AAPS PharmSciTech

, Volume 15, Issue 2, pp 253–260 | Cite as

Characterisation of Crystalline-Amorphous Blends of Sucrose with Terahertz-Pulsed Spectroscopy: the Development of a Prediction Technique for Estimating the Degree of Crystallinity with Partial Least Squares Regression

Research Article


The control of the amorphous and crystalline states of drugs and excipients is important in many instances of product formulation, manufacture, and packaging, such as the formulation of certain (freeze-dried) fast melt tablets. This study examines the use of terahertz-pulsed spectroscopy (TPS) coupled with two different data analytical methods as an off-line tool (in the first instance) for assessing the degree of crystallinity in a binary mixture of amorphous and polycrystalline sucrose. The terahertz spectrum of sucrose was recorded in the wave number range between 3 and 100 cm−1 for both the pure crystalline form and for a mixture of the crystalline and amorphous (freeze-dried) form. The THz spectra of crystalline sucrose showed distinct absorption bands at ∼48, ∼55, and ∼60 cm−1 while all these features were absent in the amorphous sucrose. Calibration models were constructed based on (1) peak area analysis and (2) partial least square regression analysis, with the latter giving the best LOD and LOQ of 0.76% and 2.3%, respectively. The potential for using THz spectroscopy, as a quantitative in-line tool for percent crystallinity in a range of complex systems such as conventional tablets and freeze-dried formulations, is suggested in this study.

