Operation Strategy Development for Grignard ... - ACS Publications

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Operation Strategy Development for Grignard Reaction in a Continuous Stirred Tank Reactor Sze-Wing Wong,*,† Shujauddin M. Changi,† Richard Shields,‡ Willis Bell,‡ Bernard McGarvey,‡ Martin D. Johnson,† Wei-Ming Sun,† Tim M. Braden,† Michael E. Kopach,† Richard D. Spencer,§ Gordon Flanagan,§ and Michael Murray§ †

Small Molecule Design & Development, ‡Process Engineer Center, and §Tech Services/Manufacturing Science, Eli Lilly and Company, Indianapolis, Indiana 46285, United States ABSTRACT: This paper presents a case study in establishing the operation space of a Grignard reaction in a continuous stirred tank reactor (CSTR). The operation space is the multivariate space with the boundary defined by the proven acceptable range of every CSTR process parameter such as flow rates and temperature. The mapping of the operation space was conducted by a thorough understanding of reaction kinetics, magnesium (Mg) sequestration efficiency, equipment characterization, and the impact of process disturbances has on steady state. A fit-for-use reaction kinetics model was developed to parametrize the kinetics and mass transfer rates of the batch Grignard reaction across different scales from 250 mL to 500 gallons. The reaction kinetics model was applied to design the Mg recharge frequency accounting operational variability to ensure a state of control can be maintained. Furthermore, reactor temperature was determined to be suitable to detect process failures to ensure process safety and product quality at manufacturing scale. Computational fluid dynamics (CFD) models were also applied to aid equipment design to maximize Mg sequestration in the CSTR. Based on the optimal equipment design, the unit operation was scaled-down to test the sequestration efficiency. The resulting process understanding enabled the team to define the final operation strategy to ensure a safe and robust commercial process.

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INTRODUCTION A Grignard reaction is a hazardous reaction due to the need for magnesium (metal) activation and the overall exothermic nature of the reaction.1,2 The edivoxetine hydrochloride drug substance manufacturing process has been safely managed from development to 500 gallon scale with appropriate safety and engineering controls for batch operations. However, safety assessments at the commercial site mandated that Steps 2C to 2E reactions (Scheme 1) to be conducted in a hydrogenation facility since hydrogen is evolved when excess magnesium is quenched. The mandate also required mitigating the potential risk of acid mischarge during the Grignard reaction due to equipment set up issues or operator error. While the Lilly manufacturing site has the ability to handle Grignard reaction at scale, this facility restriction added equipment scheduling pressure as well as limited flexibility to improve process throughput throughout the lifecycle of the product. Thus, an alternative unit operation was developed to form the Grignard reagent in a continuous stirred tank reactor (CSTR). Several publications have examples of conducting Grignard reactions continuously at research, pilot, or commercial scale.3−5 This paper focuses on the CSTR development of the Step 2C Grignard reaction (Scheme 1) and the methodology applied to establish a well-defined control strategy for the whole manufacturing process per Quality by Design (QbD) principles.6 An operation space is the multivariate space of all process parameters, where multiple set-points changes within this defined space will guarantee product quality even as the process drifts into a new steady state (i.e., process parameters can be shifted to new set points and operated indefinitely without © XXXX American Chemical Society

impacting product quality). This operation space can be refined through development studies that focused on understanding the reaction kinetics and material balance (i.e., Mg sequestration efficiency) in the CSTR, to better predict and understand the process dynamics of the CSTR in the presence of process disturbances through model simulations. Development of the reaction kinetics model and characterization of the mass transfer rate leveraged historical lab and manufacturing batch data across multiple scales. The model was first utilized to design multivariate experiments to understand how process parameters affected the CSTR operation. Specifically, it was used to identify reaction conditions that would lower reaction conversion to increase impurity levels in order to better understand the impurity control downstream, especially given that the starting material (Compound D) is a genotoxic impurity. The model was subsequently verified with experimental data using the simulated processing conditions. Additional development effort on equipment design was conducted using computational fluid dynamics (CFD) models to ensure an accurate Mg mass balance in the CSTR can be achieved. The resulting settling pipe can selectively remove reaction mixture while sequestrating Mg within the CSTR tank. Based on the CFD modeling result, a prototype was made to conduct scaled-down experiments to measure Mg sequestration efficiency in the CSTR as the final part of model verification. Special Issue: Continuous Processing, Microreactors and Flow Chemistry Received: August 18, 2015

A

DOI: 10.1021/acs.oprd.5b00268 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Scheme 1. Commercial Route for Edivoxetine·HCl

Finally, the model was used to finalize the Mg recharge strategy and determine which online measurement is suitable to detect process failure (e.g., drop in conversion to ensure product quality). The combination of model simulations and experimental data verification allowed the project team to make timely decisions based on process understanding to refine the operation strategy for the CSTR Grignard reaction at commercial scale.

