T. Mah
  • Dunja Novakovic
  • Jukka Saarinen
  • Stijn Van Landeghem
  • Leena Peltonen
  • Timo Laaksonen
  • Antti IsomäkiEmail author
  • Clare J. Strachan
Research Paper



To investigate the effect of compression on the crystallization behavior in amorphous tablets using sum frequency generation (SFG) microscopy imaging and more established analytical methods.


Tablets containing neat amorphous griseofulvin with/without excipients (silica, hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC) and polyethylene glycol (PEG)) were prepared. They were analyzed upon preparation and storage using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM) and SFG microscopy.


Compression-induced crystallization occurred predominantly on the surface of the neat amorphous griseofulvin tablets, with minimal crystallinity being detected in the core of the tablets. The presence of various types of excipients was not able to mitigate the compression-induced surface crystallization of the amorphous griseofulvin tablets. However, the excipients affected the crystallization rate of amorphous griseofulvin in the core of the tablet upon compression and storage.


SFG microscopy can be used in combination with ATR-FTIR spectroscopy and SEM to understand the crystallization behaviour of amorphous tablets upon compression and storage. When selecting excipients for amorphous formulations, it is important to consider the effect of the excipients on the physical stability of the amorphous formulations.


amorphous attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy compression crystallization griseofulvin scanning electron microscopy (SEM) sum frequency generation (SFG) microscopy 



Attenuated total reflectance Fourier transform infrared


Differential scanning calorimetry


Hydroxypropyl methylcellulose acetate succinate


Hybrid detector




Microcrystalline cellulose


Nuclear magnetic resonance


Optical parametric oscillator


Polyethylene glycol


Photomultiplier tube


Scanning electron microscopy


Sum frequency generation


Second harmonic generation


X-ray powder diffractometry



This study was partially supported by the Pharmacy Grant 2013 (University of Helsinki). Elman Poole Travelling Fellowship and the University of Otago Doctoral Scholarship are gratefully acknowledged for providing Pei Ting Mah with financial support. Timo Laaksonen acknowledges funding from the Academy of Finland grant no. 258114.

Supplementary material

11095_2016_2046_MOESM1_ESM.docx (653 kb)
ESM 1 (DOCX 653 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Pei T. Mah
    • 1
    • 2
  • Dunja Novakovic
    • 2
  • Jukka Saarinen
    • 2
  • Stijn Van Landeghem
    • 2
  • Leena Peltonen
    • 2
  • Timo Laaksonen
    • 3
    • 4
  • Antti Isomäki
    • 5
    Email author
  • Clare J. Strachan
    • 2
  1. 1.School of PharmacyUniversity of OtagoDunedinNew Zealand
  2. 2.Division of Pharmaceutical Chemistry and Technology, Faculty of PharmacyUniversity of HelsinkiHelsinkiFinland
  3. 3.Division of Pharmaceutical Biosciences, Faculty of PharmacyUniversity of HelsinkiHelsinkiFinland
  4. 4.Department of Chemistry and Bioengineering, Faculty of Natural SciencesTampere University of TechnologyTampereFinland
  5. 5.Biomedicum Imaging Unit, Department of Anatomy, Medicum, Faculty of MedicineFIN-00014 University of HelsinkiHelsinkiFinland

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