Contents

LIST OF TABLES LIST OF FIGURES CHAPTER 1. INTRODUCTION ..4 2. LITERATURE REVIEW...7 . PREVIOUS WOR!" 4. OPTICAL PROBE DESIGN..11 4.1 IN SITU PROBE..11 4.2 PROCESSING CIRCUIT...1 #. E$PERI%ENTAL %ETHOD.17 &. RESULTS AND DISCUSSION.2' 7. CONCLUSION AND FUTURE WOR!..2# (. REFERENCES.2&

L)st o* T+,-es

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Table 10 Cloud points, clear points, saturated temperatures, and metastable

zone width (MSZW) of conducted experiment.

L)st o* F).12es
F).12e 10 Schematic Dia ram of !ptical "robe S#stem F).12e 20 $xperimental Setup F).12e 0 dia ram of laser holder F).12e 40 dia ram of %D& holder F).12e #0 dia ram of connector

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F).12e &0 Dia ram of %M'()) F).12e 70 "in Dia ram and Connection circuit of %M'**+ F).12e (0 "in dia ram of %M,,F).12e "0 "ower Circuit F).12e 1'0 .mplifier Circuit F).12e 110 processin circuit F).12e 120 $xperimental setup F).12e 1 0 optical probe /olta e cur/e for conc ,+ 2i ure 134 temperature profile of coolin for conc ,+ l#cine01++ water l#cine01++ water

2i ure 15 4 temperature profile of antisol/ent combined coolin cr#stallization usin l#cine.

2i ure 1*4 /olta e cur/e for coolin cr#stallization usin %6.spar ine. 2i ure 1'4 temperature profile coolin cr#stallization usin %6.spar ine.

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1.

INTRODUCTION

Cr#stallization is the (natural or artificial) process of formation of solid cr#stals precipitatin from a solution, melt or more rarel# deposited directl# from a as. Cr#stallization is also a chemical solid7li8uid separation techni8ue, in which mass transfer of a solute from the li8uid solution to a pure solid cr#stalline phase occurs. More than (+9 of the substances used in pharmaceuticals, fine chemicals, a rochemicals, food and cosmetics are isolated or formulated in their solid form. Cr#stallization is in eneral the last chemical purification step in the production of in redients. Since the properties of a solid material (pol#morphism) can dramaticall# affect the process or the product:s compliance and effect (dissolution rate for example), monitorin and controllin the isolation of solids for the /arious applications throu h cr#stallization is of paramount interest. T3e 4et+st+,-e 5one 6)7t3 8%S9W:; 63)<3 7enotes t3e 2e.)on ,et6een t3e so-1,)-)t= <12>e +n7 t3e onset o* n1<-e+t)on. It 4+2?s +n o@e2+t)n. ,o1n7+2= 712)n. so-1t)on <2=st+--)5+t)on @2o<esses to +>o)7 eA<ess)>e se<on7+2= n1<-e+t)on t31s ens12)n. t3e 2eB1)2e7 s)5e +n7 s)5e 7)st2),1t)on o* t3e *)n+- <2=st+--)ne @+2t)<-es. It +-so 2e*-e<ts t3e n1<-e+t)on ?)net)<s o* + <2=st+--)5+t)on @2o<ess +n7 3+s ,een 1se7 to eAt2+<t t3e ?)net)<s o* @2)4+2= n1<-e+t)on. ;he MSZW ma# be affected b# /arious process parameters such as supersaturation eneration rate, a itation rate , the presence of impurities. .lso, measured MSZW is <nown to be affected b# the detection techni8ue of =first nucleation e/ents>. Direct detection of nucleation e/ents is impossible because nuclei are /er# fine or in/isible. $lectric conducti/it#, turbidit#, and particle count number are used to infer the onset of nucleation. ;herefore, MSZW is defined as maximum supercoolin or supersaturation to reach a fixed /alue of number densit# after primar# nucleation. Clearl#, this number will /ar# dependin on the minimal detectable size ran e of instrument used, but the trends obtained b# /arious techni8ues are /er# similar.

