application of direct crystallization for racemic compound ketoprofen

8/10/2019 Application of Direct Crystallization for Racemic Compound Ketoprofen

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Chapter 7

Application of direct crystallization for racemic

compound ketoprofen


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7.1 Introduction

As mentioned before, the direct crystallization for partially resolvedenantiomers 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


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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 enrichedketoprofen 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.


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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 set-

up 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 sameenantiomeric 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

oC; (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


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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 AD-

H 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 Renantiomer of Kp were obtained by collecting two different


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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 Senantiomer 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 SKp 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 onChiralcel AD-H column (dimension 250mm L x 10.00 mm I.D.) under separationconditions: 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 atretention time 15.3-17 minutes and fraction (b) is collected at 17-22 minutes.


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Fig 7.3 Chromatogram of fractions (b) obtained through semi-preparative HPLCseparation of ketoprofen on Chiralcel AD-H analytical column (dimension 250mm Lx 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

pureSand eutectic composition. At first, three different start compositions (96%, 94%,

and 92% mole percent Sketoprofen) were tried at same cooling process in order to

determine from which one pure Senantiomer products can be obtained. The HPLC

analyzing results for the final crystal products of different initial composition are

shown in Fig. 7.4.


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(a)

(b)

(c)

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

mole percent (S)-Kp.


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The first peak in these figures presents theRenantiomer 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 Senantiomer will come out. Then, The start point at

high temperature, such as T1should 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.


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(a)

(b)

(c)


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Table 7.1 The optical purity of the final crystal products with different cooling degreefor ketoprofen

Experiment

Optical purity of product

(% Senantiomer) from

HPLC

Cooling degree

Exp 01 99.3

Exp 02 99.2

Exp 03 99.8

WithinTcritWith seeds

Exp 04 96.1 OutsideTcrit

Without seeds Exp 05 92.5

Primary

nucleation

occurred

From these results, the same situation found for mandelic acid in section 6.3.2.1

was observed for ketoprofen. The product crystals were almost pure (S)-enantiomer

when the end temperature was higher than 0.7oC (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


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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. Theypoint 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


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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 semi-preparative column. Then the subsequent direct crystallization started from this initial

composition, which located inside the existence region of pure Senantiomers 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.


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Chapter 8

Conclusions and Future work


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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 G0was negative and the enthalpy of fusion difference between

(RS) and (S) were positive for both of mandelic acid and ketoprofen. Their Tfwere

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


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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.


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References.

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

524

Amanullah M. and Mazzotti M., Optimization of a hybrid chromatography-

crystallization 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, 759-

766.

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


23/47

169

and comparative crystal growth study between pure enantiomer and racemic mixture

of a chiral molecule: 5-ethyl-5-Methylhydantoin, Chem. Eng. Sci., 2001, 56, 2281-

2294.

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 ofcalcium-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.


24/47

170

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,

3-109.

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

7294-7299.

Collet A., Brienne M.J. and Jacques J., Optical resolution by direct crystallization of

racemates, Chem. Rev., 1980, 80, 215.


25/47

171

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 ()-N-

acylnorfenfluramine 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

the preferential crystallization: example with (+/-)-5-(4-Bromophenyl)-5-

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

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


26/47

172

Preferential crystallization of (F)-5(4V-Bromophenyl)-5-Methylhydantoin,

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,

1977.

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,


27/47


28/47


29/47

175

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, 604-

606.

Hongo C., Shibazaki M., Yamada S., and Chibata I., Preparation of optical activepraline 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.


30/47

176

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 andmono-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.


31/47


32/47


33/47

179

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,

828-840.

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 bedchromatography 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.


34/47

180

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, 247-

248.

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, 2400-

2410.

Miller S.M., Modelling and quality control strategies for batch cooling crystallizer,

PhD Thesis, University of Texas, Austin, 1993.


35/47

181

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,

218-224.

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-performanceliquid 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.


36/47

182

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.


37/47

183

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, 468-

470.

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


38/47

184

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,

1988.


39/47

185

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 3,5-

dinitrobenzoate, 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.


40/47

186

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)-2-

Amino-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, 48-

51.

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

Optical Resolution by Preferential crystallization of Rac-2-Amino-3-(2-

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

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

Yamannashi 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.


41/47

187

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, 1363-

1367.

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

(1RS,3RS)-1,2,3,4-Tetrahydro-6,7-Dihydroxy-1-Methyl-3-Isoquinolinecarboxyli c

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,

2000.


42/47

188

Strhlein G., Schulte M., and Strube J., Hybird processes: design method for optimal

coupling of chromatography and crystallization units, Sep. Sci. Technol., 2003, 38,

3353-3383.

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.


43/47

189

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.,


44/47

190

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 thecrystallization thermodynamics of the pure enantiomer and the racemate for N-

methylephedrine, 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.


45/47

191

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,

297-305.

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, 1097-

1101.

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


46/47

192

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, 276-

282.

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

Some Nonsteroidal Antiinflammatory and Anticoagulant Drugs Using -

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


47/47

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

crystallization of ketoprofen, Presented in the RSCE2004 InternationalConference, 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.

application of direct crystallization for racemic compound ketoprofen

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