Encrustation in Continuous Pharmaceutical Crystallization Process - A

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Review

Encrustation in Continuous Pharmaceutical Crystallization Process - A Review David Acevedo, Xiaochuan Yang, Yiqing Liu, Thomas F. O'Connor, Andy Koswara, Zoltan K Nagy, Rapti Madurawe, and Celia N. Cruz Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00072 • Publication Date (Web): 08 May 2019 Downloaded from http://pubs.acs.org on May 8, 2019

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Organic Process Research & Development

Encrustation in Continuous Pharmaceutical Crystallization Process - A Review David Acevedoa, Xiaochuan Yanga*, Yiqing C. Liuab, Thomas F. O’Connora, Andy Koswarab, Zoltan K. Nagyb, Rapti Madurawea, and Celia N. Cruza a Office b

of Pharmaceutical Quality, CDER, FDA, Silver Spring, Maryland 20993-0002

Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN 47907

* [email protected] ** This publication only reflects the views of the authors and should not be construed to represent FDA’s views or policies.

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 47 48 49 50 51 52 53 54 55 56 57 58 59 60

TOC graphic: Risk diagram of encrustation formation in continuous crystallization processes


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ABSTRACT Encrustation is a risk factor that can cause product and process failure in continuous crystallization processes. Mitigation, prevention or control of encrustation have been extensively researched. Various risk mitigation strategies proposed in the literature, such as coating of crystallizer walls, use of additives to control encrustation kinetics, and periodic steady state operation show promising results in delaying or preventing encrustation. Due to increased interest in the use of continuous crystallization in industrial applications, it is important to understand this risk factor further. This review presents recent developments on dynamic models, mechanisms and risk factors of encrustation in continuous crystallization processes. Various design and control strategies to mitigate the encrustation risk are also summarized. Appropriate control strategies should be implemented during continuous crystallization to avoid the impact of encrustation on drug substance quality. Keywords: Continuous Crystallization, Encrustation, Risk Mitigation, Control Strategy, Continuous Pharmaceutical Manufacturing

1. INTRODUCTION Encrustation is the phenomenon where materials deposit on internal surfaces of equipment (e.g. inner wall of crystallizer, in-situ probes and impellers).1-4 Encrustation reduces heat transfer and/or evaporation rates and may decrease yield or cause unsustainable operation. Encrustation of heat exchanging systems in chemical, petrochemical, food and energy industries has been studied extensively and found to severely decrease heat exchanger performance.3,

5-10

A recent study

estimates the losses due to encrustation of heat exchangers in industrialized nations to be about 0.25% of their GDP.11 Encrustation can be initiated via different mechanisms, such as heterogenous nucleation at the surface, or adsorption of crystals onto the surface (The details will be discussed in the next section). Based on the type of the deposited material, encrustation can categorized into encrustation of inorganic compounds (such as encrustation of calcium salts in catheter12, 13) and encrustation of organic compounds (such as encrustation of small-molecule active ingredient14-17 or protein18, 19 in pharmaceutical crystallization). This review specifically focused on the encrustation of small molecules in pharmaceutical crystallization processes.



Traditionally, most industrial crystallizations of pharmaceuticals are batch operations and any encrustation formed is removed from crystallizers at the end of the batch operation. With the increased adoption of continuous manufacturing in the pharmaceutical industry,20-23 more research has been conducted on analyzing potential failure modes of continuous crystallization and risks to product quality. Maintaining a state of control over time in continuous operations provides assurance of continued process performance and consistency of product quality.24 The ability to maintain a state of control over time can be disturbed by encrustation of continuous crystallizers.21 Encrustation in crystallizers may significantly alter process conditions (e.g., temperature, flow rate and supersaturation) over time and cause variability in critical quality attributes of the drug substance (e.g., size, shape, purity and polymorphic form). Thus, related risk mitigation and control strategies are needed to ensure product quality.20 This review evaluates and addresses risks due to encrustation of continuous crystallizers from the perspectives of mechanisms, models, and the related risk control strategies.

2. LITERATURE REVIEW 2.1 Crystallization and Encrustation Formation Supersaturation is the driving force in crystallization processes. Supersaturation is created when solution concentration is driven above the solubility limit via thermal changes, anti-solvent addition and solvent evaporation, among others.1, 25 Crystallization is generally considered a twostep process: nucleation and growth. Nucleation is the birth of new nuclei. Nucleation events in the bulk solution are mainly homogeneous nucleation and secondary nucleation triggered by seed crystals; nonetheless, secondary nucleation is the dominating nucleation mechanism in industrial crystallizers given the wide use of seeding, while homogeneous nucleation is negligible unless the crystallization process is operating at high supersaturation zone and without seeding. In contrast, encrustation can be initiated through heterogeneous nucleation at the surface when local supersaturation is high, or by adsorption of the crystals or crystal nuclei during collision onto solid surfaces at low local supersaturation levels.26,

27

Since the growth rates of the crystals and

encrustation are expected to be similar for a given solution,1 competition between the nucleation mechanisms strongly affect the formation of encrustation. Many factors affect the rates of the different nucleation mechanisms. Properties of the active pharmaceutical ingredient (API) solute


