Progress to date in the design and operation of continuous

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Review

Progress to date in the design and operation of continuous crystallization processes for pharmaceutical applications Barbara Wood, Kevin Girard, Christopher Polster, and Denise M. Croker Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00319 • Publication Date (Web): 10 Jan 2019 Downloaded from http://pubs.acs.org on January 11, 2019

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Organic Process Research & Development

Progress to date in the design and operation of continuous crystallization processes for pharmaceutical applications Barbara Wood1, Kevin P. Girard2, Christopher S. Polster3, Denise M. Croker1,* 1Department

of Chemical Sciences & Synthesis and Solid State Pharmaceutical Centre (SSPC), Bernal Institute, University of Limerick, Ireland 2Pfizer,

Chemical Research and Development, Worldwide Research and Development, Groton, Connecticut, United States 3Small

Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States * [email protected]

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Graphical Abstract


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Abstract Continuous crystallization has gained interest in the pharmaceutical sector as part of the drive towards the transition from exclusive batch manufacturing to integrated continuous manufacturing in this industry. As a result, the design and operation of continuous crystallization processes for the preparation of pharmaceutical materials has featured strongly in recent scientific literature. This review is an effort to gather together all published understanding on continuous crystallization with a pharmaceutical focus and to benchmark progress to-date in realizing the potential benefits of transitioning this stalwart pharmaceutical unit operation from batch to continuous configurations. Key words: Continuous crystallization, pharmaceutical manufacturing, MSMPR crystallization, COBC, Plug flow crystallizers,



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1.0 Introduction Crystallization is a key unit operation in pharmaceutical manufacturing, used almost universally for the purification and isolation of solid crystalline active pharmaceutical ingredients (APIs) from mother liquors. Typically employed in batch format, there has, of late, been a dedicated interest to develop continuous pharmaceutical crystallization processes to mirror progress achieved in continuous pharmaceutical reaction chemistry 1-4 and drug product formulation 5,6 and enable end-to-end continuous manufacture of APIs and, ultimately, final drug products. Rationale for Continuous Crystallization in Pharma Benefits associated with continuous crystallization relative to batch crystallization include improved product robustness, increased product consistency, and superior control of product attributes. Continuous crystallization operates at a “steady-state” vs. time, or more accurately under a constant state of control which allows for small variations in process parameters which do not affect critical product attributes. Implementation of continuous crystallization would reduce batch-to-batch variation contributing to improved downstream processing and drug product formulation. Additionally, reduced processing footprints for continuous crystallization equipment relative to the corresponding batch piece, and hence capital expenditure, contributes towards the establishment of modular flexible processing units, which could be more easily transferred to different locations on demand. This enables agile manufacturing on demand to better meet fluctuating market needs. Most importantly, continuous crystallization has the potential to enable elimination of conventional scale-up strategies as the development scale becomes the production scale with increased operating times. Significantly, the Food and Drug Administration (FDA) in the United States has come out in strong support of continuous pharmaceutical manufacturing as a methodology to achieve improved process quality and control 7-12. Challenges Despite these benefits, there are challenges associated with continuous crystallization, mainly centred on the issues of fouling and blockages 13. Inherently involving the use of supersaturated solutions, continuous crystallizations can suffer from material depositing on reactor and transfer line surfaces. Due to the move towards lower production volumes of pharmaceutical products, continuous crystallization equipment, and more specifically transfer lines, tends to be small. This coupled with low flow rates in these systems, contributes further to the occurrence of blockages and fouling from material deposition. As continuous processes operate under a constant state of control rather than reaching equilibrium as in batch processes, the yield from continuous crystallization also tends to be lower than that from the equivalent batch process, making the continuous process less attractive from an economic perspective. Specifically relating to pharmaceuticals, there is also a quality consideration in transitioning to continuous processing, in that new procedures are required to track and test material, leading to the question of what constitutes a batch in the continuous process. Continuous crystallization is an established process, demonstrated at large production scales in many industries – sugar processing, dairy industry, minerals refining, but it becomes challenging at small scales which is where the pharmaceutical production volumes are trending. Recent review papers have focused on continuous crystallization technology and control strategy options (Wang et al 14) and the impact of the continuous crystallization on particle properties from a particle engineering perspective (Zhang et al 15). The objective of this review paper is to critically evaluate all significant studies relating to the operation of continuous crystallization for pharmaceutically relevant molecules in one location. This will identify common approaches to the continuous crystallization of pharmaceuticals and highlight any shortcomings to-date, which may re-evaluate how we research and develop 4|Page ACS Paragon Plus Environment

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continuous pharmaceutical crystallization processes. The review is divided into three main sections covering literature relating to mixed suspension mixed product removal systems (MSMPR) including single stage and multistage systems, plug flow crystallizers (PFCs) and continuous oscillatory baffled crystallizers (COBCs). While the COBC is technically a variant of the plug flow crystallizer, the operating conditions and advantages of the system are quite different and there has been an equal interest in COBCs as for PFCs for continuous crystallization of pharmaceutical ingredients. For these reasons, they are discussed in a discrete section, separately from PFCs. All systems are well characterised in traditional engineering text books 16-18. The reader is referred to any established crystallization text book for comprehensive information on the crystallization process 19,20. Each section is divided into subsections covering pertinent aspects of the technology. 2.0 MSMPR operation Successful employment of MSMPRs for crystallization relies on homogenous mixing and appropriate product slurry withdrawal mechanisms to minimise variation in residence time in the reactor and maximise sample representativeness. An advantage of MSMPR production over other continuous crystallization systems is the ability to utilize existing pilot scale stirred tank equipment for operations and their simplicity of operation and control. Disadvantages include the potential for a broad residence time distribution in the vessel, which can lead to broad particle size distributions, difficulties in scale-up due to reducing heat transfer areas, representative mixing scale up and complicated transfer mechanisms at low flow rates. All known reported studies on the employment of MSMPRs for continuous pharmaceutical operation are captured in Table 1. Prominent articles are discussed below in relation to operational aspects of the crystallization process, or attributes of the product of that process. 2.1 Operational Aspects 2.1.1 Demonstrated Production Capacities/Throughputs/Scale

Of the 35 studies reviewed in table 1, the vast majority (80%) had an operating volume of 500 mL or less and of these only four studies had an operating volume less than 100 mL. Only three studies 1,21,22 described a system with an operating volume of greater that 1 L. Scale up of continuous crystallization is rarely discussed. Suitable capacity to meet the desired production rate for the APIs is essential for the success of this type of production platform. In this section a selection of MSMPR studies at different scales are described. As part of a collection of work relating to the Novartis-MIT Center for Continuous Manufacturing, the reactive crystallization of aliskiren hemifumarate using a two stage MSMPR was investigated by Quon et al. 23. The system consisted of two 50 ml glass jacketed MSMPRs connected in series (figure 1). An operating temperature of the reactors were selected in order to prevent overly rapid generation of supersaturation and the precipitation of fumaric acid before it had reacted with the base to form the product.

Figure 1: Schematic of the continuous MSMPR apparatus for reactive crystallization of Aliskiren hemifumerate Reproduced with permission from Quon et al 23. Copyright 2012 ACS Publications. 5|Page ACS Paragon Plus Environment


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The system was run continuously for 48 hours. The process produced high purity material (99%) with a needle like habit, comparable to batch operation. A scaled up version of the same process described by Quon et al. 23 was described by Zhang et al. 21. Each crystallizer was a 15 L jacketed glass reactor with an overhead stirrer. A four hour residence time was chosen based on crystallization kinetics. 45 g/hour of API was produced. The system was operated for over 100 hours. A pilot scale continuous crystallization system was demonstrated by Polster et al. 1. This paper introduced the concept of laboratory fume hood commercialization (LHC), with commercial material produced continuously in an enclosed fume hood. A continuous reactive API crystallization was developed using a Mettler-Toledo OptiMax reactor operated at a 300 ml volume. Process solution (API HCl salt solution) and NaOH were added to the system via mixing elbows to a recirculation loop on the crystallizer (Figure 2).

Figure 2: Crystallization lab model schematic, Polster et al1. Reproduced with permission from reference Polster et al 1 Copyright 2014 ACS Publications The same system was successfully scaled up to 5 L crystallizer capable of producing 3 Kg of product per day and operated continuously for 72 hours. At any one time, only 1.2% of the campaign material was present in the crystallizer, significantly reducing processing risks. A total of 9.4 Kg of product was successfully isolated with acceptable physical property control. The continuous crystallizer used a seed loading of 1.3% by mass versus the 5-10% required for batch processing. Cole et al. published an example of a multi-step chemical synthesis of an investigational API under cGMP conditions in which the majority of the unit operations were operated linked together in continuous mode 22. The continuous crystallization step consisted of a 2 stage MSMPR, where each reactor had a volume of 3.5 L and a residence time of 60 mins, giving a total residence time of 120 mins. The process as a whole ran successfully for nearly 200 hours producing 24 Kg of product from the final step.


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With a few exceptions, the majority of work in MSMPR systems to-date has featured at the 500 ml reactor size or smaller. This could be attributed to the cost of materials for running experiments, or low production requirements for low-volume pharmaceutical products. Continuous operation in small volume equipment can yield large quantities of material on shorter timescale than the corresponding batch process, meaning that laboratory/development scale equipment is capable of meeting production demand at pharmaceutical scales. As result there are few papers which focus specifically on the scale-up of a pharmaceutical continuous crystallizer. Polster et al. and Zhang et al. demonstrate successful scale-up of MSMPR-based systems to modest scales (5 L and 15 L respectively) but there is nothing reported beyond this scale. This is most likely due to a lack of demand for higher capacities with pharmaceutical materials. In general, there is a trend of under-reporting of operational detail particularly with regard to the throughput or production rate of these systems. Also, many studies neglect to disclose the length of time the system operated. 2.1.2 Start-Up Modes Start-up of continuous MSMPR crystallizers can be a crucial component for successfully achieving a controlled state of operation. Improper start-up can cause operational issues such as fouling and even prevent achievement of a controlled state of operation. It is not advisable to begin with a dry crystallizer as this can lead to excessive nucleation and possible caking of material of vessel walls. In general crystallization processes begin with the crystallizer filled with solution or a crystalline slurry. If the process begins with a crystalline slurry, the solids present act as a seed bed. The crystalline slurry can be generated through batch crystallization. The start-up should be optimized to minimize loss of product and operational issues and also to limit time to steady state for increased efficiency. Below is an overview of selected studies where different start-up modes were compared. In the system described by Narducci et al. 24, a batch crystallization followed by continuous feeding and removal was initially attempted, with the temperature of the feed line maintained the same as the starting temperature of the batch crystallization. This start-up mode led to significant fouling and ultimate blockage of the product removal line. In a second attempt, a saturated solution was used as the starting point, and continuous hot feed and product discharge initiated to/from this saturated solution. No operating issues were encountered. The effect of the start-up mode was also examined by Hou et al. 25. Three different start-up modes were investigated. For the first mode, a saturated solution was charged at 40 °C and then cooled to 5 °C before MSMPR operation began. In the second start-up mode, a saturated solution was charged at the operating temperature of 5 °C. The third start-up mode also began with the addition of saturated solution charged at the operating temperature of 5 °C. Then isolated material from previous MSMPR operation was added to form crystalline slurry with the same “steady-state” magma density as normal operation. The product particle size distribution (PSD) was found to be independent of the start-up mode. The third start-up mode resulted in the shortest time to “steady-state” acquisition. Although for certain systems the start-up will not affect the particle size conditions when operating under a steady state of control 25, it is clear that from an operability perspective careful consideration of start-up conditions can be required. Continuous cooling crystallization of carbamazepine in ethanol and water with form control in a two stage MSMPR was demonstrated Xiaochuan Yang et al. 11. This paper is a direct demonstration of engagement of the US FDA in understanding continuous processes and helping to establish important aspects of process control strategy. It was noted that further optimization is required around the reproducibility of the start-up of the continuous crystallization. Start-up optimization can reduce the time to steady-state operation, reducing waste and increasing productivity. Results from Hou et al indicate that starting 7|Page ACS Paragon Plus Environment