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?n the past decade, man# techni8ues ha/e been de/eloped for in situ determination of the MZW durin solution cr#stallization processes. ;hese techni8ues include detection of the presence of solid particles usin focused beam reflectance measurement (2@&M), turbidit# meter, .;&62;?& b# monitorin of the solute concentration chan e /ia bul< solution propert# measurements usin attenuated reflection62ourier transform infrared (.;&62;?&), densitometer, an ultrasonic /elocit# meter, refracti/e index meterA13 etc. ?n this wor<, a new techni8ue has been tested usin optical in6situ probe to determine MSZW for coolin cr#stallization. ;he cloud point and clear point of a8ueous l#cine solution has been determined. ;he solute and sol/ent used are l#cine and Millipore water respecti/el#.

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2.LITERATURE REVIEW
Cr#stallization is one of the most widel# used and important unit operations in man# industries such as fine chemical, pharmaceutical, and a rochemical.?t has been mainl# used for the formation, separation, and purification of s#nthetic intermediates, final solid products, etc B1C. ;he MSZW ma# be affected b# /arious process parameters such as supersaturation eneration rate, a itation rate, and the presence of impurities. .lso, measured MSZW is <nown to be affected b# the detection techni8ue of =first nucleation e/ents>. Direct detection of nucleation e/ents is impossible because nuclei are /er# fine or in/isible. $lectric conducti/it#, turbidit#, and particle count number are used to infer the onset of nucleation. ;herefore, MSZW is defined as maximum supercoolin or supersaturation to reach a fixed /alue of number densit# after primar# nucleation B,C. Clearl#, this number will /ar# dependin on the minimal detectable size ran e of instrument used, but the trends obtained b# /arious techni8ues are /er# similar. ;he MSZW reflects the nucleation <inetics of a cr#stallization s#stem and has been used to extract <inetics of primar# nucleation. ;he main ad/anta e of this approach is the simplicit# of experimental procedure. !ne of the widel# used e8uations for <inetic estimation from MSZW is D#/ltEs correlation B3C. Some disad/anta es of this approach are4 it does not consider the rowth <inetics, nucleation rate is i/en in mass basis not in number basis, and it does not assume the size of nucleus in e8uations. .n important sta e in stud#in cr#stallization is determination of the saturation cur/e and metastable zone width, as the solubilit# dia ram enables the most suitable cr#stallization process to be selected. Moreo/er the operatin conditions must be adFusted to fit the shape of this dia ram and the width of the metastable zone in order to maintain an optimum supersaturation, the dri/in force of cr#stallization B3C. Se/eral methods are a/ailable for the determination of the solubilit# and metastable zone width such as .;&62;?& spectroscop#, laser bac<scatterin (2@&M), polarized li ht microscop#, turbidit#, &aman spectroscop#, etc. .ttenuated total reflection62ourier transform infrared (.;&62;?&) spectroscop# coupled with a calibration model
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constructed usin chemometric techni8ues and focused beam reflectance measurements (2@&M) is used to determine the solute concentration and to detect the metastable limits, respecti/el# B5C. .;&62;?& and 2@&M can be combined to better understand the thermod#namic and <inetic characteristics of different cr#stallization s#stems. .n in-situ .;& immersion probe is used to collect on6line infrared spectra. ;he 2;?& spectra are related to the solute concentration in the solution usin the calibration cur/e. ;his is therefore an in6line6method that can determine supersaturation. .;& spectroscop# shows reat chemical selecti/it#. ;his techni8ue can be used for solids in their nati/e state without an# sample preparation and can be applied in-situ for processes. .;& spectroscop# has been used for feedbac< and proportional control of supersaturation in coolin and antisol/ent cr#stallization of materials includin pharmaceutical compounds. 2or o/er a decade or more, there ha/e been a number of applications of .;& spectroscop# for in-situ measurement of solution concentration in spontaneous and seeded batch coolin cr#stallization and reacti/e precipitation of or anic and inor anic compounds. 2or pol#morph control, for instance, .;& pro/ides process monitorin that can be used alon with temperature control. .;&62;?& spectroscop# can be successfull# emplo#ed to monitor solubilit# and metastable limit with precision and to impro/e anal#sis of <e# phenomena (nucleation, a lomeration, seedin , etc.) .n in-situ 2@&M probe is used for ac8uirin the chord len th distribution (C%D) and for detectin the =first nuclei>, accordin to which the metastable limit is measured. 2@&M is essentiall# a particle counter and it i/es a more direct measure of slurr# densit# b# measurin the total number of cr#stals scanned per second. ;he probe is then used to determine the nucleation and dissolution of cr#stals. @esides, &aman spectroscop# for monitorin solid elaboration processes presents se/eral interests for industrial applications.