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and solvent (e.g., interfacial tension, solubility and contact angle) inherently have a significant influence on the kinetics. The rate at which encrustation forms and/or crystals grow will depend on the nucleation and growth kinetics of the system. Changes in feed liquor composition (e.g. purity) or the addition of habit modifiers may also alter, for better or worse, the encrustation characteristics of the system1; in addition, surface properties of crystallizer walls such as the surface energy and roughness can have an impact on heterogeneous nucleation.1 Other factors, such as equipment design (i.e., geometry of the reactor and impeller) and operating conditions (i.e., supersaturation level, flow and mixing conditions, etc.) may also have an impact on the nucleation rates. Figure 1 summarizes factors that may affect encrustation. The first step of encrustation is the induction period, the time required for the formation of crystal nuclei at the surface or absorption of crystals onto the wall. After the induction period, the diffusion, attachment, and deposition of solute molecules from the bulk solution to the crystal nuclei surface contribute to the growth of the encrustation layer. At the same time, other mechanisms, including dissolution, erosion and detachment of the encrustation layer occur due to shear stress imposed by fluid flow.28 Therefore, surfaces near low-velocity flow regions of the crystallizer are most prone to encrustation. Other common places for encrustation include areas of high local supersaturation such as tubing or surfaces near mixing points of different liquor streams (e.g. feed inlet) and vapor-liquor interfaces, where encrustation may be initiated due to solvent evaporation; liquid-wall and vapor-liquor-wall interfaces are also typical locations were encrustation occurs. Moreover, improper heating/insulation of transfer tubing can cause encrustation.



Figure 1. Risk diagram of encrustation formation in continuous crystallization processes. The examples in Figure 2(a) and (b) show encrustation during a 3-hour continuous cooling crystallization of carbamazepine in ethanol in a multi-stage mixed suspension mixed product removal (MSMPR) crystallizer.21 The images were obtained after system shutdown and heating the solution to dissolve any residual product remaining in the crystallizer. Despite the heating, encrustation can still be observed at the probes, stirrer, bottom of the crystallizer and surface near the liquid-vapor interface. Figure 2(c) shows encrustation during continuous cooling crystallization of Glycine in water in a plug-flow (PF) continuous crystallizer. Encrustation increased over time and the crystallizer walls were fully covered with encrustation after 3 hours of crystallization.


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t=3h

t=2h

(b)

(a)

t=1h

(c)

Figure 2. Examples of encrustation/fouling in continuous crystallizers occur: (a) metals surfaces (i.e. PAT tools, stirrers, etc.) in MSMPR, (b) wall of MSMPR and (c) plug flow system. Efforts to study encrustation in pharmaceutical crystallization processes have increased significantly due to the growing interest in continuous manufacturing. In continuous crystallizers, such as MSMPR or PF crystallizers, encrustation may cause clogging of crystallizer or transfer tubing/pipeline and thus, shut-down of the whole process. The probability that encrustation can occur in plug flow systems (e.g., oscillatory baffled and microfluidics systems) is higher due to the larger surface-area-to-volume ratio compared to MSMPR. Hence, understanding the impact and possible mitigation or control of encrustation is particularly important in plug flow systems. Nonetheless, the mitigation and control strategies discussed in this review can be adapted to both MSMPR and plug flow systems, as appropriate.

2.2 Modeling of Encrustation Encrustation models have been proposed in literature since the 1920s. In general, the process can be modeled dynamically by a simple mass balance at the encrustation layer: Encrustation formation rate = deposit rate (𝑚𝑑)– removal rate (𝑚𝑟)#(1) 𝑑𝑚𝑒 𝑑𝑡

= 𝑚𝑑 ― 𝑚𝑟#(2)



Numerous models have been developed to describe the kinetics of encrustation deposition and removal in an attempt to simulate the complex behavior of encrustation. One of the first models was proposed by Kern and Seaton8 and has been commonly used to model the fouling process in heat exchangers where solid deposition is the dominating mechanism of encrustation formation. The model accounts the competition between deposition and removal rates of encrust, as shown in Figure 3.7, 29 Deposition rate in Kern and Seaton’s model is expressed as proportional to bulk-flow velocity (wb) and foulant concentration in the bulk (Cb); the removal rate is assumed to be proportional to the wall shear stress (τ) and encrustation thickness (δ). 𝑚𝑑 = 𝐾1𝑤𝑏𝐶𝑏#(3) 𝑚𝑟 = 𝐾2𝜏𝛿#(4) Kern and Seaton focused on the effect of fluid velocity on encrustation. An increase in fluid velocity may result in: (a) promoting encrustation formation due to enhancement of the mass transfer of solute molecules from bulk to the wall surface; and (b) increasing the shear stress that causes encrustation removal from the surface or layer.28 Hence, the final effect of an increase in fluid velocity depends on which mechanism is dominant. This model considers the time dependency of the encrustation mass where deposition kinetics initially dominate and eventually become similar to the removal rate thus leading to the asymptotic ‘steady-state’ typically observed in industrial heat exchangers.8


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Figure 3. Schematic showing crust deposition and removal rate in a tubular crystallizer7 (Reprinted with permission from Müller-Steinhagen, H., Heat Transfer Fouling: 50 Years After the Kern and Seaton Model. Heat Transfer Engineering 2011, 32 (1), 1-13. Copyright 2019 Taylor & Francis Ltd). Table 1 lists a summary of several models developed to describe fouling. While Kern and Seaton’s model as well as models developed in the following decades have been successful in describing encrustation to some degree, few addressed key factors of crystallization such as the number of nucleation sites. Based on the observation that the calcium sulfate deposition rate in a plate heat exchanger is enhanced in the presence of calcium sulfate particles in the solution, Bansal et al. modified the deposition rate model to include nucleation sites as follows:29, 30 ∗ 𝑛

𝑚𝑑 = 𝐾3(𝐶𝑏 ― 𝐶 ) 𝑁

𝑛′

( ) 𝑀𝑓

𝑀𝑓𝑔

#(5)

