AAPS PharmSciTech

, 5:39 | Cite as

Influence of processing-induced phase transformations on the dissolution of theophylline tablets



The object of this investigation was to evaluate the influence of (1) processing-induced decrease in drug crystallinity and (2) phase transformations during dissolution, on the per-formance of theophylline tablet formulations. Anhydrous theophylline underwent multiple transformations (anhydrate »hydrate»anhydrate) during processing. Although the crystallinity of the anhydrate obtained finally was lower than that of the unprocessed drug, it dissolved at a slower rate. This decrease in dissolution rate was attributed to the accelerated anhydrate to hydrate transformationduring the dissolution run. Water vapor sorption studies proved to be a good predictor of powder dissolution behavior. While a decrease in crystallinity was brought about either by milling or by granulation, the effect on tablet dissolution was pronounced only in the latter. Tablet formulations prepared from the granules exhibited higher hardness, longer disintegration time, and slower dissolution than those containing the milled drug. The granules underwent plastic deformation during compression resulting in harder tablets, with delayed disintegration. The high hardness coupled with rapid anhydrate»hydrate transformationduring dissolution resulted in the formation of a hydrate layer on the tablet surface, which further delayed tablet disintegration and, consequently, dissolution. Phase transformations during processing and, more importantly, during dissolution influenced the observed dissolution rates. Product performance was a complex function of the physical state of the active and the processing conditions.


