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Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process
23 Jul 2024 | Contributor(s):: Parvaresh, Rojan, Nagy, Zoltan K.
Continuous manufacturing can show potential benefits over batch processing in lower turnaround times and smaller footprint in addition to higher productivity, adaptability, and consistent product quality. Although these possible benefits exist, there are also challenges in integrating the various...
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Towards Continuous Primary Manufacturing Processes-Particle Design through Combined Crystallization and Particle Isolation
09 Jun 2023 | Contributor(s):: Steenweg, C, Kufner, ACHabicht, J, Wohlgemuth, K
Integrated continuous manufacturing processes of active pharmaceutical ingredients (API) provide key benefits concerning product quality control, scale-up capability, and a reduced time-to-market. Thereby, the crystallization step, which is used in approximately 90% of API productions, mainly...
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Tailoring the crystal size distribution of an active pharmaceutical ingredient by continuous antisolvent crystallization in a planar oscillatory flow crystallizer
09 Jun 2023 | Contributor(s):: Cruz, P, Alvarez, CRocha, F, Ferreira, A
An active pharmaceutical ingredient is currently produced in a traditional batch antisolvent crystallization process. Although well-established, this process lacks flexibility to control the crystal size distribution (CSD). Therefore, a new process was developed to enable the control of the CSD...
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Small-Volume Continuous Manufacturing of Merestinib. Part 1. Process Development and Demonstration
09 Jun 2023 | Contributor(s):: Cole, KP, Reizman, BJHess, M, Groh, JM, Laurila, ME, Cope, RF, Campbell, BM, Forst, MB, Burt, JL, Maloney, TD, Johnson, MD, Mitchell, D, Polster, CS, Mitra, AW, Boukerche, M, Conder, EW, Braden, TM, Miller, RD, Heller, MR, Phillips, JL, Howell, JR
Development of a small volume continuous process that used a combination of batch and flow unit operations to manufacture the small molecule oncolytic candidate merestinib is described. Continuous processing was enabled following the identification and development of suitable chemical...
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Separation and Purification in the Continuous Synthesis of Fine Chemicals and Pharmaceuticals
09 Jun 2023 | Contributor(s):: O'Mahony, M, Ferguson, SStelzer, T, Myerson, A
The use to both chemists and chemical engineers working in flow synthesis, this chapter provides a summary of separation and purification operations that can be applied to flow synthesis reaction streams. Both single and biphasic separations for the liquid phase are detailed. Separation and...
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Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine
09 Jun 2023 | Contributor(s):: Yang, Xiaochuan, Acevedo, David, Mohammad, Adil, Pavurala, Naresh, Wu, Huiquan, Brayton, Alex L., Shaw, Ryan A., Goldman, Mark J., He, Fan, Li, Shuaili, Fisher, Robert J., O'Connor, Thomas F., Cruz, Celia N.
Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and the understanding of the impact on product quality is currently evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical...
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Recent Progress in Continuous Crystallization of Pharmaceutical Products: Precise Preparation and Control
09 Jun 2023 | Contributor(s):: Ma, Yiming, Joao Macaringue, Estevao, Zhang, Teng, Gong, Junbo, Wu, Songgu, Wang, Jingkang
Crystallization, as a solid−liquid separation process, is employed to purify and isolate a great diversity of crystalline pharmaceutical products. In recent years, continuous crystallization has attracted increasing attention because of the product and process robustness as well as higher...
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Reducing the mean size of API crystals by continuous manufacturing with product classification and recycle
09 Jun 2023 | Contributor(s):: Griffin, DW, Mellichamp, DA, Doherty, MF
A continuous crystallization process is proposed that can produce active pharmaceutical ingredients with a small mean size and narrow distribution. The process flowsheet consists of a new product classifier configuration where the large crystals from the classifier are recycled to a dissolver...
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Regions of attainable particle sizes in continuous and batch crystallization processes
09 Jun 2023 | Contributor(s):: Vetter, Thomas, Burcham, Christopher L., Doherty, Michael F.
Process alternatives for continuous crystallization, i.e., cascades of mixed suspension, mixed product removal crystallizers (MSMPRCs) and plug flow crystallizers (PFCs), as well as batch crystallizers are discussed and modeled using population balance equations. The attainable region approach...
