Design of a Combined Modular and 3D-Printed Falling Film Solution Layer Crystallizer for Intermediate Purification in Continuous Production of Pharmaceuticals

Abstract

A highly scalable combined modular and 3D-printed falling film crystallization device is developed and demonstrated herein; the device uses a small, complex, printed overflow-based film distribution part that ensures formation of a well-distributed heated liquid film around a modular, tubular residence time/crystallizer section, enabling extended residence times to be achieved. A model API (ibuprofen) and impurity (ibuprofen ethyl ester) were used as a test system in the evaluation of the novel crystallizer design. The proposed crystallizer was run using three operational configurations: batch, cyclical batch, and continuous feed, all with intermittent removal of product. Results were suitable for intermediate purification requirements, and stable operation was demonstrated over multiple cycles, indicating that this approach should be compatible with parallel semicontinuous operation for intermediate purification and solvent swap applications in the manufacture of drugs.

Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing

“…The required volume of solvent for dilution and the mass of the polymer binder was calculated on a g/g basis. The purity of the product was determined using the HPLC method previously described [ 22 ].…”

“…Monobasic potassium phosphate and sodium hydroxide for buffer preparation were purchased from Sigma Aldrich (Wicklow, Ireland) and Fisher Scientific (Dublin, Ireland), respectively. The ibuprofen ethyl ester impurity (91% purity) was prepared via Fischer–Speier esterification, as previously described [ 22 ].…”

“…Recent advances have managed to avoid the presence of solids by using semi-continuous falling film crystallization and re-dissolving the purified solid product in fresh solvent [ 21 , 22 ]. The development of this and similar approaches will allow the high selectivity, high productivity and low cost provided by crystallization operations to be realized and applied to a more diverse range of continuous processes [ 3 ].…”

Recent advances in melt crystallization, towards process intensification and technique development

“…Notably, the initial flow rate and concentration of the raw materials are essential for the flow process. Another solution layer crystallizer proposed by Lopez-Rodriguez et al 154 is also considered as a novel continuous device which possesses potential application in melt crystallization. The device consists of a highly scalable combined modular and 3D-printed falling film crystallization device, as shown in Fig.…”