Here, Cb denotes bulk concentration, C* represents saturation concentration, N is the function of the nucleation sites provided by particles present in solution, Mfg represents the deposit mass at the start of crystal growth and Mf denotes the deposit mass at time t; n and n’ are exponents. Table 1. A selection of encrustation models. Source McCabe & Robinson (1924)31 Kern & Seaton (1959)8 Reitzer (1964)32

Advancement Modeled deposition rate as proportional to heat flux, did not consider encrustation removal rate Considered both deposition and removal as discussed earlier Described deposition by considering mass transfer and reaction; did not consider encrustation removal



Taborek et al. (1972)33, 34 Beal (1970,1973)35, 36

Burril (1977)37 Bohnet (1987)3 Hasson (1981)38 Bott (1995)39 Bansal (1994, 2007)29, 30

Introduced the probability of particle deposition and activation energy into the deposition kinetics; also considered shear stress in removal expression Further improve deposition and removal rate by considering more detailed flow conditions Considered redissolution as the encrustation removal mechanism Fouling by crystallization was expressed as mass transfer & reaction (widely used now); also considered (separately) fouling by sedimentation Proposed a simplified fouling rate by an empirical parameter characterizing supersaturation Considered the effect of crystal growth by including crystal growth area into fouling kinetics Considered number of nucleation as discussed above

Encrustation is now generally modeled as successive events comprising of transport, reaction (i.e., attachment), and removal.7 Epstein developed a 5×5 matrix of fouling categories and sequential events based on five mechanisms that characterize most fouling situations; namely, initiation, transport, reaction/attachment, removal and ageing.9 The deposition rate due to transport expressed by Epstein is, 𝑚𝑇 = 𝛽(𝐶𝑏 ― 𝐶𝑠)#(6) where the mass transfer coefficient β is obtained from Sherwood, Reynolds and Schmidt number (Sh, Re, and Sc) relationships, Cb is the concentration of the reacting (i.e., depositing) material in the bulk solution, and Cs is the concentration of reacting material on the surface. Epstein estimated the reaction or attachment rate as, 𝑛

𝑚𝑎 = 𝐾𝑎(𝐶𝑠 ― 𝐶 ∗ ) #(7) 𝐾𝑎 = 𝐾𝐸 exp ( ―

𝐸𝐴 𝑅𝑇

)

where KE is a fitted constant, EA is the activation energy, T is the temperature at the surface/interface, and n is the order of reaction. The dominant fouling mechanism can change with operating conditions. This is observed in crystallization processes where the deposition of material


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to form the encrustation layer is diffusion controlled at very low flow velocities while it is reaction controlled at higher velocities.7 Dynamic models for encrustation in pipes and heat exchanges have been transferred to plug flow systems. A dynamic model for layer crystallization proposed by Zhou et al. predicts the temperature, concentration, and crystal thickness along the pipe length, and the concentration and temperature along the pipe radius.40 However, this model does not consider encrustation removal due to shear stress and the evolution of the crystal size distribution (CSD) during the crystallization process. Majumder and Nagy28 integrated a dynamic encrustation model with a population balance model to simulate fouling in a continuous plug flow crystallizer. The encrustation model considers the rate of solute transport from bulk solution to the PFC wall (i.e., heat transfer surface) as well as the competing mechanisms of solute deposition and removal from the wall due to shear stress induced by fluid turbulence. The population balance model assumes that only nucleation and unidirectional growth phenomena occurs; the population balance model was used to describe the continuous crystallization process in the bulk solution. As shown in Figure 4, Majumder and Nagy coupled the models with an energy balance to simulate the impact of increased thermal resistance (due to encrustation) on process performance and product quality.1, 28 Five other assumptions were made in this study: (a) no concentration and temperature gradients are in the radial direction (i.e., ideal plug flow), (b) axial and radial temperature gradients are present at the wall and crust, (c) outer crystallizer surface temperature is maintained constant, (d) changes of physical properties of the solution, encrustation and tube are negligible and (e) volumetric flow rate is constant. The study did not account for the effect of flow geometry, such as micro-mixing. Study results show that encrustation formation throughout the continuous operation depleted the level of supersaturation and resulted in variability of CSD (i.e., crystal product quality).28 A mitigation strategy was proposed and evaluated via simulation studies. The proposed mitigation strategy involves the injection of pure solvent through the crystallizer to dissolve the crust layer. The removal and dissolution of crust started at the entrance of the crystallizer and the dissolution continued forward with time. The crust was completely removed in 0.3 hour at the conditions evaluated. Other control strategies would be discussed in detail in the next sections.



Figure 4. Coupling of the encrustation formation mode, population balance and energy balance. Adapted from Majumder and Nagy.28 (Reprinted with permission from Majumder, A.; Nagy, Z. K., Dynamic modeling of encrust formation and mitigation strategy in a continuous plug flow crystallizer. Crystal Growth & Design 2015, 15 (3), 1129-1140. Copyright 2019 American Chemical Society) It is possible for encrustation to achieve a quasi-steady state where the crust grows to a certain thickness and maintains that thickness during the operation. Growth of crust on the interior wall will decrease the inner diameter of a transferring tubing or plug flow crystallizer, therefore resulting in an increase in flow rate; or the crust grows closer to the flow region right beside the stirring blades in MSMPR crystallizers. In these phenomena, the crust may stop growing and stays at a constant thickness during the rest of the operation. The supersaturation of the solution will not be affected by encrustation during the quasi-steady state. However, the existing crust layer on the interior wall may decrease the efficiency for heat exchange, and cause deviation from the intended state of control20 (if encrustation is not considered during process design). On the other hand, encrustation may experience cycles of growth and removal. For example, we observed periodic growth and removal of crust pieces at certain places in our continuous crystallization experiments in oscillatory baffled crystallizer, where particle size distribution may be disturbed.

