Applying Quality by Design to spray drying

The role of empirical and mechanistic modeling

The purpose of this work was to build different models to predict the particle size of spray dried powders and assess their usefulness in the design space establishment. Powders were obtained by spray drying solutions of a known pharmaceutical excipient (hypromellose phthalate). The powders were characterized by image analysis (for particle size and circularity), loss on drying (for residual solvent content) and helium pycnometry (for particles density). A full factorial experimental design was performed and PLS regression was used to establish a statistical model. In addition, mechanistic modeling of droplet formation based on hydrodynamic instabilities was also used to estimate the size of particles. Spherical particles, with average particle size between 3 and 9 ?m, were obtained by spray drying solutions in a lab scale unit. Particle density and residual solvent content did not vary significantly between experiments. Statistical and mechanistic approaches were compared. Both statistical and mechanistic models were able to describe the results observed, although the mechanistic model was the most accurate. The mechanistic description of droplet formation was of great assistance to understand and describe the spray drying process.

Introduction

Spray drying is a well-established and widely applied technology to manufacture a wide range of powders. It is an ideal process when the end-product quality comprises attributes such as well-defined particle size distribution, residual solvent content, bulk density and morphology (1). Spray drying involves the atomization of a liquid stream (i.e. dispersion of the liquid into very small droplets) into a chamber where the droplets are contacted with a hot gas stream leading to flash drying and particle formation (2). Efforts to understand the physical principles of spray drying were intensified in the last decade with the aim of improving powders attributes and speed up product and process development. Due to the remarkable flexibility of the technology the use of spray drying is increasing in the pharmaceutical industry. It is being used to produce, among others, amorphous materials with enhanced bioavailability, microencapsulated drugs and powders for inhalation (3). In most of the spray drying applications the particle size is considered a critical quality attribute, e.g. for inhaled or oral drugs where it affects drug aerodynamic or compr ...

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