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Chapter 7

Application of direct crystallization for racemic

compound ketoprofen


7.1 Introduction

As mentioned before, the direct crystallization for partially resolved

enantiomers can be used for the racemic compound. According the phase diagram,
whether we can obtain the desired pure enantiomer depends on the partially resolved
mixtures initial position and eutectic composition. When the crystallization initial
solution composition is located inside the existence region of pure enantiomers, this
crystallization process will afford a pure enantiomer. In the last chapter, a systematic
preferential crystallization process was successfully applied for the favorable racemic
compound mandelic acid. In this chapter this strategy was extended to another
racemic compound system: unfavorable racemic compound. For this compound, the
solubility of racemate is smaller than that of pure enantiomer and it shows the most
narrow operation region to obtain pure enantiomers by crystallization. Ketoprofen
was chosen for this study.
There were some methods already applied for the ketoprofen enantioseparation,
including chiral chromatography and enzymatic separation.
For a chromatography, several direct/indirect liquid chromatographic methods
involving a variety of chiral phases have been reported for the ketoprofen
enantioseparation and its enantiomer analysis. For example, a new chiral stationary
phase using flavoprotein, a glycoprotein present in chicken egg-white, was developed
for high-performance liquid chromatography by Nariyasu et al. in 1992. The column
with this chiral stationary phase could achieve baseline separations for ketoprofen.
Also, Zhu (1999) reported that -cyclodextrin (CD) and its derivatives HP- -CD,
DM- -CD, and TM- -CD had been employed as chiral selectors for the separation
of ketoprofen by capillary zone electrophoresis. And also, Pehourcq (2001) found that


flurbiprofen and ketoprofen were resolved from their racemic forms using a
vancomycin chiral stationary phase known as ChirobioticV. In addition, according to
Aboul-Enein (2003), ketoprofen was also resolved on Kromasil tartardiamide-DMB
chiral stationary phase. In this process, optimum resolution was achieved using a
mobile phase consisting of hexane: tert-butyl methyl ether: acetic acid (75 :25: 0.1
v/v/v) at flow rate of 1 ml/min.
An enzymatic separation can be used for ketoprofen enantioseparation too.
Antona et. al. (2002) observed that Immobilized lipase from Candida antarctica
(Novozym 435) can catalyze the enantioselective etherification of (RS)-ketoprofen.
He found that the use of methanol in dichloropropane allows large scale separation for
ketoprofen. This method gave the desired (S)-ketoprofen with 96% ee as unreacted
enantioform. The (R)-enantiomer, recovered as ester, can easily undergo chemical
racemising hydrolysis and can be reused in the process.
Though several chiral separation methods were used for the enantioseparation
of ketoprofen, few studies have reported on using direct crystallization for partially
resolved enantiomers to get the pure (S)-ketoprofen. And there is little information
available on whether the coupling the directly crystallization with chromatography
could be used for chiral separation of ketoprofen.
Therefore, this chapter presents a study to obtain a enantiomerically enriched
ketoprofen by using the HPLC with a semi-preparative column for the subsequent
systematical study of direct crystallization process. The critical supersaturation
control strategy and crystallization progression were investigated.


7.2 Experiment and methods

7.2.1 HPLC collection of ketoprofen

The collection experiments were carried out with a Shimadzu chromatographic

system and used a chiralpak preparative HPLC AD-H column (dimension 250mm L x
10mm I.D) to collect ketoprofen whose mole fraction should be more than 0.96. The
mobile phase contained 90%hexane and 10% IPA. The temperature was 25oC and
flow rate was 3.5ml/min.

7.2.2 Direct crystallization process

The crystallization experiments were carried out in the same crystallization setup as described in Fig. 4.2. The controlled cooling profile (convex) was used on the
batch direct crystallization operation of ketoprofen. The start point was the same
enantiomeric composition with the partially resolved ketoprofen from HPLC
collection. It was the 96% mole percent (S)-MA saturated solution at 20 oC in the
mixed solvent ethanol and water with volume ration 0.9/1.0. Five batches direct
crystallization experiments were carried out starting from the same solution with
different modes, which are (a) Exp_01: with seeding and final temperature at 10 oC;
(b) Exp_02: with seeding and final temperature at 7.3 oC; (c) Exp_03: with seeding
and final temperature at 6.0 oC; (c) Exp_04: with seeding and final temperature at 0.7

C; (f) Exp_05: without seeding until nucleation occurred.

The optical purity of crystal products were also measured by using HPLC. For

HPLC, the analyze AD-H column was also used to analyze product ee values. The


separation conditions are as followed: hexane/IPA (90/10 v/v) as mobile phase, at

25C column temperature, flow rate of 0.8ml/min and UV-Vis detection at 254nm.

7.3 Result and discussion

7.3.1 Semi-preparative HPLC separation of Ketoprofen

As discussed in chapter 6, the loading capacity of ketoprofen on Chiralcel ADH was determined by injecting different amount of sample onto the column. It was
found that ketoprofen shows partial separation when sample loading reaches to 5.0mg,
shown in Fig. 7.1.

Fig 7.1 Partial separation of Kp on Chiralcel AD-H semi-preparative HPLC column

(dimension 250mm L x 10mm I.D) at loadings 5.0mg per injection using hexane/IPA
(90/10 v/v) as mobile phase, at 25C column temperature, flow rate of 3.5ml/min and
UV-Vis detection at 254nm.
Through semi-preparative chiral HPLC separation, the 96% mole percent S
enantiomer and pure R enantiomer of Kp were obtained by collecting two different


fractions at two different retention time, t =17-22 mins and t =15.3-17mins, as

presented in Fig. 7.2. The optical purity of 96% mole percent S enantiomer collection
was analyzed on analytical chiral column with hexane/IPA (90/10 v/v) as the mobile
phase and a flow rate of 0.8ml/min, shown in Fig. 7.3. Then, the volume enough 0.96
mole fraction S Kp can be obtained by using continuous HPLC separation with an
antosampler and automated fraction collector.

Fig 7.2 Fraction collection under semi-preparative HPLC separation of Kp on

Chiralcel AD-H column (dimension 250mm L x 10.00 mm I.D.) under separation
conditions: hexane/IPA (90/10 v/v) as mobile phase, at 25C column temperature,
flow rate of 3.5ml/min and UV-Vis detection at 254nm.Fraction (a) collected at
retention time 15.3-17 minutes and fraction (b) is collected at 17-22 minutes.


Fig 7.3 Chromatogram of fractions (b) obtained through semi-preparative HPLC

separation of ketoprofen on Chiralcel AD-H analytical column (dimension 250mm L
x 4.6 mm I.D.) under separation conditions: hexane/IPA (90/10 v/v) as mobile phase,
at 25C column temperature, flow rate of 0.8ml/min and UV-Vis detection at 254nm.