2.3 Effect of Encrustation on Continuous Process and Crystal Attributes


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The formation of an encrustation layer can cause several effects. First, the growth of the encrustation layer depletes the supersaturation in the bulk solution. Second, in cooling crystallizations, a rise in the temperature may be observed due to the thermal resistance of the encrustation layer, further decreasing the supersaturation level. These effects are shown by the simulation results presented by Majumder and Nagy28 in Figure 5 for a continuous cooling crystallization process in a plug flow crystallizer. The results show a decrease in the supersaturation level and an increase in the temperature along the crystallizer, and a smaller size CSD compared to the simulation without encrustation. Moreover, encrustation may result in pressure build up in the crystallizer as well as fouling of Process Analytical Technologies (PAT) tools, and thus safety pre-cautions should be considered.

Figure 5. Encrustation effect on temperature, supersaturation and CSD during cooling crystallization in a plug flow system. Image obtained from Majumder and Nagy.28 (Reprinted with permission from Majumder, A.; Nagy, Z. K., Dynamic modeling of encrust formation and mitigation strategy in a continuous plug flow crystallizer. Crystal Growth & Design 2015, 15 (3), 1129-1140. Copyright 2019 American Chemical Society)

2.4 Mitigation and Control Strategies Many strategies have been developed to prevent or delay the formation of encrustation in the continuous crystallizer. Figure 6 summarizes different strategies to mitigate or reduce encrustation in crystallization processes.



Figure 6. Various encrustation mitigation methodologies that could be implemented in continuous crystallization processes.

2.4.1 Equipment Design Strategies Design of the crystallizer equipment can prevent or reduce encrustation. Crystallizer design should be carefully considered regarding the creation of dead zones and inner wall surface properties. Dead zones may cause crystal settling and local areas of high supersaturation both of which promote encrustation. Favorable chemical interactions between the inner wall and compound molecules may induce undesired nucleation and crystal growth on the wall. Adequate velocities and mixing should be implemented to avoid dead zones, and/or hotspots. Secondly, while crystallizers with a small surface-to-volume ratio may have fewer nucleation sites on the inner walls for encrustation, they are also less efficient in heat exchange with the cooling jacket. This can create large temperature drops near the inner walls adjacent during cooling crystallizations. Large temperature drops result in a locally high supersaturation, which promotes encrustation.25 Therefore, encrustation prevention should be accounted for during equipment design. Addition of mechanical devices, such as baffles, improves mixing and reduces the deposition of materials onto the crystallizer wall. Another type of mechanical device commonly used in industrial crystallizers are scrapers and rotating shafts.41,

42


Myerson and coworkers observed

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minimum encrustation on the wall, when the wall clearance motion was provided by a custommade PTFE anchor impeller with less than 1 mm clearance to the crystallizer wall.43 Stirrers with curved plates or disks have also been used for both agitation and removing any encrustation or deposition on the walls of barrels.44 These methods have been proven to be effective in increasing the batch time, although the scrapers or shaft can become encrusted and require a shut-down. A different design reported by Carter et al. combines the use of vibrating perforated plates placed at intervals along the crystallizer length and mobile bodies placed on the perforated plates to minimize encrustation.45 A compound excitation device attached to a shaft is used to produce two waveforms. A fast waveform (i.e., high frequency and low amplitude) causes the vibration of the plates resulting in the movement and collision of the mobile bodies with each other, crystallizer wall and perforation plate, thereby dislodging crystal aggregates. A slow waveform causes translational movement of the plates along the length of the heat transfer surface resulting in scraping of the encrustation surface. The system is operated counter-currently to allow for dissolution and re-growth of crystals that were removed from the wall.45 Precautions such as insulation or heating should be taken for areas that are not cleaned by the axial movement of the perforated plates, such as the fluid inlet and outlet ports. Surface modification to prevent encrustation has been widely used for many applications in the past decades, including medical applications. Hildebrandt et al. successfully prevented the surface encrustation of urological implants by covalently binding heparin to the surface of tantalum and stainless steel stents using a spacer molecule.46 Wu et al. also demonstrated that surface crystallization of indomethacin was significantly inhibited by nanocoating of gold (10 nm) and polyelectrolyte (3−20 nm).47

2.4.2 Process Design Appropriate process design can also help prevent encrustation. Reducing the operating supersaturation level could delay the formation of the encrustation,1 but would also reduce the overall yield as the inhibition effect is universal to all nucleation and crystal growth in the crystallizer. An alternative approach is to use ultrasonic vibrations during the crystallization process. Duncan and West demonstrated the benefits of using ultrasonic vibration to prevent



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encrustation on crystallizer heat-exchangers.48 However, as ultrasonic vibration may impact process dynamics and kinetics, this approach should be well investigated during process development. The use of chemical additives to reduce the deposition rates in heat exchangers is a well-known alternative to mitigate potential encrustation. However, this adds to the plant operating cost while some chemicals may be restricted by safety, health or environmental considerations.7 In crystallization processes, additives and antifoulant chemicals have been used to control the crystallization kinetics.49 Powell et al. studied the continuous crystallization of paracetamol in the presence of hydroxyl propyl methyl cellulose (HPMC).50 More stable operation, a shorter startup time and a reduction in fouling/encrustation were observed in the presence of HPMC. However, HPMC suppressed the nucleation and crystal growth and decreased the product yield. In addition, the shape of crystals differed from that of crystals obtained in the absence of HPMC. The studies in the use of polymeric excipients as nucleation inhibitors or to alter nucleation kinetics have increased throughout the recent years.51-57 Ozaki et al. studied the impact of water-soluble polymers on drug supersaturation behavior;51 and the results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. Diao et al. demonstrated that with easily tunable microstructure and chemistry, polymer microgels offer a promising approach for the rational design of materials for controlling nucleation from solution.53 Although these techniques are not designed to mitigate encrustation, the proposed techniques can alter the local solubility and/or surface morphology/chemistry which fundamentally change surface-based heterogeneous nucleation. These formulation-based concepts could be considered as potential strategies for process design to control encrustation. However, further studies are necessary to understand the extend in which it can impact encrustation. Novel operational strategies, such as periodic flow crystallization, have been proposed to reduce the impact of encrustation and fouling in continuous crystallization58,

59.

