Skip to main content
SpringerLink
Log in

Reinvestigation of the paracetamol–caffeine, aspirin–caffeine, and paracetamol–aspirin phase equilibria diagrams

  • Published:
Journal of Thermal Analysis and Calorimetry Aims and scope Submit manuscript

Abstract

Many drug candidates are poorly soluble. The formation of solid dispersion can improve their solubility, consequently their bioavailability. For this purpose, the use of eutectic mixtures is well known in the pharmaceutical field. At the eutectic composition, both components are in reduced particle size and well dispersed. In this work, we focus on the combination of paracetamol, aspirin, and caffeine, which is highly effective for the treatment of migraine headache pain. We have reinvestigated the paracetamol–caffeine, aspirin–caffeine, and paracetamol–aspirin phase equilibria diagrams taking into account the polymorphism of caffeine, paracetamol, and aspirin. The three phase diagrams are determined using X-ray diffraction and the differential scanning calorimetry from the binary mixtures. It is concluded that the paracetamol–caffeine and aspirin–caffeine systems are similar and exhibit two invariants, one eutectic and one metatectic. The paracetamol–aspirin phase diagram reveals the formation of one eutectic. The composition of the three eutectics formed is confirmed by the related Tamman’s triangles. No compound formation is found in the three systems.

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
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

References

  1. Laska E, Sunshine A, Zighelboim I, Roure C, Marrero I, Wanderling J, Olson N. Effect of caffeine on acetaminophen analgesia. Clin Pharmacol Ther. 1983;33(4):498–509.

    Article  CAS  Google Scholar 

  2. Ward N, Whitney C, Avery D, Dunner D. The analgesic effects of caffeine in headache. Pain. 1991;4:151–5.

    Article  Google Scholar 

  3. Iqbal N, Ahmad B, Janbaz KH, Gilani AH, Niazi SK. The effect of caffeine on the pharmacokinetics of acetaminophen in man. Biopharm Drug Dispos. 1995;16:481–7.

    Article  CAS  Google Scholar 

  4. Tkachenko ML, Zhnyakina LE, Kosmyninn AS. Physicochemical investigation of paracetamol–caffeine solid mixtures. Pharm Chem J. 2003;37(8):430–2.

    Article  CAS  Google Scholar 

  5. Lipton RB, Stewart WF, Ryan RE, Saper J, Silberstein S, Sheftell F. Caffeine in alleviating migraine headache painthree double-blind, randomized, placebo-controlled trials. Arch Neurol. 1998;55(2):210–7.

    Article  CAS  Google Scholar 

  6. Sekiguchi K, Obi N. Studies on absorption of eutectic mixture. I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem Pharm Bull. 1961;9:866–72.

    Article  CAS  Google Scholar 

  7. Jeanjean B, Alberola S, Terol A, Sablon F. Contribution à l’étude des associations paracetamol–théophilline et paracétamol–caféine. Ann Pharm Fr. 1979;37(3–4):95–100.

    CAS  Google Scholar 

  8. Chow YP, Repta AJ. Complexation of acetaminophen with methyl xanthines. J Pharm Sci. 1972;61(9):1454–8.

    Article  CAS  Google Scholar 

  9. Tkachenko ML. Behavior of some eutectic drug compositions under accelerated aging conditions. Pharm Chem J. 2002;36(12):683–5.

    Article  CAS  Google Scholar 

  10. Bi M, Hwang SJ, Morris KR. Mechanism of eutectic formation upon compaction and its effects on tablet properties. Thermochim Acta. 2003;404:213–26.

    Article  CAS  Google Scholar 

  11. Sangster J. Phase diagrams and thermodynamic properties of binary systems of drugs. J Phys Chem. 1999;28(4):889–930.

    CAS  Google Scholar 

  12. Klimova K, Leitner J. DSC study and phase diagrams calculation of binary systems of paracetamol. Thermochim Acta. 2012;550:59–64.

    Article  CAS  Google Scholar 

  13. Higuchi T, Zuck DA. Investigation of some complexes formed in solution by caffeine. J Am Pharm Assoc. 1953;42:138–45.