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3.PREVIOUS WORK
?n the last session Ma# G+11 to .pril G+1G Mr. Hoduru Hrishna Chaitan#a has done M;" under the uidance of "rof. D. Sar<ar has accomplished the followin wor<. Ie has de/eloped a simple laser based optical probe for determination of MSZW for an anti6 sol/ent cr#stallization process. Cr#stallization of l#cine from a8ueous solution usin ethanol as anti6sol/ent has been chosen for this stud#. ;he effects of /arious operatin parameters such as stirrer speed, anti6sol/ent addition rate, and location of anti6sol/ent addition on MSZW of l#cine has been in/esti ated. 2inall#, nucleation <inetics has been estimated from the obtained data on MSZW.

F).12e 10 Schematic Dia ram of !ptical "robe S#stem

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F).12e 20 $xperimental Setup ;here are se/eral inconsistenc# with this wor< in terms of the techni8ue used to determine the metastable zone width such as, firstl# the optical probe is not appropriatel# sensiti/e since the probe is not in6situ, secondar# the noise in the processin made of circuit is si nificantl# alterin the obser/ed output, thirdl# the optical probe onl# wor<s for the reactor lass or transparent material. ;hese inconsistenc# need to be addressed to made techni8ue more robust and the optical probe to produce accurate results reproducibl#. ;herefore we need an in situ optical probe with more ad/anced processin circuit.

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4. OPTICAL PROBE DESIGN

.n optical probe is desi ned based on the followin considerations. ;he new detection techni8ue should be capable of detectin the onset of nucleation and probe response should be sensiti/e. ;he response should be instantaneous. ;he measurement s#stem should comprise easil# a/ailable materials and the size should be such that it can be handled and installed easil#. ;he optical probe consist of two part one is the mechanical probe made up of plexi lass holdin laser and the li ht dependent resistor (%D&) and second is the processin amplif#in circuit.

4.1 In-Situ Probe

?t is an insitu probe made up of plexi lass ha/in three parts the laser holder, %D& holder and the connector. ;he laser holder is the hollow c#linder with !D G*.5 mm and two c#lindrical bore of diameter 13.5 mm and 3.5 mm placed G mm apart alon the diameter of the cross section.

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F).12e 0 dia ram of laser holder

?t is 1++ mm in len th. ;he connector is hollow c#linder of !D 3 mm and ?D G mm and G5+ mm in len th, which connect the laser holder and the %D& holder carr#in wire comin out of the

F).12e 40 dia ram of %D& holder

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%D&. ;he %D& holder is a tablet shaped structure desi ned to hold %D& with c#lindrical ca/it# of ' mm diameter and , mm depth and 3 mm c#lindrical bore to connect the connector. ;he top

F).12e #0 dia ram of connector

F).12e &0 dia ram of in situ optical probe

and bottom portion of the %&D holder is sealed with lamination plastic usin acr#lic resin ma<in it water ti ht.