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Raman Spectroscopy for Monitoring the Continuous Crystallization of Carbamazepine
09 Jun 2023 | Contributor(s):: Acevedo, D, Mohammad, Adil, Pavurala, Naresh, Wu, Wei-Lee, O'Connor, Thomas F., Nagy, Zoltan K, Yang, Xiaochuan, Cruz, CN
Crystallization has a significant impact on the properties of the active pharmaceutical ingredient (API) since it is the final step in the manufacturing of the drug substance and determines particle size distribution, purity, shape, and polymorphs. Many publications have focused on the...
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Progress of Pharmaceutical Continuous Crystallization
09 Jun 2023 | Contributor(s):: Zhang, DJ, Xu, SJDu, SC, Wang, JK, Gong, JB
Crystallization is an important unit operation in the pharmaceutical industry. At present, most pharmaceutical crystallization processes are performed in batches. However, due to product variability from batch to batch and to the low productivity of batch crystallization, continuous...
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Progress to Date in the Design and Operation of Continuous Crystallization Processes for Pharmaceutical Applications
09 Jun 2023 | Contributor(s):: Wood, Barbara, Girard, Kevin, Polster, Christopher, Croker, Denise
Continuous crystallization has gained interest in the pharmaceutical sector as part of the drive toward thetransition from exclusive batch manufacturing to integrated continuous manufacturing in this industry. As a result, the design and operation of continuous crystallization processes for the...
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Process intensification through continuous spherical crystallization using a two-stage mixed suspension mixed product removal (MSMPR) system
09 Jun 2023 | Contributor(s):: Peña, Ramon, Nagy, Zsombor K.
Of utmost importance in the crystallization of active pharmaceutical ingredients (APIs) in the pharmaceutical industry is to produce crystals of good physical, processing, and biopharmaceutical properties. The definition of good physical properties depends on what the end goal and the drug...
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Process Design and Optimization for the Continuous Manufacturing of Nevirapine, an Active Pharmaceutical Ingredient for HIV Treatment
09 Jun 2023 | Contributor(s):: Diab, S, McQuade, DTGupton, BF, Gerogiorgis, DI
The development of efficient and cost-effective manufacturing routes toward HIV active pharmaceutical ingredients (APIs) is essential to ensure their global and affordable access. Continuous pharmaceutical manufacturing (CPM) is a new production paradigm for the pharmaceutical industry whose...
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Oscillatory Flow Reactors (OFRs) for Continuous Manufacturing and Crystallization
09 Jun 2023 | Contributor(s):: McGlone, Thomas, Briggs, Naomi E. B., Clark, Catriona A., Brown, Cameron J., Sefcik, Jan, Florence, Alastair J.
Continuous crystallization is an attractive approach for the delivery of consistent particles with specified critical quality attributes (CQAs), which are attracting increased interest for the manufacture of high value materials, including fine chemicals and pharmaceuticals. Oscillatory flow...
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On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Implementation and in Situ Control of Downstream Production
09 Jun 2023 | Contributor(s):: Capellades, Gerard, Neurohr, Clemence Briggs, Naomi Rapp, Kersten, Hammersmith, Gregory, Brancazio, David, Derksen, Bridget, Myerson, Allan S.
Traditional pharmaceutical manufacturing operates around a supply chain that is subject to complex logistics and is vulnerable to spikes in demand and interruptions. In this context, continuous pharmaceutical manufacturing in portable, refrigerator-sized factories is a promising solution with...
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No More Than Three: Technoeconomic Mixed Integer Nonlinear Programming Optimization of Mixed Suspension, Mixed Product Removal Crystallizer Cascades for Melitracen, an Antidepressant API
09 Jun 2023 | Contributor(s):: Diab, S, Gerogiorgis, DI
Mixed Suspension, Mixed Product Removal (MSMPR) crystallizers have been considered in numerous cases as a continuous mode of operation in the production of Active Pharmaceutical Ingredients (APIs). The steady-state continuous MSMPR crystallization of melitracen via cooling has been recently...
