Structuring microspheres

Encapsulation and use of capsules for controlled release has several applications in pharmaceuticals, foods, cosmetics, detergents and many other products for consumers. It can contribute to sustainability, since it allows an efficient use of active materials, delivery at the required site and possibly a longer shelf life of the products. Many encapsulation systems are basically very thin shells (10 nm – 10 µm) around microscopic reservoirs (100 nm – 100 µm), in which active ingredients are trapped. The release properties are strongly dependent on the material properties of the shell, but also on their size and uniformity. The overall objective of this research is to understand the formation process of microcapsules and microspheres by using phase separation in well-defined droplets of a polymeric solution. The primary droplets were produced with microsieve emulsification. The polymer used was Eudragit FS 30D (a commercial copolymer of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1), which contains charged carboxylate groups that make the polymer water-soluble at higher pH (>7), allowing for release by a change in pH. Chapter 2 presents results that give more insight into microsieve emulsification with high porosity micro-engineered membranes. The droplet formation was strongly influenced by the dynamics of surfactant adsorption. The presence of suitable surfactants in both phases prevents the coalescence of droplets and wetting of the microsieve membranes by the dispersed phase during oil droplet formation. This resulted in the formation of stable emulsions of droplets with a narrow size distribution. The flux of the dispersed phase could be increased an order of magnitude compared to previous methods, without loss of size-distribution of the droplets. Thus, use of a high-porosity membrane, in combination with suitable surfactants in both the dispersed and continuous phases resulted in a much more effective and efficient emulsification process. In Chapter 3 crossflow microsieve emulsification was used to prepare porous microcapsules with an average size of about 30 µm. A mixture of Eudragit and hexadecane in dichloromethane (DCM) was emulsified in water.Being a poor solvent for this polymer, demixing of the droplet into a polymeric shell and a hexadecane-rich core occurred upon extraction of the DCM into the water phase. At a low ratio of polymer to hexadecane, the resulting shells were found to be porous. Increasing this ratio resulted in a reduction of the porosity and pore size of the shell. The Eudragit has a pH-dependent solubility. It is insoluble at acidic conditions and rapidly dissolves at alkaline conditions. The capsules were found to be stable at a pH lower than 7.0, whereas the oil core was released within half an hour at pH 7.1 and within a minute at pH 8.0. The morphology of the microcapsules can be adapted with a careful choice of the concentrations of polymer, hexadecane and solvent. At higher concentrations of polymer, the tiny oil droplets that were captured in the forming Eudragit shell were unable to coalesce completely and small, isolated pores were formed within the shell matrix. The potential for new microcapsule morphologies was further explored in Chapter 4 where the formation of Eudragit capsules with other oils instead of hexadecane was studied, and in Chapter 5 where a blend of poly(methyl methacrylate) (PMMA) and Eudragit was used. In Chapter 4 the effects of chain lengths of vegetable oils on the formation of porous microcapsules with hollow and multi-compartment structures is discussed. The encapsulation of oil and the morphology of the resulting microcapsules depends on the interaction between the Eudragit polymer and the type of oil that was used. Microcapsule formation using long chain length oils such as sunflower oil, olive oil and coconut oil resulted in well-defined microcapsules with a single encapsulated oil droplet, covered with a Eudragit-rich shell. On the other hand, capsules prepared with relatively short chain length oils, such as medium chain triglyceride oil, resulted in capsules with many individual small oil droplets encapsulated in an Eudragit matrix. Extraction of the oil from the microcapsules with hexane results in the formation of hollow porous shells as was investigated with optical microscopy and SEM. These structures are formed during microcapsule formation due to the complex phase separation processes in the Eudragit-water-oil-DCM quaternary system. In Chapter 5 the formation of microcapsules is further explored by using a blend of PMMA and Eudragit. Microspheres formed with this blend were found to consist of a PMMA core inside an Eudragit-rich shell, which tends to be porous. As the amount of Eudragit is increased, a thicker and more porous outer shell is formed due to the enhanced interaction of water with Eudragit. After dissolution of the Eudragit at high pH, different core surface structures resulted, from irregular surfaces to microspheres with a fiber-like, swollen corona around it, and to a surface covered with small nodular structures, dependent on the concentrations of PMMA and Eudragit in the initial mixture. As already indicated above, these structures are formed as a result of complex phase separation processes between polymers and (non)solvents, and between the two polymers. In Chapter 6 the results described in this thesis were compared with existing literature, yielding an outlook on the field of microencapsulation through phase separation. A general concept is discussed on how to obtain various interesting complex structures with phase separation combined with microsieve emulsification. Finally, a conceptual process design is discussed for industrial scale production of microcapsules and microspheres with use of microsieve emulsification. This thesis has yielded insight in the formation of a range of microcapsule morphologies by investigating a range of new production methods (microsieves and demixing conditions) and formulations (different concentrations, oils and using one polymer or a blend), and through this provides better insight into the mechanisms of microcapsule formation. While some of the structures may be directly used for microcapsule formation, some other structures may well have potential for other applications.                                                                                       Figure. Examples of structured microcapsules and microspheres developed in this thesis.&nbsp