Journal of Industrial and Engineering Chemistry 54 (2017) 14–29

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Journal of Industrial and Engineering Chemistry

journal homepage: www.elsevier.com/locate/jiec

Review

Recent progress of continuous crystallization

Ting Wanga,b , Haijiao Lua,b , Jingkang Wanga,b , Yan Xiaoa,b , Yanan Zhoua,b , Ying Baoa,b ,
Hongxun Haoa,b,*
a
National Engineering Research Center of Industry Crystallization Technology, School of Chemical Engineering and Technology, Tianjin University,
Tianjin 300072, China
b
Co-Innovation Center of Chemical Science and Engineering, Tianjin 300072, China

A R T I C L E I N F O A B S T R A C T

Article history:
Received 24 January 2017 Continuous crystallization has always been a hot topic in industrial crystallization. Many efforts have
Received in revised form 27 March 2017 been made to improve the continuous crystallization, either by designing novel continuous crystallizers
Accepted 5 June 2017 or by proposing improved design and operation of conventional continuous crystallizers. Some new
Available online 15 June 2017 models for continuous crystallization processes have also been proposed and tested in recent years. In
this work, the development of continuous crystallization in recent years, including novel crystallizers,
Keywords: control strategies, models and some assistive technologies, is summarized. Promising as it is, continuous
Continuous crystallization crystallization is still not as universal as batch crystallization due to the existence of the drawbacks, such
Control strategies
as blockage and encrustation. Therefore, further efforts are needed before wider application of
Predictive models
continuous crystallization.
Novel crystallizers
© 2017 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights
reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Theoretical models for continuous crystallization . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Population balance equation (PBE) model . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Computational fluid dynamics (CFD) and discrete element method (DEM) ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Control strategies of continuous crystallization process . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Model-free control strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Model-based control strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Hybrid control strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Continuous crystallizers and their applications . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
MSMPR crystallizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Single-stage MSMPR crystallizer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Multi-stage MSMPR crystallizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Plug-plow crystallizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Continuous oscillatory baffled crystallizer (COBC) . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Continuous laminar shear crystallizers and continuous Couette–Taylor (CT) crystallizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Continuous microfluidic crystallizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Fluidized bed crystallizer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Forced circulation crystallizer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Draft tube (DT) crystallizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Falling film crystallizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

* Corresponding author at: National Engineering Research Center of Industry Crystallization Technology, School of Chemical Engineering and Technology, Tianjin
University, Tianjin 300072, China. Fax: +86 22 27374971.
E-mail addresses: hongxunhao@tju.edu.cn, hhx73@hotmail.com (H. Hao).

http://dx.doi.org/10.1016/j.jiec.2017.06.009
1226-086X/© 2017 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights reserved.
 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29 15

Applications of new technologies in continuous crystallization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Process analytical technologies (PAT) . . . . . ............ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Ultrasonic technique . . . . . . . . . . . . . . . . . . ............ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Coupled with membrane distillation . . . . . ............ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Conclusions and future scopes . . . . . . . . . . . . . ............ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . ............ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Introduction Based on the following assumptions: (1) the grow rate is

Crystallization is one of the most important separation and
purification processes in chemical engineering industries, espe-
cially in pharmaceutical industries. It is believed that approxi-
mately 90% of the active pharmaceutical ingredients (APIs) are
organic crystals and crystallization process is one of key unite
operations which determine the products’ final qualities [1]. In
crystallization industry, batch crystallization has been the most
frequently used technique for many years. However, batch
crystallization has some drawbacks, such as variation of product
quality, low capacity, high requirements of human intervention,
high facility cost, etc. [2]. In contrast, continuous process provides
many advantages, such as consistence of the product quality,
improved yield and capacity, and lower facility cost and space
requirement [3,4]. Hence, it is attracting the interests of more and
more researchers in recent years, especially in the field of
pharmaceutical crystallization.
After Randolph and Larson [5] introduced the concept of
population balance to crystallization, continuous crystallization
process could be more precisely controlled than ever. Though
promising, continuous crystallization is still not as universal as
batch crystallization in industries. Problems, such as blockage and
encrustation, need to be solved by some cost-effective solutions
before wider application of continuous crystallization [6]. Besides,
mixed suspension and mixed product removal (MSMPR) crystal-
lizer, one of the typical continuous crystallizers, often causes
cyclical oscillations in the crystal size distribution (CSD), which is
also challenging for continuous crystallization.
In this work, the progresseses of continuous crystallization in
recent years, especially in pharmaceutical area, are summarized to
give a brief review on the state of art and future research directions
of continuous crystallization. Theoretical models of continuous
crystallization are firstly introduced. Then, continuous crystallizers
and their applications are summarized. Furthermore, new
emerged assistive technologies for continuous crystallization are
also outlined and discussed.
Theoretical models for continuous crystallization
Population balance equation (PBE) model
Population balance equation (PBE) models are the most
common models for the simulation of continuous crystallization.
If a PBE model is applied to describe the crystal size distribution in
a stirred tank, the model can be specially expressed as [7]:
@n @ðGnÞ dðlogV Þ n Q
þ þn ¼ B  D  Sk k k
@t @L dt V
where n is the population of crystals, which is relative to time and
particle size, G is the linear growth rate of crystal, L is the size of the
crystal and V is the volume of the solution. B and D represents the
birth and death rates of the crystal due to aggregation and
breakage, respectively. Qk is the flow rate of influent and effluent
streams.
independent of the crystal size; (2) there are no seeds in feed flow;
(3) the whole system maintains a steady state; (4) the solution in
the tank is well mixed, which means that, the crystal population
and size distribution are the same anywhere inside the tank and
the condition of the withdraw flow is the same with the suspension
in the tank; (5) the crystal size distribution curve in the system is
continuous; (6) aggregation and breakage are ignored; (7) the
mean resident time can be described by t = V/Qk,
B = D = 0, t = V/Qk,ninlet = 0, and the right-hand side of Eq. (1) can
be changed as:
nk Q k n
Sk ¼ ð2Þ
V t
When the system reaches a steady state, n and V would not
change with time, then
@n dðlogV Þ
¼n ¼0 ð3Þ
@t dt
Finally, the model can be simplified as:
dðGnÞ n
þ ¼0 ð4Þ
dL t
If the crystal growth is assumed to be independent of particle
size, Eq. (4) can be further simplified into Eq. (5).
Gdn n
þ ¼0 ð5Þ
dL t
Therefore, it can be solved by integration as:
 