7.3.2 Preferential crystallization operation for ketoprofen

Based on the phase diagram of Kp in the chapter 4, if we want to get the pure S
enantiomer, the initial composition of the cooling crystallization should be between
pure S and eutectic composition. At first, three different start compositions (96%, 94%,
and 92% mole percent S ketoprofen) were tried at same cooling process in order to
determine from which one pure S enantiomer products can be obtained. The HPLC
analyzing results for the final crystal products of different initial composition are
shown in Fig. 7.4.




Fig 7.4 The HPLC analyzing results for the crystal products of different initial
composition, (a) 92% mole percent (S)-Kp; (b) 94% mole percent (S)-Kp; (c) 96%
mole percent (S)-Kp.


The first peak in these figures presents the R enantiomer of ketoprofen, while
the second one is S enantiomer. We can see from these HPLC results that the first
peak area was almost negligible compared with the second peak only in Fig. 7.4 c.
That means only final crystal product from 96% mole fraction (S)-Kp initial
composition was almost pure S enantiomer considering the measure error in HPLC
and impurities in products.
It can be explained by the Fig. 7.5 (Lorenz and Seidel-Morgenstern, 2002). If
we want to get the pure (S)-Kp, the system point should locate inside the pure
enantiomer existence region at ending temperature. When start point P cooling to a
lower temperature T2, the pure S enantiomer will come out. Then, The start point at
high temperature, such as T1 should be higher than the eutectic point. The bigger the
cooling temperature range, the higher the start point. Generally the start point always
need higher than the eutectic point. Therefore, in this work, the crystallization
operations with start composition of 92% and 94% can not produce the optical pure
ketoprofen, though their start composition was higher than eutectic point.


Fig 7.5 Cooling process to obtain pure enantiomer.

The start composition for the preferential crystallization of ketoprofen was the
saturated solution at 20oC with 96% mole percent S enantiomer. This saturated
solution was saturated in the eutectic composition of Kp at 7.3 oC and saturated in the
(RS)-Kp at 0.7 oC. The strategy used for the progression of preferential crystallization
for mandelic acid was extended to unfavorable racemic compound system ketoprofen.
When the controlled cooling profile was used, five batch crystallizations described in
section 7.2.2 were carried out. The optical purities of each experiment final product
were analyzed by HPLC and the results are shown in Fig. 7.6. The optical purities of
the final crystals with different cooling degree analyzed by HPLC are listed in Table







Fig 7.6 HPLC results of the final crystal products with different cooling degree for
ketoprofen: (a) Exp 01; (b) Exp 02; (c) Exp 03; (d) Exp 04; (e) Exp 05.


Table 7.1 The optical purity of the final crystal products with different cooling degree
for ketoprofen
Optical purity of product

(% S enantiomer) from

Cooling degree

Exp 01


Exp 02


Exp 03


Exp 04


With seeds

Within Tcrit

Outside Tcrit

Without seeds

Exp 05



From these results, the same situation found for mandelic acid in section
was observed for ketoprofen. The product crystals were almost pure (S)-enantiomer
when the end temperature was higher than 0.7 oC (Exp_01-03), which was saturated
temperature for the (RS)-Kp. In this region, only (S)-Kp is supersaturated. When the
crystallization final temperature was lower than this (RS)-Kp saturated temperature,
(RS)-Kp began to supersaturate which resulted in the product crystals in the form of
mixture of (RS)-Kp and (S)-Kp, for example Exp 04. It may further prove that there is
no selectivity of crystal growth of the pure enantiomer and racemate for a racemic
compound when both (S) and (RS) reach supersaturation. The primary nucleation
occurred in Exp 05 when the solution was cooled to around 0.2oC without seeding.
The products of Exp 05 were not optical pure enantiomer because of the racemic
compound property: no selectivity of nucleation between pure enantiomer and
racemate. All these results prove that the key factor to obtain pure enantiomer


products in direct crystallization of racemic compound is its solubility characteristic.

Only within the safe supersaturation critical limit, can pure enantiomer crystal
products be obtained from the preferential crystallization with seeding.
For the optimal cooling profile consideration, based on the ketoprofen MSZW
data in chapter 4, the supersaturation should be kept within circa 2oC to avoid
spontaneous nucleation of both its enantiomer and racemate. However, as discussed
before, the supersaturation should be kept lower than it measured under homogenous
condition. So, a suitable critical supercooling chosen for ketoprofen was controlled at
around 0.5-1 oC. The corresponding c should be ca. 0.0015-0.0025g/ml. It is very
narrow feasible supersaturation control range compared with 0.027g/ml for mandelic
acid. It suggests that it is more difficult to control the supercooling for the preferential
crystallization for ketoprofen and the nucleation of enantiomer and racemate of
ketoprofen may be easy to occur. On the other hand, considering the crystal growth
kinetics of the ketoprofen (Eq 5-23), the crystal growth rate should be very small in
order to control the supersaturation level within the chosen narrow range. It means the
batch operation time should be very long which can result in the low efficient for the
whole crystallization operation.
In addition, some researchers (Strhlein et al., 2003) proposed a general design
method for the hybrid process of a chromatographic and a crystallization unit. They
point that coupled chromatography and crystallization processes in which both units
contribute to purification are useful and efficient, only if the considered crystallization
system possesses a low eutectic point. But, for the ketoprofen, an unfavorable racemic
compound system, the eutectic point is high about 92% more percent (S)-Kp, which
leads to our crystallization unit should start at very high composition, even as 96%
more percent (S)-Kp in order to obtain the pure desired enantiomer. That situation


may make the whole coupling process less effective and less economical for the
ketoprofen separation.

7.4 Conclusion

In this chapter, a system preferential crystallization was applied for the

unfavorable racemic compound ketoprofen coupling with the HPLC. The partially
resolved 96% mole percent (S)-Kp was obtained by HPLC collection with semipreparative column. Then the subsequent direct crystallization started from this initial
composition, which located inside the existence region of pure S enantiomers in the
phase diagram. Based on the solubilities and MSZWs of ketoprofen, the direct
crystallization progression was clearly investigated. The optical purities of the final
crystals product were analyzed by HPLC. It was found that the optical pure product
could be obtained by direct crystallization with seeding within certain safe
supersaturation limit. It may be further proved that there was no selectivity of crystal
growth and nucleation of the pure enantiomer and racemate for a racemic compound.
On the other hand, the supersaturation control is especially critical for the unfavorable
ketoprofen system due to its high eutectic composition and narrow metastable zone
widths, which cause narrow feasible region and more difficulty to control for direct
crystallization. Direct crystallization could be less effective and less economical as an
enantioseparation process for the ketoprofen system.


