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# 2004 Institution of Chemical Engineers
Trans IChemE, Part A, December 2004
Chemical Engineering Research and Design, 82(A12): 1567–1570

INDUSTRIAL CRYSTALLIZATION
Developments in Research and Technology
J. ULRICH and M. J. JONES
Martin-Luther-Universität Halle-Wittenberg, Institut für Verfahrenstechnik/TVT, Fachbereich Ingenieurwissenschaften, Halle (Saale), Germany

I
n this review paper developments in industrial crystallization are discussed with empha-
sis on recent highlights in the field. One of the most important past developments can be
found in the introduction of the population balance concept. This will be discussed
together with more recent developments and topics currently of great interest such as molecu-
lar modelling, polymorphism and polymorph prediction at the fundamental scientific level as
well as melt crystallization equipment, eutectic freezing crystallization and crystallization
control by means of on-line techniques at the applied, industrial level. Potential future direc-
tions for industrial crystallization are discussed with reference to past and present deve-
lopments. The future of industrial crystallization is envisaged to lie in areas such as
nano-particle production by means of crystallization and protein crystallization, in addition
to some of those mentioned above.

Keywords: industrial crystallization; molecular modelling; polymorphs/pseudopolymorphs;

crystallizer control; precipitation.

INTRODUCTION
Industrial crystallization as a thermal unit operation is still
a technology with many poorly understood aspects. Over
the past 30 years, large strides have been taken away
from crystallization as an ‘art’ and towards putting indus-
trial crystallization onto a firm scientific basis. One of the
highlights among the many important developments was
the introduction of the population balance concept into
industrial crystallization by Randolph and Larson (1971).
However, there remain many open questions both in
crystallizer design and in crystallization kinetics. Today,
a number of new tools are available such as molecular
simulation programs or measuring devices which not only
encourage new trends in research but also provide the
basis for faster progress in the field. Of course new chal-
lenges constantly arise from new industrial needs. On the
other hand there is a noticeable trend away from the classi-
cal engineering research of the past and towards research at
the molecular or interfacial level (including computer-
based molecular modelling of crystals and the prediction
of polymorphs and pseudopolymorphs) or research on com-
plicated substances such as drugs or proteins on one side
and sensor development for the on-line control of crystalli-
zers or precipitation processes on the other.
Software for computer simulations of crystallization
processes is by far more developed when compared to the

Correspondence to: Professor J. Ulrich, Department of Chemical
Engineering, Martin-Luther-Universität Halle-Wittenberg, D-06099
Halle (Saale), Germany.
E-mail: joachim.ulrich@iw.uni-halle.de
available sensors, despite the obvious and urgent need for
progress in the measurement of accurate and reliable pro-
cess data. To control crystal growth at a constant and opti-
mum level requires constant information regarding the
position of the process with respect to both the supersatura-
tion of the system and the metastable zone width under the
pertinent process conditions.
The optimum growth conditions are those that maximise
the product yield while producing high quality crystals. This
means producing the required crystal size distribution as
well as the desired purity of crystals or crystal agglomerates.
The metastable zone width depends upon various process
parameters such as temperature, rate of attainment of super-
saturation (i.e. cooling or evaporation rate), presence or
absence of (seed) crystals and, most importantly, the com-
position of the solution (e.g. impurity enrichment in batch
processes or concentration fluctuations in the feed stream
of a continuous process can have a significant influence
on the width of the metastable zone).
THE PAST
Up until the end of the 1980s, the development of engi-
neering tools to improve the design and operation of large
scale, continuously operating crystallization processes was
one of the key areas in research and development of indus-
trial crystallization.
The introduction of the population balance concept into
industrial crystallization was one of the more important
developments (Randolph and Larson, 1971). The introduc-
tion of growth rate dispersion (White and Wright, 1971;