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a continuous crystallization process with a crystalline slurry where the particle attributes are close to those of the steady state material gives the shortest time to steady state. The study by Narducci et al demonstrates that in some cases a saturated solution is a better start up option than using a slurry produced by a batch crystallization. It is clear that further research and reporting of results is required around the commonalities of different options for start-up procedure and optimization approaches. For form selection, seeding during startup may be essential to produce the desired form where the process is kinetically controlled. Increased reporting on the impact of start-up conditions on operability and time taken to reach a state of control would be beneficial. 2.1.3 Slurry transfer methods While much continuous chemistry can be performed homogeneously, continuous crystallization is naturally a two-phase system which surfaces a whole host of issues. Product classification can occur, resulting in unrepresentative transfer volumes and non-robust product characteristics. Adequate mixing can be problematic in any transfer piping and especially tubular crystallizers, as turbulence is required to maintain adequate suspension and prevent blockages, which are very common. Due to the small size piping necessary for lower throughputs in pharmaceutical applications, maintaining turbulent conditions can be a challenge. The liquid phase of the slurry is generally supersaturated under steady-state conditions which can cause further crystallization in the transfer lines, causing fouling and encrustation. This in turn results in product loss, blockages, and in some cases process failure. This section gives an overview of different methods used for slurry transfer in MSMPR continuous crystallizations and discusses recent publications which have specifically investigated this issue. Continuous crystallization requires that material is constantly fed into, and removed from, each crystallizer. For the first crystallizer in the process line the feed will be a clear solution, but all transfers from this point onwards will require moving a volume of suspension. It is important that these transfers are representative of the bulk contents, but also that they do not have the chance to change composition before they reach the next vessel and the desired operating conditions. It is recommended that the transfers take place quickly to limit the possibility of crystallization occurring in pipework. This will not only change the concentration in solution but can also contribute to the build - up of blockages in pipework. Rapid intermittent transfer of a “shot” of slurry is an efficient and popular means of successful transfer. To assist with the maintenance of steady state in each vessel it has been suggested that the volume of the transfer slug should be less than 10% of the operating volume in the vessel 25. Below 10% no significant disturbance in particle size should occur and a state of control can be maintained where a consistent particle size distribution is produced by the system 26. If possible, transfer pipework should be Teflon or some material with a low fouling index. It should be blown clean after each transfer or intermittently cleaned. There are three main methods of achieving slurry transfers during continuous crystallization: 1. Pump driven transfer Here pumps are used to transfer slurry, either continuously or intermittently. In 2011, Narducci et al. 24 utilized overflow with intermittent withdrawal for removal of slurry. The author highlighted the importance of intermittent product removal at lab scales to avoid product classification. Quon et al. 23 discusses intermittent slurry transfer in a two stage MSMPR. Because of difficulties with blockages in the transfer lines, slurry was moved from reactor 1 to reactor 2 intermittently at high flowrates. Every 20 minutes less than 10% of the slurry was transferred to reactor 2. Pumps operating intermittently were utilized to achieve this. Wider tubing was also used to decrease the chance of blockages. Heated metal tubing was used for addition to the second crystallizer in order to maintain the solution temperature and prevent the fumaric acid precipitating in the line. 8|Page ACS Paragon Plus Environment

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A paper by Li et al. 27 investigated the effect of operating conditions on yield and purity in continuous crystallization of cyclosporine using single stage, three stage and five stage MSMPR set-ups were investigated. Transfers were achieved using intermittent operation of a peristaltic pump at the maximum flow rate. Residence times of 9, 6 and 3 hours at each stage were achieved by changing the flow rate to the system (the operating volume remained constant at 155 mL). Transfers of 10% of the slurry volume were taken 10 times for each residence time. Methods for material transfer in a two stage MSMPR were investigated by X. Yang et al. in the development of a continuous crystallization system for carbamazepine 11. Intermittent withdrawal was found to transfer solids more effectively than continuous withdrawal but did result in an increase in fouling. Continuous withdrawal from the bottom of the vessel using a dip pipe was found to be the most efficient. 2. Use of transfer zones The transfer zone concept is based on the coordinated use of vacuum to extract a volume of suspension from one crystallizer into an intermediate holding zone (typically a length of tubing), and nitrogen pressure, to propel this volume into the next vessel. A dip pipe is used to limit the volume of the transfer slug. Operationally complex, this necessitates the use of a number of automated valves and a control recipe to oversee material transfers, but limited the time the suspension spent in transit, limiting the potential for fouling or unwanted crystallization in the transfer volume. Johnson et al. 3 used an intermittent pressure swing chamber referred to in subsequent publications as the pressure transfer zone and is the first reference in literature for use in continuous crystallization of APIs. Polster et al. 1 used transfer zones for slurry transfer, for each transfer, approximately of the total volume was removed. In this case transfers were performed every 5 minutes, with a residence time of 30 minutes. The lines were then purged with nitrogen to ensure there was no material left in the transfer line. 3. Pressure driven transfer This involves generating a pressure differential between the vessels to effectively propel suspension between one vessel and the next. In some cases, a valve in the transfer line allows for intermittent slurry transfer at high velocity, reducing the residence time in the transfer line. The the use of dip pipe in the first crystallizer limits the transfer volume, maintaining a minimum volume in the tank. This achieves the same net result as the transfer zone concept but is less operationally demanding. Cui at al. describes a two stage continuous crystallizer utilizing a “pressure driven flow crystallizer” (PDFC)28. A pressure differential between stages is created using a pressurizing pump in order to pump nitrogen into the reactor head space (figure 3). A dip pipe on the transfer line allowed for fixed volume transfers but maintained a minimum volume after intermittent transfer. A continuous cooling crystallization of azithromycin in acetone and water was performed in the system with a 31.5 ml operating volume in each stage. 24 hours (12 residence times of two hours) of operation was demonstrated. During operation the dissolved concentration was constant after 1 residence time in the system. The particle size was constant after 8 hours – two mean residence times. The PFA (perfluoroalkoxy alkanes) tubing used for transfers was compatible with various solvents. It was stated that evaporation of the solvent could occur through the pressurization of transfers and suggested that this could be reduced by minimizing the time for transfer or by saturating the nitrogen with the operating solvent.



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Figure 3. Pressure driven transfer system, as described by Cui et al. 28 No – normally open, Nc – normally closed. Reproduced with permission from reference Cui et al 28. Copyright 2016 ACS Publications Hou et al25 used vacuum transfer, a hybrid of methods 2 and 3. Rather than pressurizing the crystallizer a vacuum was drawn on the crystallizer via a collection tank. Slurry was transferred intermittently to the collection tank and the system is re-pressurized with nitrogen which also cleared the transfer lines. While pumps are still popular for transfers, pressure driven transfer and the use of transfer zones have several advantages. They require less maintenance and have a lower cost. The impact on the particle size is also reduced compared to a pump. Where the material is supersaturated or the slurry is at a high temperature compared to ambient, the potential for fouling and blockages is high, leading to increased risk and maintenance costs. Early studies predominantly relied on the use of peristaltic pumps to achieve suspension transfer 29-32. Approximately 46% of the MSMPR studies discussed in this review use pumps for slurry transfer vs 43% using pressure transfer zones. Recently, direct pressure driven transfer has gained popularity 28,33. Representative transfer of the crystalline suspension from one crystallizer to the next is challenging at pharmaceutical scales. There has been somewhat of a revolution during the last number of years in terms of the mechanisms employed to achieve material transfer across. While peristaltic pumps continue to be used successfully and are reported for material transfer in MSMPRs in recent studies 11,34, pressure transfer and intermittent slurry transfer allows for rapid transfer of representative slurry samples while minimizing associated issues with fouling and blockages. The successful use of simpler transfer methods vs. utilization of more complex methods indicates that some systems are more sensitive than others to slurry transfer issues. It would be useful for future publications to discuss why a certain transfer method was chosen, especially if other modes were tested and led to failures. Beyond simply as a method of representative slurry transfer, are there distinct operational advantages for one method over another. There are currently an insufficient number of publications to state conclusively why one method should be chosen over another and no methodology available for suitable selection. As previously discussed, there is little published on continuous crystallization processes performed at scales of greater than 1 L and none on the benefits of different transfer methods for different operating volumes. 10 | P a g e ACS Paragon Plus Environment

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2.1.4 Fouling During Continuous Crystallization Processes A common challenge with continuous crystallization is the overwhelming tendency of systems to foul and coat, resulting in encrustation on vessel walls and blockages in process lines. In MSMPR operation there is a constant steady-state supersaturation in the system which is the driving force for crystallization. If the system tends to foul under these conditions, it will continue for the full duration of the process. As well as causing operational challenges such as blockages and heat transfer issues, fouling can lead to a reduced yield as high value product is lost from the slurry removed from the system. Fouling naturally leads to changes in the mean residence time due to hold up in the system and changes in transfer rates which can result in a drift from the desired/intended state of control, possibly affecting critical product attributes. Because of these issues fouling is a major demotivating factor in the uptake of continuous processing by the pharmaceutical industry. Fouling can be reduced and sometimes prevented by choosing appropriate operating conditions. Management of fouling through in-line cleaning during operation can prevent catastrophic build-up of coating which may lead to blockages, thereby preventing process stoppages and failures. Alverez et al. 31 reported a total run time of 35 hours and 20 minutes in a three stage MSMPR with no fouling. Reactive crystallization of aliskiren hemifumarate using a two stage MSMPR was investigated by Quon et al. 23. As mentioned in section 2.1.3 slurry transfers were optimized to reduce fouling. Heated metal tubing was used for addition to the second crystallizer in order to maintain the solution temperature and prevent the fumaric acid precipitating in the line. In the pilot scale continuous crystallization system described by Polster et al. 1 fouling occurred in the crystallization loop after 66 hours of operation requiring the only stoppage during the process. Intermittent cleaning was successfully implemented for the system to prevent process failure due to fouling. Powell et al. 35 also reported successful operation of periodic steady-state flow crystallization of paracetamol using MSMPR operation for 11 residence times without blockages or fouling. This system is discussed in more detail in section 2.2.1. Powell et al. also investigated the use of an integrated PAT (process analytical technologies) array and multivariate methods to monitor continuous crystallization of form I paracetamol in the presence and absence of an additive – hydroxyl propyl methyl cellulose (HPMC) 36. A single stage MSMPR was used to investigate the effectiveness of the presence of HPMC for reducing fouling and encrustation during continuous operation. The system operated in a closed-loop, with product slurry re-dissolved and recycled as feed. The additive was found to reduce fouling by suppressing both nucleation and growth but with an associated reduction in yield. X. Yang et al. noted that developing an automated system for detecting clogging issues during continuous crystallization operations would be desirable 11. Steenham et al. 37 used a single stage MSMPR to achieve continuous crystallization of enantiopure crystals of sodium bromate from an achiral solution. Fouling of both chiral forms occurred for low feed concentrations and shorter residence times, demonstrating that manipulation of processing conditions can reduce fouling. While most of the literature refers to fouling, apart from the aforementioned studies, there is little specific detail on how fouling was encountered during continuous operation or what mitigation strategies were employed to combat it. Where publications are cited in this review but not mentioned in the section, it is assumed that fouling was not an issue, however this may not be the reality experienced during the development of these processes. Few of the publications which discuss fouling actually quantify the yield losses due to fouling. Increased emphasis on the practical aspects of fouling will generate a more fundamental understanding of the factors which influence it, ultimately enabling superior control and management of fouling issues. Without the ability to run for extended time without fouling issues, some of the gains in using continuous crystallization will not be realized 11 | P a g e ACS Paragon Plus Environment