Key words

crystallinity partial least squares sugars terahertz-pulsed spectroscopy 


  1. 1.
    Fu YR, Yang SC, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: Developments, technologies, taste-masking and clinical studies. Crit Rev Ther Drug Carr Syst. 2004;21(6):433–75. PubMed PMID: ISI:000227160800001. English.CrossRefGoogle Scholar
  2. 2.
    Yu LX, Lionberger RA, Raw AS, D’Costa R, Wu H, Hussain AS. Applications of process analytical technology to crystallization processes. Adv Drug Deliv Rev. 2004;56(3):349–69.PubMedCrossRefGoogle Scholar
  3. 3.
    Jenkins R, Snyder R. Introduction to X-ray powder diffractometry. New Jersey: Wiley; 2012.Google Scholar
  4. 4.
    The United States Pharmacopoeial Convention. X-Ray Diffraction, General test-941. In: United States Pharmacopoeia 25, editor. 25. Rockville, MD, 2001. pp. 2088–9.Google Scholar
  5. 5.
    Févotte G. In situ raman spectroscopy for in-line control of pharmaceutical crystallization and solids elaboration processes: A review. Chem Eng Res Des. 2007;85(7):906–20.CrossRefGoogle Scholar
  6. 6.
    Taday PF, Bradley IV, Arnone DD, Pepper M. Using terahertz pulse spectroscopy to study the crystalline structure of a drug: A case study of the polymorphs of ranitidine hydrochloride. J Pharm Sci. 2003;92(4):831–8. PubMed PMID: ISI:000181954200012.PubMedCrossRefGoogle Scholar
  7. 7.
    Shen Y-C. Terahertz pulsed spectroscopy and imaging for pharmaceutical applications: A review. Int J Pharm. 2011;417(1–2):48–60.PubMedCrossRefGoogle Scholar
  8. 8.
    Chantry GW. Submillimetre spectroscopy: A guide to the theoretical and experimental physics of the far infrared. London: Academic Press; 1971.Google Scholar
  9. 9.
    Mantsch HH, Naumann D. Terahertz spectroscopy: The renaissance of far infrared spectroscopy. J Mol Struct 964(1–3):1–4.Google Scholar
  10. 10.
    Strachan CJ, Rades T, Newnham DA, Gordon KC, Pepper M, Taday PF. Using terahertz pulsed spectroscopy to study crystallinity of pharmaceutical materials. Chem Phys Lett. 2004;390(1–3):20–4.CrossRefGoogle Scholar
  11. 11.
    Strachan CJ, Taday PF, Newnham DA, Gordon KC, Zeitler JA, Pepper M, et al. Using terahertz pulsed spectroscopy to quantify pharmaceutical polymorphism and crystallinity. J Pharm Sci. 2005;94(4):837–46. PubMed PMID: WOS:000228150400014.PubMedCrossRefGoogle Scholar
  12. 12.
    Walther M, Fischer BM, Uhd JP. Noncovalent intermolecular forces in polycrystalline and amorphous saccharides in the far infrared. Chem Phys. 2003;288(2–3):261–8.CrossRefGoogle Scholar
  13. 13.
    Bai SJ, Rani M, Suryanarayanan R, Carpenter JF, Nayar R, Manning MC. Quantification of glycine crystallinity by near-infrared (NIR) spectroscopy. J Pharm Sci. 2004;93(10):2439–47.PubMedCrossRefGoogle Scholar
  14. 14.
    Rumondor ACF, Taylor LS. Application of partial least-squares (PLS) modeling in quantifying drug crystallinity in amorphous solid dispersions. Int J Pharm. 2010;398(1–2):155–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Shao X, Bian X, Cai W. An improved boosting partial least squares method for near-infrared spectroscopic quantitative analysis. Anal Chim Acta. 2010;666(1–2):32–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Shen Y-C, Taday PF, Pepper M. Elimination of scattering effects in spectral measurement of granulated materials using terahertz pulsed spectroscopy. App Phys Lett. 2008;92.Google Scholar
  17. 17.
    Smith G, Polygalov E, Arshad MS, Page T, Taylor J, Ermolina I. An impedance-based process analytical technology for monitoring the lyophilisation process. Int J Pharm. 2013;449(1–2):72–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Oetjen GW. Freeze-drying. New York: Wiley; 2008.Google Scholar
  19. 19.
    Oetjen GW, Haseley P. Foundations and process engineering. In: Oetjen GW, Haseley P, editors. Freeze-drying. Weinheim: Wiley; 2008. p. 1–154.Google Scholar
  20. 20.
    Beard MC, Turner GM, Schmuttenmaer CA. Terahertz spectroscopy. J Phys Chem B. 2002;106(29):7146–59. PubMed PMID: WOS:000176955900004.CrossRefGoogle Scholar
  21. 21.
    Dorney TD, Baraniuk RG, Mittleman DM. Material parameter estimation with terahertz time-domain spectroscopy. J Opt Soc Am A Opt Image Sci Vis. 2001;18(7):1562–71. PubMed PMID: WOS:000169453600018.PubMedCrossRefGoogle Scholar
  22. 22.
    Yamamoto K, Tominaga K, Sasakawa H, Tamura A, Murakami H, Ohtake H, et al. Terahertz time-domain spectroscopy of amino acids and polypeptides. Biophys J. 2005;89(3):L22–4.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Darkwah J, Smith G, Ermolina I, Mueller-Holtz M. A THz spectroscopy method for quantifying the degree of crystallinity in freeze-dried gelatin/amino acid mixtures: An application for the development of rapidly disintegrating tablets. Int J Pharm. 2013; (in press).Google Scholar
  24. 24.
    R Core Team R: A Language and Environment for Statistical Computing Vienna, Austria. 2008. Available from: http://www.r-project.org/.
  25. 25.
    Garthwaite PH. An interpretation of partial least squares. J Am Stat Assoc. 1995;89(425):122–7.CrossRefGoogle Scholar
  26. 26.
    Yenia O, Goktas A. A comparison of partial least squares regression with other prediction methods. Hacettepe Journal of Mathematics and Statistics. 2002;31:99–111.Google Scholar
  27. 27.
    ICH. Validation of analytical procedures: test and methodology. 1996.Google Scholar
  28. 28.
    Sarsfield BA, Davidovich M, Desikan S, Fakes M, Futernik S, Hilden JL, et al., editors. Powder x-ray diffraction detection of crystalline phases in amorphous pharmaceuticals. Denver X-ray Conferences; 2006; Denver.Google Scholar
  29. 29.
    Lappalainen M, Pitkänen I, Harjunen P. Quantification of low levels of amorphous content in sucrose by hyperDSC. Int J Pharm. 2006;307(2):150–5.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  1. 1.Leicester School of PharmacyDe Montfort UniversityLeicesterUK

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