Skip to main content
SpringerLink
Log in

Perspectives on the Wetting of Solids in Pharmaceutical Systems

  • Review Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The ability of water and aqueous solutions to wet relatively nonpolar pharmaceutical solids during the processing and administration of solid dosage forms is an important part of development.

Results

Various factors, both fundamental and technological, which are important to wettability are reviewed and analyzed. Initially, the ideal thermodynamic importance of liquid surface tension and solid surface energetics, determined by the contact angle and the polarity of the solid surface, are established. Then, emphasis is placed on various factors that change the surface energetics due to crystal defects, polymorphism, varying Miller Indices, crystal habit, amorphous structure, variable surface concentration of components in a formulation mixture, surface roughness, and complex pore structure. Case studies cover single component systems (APIs and excipients), binary mixtures (amorphous solid dispersions and physical mixtures), multicomponent systems (granules and tablets), as well as disintegration and dissolution of solid oral dosage forms.

Conclusions

This perspective and analysis indicates the primary importance of understanding and modifying solid surface energetics, surface chemical and physical heterogeneities, and pore structure to promote wettability in pharmaceutical 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
Fig. 15

Similar content being viewed by others

References

  1. Zografi G, Tam SS. Wettability of pharmaceutical solids: Estimates of solid surface polarity. J Pharm Sci. 1976;65:1145–9.

    Article  CAS  PubMed  Google Scholar 

  2. Lerk CF, Schoonen AJM, Fell JT. Contact angles and wetting of pharmaceutical powders. J Pharm Sci. 1976;65:1145–9.

    Article  Google Scholar 

  3. Hyun SM, Lee BJ, Abuzar SM, Lee S, Joo Y, Hong SH, Kang H, Kwon KA, Velaga S, Hwang SJ. Preparation, characterization and evaluation of celecoxib eutectic mixtures with adipic acid / saccharin for improvement of wettability and dissolution. Int J Pharm. 2019;554:61–71.

    Article  CAS  PubMed  Google Scholar 

  4. Shuttleworth R. The surface tension of solids. Proc Phys Soc Sec A. 1950;63:444–56.

    Article  Google Scholar 

  5. Fowkes FM. Attractive forces at interfaces. Ind Eng Chem. 1964;56:40–52.

    Article  CAS  Google Scholar 

  6. Girafalco LA, Good RJ. A theory of the estimation of surface and interfacial energies. I. Derivation and application of interfacial tension. J Phys Chem. 1957;61:904–9.

    Article  Google Scholar 

  7. Wu S. Calculation of interfacial tension in polymer systems. J Polym Sci Part C. 1971;34:19–30.

    Article  Google Scholar 

  8. Fowkes FM, Mostafa MA. Acid-base interactions in polymer adsorption. Ind Eng Chem Prod Res Dev. 1978;17:3–7.

    Article  CAS  Google Scholar 

  9. Volpe CD, Siboni S. Some reflections on acid-base solid surface free energy theories. J Colloid Interf Sci. 1997;195:121–36.

    Article  CAS  Google Scholar 

  10. Coble RL. Sintering crystalline solids I. Diffusion models J Appl Phys. 1961;32:787–92.

    Article  CAS  Google Scholar 

  11. Puri V, Dantuluri AK, Kumar N, Bansal AK. Wettability of crystalline and amorphous forms of a poorly water soluble drug. Europ J Pharm Sci. 2011;40:84–93.

    Article  Google Scholar 

  12. Law KL. Definitions for hydrophilicity, hydrophobicity, and superhydrophobicity: Getting the basics right. J Phys Chem Lett. 2014;5:686–8.

    Article  CAS  PubMed  Google Scholar 

  13. Marmur A. Equilibrium contact angles: theory and measurements. Colloids Interfaces A, Physiochem Eng Aspects. 1996;116:55–61.

    Article  CAS  Google Scholar 

  14. Marmur A. Interfaces at equilibrium: A guide to fundamentals. Adv Colloid Interf Sci. 2017;244:164–73.

    Article  CAS  Google Scholar 

  15. Zarmpi P, Flanagan T, Mechan E, Mann J, Fotaki N. Imapct of magnesium stearate presence and variability on drug apparent solubility based on drug physiochemical properties. AAPS J. 2020;22:75.

    Article  CAS  PubMed  Google Scholar 

  16. Heng JYY, Bismarck A, Williams DR. Anisotropic surface chemistry of crystalline pharmaceutical solids. AAPS PharmSciTech. 2006;7:E12–20.

