3788 Ind. Eng. Chem. Res.

2005, 44, 3788-3798

Experimental Determination of Solid-Liquid Equilibrium Phase

Diagrams for Crystallization-Based Process Synthesis
Kui S. Kwok, Hok C. Chan, Chak K. Chan, and Ka M. Ng*
Department of Chemical Engineering, Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong

A systematic scheme for the experimental determination of isobaric solid-liquid equilibrium

(SLE) phase diagrams at atmospheric pressure is presented. Driven by process objectives and
aided by techniques for representing/visualizing phase diagrams, the scheme helps to generate
such diagrams exhibiting features (for example, feasible crystallization product region) that are
useful for the synthesis and design of crystallization-based process flowsheets. To illustrate the
execution of this scheme, the isobaric SLE phase diagrams of two organic systems were measured.
These include a system containing phenol, bisphenol A, and water and a polymorphic system
consisting of sulfamerazine and dimethyl sulfoxide.

Introduction high-dimensional phase diagrams. It focuses on the

With the rising demand for pure intermediates/
products in solid form in the pharmaceutical, chemical,
and food industries, crystallization has received renewed
interest in the research community. In particular,
systematic methods and procedures for synthesizing and
designing various types of crystallization-based separa-
tion processes have been established.1-11
In all of these systematic synthesis methods, the
starting point is to acquire reliable solid-liquid equi-
librium (SLE) data of the chemical system involved in
the crystallization process and represent them in the
form of a phase diagram. Once the appropriate phase
diagram with salient features such as thermodynamic
boundaries and a feasible crystallization product region
are available, proposed process paths can be drawn on
it, and a flowsheet of the corresponding crystallization-
based process can be generated accordingly.7,8 The use
of SLE phase diagrams and systematic procedures
rather than a trial-and-error approach would greatly
reduce the process development time and cost.
Despite the availability of solubility data for many
chemical systems, process engineers often find that the
required SLE phase diagram of a chemical system,
particularly those for new pharmaceutical entities,
cannot be found in the literature. To overcome this
problem, one can use standard thermodynamic models,
such as UNIFAC, UNIQUAC, etc., to calculate the
phase diagram, provided the parameters for these
chemical species are available. Unfortunately, the pre-
dictions are often poor because the parameters in these
models are derived from vapor-liquid equilibrium data,
not SLE data. The only reliable option is thus to
experimentally determine the phase diagram.
This work presents an objective-driven generic scheme
that assists scientists or engineers in systematically
determining the isobaric SLE phase diagrams through
experiments. With the established procedures for the
visualization of high-dimensional phase diagrams,12 this
scheme is applicable for multicomponent systems by
taking appropriate cuts or projections of the original
* To whom correspondence should be addressed. Tel.: +852-
23587238. Fax: +852-23580054. E-mail: kekmng@ust.hk.
10.1021/ie048741m CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/25/2005
determination of the important features of phase dia-
grams that are crucial for process synthesis, such as the
boundaries of crystallization compartments. In the
following section, we discuss each step of the generic
scheme, which is then illustrated by using the solid-
disappearance method to construct two isobaric SLE
phase diagrams. The first is a ternary system compris-
ing phenol, bisphenol A (BPA), and water. The second
one involves sulfamerazine (SMZ), which is a polymor-
phic drug, and dimethyl sulfoxide (DMSO).
This paper contains a number of technical terms that
are specific to SLE phase diagrams. Readers unfamiliar
with this area are referred to the papers of Dye and Ng,2
Schroer and Ng,10 and Wibowo et al.13 for additional
information. A glossary of these terms is presented in
Table 1.
Generic Scheme
The scheme used for the construction of SLE phase
diagrams consists of five steps.
Step 1. Specify the process objectives and input
information, select components to be included in
the system, and anticipate the potential configu-
ration of the process flowsheet.
The first step in constructing the SLE phase diagram
of any system is to specify the objectives of the crystal-
lization-based processes and related input information.
For example, what are the products and byproducts to
be recovered? What is the purity requirement? What
are the components and their concentrations in the
stream entering the crystallizer? What are the physical
and chemical properties of the solvents? On this basis,
we can make qualitative and quantitative decisions on
the components of the system to be examined, as well
as on the conditions (usually temperature and pressure)
under which the phase diagram of the system is
determined. In principle, an SLE phase diagram that
is of utility for process synthesis should include all of
the components in the process streams. However,
because almost all industrial systems comprise many
components and the construction of high-dimensional
SLE phase diagrams is rather involved, one has to strike
a balance between the complexity of the system selected
 Ind. Eng. Chem. Res., Vol. 44, No. 10, 2005 3789