L
n ¼ n0 exp  ð6Þ
Gt
Eq. (6) is the final form of the basic PBE model, in which n0 is the
population of nucleus. On the basis of Eq. (6), the fluctuation of the
CSD in the stirred tank during the process can be monitored and
thus operating conditions can be adjusted in time to control the
process.
Since 1980s, the PBE models have been used for crystallization
process modeling [8], such as the simulation of CSD, the nucleation
process [9–11], the design of continuous crystallizers [12,13], the
optimization of operating conditions [14,15], and the avoidance of
unwanted problems such like fouling [16], etc. Because the
conditions in the crystallizers are not always as ideal as
assumptions, the neglect of some variables, such as breakage,
aggregation and growth rate dispersion, might result in inaccuracy
of the models. On the other hand, too many variables will lead to a
highly-complicated simulation, which is also not desirable.
Fortunately, due to the assistance of high-performance computers,
ð1Þ new algorithms have been proposed [17–22], and models
concerning factors such like aggregation and breakage could be
solved effectively [23–26]. Fevotte and Fevotte [27] studied the
effects of industrial impurities on the crystallization of citric acid
using the PBE model. The impacts of the unsteady-state behavior of
the absorption of impurities on the yield and CSD of the product
were simulated and the results were used for the design of the
model-based control strategies.
16 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29
Basically, one-dimensional PBE uses one characteristic length to
define the crystal size. This would be applicable for spherical or
cubic crystals or particles which are of the same shape. But if the
shapes of the crystals inside the crystallizer are different, a multi-
dimensional PBE model need to be implemented in order to
capture the dynamics of the process [28]. It has been reported that
a two-dimensional PBE model was successfully used to simulate
the size-independent growth of hydroquinone in MSMPR crystal-
lizer. The simulation results demonstrated the low-frequency
oscillatory behaviors in the case of insufficient secondary
nucleation [29]. On the basis of the multi-dimensional PBE models,
researches on CSD, the agglomeration and breakage [30], and the
comparison of accuracy validation of different methods [31] have
been reported in recent years.
Computational fluid dynamics (CFD) and discrete element method
(DEM)
Computational fluid dynamics can be used to solve and
analyze fluid flow problems by numerical analysis and algo-
rithms. It is helpful to obtain solutions for single or multi-phase
flow analysis, temperature and chemical composition distribu-
tion and so on. For the analysis of crystallization process, CFD is of
great importance when the crystallization is at a large scale
because the solution in large crystallizers is typically not well-
mixed. Conditions such as concentration and temperature might
vary a lot with different positions inside the vessel. In this case,
PBE alone will not be enough to describe the CSD in the
crystallizer [32]. To solve this problem, PBE is often combined
with CFD to give more reliable results. There are many reports
about the PBE-CFD models, such as the simulation of CSD [33], the
scale-up of a crystallizer [34] and the optimization design of the
crystallizers [35]. In some studies, CFD-PBE models could be
further combined with a third model to achieve more precise
analysis of continuous crystallization [36,37].
Compartmental models are one of the effective CFD models to
simulate the flow conditions in the crystallizers. In compartmental
models, the crystallizer is divided into several parts and each part
is simulated separately [38]. Particularly, segregated feed models
(SFM) divide the crystallizer into three parts: two feed zones and a
bulk zone. SFM has been used for the investigation of semi-batch
crystal precipitation [39]. Zauner and Jones [40] used the SFM to
predict the effects of mixing on crystallization. It was predicted
that it would take about ten resident times to reach the steady state
and the overall nucleation rate was dependent on the mixing
conditions. What highlighted this study was that the predictions
were verified by both continuous and batch crystallization
processes of calcium oxalate, making SFM potential for real
applications.
Discrete element method is another kind of simulation which is
common in pharmaceutical industry. In a DEM simulation,
Newton’s equations of motion in all three coordinate directions
are evaluated for all the particles in the system, ensuring accuracy
of particle movement trajectories [41]. In recent years, DEM or the
combination of DEM with other models has been widely applied to
improve the understanding of pharmaceutical process, such as the
particulate processes [42,43], the coating processes [44], crystalli-
zation [45] and so on. Grof et al. [46] combined DEM-PBE model
with experiments to determine the breakage kernel and the
daughter distribution functions (breakage functions) of needle-
shaped crystals during the crystallization. Quantitative agreement
between simulation and experiment was obtained, suggesting that
the method was reliable and could significantly reduce the
experimental effort. However, it is impractical to use DEM in
applications such as sensitivity analysis or optimization which
require numerous calls to the process model, because much higher
computational cost would be needed in comparison with any other
models [47].
In addition, turbulence model is also a kind of model to simulate
the flow field. Crystallizers such like the fluidized bed and baffled
stirred bank, where there is always turbulence flow, often need to
use turbulence models to simulate the turbulence flow inside
crystallizers to get a better understanding of the CSD in
crystallizers [48–52]. Meanwhile, there are also reports on
simulation of the fouling effects [53] as well as the production
of nanocrystals [54]. In particular, a kind of turbulence model
called large eddy simulation (LES) turbulence model can help to
simulate the melt crystallization very well [55–57].
Control strategies of continuous crystallization process
In a crystallization process, a control system is always essential
to maintain the product quality, to suppress the influence of
process disturbances and to economically optimize the process
performance. Because the main properties of crystals — CSD and
crystal shape are the consequence of crystal nucleation and
growth, manipulating variables such as temperature profiles,
solution concentration and the addition of additives or impurities
to control the nucleation and growth of crystals are crucial to the
success of a control strategy. In most industrial crystallization
processes, feedback controls such like proportional–integral–
derivative (PID) control and cascade control are the most common
systems to follow simple operating policies mentioned above [58].
Some model predictive control strategies and automatic control
systems have also shown promise in recent years. Generally, three
kinds of control systems can be applied: model-free control,
model-based control and hybrid control.
Model-free control strategies
Model-free control strategies are based on the direct use of
PAT-based measurements and are widely used because of their
simplicity. Consistent properties of the products can be
obtained by the application of a model-free feedback controller,
and it has been applied in the control of CSD [59], crystal shape
[60], polymorph [6], etc. Sen et al. [61] developed an efficient
control system for the crystallization of APIs, which was based
on a PID controller consisted of both single and cascade control
loops. It was demonstrated that a closed-loop control was much
better than an open-loop one under the condition of random
disturbances. With the rapid development of automatic technol-
ogy, control systems are moving toward the direction of
intelligence and automation in recent years. For example, Powell
