Journal of Solution Chemistry

, Volume 44, Issue 8, pp 1723–1748 | Cite as

Glass Formation in Binary Solutions of Acetaminophen with Guaifenesin and Mephenesin



Dielectric behavior and glass formation in supercooled liquid guaifenesin (GFN) and its binary liquids with acetaminophen (ACT), and of ACT with mephenesin (MP), are reported using dielectric spectroscopy (10−3 Hz–2 MHz) and differential scanning calorimetry down to liquid nitrogen temperature. Solid–liquid phase equilibria of ACT + GFN and ACT + MP exhibit a simple eutectic of complete miscibility in the liquid state with eutectic points at 344.6 (±1) K and 337.5 (±1.4) K, respectively, and separate into two crystalline components in the solid state. The glass transition temperature (T g) measured for quenched binary liquids obeys a mixture rule. The primary relaxation process (α-process), can be well described by the Havriliak–Negami equation. A secondary relaxation process (β-process), found below T g, is Arrhenius in its temperature dependence, but may not be of inter-molecular or Johari–Goldstein (JG) type in nature. The “fragility” of the samples is discussed in the context of a coupling model. The supercooled liquid samples and binary liquids studied here are found to be “very fragile” in nature.


Binary mixture of pharmaceuticals Dielectric spectroscopy Differential scanning calorimetry (DSC) Glass transition Guaifenesin 



The authors like to thank Dept. of Science & Technology & UGC, Govt. of India for the financial support. One of the authors (Manoj K. Saini) acknowledges the Research fellowship from UGC, India.

Supplementary material

10953_2015_364_MOESM1_ESM.pdf (285 kb)
Supplementary material 1 (PDF 285 kb)