    Article  CAS  Google Scholar 

  14. Khalil SA, Moustafa MA, Ghaly GM, Gouda MW, Motawi MW. In vitro availability of some salicylates from their caffeine complexes. Can J Pharm Sci. 1975;10:83–8.

    CAS  Google Scholar 

  15. Lee KC, Hersey JA. Complexation of aspirin by caffeine. Aust J Pharm Sci. 1979;8(2):57–60.

    CAS  Google Scholar 

  16. El-Bana HM. Solid dispersion of pharmaceutical ternary systems I: phase diagram of aspirin–acetaminophen–urea system. J Pharm Sci. 1977;67(8):1109–11.

    Article  Google Scholar 

  17. Jain H, Khomane KS, Bansal AK. Implication of microstructure on the mechanical behaviour of an aspirin–paracetamol eutectic mixture. CrystEngComm. 2014;16:8471–8.

    Article  CAS  Google Scholar 

  18. Watters KL, Beal GD. Notes on the water content of crystalline caffeine. J Am Pharm Assoc. 1946;35:12–4.

    Article  Google Scholar 

  19. Sutor DJ. The structure of the pyrimidines and purines. VII. The crystal structure of caffeine. Acta Cryst. 1958;11:453–8.

    Article  CAS  Google Scholar 

  20. Gerdil R, March RE. On the arrangement of the water molecules in the crystal structure of caffeine. Acta Cryst. 1960;13:166–7.

    Article  CAS  Google Scholar 

  21. Both H, Cammenga K. Composition, properties, stability and thermal dehydration of crystalline caffeine hydrate. Thermochim Acta. 1980;40:29–39.

    Article  Google Scholar 

  22. Bogardus JB. Crystalline anhydrous–hydrate phase changes of caffeine and theophylline in solvent–water mixtures. J Pharm Sci. 1983;72:837–8.

    Article  CAS  Google Scholar 

  23. Suzuki E, Shirotani K, Tsuda Y, Sekiguchi K. Water content and dehydration behaviour of crystalline caffeine hydrate. Chem Pharm Bull. 1985;33:5028–35.

    Article  CAS  Google Scholar 

  24. Pirttimaki J, Laine E. The transformation of anhydrate and hydrate forms of caffeine at 100% RH and 0% RH. Eur J Pharm Sci. 1994;1:203–8.

    Article  CAS  Google Scholar 

  25. Griesser UJ, Burger A. The effect of water vapor pressure on desolvation kinetics of caffeine 4/5 hydrate. Int J Pharm. 1995;20:83–93.

    Article  Google Scholar 

  26. Edwards HGM, Lawson E, De Matas M, Shields L, York P. Metamorphosis of caffeine hydrate and anhydrous caffeine. J Chem Soc Perkin Trans. 1997;2:1985–90.

    Article  Google Scholar 

  27. Dichi E, Legendre B, Sghaier M. Physico-chemical characterization of a new polymorph of caffeine. J Therm Anal Calorim. 2014;115(2):1551–61.

    Article  CAS  Google Scholar 

  28. Lehmann Ch, Stowasser F. The crystal structure of anhydrous β-caffeine as determined from X-ray powder-diffraction data. Chem Eur J. 2007;13:2908–11.

    Article  CAS  Google Scholar 

  29. Enright GD, Terskikh VV, Brouwer DH, Ripmeester JA. The structure of two anhydrous polymorphs from single-crystal diffraction and ultrahigh-field solid-state 13C NMR spectroscopy. Cryst Growth Des. 2007;7(8):1406–10.

    Article  CAS  Google Scholar 

  30. Derollez P, Correia NT, Danède F, Capet F, Affouard F, Lefebvre J, Descamps M. Ab initio structure determination of the high-temperature phase of anhydrous caffeine by X-ray powder diffraction. Acta Crystallogr B. 2005;61:329–34.

    Article  Google Scholar 

  31. Carlucci L, Gavezzotti A. Molecular recognition and crystal energy landscapes: an X-ray and computational study of caffeine and other methylxanthines. Chem Eur J. 2005;11(1):271–9.