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Continuous Grignard Reaction Development Goals. The motivation to develop an alternative process for the Grignard reaction (Step 2C) was to ensure a safe operation and allow flexibility in equipment configuration to modify process throughput at commercial scale. The design criteria included: (1) robust Grignard initiation and metal activation; (2) reduce amount of activated Mg present in the reactor during production; (3) reaction exotherm management; (4) reduce hydrogen evolution during quench by maximizing Mg sequestration in the Grignard reagent formation reactor; (5) no impact on the overall impurity control strategy for the process. Operating the Grignard reaction in a continuous stirred tank reactor (CSTR) easily satisfied the first three design criteria. First, the CSTR only required one reaction initiation/metal activation as the active Grignard reagent in the reaction mixture will activate metal surface each time fresh Mg is charged.5 Second, the CSTR volume is only 2.5% of the batch reactor at equivalent commercial scale. The surface area to volume ratio increases as the reactor size decreases, which improves heat removal. Better heat removal along with engineering control to the addition rate of limiting reagent allows for better reaction exotherm management. Furthermore, Mg is periodically replenished under inert environment via charge bottle in the CSTR, thereby reducing the amount of activated Mg in the reactor at any given time. Thus, the main focuses for the team were to (1) map the corresponding operation space to ensure the continuous Grignard reaction process would not impact the overall impurity control strategy for the manufacturing process; (2) maximize Mg sequestration in the CSTR to minimize hydrogen evolution and to have better Mg mass balance for model predictions; (3) develop Mg recharge strategy based on

BACKGROUND

Synthetic Route. Edivoxetine·HCl is a norepinephrine reuptake inhibitor in clinical trials for the treatment of depression and attention deficit hyperactivity disorder (ADHD). The synthetic route of the edivoxetine·HCl is shown in Scheme 1. In the first GMP step, API SM 1 is converted to its freebase form (Compound A) and then reacted with the Grignard reagent (Compound B) derived from API SM 2 to produce pyranyl ketone intermediate (Compound C). The Step 1 intermediate is isolated as a mesylate salt. Preparation of the Step 2 intermediate involves the generation of the benzyl bromide (Compound D) in excess by bromination of API SM 3; a Grignard reagent (Compound E) is formed from Compound D and is reacted with a free base ketone (Compound C) derived from Step 1 intermediate. The resulting tertiary alcohol (Compound F) is crystallized as the fumarate salt to afford the Step 2 intermediate. The manufacture of the drug substance involves the debenzylation of the final intermediate. The drug substance is isolated as the hydrochloride salt and milled to meet the final API specification. B



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Figure 1. (a) Original batch operation. (b) Modified Grignard reaction with CSTR equipped with an accumulation tank.

Table 1. CSTR Process Parameters and Operation Ranges process parameter residence time (min) reaction temperature (°C) compound D solution concentration (wt %) total Mg charge (equiv) initial Mg amount for initiation (equiv) first Mg rechargea (min) predicted conversion rate (%) a

normal operation target

stressed study no. 1 (compound D)

stressed study no. 2 (compound D)

stressed study no. 3 (Wurtz coupling impurity)

60 0 26

30 −25 20

30 25 26

60 25 26

1.25 0.4

1.15 0.04

1.25 0.04

1 0.06

300 NLT 95

50 80

50 80

90 90

The first Mg recharge time denote the period before a Mg charge.

applied to model the Grignard reaction as shown in eq 1 to 3. The model assumes the Mg particles to be spheres. The model development process is described in detail elsewhere.9

model predictions to ensure a safe and robust commercial operation. It should be noted that the overall Step 2 manufacturing process with the CSTR is considered a hybrid process (Figure 1). The incoming reagent, Compound D, is made up in a separate reactor and fed into the CSTR (Figure 1b). The exit stream from the CSTR is accumulated in a separate reactor. Upon completion of the Compound D addition to the Grignard CSTR, a small heel of the Grignard reaction mixture is left in the CSTR for the subsequent batch, while the rest of the Grignard reagent proceeds to the coupling reaction in the accumulation tank. The reaction mixture undergoes the same work up and isolation of the Step 2 intermediate in a batch manner as the original process. The CSTR is designed to sequestrate any excess Mg in the reactor, thereby eliminating the need to conduct the quench operations in a hydrogenator.

rGrignard = k(CMg)(C BzBr)

dCMg dt a=

* − C bulk ) = k SLa(CMg Mg ⎛m

0 ⎜ aMg ⎜

(1)

(2)

⎞2/3

Mg,s ⎟ ⎟ 0 ⎝ mMg,s ⎠

(3)

where the following nomenclature is used: • r = reaction rate • k = reaction rate constant • ksL = solid/liquid mass transfer rate • Ci = concentration of species i (mol/L) • C*Mg = solubility of Mg (mol/L) • a0 = initial surface area of Mg • m0Mg = initial mass of Mg • BzBr = Compound D This fit-for-use model is intended to help guide process development with the following objectives: (1) determine whether a new steady state due to a step changes in process parameter would impact product quality; (2) design a Mg recharge strategy by calculating the minimal Mg amount needed to maintain constant conversion at a given residence time [The residence time is based on the inlet and outlet flow rate of the CSTR operating at a constant reaction volume assuming material inside the CSTR is well mixed] and reaction temperature; (3) incorporate heat balance to determine whether reactor temperature may be used to detect process failure.