    Article  PubMed Central  Google Scholar 

  17. Zisman WA. Relation of the equilibrium contact angle to liquid and solid constitution. In: Fowkes FM, editor. Contact angle, wettability, and adhesion. Washington DC: Advances in Chemistry, American Chemical Society; 1964. p. 1–51.

  18. Fox HW, Zisman WA. The spreading of liquids on low-energy surfaces. II. Modified tetrafluoroethylene polymers. J Colloid Sci. 1952;7:109–21.

    Article  CAS  Google Scholar 

  19. Bergfreunde J, Siegenthaler S, Lutz-Bueno V, Bertsch P, Fischer P. Surfactant adsorption to different fliud interfaces. Langmuir. 2021;37:6722–7.

    Article  Google Scholar 

  20. Gau C-S, Zografi G. Relationships between adsorption and wetting of surfactant solutions. J Coll Interf Sci. 1990;140:1–9.

    Article  CAS  Google Scholar 

  21. Zhang R, Somasundaran P. Advances in adsorption of surfactants and their mixtures at solid/solution interfaces. Adv Colloid and Interf Sci. 2006;123–126:213–29.

    Article  Google Scholar 

  22. Williams DR. Particle engineering in pharmaceutical solids processing: Surface energy considerations. Curr Pharm Des. 2015;21:2677–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kaur A, Kale DP, Bansal AK. Surface characterization of pharmaceutical solids. Trends in Chem. 2021;138: 116228.

    Article  CAS  Google Scholar 

  24. Lapham GS, Dowling DR, Schultz WW. In situ force-balance tensiometery. Exper In Fluids. 1999;27:157–66.

    Article  CAS  Google Scholar 

  25. Wenzel RN. Resistance of solid surfaces in wetting by water. Trans Faraday Soc. 1936;40:546–51.

    Google Scholar 

  26. Wolansky G, Marmur A. Apparent contact angles on rough surfaces: the Wenzel equation revisited. Colloids Surfaces A Physicochem Eng Aspects. 1999;156:381–8.

    Article  CAS  Google Scholar 

  27. Cassie ABD, Baxter S. Wettability of porous surfaces. Trans Faraday Soc. 1944;40:546–51.

    Article  CAS  Google Scholar 

  28. Milne AJB, Amiirfazli. The Cassie equation: How it is meant to be used. Adv Colloid Interf Sci. 2012;170:48–55.

    Article  CAS  Google Scholar 

  29. Choi W, Tuteja A, Mabry JM, Cohen RE, McKinley GH. A modified Cassie-Baxter relationship to explain contact angle hysteresis and anisotropy on non-wetting textured surfaces. J Colloid Interf Sci. 2009;339:208–16.

    Article  CAS  Google Scholar 

  30. Zografi G, Johnson BA. Effects of roughness on advancing and receding contacts angles. Int J Pharm. 1984;22:159–76.

    Article  CAS  Google Scholar 

  31. Rapacchietta AV, Neumann AW. Force and free energy analysis of small particles at fluid interfaces. J Colloid Interf Sci. 1977;59:555–67.

    Article  Google Scholar 

  32. Cappelli S, Xie Q, de Jong AM, Prins MWJ. Dynamic wetting status and prospective of single particle-based experiments and simulations. New Biology. 2015;32:420–32.

    CAS  Google Scholar 

  33. Marmur A, Chen W, Zografi G. Characterization of particle wettability by the measurement of floatability. J Colloid Interf Sci. 1986;113:114–20.

    Article  CAS  Google Scholar 

  34. Feng D, Nguyen AV. The floatability of single spheres versus their pairs on the water surface. Langmuir. 2016;32:13627–34.

    Article  CAS  PubMed  Google Scholar 

  35. Li M, Callegari G, Drazer G. Effective capillary pressure, and permeability of a granular material during imbibition in a closed column. Colloids Surfaces A, Physiochem Eng Aspects. 2022;648:129280.

    Article  CAS  Google Scholar 

  36. Liu H, Cao G. Effectiveness of the Young-Laplace equation at nanoscale. Sci Rpts. 2016;6:23936.

    CAS  Google Scholar 

  37. Pfitzner J. Poiseuille and his law Anesthesia. 1976;31:273–5.

    Article  CAS  Google Scholar 

  38. Washburn EW. The dynamics of capillary flow. Phys Rev. 1921;17:273–83.

    Article  Google Scholar 

  39. Fisher LR, Lark PD. An experimental study of the Washburn equation for liquid flow in very fine capillaries. J Colloid Interf Sci. 1979;69:486–91.

