Skip to main content
SpringerLink
Log in

Are Crystallinity Parameters Critical for Drug Solubility Prediction?

  • Published:
Journal of Solution Chemistry Aims and scope Submit manuscript

Abstract

Solubility is one the most important physicochemical properties in various stages of drug discovery and development. Different quantitative structure–property relationship models, using diverse parameters, have been proposed to predict the aqueous and non-aqueous solubilities of pharmaceutical compounds. In this study, the effects of these parameters, especially crystallinity parameters, were examined for prediction of the solubility of drug and drug-like molecules in water and octanol. The descriptors, i.e. octanol–water partition coefficient (log10 P), topological polar surface area, Abraham solvation parameters and crystallinity parameters, were computed or extracted from the literature. The results demonstrate that log10 P is the key parameter in aqueous solubility prediction and none of the other descriptors was superior to the others. However, the models, which are composed of calculated parameters such as the Abraham solvation parameters, can be applied to virtual compounds in drug discovery. On the other hand, crystallinity parameters are crucial in predicting the solubility of pharmaceutical compounds in octanol, and these parameters should be considered in developing models.

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

Similar content being viewed by others

References

  1. Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J.: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 64, 4–17 (2012)

    Article  Google Scholar 

  2. Unger, K.K., Liapis, A.I.: Adsorbents and columns in analytical high-performance liquid chromatography: a perspective with regard to development and understanding. J. Sep. Sci. 35, 1201–1212 (2012)

    Article  CAS  Google Scholar 

  3. Alsenz, J., Kansy, M.: High throughput solubility measurement in drug discovery and development. Adv. Drug Deliv. Rev. 59, 546–567 (2007)

    Article  CAS  Google Scholar 

  4. Wang, J., Hou, T.: Recent advances on aqueous solubility prediction. Comb. Chem. High Throughput Screen. 14, 328–338 (2011)

    Article  CAS  Google Scholar 

  5. Dearden, J.C.: In silico prediction of aqueous solubility. Expert Opin. Drug Discov. 1, 31–52 (2006)

    Article  CAS  Google Scholar 

  6. Jouyban, A.: Handbook of Solubility for Pharmaceuticals. CRC Press, Boca Raton (2010)

    Google Scholar 

  7. McDonagh, J.L., Nath, N., De Ferrari, L., Van Mourik, T., Mitchell, J.B.: Uniting cheminformatics and chemical theory to predict the intrinsic aqueous solubility of crystalline druglike molecules. J. Chem. Inf. Model. 54, 844–856 (2014)

    Article  CAS  Google Scholar 

  8. Jouyban, A., Fakhree, M.A., Shayanfar, A.: Solubility prediction methods for drug/drug like molecules. Res. Pat. Chem. Eng. 1, 220–231 (2008)

    Article  CAS  Google Scholar 

  9. Faller, B., Ertl, P.: Computational approaches to determine drug solubility. Adv. Drug Deliv. Rev. 59, 533–545 (2007)

    Article  CAS  Google Scholar 

  10. Box, K., Comer, J.: Using measured pK a, logP and solubility to investigate supersaturation and predict BCS class. Curr. Drug Metab. 9, 869–878 (2008)

    Article  CAS  Google Scholar 

  11. Hansch, C., Quinlan, J.E., Lawrence, G.L.: Linear free-energy relationship between partition coefficients and the aqueous solubility of organic liquids. J. Org. Chem. 33, 347–350 (1968)

    Article  CAS  Google Scholar 

  12. Shayanfar, A., Fakhree, M., Jouyban, A.: A simple QSPR model to predict aqueous solubility of drugs. J. Drug Deliv. Sci. Technol. 20, 467–476 (2010)

    Article  CAS  Google Scholar 

  13. Ran, Y., Jain, N., Yalkowsky, S.H.: Prediction of aqueous solubility of organic compounds by the general solubility equation (GSE). J. Chem. Inf. Comput. Sci. 41, 1208–1217 (2001)

    Article  CAS  Google Scholar 

  14. Chu, K.A., Yalkowsky, S.H.: Predicting aqueous solubility: the role of crystallinity. Curr. Drug Metab. 10, 1184–1191 (2009)

    Article  CAS  Google Scholar 

  15. Grant, D.J.W., Mehdizadeh, M., Chow, A.H.L., Fairbrother, J.E.: Non-linear van’t Hoff solubility-temperature plots and their pharmaceutical interpretation. Int. J. Pharm. 18, 25–38 (1984)

    Article  CAS  Google Scholar 

  16. Yalkowsky, S.H., Wu, M.: Estimation of the ideal solubility (crystal–liquid fugacity ratio) of organic compounds. J. Pharm. Sci. 99, 1100–1106 (2010)