Chapter 8
Conclusions and Future work


8.1 Conclusions
In this present work, the preferential crystallization process itself was studied
for the two racemic compound systems, namely more favorable racemic compound
mandelic acid and unfavorable racemic compound ketoprofen, combining the aspects
of thermodynamics, kinetics, and optimal operation. A systematic preferential
crystallization was studied on solubility, metastable zone, kinetics and supersaturation
control profile to obtain crystal product with good quality.
In Chapter 3, two kind of racemic species, namely mandelic acid and
ketoprofen, were characterized by the various spectroscopic techniques, thermal
analysis, thermodynamic calculation and binary phase diagram. The spectra of FTIR,
Raman and PXRD were different between the pure enantiomer and racemate for the
mandelic acid and ketoprofen, which indicates that the mandelic acid and ketoprofen
both belong to the racemic compound. Through the thermal analysis and calculation,
it was found that the G0 was negative and the enthalpy of fusion difference between
(RS) and (S) were positive for both of mandelic acid and ketoprofen. Their Tf were
both far away from -30oC which implies that the racemic species is likely to be a
conglomerate. All these results suggest that the mandelic acid and ketoprofen are in
form of racemic compound. The binary melting phase diagrams were constructed for
the mandelic acid and ketoprofen based on Schrder-Van Laar equation, the
Prigogine-Defay equation and DSC measurements. The calculated results were in
good agreement with the DSC experiment data. The shape of binary phase diagrams
of mandelic acid and ketoprofen both show the typical shape of racemic compound
system, just the more favorable racemic compound system for mandelic acid and
unfavorable racemic compound system for ketoprofen. From the binary phase


diagram, the eutectic point was determined as 70% of (S)-MA for mandelic acid and
91.6% of (S)-Kp for ketoprofen.
In chapter 4, the thermodynamic properties in solution were studied for the
mandelic acid and ketoprofen using the Lasentec FERM. The solubilities, ternary
phase diagram and metastable zone width at different mole percent of S enantiomer
were obtained for mandelic acid in water and ketoprofen in mixed solvent of ethanol
and water with volume ration 0.9:1.0. For the case of mandelic acid, the solubility
ratio of (RS) to (S)-MA decreases with the temperature in the range 35-5oC which
suggests that the preferential crystallization of mandelic acid in the chosen solvent is
more favorable as temperature decreases. All the MSZW results of mandelic Acid
were higher than 5 oC which are favorable for preferential crystallization process. Its
ternary phase diagram showed a typical shape of more favorable racemic compound,
which further proves that the mandelic acid is a kind of more favorable racemic
compound. On the other hand, the ternary phase diagram of ketoprofen shows the
typical properties of an unfavorable racemic compound system. The MSZWs of high
mole percent (S)-Kp were all narrow around 2oC. It is more difficult to control the
supsaturation level of pure enantiomer to inhibit its spontaneous nucleation during the
crystallization process. Through the study of the main four effects of MSZW by
fractional experiment design for ketoprofen, it is obvious that the water/ethanol
volume ratio in the solvent should have the most significant effect on the MSZW of
Kp. MSZW would increase with decreasing ethanol ratio. The temperature, stirring
rate and cooling rate may affect the process slightly. MSZW would also be inversely
proportional to the temperature, but would be directly proportional to the cooling rate.
However, the MSZW of high mole percent ketoprofen are still not satisfied even in
the optimal condition derived by fractional experiment design.


In chapter 5, the classical Laplace transform analysis was used for deriving the
crystal growth rate and nucleation rate in the batching crystallization process for both
(S) and (RS) mandelic acid and ketoprofen. Also the kinetics of (S) and (RS)-Kp were
determined by the moment analysis method and the kinetic results of moments
analysis are comparable with those of Laplace transform analysis for ketoprofen. The
enantiomer and racemate show different characteristics in crystal nucleation and
growth for racemic compound mandelic acid and ketoprofen.
In chapter 6, a systematic preferential crystallization combining the solubility,
metastable zone, kinetics and supersaturation control profile to obtain crystal product
with good quality was proposed for mandelic acid. At first, the 80% mole percent S
enantiomer enantiomerically enriched mandelic acid was obtained from a racemic
composition by using a HPLC with a semi-preparative chiral column. Then, through
the study on the direct crystallization progression for the mandelic acid system, it was
found that the optical pure product could be obtained by direct crystallization with
seeding within certain safe supersaturation limit and the relative solubility and critical
supersaturation control of the pure enantiomer and racemate were essential to obtain
the pure enantiomer. Subsequently, based on the thermodynamic and kinetic
consideration, an optimal temperature control profile was derived to control the
critical supersaturation in order to inhibit the induced nucleation of the racemate.
Compared with the forced and linear cooling profile, the final crystal products of our
proposed control cooling profile were almost optical pure with high yield and good
crystal size distribution. The optical purity of product crystal was measured by HPLC,
Polarimeter, and DSC. Finally, Seed size effect on crystal size distribution was
studied. It was found that the weight mean size of final crystal product increased with
the seed size increasing because the amount of solid deposited on crystal surfaces is


constant at constant yield. However, the final product mean crystal size did not
increased significantly at high seed size.
In this chapter 7, a system preferential crystallization was also applied for the
unfavorable racemic compound ketoprofen. The partially resolved 96% mole percent
(S)-Kp was obtained by HPLC collection with semi-preparative column. Based on the
solubilities and MSZWs of ketoprofen, the direct crystallization progression was
clearly investigated. It was found that the optical pure product could be obtained by
direct crystallization with seeding within certain safe supersaturation limit. There was
no selectivity of crystal growth and nucleation of the pure enantiomer and racemate
for a racemic compound. Because of the narrow metastable zone width of S
enantiomer, the supersaturation control is especially critical for the unfavorable
ketoprofen system. The narrow metastable zone widths can cause narrow feasible
region and more difficulty to control for direct crystallization. Direct crystallization
could be less effective and less economical as an enantioseparation process for the
ketoprofen system because of its narrow MSZW and high eutectic composition. The
ketoprofen eutectic point is high around 92% more percent (S)-Kp, which means that
the crystallization unit should start at very high composition, even as 96% more
percent (S)-Kp, in order to obtain the pure desired enantiomer and the existence
region of pure S enantiomers in phase diagram should be very limited.

8.2 Future work

The HPLC can be used to obtain an enantiomeric enrichment exceeding the
eutectic composition in the racemic compound system, which sets the threshold for a
subsequent enantioselective crystallization process. However, the trend in preparative


scale chromatography is rapidly moving the emphasis to supercritical fluid

chromatography (SFC).
SFC has two main advantages for preparative separations. One is speed: a
higher production rate can be obtained from a given column since the mobile phase
viscosity is very low and fast, efficient separations can be achieved. The other
advantage is the small quantity of organic solvent used: between 10% and 20% of that
needed for a HPLC separation. This not only decreases the total quantity of solvent
used for the separation, but also makes it easier and faster to recover the products
from the small modifier volumes remaining after condensation from the CO2.
Therefore, Coupling the SFC and preferential crystallization will be suggested for the
racemic compound system in the future.
In addition, the different seeding preparation methods were suggested to be
studied in order to obtain the optimal operation strategy and get the good quality of
final products.