    Article  CAS  Google Scholar 

  40. Sun Z, Santamarina JC. Haines jumps: Pore scale mechanisms. Phys Rev E. 2019;100: 023115.

    Article  CAS  PubMed  Google Scholar 

  41. Hapgood KP, Lister JD, Biggs SR, Howes T. Drop penetration into porous powder beds. J Colloid Interf Sci. 2002;253:353–66.

    Article  CAS  Google Scholar 

  42. Li M, Callegari G, Drazer G. Capillary rise in a closed column: Application to the characterization of powders. Colloids Surf A. 2020;602: 124822.

    Article  CAS  Google Scholar 

  43. Liu Z, Wang Y, Muzzio FJ, Callegari G, Drazer G. Capillary drop penetration method to characterize the liquid wetting of powders. Langmuir. 2017;33:56–65.

    Article  CAS  PubMed  Google Scholar 

  44. Yang YW, Miller Zografi G, EE. Capillary flow phenomena and wettability in porous media: Static characteristics. J Colloid Interf Sci. 1988;122:24–34.

    Article  CAS  Google Scholar 

  45. Yang YW, Zografi G, Miller EE. Capillary flow phenomena and wettability in porous media: Dynamic flow studies. J Colloid Interf. 1988;122:35–46.

    Article  CAS  Google Scholar 

  46. Yang YW, Zografi G. Use of the Washburn-Rideal equation for studying capillary flow in porous media. J Pharm Sci. 1986;75:719–21.

    Article  CAS  PubMed  Google Scholar 

  47. Studebaker ML, Snow CW. The influence of ultimate composition upon the wettability of carbon blacks. J Phys Chem. 1955;59:973–6.

    Article  CAS  Google Scholar 

  48. Buckton G. Contact angle, adsorption and wettability- a review with respect to powders. Powder Technol. 1990;61:237–43.

    Article  CAS  Google Scholar 

  49. Yuan Y, Lee RT. Contact angle and wetting properties. In: Bracco GH, Holst B, editors. Surface Science Techniques. Springer-Verlag: Hiedelberg; 2013. p. 2–22.

    Google Scholar 

  50. Pepin X, Blanchon S, Courraze G. A new approach for determination of powder wettability. Int J Pharm. 1997;152:1–5.

    Article  CAS  Google Scholar 

  51. Thakker M, Karde V, Hhah DO, Shukla P, Ghorol C. Wettability measurement apparatus for porous material using modified Washburn method. Meas Sci Technol. 2013;24: 125902.

    Article  Google Scholar 

  52. Dove JW, Buckton G, Doherty C. A comparison of two contact angle measurement methods and inverse gas chromatography to assess the surface energies of theophylline and caffeine. Int J Pharm. 1996;138:199–206.

    Article  CAS  Google Scholar 

  53. Pepin X, Blanchon S, Courraze G. Powder dynamic contact angle data in the pharmaceutical industry. PSIT. 1999;2:111–8.

    CAS  Google Scholar 

  54. Mohammadi-Jam S, Waters KE. Inverse gas chromatography applications: a review. Adv Coll Int Sci. 2014;212:21–44.

    Article  CAS  Google Scholar 

  55. Voelkel A, Strzemiecka B, Adamska K, Milczewska. Inverse gas chromatography as a source of physicochemical data. J Chrom. 2009;1216:1551–66.

    Article  CAS  Google Scholar 

  56. Muster TH, Prestidge CA. Application of time-dependent sessile drop contact angles on compacts to characterize the surface energetics of sulfathiazole crystals. Int J Pharm. 2002;234:43–54.

    Article  CAS  PubMed  Google Scholar 

  57. Fataraie E, Jankauskaite V, Marazas G, Milasiene D, Sukiene K. Viscosity and surface properties of melamine-formaldehyde resin composition. Mat Sci (Medziagotyra). 2009;15:250–4.

    Google Scholar 

  58. Wong J, Kuu W-Y, Kajimoto J, Kazama H. Correlation of the intravenous in-line drug delivery kinetics with the diluent flow rate, angle of internal flow, wettability, solubility and particle surface area. Int J Pharm. 1996;14:177–86.

    Article  Google Scholar 

  59. Chan IW, Chow KT, Heng PWS. Investigation of wetting behavior of nonaqueous ethylcellulose gel matrices using dynamic contact angle. Pharm Res. 2006;23:408–21.