4.2 Processing Circuit

;he /olta e across the resistance when connected to a constant dc suppl# is amplified b# an indi enousl# desi ned processin circuit. %D& enerates a /ariable resistance dependin on the intensit# of li ht incident on it. ;he resistance is connected to fix <nown input /olta e

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source. ;he /olta e across the resistance is the re8uired output. ;o measure the li ht intensit# of the laser on the %D& we use the followin circuit. ;he circuit consists of the followin components4 1) %M'(1G G) %M'(+5 ,) %M'**+ 3) %M,G5) &esistances *) Capacitances ') &heostats. . description of each of the ?Cs is i/en below4
L !"12 #n$ L !"%&'

%M'()) are a series of three terminal /olta e re ulators that enerate a constant DC /olta e output when the input is within a certain ran e. ;here are three main ?Cs in this series4 %M'(+5, %M'(1G and %M'(15. ?n this circuit %M'(1G and %M'(+5 are used. %M'(1G enerates a constant /olta e of 1G /olts while %M'(+5 enerates a constant /olta e of 5 /olts at the Joutput: terminal.

2i ure *4 Dia ram of %M'())

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;he 1G /olts suppl# is needed to power the operational amplifier circuit (for%M,G3) while the 5 /olts suppl# is used to transduce the %D&:s resistance into a /olta e which is in the linear input ran e of the amplifier. L !((% ' %M'**+ is a DC6to6DC /olta e con/erter. ?t is used here to enerate a ne ati/e

counterpart /olta e of the input /olta e of K1GL. Ience, usin %M'**+ we can enerate a 61GL suppl#. Man# circuits such as .6to6D con/erters, D6to6. con/erters, !perational .mplifiers (circuits used here) and multiplexers need a ne ati/e /olta e suppl# alon with a positi/e /olta e suppl#. ?n such cases this circuit can be used to enerate the re8uired suppl#.

2i ure !4 "in Dia ram and Connection circuit of %M'**+ L 33)' %M,,- is an ?C that consists of 3 operational amplifiers which operate from a sin le power suppl#. ;he ?C re8uires a suppl# /olta e of K1GL and 61GL. ;he pin dia ram of the ?C is presented here.

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2i ure (4 "in dia ram of %M,,-

.s we can see in fi ure ', the external /olta e source is connected to the pin1 (input pin) of '(1G. . 1GL Zener diode is connected across the output terminal and round terminal to support the ?C. ;he output of '(1G is connected to pin ( of %M'**+ which is used to enerate the re8uired ne ati/e suppl# /olta e. .s can be seen two capacitors (1+ M2 each) are connected Po*er Circuit'

2i ure -4 "ower Circuit

across pins G N 3 and ( N 5 with the correct polarit#. "in , needs to be rounded. ;he output of '(1G is also fed into the input pin (pin1) of '(+5 which enerates a K5L suppl# for the %D& circuit.
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A+,-i.ier Circuit'

2i ure 1+4 .mplifier Circuit ?n the circuit (2i . () three sta es ha/e been used. ;he first sta e is the input sta e which buffer:s (reciprocates) the input /olta e across the %D& to the output but in the ne ati/e direction. ;he second and third sta es are used as ain sta es. ;he third sta e also wor<s as an output sta e i.e., it presents a low output resistance (impedance) to the data ac8uisition unit hence transferrin most of the /olta e enerated at the output. ;he ain of the first sta e is 61 (as it is Fust a buffer circuit). ;he ain of the second sta e can /ar# from 1.( to G and hence it wor<s as a coarse ain adFustment sta e. ;he ain of the third sta e can /ar# from * to 1( and hence acts as a finer ain adFustment sta e. Ience the maximum ain of the circuit can be ,* and minimum ain can be 1+.(. ;he resistance /alues used in the circuit is presented in the dia ram itself. ?n practice the resistances are not realized exactl# which can cause the circuit to not function as desired. Ience the ain adFustment rheostats can be used to brin bac< the circuit into proper operation.

