In-Process Cleaning of a Micro Heat Exchanger With Ultrasound During the Continuous Crystallization of Solid Lipid Nanoparticles

Process intensification by the application of microscale process engineering in reaction and heat transfer processes provides the opportunity of moving from batch to continuous manufacturing, mainly due to enhanced heat and mass transfer. These effects are primarily caused by the very high surface to volume ratio in microstructured devices. Further advantages, particularly suitable for sensitive products, are the low shear stress in the typically occurring laminar regime and the short residence time. The crystallization of drug carrying lipid nanoparticles (LNP) is a typical batch process for pharmaceutical products and is used here to demonstrate benefits, challenges and application possibilities of the conversion into a continuous microscale process. During the continuous crystallization of various LNP formulations in a micro-crystallizer, designed as a micro heat exchanger with square channels, several formulations led to fouling and blocking of small passages in the micro heat exchanger. To investigate the fouling behavior of different LNP formulations in detail, integral pressure drop measurements over the micro heat exchanger were performed. This contribution addresses the in-process cleaning of a micro heat exchanger for the continuous crystallization using ultrasound. Different ultrasound amplitudes and operation procedures were investigated. During processing the overall pressure drop was decreased significantly by induced ultrasound pulses. The investigations showed that in-process cleaning of a micro heat exchanger with ultrasound is possible for screening as well as for long term production of LNP. Also the product quality, given by the particle size and particle size distribution, is not affected by the ultrasound input.