    Article  CAS  PubMed  Google Scholar 

  60. Parsons GE, Buckton G, Chatham SM. The use of surface energy and polarity determinations to predict physical stability of non-polar, non-aqueous suspensions. Int J Pharm. 1992;83:163–70.

    Article  CAS  Google Scholar 

  61. Rillosi M, Buckton G. Modelling Mucoadhesion by use of surface energy terms obtained from the Lewis acid-Lewis base approach. II. Studies on anionic, cationic, and unionisable polymers. Pharm Res. 1995;112:669–75.

    Article  Google Scholar 

  62. Karde V, Ghoroi C. Influence of surface modification on wettability and surface energy characteristics of pharmaceutical excipient powders. Int J Pharm. 2014;475:351–63.

    Article  CAS  PubMed  Google Scholar 

  63. Pinto JF, Buckton G, Newton JM. Relationship between surface free energy and polarity data and some physical properties of spheroids Int. J Pharm. 1995;118:95–101.

    CAS  Google Scholar 

  64. Lippold BC, Ohm A. Correlation between wettability and dissolution rate of pharmaceutical powders Int. J Pharm. 1986;28:67–74.

    CAS  Google Scholar 

  65. Mohammad HAH, Fell JT. Surface free energy characteristics of mixtures. Int J Pharm. 1983;17:39–46.

    Article  Google Scholar 

  66. Zhang D, Flory JH, Panmai S, Batra U, Kaufman MJ. Wettability of pharmaceutical solids: its measurement and influence on wet granulation. Colloids Surf A. 2002;206:547–54.

    Article  CAS  Google Scholar 

  67. Malamataris S, Klortsis S. Wettability parameters and deformational behaviour of powder–liquid mixes in the funicular agglomeration phase. Int J Pharm. 1997;154:9–17.

    Article  CAS  Google Scholar 

  68. Singh P, Desai AJ, Simonelli AP, Higuchi WI. Role of wetting on the rate of drug release from inert matrices. J Pharm Sci. 1968;57:217–26.

    Article  CAS  PubMed  Google Scholar 

  69. Rahman M, Coelho A, Tarabokija J, Ahmad S, Ragman K, Bilgili E. Synergistic and antagonistic effects of various amphiphilic polymer combinations in enhancing griseofulvin release from ternary amorphous solid dispersions. Eur J Pharm Sci. 2020;150: 105354.

    Article  CAS  PubMed  Google Scholar 

  70. Yang B, Xu L, Wang Q, Li S. Modulation of the wettability of excipients by surfactant and its impacts on the disintegration and release of tablets. Drug Dev Ind Pharm. 2016;42:1945–55.

    Article  CAS  PubMed  Google Scholar 

  71. Mundozah AL, Tridon CC, Cartwright JJ, Salman AD, Hounslow MJ. Wetting of binary powder mixtures. Int J Pharm. 2019;572:11870.

    Article  Google Scholar 

  72. Wang Y, Liu A, Muxxio F, Draxer G, Callegari G. A drop penetration method to measure powder blend wettability. Int J Pharm. 2018;538:112–8.

    Article  CAS  PubMed  Google Scholar 

  73. Heng JYY, Thielman F, Williams DR. The effect of milling on the surface properties of Form I paracetamol crystals. Pharm Res. 2006;23:1918–27.

    Article  CAS  PubMed  Google Scholar 

  74. Dahlberg C, Millqvist-Fureby A, Schuleit M. Surface composition and contact angle relationships for differently prepared solid dispersions. Eur J Pharm Biopharm. 2008;70:478–85.

    Article  CAS  PubMed  Google Scholar 

  75. Dahlberg C, Millqvist-Fureby A, Schuleit M, Furo I. Polymer–drug interactions and wetting of solid dispersions. Eur J Pharm Sci. 2010;39:125–33.

    Article  CAS  PubMed  Google Scholar 

  76. Jiang T, Han L, Lu E, He W, Du S, Sha X. Design and Characterization of HY-038 solid dispersions via spray drying technology: In vitro and in vivo evaluations. AAPS PharmSciTech. 2021;22:267.

    Article  CAS  PubMed  Google Scholar 

  77. Rowe RC. Surface free energy and polarity effects in the granulation of a model system. Int J Pharm. 1989;53:75–8.

    Article  CAS  Google Scholar 

  78. Rowe RC. Polar/non-polar interactions in the granulation of organic substrates with polymer binding agents. Int J Pharm. 1989;56:117–24.

