Mini-Monoplant Technology for Pharmaceutical Manufacturing

Doyle, Brendon J.; Elsner, Petteri; Gutmann, Bernhard; Hannaerts, Olivier; Aellig, Christof; Macchi, Arturo; Roberge, Dominique M.

doi:10.1021/acs.oprd.0c00207

Cited by 14 publications

(5 citation statements)

References 77 publications

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“…Lab-Based Development of the Continuous Reaction System. 32 A general and simplified process flow diagram of the continuous flow reaction system is shown in Figure 2. The system can be divided into two regions, namely, region 1 which consists of the mixing point and all upstream components from the crystallization coil entrance and region 2 which consists of all components downstream from and including the crystallization coil.…”

Section: Zs-9 Crystallizationmentioning

confidence: 99%

Continuous Production of an API Suspension (ZS-9) under Oscillatory Flow at Intensified Temperature and Pressure

Doyle,

Vrbanec,

Aellig

et al. 2024

Org. Process Res. Dev.

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A baffleless oscillatory flow coil reactor is implemented for the continuous production of a sodium zirconium cyclosilicate (SZC) species (ZS-9) suspension at elevated temperature and pressure. Development of the process and the resulting effects on product quality are outlined, including both mechanical changes to the reaction system itself and parametric tests of the operating conditions. The reaction apparatus proceeded through several iterations, where physical changes upstream of the crystallization coil from a simple T-junction mixing point to the final system containing a prefilled seeding loop led to significant improvements in product quality. The effects of system temperatures, fluid space times, and oscillation intensity are then outlined, leading to final operating conditions consisting of a 1 h crystallization fluid space time at 245 °C and up to 75 bar, a 173 °C seeding temperature, and a velocity ratio (Re o/Re n) ratio of 175 and a ZS-9 production rate of 40 g/h.

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Section: Zs-9 Crystallizationmentioning

confidence: 99%

Continuous Production of an API Suspension (ZS-9) under Oscillatory Flow at Intensified Temperature and Pressure

Doyle,

Vrbanec,

Aellig

et al. 2024

Org. Process Res. Dev.

Self Cite

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“…The main benefits of continuous manufacturing compared to batch are safer processes by minimizing the explosive risk through using smaller volume reactors at manufacturing scale; shorter cycle time by requiring less cleaning time for smaller volume reactors; improved sustainability by using less catalyst and energy for heating and cooling the reactor; and greater intensification (higher mass throughput in smaller footprint equipment) using a wider range of process conditions. Additional advantages have been previously highlighted by Bristol-Myers Squibb (BMS), Eli Lilly, GSK, and Pfizer. ,,,− …”

Section: Introductionmentioning

confidence: 99%

Fixed Bed Continuous Hydrogenations in Trickle Flow Mode: A Pharmaceutical Industry Perspective

Masson

Maciejewski

Wheelhouse

et al. 2022

Org. Process Res. Dev.

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Since the 1930s, fixed bed reactors (FBR) have been operated for continuous hydrogenation reactions in the petrochemical/fine chemical industries, with publications each year detailing engineering principles, scientific breakthroughs, equipment design and setup, from these industries. Only in the last two decades, FBR have started to be utilized in the pharmaceutical industry as a result of sustainability commitment and growing demand of complex and specialized drugs. Most of the engineering knowledge is transferable across industries; however, there are differentiators inherent to each industry, with the pharmaceutical industry having its own unique challenges. One of the main differentiators between industries is the reactor scale and, consequently, reactor catalyst requirements. Petrochemicals or fine chemicals operate on a large industrial scale, with up to 72 m high reactors, with an internal diameter on the order of 5 m (China Petroleum & Chemical Corporation), and require large volumes of catalysts because of the high product demand for thousands of tonnes per year, while for the pharmaceutical industry, a smaller scale reactor is required for product demand in the thousands of kilograms per year range. It is the reactor size that defines catalyst specifications, such as particle size and geometry. Many transformations have emerged from academic and medicinal chemistry groups utilizing the ThalesNano H-Cube; however, there are relatively few reported processes that have been scaled within the pharmaceutical industry. This Perspective outlines a review of continuous flow hydrogenation technologies; focusing on the trickle bed reactor (TBR) and the respective process operation and effect of process variables on reaction rate requirements for the pharmaceutical industry; it also reflects on transformation examples using TBR across the pharmaceutical industry.

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“…Today, mainly batch reactors are used to produce fine chemicals in the range of up to 100 t/y [1]. As the industry is striving for process intensification, the changeover from a multifunctional batch plant to a smaller continuous monoplant can make economic sense, as there is no need for cleaning, charge and discharge [2]. In addition, continuous reactors are smaller for the same production capacity since higher temperatures and pressures allow a shorter residence time than batch reactors [3].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of enthalpy of mixing and reaction using milli-scale continuous flow calorimetry

Steinemann

Rütti

Moser³

et al. 2022

J Flow Chem

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A simultaneous determination of the enthalpy of mixing and reaction in a scalable continuous milli-scale flow calorimeter is investigated. As obtained calorimetric data is pivotal for the safety assessment of chemical reactions and processes. The acid-catalysed selective, homogeneous hydrolysis of acetic anhydride with half-lives from a few seconds to a few minutes is investigated as a model reaction. For the enthalpy of mixing 7.2 ± 2.8 kJ/mol and for the enthalpy of reaction −60.8 ± 2.5 kJ/mol were determined. For reactions that show complete conversion in the continuous reactor, a technique is introduced to further improve the accuracy of the reaction enthalpy determination. Thereby, the resolution of the observed temperature profile is increased by measuring the profile at different flow rates. Applying this procedure, the reaction enthalpy of −62.5 kJ/mol was determined which is in good agreement with literature values for this model reaction. Graphical abstract

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Mini-Monoplant Technology for Pharmaceutical Manufacturing

Cited by 14 publications

References 77 publications

Continuous Production of an API Suspension (ZS-9) under Oscillatory Flow at Intensified Temperature and Pressure

Continuous Production of an API Suspension (ZS-9) under Oscillatory Flow at Intensified Temperature and Pressure

Fixed Bed Continuous Hydrogenations in Trickle Flow Mode: A Pharmaceutical Industry Perspective

Simultaneous determination of enthalpy of mixing and reaction using milli-scale continuous flow calorimetry

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