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OPERATION SPACE MAPPING A continuous process is subjected to the same rigor in control strategy development as a batch process. A continuous process benefits from operating under a “state-of-control”,7 which by definition minimizes process variability. However, the effect from a process disturbance on steady state and the downstream operations must be understood. A recent paper presented a case study where an integrated plant-wide control approach was applied to a fully continuous process and demonstrated that the critical quality attributes (CQAs) of the final product can be kept close to specification in the presence of significant and persistent disturbance.8 Nevertheless, the operation space along with the process dynamics must be understood before such a process controller scheme can be designed. Grignard Reaction Kinetics Model Development. A combined mass transfer and reaction kinetics model was C



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Scheme 2. Formation of the Wurtz Coupling Impurity

Figure 2. Model simulation for Compound D stressed study at −25 °C.

Operation Ranges for Process Parameters. To ensure product quality, the End of Reaction (EoR) target in the CSTR is set to be not less than 95% based conservatively on the rejection limit of each impurity under standard operating conditions. However, the proven acceptable ranges for the process parameters could be expanded based on understanding the impact of multivariate perturbations has on reaction conversion or impurity profile. For example, if the reaction conversion dropped from 95% to 85% (outside of EoR target) due to process disturbance, experimental data showed that up to 17% of the unreacted Compound D can be rejected in the isolation step resulting in no impact on product quality. While the process is intended to operate around the targeted set points, it is important to understand the multivariate operating space, in which movement within has no impact on product quality. The Grignard CSTR model was applied to map the corresponding operation space of the input process parameters based on a given reaction conversion rate or impurity profile. In addition to controlling process parameters such as temperature and flow rate, another important aspect to product quality is around Mg concentration inside the CSTR. The project team decided against charging Mg continuously into the CSTR via any hopper or screw feeder system due to equipment constraints and safety concerns. Instead, Mg is designed to be charged periodically, resulting in a sawtooth pattern for Mg concentration. To ensure simplicity of operations, the Mg charge amount and charge frequency were planned to remain constant in commercial production. Therefore, the timing of the first Mg recharge determined the minimum Mg concentration in the CSTR prior to subsequent Mg charges for a given reactor temperature and residence time combination. The reaction conversion rate in the CSTR can be maintained above 95% for as long as the Mg concentration is

Impurity Control Strategy for CSTR. The baseline processing condition is defined in Table 1 under normal operating conditions, in which the reaction conversion is controlled to be not less than 95%. There are two main impurities originating from the Grignard reaction, the unreacted Compound D and the Wurtz coupling impurity (Scheme 2). The Compound D concentration in the CSTR exit stream is controlled by the residence time, Mg surface area, and reaction temperature. Compound D is a genotoxic impurity that is highly soluble in the crystallization solvent system at 12 wt % and is controlled to be not more than (NMT) 80 ppm in the isolated Step 2 intermediate. Based on solubility and spiking study results, the Step 2 isolation step can reject up to 17 mol % of unreacted Compound D from the Grignard reaction mixture to give acceptable material. Any unreacted Compound D can further react with the Grignard reagent to form the Wurtz coupling impurity as shown in Scheme 2. The measured reaction kinetics for the formation of the Wurtz coupling impurity is 3 orders of magnitude less than the Grignard formation rate at the CSTR operating temperature. Based on the selectivity between the two reactions, the Mg concentration is kept much higher than the incoming Compound D concentration to ensure a high conversion rate in the CSTR, thereby suppressing the Wurtz coupling impurity formation. However, any unreacted Compound D in the accumulation tank will react with the Grignard reagent to form the Wurtz coupling impurity over time in the absence of Mg. While the Step 2 isolation step can reject high level of Compound D, there is a lower rejection efficiency for the Wurtz coupling impurity at 8 mol %. Therefore, the conversion target of the Grignard reaction in the accumulation tank is controlled tightly to not less than 95% to ensure product quality. D



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Figure 3. Model simulation for the Compound D stressed study at 28 °C. (a) Predicted conversion rate and Compound D (BzBr) concentration profile compared with IR data. (b) Temperature profile of the CSTR between experimental data and model simulation.