et al. [62] applied a so-called automated intelligent decision
support (IDS) framework to monitor the continuous crystalliza-
tion and determined the steady state of paracetamol. Yang et al.
[63] studied the automated direct nucleation control (ADNC) in
their studies, which was a focused beam reflectance measure-
ment (FBRM)-based feedback control approach in the continuous
cooling crystallization in a MSMPR crystallizer, including single-
stage and multi-stage. This control system could achieve a quick
startup and a good control of CSD and provide a highly
automated and effective disturbance suppression. Furthermore, a
novel control system, named as wet milling-based automated
direct nucleation control (WMADNC), has been put forward [64].
This system was implemented upstream to provide closed-loop
controlled primary kinetics as well as seed crystals, and
downstream to provide closed-loop controlled secondary nucle-
ation kinetics and reduce crystal sizes in a continuous cooling
crystallization process. With this close-loop control approach,
the process critical quality attributes (CQA) can be well
controlled. Moreover, based on the success of pilot-scale tests,
 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29
automated control strategies have been tested in the industrial
continuous crystallization [65].
Model-based control strategies
Model-based control strategies have made a significant
progress since they were proposed, especially in the last decades
[66]. Model-based control strategies can not only give an increased
understanding of process control, but also provide a theoretically
optimal operating condition, which helps to minimize the demand
of experiments [58]. PBE models are commonly used in the design
of model-based control strategies. However, sometimes PBEs
might not applicable in the practical controllers because of the
infinite-dimensional nature of PBE models. Therefore, nonlinear
reduced-order-models have been derived using reduced order
modeling technique (ROM) and applied in the control of CSD in
continuous process [67]. Geyyer et al. [68] tried to stabilize the
crystallization process in the presence of uncertainties and
external disturbances using control strategy based on reduced-
order model. Two configurations of continuous crystallization
processes –– with and without fines dissolution loop, were
described by a nonlinear model with distributed parameters. And
finally, a H1-loop-shaping controller design was performed using
reduced-order models. Similarly, Gámez-García et al. [69]
designed two practical robust control strategies, modeling error
compensation and integral high order sliding model control
respectively, to suppress the influence caused by nonlinear
oscillation. For large molecules such like proteins, model-based
control strategies are also applicable [60,70]. With the assistance of
simulation software, more precise results can be obtained [71].
It is worth mentioning that a combination of PBE model with
feedback control has been proposed in the process control.
Majumder and Nagy [72] used a bivariate PBE model to predict
the shape distribution of potassium dihydrogen phosphate in the
presence of crystal growth modifiers (CGMs), in which a
combination of PBE and crystal impurity model was proposed.
Furthermore, a hybrid batch-continuous crystallization control
was set up for the process. Su et al. [73] developed a general and
rigorous mathematical modeling framework to realize the
transformation from batch to continuous process. A C-control
which focused on the variation of concentration was applied to
ensure that the start-up procedures and on-line control conditions
fell within the design-space of the original batch operation, and its
ability against uncertainties was demonstrated.
Model predictive control (MPC) is a promising control strategy
in continuous crystallization [74,75]. It is based on the usage of
models, such as PBE, to simulate the variations of the process
CQA. PID control framework needs a change of control structure
when a relatively large operating region is essential. However, the
MPC, which provides fast closed loop response and large
attainable region, has a better performance in view of CSD and
yield [76]. Yang and Nagy [74] applied a nonlinear model
predictive control to a two-stage MSMPR crystallizer based on
Table 1
The comparison between model-free control and model-based control.
Control strategies Advantages
Model-free control 1. Simple to apply in progress
2. Can avoid the errors related to the choice of a model
Model-based control 1. Can provide optimal operation conditions with fewer experiments
for identification
2. Increase the understanding of process
17
PBE. This control system considered both yield and CSD as
objectives and the process was controlled by adjusting the
temperatures and anti-solvent dosing rate in cooling and anti-
solvent crystallization. MPC has also been successfully applied in
plant scale. Mesbah et al. [77] investigated the plant-wide end-to-
end continuous pharmaceutical manufacturing process with
nearly 8000 state variables in the chemical synthesis and the
crystallization steps. The closed-loop simulation results indicated
that the plant-wide MPC was able to facilitate flexible process
operation and could give an effective regulation of quality
attributes of tablets. However, it should be noted that the
accuracy of the model could have a significant effect on the
performance of the MPC.
Furthermore, crystal shape (crystal morphology) could remark-
ably influence the final quality of the product. Changes in crystal
shape can be caused by varieties of factors, such as temperature,
supersaturation, solvent, additives, impurities and so on [78]. Since
the process of forming crystal shape is kinetically controlled rather
than thermodynamically controlled, the growth mechanism is the
key to shape control [79]. Generally, image analysis and model-
based control are the two main ways to investigate and control the
crystal shape. However, image analysis is not suitable for
quantitative determination of shape distribution [66]. For mod-
el-based control, kinetic Monte Carlo (kMC) models are one of the
effective methods to simulate crystal shape. It was found that the
kMC simulation can be used to predict the crystal growth dynamics
at the operating conditions where experimental data are not
available. Because kMC models are not readily available in a closed
form, a population balance model is presented and the method of
moments is applied to derive a reduced-order ordinary differential
equation (ODE) model [70]. Motivated by this, Kwon et al. [60]
used a kMC to model the nucleation, growth and dissolution
process in a continuous crystallization process with fines trap,
where the interplay of inflow/outflow in the crystallizer was
included in the mass and energy balance equations. A model
predictive controller was designed, which could allow for crystals
with desired shape even under undesired effects such as process
disturbances and measurement noise, and it has been successfully
applied in a plug-flow crystallizer as well [80]. The advantages and
disadvantages of model-free controls and model-based controls
are compared in Table 1.
Hybrid control strategies
In consideration of the advantages of both model-free and
model-based control approaches, the combination of these two
strategies is a new direction which is worth studying in the future.
Though this control strategy was not common in continuous
crystallization, some researchers have already made a promising
start in this area in recent years. For instance, Sen et al. [81]
compared the performance of a MPC-PID scheme with a PID-only
control scheme and demonstrated that the hybrid control scheme
could significantly improve the efficiency of the control system.
Disadvantages
1. May need a lot of trials before application in practical
2. Cannot make an adjustment in time if there is a change in the system
1. May need much time and effort for the model development in some
complex situations
18 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29

