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Heterogeneous Crystallization as a Process Intensification Technology in an ICM Process for Pharmaceuticals

Introduction

The pharmaceutical industry continues to employ batch manufacturing processes despite the many challenges associated with this outdated production method, including its cost, quality control and assurance, sustainability, and reliability. However, a different method of production, integrated continuous manufacturing (ICM), is gaining interest from drug manufacturers, regulatory agencies, equipment manufacturers, and academia because of its many advantages. ICM is a manufacturing platform characterized by a series of integrated (i.e., connected) unit operations whose outputs are continuously fed to the next processing step.

The complete processing train is monitored and controlled with a plant-wide control system, which generally utilizes process analytical technologies (PAT).9−12 The continuous manufacture of pharmaceuticals has potential to reduce batch-to-batch variation, out-of-specification products, ecological and physical footprints, time-to-market (e.g., easier scale-up), capital investment, and operating costs. The manufacture of small-molecule active pharmaceutical ingredients (APIs) and oral solid dosage forms (OSDs) requires multiple unit operations, including reaction, crystallization, filtration,drying, and downstream processing steps (e.g., milling, sieving, blending, granulation, and direct compression). The advancement of continuous crystallization technologies, in particular, is critical to the success of the pharmaceutical industry’s transition from batch to continuous production because over 90% of APIs are crystalline. Crystallization processes are needed to separate and purify the API, as well as control the shape, size, and polymorphic form. With heterogeneous crystallization, the API nucleates and grows directly on a foreign substrate. The energy required for nucleation is reduced in the presence of these surfaces (i.e., heterosurfaces) because they help form prenucleation aggregates that favor crystallization. There are two broad categories of these surfaces commonly used amorphous polymer materials and crystalline substrates.

Crystallization processes employing heterogeneous nucleation mechanisms may offer benefits in nucleation kinetics, polymorphism control, shape and size control, product stability, and downstream filtration. In addition, the use of heterogeneous crystallization can reduce the need for complex downstream processing (e.g., milling, sieving, dry/wet granulation, and blending), making it an attractive process intensification technology (PIT) to be integrated into continuous processes. As a result, the overall process complexity, capital investment, and operating costs can be reduced.

Abstract

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 >4× 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.

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