Research ArticleThermodynamic Study of Racemic Ibuprofen Separation byLiquid Chromatography Using Cellulose-Based Stationary Phase
Wilson M Ferrari Ana C Nascimento Jean V Moreira and Marco A Cremasco
Chemical Engineering School University of Campinas (UNICAMP) Av Albert Einstein 500 Zip Code 13083-852 Campinas SP Brazil
Correspondence should be addressed to Wilson M Ferrari wmcferrarigmailcom
Received 28 April 2016 Revised 12 August 2016 Accepted 25 August 2016
Academic Editor Masami Shibukawa
Copyright copy 2016 Wilson M Ferrari et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) also known for its significant antipyretic and analgesic propertiesThis chiral drug is commercialized in racemic form however only S-(+)-ibuprofen has clinical activities In this paper the effectof temperature change (from 28815 to 30815 K) on the ibuprofen resolution was studied A column (250 times 46mm) packed withtris(35-dimethylphenylcarbamate) was used to obtain the thermodynamic parameters such as enthalpy change (Δ119867) entropychange (Δ119878) variation enthalpy change (ΔΔ119867) variation entropy change (ΔΔ119878) and isoenantioselective temperature (119879iso) Themobile phase was a combination of hexane (99) isopropyl alcohol (1) and TFA (01) as an additive The conditions led to aselectivity of 120 and resolution of 455 The first peak R-(minus)-ibuprofen presented an enthalpy change of 721 kJmol and entropychange of 4288 kJKsdotmol the last peak S-(+)-ibuprofen has an enthalpy change of 876 kJmol and 4940 kJKsdotmol of entropychange
1 Introduction
The importance of stereochemical compound has been stud-ied since Louis Pasteur observed the chiral phenomenonin 1848 Chiral recognition and enantiomer distinction arefundamental phenomena in nature and chemical systemsThey are present in several fields in particular bioactivecompounds drugs pollutants agrochemicals food additivesand flavors The most significant developments in chirotech-nologies were spurred by demands of drug discovery inpharmaceutical industries The liquid chromatography hasbeen used to provide support in drug discovery analyticalmethods and advances in preparative technique of purifica-tion [1 2]
(RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid alsoknown as ibuprofen is one of the most widely used nons-teroidal anti-inflammatory drugs (NSAIDs) for the treatmentof arthropathies This enantiomer is a prostaglandin andthromboxane inhibitor [3] While most currently marketedibuprofen products are in the form of racemate it has longbeen recognized that the two enantiomers have differentpharmaceutical activities [4ndash6] The ibuprofen structure isshown in Figure 1
The fundamental basis for distinction of enantiomers(biological or chromatographic system) is the transformationof enantiomers to diastereomers or creation of a diastere-omeric relationship between ligated enantiomers (selectandSA) and a receptor (chiral selector CS) Equilibrium processsuch as the CS-SA complexation can be explained by energybalance of free and complexed state and is often studiedbased on thermodynamic considerations Thermodynamicquantities of chromatographic equilibrium processes such asthe direct enantiomer separation with chiral stationary phase(it uses adsorbents with a chiral selector) can be deducedby measurement of the chromatographic parameters over acertain temperature range from vanrsquot Hoff [1 7ndash9]
This paper aims to study the adsorption of ibuprofen oncellulose tris(35-dimethylphenylcarbamate) and to evaluatethe effect of temperature in chiral separation The followingparameters were analyzed enthalpy change (Δ119867) entropychange (Δ119878) and isoenantioselective temperature (119879iso)
2 Material and Methods
21 Reagents Racemic ibuprofen (molar mass 20629 gmoland purity 98) and 135-tri-tert-butylbenzene (TTBB
Hindawi Publishing CorporationChromatography Research InternationalVolume 2016 Article ID 7484731 6 pageshttpdxdoiorg10115520167484731
2 Chromatography Research International
COOH
H3C
CH3
CH3
lowast
Figure 1 Ibuprofen molecular structure
molar mass 24644 gmol and purity 97) were purchasedfrom Sigma-Aldrich The chiral analytical column (250mmtimes 46mm) was purchased from Phenomenex and originallypacked with silica (5120583m) coated with cellulose tris(35-dimethylphenylcarbamate)
22 Instrumentation The experiments were carried out ina HPLC system it consisted of a system controller (modelCBM-20A) an UV-vis detector (SPD-20A) and two pumps(LC-10AD)The components were originally purchased fromShimadzu Japan The column and mobile phase were tem-perature-controlled using a Quimis Q214M2 (Brazil) circu-lating water bath The elution order was determined by apolarimeter model P1010 (Japan)
23 Thermodynamic Parameters The resolution of racematewas studied by means of thermodynamic parameters VanrsquotHoff approach was used to obtain the enthalpy change (Δ119867)and entropy change (Δ119878) A similar approach was also usedto calculate the difference of enthalpy change (ΔΔ119867) andentropy change (ΔΔ119878) for the racemic ibuprofen respectivelyThese values are important to obtain the isoenantioselectivetemperature (119879iso) The determination of these parameterscan be based on the chromatographic parameters such asthe retention factor (119896
119894) and the selectivity (120572) To obtain
the isoenantioselective temperature it is necessary to knowthe porosity (120576) which was determined by moment analysis[10]
24 Chromatographic Parameters The retention factor is therelation between the number of analytes in stationary phaseand the molecule numbers in mobile phase This parameteris written in terms of analyte retention time (119905
119877119894) and column
dead time (1199050) as presented in [11]
119896119894=119905119877119894minus 1199050
1199050
= 120601119870119863119894 (1)
where 120601 represents the volume phase ratio between thevolume of stationary phase and mobile phase also equal to(1 minus 120576
119905)120576119905
The selectivity (120572) of separation of two components isdetermined by dividing their retention factors
120572 =
119896119895
119896119894
=
119905119877119895minus 1199050
119905119877119894minus 1199050
(2)
Chromatography resolution (119877119878) and number of plates
(119873119894) are other important parameters to establish the separa-
tion condition
119877119904=radic119873119894
4(119896119894
119896119894+ 1)(120572 minus 1
120572) = 1177
119905119877119895minus 119905119877119894
119908119894+ 119908119895
119873119894= 5545 (
119905119877119894
119908119894
)
2
(3)
where 119908119894is the peak width at half-height [12]
25 Effect of Temperature Equation (4) describes the linearrelation between natural logarithmof the retention factor andinverse of the temperature in which slope provides enthalpychange and the intercept supplies entropy change This ismodified Vanrsquot Hoff equation where 119870
119863119894from the original
equation was substituted for 119896119894 The parameters ΔΔ119867 and
ΔΔ119878 can be obtained analogously for (4) as shown in (5)These parameters represent the difference between the lessand the more retained compounds ldquo119894rdquo and ldquo119895rdquo respectively[13ndash15]
ln 119896119894= minus1
119879
Δ1198670
119894
119877+Δ1198780
119894
119877+ ln 1 minus 120576120576 (4)
ln120572 = minus 1119879
ΔΔ1198670
119895119894
119877+
ΔΔ1198780
119895119894
119877 (5)
where 119879 is temperature and 119877 is gas constantThe last term of (4) is related to the physical properties of
the stationary phase thus it can be considered as a constantsince its limitations are not exceeded If one simplifies thefirst absolute moment the total porosity can be obtainedexperimentallyTherefore total porosity is determined by (6)in which ] is superficial velocity and 119871 is bed length [10 14 15]
