Towards Colloidal Size Control by Precipitation

Towards colloidal size control by precipitation Jer´ omeˆ George Joseph Louis Lebouille Thesis committee Promoters Prof. Dr M.A. Cohen Stuart Professor of Physical Chemistry and Colloid Science Wageningen University Prof. Dr F.A.M. Leermakers Personal chair at the Laboratory for Physical Chemistry and Colloid Science Wageningen University Prof. Dr R. Tuinier Professor by Special Appointment of Colloid-Polymer Mixtures at the Department of Chemistry Utrecht University Principal Scientist Colloids and Interfaces DSM ChemTech R&D Geleen Other members Prof. Dr G. ten Brinke, University of Groningen Dr G.M.H. Meesters, Delft University of Technology Dr C.F. van Nostrum, Utrecht University Prof. Dr J.T. Zuilhof, Wageningen University This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Towards colloidal size control by precipitation Jer´ omeˆ George Joseph Louis Lebouille Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Thursday 1 May 2014 at 11 a.m. in the Aula. Jérôme G.J.L. Lebouille Towards colloidal size control by precipitation, 160 pages. PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-867-7 Voor Ilse, Lyzl en Lien ”In the warriors code, there’s no surrender, though his body says stop, his spirit cries, never, deep in our soul a quiet ember, know it’s you against you, it’s the paradox that drives us on, it’s a battle of wills, in the heat of attack it’s the passion that kills.”1 - Burning heart. 1Jim Peterik and Frankie Sullivan; Survivor (1985). Table of Contents 1 Introduction 3 1.1 Towards colloidal size control ......................... 3 1.2 Self-assembly .................................. 4 1.3 Surfactants; stabilizers of colloidal particles .................. 5 1.4 Critical micelle concentration (CMC) ..................... 8 1.5 Block copolymers ................................ 8 1.6 Nanoprecipitation ................................ 10 1.7 Aim of this thesis ................................ 12 1.8 Outline of this thesis .............................. 13 2 Nanoprecipitation of polymers in a poor solvent 19 2.1 Introduction ................................... 21 2.2 Theoretical framework ............................. 22 2.2.1 Diffusion limited coalescence in a polymer suspension ........ 23 2.2.2 Coalescence in the presence of surfactant ............... 25 2.2.3 Implications of the model for experiments ............... 30 2.3 Materials and methods ............................. 32 2.3.1 Materials ................................ 32 2.3.2 Particle size analysis .......................... 32 2.3.3 Rheology of PVA solutions ....................... 33 2.3.4 Nanoprecipitation / nanoparticle preparation method ......... 33 2.4 Results and discussion ............................. 34 2.4.1 Cryo-TEMimages of NPs ....................... 34 2.4.2 Influence of polymer concentration on size .............. 35 2.4.3 NP size dependence on polymer molar mass .............. 36 2.4.4 Influence of mixing time on particle size ................ 36 2.4.5 Surfactant molar mass influence .................... 39 2.5 Conclusions ................................... 41 3 SF-SCF predictions for spherical biocompatible triblock copolymer micelles 45 3.1 Introduction ................................... 47 3.2 SF-SCF Theory ................................. 48 3.2.1 Thermodynamic considerations .................... 48 3.2.2 SF-SCF machinery ........................... 49 viii Table of Contents 3.2.3 TheKuhn lengths ............................ 54 3.2.4 The Flory-Huggins parameters ..................... 55 3.3 Results ...................................... 56 3.3.1 Radial density profiles and micelle size ................ 59 3.4 Conclusions ................................... 64 4 Controlled block copolymer micelle formation 69 4.1 Introduction ................................... 71 4.2 Experimental aspects .............................. 73 4.2.1 Copolymers and amphiphiles ...................... 73 4.2.2 Stability; dynamic, static or dead/frozen micelles ........... 73 4.2.3 Self-consistent field theory and molecular model ........... 74 4.3 Materials and methods ............................. 77 4.3.1 Materials ................................ 77 4.3.2 Methods ................................ 77 4.4 Results ...................................... 83 4.4.1 DLS results on reproducibilityon empty and active ingredient loaded micelles ................................. 83 4.4.2 DLS results of single excipient, homopolymer, loaded micelles .... 84 4.4.3 Size stability of single component, homopolymerand active ingredient (rapamycin and β-carotene) loaded micelle formulations in time . 