Scale-up methodology for pharmaceutical spray drying

Spray drying is presently one of the most interesting technologies in the pharmaceutical industry. The process shows a remarkable capability in manipulating powder/particle attributes such as size, morphology, density and level of residual solvents. This flexibility led to its application in a variety of powder formulations and advanced solid forms: from very fine powders for inhalation to large particles for direct compression, and from solid dispersions for enhanced bioavailability to microcapsules for drug protection or controlled release. Moreover, the technique is also applied to process difficult-to-crystallize materials and temperature sensitive compounds (the relative short exposure to temperature makes it a gentle process, suitable for handling most sensitive materials). Spray drying is a unit operation in which a liquid stream (solution, suspension or emulsion) is continuously divided into very fine droplets (a process known as atomization) into a chamber where they are contacted with a hot gas and dried into particles, which are separated from the drying gas using a cyclone or a bag-filter. Hence the spray drying process can be described as consisting of four events: i) atomization of the liquid into droplets , ii) contact of the droplets with the hot drying gas, iii) drying of the droplets into particles and iv) separation of the particles from the drying gas. Spray driers can operate in open cycle mode (where the drying gas is passed through the chamber and vented to the appropriate waste stream) or in closed-loop mode (where the drying gas is recycled typically via a condenser or a scrubber unit). A key feature in any spray drying process is the atomization system since it controls droplet size and hence particle size. Rotary, pressure, two-fluid and ultrasonic nozzles are the most common systems. For each type of atomizer, a wide range of designs were developed to handle the diversity of feed materials and to meet specific dried-product characteristics. In the pharmaceutical industry pressure and two-fluid nozzles are the most common, due to their simplicity (and easy cleaning), flexibility and ability to handle most feedstocks (1). Spray dryers in the pharmaceutical industry are available in a wide range of scales: from lab units where milligrams of material can be produced to very large commercial units capable of handling several tons per day. One particular concern during development of pharmaceutical spray dried materials is the effect of scale-up on critical quality attributes. Moreover, a less careful scale-up strategy may lead to considerable losses of very expensive materials and jeopardize the timelines of a clinical program. Mathematical modelling is a very powerful tool to support the scale-up of spray drying processes. Process simulation has been used in chemical and oil industries since the early of 1960s and more recently pharmaceutical development scientists have also begun to make use of it during development, scale-up and manufacturing (2). The use of process simulation should result in more robust processes, faster development at a lower cost and in higher quality products (3). This enhanced understanding is also in line with the Quality by Design initiative and the Desired State of the industry. This paper describes a scale-up methodology for spray drying processes based on scientific first principles simulation models and process characterization techniques. Such methodology aims to ensure that scale-up is as straightforward and predictable as possible.