continuously to maintain a 30 min residence time and the operation volume of CSTR is controlled by the outlet tube position (see Settling Pipe Design section for details). As the Mg is being charged periodically into the CSTR, the total Mg concentration operated as a sawtooth pattern as shown in Figure 2. A second stressed study was designed to maintain the same conversion rate at 80% while changing only the reaction temperature to 28 °C as compared to stressed study no. 1 (Figure 3). While more Wurtz coupling product was formed in the accumulation tank at the elevated temperature, the second study was intended to show how different processing conditions can be used to achieve the same conversion rate. The Wurtz coupling impurity level as demonstrated in the third stressed study is controlled by limiting the Compound D concentration in the accumulation tank by tightly controlling the conversion rate of Grignard reagent in the CSTR. Figure 3 shows a favorable comparison between the simulated profile and the calibrated IR data verifying the model’s capability in predicting the critical Mg level. Furthermore, the reaction kinetics model was coupled with an energy balance to verify whether the reaction temperature can be used to monitor conversion rate as shown in Figure 3b. As demonstrated in the first two case studies, the Mg concentration is key to controlling the conversion rate at a fixed residence time and reaction temperature. The model is crucial in identifying the critical Mg concentration at different reaction temperatures with the same residence time. During normal operation, the Mg mass in the CSTR at all times is designed to be kept well above the minimal concentration such that the conversion rate would remain smooth throughout the operation. The third stressed study was designed to make material at the thermodynamic rejection limit of the Wurtz coupling impurity based on the solubility study. The reaction mixture was then forward processed to the isolation step to establish a maximum rejection level. Given the relatively slower reaction kinetics of impurity formation, the stressed study was designed to control the conversion rate between 90 and 95% while keeping the reaction temperature at 25 °C with a 60 min residence time. Any unreacted Compound D was then allowed to further react with Grignard reagent to form the Wurtz coupling impurity in the accumulation tank. The 90−95%

above the minimal amount established by reaction kinetics, mass transfer, and Mg removal via the settling pipe. Hence, reaction temperature and residence time were used as inputs to the kinetics model in order to calculate the frequency and amount of Mg charge to maintain a specified reaction conversion rate. It should be noted that the CSTR is never at steady state due to the constantly changing Mg concentration in the CSTR. However, the CSTR is operating under a state of control where the reaction conversion remain constant during production to give quality product. Table 1 below summarizes the main CSTR process parameters that control the conversion rate. The model simulated conditions at the edge of the operation boundaries, where the CSTR produced material with the maximum allowable impurity levels that meets product specifications. These stressed studies [While there might be multiple combinations of processing conditions that met the prespecified conversion rate, the three examples as shown below were used as part of model verification] implemented the simulated processing conditions that were designed to maximize Compound D and the Wurtz coupling impurity concentration in the accumulation tank. The reaction temperature and residence time were kept constant throughout the stressed study experiments such that reaction conversion was manipulated only by Mg concentration. The experiments were designed to operate around the predicted critical Mg level in which the Mg concentration was controlled through Mg recharge frequency and charge amount. The model verification was done by comparing the measured and predicted conversion rate over the course of the experiment. In the first stressed study, the residence time was set at 30 min with reaction temperature at −25 °C to control the conversion rate between 80 and 85% in order to maximize Compound D concentration at the CSTR exit stream. The lower reaction temperature was designed to minimize the formation of Wurtz coupling impurity in the accumulation tank. Figure 2 depicts the model prediction overlaid with HPLC and mid-IR data collected over time to verify model accuracy. The IR data was calibrated based on HPLC samples to determine the conversion rate and Compound D concentration as detailed elsewhere.9 In order to maintained the 80−85% conversion, a Mg recharge of every 50 min was required as shown in Figure 2. The Compound D solution was added to the CSTR E



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Figure 4. Model simulation for the Wurtz coupling impurity stressed study at 25 °C.

Figure 5. (a) Draft tube simulation geometry. (b) Corresponding flow field (streamline plot). (c) Particle trajectory for 15 μm particles.

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MG SEQUESTRATION EFFICIENCY One of the main assumptions of the reaction model is that only negligible amount of Mg left the CSTR in the mass balance. Since Mg concentration is one of the key process parameters controlling the conversion rate in the CSTR at a given residence time and temperature, there was a separate effort to design the equipment to better sequester Mg inside the CSTR using Computational Fluid Dynamics (CFD) modeling. The Mg concentration is controlled by the Mg consumption rate, Mg recharge frequency, and the removal of Mg from CSTR via the settling pipe/Mg trap. In addition, an operation variability analysis was conducted to determine the Mg concentration based on variability in charge amounts. This combined efforts lead to the final definition of the operational strategy. Settling Pipe Design. The settling pipe allows Mg particles to drop to the bottom of the pipe by gravity and then slide back down into the CSTR. The angle of the pipe shortens the settling distance to aid with the solid−liquid separation. A smaller diameter outlet tube is positioned inside the settling

Grignard conversion is designed to generate approximately 8 mol % of the Wurtz coupling product to verify rejection efficiency downstream. The Mg charging time in the experiment was implemented based on model prediction (Figure 4). The IR measured conversion rate along with HPLC data were used for reaction kinetics model verification. These case studies demonstrate that both the conversion rate and the impurity profile can be controlled by one or all of the process parameters. The reaction kinetics model explains the correlation between process parameters and conversion rate. These experiments verified the model’s capability in predicting conversion rate or impurity profile based on the input processing conditions. More importantly, the model provides valuable information on the process dynamics as process disturbances are introduced and the subsequent impact on product quality as a function of time. F



