Towards colloidal size control by precipitation

J.G.J.L. Lebouille

Research output: Thesisinternal PhD, WU


Many active ingredients like drugs, preservatives and vitamins are hydrophobic. In most applications for food and pharma, however, they need to be functional in aqueous environments. In order to facilitate their usage in aqueous environments one needs a way to enable the dispersion of hydrophobic compounds into submicron particles in water in a controlled manner. We investigated the stabilization by surfactants and encapsulation into micelles of hydrophobic compounds using the nanoprecipitation method. The research described in this thesis is about building more understanding of the nanoprecipitation method in relation to the relevant physical chemical parameters.  The theoretical results led to predictions that were compared to experimental data. For water-soluble surfactants as stabilizers in the nanoprecipitation process a new theory was developed to relate the process parameters to the final particle size. For non-water-soluble surfactants self-consistent field theory was used in order to unravel the structure-function relationship between used copolymer chemistry and the form and morphology of the obtained particles, spherical micelles and their size.

We analyzed new and existing experiments on the nanoprecipitation method using water-soluble surfactants as stabilizers in a systematic manner. These were interpreted in terms of a new theory that links the process and material properties to the final particle size. The nanoprecipitation procedure consists of quenching a polymer solution from a good to a poor solvent containing surfactant solution. Three characteristic time scales can be identified which affect the final particle size. First, the mixing time (τmix) was identified; the time needed to mix the polymer solution (polymer in good solvent) into the surfactant solution (poor solvent). Second, the coalescence time (τcls) was identified; the time needed for the collapsed polymer chains to coalesce into bigger droplets and subsequently to harden out into particles with long term storage stability. Last, the protection time (τpro) was identified; the time that the surfactant molecules need to completely cover the coalescing droplets and by this stop the coalescence of the collapsed polymer chains/droplets. The two latter characteristic times are intrinsic properties of the used solvents, surfactants and polymers and cannot be changed without addition of extra/new molecules. However, the mixing time is the only parameter which can be changed without modifying the material properties of the system. The mixing time can be easily varied by the method of mixing the good and the poor solvent.  Using a pipette to mix the two solutions will result in a 'slow' mixing time regime and utilizing for instance an impingent jet mixer can result in a 'fast' mixing regime. For both mixing regimes a clear analytical expression could be derived enabling more efficient experimentation in order to obtain a specific final particle size. For the 'slow' mixing regime the relation between final particle size ()was found only to be dependent of the used polymer concentration (cmp) as  ~cmpThe practical interpretation of this analytical expression is rather simple; an eight times higher polymer concentration will result in a two times bigger final particle size. For the 'fast' mixing regime the analytical expression can be interpreted also in an easy way; the faster the mixing the smaller the final particle size. Below a certain value for the mixing time the final particle size attains a plateau value; even faster mixing will not further decrease the final particle size. When using water-soluble surfactants the release of the cargo, which in practice often takes place after significant dilution, is expected to be fast. In order to increase the release of the encapsulated compound(s) in time we incorporated the surfactant functionality into a non-water soluble triblock copolymer. This results, even upon huge dilution, in an extended release profile in time.

We employed self-consistent field theory for non-water-soluble surfactants in order to relate the (block copolymer) surfactant chemistry to the size and composition of the resulting spherical equilibrium micelles. The surfactants, triblock copolymers synthesized via ring-opening polymerization, were employed in the nanoprecipitation process in order to make spherical micelles. The theoretical predictions were compared to the experimental results and it was concluded that self-consistent field theory is an accurate theoretical tool to predict the size of spherical micelles given a certain chemistry and composition of the copolymers and the conditions required to form these micelles.

We experimentally studied whether hydrophobic compounds (polymers, different active ingredients or a mixture of the two) were added in order to verify whether these spherical micelles could be loaded by these compounds. We investigated the encapsulation behavior of these micelles for hydrophobic compounds both theoretically and experimentally and considered the influence of the size for the micelles. From both the theoretical predictions and the experimentally obtained data it followed that these micelles can be used for encapsulation of hydrophobic compounds. Moreover, the theoretical predictions matched with the experimentally obtained data. It was concluded that self-consistent field predictions can be used to predict the size and stability of spherical micelles with encapsulated hydrophobic compounds.

Tuning size and loading is mandatory for passive targeting applications because the particle size mainly determines the biologic faith. In order to enable active targeting, utilizing a targeting moiety and (specific) receptor interaction is needed while maintaining the stealthy nature of the spherical particles. We performed a theoretical self-consistent field study on spherical block copolymer micelles to investigate whether it is feasible to hide the targeting moiety within the micellar corona while maintaining receptor interaction.  We determined the maximum interaction distance wherefrom targeting moiety receptor connection can be established and the required energy barrier at different distances. The outcome of these calculations was used to design a (theoretical) optimized system for active targeting.

We used self-consistent field theory to calculate the size, loading and targeting capability of triblock copolymer based micelles enabling both passive and active targeting and verified our calculation results experimentally. Although the active targeting predictions were not verified experimentally we established a design for passive and active targeting micellar applications for, for instance, drug delivery applications while maintaining the stealthy nature of these micelles.

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
  • Cohen Stuart, Martien, Promotor
  • Leermakers, Frans, Promotor
  • Tuinier, R., Promotor, External person
Award date1 May 2014
Place of PublicationWageningen
Print ISBNs9789461738677
Publication statusPublished - 2014


  • micelles
  • colloids
  • nanotechnology
  • particle size
  • particle size distribution

Fingerprint Dive into the research topics of 'Towards colloidal size control by precipitation'. Together they form a unique fingerprint.

Cite this