119905119877=119871
V120576 (6)
Isoenantioselective temperature (119879iso) is the condition inwhich the separation does not occur due to both compoundsrsquocoelute If the condition 120572 = 1 is applied in (5) it is possibleto write (7) as follows
119879iso =ΔΔ1198670
119895119894
ΔΔ1198780
119895119894
(7)
3 Results and Discussion
31 Resolution Conditions and Elution Order The resolutionconditions were based on [16ndash18] at which cellulose tris(35-dimethylphenylcarbamate) is the chiral selector Thus itwas decided to use a longer column (250mm times 46mm)packed with smaller particles (5 120583m) Both parameters havecontributed to increasing efficiency
Some mobile phases were tested to resolve the racemicmixture but only the mobile phase based on hexane pro-moted satisfactory results The mobile phase composed of
Chromatography Research International 3
Table 1 Chromatographic parameters of racemic ibuprofen separa-tion at 30815 K column (250mmtimes 46mm) packed with cellulosetris(35-dimethylphenylcarbamate)
Mobile phase 120572 119877119878119873119894119873119895
Hexaneisopropyl alcohol (991) 120 455 12976 12355
0 3 6 9 12 15 18 21 2400
0 3 6 9 12 15 18 21 2400
R-(minus)-ibuprofenS-(+)-ibuprofen
Det
ecto
r sig
nal (
mAU
)D
etec
tor s
igna
l (m
AU)
Time (minute)
Time (minute)
TTBB
80
60
40
20
40
32
24
16
08
times105
times104
Figure 2 Chromatograms of ibuprofen enantiomeric resolution at30815 K and 05 gmL and TTBB Flow ratio 1mLmin wavelength220 nm for ibuprofen and 254 nm for TTBB mobile phase hex-aneisopropyl alcohol (991)
hexane and isopropyl alcohol in the proportion 991 waschosen for chiral resolution Trifluoroacetic acid (TFA) wasalso used as an additive its proportion on mobile phasewas 01 in volumetric base All the conditions set forthe chromatographic resolution provided values of 120572 and119873119894above minimum levels required for effective chromato-
graphic resolution (120572 gt 120 119877119878gt 150 and 119873
119894gt 2000)
Table 1 summarizes all the mentioned values [19]After setting the separation conditions the elution order
was defined through a polarimetric technique For this theHPLC was used in batch mode to resolve the racemic mix-ture in R-ibuprofen and S-ibuprofen The rotary evaporatorreduced each sample for the polarimeter sample cell volumeA calibration curve provided the concentration of bothsamples 04 gL for S-ibuprofen and 111 gL for R-ibuprofenFinally the polarimeter identified the less and more retainedcompounds as (minus)-ibuprofen and (+)-ibuprofen respectivelyThus in Figure 2 the first peak is R-(minus)-ibuprofen while thesecond peak is S-(+)-ibuprofen
32 Total Porosity Porosity was calculated from the firstmoment method (6) This method requires a tracer com-pound small enough to pass through both particle and bedvoids TTBB was used to determine the porosity of chiral
00 02 04 06 08 100
3
6
9
12
15
t998400 R(m
in)
1 (mincm)
Figure 3 Total porosity
Table 2 Retention factor obtained in racemic ibuprofen separation
119879 (K) 119896119894
119896119895
120572
28815 472 543 11529315 488 568 11629815 511 596 11730315 538 637 11830815 574 690 120
columns packed with cellulose tris(35-dimethylphenyl-carbamate) The flow rate was changed from 02 up to16mLmin with a 02mLmin step The results are shown inFigure 3
The slope presented in Figure 3 provides the value of0647 for porosity
33 Thermodynamic Parameters The adsorption phenome-non of the enantiomeric compounds is macroscopic ther-modynamic quantities which does not consider the surfaceheterogeneity of the stationary phase and the associateddistinct adsorption behavior of enantiomers at different sitesUnder the circumstances Vanrsquot Hoff analysis is useful todetermine global information about the phenomenon [1]
Using (4) modified Vanrsquot Hoff equation one can obtainthe thermodynamic parameters The temperatures chosenwere 28815 29315 29815 30315 and 30815 K At each tem-perature racemic ibuprofen samples were injected at 05 gLFigure 4 and Table 2 present a summary of chromatogramsand chromatographic values obtained from these resolutions
In Figure 4 an increase in retention time value wasobserved as temperature rises This behavior has beenreported in literature however it is not the most commonone [1] This condition will be discussed later in this paper
The retention factors from Table 2 were used to plotFigure 5 From this figure and utilizing (4) it was possible toobtain Δ119867 and Δ119878 for ibuprofen enantiomers as presentedin Table 3 The errors for enthalpy and entropy change wererespectively 6 and 9
4 Chromatography Research International
0 6 12 18 240
0 6 12 18 24
0 6 12 18 24
0 6 12 18 24
0 6 12 18 24
Det
ecto
r res
pons
e (m
UA)
Time (minute)
8
4
0
8
4
0
8
4
0
8
4
0
8
4
288K
293K
298K
303K
308K
times105
times105
times105
times105
times105
Figure 4 Chromatograms of the racemic ibuprofen at severaltemperatures Flow rate 1mLmin
Table 3 Thermodynamic parameters of racemic ibuprofenadsorbed on cellulose tris(35-dimethylphenylcarbamate)
Compound Δ119867 (kJmol) Δ119878 (kJKsdotmol) 1198772
R-(minus)-ibuprofen 721 4288 0975S-(+)-ibuprofen 876 4940 0972
Both relations presented in Figure 4 are linear suggestingthat multiple mechanisms of retention do not occur [19 20]Furthermore Δ119867 of compounds is lower than 50 kJmoldemonstrating physical adsorption [11] The interactions ofphysisorption are characterized by relatively weak bondsOtherwise it would be necessary to modify the chromato-graphic system to elute analytes
According to [1] the adsorption phenomenon in liquidchromatographic enantiomer resolution is driven by (mostlyelectrostatic type) noncovalent interactionsThermodynamicquantities have shown negative heats of adsorption for awide variety of different mobile phase stationary phaseand analyte Additionally there is a decrease in retentiontime as temperature rises this occurs due to exothermiccharacteristic of adsorption as [1] alsomentioned that inmostof cases the compensation effect (also called enthalpy-entropycompensation) occurs However both enthalpy changes fromTable 3 presented positive values indicating an endothermicphenomenon Furthermore the retention times in Figure 4increase together as temperature rises This aspect can belinked with a favorable entropy contribution This indicatesthat when the analyte is bound to the stationary phase thesolvent molecules overload the adsorption site favoring theentropy increase
00032 00033 00034 0003515
16
17
18
19
20
R-(minus)-ibuprofenS-(+)-ibuprofen
1T (1K)
ln(k)
Figure 5 Vanrsquot Hoff plots for the determination of Δ119867 and Δ119878
00032 00033 00034 00035010
012
014
016
018
020
1T (1K)
ln(120572)
Figure 6 Linearization for determining of ΔΔ119867 and ΔΔ119878
The selectivity from Table 2 was also employed to analyzethe separation betweenR-(minus)-ibuprofen and S-(+)-ibuprofenParameters ΔΔ119867 and ΔΔ119878 were calculated by means of (5)The linearization proposal for this equation is presented inFigure 6
The linearization of ln(120572) versus 1119879 provided values of155 kJmol and 652 J(molsdotK) for ΔΔ119867 and ΔΔ119878 respec-tively and it also presented a 119904-squared of 0915 Error forΔΔ119867 was 12 and error for ΔΔ119878 was 15 Equation (7)provided 23738 K for 119879iso
Thermodynamic parameters are global informationabout the adsorption mechanism in a chromatographic col-umn The adsorption phenomenon involved in this processdepends on solute type mobile phase and stationary phase[1] For enantiomeric separation the adsorption mechanismis related to the chiral recognition According to informationfrom Figure 6 the adsorption is controlled by entropy(|119879 sdot ΔΔ119878| gt |ΔΔ119867|) because entropy contribution is more
