A PAT Strategy for Microparticle Production Processes

Abstract
Microparticles are widely used in the pharmaceutical industry as delivery forms for proteins, peptides or other drugs. Polymeric microparticles have been extensively studied as drug carriers in the pharmaceutical field and microparticles show promise as carriers for active pharmaceutical ingredients (APIs). The idea behind a controlled drug delivery system is to incorporate the drug within a polymeric carrier that controls the drug delivery and the release rate of the drug in the therapeutic window.

Among the different classes of biodegradable polymers, the poly(lactide-co-glycolide) (PLGA) is most commonly used as drug carrier due to its excellent biocompatibility, biodegradability, as well as mechanical strength. Solvent evaporation method is the most popular technique of preparing microparticles. Microsphere preparation by solvent extraction/evaporation basically consists of four major steps:

1. dissolution or dispersion of the bioactive compound (API) in an organic solvent containing the matrix forming material (PLGA polymer);
2. emulsification of this organic phase in a second continuous (frequently aqueous) phase; the emulsification step is the most important step of the process because it determines the size (distribution) of the microspheres. The size of the microspheres has a significant effect on the rate of drug release and on the encapsulation efficiency;
3. extraction of the dispersed phase by solvent removal and transforming the droplets into solid microspheres;
4. harvesting and drying of the microspheres.

The aim of the project is to analyze these steps in detail in order to provide a better understanding of microparticle production processes. Furthermore, the establishment of a predictive model for emulsion and particle formation is an objective of the work.

The final goal of A PAT Strategy for Microparticle Production Processes is the development of product and process design spaces according to the Quality by Design (QbD) principles. This is achieved both theoretically by using simulation models and experimentally with laboratory measurements.

Project Goals

• Process Analytical Technology (PAT) and Quality by Design (QbD): the development of a quantitative relationship between the process parametes (design variables) and the product properties (particle size distribution, morphology, residual moisture content of the particles, etc.)
• Definition of the Critical Quality Attributes (CQAs)
• Definition of the Design Spaces
• Development of a robust and scalable production process producing microparticles with a tight particle size distribution and homogenous API
• Research on simulation models and experimental verification to predict the particle size and particle size distribution
• Research on the extraction process step in order to optimize the particle properties (size, porosity, etc.)
• Reserch on the effects of the microparticle harvesting on the product size and morphology

Present Project Results
The first work package of the project analyses the emulsification step using a static mixer. The objective of our study was to characterize oil-in-water emulsions produced with SMX static mixers in the laminar flow regime. In order to characterize and quantify this complex engineering problem, dimensional analysis was applied. This analytical method involves the conversion of process parameters into a smaller number of dimensionless groups. We used this method for the prediction of scale-up processes and to develop a relationship between the dimensionless groups and the resulting microparticle diameter, as well as to minimize the experimental effort for future process optimization steps. Material properties (density, viscosity, interfacial tension, etc.) have been measured and an experimental design has been constructed. Emulsion production experiments using SMX static mixers with two different diameters were carried out with the mixing of the two liquids taking place in the laminar flow regime. In our first paper [1] we provide results covering a wide range of all process parameters, which were identified influencing the droplet size of the emulsion. The correlation achieved is related to the non-dimensional drop-size based Ohnesorge number of the emulsification process and allows for the prediction of the mean oil droplet size with good accuracy, which is an essential information about the emulsion properties relevant for the pharmaceutical application.

The studied emulsification process is the first step in the production of polymeric microparticles by the emulsion extraction method, which is a common technique for the preparation of controlled-release biodegradable microparticles for pharmaceutical applications.

In the second part of our work particle formation experiments were carried out in an agitated vessel at different agitation speeds, emulsion injection points and with different droplet size spectra of the initial emulsion as particle precursor. The local flow conditions in these experiments, i.e. local shear rates, dissipation rates and the particle-liquid mass transfer rate were examined by computer simulation.

Scanning electron microscopy (SEM) analysis showed that the API distribution in the cross section of the particles strongly depends on the extraction rate and local flow situation in the stirred vessel, where the emulsion was injected.

The particle size spectra, porosity, residual solvent and API content were also affected by the controlling flow regime. Our results demonstrate how the stirrer speed, the emulsion injection point and the droplet size of the initial emulsion affect particle properties.

Project Challenges
The release behaviour of polymer-based biodegradable microparticles is strongly affected by the final particle properties, which are decided during the production process. Therefore, it is important to understand the influence of the manufacturing process parameters on the microparticle properties in order to control the process accordingly. The parameters porosity, particle size and API distribution in relation to the release behaviour of controlled release microspheres are well discussed. Although, the influence of the process parameters of the emulsion extraction technique on the mentioned particle properties is rarely investigated. Scale-up difficulties are also frequent, since the final particle properties are strongly dependent on the formation parameters, which are related to the batch size.

Computer simulation tools also allow us to control the particle formation process accordingly in different batch sizes and provide a basis for the scale-up and optimization of the process. In this work we will add computer simulation results to the particle formation lab-experiments. CFD (Computational Fluid Dynamics) models should enhance the understanding of the flow situation in the extraction vessel, in which the polymeric microparticles are produced.

Project related Publications
[1] 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. Chemical Engineering Science 66 , 5084 - 5094

[2] Kiss, N.; Brenn, G.; Scheler, S.; Jennewein, H.; Suzzi, D.; Khinast, J., 2011. 
Formation of O/W Emulsions and Production of Microparticles for Pharmaceutical Applications. Poster presentation at the 8th European Congress of Chemical Engineering, Berlin

[3] Kiss, N.; Brenn, G.; Scheler, S.; Jennewein, H.; Suzzi, D.; Khinast, J., 2011. 
Formation of O/W Emulsions and Production of Microparticles for Pharmaceutical Applications. Presentation at the 5th International Congress on Pharmaceutical Engineering (ICPE) 2011, Graz

[4] Kiss, N.; Brenn, G.; Scheler, S.; Jennewein, H.; Suzzi, D.; Khinast, J., 2011. 
Formation of O/W Emulsions and Production of Microparticles for Pharmaceutical Applications. Presentation at the AIChE Annual Meeting 2011, Minneapolis, MN