Table 1. Glossary of Selected Technical Terms Specific to the SLE Phase Diagram
technical term meaning
crystallization compartment/region a region of the phase diagram where the crystallization of one or more
chemical species is thermodynamically feasible
cut what one sees on the cutting plane after one or more variables defining the phase
diagram is/are fixed; most common are isothermal and isoplethal cuts, which
are obtained by fixing the temperature and composition, respectively
projection what one sees on the projective subspace obtained by shining light on a portion of the
phase diagram; most common is the polythermal projection, obtained by
projection along the temperature axis of the phase diagram
saturation point a point on a phase diagram representing the equilibrium condition of a mixture in
which one or more component(s) is/are saturated; single, double, and triple
saturation points refer to the number of components that are saturated at
that point
saturation boundary/curve a one-dimensional curve on a phase diagram representing the equilibrium condition
of a collection of mixtures in which one or more component(s) is/are
saturated; single, double, and triple saturation curves refer to the number of
components that are saturated along that curve; a single saturation curve is
also referred to as a solubility curve
saturation surface a two-dimensional surface on a phase diagram representing the equilibrium
condition of a collection of mixtures in which one or more component(s) is/are
saturated; single, double, and triple saturation surfaces refer to the number
of components that are saturated on that surface; a single saturation surface
is also referred to as a solubility surface