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2.2 Particle Attributes 2.2.1 Particle Size Control

In this section, continuous crystallization studies are discussed where particle size control is examined. Also included in this section are studies where the impact of process parameters on agglomeration have been investigated or reported. Product consistency is an important element in the crystallization of APIs, affecting downstream processing and formulation. Understanding the impact of different process parameters on the particle size produced by continuous crystallization is essential for the successful uptake of continuous crystallization by the pharmaceutical industry. Alverez et al. 31 investigated the cooling crystallization of cyclosporine, comparing batch and continuous operation with the goal of improving the yield. A model was generated from experimental data, predicting that particle size would decrease when the temperature was decreased to improve yield. The author observed that this behaviour indicated that the crystal growth kinetics are more sensitive to the decrease in temperature than the nucleation kinetics. This study highlights the significance and complex nature of the role of crystallization kinetics in optimization of MSMPR continuous crystallization processes, particularly regarding particle size. Narducci et al. 24 applied ultrasound to a continuous crystallization to investigate in the impact on particle size and yield. Ultrasound was observed to reduce the particle size achieved in a residence time relative to operation without ultrasound. Power et al 38 utilized a single and two stage MSMPR for the cooling crystallization of paracetamol. An increase in residence time resulted in an increase in particle size, as measured by FBRM CLD. Powell et al. in 2015 35 describes the crystallization of paracetamol using a periodic MSMPR (PMSMPR) system. This system maintains itself at defined conditions despite controlled periodic disruptions. In this way the residence time can be increased by alternating batch operation with continuous MSMPR operation. Though oscillations occur the system is always in a controlled state of operation. The system was tested in a single and two-stage PMSMPR for the cooling crystallization of paracetamol. The two stage PMSMPR operation which had no recycle stream produced the material with the largest mean crystal size. PMSMPR operation was further investigated in 2017 by Su et al 39. Crystallization mechanisms and kinetics for the batch cooling crystallization of glycine in water were used to build a dynamic flow model. Periodic MSMPR crystallizations in single reactor and three stage crystallizers were performed in order to validate the model. The experimental value for the D4,3 (from Malvern analysis of the final steady state material) produced by the three stage MSMPR vs the three stage PMSMPR increased from 342.16 µm to 696.76 µm A 2015 paper by Yang et al. describes the use of a wet mill integrated with an MSMPR crystallizer to achieve particle size control 40. The cooling crystallization of paracetamol in ethanol was investigated. Downstream wet milling was found to increase the time to steady-state operation (from 6 residence times to 9) but did efficiently reduce particle size and produce a narrow size distribution of uniform crystals through controlled secondary nucleation. The wet mill applied upstream was used to continuously generate seed by utilizing high shear primary nucleation kinetics. A large uniform crystal size can be generated by applying the mill upstream and controlling mixing conditions, presumably to limit secondary nucleation. The use of wet milling with continuous crystallization was further investigated by the same group the following year on the use of automated direct nucleation control in continuous cooling crystallization of paracetamol 41. A similar setup was used as in the previous study 40. Wet milling-based automated direct nucleation control (WMBADNC) was implemented for continuous crystallization in an MSMPR. Two configurations were tested, with the wet mill on the feed line to the MSMPR and the wet mill on a recirculation 12 | P a g e ACS Paragon Plus Environment

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loop connected to the MSMPR. At steady-state operation it was demonstrated that the total FBRM counts could be tailored using the WMBADNC by changing the controlled set point. While process parameters such as residence time and temperature in MSMPRs have been found to the affect the particle size 31,38, process configuration also has an impact on particle size 28,32. Optimizing the process for particle size must be balanced with yield considerations and this is further discussed in section 2.4. Understanding the crystallization kinetics can be of high importance for correct process design and optimization with regard to particle size 31,38. The application of ultrasound and wet milling for manipulating particle size regardless of process parameters such as residence time and temperature, have all been demonstrated 24,40,41. The utilization of these external operations in MSMPR crystallization may become a key tool for dialling in a desired product PSD. Further research into these operations is required, not only for their effect on PS but also on operability, time to steady state and yield. It is important to note that these techniques impact the particle size through their effect on the nucleation kinetics in the system again highlighting the importance role of nucleation kinetics in MSMPR design. 2.2.2 Polymorph and Chiral control using MSMPR Continuous Crystallization The use of continuous crystallization to selectively produce a desired crystal form or to control chiral purity has been demonstrated by only a small percentage of the publications referenced in this review. Continuous crystallization can be particularly advantageous for form control. When operating under a state of control, the system remains at one point in the design space, while for batch crystallization a controlled path way through the design space must be considered for form control. Selected recent MSMPR continuous crystallization studies where kinetic control is investigated are discussed in this section Johnson et al. 3 demonstrated kinetic impurity rejection by starting the continuous process where the solids were ~95 % enantiomeric excess (ee) and observing an increase in % ee to the steady-state value of ~99.5 % ee. The rejection of the enantiomer was additionally linked to the relative flow rate of antisolvent. Lai et al. 42 demonstrated the use of MSMPR continuous crystallization to selectively produce the desired polymorph of L-glutamic acid by manipulating the residence time and temperature in the system. Multiple experiments were performed with different combinations of operating temperature and residence times. It was found that the polymorph obtained under steady-state conditions was independent of the seed material used for the process. At lower temperatures, when seeded with the stable form β, there is a transition to the metastable polymorph α. It is stated that this is as a result of competition between the crystallization kinetics of the two polymorphs rather than thermodynamic driving forces which control traditional solvent mediated transformations. Long residence times of greater than 17.4 hours are required to generate the stable form β. Polymorph control of p-aminobenzoic acid using the same MSMPR continuous system was investigated by Lai et al. 43. With a transformation point for p-aminobenzoic acid of 15 °C, it was found that for a single stage MSMPR, operating temperature of 5 °C, the β polymorph is produced at steady-state. By moving to a twostage MSMPR with stage one at a higher temperature of 30 °C and stage two at 5 °C, the α polymorph ratio was increased to 75 wt% in an unseeded system (100 wt% in a seeded system). At 30 °C (above the transition point) the α polymorph is stable. The constant supply of α to stage two facilitated the kinetic competition of α at the lower temperature of 5 °C (below the transition point) and allowed for high purity of the α polymorph in the product slurry. In the first account of a continuous crystallization specifically targeting a metastable polymorph, metacetamol was used as a templating agent to aid the crystallization of the metastable form II polymorph of paracetamol 33. The author defines the templating agent as a structurally similar molecule which forces crystallization of a 13 | P a g e ACS Paragon Plus Environment


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specific polymorphic form without being present in the final crystal structure 44. The FII polymorph could not be obtained from the equivalent batch crystallization operation at the same form purity. A two-stage MSMPR system and a COBC system were both investigated. FII was successfully produced in the COBC, but always with some impurity and clogging was an issue. Pure FII was obtained at low supersaturations (higher operating temperatures) in the MSMPR system. Xiaochuan Yang et al described the development of a continuous crystallization system for carbamazepine involving a two stage MSMPR 11. Continuous cooling crystallization of carbamazepine in ethanol and water with form control (desired form III, most stable at room temperature) was demonstrated. A single stage MSMPR operation with in-situ PAT (FBRM and Raman) was also demonstrated for the transition of polymorphic form II to form III. A single stage MSMPR was utilized to achieve continuous crystallization of enantiopure crystals of sodium bromate from an achiral solution 37. Particle size, concentration and enantiomeric excess of the product were continuously monitored. At the start of the process a clear supersaturation achiral solution was seeded with enantiopure crystals. For some experiments an IKA T18 Ultra Turrax digital homogenizer was used in the system to increase secondary nucleation. Twelve experiments were performed using this system for various feed concentrations, residence times and operating temperatures. It was found that the solids consisted of the same chiral form as the seed material at long residence times and high concentration feed. This study demonstrates the feasibility of producing chirally pure pharmaceutical products by continuous crystallization. In all cases the operating temperature was utilized to control the product form, sometimes combined with residence time. Start-up mode is also investigated in some cases with seeding demonstrated to influence form 37,42,43. Some of the studies discussed in this section demonstrate improved form or chiral purity with continuous operation when compared to batch 33. Continuous operation allows for the production of material at a constant temperature, at a single point in the solubility design space or phase diagram which can make it not only amenable for production when form control is a concern but in some cases is favourable over batch operation. Continuous crystallization allows for operation at a kinetically stable point in the design space. For two stage crystallizers it is possible to crystallize a kinetically stable form and use this slurry to seed the second crystallize, where the presence of this desired form with suppress nucleation of the undesired form/forms 43. 2.3 Yield, Recycle & Purity Product yield from crystallization processes is an important factor in decisions around the feasibility of producing material continuously vs. batch. API is a high value product and increasing yield is a motivating factor for next generation processes and process improvement. Conversely, a decrease in product yield of 1 or 2 % can prevent a process change. Some of the reluctance of industrial adoption of continuous crystallization is due to the impression that it will result in a lower yield from the crystallization step. In general, the yield from a MSMPR continuous crystallizer tends to be lower than the corresponding batch process as the batch process has the potential to fully desupersaturate while a continuous system has a steady-state dissolved concentration higher than the solubility concentration as a driving force for crystallization. For the three stage continuous crystallization system, with and without a recycle stream, investigated by Alvarez et al. 31 it was found that the batch crystallization produced a higher yield than the continuous system with no recycle (71% vs 74% for the batch). The implementation of a recycle stream increased the yield to 87% but was accompanied by a decrease in purity from 96% to 95%. Narducci et al. 24 investigated the application of ultrasound to the continuous cooling crystallization of adipic acid in an MSMPR configuration. 14 | P a g e ACS Paragon Plus Environment

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The yield was found to increase with application of sonication to the continuous system by up to 34 % at the same residence time. A combined anti-solvent and cooling continuous crystallization operation using a two stage MSMPR process was developed by Zhang et al. 32. Data from the experiments was used to generate a model in order to investigate the impact of process parameters on the system. The model results showed that the stage temperature was found to affect the yield, with a decrease in yield from 89.8% to 85.7% when the stage temperature was increased by 15 °C. An increased yield did result in decreased purity, with a maximum difference of 0.7 % according to the model, with the authors considering this “not so significant”. The residence time was also found to influence the yield with an increase in yield with increased residence time from 87.5% to 91% again this resulted in a slight decrease in purity from 91.6% to 91%. The authors propose that this model could be used to choose optimal conditions to maximize yield while keeping impurities within acceptable limits. A 2013 study by Ferguson et al. 45 successfully incorporated a nanofiltration membrane recycle which preferentially concentrated the mother liquor from a continuously operated MSMPR API crystallization to increase the yield from 70.3% to 98%. This was an improvement on the current commercial batch yield of 92%. All processes met the regulatory specifications with regard to impurities, with comparable impurity levels for all operating modes. Reactive crystallization of aliskiren hemifumarate using a two stage MSMPR was investigated by Quon et al. 23. A model was developed incorporating the crystallization kinetics of the system with a population balance equation in order to select optimum operating conditions to maximize the yield and purity of the system. The residence time at each stage as well as the stage temperature were found to affect the yield and purity. For the same overall residence time (720 min), it was found that a higher yield (90.8 %) resulted from a longer residence time in vessel 1 (600 min) versus vessel 2 (120 min) than for the reverse case where the yield was only 81.2%. The author attributed this to the increased growth rate at higher temperatures. The study emphasises the importance of the crystallization kinetics for optimizing the process with regard to yield. The optimized process produced aliskiren hemifumarate with a high purity of >99% with a yield of >92%. Two processes were developed for the cooling crystallization of cyclosporine and antisolvent crystallization of deferasirox using a single stage MSMPR by Wong et al. 46. Figure 4 shows the equipment setup with a recycle system.