Chromatography Research International 5
relevant than enthalpy contribution for the ibuprofen re-tention mechanism in cellulose tris(35-dimethylphenylcar-bamate)
However the separation will not be driven by entropy forall temperature ranges this happens due to 119879iso it is a bound-ary temperature for driven forces in this case This becomesevident when the conditions for 119879iso are applied in Gibbs-Helmholtz equation and the result is zero for energy change(Δ119866) For this case adsorption phenomenon at temperaturesbelow 119879iso 23738 K will be driven by entropy on the otherhand temperatures above 119879iso will be driven by enthalpy It iscommon that the adsorption phenomenon is exothermic andit occurs above 119879iso [18 20ndash23] Probably the elution order ofcompounds could be inverted in temperature lower than119879isoMoreover the phenomenon would be controlled by enthalpychange the selectivity would decrease as temperature risesand the adsorption would be exothermic if ibuprofen wereseparated below 119879iso [20 22 23]
4 Conclusions
Racemic ibuprofen can be separated using a chiral stationaryphase based on cellulose tris(35-dimethylphenylcarbamate)and a high nonpolar mobile phase The mobile phase com-posed of hexane (99) and isopropyl alcohol (1)was chosento separate the mixture Trichloroacetic acid at 01 wasemployed as an additive on this configuration of mobilephase and stationary phase the S-(+)-ibuprofen is the mostretained enantiomer
Thermodynamic parameters obtained from Figure 4demonstrated that the adsorption is physical and the separa-tion phenomenon is endothermic It shows that high temper-atures favored the separation Furthermore the parametersfrom Figure 5 show that phenomenon of separation is con-trolled by entropy (|119879 sdotΔΔ119878| gt |ΔΔ119867|) at temperatures above119879iso
Nomenclature
Symbols
ΔΔ119867 Variation of enthalpy change betweenmore and less retained compound (Jmol)
ΔΔ119878 Variation of entropy change between moreand less retained compound (JKsdotmol)
Δ119867 Standard enthalpy change (Jmol)Δ119866 Standard Gibbs free energy change (Jmol)Δ119878 Standard entropy change (JKsdotmol)119896119894 Retention factor of the least retained
compound119896119895 Retention factor of the most retained
compound119871 Column length (cm)119873119894 Number of plates of the least retained
compound119873119895 Number of plates of the most retained
compound119877 Universal gas constant (83144 JmolsdotK)119877119878 Resolution
119879 Absolute temperature (K)1199050 Column dead time (min)119879iso Isoenantioselective temperature (K)119905119877119894 Retention time of the least retainedcompound plus dead time (min)
119905119877119895 Retention time of the most retainedcompound plus dead time (min)
119908119894 Peak width at half-height of the least
retained compound119908119895 Peak width at half-height of the mostretained compound
Greek Letters
120572 Selectivity120576 Porosity] Superficial velocity (cmmin)
Competing Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The financial support of this research by CNPq (Brazil) isgratefully acknowledged
References
[1] M Lammerhofer ldquoChiral recognition by enantioselective liquidchromatography mechanisms and modern chiral stationaryphasesrdquo Journal of Chromatography A vol 1217 no 6 pp 814ndash856 2010
[2] I Ali S D Alam Z A Al-Othman and J A Farooqi ldquoRecentadvances in SPE-chiral-HPLC methods for enantiomeric sep-aration of chiral drugs in biological samplesrdquo Journal of Chro-matographic Science vol 51 no 7 pp 645ndash654 2013
[3] J S Yoon D-C Jeong J-W Oh et al ldquoThe effects and safetyof dexibuprofen compared with ibuprofen in febrile childrencaused by upper respiratory tract infectionrdquo British Journal ofClinical Pharmacology vol 66 no 6 pp 854ndash860 2008
[4] M Venu Madhav and C B Ching ldquoStudy on the enzymatichydrolysis of racemic methyl ibuprofen esterrdquo Journal of Chem-ical Technology and Biotechnology vol 76 no 9 pp 941ndash9482001
[5] M Yousefi M Mohammadi and Z Habibi ldquoEnantioselectiveresolution of racemic ibuprofen esters using different lipasesimmobilized on octyl sepharoserdquo Journal of Molecular CatalysisB Enzymatic vol 104 pp 87ndash94 2014
[6] H Li X Jiang W Xu Y Chen W Yu and J Xu ldquoNumer-ical determination of non-Langmuirian adsorption isothermsof ibuprofen enantiomers on Chiralcel OD column usingultraviolet-circular dichroism dual detectorrdquo Journal of Chro-matography A vol 1435 pp 92ndash99 2016
[7] Z Pataj I Ilisz A Aranyi et al ldquoLC separation of 120574-amino acidenantiomersrdquo Chromatographia vol 71 no 1 pp S13ndashS19 2010
[8] A Cavazzini L Pasti A Massi N Marchetti and F DondildquoRecent applications in chiral high performance liquid chro-matography a reviewrdquo Analytica Chimica Acta vol 706 no 2pp 205ndash222 2011
6 Chromatography Research International
[9] I Ilisz N Grecso M Palko F Fulop W Lindner and A PeterldquoStructural and temperature effects on enantiomer separationsof bicyclo[222]octane-based 3-amino-2-carboxylic acids oncinchona alkaloid-based zwitterionic chiral stationary phasesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 98 pp130ndash139 2014
[10] M A Cremasco B J Hritzko Y Xie and N H L WangldquoParameters estimation for amino acids adsorption in a fixedbed by moment analysisrdquo Brazilian Journal of Chemical Engi-neering vol 18 no 2 pp 181ndash194 2001
[11] A Seidel-MorgensternM Schulte andA Epping ldquoFundamen-tals and general terminologyrdquo in Preparative Chromatographypp 7ndash46 2nd edition 2012
[12] C H Collins G L Braga and P S Bonato Fundamentos deCromatografia Unicamp 2006
[13] A L Myers and J M Prausnitz ldquoThermodynamics of mixed-gas adsorptionrdquo AIChE Journal vol 11 no 1 pp 121ndash127 1965
[14] D M Ruthven Principles of Adsorption and Adsorption Pro-cesses John Wiley amp Sons 1984
[15] G Guiochon A Felinger and D G Shirazi Fundamentals ofPreparative and Nonlinear Chromatography Academic Press2006
[16] ADucretM Trani P Pepin andR Lortie ldquoComparison of twoHPLC techniques for monitoring enantioselective reactions forthe resolution of (RS)-ibuprofen chiral HPLC vs achiral HPLClinked to an optical rotation detectorrdquoBiotechnology Techniquesvol 9 no 8 pp 591ndash596 1995
[17] P S Bonato M P F M Del Lama and R de Carvalho ldquoEnan-tioselective determination of ibuprofen in plasma by high-performance liquid chromatography-electrospray mass spec-trometryrdquo Journal of Chromatography B Analytical Technologiesin the Biomedical and Life Sciences vol 796 no 2 pp 413ndash4202003
[18] W M Ferrari and M A Cremasco ldquoThermodynamic studyof the separation of racemic ibuprofen by chiral liquid chro-matographrdquo in Anais do XX Congresso Brasileiro de EngenhariaQuımicamdashCOBEQ 2014 vol 1 Blucher Sao Paulo Brazil 2015
[19] V R Meyer Practical High-Performance Liquid Chromatogra-phy John Wiley amp Sons 2013
[20] T D Booth and I W Wainer ldquoMechanistic investigationinto the enantioselective separation of mexiletine and relatedcompounds chromatographed on an amylose tris(35-dimeth-ylphenylcarbamate) chiral stationary phaserdquo Journal of Chro-matography A vol 741 no 2 pp 205ndash211 1996
[21] C B Castells and P W Carr ldquoA study of the thermodynam-ics and influence of temperature on chiral high-performanceliquid chromatographic separations using cellulose tris(35-dimethylphenylcarbamate) coated zirconia stationary phasesrdquoChromatographia vol 52 no 9-10 pp 535ndash542 2000
