Skip to main content

Advertisement

SpringerLink
Log in

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

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Purpose

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

aW :

water activity

EC:

Ethylcellulose

HPC:

hydroxypropyl cellulose

HPLC:

high-performance liquid chromatography

HPMC:

hydroxypropyl methylcellulose

HPMC-AS:

hydroxypropyl methylcellulose acetate succinate

MC:

methylcellulose

MCC:

microcrystalline cellulose

MT:

theophylline monohydrate

Na-CMC:

sodium carboxy methylcellulose

NIST:

National Institute of Standards and Technology

PAA:

cross-linked polyacrylic acid

PVP:

polyvinyl pyrrolidone

SDS:

sodium dodecyl sulfate

SEM:

scanning electron microscopy

SMT:

solvent-mediated transformation

TP:

Theophylline

USP:

United States Pharmacopeia

UV:

ultraviolet

XRPD:

powder X-ray diffractometry

References

  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. 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. S. R. Byrn. Solid State Chemistry of Drugs, Academic, New York, NY, USA, 1982.

    Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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. 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).

    Article  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  9. N. Rodríguez-Hornedo, and H. J. Wu. Crystal-growth kinetics of theophylline monohydrate. Pharm. Res. 8:643–648 (1991).

    Article  PubMed  Google Scholar 

  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.

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

  20. Theophylline capsules. USP28-NF23, Vol. S2, United States Pharmacopeia, Rockville, MD, USA, 2005.

  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).

    Article  PubMed  CAS  Google Scholar 

  22. D. J. W. Grant, and T. Higuchi. Solubility Behavior of Organic Compounds, Wiley, New York, NY, USA, 1990.

    Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  24. P. T. Cardew, and R. J. Davey. The kinetics of solvent-mediated phase-transformations. Proc. R Soc. Lond. A. 398:415–428 (1985).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  27. J. W. Gibbs. On the equilibrium of heterogeneous substances. Trans. Conn. Acad. 3:343–524 (1878).

    Google Scholar 

  28. J. W. Mullin. Crystallization, Elsevier, Oxford, UK, 2001.

    Google Scholar 

  29. T. P. Melia, and W. P. Moffitt. Secondary nucleation from aqueous solution. Industrial Eng. Chem. 3:313–317 (1964).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA

    Håkan Wikström, William J. Carroll & Lynne S. Taylor

Authors
  1. Håkan Wikström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William J. Carroll
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lynne S. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lynne S. Taylor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wikström, H., Carroll, W.J. & Taylor, L.S. Manipulating Theophylline Monohydrate Formation During High-Shear Wet Granulation Through Improved Understanding of the Role of Pharmaceutical Excipients. Pharm Res 25, 923–935 (2008). https://doi.org/10.1007/s11095-007-9450-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-007-9450-x

Key words

Search

Navigation