    Article  Google Scholar 

  32. Egawa T, Kamiya A, Takeuchi H, Konaka S. Molecular structure of caffeine as determined by gas electron diffraction aided by theoretical calculations. J Mol Struct. 2006;825:151–7.

    Article  CAS  Google Scholar 

  33. Sabon F, Alberola S, Térol A, Jeanjean B. Sur le polymorphisme et la solubilité. Travaux de la Société de pharmacie de Montpellier. 1979;39:19–24.

    CAS  Google Scholar 

  34. Bothe H, Cammenga HK. Phase transitions and thermodynamic properties of anhydrous caffeine. J Therm Anal Calorim. 1979;16:267–75.

    Article  CAS  Google Scholar 

  35. Cesaro A, Starec G. Thermodynamic properties of caffeine crystal forms. J Phys Chem. 1980;84:1345–6.

    Article  CAS  Google Scholar 

  36. Epple M, Cammenga HK, Sarge SM, Diedrich R, Balek V. The phase transformation of caffeine: investigation by dynamic X-ray diffraction and emanation thermal analysis. Thermochim Acta. 1995;250:29–39.

    Article  CAS  Google Scholar 

  37. Lehto VP, Laine E. A kinetic study of polymorphic transition of anhydrous caffeine with microcalorimeter. Thermochim Acta. 1998;317:47–58.

    Article  CAS  Google Scholar 

  38. Griesser UJ, Szelagiewicz M, Hofmeir UCh, Pitt C, Cianferan S. Vapor pressure and heat of sublimation of crystal polymorphs. J Therm Anal Calorim. 1999;57:45–60.

    Article  CAS  Google Scholar 

  39. Haisa M, Kashino S, Kawai R, Maeda H. The monoclinic form of p-hydroxyacetanilide. Acta Crystallogr B. 1976;32:1283–5.

    Article  Google Scholar 

  40. Haisa M, Kashino S, Maeda H. The orthorhombic form of p-hydroxyacetanilide. Acta Crystallogr B. 1974;30:2510–2.

    Article  Google Scholar 

  41. Nichols G, Frampton CS. Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution. J Pharm Sci. 1998;87:684–93.

    Article  CAS  Google Scholar 

  42. Naumov DY, Vasilchenko A, Howard JAK. The monoclinic form of acetaminophen at 150 K. Acta Crystallogr C. 1998;54:653–5.

    Article  Google Scholar 

  43. Di Martino P, Guyot-Hermann AM, Conflant P, Drache M, Guyot JC. A new pure paracetamol for direct compression: the orthorhombic form. Int J Pharm. 1996;128:1–8.

    Article  CAS  Google Scholar 

  44. Sohn YT. Study on the polymorphism of acetaminophen. J Kor Pharm Sci. 1990;20:97–104 (abstract).

    CAS  Google Scholar 

  45. Bürger A. Zur interpretation von polymorphie-untersuchungen. Act Pharm Technol. 1982;28:1–20.

    Google Scholar 

  46. Yu L. Inferring thermodynamic stability relationship of polymorphs from melting data. J Pharm Sci. 1995;84:966–74.

    Article  CAS  Google Scholar 

  47. Sacchetti M. Thermodynamic analysis of DSC data for acetaminophen polymorphs. J Therm Anal Calorim. 2001;63:345–50.

    Article  CAS  Google Scholar 

  48. Xu F, Sun LX, Tan ZC, Liang JG, Zhang T. Adiabatic calorimetry and thermal analysis on acetaminophen. J Therm Anal Calorim. 2006;83:187–91.

    Article  CAS  Google Scholar 

  49. Boldyreva EV, Drebushchak VA, Paukov IE, Kovalevskaya YA, Drebushchak TN. DSC and adiabatic calorimetry study of the polymorphs of paracetamol. J Therm Anal Calorim. 2004;77:607–23.

    Article  CAS  Google Scholar 

  50. Espeau P, Ceolin R, Tamarit JL, Perrin MA, Gauchi JP, Leveiller F. Polymorphism of paracetamol: relative stabilities of the monoclinic and orthorhombic phases inferred from topologica pressure–temperature and temperature–volume phase diagrams. J Pharm Sci. 2005;94:524–39.