Continuous crystallizers and their applications

Basically, there are two types of continuous crystallizers:

MSMPR crystallizers and the plug-flow (PF) crystallizers. MSMPR
crystallizers feature their well internal mixing as well as a
relatively long residence time, while PF crystallizers have a much
shorter residence time and can produce products with smaller size
than MSMPR crystallizers. On the basis of them, some other
continuous crystallizers have been developed. Continuous
oscillatory baffled crystallizers (COBC) and microfluidic crystal-
lizers are derived from PF crystallizers. Laminar shear crystallizers,
Couette–Taylor crystallizers and fluidized bed crystallizers are
more or less similar to the MSMPR crystallizers because of the long
residence time. Details of continuous crystallizers mentioned
above and some others are provided in the following sections.

MSMPR crystallizers

MSMPR crystallizer is one of the most common continuous

crystallizers at present. Products with narrow CSD, high yield and
purity, as well as stable polymorph, can be obtained by using
MSMPR crystallizers [82–85]. Apart from common crystallization
processes, MSMPR crystallizers are also suitable for processes such Fig. 1. Schematic diagram of a single-stage MSMPR crystallizer. The feed solution
continuously enters into the vessel and the crystal slurry is continuously withdrawn
as continuous co-crystallization [86], chiral separation [87] and
from the vessel.
wastewater treatment [88,89].

Single-stage MSMPR crystallizer
Generally, a single-stage MSMPR crystallizer has only one tank
(Fig. 1) and is often used to study nucleation and CSD in continuous
crystallization processes [90,91]. Gerard et al. [92] studied the
impacts of calcium ions addition on the reaction crystallization of
sodium bicarbonate in a single-stage MSMPR crystallizer. The
nucleation and growth rates could be determined when the steady
state was reached. It was indicated that the calcium based
additives had a significant influence on both the morphology and
CSD. Peng et al. [93] studied the CSD of calcium sulfate dehydrate
crystals in a continuous reactive crystallizer. The process was
operated at different temperatures and supersaturations to
estimate the growth and nucleation kinetics. It was found that
the simulated CSD and supersaturation were consistent with
experimental results between 25  C and 60  C. In addition, some
efforts have been made to improve the performance of single-stage
MSMPR crystallizers, such as recycling part for mother liquor [94]
to improve the yield and periodically purging nitrogen to avoid
fouling [16]. However, common MSMPR crystallizers may not be
able to achieve an ideal mixing state in some anti-solvent
crystallization and reaction crystallization processes. Therefore,
some modifications have been suggested for specific crystalliza-
tion process. For example, a novel impinging jet (Fig. 2) was
specially designed for reaction crystallization process. Two liquid

Fig. 2. 1L novel continuous crystallizer with impinging jet mixer: the schematic diagram (1 — the sodium lactate solution feeding; 2 — the acid cefuroxime solution feeding;
3 — digital stirrer; 4 — the 1L tank reactor with a jacket; 5 — the tubular reactor; 6 — the novel impinging jet mixer) Two liquid streams (1 and 2) in the form of narrow, coplanar
jets at high velocities impinge upon each other inside a small mixing zone to achieve a good mixing as well as high supersaturation. Reprinted from Ref. [95] with permission.
Copyright© 2016 Elsevier Ltd.
 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29 19

Fig. 3. Schematic diagram of a multistage MSMPR crystallizer. The former MSMPR crystallizer’s product goes directly into the next MSMPR crystallizer.

streams in the form of narrow, coplanar jets at high velocities
impinged upon each other inside a small mixing zone to achieve a
good mixing state, which could produce products with uniform
CSD and superior crystallinity [95].
Multi-stage MSMPR crystallizers
Multi-stage MSMPR crystallizers are a cascade of two or more
MSMPR crystallizers, in which the former one’s outlet line
connects directly to the next one as a feed line (Fig. 3). In
comparison with single-stage MSMPR, multi-stage MSMPR can
generate product with narrower CSD, use energy more efficiently,
relieve fouling [96], give a greater throughput [97], increase mean
crystal size [98,99] and improve crystal purity [100].
Studies of multi-stage MSMPR crystallizers have been reported
in recent years [15,101]. Vetter et al. [102] applied the attainable
region approach to identify attainable regions in a diagram of mean
product particle size vs. total process residence time, in cascades of
MSMPR crystallizers, plug-flow crystallizers and batch crystal-
lizers. Three different experiments, including cooling crystalliza-
tion, anti-solvent crystallization, and the combination of them,
were carried out. The boundaries of these attainable regions could
be found numerically by solving appropriate optimization prob-
lems. It was found that MSMPR crystallizers with low number of
cascades could produce crystals with larger particle size. By
adjusting operating variables according to proper models, multi-
stage MSMPR crystallizers could produce products with different
mean sizes and improve the yield as well as purity [103,104].
Similar to single-stage MSMPR crystallizers, the yield of multi-
stage MSMPR crystallizers can be improved by combining with a
recycle system. A two-stage MSMPR crystallizer with solids recycle
was reported to improve the yield of cyclosporine to 79.8%. And the
yield could even be increased to 83.9% (nearly the same with that of
batch process (86%)) by using a four-stage MSMPR crystallizer
[105]. What is more, multi-stage MSMPR crystallizers can be
decoupled into different steps during the crystallization processes,
resulting in a more flexible control. Motivated by this, Peña and
Nagy [106] designed a novel two-stage MSMPR crystallizer for
continuous spherical crystallization. The structure of the two-stage
MSMPR crystallizer is shown in Fig. 4. The first stage was
designated for the nucleation and growth while the second one
was designated for agglomeration. Decoupling the nucleation and
growth from the agglomeration could help to satisfy the require-
ments of both manufacturing process and biopharmaceutics and
offer more degrees of freedom in the control of each mechanism.
Similarly, Zhang et al. [101] applied a two-stage MSMPR
crystallizer with cooling process in the first stage and a
combination of cooling and anti-solvent in the second stage to
improve the properties of the final crystals. Multi-stage MSMPR
crystallizers were also applied to so-called preferential crystalli-
zation, especially chiral separation. Take Vetter’s research [107] for
example, two continuous crystallizers were coupled to exchange
their clear liquid phases, each of which was connected to a
suspension mill in charge of in situ seed generation through
particle breakage. The system was proved to have the ability of
recovery from the sudden appearance of undesired “seeds” of the
counter-enantiomer in the crystallizers. This type of crystallizers
has demonstrated its ability in preferential crystallization of
enantiomers and been widely used in recent years [108,109]. The