Aboul-Enein H.Y., Chiral separation of some non-steroidal anti-inflammatory drugs
on tartardiamide DMB chiral stationary phase by HPLC, J. Sep. Sci., 2003, 26, 521

Amanullah M. and Mazzotti M., Optimization of a hybrid chromatographycrystallization process for the separation of trgers base enantiomers, J. Chromatogr.
A, 2006, 1107, 36-45.

Angelov I., Raisch J., Elsner M.P., and Seidel-Morgenstern A., Optimization of the
initial conditions for preferential crystallization, Ind. Eng. Chem. Res., 2006, 45, 759766.

Antona N.D., Lombardi P., Nicolosi G. and Salvo G., Large scale preparation of
enantiopure S-ketoprofen by biocatalysed kinetic resolution, Process Biochem., 2002,
38, 373-377.

Arai K., Isomerization-crystallization methods in optical resolution, J. Synth. Org.

Chem. Jpn., 1986, 44, 486.

Arins E.J., Soudjin W., and Timmerman P.B., Stereochemistry and biological
activity of drugs. London, Blackwell scientific Publications, 1983.

Beilles S., Cardinael P., Ndzi E., Petit S. and Coquerel G., Preferential crystallization

and comparative crystal growth study between pure enantiomer and racemic mixture
of a chiral molecule: 5-ethyl-5-Methylhydantoin, Chem. Eng. Sci., 2001, 56, 22812294.

Berry D.A. and Ng K.M., Synthesis of crystallization-distillation hybrid separation

process, AIChE J., 1997, 43, 1751-1762.

Bijvoet O.L.M., Blomen L., Will E.J. and Vanderlinden H., Growth-kinetics of
calcium-oxalate monohydrate .3. variation of solution composition, J. Cryst. Growth,
1983, 64, 316-325.

Black S.N., Williams L.J., Davey R.J., Moffatta F., Jones R.V.H., Mcewan D.,M. and
Sadler D.E., The preparation of enantiomers of paclobutrazol: A crystal chemistry
approach, Tetrahedron, 1989, 45, 2677-2682.

Blehaut J. and Nicoud R.M., Recent aspects in simulated moving bed, Analusis, 1998,
26, 60-70.

Blomen L., Will E.J., Bijvoet O.L.M. and Vanderlinden H., Growth-kinetics of
calcium-oxalate monohydrate .2. the variation of seed concentration, J. Cryst. Growth,
1983, 64, 306-315.

Brock, C.P. and Dunitz, J.D., Towards a Grammar of Crystal Packing, Chem. Mater,
1994, 6, 1118-1127.


Brugidou J., Christol H. and Sales R., Appareil pour le ddoublement de

conglomerates, Bull. Soc. Chim. Fr., 1974, 2033.

Bukley H.E., Crystal Growth, New York, Wiley, 1951.

Caddick S., and Jenkins K., Dynamic resolutions in asymmetric synthesis, Chem. Sco.
Rev., 1996, 25, 447-448.

Cahn R.S., Ingold C.K, and Prelog V., Specification of molecular chirality, Angew.
Chem. Inter. Ed., 1966, 5, 385-415.

Ceschel, G.C., Maffei P., and Lombardi Borgia S., Correlation between the
transdermal permeation of ketoprofen and its solubility in mixtures of a PH 6.5
phosphate buffer and various solvents, Drug deliv., 2002, 9, 39-45.

Challener C.A., Chiral Intermediates, New York, John Wiley & Sons Limited, 2001,

Chen C.S., Fujimoto Y., Girdaukas G., and Sih C.J., Quantitative analyses of
biochemical kinetic resolution of enantiomers, J. Am. Oil Chem. Soc., 1982, 104,

Collet A., Brienne M.J. and Jacques J., Optical resolution by direct crystallization of
racemates, Chem. Rev., 1980, 80, 215.


Collet A., Resolution of racemates: did you say classical?, Angew. Chem. Int. ed.,
1998, 37, 3239-3241.

Collet A., Separation and purification of enantiomers by crystallization methods,

Enantiomer, 1999, 4, 157-172.

Collins A.N., Sheldrake G.N. and Crosby J., Chirality in industry II, Chichester, John
Wiley and Sons, 1997.

Coquerel G., Bouaziz R. and Brienne M.J., Optical resolution of ()-Nacylnorfenfluramine derivatives by preferential crystallization, Tetrahedron lett., 1990,
31, 2143-2144.

Coquerel G., Petit M.N. and Bouaziz R., Method of optical resolution by
crystallization, PCT Int. Appl., 1995,

Coquerel G., Chirality and Crystallization, Present and Prospects, Chimica Oggi,
2003, 21, 56-57.

Courvoisier L., Ndzi E., Petit M.N., Hedtmann U., Sprengard U. and Coquerel G.,
Influence of the process on the process on the mechanisms and the performances of






Methylhydantoin, Chem. Lett., 2001, 4, 364-365.

Courvoisier L., Mignot L., Petit M.N., Sprengard U., Hedtmann U. and Coquerel G.,






Comparison between SIPC and AS3PC process at 2L and 10L scales, Proceedings of
the 9th international workshop on industrial crystallization (BIWIC), 2002, Germany.

Dash S.R. and Rohani S., Iterative parameter-estimation for extraction of

crystallization kinetics of Potassium-Chloride from batch experiments, Can. J. Chem.
Eng., 1993, 71, 539-548.

David R., Villermaux J., Marchal P. and Klein J. P., Crystallization and precipitation
engineering .4. Kinetic-model of Adipic Acid crystallization, Chem. Eng. Sci., 1991,
46, 1129-1136.

Del Vecchio R.J., Understanding Design of Experiments, New York, Hanser/Gardner,


Ding M.S., Xu K. and Jow T.R., Phase diagram of EC-DMC binary system and
enthalpic determination of its eutectic composition, J. Therm. Anal. Calorim., 2002,
62, 177-186.

Doki N., Kubota N., Sato A., Masaaki Y., Hamada O. and Masumi F., Scale up
experiments on seeded batch cooling crystallization of potassium alum, AIChE J.,
1999, 45, 2527-2533.

Doki N., Kubota N., Sato A. and Yokota M., Effect of cooling mode on product
crystal size in seeded batch crystallization of potassium alum, Chem. Eng. J., 2001, 81,



Dolling U.H., Douglas A.W., Grabowski E.J.J., Schoenewaldt E.F., Sohar P. and
Sletzinger M., Synthesis and resolution of 3-fluoro-DL-alanine-2-d: a selective
deuteration via reductive amination with sodium borodeuteride, J. Org. Chem., 1978,
43, 1634.