    Article  CAS  Google Scholar 

  51. Perlovich GL, Volkova TV, Bauer-Brandl A. Polymorphism of paracetamol relative stability of the monoclinic and orthorhombic phase revisited by sublimation and solution calorimetry. J Therm Anal Calorim. 2007;89:767–74.

    Article  CAS  Google Scholar 

  52. Ledru J, Imrie CT, Pulham CR, Ceolin R, Hutchinson JM. High pressure differential scanning calorimetry investigations on the pressure dependence of the melting of paracetamol polymorphs I and II. J Pharm Sci. 2007;96(10):2784–94.

    Article  CAS  Google Scholar 

  53. Perrin MA, Neumann MA, Elmaleh H, Zaske L. Crystal structure determination of the elusive paracetamol form III. Chem Commun. 2009;22:3181–3.

    Article  Google Scholar 

  54. Di Martino P, Conflant P, Drache M, Huvenne JP, Guyot-Hermann AM. Preparation and physical characterization of forms II and III of paracetamol. J Therm Anal Calorim. 1997;48(3):447–58.

    Article  Google Scholar 

  55. Burleya JC, Duera MJ, Steina RS, Vrcelj RM. Enforcing Ostwald’s rule of stages: isolation of paracetamol forms III and II. Eur J Pharm Sci. 2007;31:271–6.

    Article  Google Scholar 

  56. Neumann MA, Perrin MA. Can crystal structure prediction guide experimentalists to a new polymorph of paracetamol? CrystEngComm. 2009;11:2475–9.

    Article  CAS  Google Scholar 

  57. Di Martino P, Palmieri GP, Martelli S. Molecular mobility of the paracetamol amorphous form. Chem Pharm Bull. 2000;48(8):1105–8.

    Article  Google Scholar 

  58. Gunawan L, Johari GP, Shanker RM. Structural relaxation of acetaminophen glass. Pharm Res. 2006;23(5):967–79.

    Article  CAS  Google Scholar 

  59. Nanubolu JB, Burley JC. Investigating the recrystallization behavior of amorphous paracetamol by variable temperature raman studies and surface raman mapping. Mol Pharm. 2012;9:1544–58.

    Article  CAS  Google Scholar 

  60. Parkin A, Parsons S, Pulham CR. Paracetamol monohydrate at 150 K. Acta Cryst E. 2002;58:1345–7.

    Article  Google Scholar 

  61. Fabbiani FPA, Allan DR, David WIF, Moggach SA, Parsons S, Pulham CR. High-pressure recrystallization—a route to new polymorphs and solvates. CrystEngComm. 2004;6(82):504–11.

    Article  CAS  Google Scholar 

  62. McGregor PA, Allan DR, Parsons S, Pulham CR. Preparation and crystal structure of a trihydrate of paracetamol. J Pharm Sci. 2002;91:1308–11.

    Article  CAS  Google Scholar 

  63. Fabbiani FPA, Allan DR, Dawson A, David WIF, McGregor PA, Oswald IDH, Parsons S, Pulham CR. Pressure-induced formation of a solvate of paracetamol. Chem Commun. 2003;24:3004–5.

    Article  Google Scholar 

  64. Vrcelj RM, Clark NIB, Kennedy AR, Sheen DB, Shepherd EEA, Sherwood JN. Two new paracetamol/dioxane solvates—a system exhibiting a reversible solid-state phase transformation. J Pharm Sci. 2003;92(10):2069–73.

    Article  CAS  Google Scholar 

  65. Oswald IDH, Allan DR, McGregor PA, Motherwell WDS, Parsons S, Pulham CR. The formation of paracetamol (acetaminophen) adducts with hydrogen-bond acceptors. Acta Cryst. 2002;B58:1057–66.

    Article  CAS  Google Scholar 

  66. Oswald IDH, Motherwell WDS, Parsons S, Pulham CR. A paracetamol–morpholine adduct. Acta Cryst. 2002;E58:1290–2.

    Google Scholar 

  67. Andre V, da Piedade MFM, Duarte MT. Revisiting paracetamol in a quest for new co-crystals. CrystEngComm. 2012;14:5005–14.