Figure 4: MSMPR system used by Wong et al46. Reproduced with permission from Wong et al Copyright 2012 ACS Publications.

46.

Feed solution (cyclosporine in acetone 31.8% w/w at 53 ± 0.5 °C) was continuously added to the crystallizer using a peristaltic pump. Slurry was removed, and solids were separated using a filtration unit. The mother liquor was concentrated by evaporation. The continuous cooling crystallization of cyclosporine with recycle resulted in a maximum yield of 91.8% with a purity of 94%, achieved at an operating temperature of 20 °C. 15 | P a g e ACS Paragon Plus Environment


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This was 5.5% higher than the 3 stage MSMPR equivalent setup and significantly higher than the equivalent batch system which had a yield of 74%. The antisolvent crystallization of deferasirox resulted in a maximum yield of 89.1%. The crude material which was recrystallized had 21 ppm of an impurity A which was reduced to 0.25 ppm in the product material. Li et al. 47 investigated the incorporation of solids recycle with a two stage MSMPR to improve yield in order to overcome the long residence time required for a high yield where growth kinetics are slow. The yield increased from 65% (in a two stage MSMPR with no recycle) to 69% with 75 % solids recycle, and to 74.1% with 90 % solids recycle. For continuous recycle, the column was used to concentrate the slurry utilizing a gravity driven separation. Clear liquor was removed off the top of the column to give the correct recycle ratio. With recycle ratio of 90 %, the yield increased from 74.1% to 75.2% for continuous solids recycle to the second stage. This was further increased to 79.8% with the solids recycle split equally and returned to both stages. Yang et al. describes the use of a “yield index” in a 2015 paper on the application of wet milling to MSMPR crystallization 40. The yield index is based on the FBRM data from the process: Yield index (YI) = Square weighted mean chord length3 x Total counts This is based on the principle that yield is dependent on the particle size and the number of particles. The author states: “The yield index (YI) is a very simple and convenient measure that combines both particle size and particle number information which are inferred from chord length and chord counts. Due to the limitations of FBRM (e.g., chord length is measured instead of particle size), the approach stated above is not accurate for yield calculation. However, it is suitable in terms of qualitative comparative analysis of the proposed approaches”. Where experiments are performed in the same experimental setup with a similar volume and measurements for comparative purposes are taken under the same mixing conditions, YI provides a useful method for understanding the effect of process parameter on yield. In an attempt to control impurity build-up during recycle, solution complexation accompanied by nanofiltration was successfully employed in combination with a recycle line in MSMPR configuration (figure 5) in a recent study by Vartak & Myerson 48. Complexing agents designed specifically for known impurities in two API systems increased the size of the impurities to the point where they were differentiated from the API and could be separated via membrane filtration. The permeate stream from the filtration unit, clarified of impurity, was recycled back to the crystallizer. A 13% improvement in yield was identified relative to MSMPR operation in the absence of recycle, and solution complexation significantly reduced impurity incorporation.

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Figure 5: Schematic illustration of the implementation of a recycle loop with nanofiltration and impurity complexation for the continuous crystallization of API 48. Reproduced with permission from Varkak et al 48. Copyright 2017 ACS Publications Implementation of a recycle loop has been demonstrated to have a dramatic improvement on yield, often improving yield by more than 10% and surpassing the comparable batch yield. It appears to be generally accepted that yield increase from recycling will be accompanied by an increase in the impurity level in the mother liquor, but there is little experimental evidence available to validate. Where studies have been conducted findings indicate considerable scope to tune the process design to maximize yield while minimizing impurities. Many of the studies discussed here demonstrate the potential to optimize the yield through selecting optimum process conditions. The crystallization kinetics, solubility data for the system both need to be considered. Adding sonication was found to increase the yield significantly presumably by increasing the rate of nucleation. This may be more effective than increasing residence times in systems thereby reducing the overall productivity. Product requirements around form control can make optimizing the yield complex. Lai et al. 42 highlights the difficulty of obtaining a strong yield if a higher operating temperature in the MSMPR is required in order to generate the desired polymorph. Here a two stage MSMPR system, where the first stage is effectively a nucleator and the second is a growth vessel, seeded by the first, can be utilized to improve yield and produce the desired form43. Though yield may be inferred from some studies where steady-state and feed concentrations are provided 38, it can be seen in table 1 that many of the studies included in this review neglect to report on the yield of the system. The concept of a yield index proposed by Yang et al. 40, describe above is particularly useful for comparing the yield where the continuous crystallization is perform under the same scale and mixing conditions. In general, reporting of the dissolved concentration measurement taken under steady-state (or at a controlled state of operation) would be sufficient. Given the importance of yield from an economic perspective, it is imperative that studies of continuous crystallization for API production consistently report on product yield, if such processes are to be adopted by the manufacturing industry. A focused research effort in the area may help to elevate understanding and enable consistently higher yields for continuous crystallizations while maintaining acceptable levels of impurities.



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2.4 Integration with Upstream/Downstream steps Integration of continuous crystallization steps with flow chemistry has been demonstrated by a small number of publications from industrial groups and academic collaborations 1,3,21,22. Integration with downstream steps has also been investigated in a small number of cases 49,50. A two stage MSMPR continuous antisolvent crystallization step was incorporated into a fully continuous process for synthesising an API intermediate, as described in a 2012 publication by Johnson et al. 3. The labscale system produced the same weekly throughput as a plant system with 400 L vessels. The process was run for 48 to 91 hours depending on requirements and was not stopped due to fouling or blockages, but rather as the feed material was exhausted. The start-up and shut down process was a batch crystallization in each stage, eliminating waste. The residence time in each crystallizer was 1.5 hours. Demonstration of kinetic impurity rejection was achieved by starting the continuous process where the solids were ~95 % ee and observing an increase in % ee to the steady-state value of ~99.5 % ee. The rejection of the enantiomer was additionally linked to the relative flow rate of anti-solvent. Two papers from the Novartis-MIT Center for Continuous Manufacturing cover a plant wide dynamic model for continuous pharmaceutical manufacture 51,52. In the first, Benyahia et al. 51 investigates several design parameters for their effect on the productivity and quality, as well as investigating different start up scenarios. The model includes multiple unit operations including reaction steps, continuous crystallization, adsorption, liquid-liquid separation, filtration, drying and tabletting steps. Much valuable information is revealed by the model, including sensitivity to impurities and significance of purge ratios and wash factors. Prefilling the units was shown to reduce the time to steady state operation. This study demonstrates the feasibility of integrated continuous manufacturing. The second study by Lakerveld et al. 52, presents a plant wide dynamic model for a similar plant but with simulations for selected disturbances, providing a basis for the synthesis of control loops. The model demonstrated the capability to respond to disturbances and the flexibility of the system abour setpoint of critical quality attributes. In 2017 a further publication on model predictive control of an integrated continuous pharmaceutical manufacturing pilot plant was presented by Mesbah et al. 53. Two model predictive control designs are presented for the pilot plant using the quadratic dynamic matrix control algorithm. Qualityby-design considerations can be incorporated into the control system through input and output constraints. The authors stress that the choice of modelling approach depends on the availability of process data or first principles models for the specific application. On a whole this group of publications demonstrates that it is possible manufacture pharmaceuticals continuously and meet the regulatory requirements of the pharmaceutical industry using appropriate control design. Cole et al. published an example of a multi-step chemical synthesis of an investigational API under Cgmp conditions in which the majority of the unit operations were operated linked together in continuous mode22. The penultimate of the synthetic route was purified and isolated utilizing a two stage MSMPR crystallizer and automated semi-continuous filtration. The filtration and subsequent dissolution of penultimate material was important to enable downstream flow chemistry as well as avoid operator contact with solids with an occupational exposure limit of 1 µg/m3. Acevedo et al. 49 coupled an MSMPR crystallizer with a continuous filtration system. The system was tested with an antisolvent crystallization of benzoic acid and a cooling crystallization of paracetamol, performed continuously in a single stage MSMPR, in order to test the filtration system and the feasibility of operating the two unit operations in sequence. A pressure vacuum transfer line allowed for intermittent transfer of up to 32 ml of slurry in 15 seconds from the MSMPR. Product slurry was transferred to a 2.5 L hold vessel connected to the continuous filtration carousel (CFC system from Alconbury Weston Ltd). The system is connected to a 18 | P a g e ACS Paragon Plus Environment

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solvent line for automated cleaning-in-place and a wash solvent for cake washing (figure 6). The system has five cylindrical chambers that rotate counter clockwise after each slurry transfer. The slurry is washed and filtered in positions 2-4 and discharged through position 5. In this way material is filtered and washed in a semi continuous manner. Consistent filtration of material was possible through optimization of filtration parameters.