  1. 1.
    Wang, J., Angell, C.A.: Glass Structure by Spectroscopy. Marcel Dekkar, New York (1976)Google Scholar
  2. 2.
    Johari, G.P., Goldstein, M.: Viscous liquids and the glass transition III. Secondary relaxations in aliphatic alcohols and other non-rigid molecules. J. Chem. Phys. 55, 4245–4252 (1971)CrossRefGoogle Scholar
  3. 3.
    Johari, G.P., Goldstein, M.: Viscous liquids and the glass transition II. Secondary relaxations in glasses of rigid molecules. J. Chem. Phys. 53, 2372–2388 (1970)CrossRefGoogle Scholar
  4. 4.
    Okamoto, N., Oguni, M.: Discovery of crystal nucleation preceding much below the glass transition temperature in a supercooled liquid. Solid State Commun. 99, 53–56 (1996)CrossRefGoogle Scholar
  5. 5.
    Hikima, T., Hanaya, M., Oguni, M.: β-Molecular rearrangement process, but not an α-process, as governing the homogeneous crystal-nucleation rate in a supercooled liquid. Bull. Chem. Soc. Jpn. 69, 1863–1868 (1996)CrossRefGoogle Scholar
  6. 6.
    Hikima, T., Hanaya, M., Oguni, M.: Microscopic observation of a peculiar crystallization in the glass transition region and β-process as potentially controlling the growth rate in triphenylethylene. J. Mol. Struct. 479, 245–250 (1999)CrossRefGoogle Scholar
  7. 7.
    Paladi, F., Oguni, M.: Anomalous generation and extinction of crystal nuclei in nonequilibrium supercooled liquid o-benzylphenol. Phys. Rev. B. 65, 144202–144208 (2002)CrossRefGoogle Scholar
  8. 8.
    Paladi, F., Oguni, M.: Generation and extinction of crystal nuclei in an extremely nonequilibrium glassy state of salol. J. Phys. Condens. Matter. 15, 3909–3917 (2003)CrossRefGoogle Scholar
  9. 9.
    Hatase, M., Hanaya, M., Hikima, T., Oguni, M.: Discovery of homogeneous-nucleation-based crystallization in simple glass-forming liquid of toluene below its glass-transition temperature. J. Non-Cryst. Solids 307–310, 257–263 (2002)CrossRefGoogle Scholar
  10. 10.
    Murthy, S.S.N., Nayak, S.K.: Experimental study of the nature of the glass transition process in monohydroxy alcohols. J. Chem. Phys. 99, 5362–5368 (1983)CrossRefGoogle Scholar
  11. 11.
    Johari, G.P.: Glass transition and secondary relaxations in molecular liquids and crystals. Ann. New York Acad. Sci. 279, 117–140 (1976)CrossRefGoogle Scholar
  12. 12.
    Reid, C.J., Evans, M.W.: Dielectric and far infrared study of solutions in the glassy state from 100 Hz to 10 THz: discovery and characterization of the universal γ process. J. Chem. Phys. 76, 2576–2584 (1982)CrossRefGoogle Scholar
  13. 13.
    Wu, L., Nagel, S.R.: Secondary relaxation in o-terphenyl glass. Phys. Rev. D. 46, 11198–11200 (1992)CrossRefGoogle Scholar
  14. 14.
    Gangasharan, Murthy, S.S.N.: Study of α-, β-, and γ-relaxation processes in some supercooled liquids and supercooled plastic crystals. J. Chem. Phys. 99, 9865–9873 (1993)CrossRefGoogle Scholar
  15. 15.
    Shahin, Md, Murthy, S.S.N.: Sub-T g relaxations due to dipolar solutes in nonpolar glass-forming solvents. J. Chem. Phys. 122, 014507 (15) (2005)CrossRefGoogle Scholar
  16. 16.
    Johari, G.P., Kim, S., Shanker, R.M.: Dielectric relaxation and crystallization of ultraviscous melt and glassy states of aspirin, ibuprofen, progesterone, and quinidine. J. Pharm. Sci. 96, 1159–1175 (2007)CrossRefGoogle Scholar
  17. 17.
    Barro, M., Espeau, P., Tamarit, J.L., Perrin, M.A., Veglio, N., Ceolin, R.: Polymorphism of progesterone: relative stabilities of the orthorhombic phases I and II inferred from topological and experimental pressure temperature phase diagrams. J. Pharm. Sci. 98, 1657–1670 (2009)CrossRefGoogle Scholar
  18. 18.
    Kerc, J., Srcic, S., Mohar, M., Korbar, J.S.: Some physicochemical properties of glassy felodipine. Int. J. Pharm. 68, 25–33 (1991)CrossRefGoogle Scholar
  19. 19.
    Sailaja, U., Thayyil, M.S., Kumar, N.S.K., Govindaraj, G.: Molecular dynamics in liquid and glassy states of non-steroidal anti-inflammatory drug: ketoprofen. Eur. J. Pharm. Sci. 49, 333–340 (2013)CrossRefGoogle Scholar
  20. 20.
    Mahe, N., Perrin, M.A., Barrio, M., Nicolai, B., Rietveld, I.B., Tamarit, J.L., Ceolin, R.: Solid state studies of the triclinic (Z = 2) antiprotozoal drug ternidazole. J. Pharm. Sci. 100, 2258–2266 (2011)CrossRefGoogle Scholar
  21. 21.
