Investigation of the Multi-Step Dehydration Reaction of Theophylline Monohydrate Using 2-Dimensional Powder X-ray Diffractometry
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(i) To study the dehydration kinetics of theophylline monohydrate using 2-dimensional (2D) powder X-ray diffractometry (XRD), and (ii) to investigate the effect of polyvinylpyrrolidone (PVP) on the dehydration pathway and kinetics.
Theophylline monohydrate (C7H8N4O2·H2O; M) was recrystallized from aqueous PVP solutions of different concentrations. Dehydration kinetics was studied isothermally, at several temperatures, from 35 to 130°C. The experimental set-up comprised of a high intensity X-ray source (synchrotron radiation or 8 kW rotating anode), a heating chamber, and a 2D area detector. Diffraction patterns were collected continuously, with a time resolution ranging from 40 ms to 30 s, over the angular range of 3 to 27°2θ.
Dehydration of M resulted in either the stable (C7H8N4O2; A), or the metastable anhydrate (A*), with the latter having a tendency to transform to A. The XRD technique allowed simultaneous quantification of M, A* and A during the dehydration reaction. The rate constants for individual reaction steps (M→A*; M→A and A*→A) were determined by fitting the data to solid-state reaction models. In presence of PVP, there was a decrease in the magnitude of the rate constant associated with the M→A transition, resulting in an increased build-up of A* in the product. The inhibitory effect of PVP on M→A transition was more pronounced at lower dehydration temperatures, and was proportional to the concentration of PVP.
Two dimensional powder X-ray diffractometry, using a high intensity source, is a powerful technique to study kinetics of rapid solid-state reactions. The inhibitory effect of excipients can have profound effect on phases formed during pharmaceutical processing.
Key wordsanhydrate dehydration metastable polymorph synchrotron theophylline monohydrate two-dimensional X-ray diffraction
- 2.C. Sun, D. Zhou, D. J. W. Grant, and V. G. Young, Jr. Theophylline monohydrate. Acta Crystallogr. E58:368–370 (2002).Google Scholar
- 5.C. T. Lin and S. R. Byrn. Desolvations of solvated organic crystals. Molr. Cryst. Liq. Cryst. 50:99–104 (1979).Google Scholar
- 14.ICH (International Conference on Harmonisation). Draft guidance on Q6A specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. Federal Register 65(251):83041–83063 (2000).Google Scholar
- 15.Process analytical technology—a framework for innovative pharmaceutical manufacturing and quality assurance. Draft guidance. U.S. Department of Health and Human Services. Food and Drug Administration. Federal Register 68(172):52781–52782 (2003).Google Scholar
- 21.D. Giron. Characterization of pharmaceuticals by thermal analysis. Am. Pharm. Rev. 3:53–54, 56, 58–61 (2000).Google Scholar
- 22.H. P. Klug and L. E. Alexander. X-ray Diffraction Procedures for Polycrystalline and Amorphous Materials. Wiley, New York, 1974.Google Scholar
- 23.R. Suryanarayanan. X-ray powder diffractometry. In H. G. Brittain (ed.), Physical Characterization of Pharmaceutial Solids, Marcel Dekker, New York, 1995, pp. 187–221.Google Scholar
- 24.M. Otsuka, N. Kaneniwa, K. Otsuka, K. Kawakami, and O. Umezawa. Effect of tableting pressure and geometrical factor of tablet on dehydration kinetics of theophylline monohydrate tablets. Drug Dev. Ind. Pharm. 19:541–557 (1993).Google Scholar
- 27.J. Tank. Changes in Solid-State of Theophylline upon Wet Granulation, M.S. dissertation, Department of Pharmaceutics, University of Minnesota, 1997.Google Scholar
- 32.C. Nunes. Use of High-Intensity X-radiation in Solid-State Characterization of Pharmaceuticals, Ph.D. dissertation, Department of Pharmaceutics, University of Minnesota, 2005.Google Scholar
- 34.Powder Diffraction File-2. International Centre for Diffraction Data. Newtown Square, Pennsylvania, 1996.Google Scholar
- 36.D. C. Monkhouse and L. Van Campen. Solid state reactions—theoretical and experimental aspects. Drug Dev. Ind. Pharm. 10:1175–1276 (1984).Google Scholar
- 37.E. Suzuki, K. Shimomura, and K. Sekiguchi. Thermochemical study of theophylline and its hydrate. Chem. Pharm. Bull. 37:493–497 (1989).Google Scholar
- 38.W. J. Dunning. Theory of crystal nucleation from vapour, liquid and solid systems. In W. E. Garner (ed.), Chemistry of the Solid State, Academic, New York, 1955, pp. 159–183.Google Scholar
- 39.Y. V. Mnyukh. Molecular mechanism of polymorphic transitions. Molr. Cryst. Liq. Cryst. 52:467–503 (1979).Google Scholar
- 41.Y. V. Mnyukh and N. N. Petropavlov. Polymorphic transitions in molecular crystals. I. Orientations of lattices and interfaces. J. Phys. Chem. Solids 33:2079–2087 (1972).Google Scholar
- 42.F. C. Tompkins. Decomposition reactions. In N. B. Hannay (ed.), Reactivity of Solids, Plenum, New York, 1976, pp. 193–232.Google Scholar
- 43.H. Schmalzried. Solid-state reactions. In N. B. Hannay (ed.), Reactivity of Solids, Plenum, New York, 1976, pp. 233–280.Google Scholar
- 44.A. K. Galwey. The reactivity of solids in thermal decomposition (crystolysis) reactions. In V. V. Boldyrev (ed.), Reactivity of Solids: Past, Present and Future, Blackwell Science, Malden, Massachusetts, 1996, pp. 15–42.Google Scholar
- 48.E. D. L. Smith, R. B. Hammond, M. J. Jones, K. J. Roberts, J. B. O. Mitchell, S. L. Price, R. K. Harris, D. C. Apperley, J. C. Cherryman, and R. Docherty. The determination of the crystal structure of anhydrous theophylline by X-ray powder diffraction with a systematic search algorithm, lattice energy calculations, and 13C and 15N solid-state NMR: a question of polymorphism in a given unit cell. J. Phys. Chem. B. 105:5818–5826 (2001).CrossRefGoogle Scholar