for study and the effort of experimental measurements.
We should only select those componentssproducts,
byproducts, solvents, and high-concentration impuritiess
that greatly affect the SLE behavior of the actual
process mixture. Minor impurities or components that
have little influence on the overall SLE behavior can
be excluded from the system to be studied. After
selecting the system for investigation, we also need to
specify the composition ranges of the components in
correspondence with the actual process stream condi-
tions.
In addition to the information on the components, it
is necessary to decide on the range of temperature and
pressure within which the phase behavior of the system
is to be represented on the phase diagram. Obviously,
this decision should be made based on the operating
conditions of the desired process. For example, if a
process is expected to run in a temperature range of 25-
100 °C and the operating pressure is between 1 and 5
bar, the SLE phase diagrams to be constructed should
be able to depict the phase behavior of the system under
these conditions. Nevertheless, because SLE is generally
insensitive to the change in pressure, the effect of
pressure is seldom considered for its own sake. It is set
by the solvent vapor pressure at the selected operating
temperature. With no pressure effect or at constant
pressure, one just needs to decide whether a polyther-
mal or an isothermal phase diagram is required.
After identifying the separation objectives and the
related input data, we should speculate what the phase
diagram might look like based on whatever information
is available in the literature, and/or from thermody-
namic modeling, etc., and then synthesize a preliminary
process flowsheet using a design procedure such as the
one proposed by Wibowo and Ng.7 This exercise will
clarify which parts and what features of the phase
diagram are essential for process synthesis and thus
helps us to recognize what needs to be measured. We
can, hence, use minimal experimental efforts to generate
data that are of the highest utility. However, people
unfamiliar with the SLE phase diagram may find it
difficult to perform the above conceptual exercise. They
are advised to first skip this part of step 1 and go
directly to step 2. After working out the general picture
and some important features of the desired phase
diagram using steps 2-5, they can reiterate the entire
scheme to obtain the diagram with all of the features
necessary for the synthesis of the process flowsheet.
Step 2. Select an appropriate experimental tech-
nique to carry out the SLE measurements and test
its suitability.
To choose a suitable experimental technique for SLE
measurement, a number of factors have to be consid-
ered, including the system conditions, nature of the
components, amount of sample available, accuracy of
the phase diagram required, and so on. In some cases,
the construction of an accurate SLE phase diagram may
require a combination of two or even more different
experimental techniques. The operating principles, ad-
vantages, and disadvantages of major SLE measure-
ment techniques have been extensively reviewed.14-17
Of these techniques, the analytical method, solid-
disappearance method, and differential scanning calo-
rimetry (DSC) are the most frequently adopted. The
polythermal solid-disappearance method has been re-
fined in this study and will be discussed in detail later
in examples 1 and 2, respectively. To confirm the
reliability of the solubility data, it is advisable that
whenever possible, the results should be compared with
the literature data of relevant systems to evaluate
whether the selected technique performs satisfactorily.
Step 3. Identify and represent the desired pro-
jections and cuts of the SLE phase diagram.
Prior to the conduction of the SLE measurements, a
proper projection or cut is chosen to represent the
experimental results on the phase diagram. For a given
system, the degrees of freedom F can be deduced from
the Gibbs phase rule
F)C+2-P-s (1)
where C represents the number of components in the
system, P the number of phases present, and s the
number of extra constraints imposed on the system.
Setting P ) 1 (because there is at least one phase
present in the system) and substituting the values of
C, s, and the conditions of the selected system, the value
of F calculated from eq 1 will give the number of
independent coordinates required to represent the
desired SLE phase diagram. If F is a positive integer
3790 Ind. Eng. Chem. Res., Vol. 44, No. 10, 2005
equal to 2 or 3, the resulting phase diagram can be seen
as a two- or three-dimensional figure. If F is an integer
greater than 3, the phase diagram of the system is a
high-dimensional one and cannot be drawn on a piece
of paper. The degree of freedom can be reduced by fixing
the temperature and/or composition. A series of such
isothermal or isoplethal cuts would provide a mental
picture of the original high-dimensional phase diagram.
Similarly, various projectionssJänecke, orthogonal, and
polythermalscan also be used to reduce the dimension-
ality. However, which cuts or projections should be made
must be based on their usefulness for the process
synthesis. For example, a polythermal projection is
suitable for the synthesis of cooling crystallization,
whereas an isothermal cut is used in evaporative
crystallization. The details of cuts and projections, as
well as the related coordinates, have been discussed by
Wibowo and Ng.18
Step 4. Devise an experimental plan and deter-
mine the solubility data in the cuts or projections
identified in step 3.
On the basis of the shape of the cuts and projections