[22] K Fulde and A W Frahm ldquoTemperature-induced inversion ofelution order in the enantioseparation of sotalol on a cellobio-hydrolase I-based stationary phaserdquo Journal of ChromatographyA vol 858 no 1 pp 33ndash43 1999
[23] B Yao F Zhan G Yu et al ldquoTemperature-induced inversion ofelution order in the chromatographic enantioseparation of 111015840-bi-2-naphthol on an immobilized polysaccharide-based chiralstationary phaserdquo Journal of Chromatography A vol 1216 no28 pp 5429ndash5435 2009
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CatalystsJournal of
2 Chromatography Research International
COOH
H3C
CH3
CH3
lowast
Figure 1 Ibuprofen molecular structure
molar mass 24644 gmol and purity 97) were purchasedfrom Sigma-Aldrich The chiral analytical column (250mmtimes 46mm) was purchased from Phenomenex and originallypacked with silica (5120583m) coated with cellulose tris(35-dimethylphenylcarbamate)
22 Instrumentation The experiments were carried out ina HPLC system it consisted of a system controller (modelCBM-20A) an UV-vis detector (SPD-20A) and two pumps(LC-10AD)The components were originally purchased fromShimadzu Japan The column and mobile phase were tem-perature-controlled using a Quimis Q214M2 (Brazil) circu-lating water bath The elution order was determined by apolarimeter model P1010 (Japan)
23 Thermodynamic Parameters The resolution of racematewas studied by means of thermodynamic parameters VanrsquotHoff approach was used to obtain the enthalpy change (Δ119867)and entropy change (Δ119878) A similar approach was also usedto calculate the difference of enthalpy change (ΔΔ119867) andentropy change (ΔΔ119878) for the racemic ibuprofen respectivelyThese values are important to obtain the isoenantioselectivetemperature (119879iso) The determination of these parameterscan be based on the chromatographic parameters such asthe retention factor (119896
119894) and the selectivity (120572) To obtain
the isoenantioselective temperature it is necessary to knowthe porosity (120576) which was determined by moment analysis[10]
24 Chromatographic Parameters The retention factor is therelation between the number of analytes in stationary phaseand the molecule numbers in mobile phase This parameteris written in terms of analyte retention time (119905
119877119894) and column
dead time (1199050) as presented in [11]
119896119894=119905119877119894minus 1199050
1199050
= 120601119870119863119894 (1)
where 120601 represents the volume phase ratio between thevolume of stationary phase and mobile phase also equal to(1 minus 120576
119905)120576119905
The selectivity (120572) of separation of two components isdetermined by dividing their retention factors
120572 =
119896119895
119896119894
=
119905119877119895minus 1199050
119905119877119894minus 1199050
(2)
Chromatography resolution (119877119878) and number of plates
(119873119894) are other important parameters to establish the separa-
tion condition
119877119904=radic119873119894
4(119896119894
119896119894+ 1)(120572 minus 1
120572) = 1177
119905119877119895minus 119905119877119894
119908119894+ 119908119895
119873119894= 5545 (
119905119877119894
119908119894
)
2
(3)
where 119908119894is the peak width at half-height [12]
25 Effect of Temperature Equation (4) describes the linearrelation between natural logarithmof the retention factor andinverse of the temperature in which slope provides enthalpychange and the intercept supplies entropy change This ismodified Vanrsquot Hoff equation where 119870
119863119894from the original
equation was substituted for 119896119894 The parameters ΔΔ119867 and
ΔΔ119878 can be obtained analogously for (4) as shown in (5)These parameters represent the difference between the lessand the more retained compounds ldquo119894rdquo and ldquo119895rdquo respectively[13ndash15]
ln 119896119894= minus1
119879
Δ1198670
119894
119877+Δ1198780
119894
119877+ ln 1 minus 120576120576 (4)
ln120572 = minus 1119879
ΔΔ1198670
119895119894
119877+
ΔΔ1198780
119895119894
119877 (5)
where 119879 is temperature and 119877 is gas constantThe last term of (4) is related to the physical properties of
the stationary phase thus it can be considered as a constantsince its limitations are not exceeded If one simplifies thefirst absolute moment the total porosity can be obtainedexperimentallyTherefore total porosity is determined by (6)in which ] is superficial velocity and 119871 is bed length [10 14 15]
119905119877=119871
V120576 (6)
Isoenantioselective temperature (119879iso) is the condition inwhich the separation does not occur due to both compoundsrsquocoelute If the condition 120572 = 1 is applied in (5) it is possibleto write (7) as follows
119879iso =ΔΔ1198670
119895119894
ΔΔ1198780
119895119894
(7)
3 Results and Discussion
31 Resolution Conditions and Elution Order The resolutionconditions were based on [16ndash18] at which cellulose tris(35-dimethylphenylcarbamate) is the chiral selector Thus itwas decided to use a longer column (250mm times 46mm)packed with smaller particles (5 120583m) Both parameters havecontributed to increasing efficiency
Some mobile phases were tested to resolve the racemicmixture but only the mobile phase based on hexane pro-moted satisfactory results The mobile phase composed of
Chromatography Research International 3
Table 1 Chromatographic parameters of racemic ibuprofen separa-tion at 30815 K column (250mmtimes 46mm) packed with cellulosetris(35-dimethylphenylcarbamate)
Mobile phase 120572 119877119878119873119894119873119895
Hexaneisopropyl alcohol (991) 120 455 12976 12355
0 3 6 9 12 15 18 21 2400
0 3 6 9 12 15 18 21 2400
R-(minus)-ibuprofenS-(+)-ibuprofen
Det
ecto
r sig
nal (
mAU
)D
etec
tor s
igna
l (m
AU)
Time (minute)
Time (minute)
TTBB
80
60
40
20
40
32
24
16
08
times105
times104
Figure 2 Chromatograms of ibuprofen enantiomeric resolution at30815 K and 05 gmL and TTBB Flow ratio 1mLmin wavelength220 nm for ibuprofen and 254 nm for TTBB mobile phase hex-aneisopropyl alcohol (991)
hexane and isopropyl alcohol in the proportion 991 waschosen for chiral resolution Trifluoroacetic acid (TFA) wasalso used as an additive its proportion on mobile phasewas 01 in volumetric base All the conditions set forthe chromatographic resolution provided values of 120572 and119873119894above minimum levels required for effective chromato-
graphic resolution (120572 gt 120 119877119878gt 150 and 119873
119894gt 2000)
Table 1 summarizes all the mentioned values [19]After setting the separation conditions the elution order
was defined through a polarimetric technique For this theHPLC was used in batch mode to resolve the racemic mix-ture in R-ibuprofen and S-ibuprofen The rotary evaporatorreduced each sample for the polarimeter sample cell volumeA calibration curve provided the concentration of bothsamples 04 gL for S-ibuprofen and 111 gL for R-ibuprofenFinally the polarimeter identified the less and more retainedcompounds as (minus)-ibuprofen and (+)-ibuprofen respectivelyThus in Figure 2 the first peak is R-(minus)-ibuprofen while thesecond peak is S-(+)-ibuprofen
32 Total Porosity Porosity was calculated from the firstmoment method (6) This method requires a tracer com-pound small enough to pass through both particle and bedvoids TTBB was used to determine the porosity of chiral
00 02 04 06 08 100
3
6
9
12
15
t998400 R(m
in)
1 (mincm)
Figure 3 Total porosity
Table 2 Retention factor obtained in racemic ibuprofen separation
119879 (K) 119896119894
119896119895
120572
28815 472 543 11529315 488 568 11629815 511 596 11730315 538 637 11830815 574 690 120
columns packed with cellulose tris(35-dimethylphenyl-carbamate) The flow rate was changed from 02 up to16mLmin with a 02mLmin step The results are shown inFigure 3