Drayer D.E., Pharmacodynamic and pharmacokinetic differences between drug

enantiomers in human: an overview, Clin. Pharmacol. Ther., 1986, 40, 125-133.

Duan G. and Ching C.B., Preparative scale enantioseparation of flurbiprofen by

lipase-catalyzed reaction, Biochem. Eng. J., 1998, 2, 237-245.

Dufour F., Gervais C., Petit M.N., Perez G., and Coquerel G., Investigation on the
reciprocal ternary system ()-2-Phenylpropionic acid-()--Methykbenzylamine.
Impact of an unstable racemic compound on the simultaneous resolution of chiral
acids and bases by preferential crystallization, J. Chem. Soc., 2001, Perkin
Transactions 2, 2022-2036.

Ebber E.J., Arians G.J.A., Houbiers J.P.M., Bruggink A., and Zwanenburg B.,
Controlled racemization of optically active organic compounds: prospects for
asymmetric transformation, Tetrahedron, 1997, 53, 9417-9476.

Eliel E.L., Wilen S.H. and Mander L.N., Stereochemistry of organic compounds, New
York, John Wiley & Sons Inc., 1994.


Elsner M.P., Menendez D.F., Muslera E.A. and Seidel-Morgenstern A., Experimental
study and simplified mathematical description of preferential crystallization, Chirality,
2005, 17, 183-195.

Espitalier F., Biscans B. and Lagurie C., Particle design part A: nucleation kinetics
of ketoprofen, Chem. Eng. J., 1997, 68, 95-102.

FDAs Policy Statement for The Development of New stereoisomeric Drugs,

Chirality, 1992, 4, 3238-3340.

Francotte E. and Junker-Buchheit A., Preparative chromatographic separation of

enantiomers, J. Chromatogr., 1992, 576, 1-45.

Francotte E., Enantioselective chromatography as a powerful alternative for the

preparation of drug enantiomers, J. Chromatogr. A, 2001, 906, 379-397.

Espitalier F., Biscans B. and Lagurie C., Particle design part A: nucleation kinetics
of ketoprofen, Chem. Eng. J., 1997, 68, 95-102.

Garside J., Gibilaro L.G. and Tavare N.S., Evaluation of crystal-growth kinetics from
a desupersaturation curve using initial derivatives, Chem. Eng. Sci., 1982, 37, 16251628.

Guiochon G., Golshan-Shirazi S. and Katti A., Fundamentals of preparative and


nonlinear chromatography, Boston, Academic Press, 1994.

Harada K., Optical resolution of monoammonium DL-Malate by preferential

crystallization, Chem. And Indu, 1986, 20, 68-69.

Harrington P.J. and Lodewijk E., Twenty years of naproxen technology, Org. Process
Res. Dev., 1997, 1, 72-76.

Henderson G. M. and Rule H. G., A new method of resolving a racemic compound, J.

Chem. Soc., 1939, 1568.

Heydron W.E., Developing racemic mixtures vs. single isomers in the U.S., Pharm.
News., 1995, 2, 19-21.

Hlozny L., Sato A. and Kubota N., On-line measurement of supersaturation during
batch cooling crystallization of ammonium alum, J. Chem. Eng. Jpn., 1992, 25, 604606.

Hongo C., Shibazaki M., Yamada S., and Chibata I., Preparation of optical active
praline optical resolution of N-Acyl-DL-Proline by preferential crystallization
procedure, J. Agri. Food Chem., 1976, 24, 903-906.

Hongo C., Tohyama M., Yoshioka R., Yamada S. and Chibata I., Asymmetric
transformation of Dl-p-hydroxyphenylglycine by a combination of preferential
crystallization and simultaneous racemization of the o-toluenesulfonate, Bull. Chem.


Sco. Jpn., 1985, 58, 433.

Hongo C., Yamada S., and Chibata I., The prediction of the optical resolution process
by the use of the preferential crystallization procedure, Bull. Chem. Sco. Jpn., 1981,
54, 1911-1913.

Hossein H. and Rohani S., Cooling and seeding effect on supersaturation and final
crystal size distribution (CSD) of ammonium sulphate in a batch crystallizer, Chem.
Eng. and Processing, 2005, 44, 949-957.

Hussain K., Thorsen G. and Malthe-Srenssen D., Nucleation and metastability in

crystallization of vanillin and ethyl vanillin, Chem. Eng. Sci., 2001, 56, 2295-2304.

Jacques J., The molecule and its double, New York, McGraw-Hill, 1993.

Jacques J., Collet A., and Wilen S.H., Enantiomers, racemates, and resolutions, New
York, Wiley, 1981.

Jagadesh D., Kubota N., Yokota M., Doki N., Sato A. and Tavare N., Large and
mono-size product crystals from nature cooling mode batch crystallization, J. Chem.
Eng. Jpn.,1996, 29, 865-873.

Jagadesh D., Kubota N., Yokota M., Doki N. and Sato A., Seeding effect on batch
crystallization of potassium sulphate under nature cooling mode and a simple design
method of crystallizer, J. Chem. Eng. Jpn., 1999, 32, 514-520.


Juaristi E., Introduction of Stereochemistry and conformational analysis, New York,

John Wiley & Sons, Inc., 1991.

Juza M., Mazzotti M. and Morbidelli M., Simulation moving bed chromatography and
its application to Chirotechnology, Tibtech, 2000, 18, 108-118.

Kamphuis J., Boesten W.H.J., Kaptein B., Hermes H.F.M., Sonke T., Broxterman
Q.B., Van den TweeW. J.J.J and Schoemaker H.E., Chirality in Industry, New York,
Wiley, 1994.

Kauffman G.B. and Myers R.D., The resolution of racemic acid. A classic
stereochemical experiment for the undergraduate laboratory, J. Chem. Ed., 1975, 52,

Kim K.J. and Mersmann A., Estimation of metastable zone width in different
nucleation processes, Chem. Eng. Sci., 2001, 56, 2315-2324.

Kim K.J. and Ryu S.K., Nucleation of thiourea adduct crystal with cyclohexane
methylcyclopentane. Chem. Eng. Commun., 1997, 159, 51.

Kinbara K. and Sakai K., Design of resolving argents: P-Substituted mandelic acids as
resolving reagents for 1-arylalkylamines, Tetrahedron Asym., 1996, 7, 1539-1542.

Kinbara K., Tagawa Y., and Saigo K., Probability of spontaneously resolvable


conglomerate for racemic acid /racemic amine salts predicted on the basis of the
results of diastereomeric resolutions, Tetrahedron Asym., 2001, 12, 2927-2930.

Kitamura M., Tokunaga M., and Noyori R., Stereoselective organic synthesis via
dynamic kinetic resolution, Bull chem. Sco. Jpn., 1995, 68, 36-55.

Kubota N., Doki N., Yokota M. and Sato A., Seeding policy in cooling crystallization,
Power Technol., 2001, 21, 31-38.

