Pharmaceutical Research

, Volume 25, Issue 4, pp 923–935 | Cite as

Manipulating Theophylline Monohydrate Formation During High-Shear Wet Granulation Through Improved Understanding of the Role of Pharmaceutical Excipients

  • Håkan Wikström
  • William J. Carroll
  • Lynne S. Taylor
Research Paper


To investigate the effect of common pharmaceutical excipients on the kinetics of theophylline monohydrate formation during high-shear wet granulation.

Materials and methods

A mixture of anhydrous theophylline and the excipient was granulated in a high-shear granulator, using water as the granulation liquid. Non-contact Raman spectroscopy was used to monitor the rate of transformation of anhydrate to hydrate during the granulation process. The kinetics of conversion was also monitored in slurries of theophylline whereby the excipients were added to the aqueous phase. Optical microscopy was used to visualize the transformation and to measure the linear growth rates of hydrate crystals in the presence and absence of the excipients.


At pharmaceutically relevant amounts of excipient, the transformation kinetics of theophylline was unchanged for the majority of excipients tested. However, when granulating with low concentrations of some commonly used polymeric binders, the transformation kinetics could be significantly retarded. For example, methylcellulose polymers delayed both the onset of hydrate formation as well as retarding the transformation rate. When 0.3% (w/w) of hydroxypropyl methylcellulose was added to a model formulation containing 30% (w/w) theophylline anhydrous, the formation of the monohydrate could be completely prevented over the time period of the granulation experiment, without significantly affecting the granular properties. Microscopic observations of hydrate formation in the presence of the polymer revealed that the polymers that inhibited hydrate formation reduced the hydrate crystal growth rates and influenced hydrate morphology.


Raman spectroscopy is a useful technique to monitor hydrate formation during wet granulation. Some commonly used polymeric pharmaceutical excipients can be used to manipulate theophylline hydrate formation in aqueous pharmaceutical environments. These excipients may affect either the nucleation and/or the growth of the hydrate phase.

Key words

additive crystal growth excipients high-shear wet granulation hydrate formation Raman spectroscopy 



water activity




hydroxypropyl cellulose


high-performance liquid chromatography


hydroxypropyl methylcellulose


hydroxypropyl methylcellulose acetate succinate




microcrystalline cellulose


theophylline monohydrate


sodium carboxy methylcellulose


National Institute of Standards and Technology


cross-linked polyacrylic acid


polyvinyl pyrrolidone


sodium dodecyl sulfate


scanning electron microscopy


solvent-mediated transformation




United States Pharmacopeia




powder X-ray diffractometry



Dr. Alan Gift, Daniel Sage and Margaret K. Kunkel (all Purdue University) are gratefully acknowledged for assistant with data analysis and experimental support. Jerry J. Sheppard (Purdue University) is acknowledged for his assistance with designing the small-scale granulator, and the general machine shop of Purdue University is thanked for building it. The authors are grateful to Mary A. Albrecht (SSCI, Inc.) for providing the SEM pictures. Sharon Deram (SBI Analytical, Inc.) and Kaiser Optical Systems, Inc., are acknowledged for their assistance with instrumentation. The Dow Chemical Company, BASF and ISP Technologies, Inc. are thanked for supplying the majority of the polymers used for this study. The Dane O. Kildsig Center for Pharmaceutical Processing Research and AstraZeneca R&D Mölndal are acknowledged for funding.