Fig. 4. Schematic representation of a two-stage MSMPR crystallizer for continuous spherical crystallization. The first one is designated for nucleation and growth while the
second one is designated for agglomeration. Reprinted with permission from Ref. [106]. Copyright© 2015 American Chemical Society.
20 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29

applications of continuous preferential crystallization to enantio-

pure chemicals separation have been discussed in detail in a
related review [110].
Unfortunately, fouling is also a serious issue in multi-stage
MSMPR crystallizers. Moreover, the secondary nucleation, caused
by the breakage of large crystals, intensifies the problem. To avoid
this, Cui et al.[111] designed a new type of pressure-driven flow
crystallizer (PDFC) on the basis of traditional MSMPR design, which
could prevent the suspension from passing through pumps or
valves. Moreover, it was applicable to a variety of crystallization
methods. It should be mentioned that the number of the stages of
multi-stage MSMPR crystallizers might be limited considering the
space requirements and the cost of the processes. Therefore, it is
crucial to improve the efficiency of every stage of multi-stage
MSMPR crystallizers.

Plug-plow crystallizers

Plug-flow (PF) crystallizers are a kind of tube-like crystallizers

(see Fig. 5). Studies such as the kinetic identification, experimental
validation [112], and in-situ monitoring and characterization of PF
crystallizers [113] have been well demonstrated.
PF crystallizers with recycle systems have also been introduced
[114,115]. It was found that they could effectively improve the yield
of the product and be scaled up for industrial applications. In PF
crystallizers, as the supersaturation is often achieved in a short
time, fine crystals are inevitable due to the intense nucleation in PF
crystallizers. To surmount this problem, a slight temperature rise
for dissolving fine particles has been suggested. Majumder and
Nagy [116] attempted to obtain the optimal temperature profile in
their study, in which the crystallizer was consisted of multiple
segments so that the temperature of each segment could be
controlled individually. The results suggested that the size- Fig. 5. Schematic diagram of one type of plug-flow crystallizer. Two feed flows are
dependent growth and dissolution kinetics determined the success mixed in the mixer and then crystallization occurs in the tubular section. Reprinted
of dissolution steps without compromising the final size of the with permission from Ref. [112]. Copyright© 2015 Elsevier Ltd.

crystalline products.
Fouling is prone to happen in plug-plow crystallizers as the
particles can attach to the shells of tube and block the tube in some
conditions [117]. Majumder and Nagy [118] applied an encrust
formation model coupled with the PBE model to predict the
encrust thickness, concentration, temperature profiles and the CSD
of a plug-flow crystallizer. It turned out that the influence of
blockage on product CSD was serious because of the synthetic
effects of the reduction of driving force and residence time. A
strategy was proposed to solve the problem by the injection of pure
solvent. Besides, a heating and cooling cycle has also been put
forward to solve the fouling problem without affecting crystal
mean size [119].
In recent years, some novel PF crystallizers have been proposed,
such as the multi-segmented, multi-addition plug-flow crystal-
lizers (MSMA-PFC) [12,120]. The crystallizer can be divided into
many segments by the addition of anti-solvent, so each of them
makes an independent crystallization process (Fig. 6). In addition,
there is another kind of crystallizer similar to MSMA-PFC called
slug-flow crystallizer [121–123]. Generally, the solution in a slug-
flow crystallizer could be segmented by an immiscible fluid. The
size and the number of the slugs could be controlled by the amount
and the frequency of immiscible fluid added to the crystallizer, and
each slug mixes very well. However, this method will lead to an
extra separation process. To solve this, Jiang et al. [124] designed a
slug-flow crystallizer with liquid and gas introduced into one end
of the tube to spontaneously generate slugs of liquid and gas (see
Fig. 7). The slugs remained stable during the crystallization
process, and it had been demonstrated to be able to produce large
and uniform L-asparagine monohydrate crystals in less than 5 min.
Moreover, there will be no extra separation process, saving a lot of
time. With pure solvent frequently added between the air bubbles
in the system, crust can also be relived. This kind of design has also
been utilized in the continuous crystallization of proteins, such as
the crystallization of enzyme lysozyme [125] and hen-egg-white
lysozyme [58].