derived in step 3, an experimental plan is devised to
systematically determine the solubility data. The basic
approach is to first divide the cuts and projections into
a series of two-dimensional planes. The solubility data
on these planes are then measured via two different sets
of procedures depending on whether the temperature
is fixed. If the temperature is not fixed, mixtures of
varying compositions are prepared and their dissolution
points are then determined upon an increase of the
temperature. For the isothermal situation, different
mixtures containing excess solute are first prepared.
Next, a solvent component is added dropwise to dissolve
the mixtures at the required temperature. Irrespective
of which procedure is adopted, the solubility data are
combined to reveal the saturation curves of the phase
diagram. Again, the solubility data points should be
obtained for regions of the phase diagram where the
process points of the preliminary flowsheet determined
in step 1 are located.
Step 5. Sample and analyze crystals to provide
auxiliary information for the phase diagram.
Taking all of the temperature-composition data
determined in step 4 collectively, the desired isobaric
SLE phase diagram is in place. Nevertheless, this may
not be sufficient for clearly identifying the saturation
boundaries, especially for the locations of their discon-
tinuous points, which are key features indicating the
transition between the crystallization regions of two
different chemical species or two polymorphs of the
same species. To provide auxiliary information, crystals
are taken out from various samples and their identities
are determined to verify the position of the boundary,
as well as to locate the crystallization regions of different
species.
The following is the general experimental procedure
of crystal sampling. First, crystals are formed from a
slightly saturated equilibrium mixture of a composition
that is located close to the saturation boundary esti-
mated in step 4. They are then extracted from the
solution by using a suitable sampling technique and
devices such as those introduced by Nývlt.19 Throughout
this study, crystal sampling is achieved by fast suction
filtration, which will be discussed later. The identity of
the collected crystals is determined by using common
analytical techniques such as high-performance liquid
chromatography (HPLC) and ion chromatography.
Experimental Results and Discussion
In the following, two examples are used to demon-
strate how the generic scheme is implemented to
construct the desired SLE phase diagrams.
Example 1: Determination of the isobaric SLE
phase diagram of phenol, BPA, and water at 1
atm.
Step 1. The system consisting of phenol, BPA, and
water is of interest because the phase diagram will be
useful for the synthesis of the crystallization-based
purification processes of BPA. BPA [2,2-bis(4-hydroxy-
phenyl)propane], the starting material for the manu-
facture of polycarbonate and epoxy resins, is generally
produced by the condensation reaction between phenol
and acetone. In addition to BPA, the reactor effluent
also contains unreacted phenol, acetone, water, and a
small amount of isomers of BPA and other impurities.
A process that isolates pure BPA by crystallization can
be designed based on an SLE phase diagram containing
the most abundant components in the stream. Because
acetone can be easily removed by distillation and it has
been suggested that crude BPA can be purified by water
crystallization,20,21 BPA, phenol, and water are selected
to form the system for investigation at 1 atm.
It is well-known in the literature that an incongruent
melting 1:1 molar adduct of phenol and BPA is
present.22,23 Thus, it is easy to come up with a rough
sketch of the polythermal phase diagram of phenol,
BPA, and water, which shows the crystallization com-
partments of adduct and BPA (Figure 1a). Following
Wibowo and Ng,7 a flowsheet for a two-step crystalliza-
tion processsadduct followed by BPA crystallizations
can be synthesized (Figure 1b). While the recycle
destinations have not been designated, it is clear that
the boundary that separates the crystallization regions
of adduct and BPA determines the yield of the BPA
crystallizer.
Step 2. Because of its simplicity and flexibility, the
polythermal solid-disappearance method is selected to
perform the solubility measurement. The experimental
apparatus is shown in Figure 2. It mainly comprises a
jacketed glass vessel that is connected to a temperature
bath by two Viton tubes. The inner tube of the glass
vessel has a capacity of 40 mL for chemical mixtures
and is sealed with a Teflon thermocouple adapter. The
outer jacket allows circulation of heat-transfer fluid from
a temperature bath (Huber, model Unistat 360 HT),
which has an operating temperature range of -75 to
+300 °C with a precision of (0.01 °C and is capable of
providing a programmable heating/cooling profile at a
rate as low as 0.01 °C/min. DW-Therm, a thermofluid
with a working range from -90 to +200 °C, serves as
the heat-transfer medium. A Digi-Sense J-T-E-K
thermocouple thermometer that is equipped with a
K-type thermocouple with a precision of (0.1 °C is used
for temperature measurement. Thorough agitation is
achieved with a magnetic stirrer (Heidolph Instrument
Company, model MR 3001). For below-room-tempera-
ture measurements, blowing compressed air on the
surface of the vessel prevents condensation of the
atmospheric moisture. For even lower temperatures,
such as below 0 °C, an alternative glass vessel with an
additional vacuum jacket will be used.
During the measurement, a sample mixture of usually
about 6-7 g was first prepared. After a stir bar was