  1. 1.
    L. L. Augsburger, and M. K. Vuppala. Theory of granulation. In D. M. Parikh (ed.), Handbook of Pharmaceutical Granulation Technology, Vol. 81, Marcel Dekker, New York, NY, 1997, pp. 7–23.Google Scholar
  2. 2.
    P. Holm. High shear mixer granulators. In D. M. Parikh (ed.), Handbook of Pharmaceutical Granulation Technology, Vol. 81, Marcel Dekker, New York, NY, USA, 1997, pp. 151–203.Google Scholar
  3. 3.
    S. R. Byrn. Solid State Chemistry of Drugs, Academic, New York, NY, USA, 1982.Google Scholar
  4. 4.
    K. R. Morris, U. J. Griesser, C. J. Eckhardt, and J. G. Stowell. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv. Drug Deliv. Rev. 48:91–114 (2001).PubMedCrossRefGoogle Scholar
  5. 5.
    H. G. Brittain. Methods for the characterization of polymorphs and solvates. In H. G. Brittain (ed.), Polymorphism in Pharmaceutical Solids, Vol. 95, Marcel Dekker, New York, NY, 1999, pp. 227–278.Google Scholar
  6. 6.
    Y. Qiu, X. Z. Qu, X. Q. Song, J. X. Chen, and F. T. Chau. Construction of a CCD multichannel fiber-optic spectrometer and its application. Instrum. Sci. Technol. 24:143–150 (1996).CrossRefGoogle Scholar
  7. 7.
    H. Wikström, P. J. Marsac, and L. S. Taylor. In-line monitoring of hydrate formation during wet granulation using Raman spectroscopy. J. Pharm. Sci. 94:209–219 (2005).PubMedCrossRefGoogle Scholar
  8. 8.
    E. Räsänen, J. Rantanen, A. Jørgensen, M. Karjalainen, T. Paakkari, and J. Yliruusi. Novel identification of pseudopolymorphic changes of theophylline during wet granulation using near infrared spectroscopy. J. Pharm. Sci. 90:389–396 (2001).PubMedCrossRefGoogle Scholar
  9. 9.
    N. Rodríguez-Hornedo, and H. J. Wu. Crystal-growth kinetics of theophylline monohydrate. Pharm. Res. 8:643–648 (1991).PubMedCrossRefGoogle Scholar
  10. 10.
    Specifications: Test procedures and acceptance critera for new drug substances and new drug products: Chemical substances Q6A, ICH Steering Committee, International Conference on Harmonization, Geneva, Switzerland, 1999, p. 31.Google Scholar
  11. 11.
    I. Katzhendler, R. Azoury, and M. Friedman. Crystalline properties of carbamazepine in sustained release hydrophilic matrix tablets based on hydroxypropyl methylcellulose. J. Control Release. 54:69–85 (1998).PubMedCrossRefGoogle Scholar
  12. 12.
    I. Katzhendler, K. Mader, R. Azoury, and M. Friedman. Investigating the structure and properties of hydrated hydroxypropyl methylcellulose and egg albumin matrices containing carbamazepine: EPR and NMR study. Pharm. Res. 17:1299–1308 (2000).PubMedCrossRefGoogle Scholar
  13. 13.
    I. Katzhendler, R. Azoury, and M. Friedman. The effect of egg albumin on the crystalline properties of carbamazepine in sustained release hydrophilic matrix tablets and in aqueous solutions. J. Control Release. 65:331–343 (2000).PubMedCrossRefGoogle Scholar
  14. 14.
    M. Otsuka, T. Ohfusa, and Y. Matsuda. Effect of binders on polymorphic transformation kinetics of carbamazepine in aqueous solution. Colloid. Surf. B-Biointerfaces. 17:145–152 (2000).CrossRefGoogle Scholar
  15. 15.
    N. Rodríguez-Hornedo, and D. Murphy. Surfactant-facilitated crystallization of dihydrate carbamazepine during dissolution of anhydrous polymorph. J. Pharm. Sci. 93:449–460 (2004).PubMedCrossRefGoogle Scholar
  16. 16.
    F. Tian, D. J. Saville, K. C. Gordon, C. J. Strachan, J. A. Zeitler, N. Sandler, and T. Rades. The influence of various excipients on the conversion kinetics of carbamazepine polymorphs in aqueous suspension. J. Pharm. Pharmacol. 59:193–201 (2007).PubMedCrossRefGoogle Scholar
