(748b) Formation of O/W Emulsions by Static Mixers and Production of Microparticles for Pharmaceutical Applications

Authors: 
Kiss, N., Research Center Pharmaceutical Engineering (RCPE)
Brenn, G., Graz University of Technology (TUG)
Pucher, H., Research Center Pharmaceutical Engineering (RCPE)
Wieser, J., Research Center Pharmaceutical Engineering (RCPE)
Scheler, S., Sandoz GmbH, Sandoz Development Center Austria
Jennewein, H., Sandoz GmbH, Sandoz Development Center Austria
Suzzi, D., Research Center Pharmaceutical Engineering (RCPE)
Khinast, J. G., Research Center Pharmaceutical Engineering GmbH


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

applications

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

Email for correspondence: nikolett.kiss@tugraz.at

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.

References

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