(355e) Characterization of Flash Crystallization Process Using PAT

The objective of this project is to investigate flash crystallization. Flash crystallization is not well defined within available literature so the combination of in situ PAT such as FBRM, ATR-FTIR and PVM to characterize the process are key. Flash crystallization is a technique which utilizes a change in reactor pressure to drive crystallization. The overall aim is to produce a small narrow particle size distribution which is comparable to a typical micronization step. The adiabatic flash of solution causes a fast temperature change - a strong driving force for nucleation. The solution is also atomized by a nozzle upon entering the reactor which further promotes the formation of small particles by impeding growth. Adipic acid was chosen as the model system for this study. Flash crystallization was compared to various cooling crystallization strategies as well as different solvent systems. The use of FBRM ATR-FTIR and PVM were essential in the development of such comparisons. A flash crystallization process was developed incorporating a 2L jacketed vessel and vacuum pump with pressure control system. The pump maintains the system pressure as well as controlling the flow of solution to the reactor resulting in a dynamic system. The effect of temperature, pressure and flow rate as well as nozzle configuration and solvent selection on the final CLD are investigated. Solubility design space information was obtained which allowed for the development of cooling crystallizations. The use of extreme cooling profiles for the production of small particles with a narrow size distribution were examined, as well as more traditional cooling strategies. Various cooling rates and profiles were assessed for their impact on the systems' metastable zone width and particle dimension. Inline ATR-FTIR was used for assessing the dissolved concentration/supersaturation during the crystallization process. FBRM, PVM and SEM analysis show that the particles obtained via flash crystallization are much smaller in size, with a decrease in the FBRM mean square weight from 185 micron to 40 micron evident, when compared with the developed cooling crystallization. Additionally, the obtained CLDs are narrower in shape when compared with the developed cooling crystallization. Ethanol and water solvent systems were examined using traditional cooling strategies with the ethanol system resulting in a smaller CLD.