Li Z.J., Implication of chirality for the physicochemical properties and crystallization

of chiral drugs, Ph.D. thesis, University of Minnesota, 1997.

Li Z.J. and Grant D.J.W., Relationship between physical properties and crystal
structures of chiral drugs, J. Pharm. Sci., 1997, 86, 1073-1078.

Li Z.J., Zell M.T., Munson E.J. and Grant D.J.W., Characterization of racemic species
of chiral drugs using thermal analysis, thermodynamic calculation, and structural
studies, J. Pharm. Sci., 1999, 88, 337-346.

Lim B.G., Ching C.B., Tan R.B. H. and Ng S.C., Recovery of (-)-praziquantel from
racemic mixtures by continuous chromatography and crystallization, Chem. Eng. Sci.,
1995 a, 50, 2289-2298.

Lim B.G., Tan R.B.H., Ng S.C. and Ching C.B., Solubility phase diagram of
praziquantel enantiomeric system, Chirality, 1995 b, 7, 74-81.


Lin C.N., and Tsai S.W., Dynamic kinetic resolution of suprofen thioester via coupled
trioctylamine and lipase catalysis, Biotechnol. Bioeng., 2000, 69, 31-38.

Livk I., Gregorka M. and Pohar C., Model identification of batch crystallization
processes (estimate of kinetic-parameters of Sodium-Perborate precipitation), Comput.
Chem. Eng., 1995, 19, 241-246.

Lorenz H., Perlberg A., Sapoundjiev D., Elsner M.P. and Seidel-Morgenstern A.,
Crystallization of enantiomers, Chem. Eng. and processing, 2006a, 45, 863-873.

Lorenz H., Polenske D. and Seidel-Morgenstern A., Application of preferential

crystallization to resolve racemic compounds in a hybrid process, Chirality, 2006b, 18,

Lorenz H. and Seidel-Morgenstern A., Binary and ternary phase diagrams of two
enantiomers in solvent systems, Thermochim Acta, 2002, 382, 129-142.

Lorenz H., Sheehan P. and Seidel-Morgenstern A., Coupling of simulated moving bed
chromatography and fractional crystallization for efficient enantioseparation, J.
Chromatogr. A, 2001, 908, 201-214.

Lu C.H., Cheng, Y.C., and Tsai S.W., Integration of reactive membrane extraction
with lipasehydrolysis dynamic kinetic resolution of naproxen 2,2,2- Trifluoroethyl
Thioester in Isooctane, Biotechnol. Bioeng., 2002, 79, 200-210.


Maier N. M., Franco P and Lindner W., Separation of enantiomers: needs, challenges,
perspectives, J. Chromatogr. A, 2001, 906, 3-33.

Marchal P., David R., Klein J.P. and Villermaux J., Crystallization and precipitation
engineering .1. an efficient method for solving Population Balance in crystallization
with agglomeration, Chem. Eng. Sci., 1988, 43, 59-67.

Marciniak B., Density and ultrasonic velocity of undersaturated and supersaturated

solutions of fluoranthene in trichloroethylene, and study of their metastable zone
width, J. Cryst. Growth, 2002, 36, 347-356.

Merk Company, Merck Achievement-first commercial, Continuous process to use

selective crystallization separation optically active isomers, Chem. Eng., 1965, 8, 247248.

Mersmann A., Angerhfer M., Gutwald T., Sangl R. and Wang S., General prediction
of median crystal sizes, Sep. Technol., 1992, 2, 85-97.

Migliorini C., Gentilini A., Mazzotti M. and Morbidelli M., Design of simulated
moving bed units under nonideal conditions, Ind. Eng. Chem. Res., 1999, 38, 24002410.

Miller S.M., Modelling and quality control strategies for batch cooling crystallizer,
PhD Thesis, University of Texas, Austin, 1993.


Mohon R., Lorenz H. and Seidel-Morgenstern A., Solubility measurement using

differential scanning calorimetry, Ind. Eng. Chem. Res., 2002, 41, 4854-4862.

Mughal R.K., Davey R.J. and Blagden N., Application of crystallization inhibitors to
chiral separation. 1. design of additives to discriminate between the racemic
compound and the pure enantiomer of mandelic acid, Cryst. Growth Des., 2007, 7,

Mullin J.W., Crystallization, Boston, Butterworth-Heinemann, 2001.

Mullin J.W. and Jancic S.J., Interpretation of the metastable zone width, Trans. Inst.
Chem. Eng., 1979, 57, 188-193.

Nation R.L., Chirality in new drug development: clinical and pharmacokinetic

considerations, Clin. Pharmacokin., 1994, 27, 249-255.

Nariyasu M., Yoshiya O., Naoki A., Yutaka Y. , Tadashi S. and Toshinobu M.,
Development of a flavoprotein column for chiral separation by high-performance
liquid chromatography, J. Chromatogr., 1992, 623, 221-228.

Ndzi E., Cardinael P., Schoofs A.R. and Coquerel G., An efficient access to the
enantiomers of -Methyl-4-Carboxyphenylglycine via a hydantoin rout using a
practical variant of preferential crystallization. AS3PC (Auto Seeded Programmed
Polythermic Preferential Crystallization), Tetrahedron Asym., 1997, 8, 2913-2920.


Neau S.H., Shinwari M.K. and Hellmuth E.W., Melting phase diagrams of free base
and hydrochloride salts of beventolol, pindolol and propranolol, Int. J. Pharm., 1993,
99, 303-310.

Nicoud R.M., Bioseparation and Bioprocessing, Subramanian G. (Ed.), New York,

Wiley-VCH, 1998.

Nyvlt J., Kinetics of nucleation in solutions, J. Cryst. Growth, 1968, 3-4, 377-383.

Nyvlt J., Kocova H. and Gerny M., Size distribution of crystals from a batch
crystallizer, Collect. Czech. Chem. Commun., 1973, 38, 3199-3209.

Nyvlt J., Sohnel O., Matuchova M. and Broul M., The kinetics of industrial
crystallization, Amsterdam, Elsevier, 1985, 47-65.

Ockenfels H., Khler F. and Meise M., Teratogenic effect and stereospicificity of a
thalidomide metabolite, Pharmazie., 1976, 31, 492-493.

Pais L.S., Loureiro J.M. and Rodrigues A.E., Chiral Separation by SMB
chromatography, Sep. Purif. Technol., 2000, 20, 67-77.

Palwe B. G., Chivate M. R. and Tavare N. S., Growth kinetics of ammonium nitrate
crystals in a draf tube baffle agitated batch crystallizer, Ind. Eng. Chem. Process Des.
Dev., 1985, 24, 914.


Pasteur L., Mmoire sur la relation qui peut exister entre la forme crystalline et la
compositon chimique, et sur la cause de la polarization rotatoire, Compt. Rend. Acd.
Sci., 1848, 26, 535-538.

