Ciencias Exactas y Ciencias de la Salud

The current scenario of the pharmaceutical industry, where final product quality has a fundamental priority, justifies the need for process intensification in order to shift from inefficient conventional batch production to continuous production methods. An alternative to reducing energy consumption in the purification step of pharmaceutical products is antisolvent continuous crystallization, a separation and purification technique that aims to produce particles of controlled size and purity by controlling the antisolvent addition rate, on which crystal birth and growth rates depend. This work experimentally studies the antisolvent continuous crystallization process of flufenamic acid, an active pharmaceutical ingredient (API), using the coiled flow inverter (CFI) as a novel crystallization device. Two strategies were studied as means to control crystal size distribution in the CFI technology: multistage antisolvent addition and a varied number of the reactor’s 90-degree bends. Experimental results show that mean crystal size of the studied API, increased with an increasing number of antisolvent addition points, thus suggesting a growth dominated process. On the other hand, mean crystal size decreased as the number of 90-degree bends increased, suggesting a nucleation dominated process. A narrower crystal size distribution (CSD) was also observed with an increased number of 90-degree bends. When compared to the CFI, mean crystal size and coefficient of variation were, in average, 1.8 and 3.5 times larger for the Kenics type crystallizer, respectively. This can be attributed to the high supersaturation induced by the effective mixing. Using the Population Balance Equation, as a mathematical model to describe the plug flow crystallization, crystal mass population density was calculated and compared with the obtained experimental data. High regression coefficients were obtained (0.96-0.99), which indicate that near plug flow behavior was achieved. Consequently, undesired crystallization process phenomena such as agglomeration, dissolution and breakage were successfully avoided, as they can lead to operational problems and a broad CSD. Process intensification (PI) was measured considering mean crystal size (µm) and coefficient of variation (CV) as product quality indicators. On the other hand, crystallization and pre-expansion temperatures, as well as extraction pressure, were considered as both energy savings and operational safety indicators. Six crystallizers of flufenamic acid were compared (batch, reactor without static mixers, Kenics type crystallizer, Kenics optimized, helical coil and RESS) to a CFI with three 90-degree bends. The CFI was the most intensified technology of all six, with IFtotal ranging from 2 (helical coil) to 392 (RESS). For this reason, it can be concluded that the main objective of this thesis, which was to intensify antisolvent crystallization processes, was achieved.

Ciencias Exactas y Ciencias de la Salud

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