    Article  CAS  Google Scholar 

  17. Jain, N., Yalkowsky, S.H.: Estimation of the aqueous solubility I: application to organic nonelectrolytes. J. Pharm. Sci. 90, 234–252 (2001)

    Article  CAS  Google Scholar 

  18. Wassvik, C.M., Holmén, A.G., Bergström, C.A., Zamora, I., Artursson, P.: Contribution of solid-state properties to the aqueous solubility of drugs. Eur. J. Pharm. Sci. 29, 294–305 (2006)

    Article  CAS  Google Scholar 

  19. Abraham, M.H., Le, J.: The correlation and prediction of the solubility of compounds in water using an amended solvation energy relationship. J. Pharm. Sci. 88, 868–880 (1999)

    Article  CAS  Google Scholar 

  20. Abraham, M.H., Acree Jr, W.E.: The solubility of liquid and solid compounds in dry octan-1-ol. Chemosphere 103, 26–34 (2014)

    Article  CAS  Google Scholar 

  21. Abraham, M.H., Ibrahim, A., Zissimos, A.M.: Determination of sets of solute descriptors from chromatographic measurements. J. Chromatogr. A 1037, 29–47 (2004)

    Article  CAS  Google Scholar 

  22. ACD/Labs, Pharmaalgorithm software, https://ilab.acdlabs.com

  23. Sepassi, K., Yalkowsky, S.H.: Solubility prediction in octanol: a technical note. AAPS PharmSciTech 7, E184–E191 (2006)

    Article  Google Scholar 

  24. Admire, B., Yalkowsky, S.H.: Predicting the octanol solubility of organic compounds. J. Pharm. Sci. 102, 2112–2119 (2013)

    Article  CAS  Google Scholar 

  25. Jain, P., Yalkowsky, S.H.: Prediction of aqueous solubility from SCRATCH. Int. J. Pharm. 385, 1–5 (2010)

    Article  CAS  Google Scholar 

  26. Jain, P., Sepassi, K., Yalkowsky, S.H.: Comparison of aqueous solubility estimation from AQUAFAC and the GSE. Int. J. Pharm. 360, 122–147 (2008)

    Article  CAS  Google Scholar 

  27. Shayanfar, A., Jouyban, A.: Comparison of four models to predict intrinsic solubility of drugs. Lat. Am. J. Pharm. 30, 1525–1530 (2011)

    CAS  Google Scholar 

  28. Salahinejad, M., Le, T.C., Winkler, D.A.: Aqueous solubility prediction: Do crystal lattice interactions help? Mol. Pharm. 10, 2757–2766 (2013)

    Article  CAS  Google Scholar 

  29. Bergström, C.A., Wassvik, C.M., Norinder, U., Luthman, K., Artursson, P.: Global and local computational models for aqueous solubility prediction of drug-like molecules. J. Chem. Inf. Comput. Sci. 44, 1477–1488 (2004)

    Article  Google Scholar 

  30. Louis, B., Agrawal, V.K., Khadikar, P.V.: Prediction of intrinsic solubility of generic drugs using MLR, ANN and SVM analyses. Eur. J. Med. Chem. 45, 4018–4025 (2010)

    Article  CAS  Google Scholar 

  31. Hughes, L.D., Palmer, D.S., Nigsch, F., Mitchell, J.B.: Why are some properties more difficult to predict than others? A study of QSPR models of solubility, melting point, and log P. J. Chem. Inf. Model. 48, 220–232 (2008)

    Article  CAS  Google Scholar 

  32. Jouyban, A.: Solubility prediction of drugs in water–polyethylene glycol 400 mixtures using Jouyban–Acree model. Chem. Pharm. Bull. 54, 1561–1566 (2006)

    Article  CAS  Google Scholar 

  33. Machatha, S.G., Yalkowsky, S.H.: Comparison of the octanol/water partition coefficients calculated by ClogP, ACDlogP and KowWin to experimentally determined values. Int. J. Pharm. 294, 185–192 (2005)

    Article  CAS  Google Scholar 

  34. Ali, J., Camilleri, P., Brown, M.B., Hutt, A.J., Kirton, S.B.: Revisiting the general solubility equation: in silico prediction of aqueous solubility incorporating the effect of topographical polar surface area. J. Chem. Inf. Model. 52, 420–428 (2012)

    Article  CAS  Google Scholar 

  35. Eisenhauer, J.G.: Regression through the origin. Teach. Stat. 25, 76–80 (2003)

    Article  Google Scholar 

  36. Acree Jr, W.E., Grubbs, L.M., Abraham, M.H.: Prediction of partition coefficients and permeability of drug molecules in biological systems with abraham model solute descriptors derived from measured solubilities and water-to-organic solvent partition coefficients. In: Acree Jr, W.E. (ed.) Toxicity and Drug Testing, pp. 91–128. InTech Publisher, New York (2012)