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then simulated 100 spherical particles of the same size into the settling pipe to solve for the particle trajectories (Figure 5c). Different particle sizes were repeated in the simulation to determine the largest particle size (critical particle size) that can exit the settling zone into the Mg trap. The model was utilized to calculate the critical particle size over various bend angles (θ = 20, 30, 40, 50, and 60°) at a fixed pipe diameter (DT = 30 mm). Figure 6 shows the critical particle size decreases with

pipe (above the bend as shown in Figure 10) at the CSTR operational level to control reaction volume by continuous withdrawal of product solution. The team focused on two areas to optimize the equipment design. The first was the settling pipe geometry, designed to maximize the solid−liquid separation, thereby, decreasing the critical particle size that can exit the settling pipe to the Mg trap [The Mg trap is a secondary container that allowed additional settling time for Mg particles prior to collecting in the accumulation tanks. Reaction mixture in the trap can be recirculate back into the CSTR in the event of Mg build up]. The second was the placement of the entrance of the settling pipe in relation to the CSTR agitator. The position was determined by the fluid flow in the CSTR minimizing Mg particles entering the settling pipe. Two separate computational models were used to guide the design followed by experimental verification. The settling pipe model first calculated the flow field pattern (Figure 5b) of the liquid moving up through a given geometry (Figure 5a) by solving the Navier−Stokes equations.10 Then, the model applied the calculated fluid flow field to solve for the trajectories of particles based on force balance on each particle (Figure 5c). The force balance as shown in eq 4, takes into account forces of gravity, drag, and the lift acting on the particles (assumed spherical).11 The model was built using the Comsol finite element software package, V4.3. It assumes the liquid flow is laminar, the liquid is incompressible, no particle−particle interaction due to low particle concentration, and the inlet velocity profile to the settling pipe is uniform.

Figure 6. Critical particle size vs settling pipe bend angle at a fixed tube diameter (30 mm) based on simulations.

increased inclination angle. Angles greater than 60° were not explored due to concerns with gravity removal of settled particles back into the CSTR. Once the bend angle was finalized, the critical particle sizes were calculated over three different settling pipe diameters at two different inlet liquid flow rate (Q, L/min) based on residence time as shown in Table 2.

2Kv1/2dij du i p 36v (uj − uj p) (ui − ui p) + = 2 dt d (2S + 1)Cc Sd(dlkdkl)1/4 ⎛ 1⎞ + ⎜1 + ⎟gi + ni(t ) ⎝ (4) S⎠ ui = ui̅ + u′i 2λ Cc = 1 + (1.257 + 0.4e−1.1d /2λ) d

dij =

1 (ui , j + uj , i) 2

Table 2. Impact of Inlet Liquid Flow Rate and Settling Pipe Diameter on Critical Particle Size for Commercial Scale Equipment

(5) (6) (7)

where the following nomenclature is used: • uiP = velocity of the particle • xi = position of particle • t = time • d = particle diameter • S = ratio of particle density to fluid density • gi = acceleration of body force • ni(t) = Brownian force per unit mass • v = kinematic viscosity • K = 2.594, the constant coefficient of Saffman’s lift force • ui = instantaneous fluid velocity based on mean fluid velocity (u̅i) and fluctuating component (u′i) as shown in eq 5 • Cc = Stokes-Cunningham slip correction given as eq 6 • λ = molecular mean free path of gas • dij = deformation rate tensor as defined in eq 7 The methodology described below was applied to optimize the settling pipe geometries (Figure 5a) limited by the physical constraints of the CSTR (i.e., dimension and clearance with agitator). The model calculated the flow field (Figure 5b) and

tube diameter (mm)

liquid flow rate (L/min)

critical particle size (μm)

25 30 35 30 35

0.8 0.8 0.8 1.17 1.17

55 47.5 45 58 55

As expected, the simulations showed that the critical particle size decreased as the settling pipe diameter increased and as the liquid flow rate decreased. Based on the model simulations, the final settling pipe design fixed the inclination angle at 60 degrees while maximizing the pipe diameter limited by clearance of the CSTR reactor. Positioning of Settling Pipe. The placement of the settling pipe in the CSTR is important to minimize entrance effects on particle settling. Thus, a separate model was constructed to understand the flow and pressure behavior in the CSTR based on the Reynolds-averaged continuity and momentum equations (Figure 7). The calculations were performed in ANSYS-Fluent v14.5. The placement of the settling pipe away from the flow direction was favored to limit the number of Mg particles entering the settling pipe. The settling pipe is also best positioned in the high pressure zone where the highest liquid level in the pipe maximized settling time. Based on model simulation, the results suggested the settling pipe be positioned either above the impeller (either G