Figure 6: MSMPR setup with pressure vacuum transfer line. Reproduced with permission from reference Acevedo 49 Copyright 2016 Elsevier Yazdanpah et al 50 investigated a novel technique for continuous crystallization of intermediates which avoids a subsequent filtration step. A novel falling film crystallizer was tested with acetaminophen and fenofibrate crystallizations. Crystal product can be dissolved from the surface of the falling film crystallizer and sent to the next process step. With an initial feed solution of 98% fenofibrate with a 2% fenofibric acid impurity, was crystallized in the falling film crystallizer to produce material with a 99.4% purity. Producing consistent API properties throughout a processing campaign is one of the biggest drivers for continuous crystallization. However, this can be limited by the return to batch isolation and drying after the continuous stage. This return to batch processing brings with it batch-to-batch variations which limit the consistency of the final delivered product. Cole et al. demonstrated that where an intermediate is continuously crystallized, drying of the solid product can be avoided by dissolving the solid in the solvent required for the subsequent step 22. While significant modelling efforts on unit operation integration and end to end processing have been presented, further published research around the practical success and challenges of integrating flow chemistry with crystallization, isolation and drying would be beneficial, particularly around matching or residence times with the product flow rate from a previous step. It is safe to say that coherent coupling of continuous crystallization unit operations to preceding upstream, or subsequent downstream, operations remains a challenge and requires additional research focus at practical scales. 19 | P a g e ACS Paragon Plus Environment


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2.5 Modelling Modelling for continuous crystallization processes is an important and growing trend in the pharmaceutical space. While dynamic flow and control models for plant-wide continuous pharmaceutical production were presented in section 2.4, the following section summarizes a selection of recent studies where modelling was specifically utilized for continuous crystallization. A virtual study of MSMPR operation with recycle and product classification was described by Griffin et al. using population balance modelling54. The authors describe an inverted R-Z classifier from which the fine product stream is taken as product and the large product stream is recycled via a dissolver to the feed tank, with the aim of producing a narrow crystal size distribution in the range 50 – 100 m in the product. The concept was modelled using aspirin. The model showed that implementation of the recycle loop resulted in a decrease in production rate due to the lag between dissolving the large crystals and product output. To maintain production rate the supersaturation level in the vessel had to be increased but maintained within the metastable zone limit. Qamar et al. presented a modelling study on the effects of residence time and seeding on the dynamics of a MSMPR crystallizer for preferential enantioselective crystallization of an amino acid55. A recycle stream was included to encourage the dissolution of fine particles. Growth rates as well as primary and secondary nucleation were included in the model. The authors found that when seeding was increased, there was a decrease in supersaturation and mean crystal size with an increase in yield, purity and productivity. Fines dissolution was shown to increase the mean crystal size, but the yield and purity decreased due to the recycle. Vetter et al. described a numerical modelling method to define attainable regions for particle size in continuous crystallization 56. The crystallization kinetics with a defined start and end point for the process are applied to a methodology to define the operating region for the process. The optimum residence time and process configuration for the continuous crystallization can be chosen using this method in order to produce the desired particle size and maintain the desired yield. Three case studies were chosen to demonstrate the method using published crystallization kinetics data. This included the cooling crystallization of paracetamol in ethanol 5759, the anti-solvent crystallization of L-asparagine in water with isopropanol as the antisolvent 60 and the combined cooling and anti-solvent crystallization of aspirin in water with ethanol as an anti-solvent 61. A control strategy for the conversion of stirred tank batch crystallization to continuous MSMPR operation was proposed by Su et al. 62. Concentration control (referred to as C-control) was utilized to facilitate selection of the operating point and start-up conditions within the original batch crystallization design space. Single stage and two stage MSMPRs were compared to the batch mode within the model. A comparable yield (not specified) was achieved in the continuous system with increased efficiency with regard to production capacity and process time. A smaller number-based mean crystal size was achieved using continuous processing when compared to batch. Morris et al. used population balance modelling to estimate the nucleation and growth kinetics of benzoic acid in a single stage MSMPR 63. Continuous cooling crystallization of benzoic acid was performed for different feed concentrations and residence times as described in section 2.1. Steady-state was assessed using in-line FBRM. Samples were taken at steady-state operation and the particle size was measured using a Malvern Mastersizer and the liquid phase concentration was measured gravimetrically. This data was used for model fitting and parameter estimation for the crystallization kinetics of the system. A strong interdependence between the kinetics and the operating conditions (temperature, supersaturation, slurry density) was revealed and a mathematical model was developed to fit the data in order to simulate the process effectively. The resulting nucleation rate was found to have a high order dependency on slurry/suspension density. It is 20 | P a g e ACS Paragon Plus Environment

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recommended in the study that segregating the contributions of nucleation and growth by combining MSMPR data with batch approaches could provide a more complete means of understanding the individual kinetic ratedriving forces. Yang et al 64, describes control approaches for combined cooling/antisolvent crystallization in a two stage MSMPR cascade. Two schemes are investigated with regard to crystal size and yield control – decentralized proportional-integral-derivative (PID) control and nonlinear model predictive control (NMPC). Aspirin in ethanol and water was the system used in the model. Several assumptions were made in order to model the system including – the vessel is ideally well-mixed, breakage and agglomeration is negligible, only nucleation, growth and dissolution are considered, and no classification occurs – i.e. slurry removed from the vessel matches the contents. Antisolvent addition rates to both vessels as well as vessel temperatures were used as operating variables in the models. The NMPC method had superior performance for disturbance rejection and fast target product property compared to the PID control method. A second study by the same author 65, also involving PBE modelling, attempted to optimize combined cooling and antisolvent crystallization (CCAC) with regard to time to steady-state, and start-up behaviour in a two stage MSMPR crystallizer. Targeting the minimum start-up time was used to optimize the system. Initial solution composition, temperature and antisolvent profiles were manipulated. Again, aspirin in ethanol and water was the model system examined. The most efficient and practical method to minimize the start-up time and reduce waste during time to steadystate was found to be through the use of dynamic antisolvent profiles during the start-up phase. Köllges & Vetter describe a model-based analysis of a novel MSMPR method for separating conglomerate forming enantiomers 66. The model included crystallization, milling and the racemization reaction in solution. Two different configurations were investigated to increase enantiomeric purity from racemic mixtures: the first where the feed to the system was a saturated solution of racemic composition and the second where the system was fed with a racemic mixture of solids. A mathematical model using population balance equations was used to study the two configurations in order to identify the operating region where high enantiomeric purity could be attained. The model demonstrated that with a saturated feed solution and by combining the MSMPR crystallizer with solvent removal (a membrane unit or distillation is suggested) an enantiopure product with 100 % yield could be achieved, but this was not experimentally validated. Rashid et al. demonstrated the design of a batch or continuous crystallizer using a streamlined design approach 67. Solubility, nucleation threshold (defined as the 1-hour secondary nucleation MSZW), nucleation and growth rates were used to design a standard batch reactor to produce 500 kg of ibuprofen, and a MSMPR continuous configuration for both size independent and size dependent growth. Many examples are presented here of regression of growth and nucleation kinetics in continuous crystallization systems. While agglomeration and breakage kernels are prevalent in crystallization modelling as a whole, seldom are these kinetics regressed from experimental continuous crystallization results. This is an area of needed growth for many industrial processes, as agglomeration and breakage are common phenomena and can be impactful on physical property control aspects of API crystallizations. Another trend obvious from this literature survey is increasing complexity and fidelity of crystallization models. Many of the earlier works cited here utilize a method of moments approach to solving population balances, but advances in computing power and calculation algorithms have enabled the use of full population balance models, including higher dimensionality models that are able to explain the impact of process impurities on crystal aspect ratio 68. This trend is also important to industrial applications, as details gleaned from full population balance models can be important to API physical property control. Finally, many of the earlier examples presented focus solely on the regression of crystallization kinetics while fewer examples focus on the application of such models. 21 | P a g e ACS Paragon Plus Environment

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

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Table 1: Summary of published studies of continuous crystallization for API in MSMPR configuration

Author

No. of Stages 1

Operating Volume 500 ml

Residence Time NS

Operating Time NS

Transfer Mechanism Peristaltic pump

Yield

1

500 ml

NS

NS

Peristaltic pump

NS

3

3 x 50 ml

8 hr 20 min (total)

34 hr 20 min

Peristaltic pump

Vitamin C

1

1L

NS

Pump

Adipic Acid

1

300 ml

900, 1800, 3600 seconds 10, 20 ,30 min

74% 93% (RR 0.9) NS

NS

Pharma intermediate API intermediate

2

2 x 30 ml

2 x 4 hr

33 hr

Overflow with intermittent withdrawal Peristaltic pump

2

2 x 400ml

91 hr

Aliskiren Hemifumerate Deferasirox Cyclosporine

2

2 x 50ml

1.5 hr (total) NS

NS

Pressure swing chamber Peristaltic pump

1

155ml

3 hr

NS

Peristaltic pump

Ferguson 2013 (PF comparison) Ferguson

Benzoic acid

1

1 x 375 ml

30 min

NS

Deferasirox

1

155ml

1 hr

10 hr

Intermittent vacuum/pressure transfer (TZs) Intermittent transfer

Hou

Paracetamol

1

515 ml

NS

Aliskiren Hemifumurate

2

2 x (8-9) L

4 hr

10 residence time 100 hr

Kougoulos Kougoulos Alvarez Wierzbowska Narducci Zhang Johnson Quon Wong

Zhang (2014)

Material NS (fine chemical) NS (fine chemical) Cyclosporine

Intermittent transfer using vacuum Peristaltic pump

NS

Additional Technology/ Considerations  Recycle  Kinetics estimation  Recycle  PAT  Recycle stream 

Calculated as 40 -95 % 85.7% – 89.6% 84%



29

31

69



24

Ultrasound

Antisolvent addition location  Impurity rejection improvement

32

3

23

 

Recycle

46

Comparison to other Continuous technologies

70



73 % (No Recycle) 98 % (Recycle) NS 91.4%

30

Draft tube MSMPR

92.3% 87%-89% 81.2%91.8% NS

REF

45

Recycle

25



Feedback control for feed concentration

21


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Polster




NS

1

300 ml

30 min

72 hr

Pressure transfer zones

92% - 95% 94.1%

Lai

L-glutamic acid

1

150 ml

30 – 120 min

Up to 140 hours

NS

Lai

p-aminobenzoic acid

2

1x 150 ml 2 x 150 ml

60 min 2 x 60 min

Li

Cyclosporine

2

2 x 155 ml

2 x 3 hr

6 to 10 residence times 24 hours

Intermittent transfer every tenth of residence time Intermittent transfer every tenth of residence time Peristaltic pump

Li

Cyclosporine

1 3 5

1 x 155 ml 3 x 155 ml 5 x 155 ml

NS

Peristaltic pump

Yang

Paracetamol

1 2

2 x 300 ml

1 x 9 hr – 9 hr 3 x 6 hr – 18 hr 5 x 3 hr – 15 hr 20 min 75 min

Pressure transfer zones

NS



Automated feedback control using the FBRM

71

Yang

Paracetamol

1

400 ml

20 min

5 to 16 residence times 4 hr

High shear wet mill

40

Paracetamol

1

400 ml

20 min

4 hr

“yield index” NS



Yang

Pressure transfer zone Pressure transfer zone

41

Powell

Paracetamol

1 2

1 x 500 ml 2 x 500 ml

20 min 2 x 20 min

pumps

31.1% 68.9%

Powell

Urea-Barbitureic Acid

3

3 x 500 ml

3 x 20 min

11 residence times 1 hr 2.8 hr 14.3 hr 24 hr

pumps

66% 100%

Automated direct nucleation control via wet milling Periodic steady-state or “state of controlled operation”  Form selection Periodic steady-state or “state of controlled operation”

Paracetamol

1

4.6 hours

pumps

Presence of HPMC additive for reducing fouling

36

Powell

1 x 727.2 ml

12.12 min

High shear mixing elbow on recirculation loop  Polymorph control 

70% - 90% 63.1 – 79.8% 76.3 – 80.8%

28% 98.8%

1

42

Polymorphic control

43



47

Recycle with modification

27

 





35

72



Page 24 of 44

 Power

Paracetamol

1 2

1 x 675 ml 2 x 675 ml

1

1) 200, 250, 300 ml 2) 400, 450, 500 ml 300 ml

15 min 20 min 30 min 60 min 15 min 20 min 30 min 45 min 1) 25 – 60 mins 2) 45 -100 mins 60 min