    Article  CAS  Google Scholar 

  68. Crowell EL, Dreger ZA, Gupta YM. High-pressure polymorphism of acetylsalicylic acid (aspirin): Raman spectroscopy. J Mol Struct. 2015;1082:29–37.

    Article  CAS  Google Scholar 

  69. Wheatley PJ. The crystal and molecular structure of aspirin. J Chem Soc. 1964;1163:6036–48.

    Article  Google Scholar 

  70. Kim Y, Machida K, Taga T, Osaki K. Structure redetermination and packing analysis of aspirin crystal. Chem Pharm Bull. 1985;33:2641–7.

    Article  CAS  Google Scholar 

  71. Bond AD, Boese R, Desiraju GR. On the polymorphism of aspirin. Angew Chem Int Ed. 2007;46:615–7.

    Article  CAS  Google Scholar 

  72. Bundgaard H. Influence of an acetylsalicylic anhydride impurity on the rate of dissolution of acetylsalicylic acid. J Pharm Pharmacol. 1974;26:535–40.

    Article  CAS  Google Scholar 

  73. Mitchell AG, Saville DJ. The dissolution of aspirin and aspirin tablets. J Pharm Pharmacol. 1967;19:729–34.

    Article  CAS  Google Scholar 

  74. Tawashi R. Aspirin-dissolution rates of 2 polymorphic forms. Science. 1968;160:76.

    Article  CAS  Google Scholar 

  75. Mitchell AG, Saville DJ. The dissolution of commercial aspirin. J Pharmacol. 1969;21:28–34.

    Article  CAS  Google Scholar 

  76. Pfeiffer RR. Aspirin polymorphism questioned. J Pharm Pharmacol. 1971;23:75–6.

    Article  CAS  Google Scholar 

  77. Schwartzman G. Does aspirin exist in polymorphic states? J Pharm Pharmacol. 1972;24:169–70.

    Article  CAS  Google Scholar 

  78. Mitchell AG, Milaire BL, Saville DJ, Griffiths RV. Aspirin dissolution: polymorphism, crystal habit or crystal Defects. J Pharm Pharmacol. 1971;23:534–5.

    Article  CAS  Google Scholar 

  79. Ouvrard C, Price SL. Toward crystal structure prediction for conformationally flexible molecules: the headaches illustrated by aspirin. Cryst Growth Des. 2004;4:1119–27.

    Article  CAS  Google Scholar 

  80. Vishweshwar P, McMahon JA, Oliveira M, Peterson ML, Zaworotko MJ. The predictably elusive form II of aspirin. J Am Chem Soc. 2005;127(48):16802–3.

    Article  CAS  Google Scholar 

  81. Bond AD, Solanko KA, Parsons S, Redder S, Boese R. Single crystals of aspirin form II: crystallisation and stability. CrystEngComm. 2011;13:399–401.

    Article  CAS  Google Scholar 

  82. McMahon JA. Crystal engineering of novel pharmaceutical forms. Tampa: University of South Florida; 2006.

    Google Scholar 

  83. Della Gatta G, Richardson MJ, Sarge SM, Stolen S. Standards, calibration, and guidelines in microcalorimetry. Pure Appl Chem. 2006;78:1455–76.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Matériaux et Santé, EA 401 Faculté de Pharmacie, Université Paris Sud, 5 rue J. B. Clément, 92296, Châtenay-Malabry, France

    Emma Dichi & Mehrez Sghaier

  2. Laboratoire SPMS, Centre de Diffraction, CentraleSupélec, Université Paris Saclay, Grande Voie des Vignes, 92295, Châtenay-Malabry Cedex, France

    Nicolas Guiblin

Authors
  1. Emma Dichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mehrez Sghaier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolas Guiblin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emma Dichi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dichi, E., Sghaier, M. & Guiblin, N. Reinvestigation of the paracetamol–caffeine, aspirin–caffeine, and paracetamol–aspirin phase equilibria diagrams. J Therm Anal Calorim 131, 2141–2155 (2018). https://doi.org/10.1007/s10973-017-6855-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10973-017-6855-6

Keywords

Search

Navigation