86 4.5 Conclusions ................................... 88 5 Design of block copolymer based micelles for active and passive targeting 95 5.1 Introduction ................................... 97 5.2 Theory ...................................... 99 5.2.1 SF-SCF theory ............................. 99 5.2.2 Landau free energy and a short case study ...............106 5.2.3 SF-SCF parameters ...........................110 5.3 Results and discussion .............................111 5.3.1 The default phase diagram .......................111 5.3.2 Optimization and discussion ......................116 5.4 Conclusions ...................................119 6 General discussion 125 Summary 135 Samenvatting 139 Educational activities 145 Acknowledgements 149 Introduction 11 1.1 Towards colloidal size control Colloids are systems that contain particles in the size range between, say, a nanometer and a micrometer which are dispersed in another substance. Colloidal particles can have differ- ent geometries including rods, discs, spheres and cubes. In this thesis we focus on spherical colloidal particles. Colloids can be divided in two groups; lyophilic (made of soluble components) and lyophobic (made of insoluble components) ones. Lyophilic colloids with water as the continuousmedium are also referred to as hydrophilic (water loving) and lyophobic colloids as hydrophobic (water fearing). Hydrophilic colloids form spontaneously upon dispersing them into water and thus are reversible and dynamic. Well-known examples of hydrophilic colloids are particles composed of water soluble surfactants, such as micelles or vesicles. To predict their size and composition thermodynamic equilibrium theories can be employed. In contrast, hydrophobic colloids are composed of non-water soluble components. These compounds aggregate or coalesce into colloidal structures. Hydrophobic colloids are only maintained in the colloidal size range if a stabilizer stops further aggregation or coalescence. These colloids are irreversible or metastable (implying that the currentphysical state is not the most stable state). Particles composed of hydrophobic components and stabilized by surfactants are here referred to as nanoparticles to make a clear distinction with reversible colloids, such as micelles. Often kinetic models are employed to predict the size and composition of hydrophobic colloids. In this thesis also the term dead or frozen micelles is used. Dead micelles are a special case of hydrophobic colloids. Upon the formation their nature switches from lyophilic to lyophobic. Initially the molecules are dissolved, however, upon changing the nature of the solvent the molecules become gradually less soluble. During this solvent switch the molecules have short time frames to assemble into micellar structures. At some point the molecules become insoluble resulting in non-dynamic or static micelles; these are referred to as dead or frozen micelles. Since there is a (short) time that these micelles are dynamic, thermodynamic equilibrium theories might be employed to predict their size and composition. Precipitation or spontaneous self-assembly is a powerful method to prepare colloids. The key example is the formation of surfactant micelles, that are assemblies the order of 102 am- 4 Introduction phiphiles that form spontaneously above a threshold concentration. The size control of these objects can directly be related to the structure of its constituents. Surfactants are molecules with two parts. One part is immiscible with water (hydrophobic)and forms the core and one block that is miscible with water (hydrophilic) and forms the corona of these micelles. These objects may have potential applications, for example as drug carriers, especially when the drug molecules are apolar and accumulate in the cores. However, the classical surfactants are extremely dynamic and typically too fragile for most drug delivery applications. This thesis deals with the use of copolymers, macromolecular analogues of surfactants, to make micellar-like nanoparticles with drug delivery as the key application. These colloids can be considered as being intermediate between lyophilic and lyophobic. The important selling point for using copolymer micelles is that these are much less dynamic in the sense that they do not immediately fall apart upon dilution. The same property presents a multitude of ’en- gineering’ challenges: the properties of the particles (size, shape and composition) depend in a sensitive way on the preparation protocol.

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