(322c) Continuous Mixing/Washing of an API Suspension in a Precipitating Environment

Continuous manufacturing has already been widely implemented in secondary pharmaceutical production in recent years. Efforts in primary manufacturing have also been made, but the linkage of the synthesis process with drug product manufacturing is still mostly completed in a batch process. Washing, filtration and drying are crucial process steps linking these production routes. Special consideration must be given to the washing and drying of crystals, which have been carefully engineered during crystallization of the active pharmaceutical ingredient (API). Particle size and morphology can easily be altered during a washing or drying step. Hence, it is very important to avoid any undesired side reactions during these processes. Continuous washing is challenging and only a few processes have been developed. In the continuous processing of API suspensions, both equipment fouling and the quality of the finished product are a challenge.

This work focuses on the application of ultrasound (US) to improve the performance of a continuous washing process in a precipitating environment. Washing in this continuous regime is carried out by dilution/mixing of the suspension with an anti-solvent, created by a filtration step to once again concentrate the suspension. These steps are repeated until the desired purity is reached. Optimized process parameters include process performance in terms of process time until blockage, avoiding changes in particle size distribution, as well as total amount of dry product produced in a single run.Ibuprofen 25 and GranuLac^® 230 were used as representative model substances in different mass fractions. The corresponding anti-solvent was used as washing agent. The process of mixing the liquid feeds was carried out in an US-chamber (Hielscher Ultrasonics GmbH, Teltow, Germany) under constant US input, at various US-levels.

This work shows that disturbance free process times and efficiency can be increased by using a process chamber with ultrasound. Furthermore, it was possible to avoid blockage or fouling of the process, enabling blockage free test runs of up to 24 hours. Particle size of the product was not changed and no agglomerates were formed. This facilitates a large step forward in the effort to link primary and secondary manufacturing lines.