    Mooter, G.V., Augustijins, P., Kinget, R.: Stability prediction of amorphous benzodiazepines by calculation of the mean relaxation time constant using the Williams Watts decay function. Eur. J. Pharm. Biopharm. 48, 43–48 (1999)CrossRefGoogle Scholar
  22. 22.
    Johari, G.P., Kim, S., Shanker, R.M.: Dielectric studies of molecular motions in amorphous solid and ultraviscous acetaminophen. J. Pharm. Sci. 94, 2207–2223 (2005)CrossRefGoogle Scholar
  23. 23.
    Espeau, P., Ceolin, R., Tamarit, J.L., Perrin, M.A., Gauchi, J.P., Leveiller, F.: Polymorphism of paracetamol: relative stabilities of the monoclinic and orthorhombic phase inferred from topological pressure temperature and temperature volume phase diagram. J. Pharm. Sci. 94, 524–539 (2005)CrossRefGoogle Scholar
  24. 24.
    Rengarajan, G.T., Beiner, M.: Relaxation behaviour and crystallization kinetics of amorphous acetaminophen. Lett. Drug Design Discov. 3, 723–730 (2006)CrossRefGoogle Scholar
  25. 25.
    Saini, M.K., Murthy, S.S.N.: Study of glass transition phenomenon in the supercooled liquid phase of methocarbamol, acetaminophen and mephenesin. Thermchim. Acta 575, 195–205 (2014)CrossRefGoogle Scholar
  26. 26.
    Johari, G.P., Kim, S., Shanker, R.M.: Dielectric study of equimolar acetaminophen–aspirin, acetaminophen–quinidine, and benzoic acid–progesterone molecular alloys in the glass and ultraviscous states and their relevance to solubility and stability. J. Pharm. Sci. 99, 1358–1374 (2010)CrossRefGoogle Scholar
  27. 27.
    Stott, P.W., Williams, A.C., Barry, B.W.: Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen. J. Control. Release 50, 297–308 (1998)CrossRefGoogle Scholar
  28. 28.
    Tu, W., Chen, Z., Gao, Y., Li, Z., Zhang, Y., Liu, R., Tian, Y., Wang, L.M.: Glass transition mixing thermodynamics of a binary eutectic system. Phys. Chem. Chem. Phys. 16, 3586–3592 (2014)CrossRefGoogle Scholar
  29. 29.
    Liu, D., Fei, X., Wang, S., Jiang, T., Su, D.: Increasing solubility and dissolution rate of drugs via eutectic mixture: itraconazole–poloxamer 188 system. Asian J. Pharm. Sci. 1, 213–221 (2006)Google Scholar
  30. 30.
    Gala, U., Pham, H., Chauhan, H.: Pharmaceutical applications of eutectic mixtures. J. Dev. Drugs. (2013). doi: 10.4172/2329-6631.1000e130 Google Scholar
  31. 31.
    McCrum, N.G., Read, D.E., Williams, G.: Inelastic and Dielectric Effects in Polymeric Solids. Wiley, New York (1967)Google Scholar
  32. 32.
    Jonscher, A. K.: Dielectric Relaxation in Solids. Chelsea, London (1983) (The dielectric loss in the frequency range 10−0.5–10−3 is obtained from the Hamon’s approximation: ε″(f) = i(t) * t/0.63C 0 V 0 with ft = 0.l, where i(t) is the discharging current at a time t, C 0 is the empty cell capacitance, and V 0 is the applied voltage)Google Scholar
  33. 33.
    Hamon, B.V.: An approximation method for deducing dielectric loss factor from direct-current measurements. Inst. Monogr. 99, 151–155 (1952)Google Scholar
  34. 34.
    Kita, Y., Koizumi, N.: Remarks on the Hamon approximation. Adv. Mol. Relax. Process. 7, 13–20 (1975)CrossRefGoogle Scholar
  35. 35.
    Bredikhin, A.A., Gubaidullin, A.T., Bredikhina, Z.A., Krivolapov, D.B., Pashagin, A.V., Litvinov, I.A.: Absolute configuration and crystal packing for three chiral drugs prone to spontaneous resolution: guaifenesin, methocarbamol and mephenesin. J. Mol. Struct. 920, 377–382 (2009)CrossRefGoogle Scholar
  36. 36.
    Brittain, H.G.: Analytic Profiles of Drug Substances and Excipients, vol. 25, pp. 121–164. Acute Therapeutics, Inc, New Jersey (1998)CrossRefGoogle Scholar
  37. 37.
    Havriliak, S., Negami, S.: A complex plane analysis of α-dispersions in some polymer systems. J. Polym. Sci. Part C. Polym. Symp. 14, 99–117 (1966)CrossRefGoogle Scholar
  38. 38.
    Murthy, S. S. N.: Phase behavior of the supercooled aqueous solutions of dimethyl sulfoxide, ethylene glycol, and methanol as seen by dielectric spectroscopy, J. Phys. Chem. B. 101, 6043–6049 (1997) {The exact relation between f m and f 0 is f m = f 0 {k′/[cos(απ/2) − sin(απ/2).k′]}1/(1 –α) where k′ = tan [(1–α)π/(2(1 + β))]}Google Scholar
  39. 39.
    Murthy, S.S.N., Kumar, D.: Glass formation in organic binary liquids studied using differential scanning calorimetry. J. Chem. Soc. Faraday Trans. 89, 2423–2427 (1993)CrossRefGoogle Scholar
  40. 40.