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Figure 7. (a) Simulation of local pressure with a retreated curve impeller (RCI @ 99 rpm, C/D = 0.25, T/D = 2, α = 60°, φ = 15°); (b) fluid flow vector of the same RCI.

axial or radial flow) in the downward pumping zone, or, if a vortex is present, toward the reactor wall where the entrance is at higher pressure zone due to liquid head. Laboratory Assessments. Prototypes of the final settling pipe design were made at two different scales (2 and 30 L CSTRs) for laboratory assessments. The prototypes were scaled down geometrically with the pipe diameter and length ratios based on the tank diameter. Since the liquid flow rate inside the settling pipe at different scales would be different, the CFD model was used to estimate the critical particle size at each scale to adjust for the different Reynolds number with the corresponding exit flow rate (Table 3). In the first scale down

on the Zwietering Njs equation,16 the geometrical constant was then corrected based on experimental data to calculate the minimal agitation speed needed at commercial scale (Table 3). During the 2 L mixing study, a significant vortex was observed at all mixing speeds above 100 rpm at the target operating liquid level. In the presence of vortex, the experimental data showed that positioning the settling pipe outward radially near the tank wall provided greater liquid height inside the settling pipe, resulting in better particle separation as compared to positioning the pipe above agitator. At the end of the run, the Mg particles that escaped the settling pipe were sampled for particle size analysis via laser diffraction. A small amount of Mg particles were captured in the Mg trap throughout the reaction, with an average measured particle size of 6 μm (Figure 8). The

Table 3. Settling Pipe Dimension across Three Scales

reactor diameter (mm) reaction volume (L)a height of operation volume (mm) settling pipe diameter (mm) bend angle (degree) vertical tube height to bend (mm) angled tube length (mm) flow rate (L/min) predicted critical particle size (μm) just suspended speed, Njs (RPM)b Sherwood number correlationc (RPM)11−14

2L reactor

30 L reactor

commercial (100 L)

140 1.01 74.8 14 60 42 73 0.017 20 200 277

400 23.4 213.4 38 60 111 192 0.39 34 83 139

508 48 271 50.8 60 141 244 0.8 36.5 67 110

Figure 8. Microscopy of Mg particles collected at the 2 L experiment.

experimental data suggested that at the tested agitation speeds, the draft tube performed much better with Mg sequestration than the CFD model prediction (Table 2). The relatively large difference between the measured and predicted Mg particle size is likely due to the spherical particles assumption used in the force balance calculation for particles trajectories. Despite the higher prediction uncertainty, the model still provided a directional guidance on settling pipe design and provided a more conservative estimation on critical particle size for assessment. In addition to testing the settling pipe position and design, the 2 L experiment also verified whether operating at the measured just suspended agitation speed (200 rpm) could maintain a similar mass transfer rate (Kla) upon scale up from 250 mL to 2 L.9 Figure 9 shows the model predication compared directly with experimental data without refitting of any parameters. The scale-up experiment was designed to verify the predicted critical Mg concentration required to maintain

a

Assumes DIN torispherical bottom. bThe Njs calculation is based on 13% solid loading. cAssumes diffusion coefficient 4.25 × 10−6 cm2/s (Stokes−Einstein equation for bromobenzene in 2-MeTHF).

experiment at 2 L, the benzyl bromide Grignard reaction was conducted to assess both the settling pipe performance with changing Mg particle size and verification of the reaction model at a larger scale. The second scale down experiment at 30 L, was designed to further assess the mixing and settling pipe performance with deactivated Mg particles in pure solvent. The 2 L reactor was equipped with a single finger-baffle, geometrically similar to the commercial reactor. The just suspended agitation speed (Njs) at the 2 L scale was experimentally determined to be 200 rpm, at which no Mg particles was observed to be stationary for more than 2 s. Based H



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Figure 9. Model prediction compared with experimental data for the 2 L scale up study.

opening position of the settling pipe inside the reactor along with different liquid withdrawn rate. The experimental setup has a recirculation loop between the settling pipe exit and a Mg trap designed to catch Mg particles that escaped from the outlet tube (Figure 10). After at least three turnovers at each condition, the Mg trap was drained for a visual observation to qualitatively compare the settling pipe positions. Due to limited baffling with the finger baffle, there was also significant vortex at the tested agitation speed. The experimental data reaffirmed the model guidance in that the positioning of the pipe should be rotated toward the reactor wall in the presence of vortex. The liquid level inside the settling pipe will therefore be higher for a given liquid volume in the CSTR. Both the 2 L and 30 L experiments showed that the settling pipe design and its placement in the CSTR effectively sequestered Mg within the CSTR even at high agitation speed. The experimental data verified one of the main model assumptions around Mg mass balance in CSTR, which allowed further utilization of the model as key component to finalize the operation strategy.