1567
1568 ULRICH and JONES
Ulrich, 1989) and its incorporation into the population
balance concept was another major step forward.
In parallel with these developments Toyokura and co-
workers introduced the ‘design chart’ (Aoyama et al.,
1989; Luo et al., 1989), aiming in the same direction.
One of the improvements in the description of the kine-
tics of industrial crystallization which was introduced into
the abovementioned concepts is the effectiveness factor
developed by Garside and Tavare (Garside, 1971; Garside
and Tavare, 1981).
Computer simulations for crystallization processes have
been, and still are, improving in precision and quality
with increasing computer power; however, almost all of
them lack from verification and their accuracy is therefore
an unknown quantity. The data from running plants neces-
sary for comparison with simulations are generally not avai-
lable and in most cases have simply never been measured!
The progress in simulation tools is mainly due to the
relatively advanced state of the available hard- and soft-
ware. In contrast, developments in sensor technology
required for on-line and in-line measurements of the physi-
cal and process properties in industrial plants are somewhat
lacking and existing techniques are not necessarily of the
required quality with regard to parameters such as sensi-
tivity, robustness and cost. The main physical/process
parameters that need to be measured on- or in-line are of
course supersaturation, width of metastable zone as well
as crystal size distribution and crystal shape. There is a
clear need to have the ability to measure process para-
meters that may influence crystal size and shape such as
impurity content. However, the influence of other chemical
species on crystal growth is poorly understood, in particular
when considering the effect of impurity concentration.
In recent years, there has been a large increase in the
number of books on industrial crystallization (Arkenbout,
1995; Hofmann, 2004; Hurle, 1994; Jones, 2002;
Mersmann, 2001; Mullin, 2000; Myerson, 2002; Myerson,
1999; Nyvlt et al., 1995; Nyvlt and Ulrich, 1995; Söhnel
and Garside, 1992; Ulrich and Glade, 2003; van der
Eerden and Bruinsma, 1995).
THE PRESENT
Current computing technology allows molecular simu-
lations of crystalline materials to be carried out with rela-
tive ease. Ideas originating in the 1950s (Hartman and
Perdock, 1955; Hartman and Bennema, 1980) and many
others (Berkovitch-Yellin, 1985, for example) have been
transferred into computer codes that have been applied to
predict morphologies of crystalline solids with varying
degrees of success.
In recent years, the idea of tailor made additives (Black,
et al., 1986; Wang, et al., 1985) has generated considerable
interest. Additives present an option for product design,
specifically by controlling and directing crystal shape.
Although the concept has been demonstrated in practice
(Davey et al., 1991), theoretical models able to account
for the effect of additives on crystal shape are still some-
what lacking. Although modifications to the abovemen-
tioned models have been proposed (for example, surface
docking and ‘build-in’ of additives Niehörster, 1997;
Mattos, 1999) and successfully applied, there are still
cases where these models fail. The reasons why these
Trans IChemE, Part A, Chemical Engineering Research and Design, 2004, 82(A12): 1567–1570
models are not able to predict the crystal morphology are
still unclear and require further investigation. In any case,
none of these models properly treat concentration effects
and the modelled additive concentrations are usually gov-
erned by the number of molecules in the crystal unit cell
that can be replaced by an additive (build-in) or by the
size of the slice used for surface docking and are therefore
unrealistically large. Considering this the more surprising it
is that these models are successful in those cases where
they predict the morphology correctly! In part, this limi-
tation is due to available computing hardware in the
academic community. At present, with the currently avail-
able computer codes, large model systems containing many
molecules need to be defined in order to approach smaller
additive concentrations. Large models, however, are
memory intensive and result in arduous, time-consuming
calculations on single processor computers. It is worth
noting, that additive influence is not the only problem
that has yet to be solved satisfactorily. Other problems
are encountered in the modelling of solvent crystallization
(where solvent effects may be viewed as the extreme case
of an ‘additive’) as well as in the prediction of polymorphs
and the conditions under which a given polymorph crystal-
lizes. Prediction of polymorphs has received some aca-
demic attention in recent years (Rovira, 2001) as well as
through the development of proprietary software (Cerius2
Polymorph Module, Accelrys Inc.) though there is still
much scope for development. Nucleation is a further area
where attempts to model the nucleation process are few
and far between (see, for example, Koishi, et al., 2003;
Mucha and Jungwirth, 1993).
Much of this interest in crystallization stems from the
field of pharmaceuticals polymorphs and pseudopoly-
morphs, which represents a major driving force in industrial
crystallization research today. This is clearly evidenced by
the number of papers in the proceedings of the last two
International Symposia on Industrial Crystallization in
Cambridge 1999 (Garside, 1999) and Sorrento 2002
(Chianese, 2002) which show a strongly increasing trend
in that particular area.
In the field of pharmaceuticals it is essential to characte-
rize a given active ingredient as thoroughly as possible
in order to understand if and under which circumstances
the drug substance exhibits polymorphism, so as to avoid
the production of the ‘wrong’ polymorph. Polymorphs gen-
erally exhibit different solubilities and rates of dissolution
and as a consequence have different bioavailability. In
extreme cases, employing the wrong polymorph can lead
to either inefficacy or overdosing of the active ingredient.
One well known example is the case of Ritonavir, an
anti-retroviral drug manufactured by Abbott Laboratories.
Only one crystal form was ever identified (Chemburkar
et al., 2000) in the drug development process. Furthermore,
it was assumed that polymorphism was immaterial to the
product, since the drug was formulated as a semi-solid or
liquid oral dosage form due to its lack of bioavailability
in the solid state. However, two years into production, a
new, more stable, solid form began to emerge in the
shape of crystalline material precipitating in the original
formulation. This new form was found to have significantly
less favourable dissolution characteristics compared to the
original polymorph. It was later established (Bauer et al.,
2001) that the new polymorph only nucleates under