Pehourcq F., Jarry C. and Bannwarth B., Chiral resolution of flurbiprofen and
ketoprofen enantiomers by HPLC on a glycopeptides-type column chiral stationary
phase, Biomed. Chromatogr., 2001, 15, 217222.

Perlberg A., Lorenz H. and Seidel-Morgenstern A., Crystal growth kinetics via
isothermal seeded batch crystallization: evaluation of measurement techniques and
application to mandelic acid in water, Ind. Eng. Chem. Res., 2005, 44, 1012-1020.

Pincombe A.H., A crystal-solute interaction theory, J. Cryst. Growth, 1982, 57, 468470.

Polenske D., Lorenz H. and Seidel-Morgenstern A., Separation of propranolol

hydrochloride enantiomers by preferential crystallization: Thermodynamic basis and
experimental verification, Cryst. Growth Des., 2007, 7, 1628-1634.

Prankerd R.J., and Elsabee M., Thermal analysis of chiral drug mixtures: the DSC
behavior of mixtures of ephedrine: HCL and pseudoephedrine. HCl enantiomers,
Thermochi. Acta., 1995, 248, 147-160.

Prelog V. and Wieland P., ber die spaltung der trgerschen base in optische


antipoden, ein beitrag zur stereochemie des dreiwertigen stickstoffs, Helv. Chim. Acta,
1944, 27, 1127-1134.

Profir V.M., Furusj E., Danielsson L.G. and Rasmuson .C., Study of the
crystallization of mandelic acid in water using in ATR-IR spectroscopy, Cryst.
Growth Des., 2002, 2, 273-279.

Profir V.M. and Rasmuson .C., Influence of solvent and the operation condition on
the crystallization of racemic mandelic acid, Cryst. Growth Des., 2004, 4, 315-323.

Qian R.Y. and Botsaris G.D., Nuclei breeding from a chiral crystal seed of NaClO3,
Chem. Eng. Sci., 1998, 53, 17451756.

Qiu Y. and Rasmuson A.C., Nucleation and growth of Succinic Acid in a batch
cooling crystallizer, AIChE J., 1991, 37, 1293.

Rajesh N.P., Raghavan P.S., Ramasamy P. and Lan C.W., Enhancement of metastable
zone of some aqueous solutions, J. Chin. Inst. Chem. Engrs., 2002, 33, 325.

Randolph A.D. and Larson M.A., Theory of particulate processes, New York,
Academic Press, 1971.

Randolph A.D. and Larson M.A., Theory of particulate processes: analysis and
techniques of continuous crystallization, Second ed., San Diego, Academic Press,


Rekoske J.E., Chiral separation, AIChE J., 2001, 47, 2-5.

Rodrigo A.A., Lorenz H. and Seidel-Morgenstern A., Online Monitoring of

Preferential crystallization of enantiomers, Chirality, 2004, 16, 499-508.

Rouhi A.M., Chiral roundup, Chem. Eng. News., 2002, 80, 43-50.

Rouhi A.M., Chiral chemistry, Chem. Eng. News., 2004, 82, 47-62.

Ruthven D.M., and Ching C.B., Counter-current and simulated counter-current

adsorption separation processes, Chem. Eng. Sci., 1989, 44, 1011-1038.

Sato N., Uzuki T., Toi K. and Akashi T., Direct resolution of lysine 3,5dinitrobenzoate, Agri. Biol. Chem., 1969, 33, 1107.

Schreiner A. and Konig A., Influence of impurities on nucleation and growth rates of
organic melts, Chem. Eng. Technol., 2002, 25, 181-187.

Schroer J.W., Wibowo C. and Ng K.M., Synthesis of chiral crystallization process,

AIChE J., 2001, 47, 369-387.

Schulte M. and Strube J., Preparative enantioseparation by simulated moving bed

chromatography, J. Chromatogr. A, 2001, 906,399-416.


Sheldon R.A., Chirotechnology: industrial synthesis of optically active compound,

New York, Marcel Dekker, 1993.

Shiraiwa T., Miyazaki H., Ohta A., Waki Y., Yasuda M., Morishita T., and Kurokawa
H., Optical resolution by preferential crystallization of (RS)--Amino butyrolactone hydrochloride, Chem. Pharm. Bull., 1996, 44, 2322-2325.

Shiraiwa T., Miyazaki H., Ohta A., Motonaka K., Kobayashi E., Kubo M., and
Kurokawa H., Optical resolution by preferential crystallization of (2RS,3SR)-2Amino-3-chlorobutanoic acid hydrochloride, Chirality, 1997 a, 9, 656-660.

Shiraiwa T., Miyazaki H., Watanabe T., and Kurokawa H., Optical resolution by
preferential crystallization of DL-Methionine Hydrochloride, Chirality, 1997 b, 9, 4851.

Shiraiwa T., Kubo M., Watanabe M., Nakatani H., Ohkubo M. and Kurokawa H.,







Carboxyethylthio) Propanoic acid, Biosci. Biotechnol. Biochem, 1998, 62, 818-820.

Shiraiwa T., Suzuki M., Sakai Y., Nagasawa H., Takatani K., Noshi D. and

K., Optiacal resolution by preferential crystallization of (RS)-2-

Benzoylamino-2-Benzyl-3-Hydroxypropanoic acid and its use in synthesizing

optically active 2-Amino-2-Methyl-3-Phenylpropanoc acid, Chem. Pharm. Bull., 2002,
50, 1362-1366.


Shiraiwa T., Saijoh R., Suzuki M., Yoshida K., Nishimura S. and Nagassawa H.,
Preparation of optically Active Threo-2-Amino-3-Hydroxy-3-Phenylpropanoic acid
(Threo--Phenylserine) via optical resolution, Chem. Pharm. Bull., 2003, 51, 13631367.

Shiraiwa T. and Kiyoe R., Optical resolution by preferential crystallization of


acid, Chem. Pharm. Bull., 2005, 53, 1197-1199.

Sohnel O. and Nvlt J., Evaluation of experimental data in width of metastable region
in aqueous solution, Collec. Czech. Chem. Commun., 1975, 40, 511.

Stinson S.C., Chiral drugs, Chem. Eng. News., 1995, 73, 44-74.

Stinson, S.C., Chiral drug market shows signs of maturity, Chem. Eng. News, 1997,
75, 38.

Stinson, S.C., Counting on chiral drugs, Chem. Eng. News, 1998, 76, 83.

Stinson, S.C., Chiral drug interactions, Chem. Eng. News, 1999, 77, 101.

Stinson, S.C., Chiral Pharmaceuticals, Chem. Eng. News, 2001, 79, 79-97.