Figure 1. Synthesis of the potential process flowsheet for the
recovery of pure BPA by crystallization: (a) rough sketch of the
phase diagram of phenol, BPA, and water based on the limited
information from the literature; (b) flowsheet for a two-step
crystallization process proposed to recover pure BPA.
loaded into the inner tube, the temperature of the
sample was raised until all of the solutes completely
dissolved to form a clear, homogeneous solution. Next,
the mixture was cooled to a level at which crystals
started to form. Then the mixture was heated again to
dissolve the crystals, with the heating rate that was set
progressively lower to as low as 0.01 °C/min when the
equilibrium temperature was nearly reached. Finally,
Figure 2. Experimental setup used for determining the solubility data by the polythermal solid-disappearance method.
Ind. Eng. Chem. Res., Vol. 44, No. 10, 2005 3791
the disappearance of the last trace of crystals was
observed, and the corresponding temperature was re-
corded as the dissolution temperature.
The reliability of our technique was tested against the
isobaric SLE phase diagram of phenol and BPA at 1 atm
in the literature.22,23 BPA (Mitsubishi Chemical Corp.,
Tokyo, Japan) and phenol (UltraPure Phenol, Gibco
BRL Co., Gaithersburg, MD), both with purity higher
than 99.5%, were used without further purification.
Each dissolution temperature data point in Figure 3 was
an averaged value of the measurement results of two
samples of identical composition. The difference between
these two measurements was within (0.5 °C for all of
the compositions, confirming the suitability and repro-
ducibility of the measurement technique. Our experi-
mental data agree well with the literature data, except
for the minor deviations near the peritectic point.
Step 3. According to the Gibbs phase rule, for the
isobaric ternary system of phenol, BPA, and water, we
have for the degrees of freedom
F)C+2-P-s)4+2-1-P-s)
5 - P - s (2)
The term “- 1” in eq 2 arises from the isobaric condition
of the system. Because there is at least one phase
present and a reaction between phenol and BPA for
adduct formation,
F)5-1-1)3 (3)
Temperature is one of the coordinates, whereas the
other two will involve the mole fractions of any two
chemical components in the system. Thus, the isobaric
SLE phase diagram of phenol + BPA + water is an
upright triangular prism (Figure 4).
Step 4. The following experimental plan was devised
to construct the phase diagram. The triangular prism
from step 3 was divided into a series of two-dimensional
isoplethal cuts of water, as illustrated in Figure 4. The
polythermal solid-disappearance method was then used
to determine the saturation boundary on each of these
isoplethal cuts. The phenol and BPA used in these
measurements were the same as those employed in the
reliability test, whereas the water was doubly deionized
and had a resistivity of 18.2 MΩ cm at room tempera-
ture.
3792 Ind. Eng. Chem. Res., Vol. 44, No. 10, 2005
Figure 3. Isobaric SLE phase diagram of phenol and BPA at
atmospheric pressure.
Figure 4. General shape of the isobaric phase diagram of phenol
+ BPA + water and its division into a series of planes of constant
mole fraction of water.
Figure 5 shows the isoplethal cuts of 0, 10, 30, 50,
and 70 mol % water. The composition axis is expressed
in terms of the relative mole percent of BPA in BPA
and phenol, leaving out water. As can be seen in Figure
5, the isoplethal curves shift to lower temperatures with
increasing water content. Except for the case of zero
water content, all curves end at a temperature below
about 110 °C because appreciable water evaporation
occurred beyond this temperature. We also notice that
the 0-40 relative BPA mol % segment of the 70 mol %
isoplethal curve has dissolution temperatures equal to
or higher than the corresponding segments of curves of
less water. Further investigation and verification reveal
that this peculiar behavior is caused by the existence
of a liquid-liquid immiscibility region and the limitation
of the experimental technique. According to Campbell
and Campbell,24 the binary system of phenol and water
has a liquid-liquid immiscibility region between 62.3
Figure 5. Experimental temperature-composition data of phenol
+ BPA + water system at 1 atm obtained in the present study.
Figure 6. Liquid-liquid immiscibility region of phenol and water.
and 98.6 mol % of water (Figure 6). On the isoplethal
cut of 70 mol % water, samples of low relative BPA mole
percent (i.e., high relative phenol mole percent) are thus
in the liquid-liquid immiscibility region and the curve
segment obtained in this composition range is actually
the liquid-liquid boundary of the system, not the solid-
liquid boundary. A supporting evidence is that the
dissolution temperature for the sample of 70 mol %
water and 30 mol % phenol (i.e., 0 relative mol % of
BPA) was measured to be 32.8 °C, which agrees with
the literature data from Campbell and Campbell24
shown in Figure 6. In the polythermal solid-disappear-
ance method, the dissolution temperature is detected
visually as the temperature at which the last trace of
solid vanishes. When a mixture of two immiscible liquid
phases is stirred, tiny liquid droplets that are visually
indistinguishable from small solid crystals are produced.
This causes a misconception that the mixture is still
oversaturated, and the actual dissolution point is missed.
Anyway, we repeated the solubility measurements for
the 70% isoplethal cut, but the mixtures were allowed
to settle to see if liquid-phase split occurred. We found
that the liquid-liquid immiscibility region started from
0 relative mol % of BPA and ended at about 51.12%.
Step 5. As indicated in step 1 and Figure 1a, the
boundary between the crystallization compartments of
adduct and BPA is of significance for the synthesis of a
BPA purification process. The location of this boundary
can be determined through crystal sampling and analy-
 Ind. Eng. Chem. Res., Vol. 44, No. 10, 2005 3793

