Heterogeneous Crystallization as a Process Intensification Technology in an Integrated Continuous Manufacturing Process for Pharmaceuticals

Continuous heterogeneous crystallization processes in mixed-suspension mixed-product removal (MSMPR) crystallizers of different configurations (e.g., single-stage cooling, multistage cooling, and multistage evaporative cooling) are developed, in which an active pharmaceutical ingredient (acetaminophen, APAP) is crystallized directly on the surfaces of both porous and nonporous polymer excipient substrates (poly(vinyl alcohol), PVA). The heterogeneous crystallization step is part of an integrated continuous manufacturing (ICM) processing train, which starts from raw materials and includes chemical synthesis, crystallization, filtration, and drying. The product from this ICM process is a stream of dried composite particles (i.e., APAP on PVA substrates) that are directly compressed into tablets, eliminating the need for any further processing steps (e.g., milling, sieving, blending, and granulation). The dried composite particles are characterized with scanning electron microscopy, differential scanning calorimetry, and X-ray powder diffraction. The use of porous polymer substrates (instead of nonporous substrates) increased the crystallization yield by >4X in one set of experiments. In subsequent experiments, the use of porous polymer substrates reduced the risk of bulk nucleation (due to increased internal free volume and surface area) in an evaporative-cooling MSMPR crystallization system. Yields as high as 71% and drug loadings as high as 61.1 +/- 2.8% were observed with this evaporative-cooling MSMPR system. Furthermore, it is shown that by altering the suspension density of the excipient particles, the drug loading of the composite particles can be controlled. Finally, the design of the ICM process is discussed. The use of heterogeneous crystallization as a process intensification technology (e.g., incorporation into an end-to-end ICM pharmaceutical production process) has the potential to reduce overall system complexity, capital investment, and operating costs on the commercial scale by reducing the number of downstream processing steps that are required.