5. E/PERI E0TAL

ET1OR2

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#teri#-s. Ol#cine (%oba chemie, --.--9), ethanol(Merc<, --.59), %6.spar ine (%oba chemie, --9) Millipore water were used as recei/ed. Ol#cine is used as solute and Millipore water is used as solution. E3,eri+ent#- ,roce$ure. ?n this wor< both coolin and anti6sol/ent combined coolin cr#stallization were conducted. .ll the experiment were conducted usin 1 litre Fac<eted lass reactor connected to circulator (Fulabo, hi h tech) to appl# controlled coolin and heatin profile.

2i ure 11 4 experimental setup

;he procedure for coolin cr#stallization usin 1. ,+ l#cine K 1++

l#cine4

wateris ta<en such that the optical probe and thermocouple is

appropriate immersed in the solution.

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G. &eactor is co/ered with thic< blac< sheet to a/oid li ht and its mouth is co/ered with paraflim sheet to a/oid e/aporation and dust. ,. Solution is maintained at 3+PC for 1+ min, then brin the temperature down to G+PC in 1 hour. 3. Solution is maintained at G+PC for 1+ min. 5. ;emperature is increased to 3+PC a ain in 1 hour. *. Solution is maintained at 3+PC for 1+ min. '. Continuousl# record and monitor the /olta e output of the MSZW probe and the temperature output of the circulator software. ;he procedure for anti6sol/ent combined coolin cr#stallization usin 1. *+ l#cine K G++ l#cine4

wateris ta<en such that the optical probe and thermocouple is

appropriate immersed in the solution. G. &eactor is co/ered with thic< blac< sheet to a/oid li ht and its mouth is co/ered with paraflim sheet to a/oid e/aporation and dust. ,. Maintain the solution and ethanol at ,'QC . 3. $thanol is added in the solution. 5. !nce cloud point is reached ethanol addition is continued for further 1+ minutes and then it is stopped. *. Solution is heated from ,'QC to *+QC in 1 hours and sta# at *+QC for G+ minutes. '. Continuousl# record and monitor the /olta e output of the MSZW probe and the temperature output of the circulator software. ;he procedure for coolin cr#stallization usin %6.spar ine4 1. *+ %6.spar ine K G++ wateris ta<en such that the optical probe and thermocouple is

appropriate immersed in the solution.

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G. &eactor is co/ered with thic< blac< sheet to a/oid li ht and its mouth is co/ered with paraflim sheet to a/oid e/aporation and dust. ,. Solution is maintained at 5+PC for G+ min, then brin the temperature down to G+PC in 1 hour. 3. Solution is maintained at G+PC for G+ min. 5. ;emperature is increased to 5+PC a ain in 1 hour. *. Solution is maintained at 3+PC for 1+ min. '. Continuousl# record and monitor the /olta e output of the MSZW probe and the temperature output of the circulator software.

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&. RESULTS A02 2ISCUSSIO0S

?n the first run the a8ueous l#cine solution that is ta<en has e8uilibrium concentration at ,'QC. When the temperature is decreased from 3+QC to G+QC at rate of ,QC0min initiall# a constant low /olta e of +.G /olts is obser/ed due to clear unsaturated solution and almost all the li ht is fallin on the %D&. Dow at point . as shown in the fi ure 1G a sharp increase in the /olta e is obser/ed at correspondin G(.+GQC. ;his is due to onset of primar# nucleation formin a sudden cloud of nuclei obstructin the path of li ht source from laser to %D&. ;his point is called cloud point. ;he /olta e continue to increase till /olta e sur es to 3.5 /olts since durin this time continuous formation of nuclei ta<es place ma<in si nificantl# lesser li ht fall on %&D thereb# i/in hi h /olta e. .t this point when almost all the possible nucleus has been formed the temperature is a ain increase from G+ C to 3+ C at the same rate thus, at point @ in the fi 1G a decrease in the /olta e is obser/ed. ;his is due to re dissol/in of the cr#stals formed till this point hence, li ht fallin on the %D& slowl# starts to increase and i/in lesser /olta e. Dow at point @ a lowest point of /olta e is obser/ed on the monotonicall# decreasin /olta e cur/e.