The slope presented in Figure 3 provides the value of0647 for porosity
33 Thermodynamic Parameters The adsorption phenome-non of the enantiomeric compounds is macroscopic ther-modynamic quantities which does not consider the surfaceheterogeneity of the stationary phase and the associateddistinct adsorption behavior of enantiomers at different sitesUnder the circumstances Vanrsquot Hoff analysis is useful todetermine global information about the phenomenon [1]
Using (4) modified Vanrsquot Hoff equation one can obtainthe thermodynamic parameters The temperatures chosenwere 28815 29315 29815 30315 and 30815 K At each tem-perature racemic ibuprofen samples were injected at 05 gLFigure 4 and Table 2 present a summary of chromatogramsand chromatographic values obtained from these resolutions
In Figure 4 an increase in retention time value wasobserved as temperature rises This behavior has beenreported in literature however it is not the most commonone [1] This condition will be discussed later in this paper
The retention factors from Table 2 were used to plotFigure 5 From this figure and utilizing (4) it was possible toobtain Δ119867 and Δ119878 for ibuprofen enantiomers as presentedin Table 3 The errors for enthalpy and entropy change wererespectively 6 and 9
4 Chromatography Research International
0 6 12 18 240
0 6 12 18 24
0 6 12 18 24
0 6 12 18 24
0 6 12 18 24
Det
ecto
r res
pons
e (m
UA)
Time (minute)
8
4
0
8
4
0
8
4
0
8
4
0
8
4
288K
293K
298K
303K
308K
times105
times105
times105
times105
times105
Figure 4 Chromatograms of the racemic ibuprofen at severaltemperatures Flow rate 1mLmin
Table 3 Thermodynamic parameters of racemic ibuprofenadsorbed on cellulose tris(35-dimethylphenylcarbamate)
Compound Δ119867 (kJmol) Δ119878 (kJKsdotmol) 1198772
R-(minus)-ibuprofen 721 4288 0975S-(+)-ibuprofen 876 4940 0972
Both relations presented in Figure 4 are linear suggestingthat multiple mechanisms of retention do not occur [19 20]Furthermore Δ119867 of compounds is lower than 50 kJmoldemonstrating physical adsorption [11] The interactions ofphysisorption are characterized by relatively weak bondsOtherwise it would be necessary to modify the chromato-graphic system to elute analytes
According to [1] the adsorption phenomenon in liquidchromatographic enantiomer resolution is driven by (mostlyelectrostatic type) noncovalent interactionsThermodynamicquantities have shown negative heats of adsorption for awide variety of different mobile phase stationary phaseand analyte Additionally there is a decrease in retentiontime as temperature rises this occurs due to exothermiccharacteristic of adsorption as [1] alsomentioned that inmostof cases the compensation effect (also called enthalpy-entropycompensation) occurs However both enthalpy changes fromTable 3 presented positive values indicating an endothermicphenomenon Furthermore the retention times in Figure 4increase together as temperature rises This aspect can belinked with a favorable entropy contribution This indicatesthat when the analyte is bound to the stationary phase thesolvent molecules overload the adsorption site favoring theentropy increase
00032 00033 00034 0003515
16
17
18
19
20
R-(minus)-ibuprofenS-(+)-ibuprofen
1T (1K)
ln(k)
Figure 5 Vanrsquot Hoff plots for the determination of Δ119867 and Δ119878
00032 00033 00034 00035010
012
014
016
018
020
1T (1K)
ln(120572)
Figure 6 Linearization for determining of ΔΔ119867 and ΔΔ119878
The selectivity from Table 2 was also employed to analyzethe separation betweenR-(minus)-ibuprofen and S-(+)-ibuprofenParameters ΔΔ119867 and ΔΔ119878 were calculated by means of (5)The linearization proposal for this equation is presented inFigure 6
The linearization of ln(120572) versus 1119879 provided values of155 kJmol and 652 J(molsdotK) for ΔΔ119867 and ΔΔ119878 respec-tively and it also presented a 119904-squared of 0915 Error forΔΔ119867 was 12 and error for ΔΔ119878 was 15 Equation (7)provided 23738 K for 119879iso
Thermodynamic parameters are global informationabout the adsorption mechanism in a chromatographic col-umn The adsorption phenomenon involved in this processdepends on solute type mobile phase and stationary phase[1] For enantiomeric separation the adsorption mechanismis related to the chiral recognition According to informationfrom Figure 6 the adsorption is controlled by entropy(|119879 sdot ΔΔ119878| gt |ΔΔ119867|) because entropy contribution is more
Chromatography Research International 5
relevant than enthalpy contribution for the ibuprofen re-tention mechanism in cellulose tris(35-dimethylphenylcar-bamate)
However the separation will not be driven by entropy forall temperature ranges this happens due to 119879iso it is a bound-ary temperature for driven forces in this case This becomesevident when the conditions for 119879iso are applied in Gibbs-Helmholtz equation and the result is zero for energy change(Δ119866) For this case adsorption phenomenon at temperaturesbelow 119879iso 23738 K will be driven by entropy on the otherhand temperatures above 119879iso will be driven by enthalpy It iscommon that the adsorption phenomenon is exothermic andit occurs above 119879iso [18 20ndash23] Probably the elution order ofcompounds could be inverted in temperature lower than119879isoMoreover the phenomenon would be controlled by enthalpychange the selectivity would decrease as temperature risesand the adsorption would be exothermic if ibuprofen wereseparated below 119879iso [20 22 23]
4 Conclusions
Racemic ibuprofen can be separated using a chiral stationaryphase based on cellulose tris(35-dimethylphenylcarbamate)and a high nonpolar mobile phase The mobile phase com-posed of hexane (99) and isopropyl alcohol (1)was chosento separate the mixture Trichloroacetic acid at 01 wasemployed as an additive on this configuration of mobilephase and stationary phase the S-(+)-ibuprofen is the mostretained enantiomer
Thermodynamic parameters obtained from Figure 4demonstrated that the adsorption is physical and the separa-tion phenomenon is endothermic It shows that high temper-atures favored the separation Furthermore the parametersfrom Figure 5 show that phenomenon of separation is con-trolled by entropy (|119879 sdotΔΔ119878| gt |ΔΔ119867|) at temperatures above119879iso
Nomenclature
Symbols
ΔΔ119867 Variation of enthalpy change betweenmore and less retained compound (Jmol)
ΔΔ119878 Variation of entropy change between moreand less retained compound (JKsdotmol)
Δ119867 Standard enthalpy change (Jmol)Δ119866 Standard Gibbs free energy change (Jmol)Δ119878 Standard entropy change (JKsdotmol)119896119894 Retention factor of the least retained
compound119896119895 Retention factor of the most retained
compound119871 Column length (cm)119873119894 Number of plates of the least retained
compound119873119895 Number of plates of the most retained
compound119877 Universal gas constant (83144 JmolsdotK)119877119878 Resolution
119879 Absolute temperature (K)1199050 Column dead time (min)119879iso Isoenantioselective temperature (K)119905119877119894 Retention time of the least retainedcompound plus dead time (min)
119905119877119895 Retention time of the most retainedcompound plus dead time (min)
119908119894 Peak width at half-height of the least
retained compound119908119895 Peak width at half-height of the mostretained compound
Greek Letters
120572 Selectivity120576 Porosity] Superficial velocity (cmmin)
Competing Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The financial support of this research by CNPq (Brazil) isgratefully acknowledged
References
[1] M Lammerhofer ldquoChiral recognition by enantioselective liquidchromatography mechanisms and modern chiral stationaryphasesrdquo Journal of Chromatography A vol 1217 no 6 pp 814ndash856 2010