    Article  CAS  Google Scholar 

  79. Rowe RC. Correlation between predicted binder spreading coefficients and measured granule and tablet properties in the granulation of paracetamol. Int J Pharm. 1990;58:209–13.

    Article  CAS  Google Scholar 

  80. Buch P, Meyer C, Langguth P. Improvement of the wettability and dissolution of fenofibrate compacts by plasma treatment. Int J Pharm. 2011;416:49–54.

    Article  CAS  PubMed  Google Scholar 

  81. Dixit D, Bunk S, Rane R, Ghoroi C. Influence of Ar plasma treatment on the wetting behavior of pharmaceutical powders. Adv Powder Tech. 2018;29:2928–40.

    Article  CAS  Google Scholar 

  82. La Zara D, Zhang F, Sun F, Bailey MR, Quayle MJ, Petersson G, Folestad S, van Ommen JR. Drug powders with tunable wettability by atomic and molecular layer deposition: From highly hydrophilic to superhydrophobic. Appl Mat Today. 2021;22: 100945.

    Article  Google Scholar 

  83. Varghese S, Ghoroi C. Improving the wetting and dissolution of ibuprofen using solventless comilling. Int J Pharm. 2017;533:145–55.

    Article  CAS  PubMed  Google Scholar 

  84. Kapsidou T, Nikolakakis Malamataris S. Improving the wetting and dissolution of ibuprofen using solventless comilling. Int J Pharm. 2001;227:97–112.

    Article  CAS  PubMed  Google Scholar 

  85. Wan LSC, Heng PWS. Technique of measuring rapid water penetration rate into tablets. Chem Pharm Bull. 1987;35:1615–7.

    Article  CAS  Google Scholar 

  86. Takasaki H, Yonemochi E, Messerschmid R, Ito M, Wada K, Terada K. Importance of excipient wettability on tablet characteristics prepared by moisture activated dry granulation (MADG). Int J Pharm. 2013;456:58–64.

    Article  CAS  PubMed  Google Scholar 

  87. Costa MDL, Baszkin A. The effect of the surface free energy of pharmaceutical tablets on liquid penetration. J Pharm Pharmacol. 1985;37:455–60.

    Article  CAS  PubMed  Google Scholar 

  88. Fukami J, Ozawa A, Yoshihashi Y, Yonemochi E, Terada K. Development of fast disintegrating compressed tablets using amino acid as disintegratation accelerator: Evaluation of wetting and disintegration of tablet on the basis of surface free energy. Chem Pharm Bull. 2005;53:1536–9.

    Article  CAS  Google Scholar 

  89. Marques MRC, Loebenberg R, Almukainzi M. Simulated biological fluids with possible application in dissolution testing. Dissol Tech. 2011;18:15–28.

    Article  CAS  Google Scholar 

  90. Hooper P, Lasher J, Alexander KS, Baki G. A new modified wetting test and an alternative disintegration test for orally disintegrating tablets. J Pharm Biomed Anal. 2016;120:391–6.

    Article  CAS  PubMed  Google Scholar 

  91. Yang B, Wei C, Yang Y, Wang Q, Li S. Evaluation about wettability, water absorption or swelling of excipients through various methods and the correlation between these parameters and tablet disintegration. Drug Dev Ind Pharm. 2018;44:1417–25.

    Article  CAS  PubMed  Google Scholar 

  92. Yu D, Fiddler F, Ibrahim A, Sanedrin R, Tremblay H, Hoag SW. Surface characterization as a tool for identifying the factors affecting the dissolution rate of amorphous solid dispersion tablets. AAPS PharmSciTech. 2022;23:282.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

No funding was obtained for this paper.

Author information

Authors and Affiliations

  1. Seventh Street Development Group, PO Box 251, Kure Beach, NC, 24889, 765-650-4462, USA

    Ann Newman

  2. School of Pharmacy, University of Wisconsin, Madison, WI, 53705, USA

    George Zografi

Authors
  1. Ann Newman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George Zografi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors made substantial contributions to the conception, writing, and critical review of the work.

Corresponding author

Correspondence to Ann Newman.

Ethics declarations

Conflict of Interest

Authors report no conflicts of interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Newman, A., Zografi, G. Perspectives on the Wetting of Solids in Pharmaceutical Systems. Pharm Res 40, 3099–3118 (2023). https://doi.org/10.1007/s11095-023-03491-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-023-03491-3

Keywords

Search

Navigation