 INDUSTRIAL CRYSTALLIZATION
conditions of high supersaturation and when seeded. Since
this observation suggests that the stable form should never
have been observed, further seeding experiments were car-
ried out with structurally similar degradation products
observed in the manufacturing process. These experiments
demonstrated, that the related compounds can lead to the
nucleation of the stable form of the drug, presumably via
a templating mechanism. One consequence of the unex-
pected production of the new, undesired, polymorph was a
prolonged investigation of the causes of and solutions to
this problem, costing the company a significant amount of
money. This example highlights the vagaries of polymor-
phism. Despite thorough polymorph screening, it cannot
be guaranteed that the results obtained cover all possibilities.
In addition, polymorphism can lead to complications in
terms of intellectual property rights and incomplete know-
ledge of polymorphism in a new drug entity leaves the
opportunity for competitors to secure patent rights on
alternative polymorphs and hence alternative formulations
of the drug, with disastrous consequences for the origina-
ting company.
Further to this, a noticeable number of papers dealing
with precipitation exist. Important features of these publi-
cations are the control of processes as well as the control
of crystal modification and of the sizes of crystals pro-
duced. The production of nano-materials (again: the idea
of product design) is one of the new aims here.
The development of the abovementioned sensors for the
control of crystallization processes is one of the most
important research topics currently emerging, as witnessed
by the many papers being published (see the abovemen-
tioned Symposia). Furthermore, sensors are also of interest
for precipitation processes and for the control of the poly-
morph that should be produced. Great strides have been
taken improving in-line and on-line control of crystallizers.
Examples can be found in the development of techniques
for measuring supersaturation using either near infra-red
spectroscopy (Dunuwila et al., 1994) and ultrasound-
based techniques (Omar and Ulrich, 1997). Both methods
have the potential to lead to a better understanding of
batch crystallization processes resulting in better crystal,
and therefore product, quality than that available from
most current processes. A proper understanding of crystal-
lization processes would allow, amongst others, better con-
trol of growth rates—ideally, the ability to keep growth
rates constant—control of nucleation and the reduction of
liquid inclusions in crystals.
There are of course many other interesting developments
which have, however, a reduced scope when compared to the
topics discussed so far, but will nonetheless have a
significant impact on developments in the area of crystalliza-
tion. It is worth mentioning a few, such as the development
of eutectic freezing technology (Drummond et al., 2002),
fractionation of oils and fats (Lüdeke et al., 2003), the sep-
aration of chiral substances (Grandeury et al., 2003) or
supercritical crystallization to produce fine particles without
solid liquid separation problems (Wubbolts, 2000).
THE FUTURE
Further development of the topics already mentioned
and where presently activity is noticeable in the industrial
Trans IChemE, Part A, Chemical Engineering Research and Design, 2004, 82(A12): 1567–1570
1569
crystallization research community can be expected. In
particular the following areas should be mentioned:
. molecular modeling;
. polymorph predicting;
. nano-particle production;
. sensor development;
. speciality process development.
It stands to reason to expect that recent developments in
computer hardware such as massively parallel computers
using inexpensive, off-the-shelf components will facilitate
further developments in the modelling of crystallization
processes. In those cases where many independent calcu-
lations are required, distributed computing is clearly
suited to reduce the real-time requirements for compu-
tations. Prime candidates for developments in this direc-
tion, in the absence of more elegant models, are habit
modelling in the presence of realistic additive concen-
trations employing large model systems as well as model-
ling of nucleation. Polymorph prediction, too, could
conceivably benefit from massively parallel computing,
where clustering approaches necessitate the investigation
of large numbers of configurations.
New topics are bound to emerge. With growing know-
ledge and growing demand for highly specialized products
the challenges to industrial crystallization are increasing
rather than diminishing. One example for the many new
challenges we are facing should be mentioned: separation
of crystalline substances with their origin in bioprocesses.
Bioprocesses result in complex solutions with variable
component concentrations. Nonetheless, bioproducts are
expected to have the same or even better quality (as
measured by their purity, for example) as those manufac-
tured in traditional and very well defined chemical
processes.
Here, proteins are worth special consideration. Proteins
are used for a range of purposes such as therapeutics/
pharmaceuticals, medical sensors and in more profane
applications such as household detergents. In the long
term, the growing understanding of the human genome
and of the functioning of the human body is likely to
draw with it further developments in protein therapy and
therefore the need to manufacture a large range of proteins
on an industrial scale. Although protein crystals have been
grown for over 150 years, much of the interest in crystalliz-
ing proteins has focussed firmly on generating good quality
single crystals for structure determination. McPherson
(1999) provides a detailed overview of current state-of-
the-art. Only few protein systems have been characterised
exhaustively in terms of solubility, crystal growth and
nucleation kinetics (Cacioppo and Pusey, 1991; Judge,
1996). From the literature it is clear that those researchers
concerned with growth of single crystals of proteins tend
to work with materials that have been meticulously purified
by other means and studiously avoid conditions typically
found in fermentation broths, namely poorly defined con-
tent and variable concentration of species present. The
knowledge accumulated in those fundamental studies avail-
able is therefore perhaps no more than a good starting point
for further investigations and potentially of limited applica-
bility to industrial applications.
1570 ULRICH and JONES
There is still much worthwhile research to be carried out
and we welcome new people to the field with—hopefully—
many new and innovative ideas.
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The manuscript was received 11 June 2004 and accepted for publication
after revision 5 November 2004.