[2] I Ali S D Alam Z A Al-Othman and J A Farooqi ldquoRecentadvances in SPE-chiral-HPLC methods for enantiomeric sep-aration of chiral drugs in biological samplesrdquo Journal of Chro-matographic Science vol 51 no 7 pp 645ndash654 2013
[3] J S Yoon D-C Jeong J-W Oh et al ldquoThe effects and safetyof dexibuprofen compared with ibuprofen in febrile childrencaused by upper respiratory tract infectionrdquo British Journal ofClinical Pharmacology vol 66 no 6 pp 854ndash860 2008
[4] M Venu Madhav and C B Ching ldquoStudy on the enzymatichydrolysis of racemic methyl ibuprofen esterrdquo Journal of Chem-ical Technology and Biotechnology vol 76 no 9 pp 941ndash9482001
[5] M Yousefi M Mohammadi and Z Habibi ldquoEnantioselectiveresolution of racemic ibuprofen esters using different lipasesimmobilized on octyl sepharoserdquo Journal of Molecular CatalysisB Enzymatic vol 104 pp 87ndash94 2014
[6] H Li X Jiang W Xu Y Chen W Yu and J Xu ldquoNumer-ical determination of non-Langmuirian adsorption isothermsof ibuprofen enantiomers on Chiralcel OD column usingultraviolet-circular dichroism dual detectorrdquo Journal of Chro-matography A vol 1435 pp 92ndash99 2016
[7] Z Pataj I Ilisz A Aranyi et al ldquoLC separation of 120574-amino acidenantiomersrdquo Chromatographia vol 71 no 1 pp S13ndashS19 2010
[8] A Cavazzini L Pasti A Massi N Marchetti and F DondildquoRecent applications in chiral high performance liquid chro-matography a reviewrdquo Analytica Chimica Acta vol 706 no 2pp 205ndash222 2011
6 Chromatography Research International
[9] I Ilisz N Grecso M Palko F Fulop W Lindner and A PeterldquoStructural and temperature effects on enantiomer separationsof bicyclo[222]octane-based 3-amino-2-carboxylic acids oncinchona alkaloid-based zwitterionic chiral stationary phasesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 98 pp130ndash139 2014
[10] M A Cremasco B J Hritzko Y Xie and N H L WangldquoParameters estimation for amino acids adsorption in a fixedbed by moment analysisrdquo Brazilian Journal of Chemical Engi-neering vol 18 no 2 pp 181ndash194 2001
[11] A Seidel-MorgensternM Schulte andA Epping ldquoFundamen-tals and general terminologyrdquo in Preparative Chromatographypp 7ndash46 2nd edition 2012
[12] C H Collins G L Braga and P S Bonato Fundamentos deCromatografia Unicamp 2006
[13] A L Myers and J M Prausnitz ldquoThermodynamics of mixed-gas adsorptionrdquo AIChE Journal vol 11 no 1 pp 121ndash127 1965
[14] D M Ruthven Principles of Adsorption and Adsorption Pro-cesses John Wiley amp Sons 1984
[15] G Guiochon A Felinger and D G Shirazi Fundamentals ofPreparative and Nonlinear Chromatography Academic Press2006
[16] ADucretM Trani P Pepin andR Lortie ldquoComparison of twoHPLC techniques for monitoring enantioselective reactions forthe resolution of (RS)-ibuprofen chiral HPLC vs achiral HPLClinked to an optical rotation detectorrdquoBiotechnology Techniquesvol 9 no 8 pp 591ndash596 1995
[17] P S Bonato M P F M Del Lama and R de Carvalho ldquoEnan-tioselective determination of ibuprofen in plasma by high-performance liquid chromatography-electrospray mass spec-trometryrdquo Journal of Chromatography B Analytical Technologiesin the Biomedical and Life Sciences vol 796 no 2 pp 413ndash4202003
[18] W M Ferrari and M A Cremasco ldquoThermodynamic studyof the separation of racemic ibuprofen by chiral liquid chro-matographrdquo in Anais do XX Congresso Brasileiro de EngenhariaQuımicamdashCOBEQ 2014 vol 1 Blucher Sao Paulo Brazil 2015
[19] V R Meyer Practical High-Performance Liquid Chromatogra-phy John Wiley amp Sons 2013
[20] T D Booth and I W Wainer ldquoMechanistic investigationinto the enantioselective separation of mexiletine and relatedcompounds chromatographed on an amylose tris(35-dimeth-ylphenylcarbamate) chiral stationary phaserdquo Journal of Chro-matography A vol 741 no 2 pp 205ndash211 1996
[21] C B Castells and P W Carr ldquoA study of the thermodynam-ics and influence of temperature on chiral high-performanceliquid chromatographic separations using cellulose tris(35-dimethylphenylcarbamate) coated zirconia stationary phasesrdquoChromatographia vol 52 no 9-10 pp 535ndash542 2000
[22] K Fulde and A W Frahm ldquoTemperature-induced inversion ofelution order in the enantioseparation of sotalol on a cellobio-hydrolase I-based stationary phaserdquo Journal of ChromatographyA vol 858 no 1 pp 33ndash43 1999
[23] B Yao F Zhan G Yu et al ldquoTemperature-induced inversion ofelution order in the chromatographic enantioseparation of 111015840-bi-2-naphthol on an immobilized polysaccharide-based chiralstationary phaserdquo Journal of Chromatography A vol 1216 no28 pp 5429ndash5435 2009
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
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Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
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Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
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Analytical ChemistryInternational Journal of
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Quantum Chemistry
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Organic Chemistry International
ElectrochemistryInternational Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
Chromatography Research International 3
Table 1 Chromatographic parameters of racemic ibuprofen separa-tion at 30815 K column (250mmtimes 46mm) packed with cellulosetris(35-dimethylphenylcarbamate)
Mobile phase 120572 119877119878119873119894119873119895
Hexaneisopropyl alcohol (991) 120 455 12976 12355
0 3 6 9 12 15 18 21 2400
0 3 6 9 12 15 18 21 2400
R-(minus)-ibuprofenS-(+)-ibuprofen
Det
ecto
r sig
nal (
mAU
)D
etec
tor s
igna
l (m
AU)
Time (minute)
Time (minute)
TTBB
80
60
40
20
40
32
24
16
08
times105
times104
Figure 2 Chromatograms of ibuprofen enantiomeric resolution at30815 K and 05 gmL and TTBB Flow ratio 1mLmin wavelength220 nm for ibuprofen and 254 nm for TTBB mobile phase hex-aneisopropyl alcohol (991)
hexane and isopropyl alcohol in the proportion 991 waschosen for chiral resolution Trifluoroacetic acid (TFA) wasalso used as an additive its proportion on mobile phasewas 01 in volumetric base All the conditions set forthe chromatographic resolution provided values of 120572 and119873119894above minimum levels required for effective chromato-
graphic resolution (120572 gt 120 119877119878gt 150 and 119873
119894gt 2000)
Table 1 summarizes all the mentioned values [19]After setting the separation conditions the elution order
was defined through a polarimetric technique For this theHPLC was used in batch mode to resolve the racemic mix-ture in R-ibuprofen and S-ibuprofen The rotary evaporatorreduced each sample for the polarimeter sample cell volumeA calibration curve provided the concentration of bothsamples 04 gL for S-ibuprofen and 111 gL for R-ibuprofenFinally the polarimeter identified the less and more retainedcompounds as (minus)-ibuprofen and (+)-ibuprofen respectivelyThus in Figure 2 the first peak is R-(minus)-ibuprofen while thesecond peak is S-(+)-ibuprofen
32 Total Porosity Porosity was calculated from the firstmoment method (6) This method requires a tracer com-pound small enough to pass through both particle and bedvoids TTBB was used to determine the porosity of chiral
00 02 04 06 08 100
3
6
9
12
15
t998400 R(m
in)
1 (mincm)
Figure 3 Total porosity
Table 2 Retention factor obtained in racemic ibuprofen separation
119879 (K) 119896119894
119896119895
120572
28815 472 543 11529315 488 568 11629815 511 596 11730315 538 637 11830815 574 690 120
