We measured nucleation and growth rates of poly(L-lactic acid) (PLLA) microparticles produced during precipitation with a compressed-fluid antisolvent (PCA). The injector/precipitator used in this study satisfied the constraints and assumptions incorporated in the development of the mixed-suspension, mixed-product-removal population balance theory. A semicontinuous operation mode with batch product filtering was developed, and results from product particle size distributions allowed nucleation and growth rates to be determined through the use of population balances. Kinetic data, obtained by operating the precipitator under various degrees of supersaturation and suspension density, were used to generate a nucleation rate model for PLLA. Model results indicate a relative kinetic order of 1 and a linear dependence of the nucleation rate on the suspension density. First-order dependence of the nucleation rate on suspension density suggests secondary nucleation mechanism(s) are operative within this PCA flow system and may explain the relative insensitivity of particle size distributions to changes in PCA operating conditions.

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Drug substance purification by crystallization is a key interface in going from drug substance synthesis to final formulation and can often be a bottleneck in process efficiency. There has been increased importance in the development of continuous crystallization systems of active pharmaceutical ingredients to produce crystals with targeted physical and biopharmaceutical properties. Continuous spherical crystallization (CSC) is a process intensification technique that can address many of the present flaws (e.g., size distribution, downstream processing efficiency) of traditional crystallization systems. In this study, a novel concept and method in the field of process intensification through continuous spherical crystallization is proposed. This study is based on performing crystallization/spherical agglomeration in an oscillatory flow baffled crystallizer (OFBC). OFBCs are comparable to plug flow crystallizers (PFCs) in that they are both tubular crystallizers; however, the OFBC has periodically spaced orifice baffles with oscillatory motion overlapped on the net flow. Independent crystallization mechanisms can theoretically be achieved through spatially distributed solution, solvent, antisolvent, and bridging liquid addition, offering more control of each mechanism. However, our studies showed that the OFBC allowed for spatially distributed addition of solvents but achieving control of each mechanism individually was not attainable due to the back mixing of the system.