Complex Micellization Behavior of the Polysorbates Tween 20 and Tween 80

Mol Pharm. 2021 Aug 2;18(8):3147-3157. doi: 10.1021/acs.molpharmaceut.1c00406. Epub 2021 Jul 12.


Polysorbates (PSs, Tweens) are widely used surfactant products consisting of a sorbitan ring connecting up to four ethylene oxide (EO) chains of variable lengths, one or more of which are esterified with fatty acids of variable lengths and saturation degrees. Pharmaceutical applications include the stabilization of biologicals in solutions and the solubilization of poorly water soluble, active ingredients. This study characterizes the complex association behavior of compendial PSs PS20 and PS80, which is fundamentally different from that of single-component surfactants. To this end, a series of demicellization experiments of isothermal titration calorimetry with different PS concentrations are evaluated. Their experiment-dependent heats of titration are converted into a common function of the state of a sample, the micellar enthalpy Qm(c). These functions demonstrate that initial micelles are already present at the lowest concentrations investigated, 2 μM for PS20 and 10 μM for PS80. Initial micelles consist primarily of the surfactant species with the lowest individual critical micelle concentration (cmc). With increasing concentration, the other PS species gradually enter these micelles in the sequence of increasing individual cmc's and hydrophilic-lipophilic balance. Concentration ranges with pronounced slopes of Qm(c) can be tentatively assigned to the uptake of the major components of the PS products. Micellization and the variation of the micelle properties progress up to at least 10 mM PS. That means the published cmc values or ranges of PS20 and PS80 may be related to certain, major components being incorporated into and forming specific micelles but must not be interpreted in terms of an absence of micelles below and constant properties, e.g., the surface activity, of the micelles above these ranges. The micellization enthalpy curves differ quite substantially between PS20 and PS80 and, in a subtler fashion, between individual quality grades such as high purity, pure lauric acid/pure oleic acid, super-refined, and China grade.

Keywords: Tween; critical micelle concentration; dynamic light scattering; isothermal titration calorimetry; micelle formation; polysorbate; protein stabilization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calorimetry / methods
  • Chemistry, Pharmaceutical / methods
  • Drug Compounding / methods
  • Drug Stability
  • Dynamic Light Scattering / methods
  • Esters / chemistry
  • Excipients / chemistry
  • Fatty Acids / chemistry
  • Hot Temperature
  • Hydrophobic and Hydrophilic Interactions
  • Lauric Acids / chemistry
  • Micelles*
  • Oleic Acid / chemistry
  • Polysorbates / chemistry*
  • Protein Stability
  • Solubility
  • Surface-Active Agents / chemistry*


  • Esters
  • Excipients
  • Fatty Acids
  • Lauric Acids
  • Micelles
  • Polysorbates
  • Surface-Active Agents
  • lauric acid
  • Oleic Acid