Figure 7. Experimental setup used for sampling crystals by suction filtration.

sis. The experimental setup used for crystal extraction

(Figure 7) is similar to that used in the polythermal
solid-disappearance method (Figure 2). The major dif-
ference is that a larger jacketed glass vessel with a 125-
mL inner flask is used to obtain a sufficient amount of
crystals for subsequent analysis. One of the necks of the
glass vessel is fitted with a glass tube with a porous
filter head (hereafter termed the filter tube). During the
experiment, the porous head of the filter tube was first
totally immersed in the sample mixture. To prevent any
liquid of the mixture from entering the filter tube
because of capillary force, the filter tube was filled with
air by connecting it to a supply of compressed air. After
going through the same heating-cooling-heating cycle
to determine the dissolution temperature, the mixture
was thermostated at a temperature of 1-2 °C below its
dissolution temperature to allow the formation of the
desired crystals. When it was found that a sufficient
amount of crystals had formed, the filter tube was
detached from the air source and then joined to the
vacuum pump via the conical flask. The stirring was
then stopped, and at the same time, the vacuum pump
was switched on to quickly suck out all of the mother
liquor from the inner flask of the vessel to the conical Figure 8. HPLC chromatographs of crystals extracted from
flask through the filter tube. Crystals were eventually binary phenol-BPA mixtures of composition (a) 30.00 mol % of
collected from the surface of the porous filter head. BPA and (b) 35.34 mol % of BPA.
Though the crystals obtained in this manner were fairly
dry, a tiny amount of mother liquor was still able to through a Microsorb MV C18 column operated at 40 °C.
adhere to the surface of the crystals as impurities. Under these operating conditions, adduct crystals de-
Therefore, the collected crystals were then washed with composed in the solution and appeared as equimolar
an optimum amount of heptane (analytical grade, purity peaks of phenol and BPA in HPLC analysis.
g 96%, Fisher Chemical Co., Pittsburgh, PA) at room Ten mixtures on the isoplethal cuts of 0, 10, 30 50,
temperature. Heptane was chosen as the washing and 70 mol % of water were studied; their compositions
solvent because BPA or adduct were only slightly are represented graphically as solid triangles in Figure
soluble in heptane. After vacuum-drying at room tem- 5. Parts a and b of Figure 8 exhibit the HPLC chro-
perature for 15 min, the crystals were dissolved in a matographs of crystals sampled respectively from binary
mixed solvent containing 45% water and 55% methanol phenol-BPA mixtures (i.e., on the isoplethal cut of 0
(HPLC grade, 99.9%, Sigma Chemical Co., Milwaukee, mol % of water) of 30.00 and 35.34 mol % of BPA. Using
WI) by volume. The resulting solutions were then calibration curves, the crystals taken from the former
analyzed by HPLC. The HPLC tests were performed by mixture were shown to have a phenol to BPA molar
a Waters Alliance HPLC System, which consisted of a ratio of about 1:1.09, which, after allowing for errors
Waters 2695 separations module and a Waters 2996 owing to the washing step and the presence of impuri-
photodiode array detector. To conduct the analysis, the ties, was consistent with the theoretical phenol to BPA
liquid samples carried by a mobile phase consisting of ratio in adduct crystals. On the other hand, only BPA
45% water and 55% methanol by volume were pumped existed in the crystals that were recovered from the
3794 Ind. Eng. Chem. Res., Vol. 44, No. 10, 2005
Figure 9. Polythermal projection of the isobaric SLE phase
diagram of phenol, BPA, and water at 1 atm.
latter mixture. For the isoplethal curves of 10, 30, and
50 mol % of water, the HPLC analysis results also
confirmed the left triangles in Figure 5 to be the adduct,
whereas those on the right were BPA. However, the
discontinuous point for the isoplethal curve of 70 mol
% of water, which has a coordinate of (51.12 relative
mol % of BPA, 70.6 °C) in Figure 5, was found not to be
a peritectic point. While the crystals obtained from the
sample of 53.39 relative mol % of BPA on this isoplethal
cut were found to be BPA solids, no crystals could be
collected from the mixture of 48.27 relative mol % of
BPA. This finding further proves that the liquid-liquid
split region comes to an end at the composition of 51.12
relative mol % of BPA. Figure 9, a polythermal projec-
tion of the original triangular prismatic SLE phase
diagram, summarizes all of these data. The shaded
portion of the projection corresponds to the crystalliza-
tion region of BPA. The boundary that separates the
crystallization regions of the adduct and BPA was
drawn manually by connecting the positions of the
peritectic points (green circles) obtained from various
isoplethal cuts of water. The locations of these peritectic
points were, in turn, determined by the positions of the
adduct crystals (red triangles) and BPA crystals (blue
triangles) obtained by suction filtration.
With this phase diagram on hand, different crystal-
lization flowsheets used to recover pure BPA can be
synthesized. Though the details of the flowsheet-
development process will not be discussed here, the
general principle is to use the basic unit operations, such
as heating and cooling, solvent addition and removal,
etc., to move the composition of the BPA crystallizer feed
into the crystallization compartment of BPA (i.e., the
shaded area in Figure 9). Because the location of the
adduct-BPA crystallization boundary is now confirmed,
we can compare the yield of different proposed flow-
sheets and evaluate which one of them is the best option
to meet our process objectives.
Example 2: Determination of the isobaric SLE
phase diagram of SMZ and DMSO at 1 atm.
Step 1. The system under consideration consists of
two components, namely, SMZ and DMSO. SMZ is a
polymorphic antibiotic for salmonoid fishes. Different
polymorphs of the same drug can have very different
physical and chemical properties. To avoid inconsistency
in drug quality and efficacy due to polymorphism, we
must find out the thermodynamic stability relationship
between the polymorphs of a drug, i.e., whether they
Figure 10. Speculation of the isobaric SLE phase diagram of SMZ
and DMSO at 1 atm.
are monotropic or enantiotropic. This example demon-
strates how the SLE phase diagram of a polymorphic
system can be constructed using the generic scheme and
shows how the thermodynamic relationship between the
polymorphs of SMZ can be determined from the phase
diagram.
SMZ is selected for study because it has only two
enantiotropic polymorphs, forms I and II,25,26 which is
ideal to serve as a model compound for which the phase
diagram is determined. In addition, various aspects
related to the polymorphs of SMZ, such as their prepa-
ration method, characterization results, and thermody-
namic relationship, are known.26-29 In particular, Zhang
et al.26 reported that the two polymorphs of SMZ had a
transition temperature lying between 51 and 54 °C. On
the basis of this information, the T-x phase diagram
of SMZ + DMSO can be speculated (Figure 10). Because
the transition temperature is a thermodynamic property
of the polymorphic substance, it is independent of the
solvent and hence we expect that the saturation bound-
aries of SMZ forms I and II in Figure 10 will cross over
near the temperature range of 51-54 °C.
Step 2. The polythermal solid-disappearance method
was selected again to carry out the SLE measurements.
However, in this case, the procedures used in example
1 have to be modified because of the polymorphic nature
of SMZ. Recall that, in the polythermal method, the
liquid solution formed in the first heating step is cooled
until crystals form, and the dissolution point is then
detected in the second heating step. If the same proce-
dure is applied for the current system, a polymorph that
is different from the starting form may be formed during
the recrystallization process in the cooling step. The
final dissolution point is thus not the solubility data of
the polymorph under consideration. To avoid the change
in the form of the polymorph in the course of the
experiment, the three-step procedure in the polythermal
method was modified to a one-step heating process.
After SMZ form I or form II + DMSO mixtures of known
composition were weighed into the glass vessel, they
were heated slowly at a rate of 0.5 °C/min under
stirring. Their dissolution temperatures were then
recorded as soon as the last trace of solid in the mixture
disappeared.
Step 3. The isobaric system in this example consists
of only two components. Clearly, we have only a simple
temperature-composition (T-x) diagram.
 Ind. Eng. Chem. Res., Vol. 44, No. 10, 2005 3795

