(510c) A Hydrodynamic Method for the Continuous Production of Nanoparticles

Recent advances in the ability to structure material on the nano-meter size scale offer the pharmaceutical industry a new tool set: (i) high potency drugs can be made into small controlled release spheres which can survive in the body for a long period and slowly release there payload keeping a steady safe concentration in the body (ii) low solubility (lipophilic) compounds can be made into nano-sized spheres which will have a very high surface area to volume ratio for improved solubility (iii) nano-sized drug carriers can be surface modified with specific proteins to target specific areas of uptake and greatly reduce the occurrence of side effects. While creating these functionalities is already a difficult task at the laboratory scale, scaling-up these techniques to the manufacturing scale poses a whole new set of challenges.

In this talk we focus on a method for creating nano sized particles at a rate suitable for full-sclae manufacturing. The basic mechanism of the Hydrodynamic Formation pathway is the creation of a nano-emulsion of which the droplets can be hardened to form nano-particles. The droplets of the emulsion are either the therapeutic agent themselves or the therapeutic agent and an encapsulation material. Initially the emulsion is rough and the droplets are on the micron size scale. The emulsion is passed through a SMX static mixer at a high rate. The shear inside the mixer causes the micron-sized drops to be reduced down into the 50-500 nano-meter range. After the size reduction the droplets are hardened by a phase shift brought about by a rapid change in temperature or solubility conditions, or by extracting a solvent.

For this set of experiments a molten (80 C) emulsion of Compritol 888 ATO and Water was used. The emulsion was stabilized with the Tween 80 Surfactant and no model drug was incorporated. The pre-emulsion was made in a jacketed beaker with a traditional impeller. The emulsion was feed to a high pressure chamber maintained at the 80C temperature. Springs were used to compress up to 1000 PSI of pressure on the fluid inside the high pressure chamber. The fluid was then released through the small SMX and into a water quench tank held at 32 C. Photon Correlation Spectroscopy (PCS) was used to analyze the size of the suspension for runs with variable numbers of static mixers and surfactants. In all cases it was found large numbers of nanoparticles ranging from 40-1000nm. While large in comparison with much of the work going on in Nanotechnology, these particles are ideally suited for many drug delivery applications. The current process is a batch operation, capable of generating nanoparticles at a rate of 60 g/s. However, the critical step in the drop formation process (application of shear in a static mixer) is essentially a continuous flow process, suggesting that this method could be easily run continuously. If current flow rates are maintained, this bench-top process has the ability to generate amount of material large enough for most pharmaceutical applications.