constant conversion rate. Thus, the team delayed a Mg recharged at 365 min where the reaction conversion is predicted to drop as part of model verification. The model was able to accurately predict the timing of the drop, thereby confirming the critical Mg concentration at the processing condition. Since Mg concentration would be maintained manually via Mg recharge at commercial scale, the critical Mg concentration became a key piece of information needed to build a robust operation strategy as discussed in the section below. The agitation speed for the commercial reactor would need to be sufficient for proper Mg particle suspension to ensure the reaction is not mass transfer limited, while keeping a minimal number of particles from entering the outlet tube. The 2 L experiment showed that with an appropriate placement of settling pipe opening at low agitation speed, the settling pipe performed satisfactorily. Thus, the project team further scaled up the settling pipe to 30 L at higher agitation speed. The maximum agitation speed at the commercial scale is 140 rpm (100 L), and the Sherwood number correlation12−15 was used to estimate the agitation speed at the 30 L scale to test the Mg sequestration efficiency (Table 4). The experiment varied the

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OPERATION STRATEGY DESIGN The reaction kinetics model and settling pipe design to maximize Mg sequestration helped define the CSTR design. Additional development work as detailed below was needed to refine the operation strategy in how the CSTR will be implemented at manufacturing over the product life cycle. The operation strategy is designed to maintain and monitor a continuous process to ensure it is always under a state of control. A state of control operation is demonstrated when it could be possible to designate large quantities of product to be of uniform quality, even though different batches of raw materials and/or different processing conditions may have been utilized during the production run.7 Thus, the rest of the paper focuses on the following: (1) identify process parameter that could be monitored in real time that is sensitive enough to reflect changes in reaction conversion; (2) develop a robust Mg recharge strategy to ensure a constant reaction conversion rate in the CSTR can be maintain throughout operation.

Table 4. Experimental Observations of the 30 L Mg Sequestration Efficiency Test test case no.

flow rate (mL/min)

speed (rpm)

settling pipe opening position

1

800

176

center (0.5 in above agitator)

2

400

176

center (0.5 in above agitator)

3a

800

176

4

1600

176

wall (0.5 in above agitator) wall (0.5 in above agitator)

sequestering efficiency ∼ 50 particle pieces drained out from Mg trap ∼20 particle pieces drained out from Mg trap ∼5 particle pieces drained out from Mg trap ∼100 particle pieces drained out from Mg trap

a

Test case no. 3 is the baseline condition for 60 min residence time at commercial scale equipment. I



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Figure 10. Experimental set up for the 30 L Mg sequestration test.

Table 5. Model Simulation of Minimum Mg Amount and Reactor Temperature at Various Conversion Ratea conversion (%)

min Mg (kg) τ = 30 min



T (°C) τ = 30 min

T (°C) τ = 60 min

T (°C) τ = 90 min

99 98 97 95 90

4.1 1.8 1.3 0.7 0.35

2.5 1.2 0.8 0.45 0.25

2.1 0.4 0.1 0.35 0.15

33.2 32.7 32.1 30.9 27.8

15.8 15.5 15 14 11.3

7.6 7.3 6.8 6.1 3.7

a

For the commercial scale, each production batch requires a totle of 35 kg Mg, which will be charged separately as shots in the CSTR to maintain the conversion rate above 95% while maintaining a constant jacket temperature at 0 °C.

Reaction Monitoring. The benzyl bromide Grignard reaction is a highly exothermic reaction with the measured heat of reaction (ΔHrxn) at −340 kJ/mol. The main concern for the project team was whether reactor temperature is sensitive enough to detect a drop in conversion rate inside the CSTR when the jacket temperature is kept constant. Table 5 summarized the model simulations at different residence times (τ, min) as Mg is being consumed using the same operating condition. The results provided two pieces of important information for the overall operation strategy. First, the model simulations calculated the minimum Mg amount required to maintain a given conversion rate for specific residence time and reaction temperature. For instance, if additional Mg is charged into the CSTR prior to the Mg level reaching 2.5 kg (in the case where τ = 60 min and Tjacket = 0 °C), the conversion rate will be maintained above 99%. Second, the model simulations showed that reactor temperature is sensitive enough to be used to monitor the CSTR conversion rate to ensure it is NLT 95%. The corresponding 1.5 °C difference in reactor temperature is above typical measurement noise of the thermocouple (±0.5 °C). It should be noted that, while the overall heat transfer coefficient is assumed constant in the calculation, a real time heat balance can be implemented at plant scale to account for the changing Mg mass in the CSTR if needed. Finally, the model provided process dynamics information which can be translated into process response time before the reaction conversion rate to drop from 99% to 95% or from 95% to 90% (Table 6). The rate of temperature drop also provide additional information for the operator to check whether a Mg charge has been missed based on recorded temperature profile at scale. For example, if the operator detects

Table 6. Model Simulation on Time Required for Different % Conversion Drops time (min)