Step 4. To construct the phase diagram, the strategy

is simply to prepare mixtures of varying composition of
DMSO and either SMZ form I or form II and then
measure their respective dissolution temperatures.
DMSO of purity 99.9% and form I of SMZ with a purity
of 99% can be purchased from RDH and Sigma Chemi-
cal Co., respectively. Nevertheless, form II is not com-
mercially available and has to be prepared from form I
using a procedure similar to that described by Zhang
et al.,26 which is based on the technique of solvent-
mediated transformation. The entire preparation pro-
cess was mainly divided into two parts. The first part
aims at purifying the purchased SMZ form I by recrys-
tallization because the presence of some structurally
related impurities, such as sulfadiazine and sulfamet-
hazine, can greatly slow or even inhibit the transforma-
tion of form I to II.29 About 13 g of powder of SMZ form
I and 900 mL of acetonitrile (HPLC grade, purity Figure 11. PXRD patterns of SMZ polymorphs: (a) SMZ form I;
greater than 99.8%, Fisher Chemical Co.) were placed (b) crystals prepared from solvent-mediated transformation.
into a 1-L jacketed glass reactor. The mixture was then
heated from room temperature to 55 °C with vigorous
stirring. After the temperature of the mixture was kept
at 55 °C for about 20 min, the mixture was allowed to
undergo spontaneous cooling to room temperature and
aged for 1 day. Throughout the experiment, the necks
of the reactor were covered with stoppers to avoid the
loss of chemicals due to evaporation. Wrapping the
reactor with aluminum foil also helped to prevent the
photodegradation of SMZ crystals. After aging, recrys-
tallized form I crystals were collected from the bottom
outlet of the reactor and dried under vacuum for about
20 min. Finally, about 7-8 g of recrystallized form I
crystals could be obtained, and they were stored in a
desiccator for future use. After the previous recrystal-
lization process was repeated once again to collect a
sufficient amount of purified SMZ form I, the second
part of the entire process could be conducted to prepare
the desired crystals of form II. Approximately 13 g of Figure 12. PXRD pattern obtained for SMZ form I and the
recrystallized form I and 900 mL of HPLC-grade aceto- crystals from solvent-mediated transformation within the range
nitrile were charged into the glass reactor. The mixture of 2θ ) 15-16.5°.
was then subjected to the same procedure as that
outlined in the first part except that the aging time was
extended from 1 day to 15 days. Around 6-7 g of SMZ diffraction pattern. A polymorph sample of about 10 mg
form II crystals could eventually be obtained. was exposed to Cu KR radiation (40 kV and 40 mA) of
a wavelength of 1.54 Å and was scanned over the
Although the above process succeeds in preparing angular range from 2θ ) 2° to 35° at 1.5°/min. The
bulk crystals of SMZ form II, they can only be produced PXRD pattern for SMZ form I and that for crystals
in a rather small quantity. To crystallize large quanti- prepared by solvent-mediated transformation are pre-
ties of SMZ form II at one time, the slurry process sented in Figure 11. After comparing these patterns
designed by Zhang et al.,26 which tried to use seed with those obtained by Caira and Mohamed25 and Zhang
crystals of form II to increase the rate of solvent- et al.,26 we concluded that form II was indeed obtained.
mediated transformation from form I to form II, was Also, according to Gu et al.,28 SMZ form I gives a
followed. About 20 g of SMZ form I was suspended in characteristic peak at 2θ ) 16.1°, whereas the charac-
400 mL of HPLC-grade acetonitrile in a 1-L round- teristic peak of form II is at 2θ ) 15.6°. It can be clearly
bottomed flask. The mixture was stirred vigorously seen in Figure 12 that our crystals give the same results.
using a combination of a magnetic stirrer and a stir bar For the DSC test, a differential scanning calorimeter
at room temperature (∼22 °C). After 2 days, about 0.3 from Perkin-Elmer (model Pyris Diamond DSC) was
g of form II crystals, which acted as the seed, was added used to generate the desired DSC traces of the SMZ
to the suspension, and the resulting mixture was aged polymorphs. A sample of about 10-15 mg sealed in an
for 15 days. The photodegradation of crystals and the aluminum pan, together with an empty aluminum
loss of chemicals due to evaporation were minimized in reference pan, was subjected to a constant-rate heating
a way similar to that described in the recrystallization process of 5 °C/min from 20 to 245 °C, with a nitrogen
process of SMZ form I. About 16 g of crystals of SMZ purge rate of 20 mL/min. Both of the DSC curves of SMZ
form II were finally obtained from this slurry process. form I and crystals prepared from solvent-mediated
The identities of the prepared SMZ crystals were transformation show an endothermic peak at about
confirmed using powder X-ray diffraction (PXRD) and 238-239 °C, which signifies the melting point of SMZ
DSC. In the PXRD test, an X-ray diffractometer from form I (Figure 13). However, there is an additional but
Philips (model PW1830) was utilized to generate the very small endothermic peak in the latter DSC trace,
3796 Ind. Eng. Chem. Res., Vol. 44, No. 10, 2005

Figure 13. DSC curves of SMZ polymorphs: (a) SMZ form I; (b) crystals prepared from solvent-mediated transformation.