Morris

Benzoic acid

1

450 – 500 ml

Pena

Benzoic acid

2

Acevedo

Paracetamol Azithromycin

2

2 x 31.5 ml

2 x 2 hr

24 hr

Vartak

API system

1

1 x 150 ml

37.5 – 75 min

Agnew

Paracetamol

2

2 x 140 ml

Yazdanpanah

Acetaminophen in ethanol

1

1 x 500 ml

2 x 30 min 2 x 45 min 30 min 45 min

Yang, X.

carbamazepine

2

2 x 400 Ml

2 x 30 min

API intermediate

2

2 x 3.5 L

2 x 60 min

Glycine

1, 3

1 x 500 mL 3 x 500 mL

1 x 20 min 3x 20 min

Cui

Cole Su

NS

Pressure transfer zone

NS

NS

Pressure transfer

NS

400 min


NS

>300 min

NS

NS

Pressure transfer zone Pressure differential between crystallizers NS

5 hours

Vacuum transfer

NS

1500 min

pumps

NS

Up to 2 hours 17min ~200 hours (8 x 24 hours) Up to 350 min

Peristaltic pumps

~45%


NS

pumps

NS

98% 65.74% 94.68%

Automated intelligent decision support (IDS) framework 38



Population balance modelling

63

Spherical crystallization

73

Continuous filtration system  Pressure driven flow crystallizer  Recycle line with nano filtration & solution complexation  Comparison to COBC  Polymorph control  Two different agitators  Comparison with fluidized bed crystallizer  Integrated semicontinuous filtration of product slurry  Integrated semicontinuous filtration/dissolution  Periodic MSMPR operation

49





28

48

33

34

11

22

39


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Steendam


Sodium bromate in water

1

1L

8 min - 169 min

> 40 residence times

Peristaltic pump



NS 

Recycle to simulate continuous operation Chiral purity achieved

37

NS – not specified; RR - recycle ratio



Page 26 of 44

3.0 Plug Flow Crystallizers (PFCs) Plug flow reactors (PFRs) are tubular reactors within which reactor contents flow at constant velocity, or plug flow. Superior heat transfer is realised in the tubular configuration relative to CSTR (continuous stirred tank reactor) types, and scale-up can be easily achieved by extending the dimensions of the reactor. Axial mixing is minimised so that very tight residence time, and hence product consistency, can be achieved. PFRs can be particularly suitable for systems with very fast kinetics74. When used for continuous crystallization, PFRs offer increased control compared to batch or MSMPR crystallization in situations where the crystallization kinetics are faster than the mixing times. However, true plug flow is only achievable with turbulent conditions which typically require very high flow rates. This is not commensurate with the nominal scale and production rate of pharmaceutical manufacturing. Other disadvantages include a tendency to foul and block 75, and complex cleaning validation for very long reactors. However, crystallization has been successfully demonstrated in PFRs for a number of pharmaceutical materials 70,75 and these are discussed below along with publications covering theoretical plug flow crystallizers (PFCs) and modelling applied to continuous crystallization in PFRs. The term PFC is used where the PFR is utilized for crystallization and in the following sections both terms are used to mean continuous crystallization in a plug flow crystallizer. Where possible, the term used by the author of the paper under discussion is retained. Process Characterization Continuous crystallization of L-glutamic acid, flufenamic acid and ketoconazole in a plug flow crystallizer with Kenics type static mixer was investigated in 2010 by Alvarez and Myerson76. The system consisted of four glass jacketed reactor modules each measuring 600 mm long, with an internal diameter of 12.7 mm and a volume of 76 cm2. This specific type of mixer has a series of alternating helical elements of 180° rotation (Figure 7).

Figure 7: Kenics mixer used in the plug flow reactor described by Alverez and Myerson 76. Reproduced with permission from reference Alverez and Myerson 76. Copyright 2010 ACS Publications The particle size increased with an increase in the flowrate due to greater mixing intensity. The steady-state solution concentration was higher at lower flowrates, indicating that less material came out of solution at lower 26 | P a g e ACS Paragon Plus Environment

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mixing intensities. The effect of the number of addition points was investigated but inconsistent results were obtained for flufenamic and glutamic acid. Eder et al. described a continuously operated tubular crystallizer for producing acetylsalicylic acid from ethanol in a cooling crystallization process77. The crystallizer consisted of a 15 m long tube with a 2 mm internal diameter. Four different flow rates (11.4, 17.2, 22.8 and 25.2 ml/min - giving four different residence times in the crystallizer) were investigated for impact on CSD and agglomeration. There was increased agglomeration due to the lack of moving parts in the crystallizer combined with this high seed loading and feed solution concentration. At higher shear rates due to higher flowrates, agglomeration decreased. The increase in diameter from the seed to the final product decreased with increasing flowrate, due to reduced agglomeration at the reduced residence time. Ferguson et al. investigated the antisolvent crystallization of benzoic acid using a plug flow system74. The use of a vortex (Roughton) mixer at the beginning of the system allowed for rapid mixing of the feed solution and antisolvent, with mixing times as low as 1 ms. The Roughton mixer (Figure 8) is ideal for a system with fast kinetics where the mixing time must be very rapid to be shorter than the induction time which is necessary for a controlled crystallization. FBRM, PVM (Particle Vision and Measurement) and ATR-FTIR (attenuated total reflectance - fourier transform infra-red) were used for inline real time monitoring of the process through the use of a flow cell. The mixer dimensions are shown in Figure 8.

Figure 8: Roughton mixer (dimensions) used for PF crystallization by Ferguson et al 74. Reproduced with permission from Ferguson et al 74. Copyright 2012 Elsevier In a modification of a plug flow reactor, Furuta et al. describe a custom built sonicated tubular reaction for the pH shift crystallization of an unspecified API 78. Crystallization was achieved initially by rapid mixing of two solutions to produce a hydrated form. The hydrated form subsequently transformed to the anhydrous form along the length of a tubular section (2 mm i.d., 20 - 40 m L) under laminar flow. A narrow PSD was achieved (1 - 7µm) in the system, which was attributed to restricted growth in the confined volume of the tubular reactor. There is currently relatively little literature on the use of PFCs for API production. Further studies around the importance of mixing characterization in this type of crystallizer for mixing sensitive systems and the advantages around increasing nucleation kinetics could be further explored. There is a lack of research around the impact or advantage is continuously seeding PFCs. For systems where multiple MSMPR stages have been shown to be advantageous with regard to yield or purity, further investigation of PFRs as a less operationally arduous alternative could be explored. An increase in research comparing these modes of continuous crystallization (as well as batch operation) would be advantageous in order to fully explore the advantages of different operating modes of continuous crystallization. 27 | P a g e ACS Paragon Plus Environment


Page 28 of 44

Fouling Due to the generally narrow diameter of plug flow reactors, there is a risk of process failure due to blockages caused by solid deposition in the system. Intermittent cleaning is not an option as a complete stoppage of the process would be required. In the case of Alverez and Myerson 76, a continuous plug flow crystallizer with fixed internals for improved mixing was operated successfully with no mention of fouling or blockages of the system. Eder et al. 77 intentionally increased seed loading to prevent fouling caused by excessive nucleation. Ferguson et al. 70,74,79 makes no reference to fouling or blockages occurring in the PFR process. Fouling or blocking were not mentioned in publications by Furuta et al. 78 and Zhao et al. 80.A model based study of fouling was published by Koswara and Nagy 81. A method of model-based anti-fouling control via temperature cycling. By controlling the temperature cycle across different sections of the PFC, encrustation can be dissolved periodically. If additional recycling is performed, encrustation can be minimized without a reduction in the mean crystal size. In a further modelling study by Majumder and Nagy 82, the formation of encrustation on the wall of the PFC is described by combining different considerations such as shear stress due to fluid turbulence, and solute transport from the solution to the wall. This is coupled with population balance modelling to describe the continuous crystallization in the PFC in order to construct a “mitigation strategy”. Here cleaning in place is proposed where solvent could be injected through the crystallizer. The model also demonstrates how the crystal size can be “severely” affected by encrustation of the PFC. The author states that further systematic studies of mitigation of encrustation will be performed. While efforts have been made to model fouling in PFCs, no mechanistic/practical studies specifically focussed on fouling in PFCs has been conducted in the sited papers. This would be a beneficial subject for further research. Indeed, experimental verification of the modelling work described in this section would be very interesting. Modelling A model was developed by Alverez and Meyerson 76 for the system described previously. This incorporated mass balance, population balance and kinetics expressions for crystal growth and nucleation. The model was compared to experimental data. Both a plug flow model and an axial dispersion model produced a CSD that was too narrow to describe the system. A growth rate dispersion model was found to best describe the process. Collisions of crystals with the mixing element, as well as with each other, were mentioned as a possible reason for wider CSDs by causing random fluctuations in growth. Controlling the generation of fine material is an extremely important consideration when designing a crystallization process with a tight PSD specification. Majumder et al. proposed a PFR design with multiple segments75. Each segment had separate temperature control. In this way, a process was designed with a spatially distributed optimal temperature profile for fines removal. This study used the high-resolution finite volume (FV) method for modelling the population balance. For the kinetics investigated, it was found that an optimal profile for the desired CSD was not possible without incorporating dissolution steps in the design. This study found that size dependent growth and dissolution kinetics play a key role for this kind of design. The suitability of different crystallization models to describe antisolvent crystallization of benzoic acid in a PFR has been investigated80. Three different models for crystal growth were examined: size independent growth, growth dispersion through random fluctuation growth and growth rate dispersion through constant crystal growth. Four different concentrations of benzoic acid solution in 50:50 water and ethanol (130.1, 95.9, 78.8 and 80.2 g/ kg solvent mixture) were tested at the same velocity for varying tube lengths. In this way the effect of residence time and supersaturation were investigated. The experimental CSDs displayed a good fit to the growth rate dispersion model with constant crystal growth kinetics. Experimental trials performed 28 | P a g e ACS Paragon Plus Environment

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subsequently demonstrated the suitability of this model to describe this crystallization process in the PFR. This publication demonstrates the importance of accurate kinetic models for the chosen system in order to design a continuous crystallization process. In a virtual study of paracetamol crystallization in an ideal plug flow reactor, Cogoni et al. observed yield enhancement and a slight increase in product particle size on implementation of a recycle loop83. The extraction position for the recycle line had an impact on both parameters, with the highest yield observed at high recycle ratio and shorter extract positions. Impurity accumulation was not considered in this study. A modelling study of crystal shape and size control in plug flow crystallization was presented by Sang-Il Kwon et al84. An optimization-based control scheme to produce crystals of tetragonal hen-egg-white (HEW) lysozyme of a desired shape and size is proposed in this work. The simulation uses growth rate equations from literature to develop a kinetic Monte Carlo (kMC) model for a PFC with five segments. The resulting PBE is used to derive a reduced-order moment model using the application of method of moments. This is used with the mass and energy balance equations to describe the dominant dynamic behaviour of the crystal volume distribution so that the jacket section temperatures and the superficial velocity can be optimized. This dynamic model can predict the average crystal shape in transient state as well as steady-state conditions. In this way control elements can be introduced for disturbances causing deviations in order to produce material of the desired attributes. Su et al propose a modelling method utilizing process systems engineering for the design and optimization of product qualities (e.g. PSD) from an antisolvent based plug-flow crystallizer85. The study focusses on a multisegment multi-addition plug-flow crystallizer (MSMA-PFC), whereby the location and the number of antisolvent addition points can be optimized along with a dynamic simulation of start-up conditions. The model utilizes the growth and nucleation kinetic models for the crystallization of paracetamol in ethanol using water as an antisolvent. Greater control of particle size is achieved by avoiding multiple nucleation events in the model framework, stating that it is desirable to introduce seeding techniques or a nucleator at the start of the PFC.