    Chapter  Google Scholar 

  37. Abraham, M.H., Ibrahim, A., Zissimos, A.M., Zhao, Y.H., Comer, J., Reynolds, D.P.: Application of hydrogen bonding calculations in property based drug design. Drug Discov. Today 7, 1056–1063 (2002)

    Article  CAS  Google Scholar 

  38. Palmer, D.S., Mitchell, J.B.: Is experimental data quality the limiting factor in predicting the aqueous solubility of druglike molecules? Mol. Pharm. 11, 2962–2972 (2014)

    Article  CAS  Google Scholar 

  39. Llinàs, A., Glen, R.C., Goodman, J.M.: Solubility challenge: Can you predict solubilities of 32 molecules using a database of 100 reliable measurements? J. Chem. Inf. Model. 48, 1289–1303 (2008)

    Article  Google Scholar 

  40. Mota, F.L., Queimada, A.J., Pinho, S.P., Macedo, E.A.: Water solubility of drug-like molecules with the cubic-plus-association equation of state. Fluid Phase Equilib. 298, 75–82 (2010)

    Article  CAS  Google Scholar 

  41. Bergström, C.A., Wassvik, C.M., Johansson, K., Hubatsch, I.: Poorly soluble marketed drugs display solvation limited solubility. J. Med. Chem. 50, 5858–5862 (2007)

    Article  Google Scholar 

  42. Wassvik, C.M., Holmén, A.G., Draheim, R., Artursson, P., Bergström, C.A.: Molecular characteristics for solid-state limited solubility. J. Med. Chem. 51, 3035–3039 (2008)

    Article  CAS  Google Scholar 

  43. Chen, X.Q., Cho, S.J., Li, Y., Venkatesh, S.: Prediction of aqueous solubility of organic compounds using a quantitative structure–property relationship. J. Pharm. Sci. 91, 1838–1852 (2002)

    Article  CAS  Google Scholar 

  44. Ruelle, P., Kesselring, U.W.: The hydrophobic effect. 2. Relative importance of the hydrophobic effect on the solubility of hydrophobes and pharmaceuticals in H-bonded solvents. J. Pharm. Sci. 87, 998–1014 (1998)

    Article  CAS  Google Scholar 

  45. Park, K.A., Lee, H.J., Hong, I.K.: Solubility prediction of bioantioxidants for functional solvent by group contribution method. J. Ind. Eng. Chem. 16, 490–495 (2010)

    Article  CAS  Google Scholar 

  46. Gaisford, S., Saunders, S.: Essentials of Pharmaceutical Preformaulation. Wiley-Blackwell, Hoboken (2012)

    Book  Google Scholar 

  47. Domańska, U., Pobudkowska, A., Pelczarska, A., Winiarska-Tusznio, M., Gierycz, P.: Solubility and pKa of select pharmaceuticals in water, ethanol, and 1-octanol. J. Chem. Thermodyn. 42, 1465–1472 (2010)

    Article  Google Scholar 

  48. Domanska, U., Pobudkowska, A., Pelczarska, A., Gierycz, P.: pKa and solubility of drugs in water, ethanol and 1-octanol. J. Phys. Chem. B 113, 8941–8947 (2009)

    Article  CAS  Google Scholar 

  49. Baird, J.A., Van Eerdenbrugh, B., Taylor, L.S.: A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J. Pharm. Sci. 99, 3787–3806 (2010)

    CAS  Google Scholar 

  50. Dołęga, A., Ciborska, A., Chojnacki, J., Walewski, M., Wojnowski, W.: Thermogravimetry of heteroleptic zinc tri-tert-butoxysilanethiolates: synthesis and crystal structure of bis(tri-tert-butoxysilanethiolato)(pyridine) zinc(II). Thermochim. Acta 429, 103–109 (2005)

    Article  Google Scholar 

  51. Mahlin, D., Bergström, C.A.: Early drug development predictions of glass-forming ability and physical stability of drugs. Eur. J. Pharm. Sci. 49, 323–332 (2013)

    Article  CAS  Google Scholar 

  52. Bauer-Brandl, A., Marti, E., Geoffroy, A., Poso, A., Suurkuusk, J., Wappler, E., Bauer, K.H.: Comparison of experimental methods and theoretical calculations on crystal energies of `isoenergetic’ polymorphs of cimetidine. J. Therm. Anal. Calorim. 57, 7–22 (1999)

    Article  CAS  Google Scholar 

  53. Varanda, F., de Pratas Melo, M.J., Caco, A.I., Dohrn, R., Makrydaki, F.A., Voutsas, E., Tassios, D., Marrucho, I.M.: Solubility of antibiotics in different solvents. 1. Hydrochloride forms of tetracycline, moxifloxacin, and ciprofloxacin. Ind. Eng. Chem. Res. 45, 6368–6374 (2006)