which indicates the transition from SMZ form II to form

I with an increase in temperature. This also proves that
the prepared crystals from solvent-mediated transfor-
mation are form II of SMZ. In our case, the transition
peak is found at about 160 °C, which is about 10 °C
higher than that reported by Caira and Mohamed 25 but
is about 15 °C lower than that observed by Zhang et
al.26
Figure 14 shows the isobaric SLE phase diagram of
the system SMZ + DMSO at 1 atm. Because of the
operating temperature limit of the experimental setup
and the fact that DMSO will decompose when heated
above its boiling point at 189 °C,30 no data were obtained
beyond 180 °C. The enlarged inset shows that the
saturation boundaries of SMZ forms I and II intersect
at the transition temperature, which indicates that
these two polymorphs are enantiotropic. The point of
Figure 14. Isobaric SLE phase diagram of the system SMZ +
intersection corresponds to a temperature of about 50 DMSO at 1 atm.
°C, which is consistent with the result obtained by
Zhang et al.26 Because SMZ form II has a lower
solubility below the transition temperature, it is more much higher than the transition temperature, SMZ form
stable at lower temperatures. From the enlarged inset, II originally present in the mixture was converted to
it can also be seen that there are five data points for form I, which was the more stable form at these higher
form II (with composition ranging from about 0.22 to temperatures.
0.31 mole fraction) overlapping with those for form I Step 5. Attempts were made to sample SMZ solids
even though SMZ form II is used as the starting from sample mixtures to verify the conversion of form
material for the experiment. The possible reason is that II to form I when the sample is heated well above the
when those samples were heated to a value that was transition temperature. However, DMSO was too vis-

cous for the recovery of sufficiently dry SMZ solids for
further physical characterization and/or chemical analy-
sis.
The phase diagram shown in Figure 14 clearly shows
the effect of the process temperature on the product
form. For example, because form II is more thermody-
namically stable than form I below about 50 °C, through
aging of the solution mixture of SMZ form I and
acetonitrile at room temperature as outlined in step 4,
bulk crystals of form II can be successfully produced and
collected.
Conclusions
Crystallization, as distillation, is capable of separating
a multicomponent mixture into the pure form of each
individual component. Yet, while distillation with a
multitude of procedures and software tools for process
design is widely regarded as the workhorse for complete
fractionation, a chemical engineer often faces a great
deal of uncertainty in designing a similar crystallization
process. This is a serious omission and an opportunity
for crystallization research and development because
more and more high-value-added products such as
pharmaceuticals and consumer chemicals are produced
in the solid form.
There are two major challenges in making advances
in the design of crystallization-based separations. In
general, the phase behavior of a solid-liquid system is
much more complex than that of the vapor-liquid state.
Solids tend to form a host of compounds and solvates
and can exist in different polymorphic forms, thereby
creating more crystallization boundaries than distilla-
tion boundaries. Crystallization is also applied to a more
diverse set of systems: electrolytes, chiral compounds,
biochemicals, as well as organics. How to systematically
synthesize a crystallization process has been a chal-
lenge. Research in the past decade has shown that,
irrespective of the complexity of the phase behavior,
separations can be achieved by devising a sequence of
operationssheating and cooling, solvent addition and
removal, stream combination and splittingsto separate
a number of components one by one in crystallizers.7
The key is to navigate the composition of the crystallizer
feed stream to reach the crystallization compartment
of the desired component on the solid-liquid phase
diagram. This is achievable, in principle, because high-
dimensional solid-liquid phase diagrams can now be
represented and indeed visualized in a systematic
manner. All we need is the input of thermodynamic
data. Unfortunately, the database for SLE is rather
limited for commonly known compounds and nonexist-
ent for new chemical entities. Thus, the second chal-
lenge is to be able to determine these SLE phase
diagrams purposefully, reliably, and expeditiously by
experiments.
This study represents our effort in this direction. A
generic scheme is formulated for determining the iso-
baric SLE phase diagram of any organic and inorganic
system. There is no point in measuring an SLE phase
diagram in its entirety and in detail. It is far better to
focus our efforts on the saturation boundaries and
crystallization regions of the desired products. As part
of our generic scheme, three experimental techniquess
polythermal solids disappearance and crystal extractions
have been developed/refined. This scheme is illustrated
with two different systems. BPA is the product in the
first example, which involves organics and the presence
Ind. Eng. Chem. Res., Vol. 44, No. 10, 2005 3797
of a compound. We showed how to pinpoint the double
saturation point. The second one is an enantiotropic
polymorph system. In all cases, accurate phase dia-
grams were generated and the crystallization regions
of the desired products were identified, using the
analytical techniques embedded in our procedure. These
experimental scheme, phase diagram representation
techniques, and process synthesis methods are expected
to form a complementary package for the synthesis of
crystallization-based processes.
Acknowledgment
Financial support from the Research Grant Council
(Grant HIA02/03 EG02) is gratefully acknowledged. We
thank Dr. Christianto Wibowo of CWB Technology for
many stimulating discussions throughout the course of
this work.
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Received for review December 28, 2004
Revised manuscript received February 24, 2005
Accepted February 28, 2005
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