Fig. 6. Schematic diagram of one type of MSMA-PFC. The crystallizer is divided into many parts, and the anti-solvent is added between the segments. Reprinted with
permission from Ref. [12]. Copyright© 2014 American Chemical Society.
 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29
Fig. 7. Schematic diagram of slug-flow cooling crystallization. The liquid (both hot and cold) and gas are introduced into one end of the tube to spontaneously generate slugs
of liquid and gas, which could remain stable during the process. Reprinted with permission from Ref. [124]. Copyright© 2014 American Chemical Society.
Continuous oscillatory baffled crystallizer (COBC)
Continuous oscillatory baffled crystallizer is a relatively new
type of continuous crystallizer. A COBC consists of a series of tubes,
with some baffles periodically arranged inside (Fig. 8). The
vibration of the baffles or the movement of a piston or bellows
produces repeating cycles of vortices, which can create strong
radial motions, giving more uniform mixing along the column than
PF crystallizers which depend on the net flow to mix the solution
[2,126].
In recent years, significant progress has been made on the
nucleation mechanisms in COBC [127,128]. Brown et al. [129] used
COBC to investigate the kinetics of the crystallization of adipic acid.
Their results showed that PBE-based method could maintain a
minimal deviation (1.2%) and the other two methods gave
increasing deviations with faster cooling rates (19.9% and 18.6%
for average absolute relative error, respectively). Callahan and Ni
[130] studied the causes of different nucleation behaviors of
Fig. 8. Schematic diagram of one type of continuous oscillatory baffled crystallizer.
Series of plug-flow crystallizers are connected head-to-tail, with baffles inside the
tubes to generate the vibration. Reprinted with permission from Ref. [133].
Copyright© 2014, Royal Society of Chemistry.
21
cooling crystallization in batch crystallizers and COBC under the
same experimental conditions. The mixing mechanism was found
to be the key factor, confirming the important influence of fluid
mechanical environment on the nucleation and growth. Besides,
some other critical conditions such as seeding [131] and impurity
[132], have also been studied. It is worth to mention that Zhao et al.
[133] have successfully used COBC in the design of a novel
co-crystal and the scaling up of the co-crystallization process. First,
a small-scale experiment was conducted, in which a proper 1:1
co-crystal of a-lipoic acid with nicotinamide was successfully
screened. Then, the process was scaled up in a COBC and products
with a purity of 99% was then obtained.
Continuous laminar shear crystallizers and continuous
Couette–Taylor (CT) crystallizers
Continuous laminar shear crystallizers consist of four main
sections [134]: feed unit, shearing mechanism, cooling system and
power unit (Fig. 9). Two concentric cylinders compose the shearing
mechanism, of which the inner cylinder is stationary with a cooling
system and the outer cylinder rotates to produce a shear force. The
gap between the two cylinders is designed for the entrance of feed
materials. Many studies on the characters of nanostructure of fats
have been carried out in continuous laminar shear crystallizers in
recent years, such as the thermal and mechanical properties [135],
the oil migration [136], the crystalline alignments [137], the
polymorph [134] and so on. As one of the unique parameters of the
continuous laminar shear crystallizers, laminar shear rate has an
apparent effect on the properties of crystals. With the shear rate
increasing, thicker crystals would be obtained with more evident
crystalline orientation [138]. However, reports about the applica-
tion and the scaling up of laminar shear crystallizers are still rare.
Continuous Couette–Taylor (CT) crystallizers are similar to the
continuous laminar shear crystallizers. CT crystallizers (see Fig. 10)
also have two concentric cylinders, but the inner one can rotate
freely. When the inner cylinder rotates at a low rate, a laminar
Couette fluid motion is induced in the coaxial cylinders. Then, with
the rotation speed increasing beyond a certain value which is
called the critical Taylor number, this flow changes into radial
vortex combined with a small axial dispersion, which is called as
Couette–Taylor vortex [139]. Due to this unique flow, this vortex
will have a significant effect on the crystallization processes, and
the hydrodynamic flow regime can be simply and accurately
adjusted from a laminar flow to a turbulent Taylor vortex just by
changing the rotation speed of the inner cylinder [140].
As Couette–Taylor vortex is still a relatively new concept,
researches on CT crystallizers have been limited in polymorph
22 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29

Fig. 9. (a) The detailed schematic drawing, showing the inner and outer tubes, water jackets with cooling water inlets and outlets. The inner cylinder is stationary with a
cooling system and the outer cylinder rotates to produce a shear force, and solution flows and crystalizes between the cylinders. (b) The manufactured continuous laminar
shear crystallizer, connected to the pump, the electromotor, and the controller. Reprinted with permission from Ref. [134]. Copyright© 2008 Elsevier Ltd.

transition [141], agglomeration [142,143], inhibition of flocculation
[144] and CSD control [145]. Especially, Nguyen et al. have done a
series of studies in CT crystallizers using guanosine 5-mono-
phosphate (GMP) as model API, including the phase transforma-
tion [139], kinetic model [146], and optimization on structure of CT
crystallizers [147]. In their studies, a multiple feed mode was
applied and was found to be able to successfully promote the phase
transformation of GMP. Another novel modified CT crystallizer has
also been proposed [145]. In this crystallizer, the inner concentric
cylinder was hotter than the outer one. This heating-cooling cycle
gave a large crystal size and narrow CSD by dissolving the fines in
the heat side and recrystallization in the cold side.
microfluidic crystallizers can be combined with ultrasound
[155] and achieve automated screening in nanoliter-scale crystal-
lization to an extent [156]. As most of microfluidic crystallizers’
tubes are made of poly (dimethylsiloxane), they are only applicable
for aqueous system. To solve this problem, a PEEK/Teflon micro-
fluidic device has been proposed to study the nucleation in both
aqueous and organic solvents [157]. However, microfluidic
crystallizers may not be suitable for systems in which the solvent
concentration is too high, because too many crystals will block the
thin tube during the crystallization process. State of the art of
continuous microfluidic crystallization system has been concluded
in literature [158].

Continuous microfluidic crystallizers Fluidized bed crystallizer

In recent years, crystallization in microfluidic system is
becoming more and more popular in continuous crystallization
due to its low consumption and tight control of supersaturation
(see Fig. 11). Moreover, just like the slug-flow crystallizers, if
droplets are segregated by immiscible fluid or gas, each one of
them can be regarded as an independent crystallizer with volume
in small range. [148,149]. These characteristics demonstrate its
great potential for systematic study on fundamental crystallization
process and fast screening of crystallization conditions [150]. Many
studies on microfluidic crystallizers have been reported, including
the nucleation process [151,152], the spherical crystallization from
water-in-oil emulsions [153] and so on. A microfluidic continuous
seeded crystallizer can act as a screening platform for process
parameter evaluation and process optimization. And it was
demonstrated that it could be used to study the growth kinetics
for three different forms of glycine [154]. In addition, the
Fluidized beds (see Fig. 12) are popular devices which have been
applied in numerous fields, such as synthesis, drying, granulation
and so on [159–162]. There have been many reports about their
applications in recovering useful substances from wastewater
[163–167]. In recent years, studies have also been focused on the
establishment of models [168,169] and controlling of CSD of
products [170]. Fluidized beds are commonly used in preferential
crystallization. For instance, Binev [171] coupled two fluidized
beds to study the continuous preferential crystallization to
separate isomers in two different systems. It was found that the
CSD of the products could reach a steady state with products’
purities higher than 97%. Though rare, there are still some studies
about the scale-up of fluidized bed crystallizers [172,173], often
assisted by the simulation of CFD. Besides, studies on combining
the crystallization with drying in fluidized bed crystallizers have
also been reported [174,175].
 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29 23

Fig. 10. Schematic diagram of continuous drowning-out crystallization of guanosine 5-monophosphate (GMP) using Couette–Taylor Crystallizer. (a) Taylor vortices in
Couette–Taylor crystallizer (1, stationary outer cylinder; 2, Taylor vortices; 3, rotating inner cylinder) and (b) experimental apparatus of multiple feeding mode system for
drowning-out crystallization (1, motor; 2, pump; 3, methanol; 4, feed GMP solution; 5, damper). The inner cylinder rotates at a high speed to generate the Couette–Taylor
vortex. Reprinted with permission from Ref. [139]. Copyright© 2010, American Chemical Society.

