Research groups supported by industry tackle the challenges of continuous crystallization and process analytical technology.
Continuous processing is attracting attention in the manufacture of both small-molecule drugs and biopharmaceuticals. In small-molecule manufacturing, flow chemistry has many advantages, including increased development speeds, improved product and process consistency and thus product quality, greater process safety when employing hazardous chemistries, the opportunity to perform reactions that cannot be run under batch conditions, and reduced capital investment and operating costs.
Continuous downstream processing operations offer many similar advantages, and there has been more focus on integrating continuous downstream processes with continuous flow synthesis. While many downstream processes can be readily adapted to run continuously, such as extraction, phase separation, and distillation, others-particularly those related to solids handling-present greater challenges.
Several research groups supported by industry have focused on continuous crystallization. The Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization (CMAC), for instance, has support from founding members such as GlaxoSmithKline, Novartis, and AstraZeneca and is developing continuous processes for all stages of crystallization that are efficient, cost-effective, scalable, sustainable, and precisely control the form, size, shape, purity, surface structure, and functionality of crystallized drug intermediates and APIs. Researchers at the Novartis-MIT Center for Continuous Manufacturing have investigated methods for the direct crystallization of APIs on polymer excipient surfaces and the incorporation of continuous crystallization processes within an integrated continuous manufacturing pilot plant, which requires careful selection of appropriate process analytical technology (PAT).
Benefits of direct nucleation
One of the advantages that can be realized by implementing integrated continuous processing is reduction of the number of processing steps typically required for completion of the same process in batch equipment. For crystallization processes, direct crystallization of a pharmaceutical intermediate or API on the surface of a polymeric excipient can lead to the simultaneous separation of impurities and formation of a drug-excipient composite. This result may cause the elimination of several solid-handling steps that are typically required for the downstream processing of solid products, according to Bernhardt L. Trout, the Raymond F. Baddour professor of chemical engineering at MIT and director of the Novartis-MIT Center for Continuous Manufacturing. “If crystallization can provide a product with the appropriate physical properties, it is possible to eliminate the need for milling, granulation, and other processes,” he says.
Importance of heterogeneous nucleation
Heteronucleation involves the formation of crystal nuclei at a solid-liquid interface and can be employed to control nucleation and, potentially, polymorphism, which is important for the production of APIs with stable forms (1). There is some evidence, according to Trout, that the surface morphology of the solid affects the crystallization process. “In particular, the use of nano-patterned substrates can affect not only the nucleation kinetics, but phase stabilization, polymorphism, and the orientation of the resultant crystals,” he adds.
Polymer excipient templates
Heteronucelation of a single compound using different polymeric substrates can provide access to a wide range of polymorphs for that compound, because the different surface morphologies of the polymers result in different interactions at the polymer-crystal interface (1). Nanoimprinting of polymers provides a way to impart specific surface geometries that can be used to influence nuclei formation and ultimately polymorphism, according to Trout. “Our supposition was, therefore, that nanoimprinting of polymers that already provide favorable surface-solid interactions to create surface geometries that lead to nanoconfinement should allow for control of crystallization behavior,” he comments. It should be noted that the functionality of the polymer and whether it is more hydrophilic or hydrophobic determines the interactions between the solute and the polymer surface, and thus the crystallization process.
Trout and his colleagues examined a range of polymer types to determine their effects on this templated crystallization process. To create the engineered polymer surfaces, a rigid, flat silicon mold with nanometer-sized and mono-dispersed pillars of varying angles was fabricated using interference lithography. Negatives of the mold were then transferred to polymer films using nanoimprint lithography. “With this method, it is possible to create both hydrophobic and hydrophilic polymer surfaces with nanopores of many different shapes and sizes. By considering the structure of the API, it may therefore be possible to choose a specific polymer and nanopore structure that will result in crystallization of a specific polymorph of the API, even metastable forms,” Trout notes. For example, favorable interactions can be observed by matching the surface geometry angles with the angles between dominant faces of the desired polymorph of a compound, according to Trout. Enhanced nucleation rates and alternation of the polymorph distribution can result.
Initially the biocompatibility of the polymers was not considered; eventually the researchers focused solely on polymers that have generally-recognized-as-safe (GRAS) status given that these polymers can be used as excipients in final drug formulations, says Trout. The processability and solubilities of the polymers were also considered. Pharmaceutically acceptable organic solvents were also screened to find an appropriate crystallization solvent.
Effective continuous crystallization in an integrated process
Continuous crystallization techniques in the pharmaceutical industry are typically developed as stand-alone processes, but in many cases, the goal will be to develop a fully integrated continuous process involving flow chemistry, purification, and final formulation. In such a setting, the crystallization process can be affected by events that occur upstream, and careful control of the crystallization conditions is required to ensure that all critical material attributes and critical process parameters are met on a continual basis.
Trout and several colleagues at MIT have investigated the implementation of continuous crystallization in the pilot plant developed at the Novartis-MIT Center, which is designed for integrated continuous manufacturing (ICM) of pharmaceutical compounds (2). “The most significant result of this study, which involved the two-stage continuous crystallization of aliskiren hemifumarate as part of an ICM pilot plant, was the determination that the use of a combination of different PAT tools and automated control loops was sufficient to maintain operational performance within specifications for extended periods of time,” Trout states. In fact, the continuous reactive crystallization was performed for more than 100 hours in the integrated process, providing product with a purity >99% and a yield of 91.4% (2).
1. V. Lopez-Mejías, A. S. Myerson, and B. L. Trout, Cryst. Growth Design, 13 (8) 3835−3841 (2013).
2. H. Zhang et al., Cryst. Growth Design, 14 (5), 2148-2157 (2014).
Article DetailsPharmaceutical Technology
Vol. 39, Issue 5
When referring to this article, please cite as C. Challener, “Considering Continuous Crystallization,” Pharmaceutical Technology 39 (5) 2015.