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Monitoring Continuous Crystallization of Paracetamol in the Presence of an Additive Using an Integrated PAT Array and Multivariate Methods
09 Jun 2023 | Contributor(s):: Powell, Keddon A., Saleemi, Ali N, Rielly, Chris D., Nagy, Zoltan K.
In this study, an automated intelligent decision support (IDS) framework was applied to monitor the continuous crystallization of form I paracetamol (PCM) and determine steady-state operation. A modified single-stage mixed suspension mixed product removal (MSMPR) crystallizer was used to...
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Modeling a seeded continuous crystallizer for the production of active pharmaceutical ingredients
09 Jun 2023 | Contributor(s):: Besenhard, M. O., Hohl, R. Hodzic, A. Eder, R. J.P., Khinast, J. G.
The approximation of a well mixed reactor is prevalent when it comes to the modeling of a crystallization process. Since temperature, concentration, and mass content vary due to inhomogeneous mixing, this approximation is a very loose one. The continuously operated seeded tubular crystallizer...
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Modeling of pharmaceutical filtration and continuous integrated crystallization-filtration processes
09 Jun 2023 | Contributor(s):: Nagy, B, Szilagyi, BDomokos, A, Tacsi, K, Pataki, H, Marosi, G, Nagy, ZK
As continuous manufacturing is evolving in the pharmaceutical industry, continuous filtration has emerged as a bottleneck for connecting the crystallization of the active pharmaceutical ingredient with the formulation of the final drug product. This work aims the modeling of filtration to improve...
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Mathematical modeling and experimental validation of continuous slug-flow tubular crystallization with ultrasonication-induced nucleation and spatially varying temperature
09 Jun 2023 | Contributor(s):: Mozdzierz, Nicholas J., Lee, Yongkyu Hong, Moo Sun Benisch, Moritz H.P., Rasche, Michael L., Tropp, Uku Erik, Jiang, Mo, Myerson, Allan S., Braatz, Richard D.
Continuous slug-flow tubular crystallization has been explored by several Research Article groups in academia and industry as a way to produce crystals while having low capital equipment costs. In this crystallization type, slugs of slurry and gas consecutively travel through a tube, with a high...
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Investigation of Wet Milling and Indirect Ultrasound as Means for Controlling Nucleation in the Continuous Crystallization of an Active Pharmaceutical Ingredient
09 Jun 2023 | Contributor(s):: Yang, YH, Ahmed, BMitchell, C, Quon, JL, Siddique, H, Houson, I, Florence, AJ, Papageorgiou, CD
This study compares the use of wet milling and indirect ultrasound for promoting nucleation and controlling the particle size during the continuous crystallization of a hard-to-nucleate active pharmaceutical ingredient (API). Both an immersion and an external wet mill installed on a recirculation...
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Incorporating Solvent-Dependent Kinetics To Design a Multistage, Continuous, Combined Cooling/Antisolvent Crystallization Process
09 Jun 2023 | Contributor(s):: Schall, JM, Capellades, GMandur, JS, Braatz, RD, Myerson, AS
Combined cooling and antisolvent crystallization enables crystallization of many pharmaceutical products, but its process design typically neglects solvent composition influences on crystallization kinetics. This paper evaluates the influence of solvent-dependent nucleation and growth kinetics on...
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Development of Continuous Filtration in a Novel Continuous Filtration Carousel Integrated with Continuous Crystallization
09 Jun 2023 | Contributor(s):: Liu, Yiqing C., Domokos, András, Coleman, Simon, Firth, Paul, Nagy, Zoltan K.
Pharmaceutical manufacturing has been largely carried out in batch mode, which has disadvantages such as batch-to-batch variations and difficult scale-up. As a result, the pharmaceutical industry is going through the paradigm shift to continuous manufacturing. Many unit operations have been...
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Designs of continuous-flow pharmaceutical crystallizers: developments and practice
09 Jun 2023 | Contributor(s):: Jiang, Mo, Braatz, Richard D.
Crystallization is an effective, low-cost purification & formulation process widely applied to pharmaceuticals and fine chemicals. This review describes recent advances in Research Article on lab-scale solution-based continuous crystallization, including (1) a 5-step general design procedure; (2)...