Straathof A.J.J and Adlercreutz P., Applied biocatalysis, Cornwall, Taylor and Francis,


Strhlein G., Schulte M., and Strube J., Hybird processes: design method for optimal
coupling of chromatography and crystallization units, Sep. Sci. Technol., 2003, 38,

Strube J., Haumreisser S., Schmidt-Traub H., Schulte M. and Ditz R., Comparison of
batch elution and continuous simulated moving bed chromatography, Org. Proc. Res.
Dev., 1998, 2, 305-319.

Subramanian G., Chiral separation techniques- A practical approach, Weinheim,

Wiley-VCH, 2000.

Tadayon A., Rohani S. and Bennett M.K., Estimation of nucleation and growth
kinetics of ammonium sulfate from transients of a cooling batch seeded crystallizer,
Ind. Eng. Chem. Res., 2002, 41, 6181-6193.

Tavare N.S., Growth-kinetics of Ammonium-Sulfate in a batch cooling crystallizer

using initial derivatives, AIChE J., 1985, 31, 1733-1735.

Tavare N.S., Batch crystallizers: A review, Chem. Eng. Commun., 1987, 16, 259-319.

Tavare N.S., Batch crystallizers, Rev. Chem. Eng., 1991, 7, 211-355.

Tavare N.S., Characterization of crystallization kinetics from batch experiments, Sep.

Purif. Methods, 1993, 22, 93-210.


Tavare N.S. and Garside J., Estimation of crystal-growth and dispersion parameters
using pulse response techniques in batch crystallizers, Trans. Inst. Chem. Eng., 1982,
60, 334-344.

Tavare N.S. and Garside J., Simultaneous estimation of crystal nucleation and
growth-kinetics from batch experiments, Chem. Eng. Res. Des., 1986, 64, 109-118.

Thirumala R.K., Mansoor A.K. and Indra K.R., Racemate and enantiomers of
Ketoprofen: phase diagram, thermodynamic studies, skin permeability, and use of
chiral permeation enhancers, J. Pharm. Sci., 1998, 87, 833-840.

Ulrich J. and Strege C., Some aspects of the importance of metastable zone width and
nucleation in industrial crystallizers, J. Cryst. Growth, 2002, 237-239, 2130-2135.

Wainer I.W., Drug stereochemistry: analytical methods and pharmacology, New York,
2nd ed., Marcel Dekker, Inc., 1993.

Wainer I.W., The therapeutic promise of single enantiomers: introduction, Hum.

Psychopharmacol. Clin. Exp., 2001, 16, 73-77.

Waldeck B., Biological significance of the enantiomeric purity of drugs, Chirality,

1993, 5, 350-355.

Walle T, Webb J.G., Bagwell E.E., Walle U.K., Daniell H.B. and Gaffney H.E.,


Stereoselective delivery and actions of beta receptor antagonists, Biochem.

Pharmacol., 1988, 37, 115-124.

Wang X., Ph.D. thesis, National University of Singapore, 2002.

Wang X. and Ching C. B., Chiral separation of -blocker drug (nadolol) by five-zone
simulated moving bed chromatography, Chem. Eng. Sci., 2005, 60, 1337-1347.

Wang X., Wang X.J. and Ching C.B., Solubility, metastable zone width, and racemic
characterization of propranolol hydrochloride, Chirality, 2002, 14, 318-324.

Wang X.J. and Ching C.B., A systematic approach for preferential crystallization of
4-hydroxy-2-pyrrolidone: thermodynamics, kinetics, optimal operation and in-situ
monitoring aspects, Chem. Eng. Sci., 2006, 61, 2406-2417.

Wang X.J., Lu J. and Ching C.B., Application of direct crystallization for racemic
compound propranolol hydrochloride. J. of Pharm. Sci., 2007, 96, 2735-2745.

Wang X.J., Wiehler H. and Ching C.B., Physicochemical properties and the
crystallization thermodynamics of the pure enantiomer and the racemate for Nmethylephedrine, J. Chem. Eng. Data., 2003, 48, 1092-1098.

Ward R.S., Dynamic kinetic resolution, Tetrahedron Asym., 1995, 6, 1475-1490.

Watanae T., and Noyori G., Optical resolution of racemic glutamic acid. VII.


Reasonable selection of resolution procedure for optical resolution by fractional

crystallization, Kogyo Kagaku Zasshi, 1969, 72, 1083-1086.

Wibowo C. and Ng K.M., Unified approach for synthesizing crystallization-based

separation process, AIChE J., 2000, 46, 1400-1421.

Wilen S.H., Collet A., and Jacques J., Strategies in optical resolutions, Tetrahedron,
1977, 33, 2725.

Will E.J., Bijvoet O.L.M., Blomen L. and Vanderlinden H., Growth-kinetics of

Calcium-Oxalate Monohydrate .1. Method and validation, J. Cryst. Growth, 1983, 64,

William K. and Lee E., Importance of drug enantiomers in clinical pharmacology,

Drugs, 1985, 30, 333-354.

Wojcik J.A. and Jones A.G., Particle disruption of precipitated CaCO3 crystal
agglomerates in turbulently agitated suspensions, Chem. Eng. Sci., 1998, 53, 10971101.

Yamada S.I., Morimatsu K., Yoshioka R., Ozaki Y., and Seko H., First practical
resolution of a 3-(4-methoxyphenyl) glycidic acid ester by preferential crystallization
and synthesis of diltiazem, Tetrahedron Asym., 1998, 9, 1713-1721.

Yokota M. and Kubota N., Apparent size-dependent growth of potash alum crystals


by agglomeration, AIChE J., 1996, 42, 1170-1173.

Zaitseva N.P., Rashkovich L.N. and Bagatyreva S.V., Stability of KH2PO4 and
K(H,D)2PO4 solutions at fast crystal growth rates, J. Cryst. Growth, 1995, 148, 276282.

Zaugg H.E., A mechanical resolution of dl-methadone base, J. Am. Chem. Soc., 1955,
77, 2910.

Zhu X.F., Lin B.C., Epperlein U., and Koppenhoefer B., Enantiomeric Resolution of







Cyclodextrins by Capillary Electrophoresis, Chirality, 1999, 11, 56-62.


List of publications

Lu Yinghong and Ching Chi Bun, Physicochemical properties, binary and ternary
phase diagrams of ketoprofen, Chirality, 2004, 16 (8), 541-548.

Lu Yinghong and Ching Chi Bun, Investigation on the metastable zone width in








Conference, Bangkok, Dec. 1-3, 2004.

Lu Yinghong and Ching Chi Bun, Study on the metastable zone width of ketoprofen,
Chirality, 2006, 18 (4), 239-244.

Lu Yinghong, Ching Chi Bun, Study on crystallization phase diagrams and kinetics
behaviors of ketoprofen, presented in the 2006 AIChE Annual Meeting, San
Francisco, Nov. 12-17, 2006.

Lu Yinghong, Wang Xiujuan and Ching Chi Bun, Application of preferential

crystallization for different types of racemic compounds, Industrial & Engineering
Chemistry Research, Revision submitted.