τ = 30 min

τ = 60 min

τ = 90 min

Δt99→95 Δt95→90

147 20

192 28

254 34

a drop in conversion based on reactor temperature profile, the operator only have 28 min (based on simulation of τ = 60 min) to add the missed charge in order to prevent conversion rate to drop from 95% to 90%. Mg Recharge Strategy. Operation variability in the Compound D solution concentration and/or Mg charge amount can be expected for a routine commercial operation. The team’s concern was forced around the lack of direct measure in Mg quantity inside the CSTR, since a heel of Grignard reaction mixture along with activated Mg would carry over from lot-to-lot for the entire campaign. Thus, a small consistent offset in concentration of either Compound D or Mg would result in over consumption or accumulation of Mg in the CSTR over time. Based on the previous analysis, reactor temperature would be used to detect over consumption of Mg as the conversion rate drops. Thus, the question to be answered with regards to Mg accumulation was whether there is a maximum Mg amount that could lead to process safety concerns. The CSTR setup at the manufacturing plant will only be connected to the Compound D reactor and to the 2MeTHF farm tank to minimize the risk of adding other reagents/solvent to the vessel. Nevertheless, a plausible scenario was identified whereby excess acid (i.e., hydrobromic acid used in bromination to prepare Compound D solution) J



Article

could be carried over around dead leg in the pipe setup or in the bromination reactor due to human error. The acid would then react with Mg to produce hydrogen, and this could lead to pressure build up in the CSTR. In order to minimize capital investment, the CSTR is vented directly to the plant’s volatile organic compound incinerator, which allowed flow rate of hydrogen at less than 10 m3/h. Based on vent sizing calculations and the restriction on hydrogen flow rate, the Compound D addition line is sized to limit flow rate to less than 1 L/min (the residence time is also limited to NLT 60 min at 0.8 L/min for proper heat removal), thus removing safety concern around maximum Mg concentration from the stand point of hydrogen evolution. While the team was concerned about Mg suspension at high quantities, experimental result confirms the fact that the Grignard reaction rate would increase with Mg concentration, thereby minimizing the effect of decreased mass transfer or reduced reaction volume/residence time due to displacement by Mg build up [The analysis assumed the CSTR agitator is still operational even as Mg mass build up. A separate alarm is designed to monitor the agitator power draw to detect potential agitation failure]. As a result, the team decided to enforce visual observation based on vessel landmark (i.e., per-marked location along agitator/baffle based on volume) on Mg quantity inside the CSTR at the end of each batch during production as there was no safety or product quality impact. The above analysis suggested that there is no upper limit with Mg amount and the lower limit is set by reaction kinetics and mass transfer rates (i.e., reaction conversion). This information coupled with the desire from manufacturing to minimize the frequency of manual charges helped to determine the Mg recharge strategy. The team looked at four different recharge schedules based on the number of charges per batch (twice per 12 h shift or once per 12 h shift) and the Mg concentration prior to recharge (3 or 5 kg based on 60 min residence time, see Table 5 for minimal Mg amount). In order to quantitatively compare different schedules, the team looked at how process variability can affect the Mg level in the tank based on different Mg recharge schedules. Statistical analysis from previous manufacturing experience suggested that the incoming Compound D concentration can vary up to ±2.6 wt %, and the Mg charges can vary up to ±1 wt %. Based on this information on process variability, 1000 simulations were run for the entire campaign (total of 7 lots) using two different random numbers per lot (assuming normal distribution) for charge variability in both starting materials. Each simulation outputs the amount of Mg particles carried over from lot-to-lot and reported the final amount of Mg particles at the end of the 7 lot campaign. The simulation results, summarized in Table 7, suggested having two Mg recharges per shift coupled with a higher Mg level provides the lowest probability of over-

consuming Mg by the end of the campaign. Furthermore, more frequent Mg recharges at higher Mg level resulted in a reduced degree of Mg concentration oscillation between charges. Based on the simulation results, the team recommended the Mg recharge strategy to manufacturing.

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CONCLUSION This paper outlined the methodology in combining modeling and experimentation in a feedback manner to map the operation space of the continuous Grignard operation and the design of the settling pipe for Mg sequestration. Furthermore, the model was applied to understand process dynamics in the presence of process disturbances such as missed Mg recharge or changes in reagent concentrations. The results showed that reactor temperature may be used to monitor the CSTR conversion rate and helped design the Mg recharge strategy to maintain a constant conversion rate. The method led the team to systematically and efficiently refining the operation strategy to ensure the CSTR will be monitored and maintained under a state of control for commercial production.

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*E-mail address: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Edivoxetine·HCl development team and management of Eli Lilly and company for the support.

Mg level prior to recharge (kg)

probability of Mg level below 0 kg

probability of Mg level below 2 kg

2 1 2 1

5 5 3 3

0.01 0.09 0.14 0.10

0.14 1.91 6.91 7.47

REFERENCES

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Table 7. Summary of 1000 Simulation To Predict Probability of Mg Amount Dropping below 0 or 2 kg (Based on 60 min Residence Time) no. of charges per shift

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