In periodic flow

crystallization, a periodic controlled disruption is applied to the inlet and outlet flow of an MSMPR crystallizer to increase the mean residence time; this is followed by an equilibration (or pause) period with no disruption. Powell et al. achieved controlled disruptions in single and multi-stage MSMPR systems through periodic withdrawal and addition of product slurry at high flow rates.59 Figure 7 shows the various attributes over time for the continuous crystallization of paracetamol


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in a single-stage periodic MSMPR system with no recycle stream. The cycling behavior of the concentration, total counts, and temperature reflects the periodic mode of operation.59 The authors describe a process being in periodic steady-state, as a system that maintains itself despite transitory effects caused by the periodic disturbances. No encrustation or blockage of transfer lines was observed over the period studied. This type of operational strategy offers advantages with respect to manufacturability since it operated as a seeded system at low supersaturation to delay/mitigate encrustation.60, 61

Figure 7. Process time diagrams for the periodic flow crystallization in a MSMPR showing realtime temperature, FBRM counts and Raman concentration data for the cooling crystallization of paracetamol. Figure obtained from Powell et al.59 (Reprinted from Powell, K. A.; Saleemi, A. N.; Rielly, C. D.; Nagy, Z. K., Periodic steady-state flow crystallization of a pharmaceutical drug using MSMPR operation. Chemical Engineering and Processing: Process Intensification 2015, 97, 195212. By Creative Commons Attribution License)

2.4.3 PAT-based and Model-based Control Strategies Real-time detection methods for encrustation formation are necessary for the development of control strategies. The food industry has used many detection methods such as: monitoring pressure drop, temperature, heat transfer parameters, electrical parameters, and acoustic methods



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such as ultrasound, and guided waves.5 The pharmaceutical industry has used multiple cameras for the early detection of fouling in an oscillatory baffled crystallizer.62 Figure 8 shows the experimental setup in which two cameras were used for the detection of fouling during the continuous crystallization of L-Glutamic acid. This method automatically detects induction time thorough Bayesian Online Change Point Detection in real-time. Statistical analysis of pixel intensity as a time series was used to distinguish crystals from the bulk solution from crystals at the encrustation surface. Although this method is limited to crystallizers with visual access to the fouling surface, it can be used to detect the occurrence of fouling at early stages and develop control strategies.

Figure 8. Experimental setup for continuous experiment with camera for early detection of encrustation formation. Image obtained from Tachtatzis et al.62 (Reprinted with permission from Tachtatzis, C.; Sheridan, R.; Michie, C.; Atkinson, R. C.; Cleary, A.; Dziewierz, J.; Andonovic, I.; Briggs, N. E.; Florence, A. J.; Sefcik, J., Image-based monitoring for early detection of fouling in crystallisation processes. Chemical Engineering Science 2015, 133, 82-90. Copyright 2019 Elsevier). Recent work demonstrated the development and implementation of automated control strategies to mitigate encrustation of continuous crystallization processes.60,


63-66

Automated Direct

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Nucleation Control (ADNC) is a novel model-free control strategy that has shown significant potential to suppress disturbances in a multi-stage MSMPR system. ADNC varies the temperature on each stage to achieve a desired count of particles using Focused Beam Reflectance Measurement (FBRM).60 The FBRM measures the number of counts, which are directly correlated to the number of particles. The control system varies the temperature (e.g. heating or cooling) to achieve a target number of counts.61 Hence, disturbances due to the detachment of crust from the surface is automatically controlled. A sudden increase on the number of counts should be expected if a detachment of the encrustation layer occurs during the continuous operation. ADNC would react to an increase in the number of counts by increasing the temperature in the reactor. A potential drawback of this strategy is the crystals quality could vary over time since this control approach does not eliminate encrustation in the system. This control strategy only reacts to observable changes in the FBRM resulting from probe fouling, operational changes (e.g. agitation speed disturbances), among others. An ON-OFF feedback control strategy was proposed by Koswara and Nagy in a model-based study in which periodic cooling (growth) and heating (dissolution) cycles on multiple segments are implemented to avoid encrustation in a plug flow crystallizer.67-69 The authors built an encrustation growth/dissolution model and a crystallization population balance model. The models were used to optimize the crystal volume mean size (L43). As shown in Figure 9B, when L43 is out of the desired product specification (100-150 μm), the material being crystallized during this period would be deviated to waste. As observed in Figure 9 A, crystals being produced achieved relatively consistent properties for quality attributes (i.e. CSD and mean size), while crystals of smaller sizes were discarded from the system. Also, the system reaches a state of control similar to the operation described for the MSMPR platform.59 However, this work is a model-based evaluation of the proposed strategy and no commercial implementation of the control strategy has been found in literature, although the approaches have been patented.54



Figure 9. Crystal size distribution and mean size of product obtained from plug flow system with ON-OFF CSD feedback controller. Image from Koswara and Nagy.68 (Reprinted with permission from Koswara, A.; Nagy, Z. K., On-Off Feedback Control of Plug-Flow Crystallization-A Case of Quality-by-Control in Continuous Manufacturing. IEEE Life Sciences Letters 2017. Copyright 2019 IEEE)