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2i ure1G. optical probe /olta e cur/e

.t this point we obser/ed a ain a clear unsaturated solution and the correspondin temperature is ,(.1 C. ;his point is called clear point represent the solubilit# of the solute ( l#cine) at the particular temperature. Dow on comparin with the literature the a8ueous l#cine solution that is ta<en has e8uilibrium concentration at ,' C. ;his de/iation from ideal to experimental is well with in the tolerable ran e of experimental error.

2i ure 1,. temperature profile of coolin cr#stallization

?n the second run the concentration of ,+

a8ueous

l#cine solution that is ta<en has e8uilibrium

l#cine01++ water and maintained at its saturation temperature that is ,'PC

. $thanol is added in this solution which is maintained at ,'PC. When ethanol is added initiall# a constant low /olta e of +.3/olts is obser/ed due to clear unsaturated solution and almost all the li ht is fallin on the %D&. .fter addition of -.G5 of ethanol at point . a sharp increase in the /olta e is obser/ed at correspondin temperature of ,*.--PC as shown in the fi ure 13. ;his is due to onset of primar# nucleation formin a sudden cloud of nuclei obstructin the path of li ht source from laser to %D&. ;his point is called cloud point. ;he saturation temperature of the solution with +.+5 anti6sol/ent composition is 51QC .;he /olta e continue to increase till /olta e sur es to ' /olts since durin this time continuous formation of nuclei ta<es place ma<in si nificantl# lesser li ht fall on %&D thereb# i/in hi h /olta e. .t this point when almost all
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the possible nucleus has been formed the temperature is a ain increase from ,'PC to *+PC in an hour. .t this sta e a decrease in the /olta e is obser/ed.

2i ure 13. optical probe /olta e cur/e for combined coolin antisol/ent cr#stallization

;his is due to re dissol/in of the cr#stals formed till this point henceA li ht fallin on the %D& slowl# starts to increase and i/in lesser /olta e. Dow at point @ a lowest point of /olta e is obser/ed on the decreasin /olta e cur/e. .t this point we obser/ed a ain a clear unsaturated solution and the correspondin temperature is 5G.,*QC. ;his point is called clear point represent the solubilit# of the solute( l#cine) at the particular temperature. ?n the third experiment a8ueous %6.spar ine solution that is ta<en has e8uilibrium concentration at 35QC. When the temperature is decreased from 5+QC to G+QC at rate of GQC 0min initiall# a constant low /olta e of +.G5 /olts is obser/ed due to clear unsaturated solution and almost all the li ht is fallin on the %D&. Dow at point . as shown in the fi ure 1* a sharp increase in the /olta e is obser/ed at correspondin G,.+3QC. ;his is due to onset of primar# nucleation formin a sudden cloud of nuclei obstructin the path of li ht source from laser to %D&. ;his point is called cloud point. ;he /olta e continue to increase till /olta e sur es to 5 /olts since durin this time continuous formation of nuclei ta<es place ma<in si nificantl# lesser li ht fall on %&D thereb# i/in hi h /olta e. .t this point when almost all the possible
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F).12e 1#0 temperature profile of antisol/ent combined coolin cr#stallization nucleus has been formed the temperature is a ain increase from G+QC to 5+QC at the same rate thus, at point @ in the fi 1*. a decrease in the /olta e is obser/ed. ;his is due to re dissol/in of the cr#stals formed till this point hence, li ht fallin on the %D& slowl# starts to increase and

2i ure 1*. /olta e cur/e for coolin cr#stallization usin %6.spar ine. P+.e / 2

i/in

lesser /olta e. Dow at point @ lowest point of /olta e is obser/ed on the

monotonicall# decreasin /olta e cur/e. .t this point we obser/ed a ain a clear unsaturated solution and the correspondin temperature is 35.(' QC. ;his point is called clear point represent the solubilit# of the solute (%6.spar ine) at the particular temperature. Dow on comparin with the literature the a8ueous l#cine solution that is ta<en has e8uilibrium concentration at 35QC. ;his de/iation from ideal to experimental is well wit in the tolerable ran e of experimental error.