    Murthy, S.S.N.: Temperature dependence of the dielectric relaxation process in glass-forming materials. J. Chem. Soc. Faraday Trans. 84, 671–677 (1988)CrossRefGoogle Scholar
  41. 41.
    Hill, N.E., Vaughan, W.E., Price, A.H., Davies, M.: Dielectric Properties and Molecular Behaviour. Van Nostrand Reinhold, London (1969)Google Scholar
  42. 42.
    Angell, C.A.: Relaxation in liquids, polymers and plastic crystals—strong/fragile patterns and problems. J. Non-Cryst. Solids 131–133, 13–31 (1991)CrossRefGoogle Scholar
  43. 43.
    Zhou, D., Zhang, G.G.Z., Law, D., Grant, D.J.W., Schmitt, E.A.: Physical stability of amorphous pharmaceuticals. Importance of configurational thermodynamic quantities and molecular mobility. J. Pharm. Sci. 91, 1863–1872 (2002)CrossRefGoogle Scholar
  44. 44.
    Espeau, P., Ceolin, R., Tamarit, J.L., Perrin, M.A., Gauchi, J.P., Leveiller, F.: Polymorphism of paracetamol. Relative stabilities of the monoclinic and orthorhombic phases inferred from topological pressure–temperature and temperature–volume phase diagrams. J. Pharm. Sci. 94, 524–539 (2005)CrossRefGoogle Scholar
  45. 45.
    Martino, P.D., Palmieri, G.F., Martelli, S.: Molecular mobility of the paracetamol amorphous form. Chem. Pharm. Bull. 48, 1105–1108 (2000)CrossRefGoogle Scholar
  46. 46.
    Klimova, K., Leitner, J.: DSC study and phase diagrams calculation of binary systems of paracetamol. Thermochim. Acta 550, 59–64 (2012)CrossRefGoogle Scholar
  47. 47.
    Capacioli, S., Nagai, K.L.: Relation between the α-relaxation and Johari–Goldstein β-relaxation of a component in binary miscible mixtures of glass-formers. J. Phys. Chem. B. 109, 9727–9735 (2005)CrossRefGoogle Scholar
  48. 48.
    Ngai, K.L., Capacioli, S.: Relation between the activation energy of the Johari–Goldstein β-relaxation and Tg of glass formers. Phys. Rev. E. 69, 031501 (5) (2004)CrossRefGoogle Scholar
  49. 49.
    Alvarez, F., Alegria, A., Colmenero, J.: Relationship between the time-domain Kohlrausch–Williams–Watts and frequency-domain Havriliak–Negami relaxation functions. Phys. Rev. B., Condens. Matter. 44, 7306–7312 (1991)CrossRefGoogle Scholar
  50. 50.
    Murthy, S.S.N., Gangasharan, Nayak, S.K.: Noval differential scanning calorimetric studies of supercooled organic liquids. J. Chem. Soc. Faraday Trans. 89, 509–514 (1993)CrossRefGoogle Scholar
  51. 51.
    Rodrigues, A.C., Viciosa, M.T., Danede, F., Affouard, F., Correia, N.T.: Molecular mobility of amorphous S-flurbiprofen: a dielectric relaxation spectroscopy approach. Mol. Pharm. 11, 112–130 (2013)CrossRefGoogle Scholar
  52. 52.
    Wang, L.M., Angell, C.A., Richert, R.: Fragility and thermodynamic in nonpolymeric glass-forming liquids. J. Chem. Phys. 125, 074505–074513 (2006)CrossRefGoogle Scholar
  53. 53.
    Wang, L.M., Angell, C.A.: Response to comment on direct determination of the fragility indices of glass forming liquids by differential scanning calorimetry: kinetic versus thermodynamic fragilities. J. Chem. Phys. 118, 10353–10355 (2003)CrossRefGoogle Scholar
  54. 54.
    Bohmer, R., Ngai, K.L., Angell, C.A., Plazek, D.J.: Nonexponential relaxations in strong and fragile glass formers. J. Chem. Phys. 99, 4201–4209 (1993)CrossRefGoogle Scholar
  55. 55.
    Shamblin, S.L., Hancock, B.C., Dupuis, Y., Pikal, M.J.: Interpretation of relaxation time constants for amorphous pharmaceutical systems. J. Pharm. Sci. 89, 417–427 (2000)CrossRefGoogle Scholar
  56. 56.
    Ngai, K.L.: Relation between some secondary relaxations and the α relaxations in glass-forming materials according to the coupling model. J. Chem. Phys. 109, 6982–6994 (1998)CrossRefGoogle Scholar
  57. 57.
    Colby, R.H.: Dynamic scaling approach to glass formation. Phys. Rev. E 61, 1783–1792 (2000)CrossRefGoogle Scholar
  58. 58.
    Drozd-Rzoska, A., Rzoska, S.J., Pawlus, S., Garcia, M., Tammarit, J.L.: Evidence for critical like behavior in ultra-slowing glass forming systems. Phys. Rev. E 82, 031501–031509 (2010)CrossRefGoogle Scholar
  59. 59.
    Martinez Garcia, J.C., Tamrit, J.L., Rzoska, S.J.: Enthalpy space analysis of the evolution of the primary relaxation time in ultra-slowing system. J. Chem. Phys. 134, 024512–024519 (2011)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.School of Physical SciencesJawaharlal Nehru UniversityNew DelhiIndia

Personalised recommendations