Page 30 of 44

Table 2: Summary of published studies of continuous crystallization in PFR configuration

Author

Material

PFR Dimensions 4 Sections Each section: 12.7 mm ID 600 mm length 76 cm3 Volume

Alvarez 2010

1. ʟ-glutamic acid 2. Flufenamic acid 3. Ketoconazole

Eder 2010 Ferguson 2012

Acetylsalicylic acid Benzoic acid

2 mm ID 15 m length 2.9 mm ID 19 cm – 980 cm length

Ferguson 2013

Benzoic acid

2.9 mm ID 5 m length 33 mL volume

Ferguson 2014

Benzoic acid

2.9 mm ID

Zhao 2015

Benzoic acid

Furuta 2016

API

2.9 mm ID 0 – 40 mm length 2 mm ID, 20 40 m length

Flowrate

Residence Time NS

Operating Time 7 RTs

Yield

248, 164, 124, 112 s NS

15 mins

NS



Constant seeding

77

NS

NS



Roughton mixer

74

Feed: 475 g/min Antisolvent: 488 g/min Feed: 151 - 407 g/min Antisolvent: 352 - 519 g/min Velocity specified of 5 m/s

2s

NS

NS

 

Roughton mixer Comparison to batch and MSMPR

70

NS

NS

NS



Continuous seeding of MSMPR

79

7 - 15 ms

> 5s

NS



Kinetics modelling

80

API feed: 1.8, 2.7, 5.4, 9, 21 ml/min

2 - 20 mins

NS

NS



Sonication

78

1. feed: 100 mL/min Antisolvent: 150 mL/min 2. feed: 100 mL/min Antisolvent: 100 mL/min 3. feed: 76 – 122 mL/min 11.4, 17.2, 22.8, 25.2 mL/min 300 - 500 mL/min

NS

Additional Technology/ Considerations  Kenics static mixer internals  Multiple antisolvent addition points

REF 76

NS – not specified 30 | P a g e ACS Paragon Plus Environment

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4.0 Continuous Oscillatory Baffled Crystallizers The continuous oscillatory baffled crystallizer (COBC), a relatively recent variant of a PFC, is a tubular crystallizer containing periodically spaced orifice baffles with oscillatory motion superimposed on the net flow86. The mixing in a COBC is provided by the generation and cessation of eddies when flow interacts with baffles and is thus decoupled from net flow driven turbulence. This allows for the cumulative generation of plug flow at net flow rates that would otherwise result in laminar flow. In this way a longer residence time under effectively turbulent conditions is possible with a smaller footprint, making the continuous oscillatory baffled reactor especially amenable to crystallizations. The ratio of oscillatory velocity to superficial velocity of the imposed flow is termed the velocity ratio and is a characteristic of the COBC system. Cited advantages of COBC’s include reduced tube length and hence footprint relative to the corresponding PFC, improved product consistency and increased throughput and productivity. Again, this system can be susceptible to fouling, and the unconventional approach to mixing can add complexity to designing and modelling the process. McGlone et al. present a detailed review of continuous crystallization and continuous manufacturing in oscillatory flow reactors (OFRs)87. Accounts of API manufacture in COBCs are reviewed below. Similarly to plug flow operation, the theoretical yield from COBCs should be higher than from MSMPR as it is possible by optimizing the process to maximize desupersaturation before the slurry exits the COBC unlike for MSMPR where a steady-state operating concentration is required. As with the PFC section, yield is not reported in any of the COBC papers reviewed. Process Characterization Lawton et al 86 investigated the continuous crystallization of an unspecified API in a 500 ml lab scale batch crystallizer COBC. The same rod crystals were generated in the OBC as in batch processing. Agglomeration did occur, but the agglomerates broke up when held under agitation. Under crash cooling conditions of 5 °C/min and 5% seeding, a cooling rate which is not possible for large reactors, the generated material had a plate-like morphology. A smaller particle size resulted from higher frequency or oscillation amplitude. All conditions resulted in a narrow size distribution. It was found that the desired rod-like morphology could be generated at relatively fast cooling rates and higher concentrations (greater than 6% w/w, the initial concentration in the batch process). Seeding the process increased the mean particle size, presumably by reducing the nucleation rate. The production of co-crystals of α-lipoic acid : nicotinamide in a COBC were described by Zhao et al 88. Three different cooling regimes were tested at a flow rate of 70 mL/min and an oscillation of 1 Hz and 30 mm. A schematic of the COBC is shown in Figure 9. The system had a volume of 4.2 L and an internal diameter of 16 mm. The material produced had a narrow PSD of spherical co-crystal agglomerates. The author noted that further characterization work is required around agglomeration and nucleation in the process.



Page 32 of 44

Figure 9: Schematic of the COBC used by Zhao et al 88. Reproduced with permission from Zhao et al 88 Copyright 2014 Royal Society of Chemistry An experimental investigation of a continuous oscillatory baffled crystallizer was conducted by Brown et al. 89, following on from a previous study in a batch configuration90. The system consisted of two 20 L stirred tanks containing feed solution and anti-solvent connected with peristaltic pumps to the COBC, which was made up of two straight sections (15 mm x 700 mm glass jacketed tubes with baffle inserts) connected to a third identical section via a y-piece (Figure 10).


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Figure 10: Schematic of the COBC used for the investigation of the antisolvent crystallization of salicylic acid 89. Reproduced with permission from Brown et al 89. Copyright 2015 Elsevier The antisolvent crystallization of salicylic acid in a COBC was studied with regard to establishing the steadystate both for mean crystal size and solute concentration. Operating time and distance along the crystallizer were considered in relation to steady-state, referred to as temporal steady-state and spatial steady-state respectively. Steady-state was defined by the author as less than 10% deviation from the mean value of the parameter of interest. Steady-state with regard to solute concentration and to particle size was achieved with. consistent material produced over an operating time of 6.25 hours. Siddique et al. described the continuous sonocrystallization of lactose in a COBC 91. Full characterization of hydrodynamics of the COBC was performed to optimize conditions for plug-flow behaviour at desired residence times of 1 – 5 hours. An OBC was utilized for batch studies with FBRM and mid-IR with sonication in order to investigate kinetic and thermodynamic properties. The COBC operation with sonication reduced the cycle time from 13-20 hours in the batch process to 4 hours in the continuous operation with no fouling or agglomeration issues (Figure 11). Similar to the work by Narducci et al. 24 it appears that the application of sonication increases the rate of nucleation. A narrower PSD was produced by the continuous process compared to the batch process. The process had a throughput of 356 g/hour over 12-16 hours of operation.

Figure 11: Schematic of the COBC used by Siddique et al. reference Siddique et al 91. Copyright 2105 ACS Publications

91

Reproduced with permission from

Kacker et al. 92described a detailed study into the mixing characteristics of a 1L COBC (i.d. 15 mm) based on variation of the flow rate, oscillation amplitude, and oscillation frequency. The velocity ratio alone was found insufficient to describe mixing, as many combinations of amplitude and frequency can yield the same velocity ratio. Different optimal conditions were defined to minimise dispersion and optimise mixing for homogenous (methylene blue in water) and heterogeneous (melamine in water) model systems. Plug flow like residence times (low dispersion) were achieved for slurries with 10 % w/w solid content. Mean residence time studies were in agreement with the general understanding that solids have a longer residence time in the system than liquid components. Peña et al. 93 describe the use of an oscillatory flow baffled crystallizer (OFBC) for the continuous crystallization of spherical agglomerates of benzoic acid. This followed an earlier study on the production of 33 | P a g e ACS Paragon Plus Environment


Page 34 of 44

spherical agglomerates using an MSMPR 73 which was discussed in the MSMPR section of this review. The OFBC was a 1250 mL Nitech DN15 (Alconbury Weston) with eight segments (figure 12). The system was jacketed for temperature control. It was possible to divide the system into four different temperature zones. In this case the first zone was maintained at 40 °C and the rest of the crystallizer was at 22 °C. The mixing intensity, solution to antisolvent ratio, the bridging liquid to solute ratio and the length of the agglomeration zone were all investigated for their effect on the mean size and agglomeration size distribution (ASD). Increasing the mixing intensity was found to improve the ASD. The author notes that due to back mixing in the system, the OFBC deviates from ideal plug flow behaviour which lead to broader ASDs than expected.

Figure 12: Oscillatory Flow Baffled Crystallizer system utilized by Peña et al permission from reference Peña et al 93. Copyright 2017 ACS Publications

93

Reproduced with

Agnew et al 33 described the continuous crystallization of the metastable form II polymorph of paracetamol by MSMPR and COBC. A 638 cm long COBC (Continuous Oscillatory Baffled Crystallizer) (i.d. 15mm) was used with a flow rate of 50 ml/min. Form-II was successfully produced in the COBC, but always with some trace presence of metacetamol hydrate. As discussed in the MSMPR section metacetamol was used as a templating agent to promote the crystallization of form II Pure form II was obtained at low supersaturations (higher operating temperatures) in the MSMPR system. Initial trials of a 970 cm long COBC has produced pure form-II in the COBC. Interestingly the author also discusses yield, stating that “Overall solids yield, relative to zero concentration… have been around 30 %, and the optimization of this yield is ongoing”. Also noted is that increasing yield and producing pure form II “is a fine balance”. These are similar comments to Lai et al. 42 who highlighted the difficulty of obtaining a strong yield if a higher operating temperature in the MSMPR is required in order to generate the desired polymorph. 34 | P a g e ACS Paragon Plus Environment