2.5 Challenges There are challenges associated with the implementation of encrustation prevention and control strategies. First, some strategies to prevent encrustation can alter process kinetics. For example, efforts such as lowering supersaturation to prevent or reduce encrustation could also suppress nucleation and crystal growth in bulk resulting in longer start-up time or lower yield.50 Secondly, detection of encrustation can be challenging as solid particles are inherently present in crystallization processes. It is difficult to separate the crystals in the bulk solution from those on


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the encrustation surface. Although changes in temperature and pressure can be used to detect encrustation, these methods will not detect encrustation until the encrustation layer is thick enough to interfere with the process. As mentioned earlier, although several other strategies have been studied to detect encrustation,5,

62

there is a lack of systematic study of the robustness of the

detection methods. Finally, there are few studies focused on developing encrustation control strategies. As mentioned earlier, Koswara and Nagy showcased a strategy utilizing the spatial gradient of a plug flow system, but has not been demonstrated in commercial scale equipment.69 A follow-up strategy is needed to handle the ‘off spec’ products to ensure consistent product critical quality attributes during the temperature cycles. There is still a need for development of robust and efficient control strategies and appropriate equipment, to reduce or mitigate encrustation while maintaining consistent crystal product during continuous crystallization.

3. CONCLUSIONS Encrustation is a risk factor that could cause process and product failure in continuous crystallization processes. Fouling rate depends on the supersaturation, crystallizer design, and crystallization kinetics, among others. The number and size distribution of crystals may be significantly reduced by encrustation formation and the decrease of the supersaturation level. Hence, the state of control in a continuous crystallization process may be affected which will result in process and product failure. Some risk mitigation and control strategies have been developed in recent work, such as periodic operation via heating-and-cooling cycles, to reduce or delay the encrustation formation. These strategies show promising for implementation, but the methods have not yet been validated.



REFERENCES 1. Mullin, J. W., Crystallization. Elsevier: 2001. 2. Kunzel, J., Method for dissolving salt encrustations in a heat exchanger. Google Patents: 1987. 3. Bohnet, M., Fouling of heat transfer surfaces. Chemical engineering & technology 1987, 10 (1), 113-125. 4. Bott, T. R., Aspects of crystallization fouling. Experimental thermal and fluid science 1997, 14 (4), 356-360. 5. Wallhäußer, E.; Hussein, M.; Becker, T., Detection methods of fouling in heat exchangers in the food industry. Food Control 2012, 27 (1), 1-10. 6. Mwaba, M.; Golriz, M. R.; Gu, J., A semi-empirical correlation for crystallization fouling on heat exchange surfaces. Applied Thermal Engineering 2006, 26 (4), 440-447. 7. Müller-Steinhagen, H., Heat Transfer Fouling: 50 Years After the Kern and Seaton Model. Heat Transfer Engineering 2011, 32 (1), 1-13. 8. Kern, D.; Seaton, R., A theoretical analysis of thermal surface fouling. British Chemical Engineering 1959, 4 (5), 258-262. 9. Epstein, N., Thinking about heat transfer fouling: a 5× 5 matrix. Heat transfer engineering 1983, 4 (1), 43-56. 10. Müller-Steinhagen, H.; Malayeri, M. R.; Watkinson, A. P., Heat Exchanger Fouling: Mitigation and Cleaning Strategies. Heat Transfer Engineering 2011, 32 (3-4), 189-196. 11. MÜLler-Steinhagen, H.; Malayeri, M. R.; Watkinson, A. P., Fouling of Heat Exchangers-New Approaches to Solve an Old Problem. Heat Transfer Engineering 2005, 26 (1), 1-4. 12. Choong, S.; Wood, S.; Fry, C.; Whitfield, H., Catheter associated urinary tract infection and encrustation. International Journal of Antimicrobial Agents 2001, 17 (4), 305-310. 13. Shaw, G. L.; Choong, S. K.; Fry, C. J. U. r., Encrustation of biomaterials in the urinary tract. 2005, 33 (1), 17-22. 14. Acevedo, D.; Nagy, Z. K., Systematic classification of unseeded batch crystallization systems for achievable shape and size analysis. Journal of Crystal Growth 2014, 394, 97-105. 15. Acevedo, D.; Tandy, Y.; Nagy, Z. K., Multiobjective optimization of an unseeded batch cooling crystallizer for shape and size manipulation. Industrial & Engineering Chemistry Research 2015, 54 (7), 2156-2166. 16. Méndez, G. C.; Kiil, S.; Dam-Johansen, K.; Mealy, M. J.; Christensen, T. V., Design of continuous crystallizers for production of active pharmaceutical ingredients. 2017. 17. Schall, J. M.; Mandur, J. S.; Braatz, R. D.; Myerson, A. S., Nucleation and Growth Kinetics for Combined Cooling and Antisolvent Crystallization in a Mixed-Suspension, Mixed-Product Removal System: Estimating Solvent Dependency. Crystal Growth & Design 2018, 18 (3), 1560-1570. 18. Yang, H.; Chen, W.; Peczulis, P.; Heng, J. Y. Y., Development and Workflow of a Continuous Protein Crystallization Process: A Case of Lysozyme. Crystal Growth & Design 2019, 19 (2), 983-991. 19. Yang, H.; Peczulis, P.; Inguva, P.; Li, X.; Heng, J. Y. Y., Continuous protein crystallisation platform and process: Case of lysozyme. Chemical Engineering Research and Design 2018, 136, 529-535. 20. Lee, S. L.; O’Connor, T. F.; Yang, X.; Cruz, C. N.; Chatterjee, S.; Madurawe, R. D.; Moore, C. M.; Lawrence, X. Y.; Woodcock, J., Modernizing pharmaceutical manufacturing: from batch to continuous production. Journal of Pharmaceutical Innovation 2015, 10 (3), 191-199. 21. Yang, X.; Acevedo, D.; Mohammad, A.; Pavurala, N.; Wu, H.; Brayton, A. L.; Shaw, R. A.; Goldman, M. J.; He, F.; Li, S.; Fisher, R. J.; O’Connor, T. F.; Cruz, C. N., Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine. Organic Process Research & Development 2017.