Forced circulation crystallizer
Forced circulation crystallizers are commercially available in
continuous crystallization industry. The proposal of them could
date back to 1970s in a patent [176]. Fig. 13 shows the basic
structure of forced circulation crystallizers, which comprises three
parts: a chamber intended to contain the solution, a circulating
pump to force the mother liquor back to the chamber, and a heater.
Forced circulation crystallizers have the advantages of flexible
design, stable operation and high flexibility [177], making them
favorable in continuous crystallization industry.
In recent years, the most common application of forced
circulation crystallizers may be water treatment, especially water
desalination. Basically, the main function of forced circulation
crystallizer is to produce salt and distilled water from the waste
water [178]. There have been some reports concerning the
modeling of forced circulation crystallizers to help to optimize
operating conditions in water desalination [179,180]. In addition,
they have also been applied in the basal aquifer water treatment in
pilot scale [181]. However, to our best knowledge, there are barely
reports about the application of forced circulation crystallizers in
other fields except one concerning the continuous crystallization
of lactose monohydrate [182] for the last decade. In recent years,
some modifications of the design of forced circulation crystallizers
have been proposed, such as a two concentrically arranged
chambers to give a more flexible control in CSD [183] and a
design of large deposit accumulation volume located at the bottom
of the crystallizer to relieve the fouling [184].
Draft tube (DT) crystallizers
DT crystallizers have been reported decades of years ago [186].
As shown in Fig. 14, it is a tank with a draft tube connected to the
bottom. This design gives a specific flow field in the crystallizer,
which has an effect on the properties of the product [187]. Some DT
crystallizers also have baffles to make a better flow field [188–190].
It is said that a DT crystallizer requires a much lower agitation
speed to achieve the inner circulation, so the power consumption
can be reduced [191]. In DT crystallizers, the nuclei are mainly
produced due to the collisions between crystals and the pump or
impeller, and reports are always focus on the variation of the
kinetics of nucleation and growth of the crystals [192,193]. As the
hydrodynamics is very sensitive to the structure of the crystal-
lizers, changes in such as the bottom shape [194] as well as the
impeller shape [35] will greatly affect the properties of products.
DT crystallizers usually use impellers to achieve the uniform
mixing of solution. However, the movement of impellers will cause
mechanical contacts with crystals, leading to attrition and
24 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29

Fig. 11. Schematic diagram of a kind of microfluidic crystallizer: (a) photograph of microfluidic chip and housing; (b) sketch of microfluidic chip. An injector pump push small
amount of solution into the microtubes slowly, in which crystals will be generated from drops of solution. Reprinted with permission from Ref. [159]. Copyright© 2011,
American Chemical Society.

breakage. To relieve attrition and breakage, airlift crystallizers are

proposed on the base of DT crystallizers (see Fig. 15). Air is purged
from the bottom to act as the function of an impeller. The shear
force is relatively low so that fewer crystals will get broken [195].
Though promising, airlift crystallizers are still not frequently
reported, with only a few reported in recent years [196,197].

Falling film crystallizers

Falling film crystallizers are popular in continuous melt

crystallization in recent years. A falling film melt crystallization
process is very attractive for its enhancement in mass transfer and
separation effect [198]. The structure of a falling film melt
crystallizer is illustrated by Fig. 16. Two tubes, one inside the
other, are positioned in a tank with jacket. There are two cooling
lines in the crystallizer: one passing through the jacket and the
other one going through the space between the two tubes from top.
Melt flows along the surface of the external tube and then is cooled
down to crystallize. Jiang et al. have carried out a series of studies

Fig. 13. Schematic diagram of a forced circulation crystallizer. The pump was used
Fig. 12. Schematic diagram of a continuous fluidized bed crystallizer. (A) Heat to transport the mother liquor back to the tank again, with the heat exchanger
exchanger and (B) fluidized bed. Solution is added into the fluidized bed adjusting the supersaturation. Reprinted from Ref. [185] with permission.
continuously. Copyright© 2000 Elsevier Ltd.
 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29 25

Fig. 14. Schematic diagram of a DT crystallizer. The draft tube in the tank gives a
different fluid field within the tank crystallizers. Reprinted from Ref. [187] with
permission. Copyright© 2012 Elsevier Ltd.

on falling film melt crystallizers, including the model develop-

ment, the simulation of dynamic sweating and the process
optimization [199,200]. Falling film crystallizers have been applied
in industrial purification and crystallization of many products
[201–203].

Applications of new technologies in continuous crystallization

In recent years, some assistive techniques, such as the process

analytical technologies (PAT), ultrasonic technique, have been
applied to help control or manipulate the continuous crystalliza-
tion processes. Here, some representative technologies are
introduced.