anhydrous theophylline crystallinity dissolution tablet hardness 


  1. 1.
    Shefter E, Higuchi T. Dissolution behavior of crystalline solvated and nonsolvated forms of some pharmaceuticals.J. Pharm Sci. 1963;52:781–791.CrossRefPubMedGoogle Scholar
  2. 2.
    Urakami K, Shono Y, Higashi A, Umemoto K, Godo M. A novel method for estimation of transition temperature for polymorphic pairs in phamaceuticals using heat of solution and solutibility data.Chem Pharm Bull. 2002;50:263–267.CrossRefPubMedGoogle Scholar
  3. 3.
    Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals?Pharm Res. 2000;17:397–404.CrossRefPubMedGoogle Scholar
  4. 4.
    Elamin AA, Ahlneck C, Alderborn G, Nystrom C. Increased metastable solubility of milled griseofulvin, depending on the formation of a disordered surface structure.Int J. Pharm. 1994;111:159–170.CrossRefGoogle Scholar
  5. 5.
    Brittain HG, Morris KR, Bugay DE, Thakur AB, Serajuddin ATM. Solid-state NMR and IR for the analysis of pharmaceutical solids: polymorphs of fosinopril sodium.J. Pharm Biomed Anal. 1993;11:1063–1069.CrossRefPubMedGoogle Scholar
  6. 6.
    Otsuka M, Matsumoto T, Kaneniwa N. Effects of the mechanical energy of multi-tableting compression on the polymorphic transformations of chlorpropamide.J. Pharm Pharmacol. 1989;41:665–669.CrossRefPubMedGoogle Scholar
  7. 7.
    Phadnis NV, Suryanarayanan R. Polymorphism in anhydrous theophylline-implications on the dissolution rate of theophylline tablets.J Pharm Sci. 1997;86:1256–1263.CrossRefPubMedGoogle Scholar
  8. 8.
    Alsaidan SM, Alsughayer AA, Eshra AG. Improved dissolution rate of indomethacin by adsorbents.Drug Dev Ind Pharm. 1998;24:389–394.CrossRefPubMedGoogle Scholar
  9. 9.
    Osawa T, Kamat M, DeLuca P. Hygroscopicity of cefazolin sodium: Application to evaluate the crystallinity of freeze-dried products.Pharm Res. 1988;5:421–425.CrossRefPubMedGoogle Scholar
  10. 10.
    Morris KR, Griesser UJ, Eckhardt CJ, Stowell JG. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes.Adv Drug Del Rev. 2001;48:91–114.CrossRefGoogle Scholar
  11. 11.
    Ono M, Tozuka Y, Oguchi T, Yamamoto K. Effects of dehydration temperatures on moisture absorption and dissolution behavior of theophylline.Chem Pharm Bull. 2001;49:1526–1530.CrossRefPubMedGoogle Scholar
  12. 12.
    Otsuka M, Hasegawa H, Matsuda Y. Effect of polymorphic transformation during the extrusion-granulation process on the pharmaceutical properties of carbamazepine granules.Chem Pharm Bull. 1997;45:894–898.CrossRefGoogle Scholar
  13. 13.
    Otsuka M, Hasegawa H, Matsuda Y. Effect of polymorphic forms of bulk powders on pharmaceutical properties of carbamazepine granules.Chem Pharm Bull. 1999;47:852–856.CrossRefGoogle Scholar
  14. 14.
    Adeyeye CM, Rowley J, Madu D, Javadi M, Sabnis SS. Evaluation of crystallinity and drug release stability of directly compressed theophylline hydrophilic matrix tablets stored under varied moisture conditions.Int J Pharm. 1995;116:65–75.CrossRefGoogle Scholar
  15. 15.
    Otsuka M, Kaneniwa N, Kawakami K, Umezawa O. Effects of tableting pressure on hydration kinetics of theophylline anhydrate tablets.J Pharm Pharmacol. 1991;43:226–231.CrossRefPubMedGoogle Scholar
  16. 16.
    Debnath S, Predecki P, Suryanarayanan R. Use of glancing angle X-ray powder diffractometry to depth profile phase transformations during dissolution of indomethacin and theophylline tablets.Pharm Res. 2004;21:149–159.CrossRefPubMedGoogle Scholar
  17. 17.
    Collett JH, Rees JA, Dickinson NA. Some parameters describing the dissolution rate of salicylic acid at controlled pH.J Pharm Pharmacol. 1972;24:724–728.CrossRefPubMedGoogle Scholar
  18. 18.
    Doherty C, York P. Mechanisms of dissolution of frusemide/PVP solid dispersions.Int J Pharm. 1987;34:197–205.CrossRefGoogle Scholar
  19. 19.
    Powder Diffraction File 26-1893 (anhydrous theophylline), 27-1977 (theophylline monohydrate) International Centre for Diffraction Data, Newtown Square, Pennsylvania; 1997.Google Scholar
  20. 20.
    Murphy DK, Rodriguez-Cintron F, Langevin B, Kelly RC, Rodriguez-Homedo N. Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder.Int J Pharm. 2002;246:121–134.CrossRefPubMedGoogle Scholar
  21. 21.
    Sebhatu T, Ahlneck C, Alderborn G. The effect of moisture content on the compression and bond-formation properties of amorphous lactose particles.Int J Pharm. 1997;146:101–114.CrossRefGoogle Scholar
  22. 22.
    Suzuki T, Nakagami H. Effect of crystallinity of microcrystalline cellulose on the compactability and dissolution of tablets.Eur J Pharm Biopharm. 1999;47:225–230.CrossRefPubMedGoogle Scholar
  23. 23.
    Imaizumi H, Nambu N, Nagai T. Stability and several physical properties of amorphous and crystalline forms of indomethacin.Chem Pharm Bull. 1980;28:2565–2569.CrossRefPubMedGoogle Scholar
  24. 24.
    Nakai Y, Yamamoto K, Terada K, Kajiyama A. Relationships between crystallinity of β-cyclodextrin and tablet characteristics.Chem Pharm Bull. 1985;33:5110–5112CrossRefPubMedGoogle Scholar
  25. 25.
    Vromans H, Bolhuis GK, Lerk CF, Kussendrager KD. Studies on tableting properties of lactose. VIII. The effect of variations in primary particle size, percentage of amorphous lactose and addition of a disintegrant on the disintegration of spray-dried lactose tablets.Int J Pharm. 1987;39:201–206.CrossRefGoogle Scholar
  26. 26.
    Solvang S, Finholt P. Effect of tablet processing and formulation factors on dissolution rate of the active ingredient in human gastric juice.J Pharm Sci. 1970;59:49–52.CrossRefPubMedGoogle Scholar
  27. 27.
    Huettenrauch R, Fricke S, Zielke P. Mechanical activation of pharmaceutical systems.Pharm Res. 1985;6:302–306.CrossRefGoogle Scholar
  28. 28.
    Sharp JH, Brindley GW, Achar BNN. Numerical data for some commonly used solids-state reaction equations.J Am Ceram Soc. 1963;52:781–791.Google Scholar
  29. 29.
    Ono M, Tozuka Y, Oguchi T, Yamamura S, Yamamoto K. Effects of dehydration temperature on water vapor adsorption and dissolution behavior of carbamazepine.Int J Pharm. 2002;239:1–12.CrossRefPubMedGoogle Scholar
  30. 30.
    Suihko E, Lehto VP, Ketolainen, J, Laine E, Paronen, P. Dynamic solidstate and tableting properties of four theophylline forms.Int J Pharm. 2001;217:225–236.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2004

Authors and Affiliations

  1. 1.College of PharmacyUniversity of MinnesotaMinneapolis

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