columns packed with cellulose tris(35-dimethylphenyl-carbamate) The flow rate was changed from 02 up to16mLmin with a 02mLmin step The results are shown inFigure 3
The slope presented in Figure 3 provides the value of0647 for porosity
33 Thermodynamic Parameters The adsorption phenome-non of the enantiomeric compounds is macroscopic ther-modynamic quantities which does not consider the surfaceheterogeneity of the stationary phase and the associateddistinct adsorption behavior of enantiomers at different sitesUnder the circumstances Vanrsquot Hoff analysis is useful todetermine global information about the phenomenon [1]
Using (4) modified Vanrsquot Hoff equation one can obtainthe thermodynamic parameters The temperatures chosenwere 28815 29315 29815 30315 and 30815 K At each tem-perature racemic ibuprofen samples were injected at 05 gLFigure 4 and Table 2 present a summary of chromatogramsand chromatographic values obtained from these resolutions
In Figure 4 an increase in retention time value wasobserved as temperature rises This behavior has beenreported in literature however it is not the most commonone [1] This condition will be discussed later in this paper
The retention factors from Table 2 were used to plotFigure 5 From this figure and utilizing (4) it was possible toobtain Δ119867 and Δ119878 for ibuprofen enantiomers as presentedin Table 3 The errors for enthalpy and entropy change wererespectively 6 and 9
4 Chromatography Research International
0 6 12 18 240
0 6 12 18 24
0 6 12 18 24
0 6 12 18 24
0 6 12 18 24
Det
ecto
r res
pons
e (m
UA)
Time (minute)
8
4
0
8
4
0
8
4
0
8
4
0
8
4
288K
293K
298K
303K
308K
times105
times105
times105
times105
times105
Figure 4 Chromatograms of the racemic ibuprofen at severaltemperatures Flow rate 1mLmin
Table 3 Thermodynamic parameters of racemic ibuprofenadsorbed on cellulose tris(35-dimethylphenylcarbamate)
Compound Δ119867 (kJmol) Δ119878 (kJKsdotmol) 1198772
R-(minus)-ibuprofen 721 4288 0975S-(+)-ibuprofen 876 4940 0972
Both relations presented in Figure 4 are linear suggestingthat multiple mechanisms of retention do not occur [19 20]Furthermore Δ119867 of compounds is lower than 50 kJmoldemonstrating physical adsorption [11] The interactions ofphysisorption are characterized by relatively weak bondsOtherwise it would be necessary to modify the chromato-graphic system to elute analytes
According to [1] the adsorption phenomenon in liquidchromatographic enantiomer resolution is driven by (mostlyelectrostatic type) noncovalent interactionsThermodynamicquantities have shown negative heats of adsorption for awide variety of different mobile phase stationary phaseand analyte Additionally there is a decrease in retentiontime as temperature rises this occurs due to exothermiccharacteristic of adsorption as [1] alsomentioned that inmostof cases the compensation effect (also called enthalpy-entropycompensation) occurs However both enthalpy changes fromTable 3 presented positive values indicating an endothermicphenomenon Furthermore the retention times in Figure 4increase together as temperature rises This aspect can belinked with a favorable entropy contribution This indicatesthat when the analyte is bound to the stationary phase thesolvent molecules overload the adsorption site favoring theentropy increase
00032 00033 00034 0003515
16
17
18
19
20
R-(minus)-ibuprofenS-(+)-ibuprofen
1T (1K)
ln(k)
Figure 5 Vanrsquot Hoff plots for the determination of Δ119867 and Δ119878
00032 00033 00034 00035010
012
014
016
018
020
1T (1K)
ln(120572)
Figure 6 Linearization for determining of ΔΔ119867 and ΔΔ119878
The selectivity from Table 2 was also employed to analyzethe separation betweenR-(minus)-ibuprofen and S-(+)-ibuprofenParameters ΔΔ119867 and ΔΔ119878 were calculated by means of (5)The linearization proposal for this equation is presented inFigure 6
The linearization of ln(120572) versus 1119879 provided values of155 kJmol and 652 J(molsdotK) for ΔΔ119867 and ΔΔ119878 respec-tively and it also presented a 119904-squared of 0915 Error forΔΔ119867 was 12 and error for ΔΔ119878 was 15 Equation (7)provided 23738 K for 119879iso
Thermodynamic parameters are global informationabout the adsorption mechanism in a chromatographic col-umn The adsorption phenomenon involved in this processdepends on solute type mobile phase and stationary phase[1] For enantiomeric separation the adsorption mechanismis related to the chiral recognition According to informationfrom Figure 6 the adsorption is controlled by entropy(|119879 sdot ΔΔ119878| gt |ΔΔ119867|) because entropy contribution is more
Chromatography Research International 5
relevant than enthalpy contribution for the ibuprofen re-tention mechanism in cellulose tris(35-dimethylphenylcar-bamate)
However the separation will not be driven by entropy forall temperature ranges this happens due to 119879iso it is a bound-ary temperature for driven forces in this case This becomesevident when the conditions for 119879iso are applied in Gibbs-Helmholtz equation and the result is zero for energy change(Δ119866) For this case adsorption phenomenon at temperaturesbelow 119879iso 23738 K will be driven by entropy on the otherhand temperatures above 119879iso will be driven by enthalpy It iscommon that the adsorption phenomenon is exothermic andit occurs above 119879iso [18 20ndash23] Probably the elution order ofcompounds could be inverted in temperature lower than119879isoMoreover the phenomenon would be controlled by enthalpychange the selectivity would decrease as temperature risesand the adsorption would be exothermic if ibuprofen wereseparated below 119879iso [20 22 23]
4 Conclusions
Racemic ibuprofen can be separated using a chiral stationaryphase based on cellulose tris(35-dimethylphenylcarbamate)and a high nonpolar mobile phase The mobile phase com-posed of hexane (99) and isopropyl alcohol (1)was chosento separate the mixture Trichloroacetic acid at 01 wasemployed as an additive on this configuration of mobilephase and stationary phase the S-(+)-ibuprofen is the mostretained enantiomer
Thermodynamic parameters obtained from Figure 4demonstrated that the adsorption is physical and the separa-tion phenomenon is endothermic It shows that high temper-atures favored the separation Furthermore the parametersfrom Figure 5 show that phenomenon of separation is con-trolled by entropy (|119879 sdotΔΔ119878| gt |ΔΔ119867|) at temperatures above119879iso
Nomenclature
Symbols
ΔΔ119867 Variation of enthalpy change betweenmore and less retained compound (Jmol)
ΔΔ119878 Variation of entropy change between moreand less retained compound (JKsdotmol)
Δ119867 Standard enthalpy change (Jmol)Δ119866 Standard Gibbs free energy change (Jmol)Δ119878 Standard entropy change (JKsdotmol)119896119894 Retention factor of the least retained
compound119896119895 Retention factor of the most retained
compound119871 Column length (cm)119873119894 Number of plates of the least retained
compound119873119895 Number of plates of the most retained
compound119877 Universal gas constant (83144 JmolsdotK)119877119878 Resolution
119879 Absolute temperature (K)1199050 Column dead time (min)119879iso Isoenantioselective temperature (K)119905119877119894 Retention time of the least retainedcompound plus dead time (min)
119905119877119895 Retention time of the most retainedcompound plus dead time (min)
119908119894 Peak width at half-height of the least
retained compound119908119895 Peak width at half-height of the mostretained compound
Greek Letters
120572 Selectivity120576 Porosity] Superficial velocity (cmmin)
Competing Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The financial support of this research by CNPq (Brazil) isgratefully acknowledged
References