    Article  CAS  Google Scholar 

  54. Spyriouni, T., Krokidis, X., Economou, I.G.: Thermodynamics of pharmaceuticals: prediction of solubility in pure and mixed solvents with PC-SAFT. Fluid Phase Equilib. 302, 331–337 (2011)

    Article  CAS  Google Scholar 

  55. Sherrington, L.A., Sherrington, A.: Guaifenesin. In: Harry, G.B. (ed.) Analytical Profiles of Drug Substances and Excipients, vol. 25, pp. 121–164. Academic Press, Waltham (1998)

    Chapter  Google Scholar 

  56. Murdande, S.B., Pikal, M.J., Shanker, R.M., Bogner, R.H.: Solubility advantage of amorphous pharmaceuticals: II. Application of quantitative thermodynamic relationships for prediction of solubility enhancement in structurally diverse insoluble pharmaceuticals. Pharm. Res. 27, 2704–2714 (2010)

    Article  CAS  Google Scholar 

  57. Sheikholeslamzadeh, E., Rohani, S.: Solubility prediction of pharmaceutical and chemical compounds in pure and mixed solvents using predictive models. Ind. Eng. Chem. Res. 51, 464–473 (2012)

    Article  CAS  Google Scholar 

  58. Bustamante, P.: Enthalpy–entropy compensation for the solubility of drugs in solvent mixtures: paracetamol, acetanilide, and nalidixic acid in dioxane–water. J. Pharm. Sci. 87, 1590–1596 (1998)

    Article  CAS  Google Scholar 

  59. Good, D.J., Rodríguez-Hornedo, N.: Solubility advantage of pharmaceutical cocrystals. Cryst. Growth Des. 9, 2252–2264 (2009)

    Article  CAS  Google Scholar 

  60. Domańska, U., Pobudkowska, A., Pelczarska, A.: Solubility of sparingly soluble drug derivatives of anthranilic acid. J. Phys. Chem B 115, 2547–2554 (2011)

    Article  Google Scholar 

  61. Shah, M., Pathak, K.: Development and statistical optimization of solid lipid nanoparticles of simvastatin by using 23 full-factorial design. AAPS PharmSciTech 11, 489–496 (2010)

    Article  CAS  Google Scholar 

  62. http://webbook.nist.gov/cgi/cbook.cgi?ID=C50704&Mask=4 (accessed September 2014)

  63. Martínez, F., Gómez, A.: Thermodynamic study of the solubility of some sulfonamides in octanol, water, and the mutually saturated solvents. J. Solution Chem. 30, 909–923 (2001)

    Article  Google Scholar 

  64. http://webbook.nist.gov/cgi/cbook.cgi?ID=C124947&Units=SI&Mask=1A8F (accessed September 2014)

  65. Araújo, A.A.S., Bezerra, M.D.S., Storpirtis, S., Matos, J.D.R.: Determination of the melting temperature, heat of fusion, and purity analysis of different samples of zidovudine (AZT) using DSC. Braz. J. Pharm. Sci. 46, 37–43 (2010)

    Article  Google Scholar 

  66. Admire, B., Yalkowsky, S.H.: Predicting the octanol solubility of organic compounds. J. Pharm. Sci. 102, 2112–2119 (2013)

    Article  CAS  Google Scholar 

  67. Yaws, C.L.: Yaws’ Handbook of Thermodynamic and Physical Properties of Chemical Compounds. McGraw-Hill, New York (2003)

    Google Scholar 

  68. Gobble, C., Gutterman, A., Chickos, J.S.: Some thermodynamic properties of benzocaine. Struct. Chem. 24, 1903–1907 (2013)

    Article  CAS  Google Scholar 

  69. Holguín, A.R., Delgado, D.R., Martínez, F., Marcus, Y.: Solution thermodynamics and preferential solvation of meloxicam in propylene glycol + water mixtures. J. Solution Chem. 40, 1987–1999 (2011)

    Article  Google Scholar 

  70. Nordström, F.L., Rasmuson, Å.C.: Solubility and melting properties of salicylamide. J. Chem. Eng. Data 51, 1775–1777 (2006)

    Article  Google Scholar 

Download references

Acknowledgments

The authors thank the Students Research Committee of Tabriz University of Medical Sciences for the partial financial support.

Author information

Authors and Affiliations

  1. Biotechnology Research Center and Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Shahram Emami

  2. Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Abolghasem Jouyban

  3. Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Hadi Valizadeh & Ali Shayanfar

Authors
  1. Shahram Emami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abolghasem Jouyban
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hadi Valizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ali Shayanfar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali Shayanfar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Emami, S., Jouyban, A., Valizadeh, H. et al. Are Crystallinity Parameters Critical for Drug Solubility Prediction?. J Solution Chem 44, 2297–2315 (2015). https://doi.org/10.1007/s10953-015-0410-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10953-015-0410-5

Keywords

Search

Navigation