Formation of O/W Emulsions by Static Mixers and Production of Microparticles for Pharmaceutical Applications

Thursday, October 20, 2011: 3:40 PM
Conrad A (Hilton Minneapolis)
Nikolett Kiss1, Günter Brenn2, Hannes Pucher1, Juliana Wieser1, Stefan Scheler3, Herwig Jennewein3, Daniele Suzzi1 and Johannes G. Khinast4, (1)Research Center Pharmaceutical Engineering (RCPE), Graz, Austria, (2)Institute of Fluid Mechanics and Heat Transfer, Graz University of Technology (TUG), Graz, Austria, (3)Sandoz GmbH, Sandoz Development Center Austria, Kundl, Austria, (4)Institute for Process and Particle Engineering, Graz University of Technology, Graz, Austria

Formation of O/W emulsions by static mixers and production of microparticles for pharmaceutical

N. Kiss,a,b G. Brenn,a H. Pucher,b J. Wieser,b S. Scheler,c H. Jennewein,c D. Suzzi,b J. Khinastb,d

a Institute of Fluid Mechanics and Heat Transfer, Graz University of Technology (TUG), Inffeldgasse 25/F, 8010 Graz, Austria

b Research Center Pharmaceutical Engineering, Inffeldgasse 21a, 8010 Graz, Austria

c Sandoz GmbH, Sandoz Development Center Austria, Biochemiestrasse 10, 6250 Kundl, Austria

d Institute for Process and Particle Engineering, TUG, Inffeldgasse 21a, 8010 Graz, Austria

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The emulsion extraction method is widely used in the pharmaceutical industry for producing controlled release polymer-based microparticles [1]. The encapsulation of the active pharmaceutical ingredient (API) in a Poly(lactic-co-glycolic acid) (PLGA) polymer carrier matrix determines several important pharmaceutical properties, including release profile and stability of the API [2]. One objective of the present work is to study the oil-in-water emulsification process, which is the first process step for the production of microparticles for pharmaceutical applications by the emulsion extraction method. Another objective of this study is to characterize the resulting solid microspheres.

The emulsification (e.g., droplet formation) step determines the size and size distribution of the resulting microspheres [3]. Emulsions were produced using SMX static mixers from Sulzer ChemTech with two different diameters (6 mm and 10 mm). In this work [4] we focused on multiphase blending in the laminar regime, reflected by the low Reynolds numbers in our experiments. The materials used for preparing the emulsions of the present study were selected based on their potential application as precursors for pharmaceutical particle formation.

An organic phase containing the dissolved PLGA and the API, and an aqueous surfactant solution were mixed by SMX static mixers. The organic phase drop size spectra in the emulsions were measured by laser diffraction, using the instrument Sympatec HELOS, H2395. The instrument provides the volume-based size spectrum and the Sauter mean diameter of the oil droplets. The influencing parameters flow velocity, diameter and number of the mixer elements, PLGA polymer concentration in the dispersed phase, oil phase hold-up, and surfactant concentration were considered as important for the emulsion formation. They are, therefore, also relevant for a scale-up of the process. In the experiments they were varied in the ranges of industrial interest. The mean oil droplet size in the emulsions was found to decrease with increasing flow velocity, with increasing number of mixer elements, with increasing concentration of surfactant and with decreased mixer element diameter. For the moderately concentrated systems presented in this work, the dispersed phase hold-up was found to not impact the emulsification process. The mean oil drop size was influenced by the PLGA polymer concentration in the dispersed phase to a moderate extent. For developing an empirical correlation of the oil droplet size on the basis of measurements, dimensional analysis was applied. This analytical method groups process parameters into a smaller number of non-dimensional groups. A non-dimensional correlation for the dispersed-phase drop size in the emulsion, in the form of a droplet Ohnesorge number, as a function of the capillary number and the viscosity ratio of the two liquids is deduced from the experimental results. The correlation allows the prediction of the Sauter mean oil droplet size as a function of the static mixer operation parameters and of the liquid properties with very high accuracy [4], which is an essential piece of information about the emulsion properties relevant for the industrial application.

The proposed correlation allows us to extract the scaling laws governing the oil drop formation in laminar emulsification by the SMX static mixers used.

Microsphere preparation by solvent extraction basically consists of four major steps: (i) dissolution or dispersion of the bioactive compound, often in an organic solvent containing the matrix forming material; (ii) emulsification of this organic phase in a second continuous (frequently aqueous) phase immiscible with the first one; (iii) extraction of the solvent from the dispersed phase by the continuous phase transforming the droplets into solid microspheres; (iv) harvesting and drying of the microspheres [3]. The second objective of the present work was to study the effect of the extraction of the solvent from the dispersed phase on the microparticle properties. The particles are formed by solvent extraction from the organic droplets in a stirred vessel. For the particle formation step, two process parameters were considered important: the emulsion droplet size produced by the SMX static mixer and the stirring rate of the anchor impeller in the 5 L tank reactor during the solvent extraction. In model experiments these two process parameters were varied to optimize microparticle properties.

Figure 1. SEM secondary electron image of a microparticle cross section (micrograph by FELMI Graz)

The size of the final solid microspheres was measured by laser diffraction. The morphology and composition (e.g., API distribution in the microparticles) were analyzed by electron microscopy (see Figure 1). Determining the porosity, skeletal volume and density of the microparticles by gas pycnometry should quantify the properties of the pore structure of the microspheres and help to understand the role of all the process parameters in the formation of the particles.


1.            Mansour, H. M., Sohn, M., Al-Ghananeem, A., DeLuca, P. P., 2010. Materials for Pharmaceutical Dosage Forms: Molecular Pharmaceutics and Controlled Release Drug Delivery Aspects. International Journal of Molecular Sciences 11, 3298-3322.

2.            Mora-Huertas, C.E., Fessi, H., Elaissari, A., 2010. Polymer-based nanocapsules for drug delivery. International Journal of Pharmaceutics 385, 113–142.

3.            Freitas, S., Merkle, H., Gander, B., 2005. Microencapsulation by solvent extraction/evaporation: reviewing the state of the art of microsphere preparation process technology. Journal of controlled Release 102, 313-332.

4.            Kiss, N., Brenn, G., Pucher, H., Wieser, J., Scheler, S., Jennewein, H., Suzzi, D., Khinast, J., 2011. Formation of O/W emulsions by static mixers for pharmaceutical applications. Submitted to Chemical Engineering Science

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