2i ure 1'0 temperature profile coolin cr#stallization usin %6.spar ine.

Solute Ol#cine (coolin cr#stallization) Ol#cine (combined coolin anti6 sol/ent cr#stallization) %6.spar ine (coolin cr#stallization)

Concentration ( solute01++ sol/ent) ,+ ,+

saturation temperature ( ; sat) (QC) ,' 51

Cloud point (.) (QC) G(.+G ,*.--

Clear point (@) (C Q) ,(.1 5G.,*

$stimated MSZW (; sat 6 .)(QC) (.-( 13.+1

35

G,.+3

35.('

G1.-*

;able 1. Cloud points, clear points, saturated temperatures, and metastable zone width (MSZW) of experiment conducted.
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6. CONCLUSION AND FUTURE WORK

?n this wor<, optical probe has been successfull# applied for MSZW determination and monitorin the solution coolin cr#stallization process of a l#cine6water solution. ;his optical prone could detect not onl# the cloud point that corresponds to the onset of nucleation but also the clear point that closel# represents the solubilit# limit when the heatin rate durin the dissolution of particles is slow. .lthou h no comparison of the results with an# established techni8ue for MSZW determination has been done nor enou h data has been enerated to stud# how MSZW /aries with the coolin rate, sensiti/it# of techni8ue. ;he present experiment also has some inconsistenc# li<e some li ht is fallin on the %D& from outside the reactor ma<in the optical probe less sensiti/e. More data is also re8uired to 8ualitati/el# understand the nucleation and the bac< dissociation process of cr#stals durin coolin cr#stallization. ?n the li ht of the present conclusion and in consistenc# in the present experiment the future wor< are as follows4 1. Comparison of the results with maFor established techni8ue for MSZW determination such as 2@&M, .;&62;?&, "LM, etc G. Oeneratin enou h data to stud# the /ariation of MSZW with the coolin rate, with concentration, different techni8ue, etc such that it allows to determine the chemical <inetics of the process.

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7. RE4ERE0CES
1. 5u#ng*en 1e6 #rtin T7#87ono 6 Pui S8#n C8o*6 Regin#-$ 9. 1. T#n6 #n$ #rc 5#r-#n$ 6 2%1%. ?n Situ Determination of Metastable Zone Width Rsin Dielectric Constant Measurement. Organic Process Research & Development 14, 14691472
2.

A K Jana T K !an"al D P C#a$%aba%&' G Da( an" P K Da( 2%%!. .n

optical probe for li8uid7li8uid two6phase flows. !easurement "cience #n$ %echnolog& 1', 1(6)1(7(
.

. Tri.:o;ic6 )64/-)6(/

. S8ei:8<#$e86 S. Ro8#ni6 2%%). Determination of metastable zone

width for combined anti6sol/ent0coolin cr#stallization. *ournal o+ ,r&stal -ro.th )11, 3. %arosla/ n#/lt, 1-*(. Kinetics o. nuc-e#tion in so-utions. Sournal of cr#stal rowth 3, ,'' 7 ,(,. 5. Mihasina &abesia<a, Catherine "orte, Sohanne @onnin6"aris, Sean6%ouis Ia/et, G++1. An #uto+#tic +et8o$ .or t8e $eter+in#tion o. s#tur#tion cur;e #n$ +et#st#b-e <one *i$t8 o. -=sine +ono8=$roc8-ori$e. Sournal of cr#stal rowth ,,G, '5 7 (+

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