Page 22 of 25

Page 23 of 25 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 47 48 49 50 51 52 53 54 55 56 57 58 59 60


22. Food, U.; Administration, D., Pharmaceutical CGMPs for the 21st Century—a risk-based approach. Final report. Rockville, MD 2004. 23. Cole, K. P.; Groh, J. M.; Johnson, M. D.; Burcham, C. L.; Campbell, B. M.; Diseroad, W. D.; Heller, M. R.; Howell, J. R.; Kallman, N. J.; Koenig, T. M., Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions. Science 2017, 356 (6343), 1144-1150. 24. Chamarthy, S. P.; Pinal, R.; Carvajal, M. T., Elucidating raw material variability—importance of surface properties and functionality in pharmaceutical powders. AAPS PharmSciTech 2009, 10 (3), 780788. 25. Mullin, J., Industrial crystallization. Springer Science & Business Media: 2012. 26. Vendel, M.; Rasmuson, Å. C., Mechanisms of initiation of incrustation. AIChE journal 1997, 43 (5), 1300-1308. 27. Vendel, M.; Rasmuson, Å. C., Initiation of Incrustation by Crystal Collision. Chemical Engineering Research and Design 2000, 78 (5), 749-755. 28. Majumder, A.; Nagy, Z. K., Dynamic modeling of encrust formation and mitigation strategy in a continuous plug flow crystallizer. Crystal Growth & Design 2015, 15 (3), 1129-1140. 29. Bansal, B.; Chen, X. D.; Müller-Steinhagen, H., Analysis of ‘classical’deposition rate law for crystallisation fouling. Chemical Engineering and Processing: Process Intensification 2008, 47 (8), 12011210. 30. Bansal, B. Crystallization fouling in plate heat exchangers. University of Auckland, New Zealand, 1994. 31. McCabe, W. L.; Robinson, C. S., Evaporator Scale Formation. Industrial & Engineering Chemistry 1924, 16 (5), 478-479. 32. Reitzer, B., Rate of scale formation in tubular heat exchangers. Mathematical analysis of factors influencing rate of decline of over-all heat transfer coefficients. Industrial & Engineering Chemistry Process Design and Development 1964, 3 (4), 345-348. 33. Taborek, J.; Aoki, T.; Ritter, R.; Palen, J.; Knudsen, J., Fouling: the major unresolved problem in heat transfer. 1972. 34. Taborek, J.; Aoki, T.; Ritter, R.; Palen, J.; Knudsen, J., Predictive methods for fouling behavior. CHEMICAL ENGINEERING PROGRESS, VOL 68, NO 7, P 69-78, JULY 1972. 17 FIG, 9 REF. 1972. 35. Beal, S. K., Deposition of Particles in Turbulent Flow on Channel or Pipe Walls. Nuclear Science and Engineering 1970, 40 (1), 1-11. 36. Beal, S. K., Model of crud and radiation-level buildup in reactor plants. Trans. Amer. Nucl. Soc 1973, 17. 37. Burrill, K. A., Corrosion product transport in water-cooled. nuclear reactors Part I: Pressurized water operation. The Canadian Journal of Chemical Engineering 1977, 55 (1), 54-61. 38. Hasson, D.; Somerscales, E.; Knudsen, J. G., Fouling of heat transfer equipment. Hemisphere Pub: 1981. 39. Bott, T. R., Fouling of heat exchangers. Elsevier: 1995. 40. Zhou, L.; Su, M.; Benyahia, B.; Singh, A.; Barton, P. I.; Trout, B. L.; Myerson, A. S.; Braatz, R. D., Mathematical modeling and design of layer crystallization in a concentric annulus with and without recirculation. AIChE Journal 2013, 59 (4), 1308-1321. 41. Brubaker, D. A., Scraper for a vessel interior surface. Google Patents: 1978. 42. Feldstein, H. H.; Kilby, H. R., Sugar crystallizer apparatus. Google Patents: 1951. 43. Wong, S. Y.; Chen, J.; Forte, L. E.; Myerson, A. S., Compact crystallization, filtration, and drying for the production of active pharmaceutical ingredients. Organic Process Research & Development 2013, 17 (4), 684-692. 44. Barrel-stirrer. Google Patents: 1897.



