Development of a continuous synthesis process for carbamazepine using validated in-line Raman spectroscopy and kinetic modelling for disturbance simulation

Glace, Matthew; Wu, Wei; F., Kraus, Harrison; Acevedo, David; Roper, Thomas D.; Mohammad, Adil

doi:10.1039/d2re00476c

Cited by 7 publications

(20 citation statements)

References 33 publications

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“…A BlazeMetrics (Quil Ceda Village, WA) 900 microscopy probe (Model B532) was applied to monitor batch and continuous crystallization. The development and validation of the Raman method for the quantitative measurement of CBZ and ISB is reported by Glace et al 22 2.2.3. X-ray Diffraction (XRD).…”

Section: Characterization Methods 221 High Pressure Liquid Chromatogr...mentioning

confidence: 99%

“…4−6,23−26 Continuous synthesis methods for CBZ from ISB have also been investigated but focused less to address workup or crystallization. 21,22 The available batch and continuous crystallization studies have relied upon purified commercial CBZ. 20,27−30 For the development of an advanced CM process for CBZ, it is necessary to understand the fate and removal of reaction impurities during the crystallization stages.…”

Section: Introductionmentioning

confidence: 99%

“…The chemistry optimization was previously described in a prior publication by our group. 22 Here within, a procedure to isolate the undesired form I polymorph from the crude reaction mixture is first designed using DOE. Using that antisolvent isolation process, the synthesis and form I polymorph isolation are scaled using a continuous oscillatory baffled reactor (COBR).…”

Section: Introductionmentioning

confidence: 99%

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Impurity Profiling for a Scalable Continuous Synthesis and Crystallization of Carbamazepine Drug Substance

Glace,

Kraus,

et al. 2024

Org. Process Res. Dev.

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A scalable continuous manufacturing process for the synthesis and crystallization of form III carbamazepine (CBZ) from iminostilbene (ISB) has been established. A high-yielding synthesis was first obtained using a plug flow reactor (PFR) and then scaled up using a continuous oscillatory baffled reactor (COBR). A real-time in-line Raman spectroscopy method was implemented to ensure that the conversion of the starting material ISB to the product CBZ was maintained above 99.0%. The monitored product stream was telescoped into a mixed-suspension mixed-product crystallizer (MSMPR-1) and a filtration unit to isolate the preliminary CBZ form I polymorph. A cooling recrystallization process was designed by using a crystal growth model derived from microscopy measurements. The impurity purging capacities and polymorph attainments were compared for the batch and flow processes. This study outlines the role of process modeling and process analytical technology (PAT) for impurity purging in a telescoped continuous manufacturing process.

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Section: Characterization Methods 221 High Pressure Liquid Chromatogr...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impurity Profiling for a Scalable Continuous Synthesis and Crystallization of Carbamazepine Drug Substance

Glace,

Kraus,

et al. 2024

Org. Process Res. Dev.

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“…PAT models are typically developed prior to CM implementation to ensure process streams are within CQA specifications. [168] In order to build an appropriate control architecture, a PAT tool is first analyzed under mock processing conditions in which a CPP is purposefully driven away from acceptable limits. The PAT tool is then assessed to determine if the technology has enough resolution to detect these variations.…”

Section: Process Analytical Technologiesmentioning

confidence: 99%

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

Hyer,

Gregory,

Kay

et al. 2024

Adv Synth Catal

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The pharmaceutical industry has traditionally employed batch processing as a means of synthesizing active pharmaceutical ingredients (APIs) on a commercial scale. Batch manufacturing enables API synthesis in large quantities in order to meet regulations. Yet, this strategy remains cumbersome, is labor‐intensive, and creates complex logistical networks. In recent decades, batch API processing has gradually eroded American economic competitiveness and has led to the off‐shoring of API manufacturing from the United States. Today it is estimated that +80% of APIs are manufactured overseas. Meanwhile, disruptions from the Coronavirus Disease (SARS‐CoV‐2) have exacerbated weaknesses in the global supply chain, culminating with widespread shortages of critical life‐saving drugs. These shortages have emphasized the importance of reshoring drug manufacturing to the U.S. and fostered a regulatory landscape that seeks advanced methods of API manufacturing in order to bolster America’s supply chain resiliency. Recently, increased attention has been directed towards continuous drug manufacturing to enable nonstop API production within modular stand‐alone flow systems. Continuous manufacturing (CM) facilitates modular automation, offers new avenues towards process intensification, and even enables in‐line analytical monitoring from raw materials to packaged products. This strategy offers better conversion, increased safety, reduced waste, and overall cost savings versus traditional batch‐style processing. The rise of advanced API manufacturing, coupled with the current regulatory landscape, offers a rare window of opportunity to convert traditional batch pharmaceutical processes into continuous, streamlined production systems to on‐shore API manufacturing and eliminate drug shortages. This review will outline the current state‐of‐the‐art in the CM of APIs and will highlight the translation of chemistry and unit operations from batch processes to modular CM systems.

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“…We were also interested in the predictive capability of our model for when the system experienced disturbances. 28,29 Thus, we simulated the influence of switching off the acrylonitrile pump at set intervals, which decreased the consumption of starting material (1). The simulated results for 1,2,4-triazole (1) are compared to the experimentallymeasured values in Fig.…”

Section: Disturbance Simulationmentioning

confidence: 99%

Accelerating reaction modeling using dynamic flow experiments, part 2: development of a digital twin

Silber¹,

Sagmeister²,

Schiller³

et al. 2023

React. Chem. Eng.

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Development of a continuous synthesis process for carbamazepine using validated in-line Raman spectroscopy and kinetic modelling for disturbance simulation

Abstract: Mitigation of failure modes in continuous synthesis (CS) of drug substance (DS) has the potential to widen the adoption of continuous manufacturing (CM) technologies by the pharmaceutical industry. This work...

Cited by 7 publications

References 33 publications

Impurity Profiling for a Scalable Continuous Synthesis and Crystallization of Carbamazepine Drug Substance

Impurity Profiling for a Scalable Continuous Synthesis and Crystallization of Carbamazepine Drug Substance

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

Accelerating reaction modeling using dynamic flow experiments, part 2: development of a digital twin

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