Process analytical technologies (PAT)

PAT tools have been used to investigate crystallization process

since they first emerged [204]. Continuous crystallization process-
es benefit a lot from PAT tools as they can give a real-time feedback
of the variations of the parameters to manage a robust control
during the whole process. In recent years, more emphases have
been put on this field due to the spread of PAT, aiming at a better
understanding of crystallization process as well as a more robust
control [205,206].
Basically, PAT tools are used to monitor the concentration and
the CSD of the system, facilitate the control of the process and help
to reveal the mechanisms of nucleation and growth [207]. Apart
from conventional solvent-based continuous crystallization, PAT
tools are also useful in solvent-free continuous co-crystallization
[208]. The crystallization process is often monitored by near
infrared reflectance at different stages to detect the formation of
co-crystals. Moradiya [209] designed a solvent-free continuous co-
crystallization process, in which PAT tools such as near infrared
reflectance and spatial filter velocimetry probes were used for in-
line process control. In addition, some new operation strategies of
the continuous crystallizers have also been proposed with the
assistance of PAT [210].
Fig. 15. Schematic diagram of an 18-L air-lift crystallizer. TT = temperature
transmitter, dPT = differential pressure transmitter. Reprinted from Ref. [197] with
permission. Copyright© 2014 American Chemical Society.
However, it is common that more than a single PAT tool is
applied in pharmaceutical industry to monitor physical and
chemical phenomena during the processes, resulting in data with
high dimensionality. Therefore, multivariate data analysis is
essential for a better control of the multivariate relationships
between these variables [211], and it has been applied in the
polymorph control with Raman [212] and infrared spectroscopy
[213]. Ferguson et al.[214] compared the CSD of benzoic acid from
plug flow, MSMPR and the equivalent fed batch crystallizers
respectively, with the help of FBRM and attenuated total
reflectance Fourier transform infrared spectroscopy (ATR-FTIR).
It turned out that the PAT tools could be used to monitor and
characterize the crystallizations processes, indicating their poten-
tial in reducing process development time and improving process
understanding.
26 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29
Fig. 16. Schematic diagram of a falling film melt crystallizer. Melt flows along the
external tube and then crystallizes. Reprinted from Ref. [201] with permission.
Copyright© 2013 Elsevier Ltd.
As mentioned above, image-based analysis facilities are
effective tools for analyzing shape evolution of the crystals during
the growth. Borne et al. [215] presented a technique to reconstruct
Fig. 17. Schematic diagram of continuous membrane crystallizer. The solution is distillated and then crystallized in A and the condensate will flow to D. (A) Membrane
crystallizer, (B) pump, (C) feed tank, and (D) permeate liquid tank.
the original 3D of crystal shapes from the measured 2D projections
of potassium dihydrogen phosphate (KDP) crystals, and the results
showed good agreement with the experimental values. However,
the technique required projection to be bounded by convex
polygon with six or eight vertices. Therefore, further studies need
to be carried out to improve the applicability of this technology.
Besides, image-based analysis can also be used to analyze the CSD
[216–218], monitor fouling [219] and evaluate the growth rate
[220].
Since the issuance of the FDA guidance of 2004, the Food and
Drug Administration (FDA) has been encouraging the application
of PAT tools. In this file, PAT is considered as “a system for
designing, analyzing, and controlling manufacturing through
timely measurements of critical quality and performance attrib-
utes of raw and in-process materials and processes to ensure final
product quality” [221]. Appropriate use of PAT tools will be of great
help in process control and optimization, and a combination of
different PAT tools may be more useful for ensuring the products’
quality. Furthermore, FDA also emphasizes the necessity of risk
analysis and multivariate methodologies. Therefore, a PAT method,
which considers a scientific, risk-based approach, is recom-
mended.
The emergence and application of PAT has promoted the
understanding of crystallization process and the improvement of
product quality. However, the application of PAT tools is still
limited because of the high cost [220]. More efforts are needed to
improve the accuracy of PAT tools and reduce cost.
Ultrasonic technique
Currently, ultrasound is mainly used to control the CSD of
products, both in the traditional MSMPR crystallizers [222] and in
the novel slug-flow crystallizers [223]. Jiang et al. [224] also
designed indirect ultrasonication-assisted nucleation process to
study the seed generation rate. However, the cost of ultrasound is
relatively high and its potential effects on other properties such as
morphology and polymorph transformation are still not well
known in continuous crystallization process.
 T. Wang et al. / Journal of Industrial and Engineering Chemistry 54 (2017) 14–29
Coupled with membrane distillation
Membrane distillation (MD) is a thermally driven separation
process in which the liquid evaporates and the vapor passes
through the hydrophobic membrane to achieve the separation (see
Fig. 17). Coupling MD with crystallization contributes to the
generation of supersaturation in a very short time. Meanwhile, the
solvent can be recycled by cooling down the vapor. Membrane
distillation crystallization has been applied in the desalination of
sea water [225]. In recent years, membrane distillation has also
been coupled with continuous crystallization. Chen et al. [226]
studied the continuous membrane distillation crystallization
process of a high concentration feed solution. The optimal
operating parameters were determined by an orthogonal fractional
factorial experiment design. The method could produce high
quality water and obtain sodium chloride crystals with a relatively
narrow CSD. Though continuous membrane distillation crystalli-
zation has been successfully applied in the recycle of concentrated
salt solution, to our best knowledge, no studies on their application
in continuous crystallization of API have been reported up to now.
However, it is worth mentioning that this technique may serve as
an alternative way for conventional continuous crystallization of
some substance whose solubility is not sensitive to temperature or
dilute feed solution.
Conclusions and future scopes
In this paper, continuous crystallization, including the catego-
ries of continuous crystallizers and their applications, the control
strategies and their related models, and some assistive technolo-
gies for continuous crystallization, are summarized. Through
decades of years of studies, significant progress, such as better
control of CSD and larger yield, polymorph and morphology, has
been achieved in the field of continuous crystallization. Some
novel continuous crystallizers have been proposed and success-
fully applied in the crystallization of many compounds. Unfortu-
nately, for some industries, such as pharmaceutical industry,
continuous crystallization is still rarely applied although many
famous pharmaceuticals companies such as Novartis [227] have
shown great interest in continuous crystallization and have made
significant progress. To promote a wider application of continuous
crystallization in pharmaceutical industry, more significant efforts
should be made in various of aspects. Specially, adaptability to
smaller product volumes, better compatibility with other process
equipment, better design to prevent blockage of transfer lines and
addressing regulatory issues (especially for pharmaceutical
products) regarding switch from batch to continuous processing,
etc., are crucial factors worthy studying in future research [228].
Although continuous crystallization is not so widespread as batch
processes at present, it is believed that progress on continuous
crystallization will surely extend its application to a great extent
due to the apparent advantages of continuous process.
Acknowledgement
This research is financially supported by National Key Research
and Development Program of China (No. 2016YFB0600504).
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