45. Carter, D. E.; Hsu, Y. C., Incrustation resistive crystallizer employing multifrequency vibrations. Google Patents: 1990. 46. Hildebrandt, P.; Sayyad, M.; Rzany, A.; Schaldach, M.; Seiter, H., Prevention of surface encrustation of urological implants by coating with inhibitors. Biomaterials 2001, 22 (5), 503-507. 47. Wu, T.; Sun, Y.; Li, N.; de Villiers, M. M.; Yu, L., Inhibiting surface crystallization of amorphous indomethacin by nanocoating. Langmuir 2007, 23 (9), 5148-5153. 48. Duncan, A.; West, C., Prevention of incrustation on crystallizer heat-exchangers by ultrasonic vibration. TRANSACTIONS OF THE INSTITUTION OF CHEMICAL ENGINEERS AND THE CHEMICAL ENGINEER 1972, 50 (2), 109-&. 49. Geddert, T.; Bialuch, I.; Augustin, W.; Scholl, S., Extending the induction period of crystallization fouling through surface coating. Heat Transfer Engineering 2009, 30 (10-11), 868-875. 50. Powell, K. A.; Saleemi, A. N.; Rielly, C. D.; Nagy, Z. K., Monitoring Continuous Crystallization of Paracetamol in the Presence of an Additive Using an Integrated PAT Array and Multivariate Methods. Organic Process Research & Development 2016, 20 (3), 626-636. 51. Ozaki, S.; Kushida, I.; Yamashita, T.; Hasebe, T.; Shirai, O.; Kano, K., Inhibition of Crystal Nucleation and Growth by Water-Soluble Polymers and its Impact on the Supersaturation Profiles of Amorphous Drugs. Journal of Pharmaceutical Sciences 2013, 102 (7), 2273-2281. 52. Arribas Bueno, R.; Crowley, C. M.; Hodnett, B. K.; Hudson, S.; Davern, P., Influence of Process Parameters on the Heterogeneous Nucleation of Active Pharmaceutical Ingredients onto Excipients. Organic Process Research & Development 2017, 21 (4), 559-570. 53. Diao, Y.; Helgeson, M. E.; Myerson, A. S.; Hatton, T. A.; Doyle, P. S.; Trout, B. L., Controlled Nucleation from Solution Using Polymer Microgels. Journal of the American Chemical Society 2011, 133 (11), 3756-3759. 54. Quon, J. L.; Chadwick, K.; Wood, G. P. F.; Sheu, I.; Brettmann, B. K.; Myerson, A. S.; Trout, B. L., Templated Nucleation of Acetaminophen on Spherical Excipient Agglomerates. Langmuir 2013, 29 (10), 3292-3300. 55. Yazdanpanah, N.; Testa, C. J.; Perala, S. R.; Jensen, K. D.; Braatz, R. D.; Myerson, A. S.; Trout, B. L., Continuous Heterogeneous Crystallization on Excipient Surfaces. Crystal Growth & Design 2017. 56. Acevedo, D. A.; Ling, J.; Chadwick, K.; Nagy, Z. K., Application of Process Analytical TechnologyBased Feedback Control for the Crystallization of Pharmaceuticals in Porous Media. Crystal Growth & Design 2016, 16 (8), 4263-4271. 57. Tan, L.; Davis, R. M.; Myerson, A. S.; Trout, B. L. J. C. G.; Design, Control of heterogeneous nucleation via rationally designed biocompatible polymer surfaces with nanoscale features. 2015, 15 (5), 2176-2186. 58. Su, Q. L.; Rielly, C. D.; Powell, K. A.; Nagy, Z. K., Mathematical Modelling and Experimental Validation of a Novel Periodic Flow Crystallization Using MSMPR Crystallizers. Aiche Journal 2017, 63 (4), 1313-1327. 59. Powell, K. A.; Saleemi, A. N.; Rielly, C. D.; Nagy, Z. K., Periodic steady-state flow crystallization of a pharmaceutical drug using MSMPR operation. Chemical Engineering and Processing: Process Intensification 2015, 97, 195-212. 60. Yang, Y.; Song, L.; Nagy, Z. K., Automated Direct Nucleation Control in Continuous Mixed Suspension Mixed Product Removal Cooling Crystallization. Crystal Growth & Design 2015, 15 (12), 5839-5848. 61. Acevedo, D.; Yang, Y.; Warnke, D. J.; Nagy, Z. K., Model-Based Evaluation of Direct Nucleation Control Approaches for the Continuous Cooling Crystallization of Paracetamol in a Mixed Suspension Mixed Product Removal System. Crystal Growth & Design 2017.


Page 24 of 25

Page 25 of 25 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 47 48 49 50 51 52 53 54 55 56 57 58 59 60


62. Tachtatzis, C.; Sheridan, R.; Michie, C.; Atkinson, R. C.; Cleary, A.; Dziewierz, J.; Andonovic, I.; Briggs, N. E.; Florence, A. J.; Sefcik, J., Image-based monitoring for early detection of fouling in crystallisation processes. Chemical Engineering Science 2015, 133, 82-90. 63. Yang, Y.; Nagy, Z. K., Advanced control approaches for combined cooling/antisolvent crystallization in continuous mixed suspension mixed product removal cascade crystallizers. Chemical Engineering Science 2015, 127, 362-373. 64. Bravi, M.; Chianese, A., Neuro-Fuzzy Control of a Continuous Cooled MSMPR Crystallizer. Chemical engineering & technology 2003, 26 (3), 262-266. 65. Kwon, J. S.-I.; Nayhouse, M.; Christofides, P. D.; Orkoulas, G., Modeling and control of crystal shape in continuous protein crystallization. Chemical Engineering Science 2014, 107, 47-57. 66. Acevedo, D.; Kamaraju, V. K.; Glennon, B.; Nagy, Z. K., Modeling and Characterization of an in Situ Wet Mill Operation. Organic Process Research & Development 2017, 21 (7), 1069-1079. 67. Koswara, A.; Nagy, Z. K., Anti-fouling control of plug-flow crystallization via heating and cooling cycle. IFAC-PapersOnLine 2015, 48 (8), 193-198. 68. Koswara, A.; Nagy, Z. K., On-Off Feedback Control of Plug-Flow Crystallization-A Case of Qualityby-Control in Continuous Manufacturing. IEEE Life Sciences Letters 2017. 69. Koswara, A.; Nagy, Z. K., Systems with anti-fouling control and methods for controlling fouling within a channel of a plug flow crystallizer. Google Patents: 2017.


Encrustation in Continuous Pharmaceutical Crystallization Process - A

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