  17. 17.
    H. Qu, M. Louhi-Kultanen, and J. Kallas. Additive effects on the solvent-mediated anhydrate/hydrate phase transformation in a mixed solvent. Cryst. Growth Design. 7:724–729 (2007).CrossRefGoogle Scholar
  18. 18.
    S. Airaksinen, P. Luukkonen, A. C. Jørgensen, M. Karjalainen, J. Rantanen, and J. Yliruusi. Effects of excipients on hydrate formation in wet masses containing theophylline. J. Pharm. Sci. 92:516–528 (2003).PubMedCrossRefGoogle Scholar
  19. 19.
    S. Airaksinen, M. Karjalainen, N. Kivikero, S. Westermarck, A. Shevchenko, J. Rantanen, and J. Yliruusi. Excipient selection can significantly affect solid-state phase transformation in formulation during wet granulation. AAPS PharmSciTech. 6: (2005).Google Scholar
  20. 20.
    Theophylline capsules. USP28-NF23, Vol. S2, United States Pharmacopeia, Rockville, MD, USA, 2005.Google Scholar
  21. 21.
    J. Rantanen, H. Wikström, F. E. Rhea, and L. S. Taylor. Improved understanding of factors contributing to quantification of anhydrate/hydrate powder mixtures. Appl. Spectrosc. 59:942–951 (2005).PubMedCrossRefGoogle Scholar
  22. 22.
    D. J. W. Grant, and T. Higuchi. Solubility Behavior of Organic Compounds, Wiley, New York, NY, USA, 1990.Google Scholar
  23. 23.
    M. D. Ticehurst, R. A. Storey, and C. Watt. Application of slurry bridging experiments at controlled water activities to predict the solid-state conversion between anhydrous and hydrated forms using theophylline as a model drug. Int. J. Pharm. 247:1–10 (2002).PubMedCrossRefGoogle Scholar
  24. 24.
    P. T. Cardew, and R. J. Davey. The kinetics of solvent-mediated phase-transformations. Proc. R Soc. Lond. A. 398:415–428 (1985).CrossRefGoogle Scholar
  25. 25.
    A. A. Noyes, and W. R. Whitney. The rate of solution of solid substances in their own solutions. J. Am. Chem. Soc. 19:930–934 (1897).CrossRefGoogle Scholar
  26. 26.
    A. W. Hixson, and J. H. Crowell. Dependence of reaction velocity upon surface and agitation I—Theoretical consideration. Industrial Eng. Chem. 23:923–931 (1931).CrossRefGoogle Scholar
  27. 27.
    J. W. Gibbs. On the equilibrium of heterogeneous substances. Trans. Conn. Acad. 3:343–524 (1878).Google Scholar
  28. 28.
    J. W. Mullin. Crystallization, Elsevier, Oxford, UK, 2001.Google Scholar
  29. 29.
    T. P. Melia, and W. P. Moffitt. Secondary nucleation from aqueous solution. Industrial Eng. Chem. 3:313–317 (1964).CrossRefGoogle Scholar
  30. 30.
    W. K. Burton, N. Cabrera, and F. C. Frank. The growth of crystals and the equilibrium structures of their surfaces. Philosophical Transactions of the Royal Society of London Series A, Mathematical and Physical Sciences. 243:299–358 (1951).CrossRefGoogle Scholar
  31. 31.
    N. Rodríguez-Hornedo, D. Lechuga-Ballesteros, and H. J. Wu. Phase-transition and heterogeneous epitaxial nucleation of hydrated and anhydrous theophylline crystals. Int. J. Pharm. 85:149–162 (1992).CrossRefGoogle Scholar
  32. 32.
    B. C. Hancock, P. York, and R. C. Rowe. The use of solubility parameters in pharmaceutical dosage form design. Int. J. Pharm. 148:1–21 (1997).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Håkan Wikström
    • 1
  • William J. Carroll
    • 1
  • Lynne S. Taylor
    • 1
  1. 1.Department of Industrial and Physical Pharmacy, School of PharmacyPurdue UniversityWest LafayetteUSA

Personalised recommendations