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Many of the COBC studies described in this review emphasise advantages of COBCs over batch operation. Continuous crystallization in a COBC was shown to significantly reduce processing time in an experimental study by Lawton et al86. Using a model API, processing time was 12 minutes compared to a batch processing time of 9 hours and 40 minutes for the same amount of material. Crystal quality with regard to morphology and size was emphasized, as well as additional processing advantages such as reduced process time, space usage, and energy consumption. The study described by Zhao et al 88 described the discovery of a novel cocrystal and its successful scale-up to a COBC system producing material of acceptable purity and narrow particle size on a kilogram scale in the lab. Here the ease of scale-up was emphasised and it was not stated whether the co-crystal could be produced by a batch operation. Brown et al 89 demonstrated the potential of the COBC to continuously produce consistent seed material over a period of 6.25 hours. The COBC operation with sonication described by Siddique et al 91 reduced the cycle time (time for processing the same amount of feed solution) from 13-20 hours in the batch process to 4 hours in the continuous operation. Briggs et al 94 demonstrated that by utilizing continuous seeding a COBC system of 38 segments and 8 bends could operate successfully for 10 hours with no blockages. The system also delivered control of polymorphic form. Pena et al 93 observed that there was improved agglomerate size distributions produced by the OFBC compared to those produced by an MSMPR73 due to differences in the mixing conditions Under optimal conditions the OFBC produces a narrower, more uniform agglomerate size distribution. The work by Agnew et al 33 demonstrates the possibility to produce metastable form II paracetamol by continuous crystallization in a COBC with a lower addition of metacetamol than that through traditional large scale batch crystallization. Increased addition of metacetamol, reduces the yield. Studies comparing different types of continuous crystallization would be beneficial where yield, form control and product purity are considered but also scale, process time and overall productivity. An advantage of COBCs over PFCs must be demonstrated in order to justify the increased operational complexity. Fouling The general perception is that the internals of COBCs can easily lead to blockages of the equipment when fouled, causing process failures. In an experimental study by Lawton et al86, continuous crystallization in a continuous oscillatory baffled crystallizer (COBC) using a model API was investigated to evaluate the COBC for industrial operation. In this successful investigation, fouling or blockages were not mentioned in the paper. In the COBC study described by Zhao et al 88, the author states that no fouling or blocking of the COBC occurred. An experimental investigation of a continuous oscillatory baffled crystallizer was conducted using a model process by Brown et al. 89, following on from a previous study in a batch configuration90. Blockages were found to be an issue in the system. The author notes that at lower oscillation amplitudes, when there was a loss in steady-state operation with respect to mean particle size, a blockage occurred soon after. However, these blockages were prevented by increasing the oscillation amplitude, and even with a change in mean particle size during operation, blockages did not occur. Replacing the baffle material within the crystallizer with smoother material (the annulus of each baffle was also removed) extended steady-state operation. Siddique et al. described the continuous sonocrystallization of lactose in a COBC 91. This was described as a feasibility study and with an initial focus on demonstrating particle size control with no fouling or blockages. However, fouling was not observed in the system. Briggs et al. reported on the continuous cooling crystallization of L-glutamic acid in a COBC, and investigated the impact of feed concentration and seed mass loading on particle growth and polymorphic form control94. Unseeded continuous crystallization in the system resulted in significant encrustation on vessel walls. This was attributed to excessive nucleation. At the same supersaturation, the  polymorph seeded crystallization could operate without significant fouling, with the exception of one experiment run at high feed concentration and low seed loading, as may have been expected. In the OFBC study by Pena et al 93, it was stated the experimental conditions investigated were mostly selected 35 | P a g e ACS Paragon Plus Environment


Page 36 of 44

in order to avoid fouling in the system. It was found that higher mixing and flow rates reduced setting of solids in the system which reduced the rate of material build up on the walls of the crystallizer. For the same reason, it was suggested that the solids loading in the system should be minimized in order to reduce clogging and fouling. It was noted that the MSMPR did not have the same issues around fouling which allows it to operate at higher supersaturations than the OFBC. Where Agnew et al 33 attempted to utilize the COBC continuously crystallize paracetamol form II, clogging was reported to be an issue in the system. While a detriment COBCs is generally believed to be its strong tendency to foul, few of the studies sited show that to be the case. It may be that only more successful experiences are generally reported. Further studies would be useful on the propensity of fouling in COBCs. Similar studies to Agnew et al 44 would be useful in order to directly compare fouling issues with different types of crystallizers.


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Table 3: Summary of published studies of continuous crystallization in COBC configuration

Author Year Lawton 2009 Zhao 2014

Material

COBC Dimensions 12 m length

Volume

Flowrate

4L

α-lipioic acid : nicotinamide cocrystals

16 mm ID 24 m length

Brown 2015

Salicylic acid

Siddique 2015

Lactose

Briggs 2015 Agnew 2017

ʟ-glutamic acid

Kacker 2017

methylene bluewater melamine-water Benzoic Acid

API

Paracetamol

Pena 2017 NS – not specified

NS

Residence Time NS

Operating Time NS

4.2 l

70 mL/min

5.4 m length

1L

Nitech DN15 (8 Segments)

100, 200, 400 mL/min 1250 mL 100 – 150 mL/min

Yield Additional Technology/ Considerations NS  Seeding  Design methodology NS  99 % purity  Novel co-crystal

REF 86

88

NS



Anti solvent crystallization

89

12 hours

NS



Sonocrystallization

91

80 mins

10 hours

NS



94

NS

NS

NS



10 mins

40 - 50 mins (4 – 5 RTs)

n/a

 

Seeding to reduce fouling Comparison to MSMPR Polymorph control Mixing conditions

8.33 min, 10 min, 12.5 min

12 RTs

NS



Spherical Crystallization

93

33

92



Page 38 of 44

5.0 Conclusion It is clear that significant progress has been realized in the last decade toward the continuous crystallization of pharmaceutical materials. The original research articles reviewed here come from mainly academic sources, as is typical, but 12% of the papers reviewed have industrial authorship demonstrating the industrial significance of this research area. It becomes apparent when reviewing the literature collectively that there is a lack of consistency in how the experimental aspects of continuous crystallization are being reported. Important details such as residence time, time to steady-state, agitation rates, total operating time, length of transfer lines, and the use of heat tracing are often omitted. Few studies include sufficient detail to enable their replication, making it difficult for newcomers to this research area to really gain from previous work-to-date. Additional scientific rigour in the reporting of such detail would be very beneficial. In so far as possible we have completed a novice statistical review of the included articles to generate the following broad trends for the application of continuous crystallization with pharmaceutical materials. The majority of experimental work to-date has been performed with MSMPR-based systems, most likely due to the fact that they are more readily available and more forgiving when it comes to encrustation and product classification. Despite the popularity and robustness of MSMPR systems, there are a number of issues around them as well, for example, a naturally wider residence time distribution than a correspondingly sized plug flow system. This is presumably a cause of wider particle size distributions, which are not usually desirable. On the industrial side, many companies have networks of plants which are largely CSTR-based, and green field construction of new facilities is slower due to the large capacity and capital already in place. The use of PFR and COBC tends to feature more strongly in academic publications. In all the studies which have been reviewed, there is no one single example of a direct comparison of the capability of an MSMPR, tubular crystallizer and COBC for the same compound and the same throughput. Only one COBC study focusses on form control and another on co-crystal production, interestingly none of the PFR continuous crystallization studies concern form control. The discussion of yield by Agnew et al 33 is the only mention of yield in any of the COBC papers included in the review. None of the PFR publications refer to yield. Theoretically the yield from a COBC or PFR crystallization should be higher than the equivalent MSMPR system as full desupersaturation may be possible in these systems unlike MSMPR operation where an operating steady-state supersaturation is required. A greater understanding of the capabilities of each system would provide for the desirable scenario where the selection of continuous crystallization equipment could be based on material attributes and kinetics. A small number of molecules feature predominantly across the reviewed literature. Benzoic acid, paracetamol, cyclosporine and aliskerin hemifurate collectively account for 44% of the experimental reports, with a further 12% accounted for by undisclosed API molecules. Cyclosporine and aliskerin hemifumarate have molecule weights in excess of 1200 g/mol, demonstrating the capability of continuous crystallization for larger more complex molecules. Modelling for continuous crystallization processes is an important and growing trend in the pharmaceutical space. Observed trends in crystallization modelling include changes to types of crystallization models considered, level of model rigor and evolution of modelling application. The applications have grown in frequency and number, and range from prediction of performance to online model based control. The most useful application to industry may be process design, as cost and timeline pressures on drug development continue to increase. Producing consistent API properties throughout a processing campaign is one of the biggest drivers for continuous crystallization but can be limited by the return to batch isolation and drying after the continuous 38 | P a g e ACS Paragon Plus Environment

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stage. This return to batch processing brings with it batch-to-batch variations which limit the consistency of the final delivered product. The integration of continuous crystallization with continuous isolation and drying (CCID) is required to realise the full potential of integrated continuous manufacturing from the reaction solution to dry API powder. The integration of a filtration step after crystallization is considered by a small number of authors in this review, but continuous drying has not yet received much attention. At larger scale, CCID has not gained significant traction in the industry, often leaving continuous chemistry and secondary manufacture with a gap in the middle. A number of barriers have been cited as the reason for which most isolation and drying activities are still performed in batch, with the most prevalent being that off-the-shelf equipment is not readily available at the scales necessary for CCID operations in pharmaceuticals. This scale is increasingly smaller as medicines become more potent and specialized – large production volume medicines are less frequent in modern pharma company portfolios. Several consortia, including a number of vendors, are working rapidly to address this gap, with products such as the Steadfast rotary drum filter and Alconbury Weston continuous filter dryer currently commercially available. Perhaps the biggest challenge to increased implementation of continuous crystallization and manufacturing as a whole is not a technical one. Traditionally, pharmaceutical manufacturing has been batch-processing dominated and in-house expertise and familiarity with batch processing has become well established. There may be a reluctance to move from this knowledge and experience base into the new territory of continuous processing. Some companies have created a “continuous culture” in order to adapt to the changes continuous processing brings about. Hiring new staff and training existing staff takes time and has been a challenge in a shrinking industry. A recent survey of industry leaders published in this journal by McWilliams et al highlights the fact that experience of continuous post-reaction processing “remain in the very early stages of development and implementation” 95. Process modelling is a vital component to continuous processing and only recently have many pharmaceutical companies begun to staff their groups with modelling experts and begun to fund the production of higher fidelity models. Entire quality organizations need to wrestle with “batch identity,” start-up and shut down procedures, and product diversion strategies, which have a significant technical component to avoid product waste but to ensure high quality products. There is much work to do on behalf of industry to re-tool their organizations and shift the mind-sets toward a continuous culture. The increasing participation of industrial authors in this research space is encouraging in this regard and indicative of an industry that is serious about change if the benefits can prove to justify the effort. 6.0 Final Commentary Continuous crystallization has been reviewed with respect to its uptake for pharmaceutical applications. Three types of crystallization configurations have been successfully demonstrated for continuous pharmaceutical crystallization: mixed suspension, mixed product removal (MSMPR), tubular crystallizers and continuous oscillatory baffled crystallizers (COBCs). Of these, MSMPRs have received most attention to-date, most likely due to historic experience with stirred tank reactors in the pharmaceutical sector. Continuous operation at modest scale has been proven capable of delivering pharmaceutical relevant production volumes. It is apparent that much has been realized in the advancement of continuous pharmaceutical crystallization. With additional research efforts in some focused areas: fouling, yield improvement, and equipment selection, any technical barriers to the uptake of continuous crystallization in the industry will have been removed, paving the way for increased uptake of this technology where appropriate across the sector.



Page 40 of 44

Acknowledgements This work was supported by the Enterprise Ireland Innovation Partnership Programme IP-2014-0356. Professor Kieran Hodnett is thanked for his helpful discussion. Abbreviations API = active pharmaceutical ingredient ATR-FTIR = attenuated total reflectance – fourier transform infra-red CLD = chord length distribution COBC = continuous oscillatory baffled crystallizer CSTR = continuous stirred tank reactor FBRM = focused beam reflectance method LHC – laboratory fume-hood commercialization MSMPR = mixed-suspension, mixed-product-removal OFBC = oscillatory flow baffled crystallizer PAT = process analytical technologies PMSMPR = periodic mixed-suspension, mixed-product-removal PSD = particle size distribution PVM = Particle Vision and Measurement RTD = residence time distribution References 1. 2. 3. 4. 5. 6. 7. 8.

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Progress to date in the design and operation of continuous

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