[1] M Lammerhofer ldquoChiral recognition by enantioselective liquidchromatography mechanisms and modern chiral stationaryphasesrdquo Journal of Chromatography A vol 1217 no 6 pp 814ndash856 2010
[2] I Ali S D Alam Z A Al-Othman and J A Farooqi ldquoRecentadvances in SPE-chiral-HPLC methods for enantiomeric sep-aration of chiral drugs in biological samplesrdquo Journal of Chro-matographic Science vol 51 no 7 pp 645ndash654 2013
[3] J S Yoon D-C Jeong J-W Oh et al ldquoThe effects and safetyof dexibuprofen compared with ibuprofen in febrile childrencaused by upper respiratory tract infectionrdquo British Journal ofClinical Pharmacology vol 66 no 6 pp 854ndash860 2008
[4] M Venu Madhav and C B Ching ldquoStudy on the enzymatichydrolysis of racemic methyl ibuprofen esterrdquo Journal of Chem-ical Technology and Biotechnology vol 76 no 9 pp 941ndash9482001
[5] M Yousefi M Mohammadi and Z Habibi ldquoEnantioselectiveresolution of racemic ibuprofen esters using different lipasesimmobilized on octyl sepharoserdquo Journal of Molecular CatalysisB Enzymatic vol 104 pp 87ndash94 2014
[6] H Li X Jiang W Xu Y Chen W Yu and J Xu ldquoNumer-ical determination of non-Langmuirian adsorption isothermsof ibuprofen enantiomers on Chiralcel OD column usingultraviolet-circular dichroism dual detectorrdquo Journal of Chro-matography A vol 1435 pp 92ndash99 2016
[7] Z Pataj I Ilisz A Aranyi et al ldquoLC separation of 120574-amino acidenantiomersrdquo Chromatographia vol 71 no 1 pp S13ndashS19 2010
[8] A Cavazzini L Pasti A Massi N Marchetti and F DondildquoRecent applications in chiral high performance liquid chro-matography a reviewrdquo Analytica Chimica Acta vol 706 no 2pp 205ndash222 2011
6 Chromatography Research International
[9] I Ilisz N Grecso M Palko F Fulop W Lindner and A PeterldquoStructural and temperature effects on enantiomer separationsof bicyclo[222]octane-based 3-amino-2-carboxylic acids oncinchona alkaloid-based zwitterionic chiral stationary phasesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 98 pp130ndash139 2014
[10] M A Cremasco B J Hritzko Y Xie and N H L WangldquoParameters estimation for amino acids adsorption in a fixedbed by moment analysisrdquo Brazilian Journal of Chemical Engi-neering vol 18 no 2 pp 181ndash194 2001
[11] A Seidel-MorgensternM Schulte andA Epping ldquoFundamen-tals and general terminologyrdquo in Preparative Chromatographypp 7ndash46 2nd edition 2012
[12] C H Collins G L Braga and P S Bonato Fundamentos deCromatografia Unicamp 2006
[13] A L Myers and J M Prausnitz ldquoThermodynamics of mixed-gas adsorptionrdquo AIChE Journal vol 11 no 1 pp 121ndash127 1965
[14] D M Ruthven Principles of Adsorption and Adsorption Pro-cesses John Wiley amp Sons 1984
[15] G Guiochon A Felinger and D G Shirazi Fundamentals ofPreparative and Nonlinear Chromatography Academic Press2006
[16] ADucretM Trani P Pepin andR Lortie ldquoComparison of twoHPLC techniques for monitoring enantioselective reactions forthe resolution of (RS)-ibuprofen chiral HPLC vs achiral HPLClinked to an optical rotation detectorrdquoBiotechnology Techniquesvol 9 no 8 pp 591ndash596 1995
[17] P S Bonato M P F M Del Lama and R de Carvalho ldquoEnan-tioselective determination of ibuprofen in plasma by high-performance liquid chromatography-electrospray mass spec-trometryrdquo Journal of Chromatography B Analytical Technologiesin the Biomedical and Life Sciences vol 796 no 2 pp 413ndash4202003
[18] W M Ferrari and M A Cremasco ldquoThermodynamic studyof the separation of racemic ibuprofen by chiral liquid chro-matographrdquo in Anais do XX Congresso Brasileiro de EngenhariaQuımicamdashCOBEQ 2014 vol 1 Blucher Sao Paulo Brazil 2015
[19] V R Meyer Practical High-Performance Liquid Chromatogra-phy John Wiley amp Sons 2013
[20] T D Booth and I W Wainer ldquoMechanistic investigationinto the enantioselective separation of mexiletine and relatedcompounds chromatographed on an amylose tris(35-dimeth-ylphenylcarbamate) chiral stationary phaserdquo Journal of Chro-matography A vol 741 no 2 pp 205ndash211 1996
[21] C B Castells and P W Carr ldquoA study of the thermodynam-ics and influence of temperature on chiral high-performanceliquid chromatographic separations using cellulose tris(35-dimethylphenylcarbamate) coated zirconia stationary phasesrdquoChromatographia vol 52 no 9-10 pp 535ndash542 2000
[22] K Fulde and A W Frahm ldquoTemperature-induced inversion ofelution order in the enantioseparation of sotalol on a cellobio-hydrolase I-based stationary phaserdquo Journal of ChromatographyA vol 858 no 1 pp 33ndash43 1999
[23] B Yao F Zhan G Yu et al ldquoTemperature-induced inversion ofelution order in the chromatographic enantioseparation of 111015840-bi-2-naphthol on an immobilized polysaccharide-based chiralstationary phaserdquo Journal of Chromatography A vol 1216 no28 pp 5429ndash5435 2009
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
4 Chromatography Research International
0 6 12 18 240
0 6 12 18 24
0 6 12 18 24
0 6 12 18 24
0 6 12 18 24
Det
ecto
r res
pons
e (m
UA)
Time (minute)
8
4
0
8
4
0
8
4
0
8
4
0
8
4
288K
293K
298K
303K
308K
times105
times105
times105
times105
times105
Figure 4 Chromatograms of the racemic ibuprofen at severaltemperatures Flow rate 1mLmin
Table 3 Thermodynamic parameters of racemic ibuprofenadsorbed on cellulose tris(35-dimethylphenylcarbamate)
Compound Δ119867 (kJmol) Δ119878 (kJKsdotmol) 1198772
R-(minus)-ibuprofen 721 4288 0975S-(+)-ibuprofen 876 4940 0972
Both relations presented in Figure 4 are linear suggestingthat multiple mechanisms of retention do not occur [19 20]Furthermore Δ119867 of compounds is lower than 50 kJmoldemonstrating physical adsorption [11] The interactions ofphysisorption are characterized by relatively weak bondsOtherwise it would be necessary to modify the chromato-graphic system to elute analytes
According to [1] the adsorption phenomenon in liquidchromatographic enantiomer resolution is driven by (mostlyelectrostatic type) noncovalent interactionsThermodynamicquantities have shown negative heats of adsorption for awide variety of different mobile phase stationary phaseand analyte Additionally there is a decrease in retentiontime as temperature rises this occurs due to exothermiccharacteristic of adsorption as [1] alsomentioned that inmostof cases the compensation effect (also called enthalpy-entropycompensation) occurs However both enthalpy changes fromTable 3 presented positive values indicating an endothermicphenomenon Furthermore the retention times in Figure 4increase together as temperature rises This aspect can belinked with a favorable entropy contribution This indicatesthat when the analyte is bound to the stationary phase thesolvent molecules overload the adsorption site favoring theentropy increase
00032 00033 00034 0003515
16
17
18
19
20
R-(minus)-ibuprofenS-(+)-ibuprofen
1T (1K)
ln(k)
Figure 5 Vanrsquot Hoff plots for the determination of Δ119867 and Δ119878
00032 00033 00034 00035010
012
014
016
018
020
1T (1K)
ln(120572)
Figure 6 Linearization for determining of ΔΔ119867 and ΔΔ119878
The selectivity from Table 2 was also employed to analyzethe separation betweenR-(minus)-ibuprofen and S-(+)-ibuprofenParameters ΔΔ119867 and ΔΔ119878 were calculated by means of (5)The linearization proposal for this equation is presented inFigure 6
The linearization of ln(120572) versus 1119879 provided values of155 kJmol and 652 J(molsdotK) for ΔΔ119867 and ΔΔ119878 respec-tively and it also presented a 119904-squared of 0915 Error forΔΔ119867 was 12 and error for ΔΔ119878 was 15 Equation (7)provided 23738 K for 119879iso
Thermodynamic parameters are global informationabout the adsorption mechanism in a chromatographic col-umn The adsorption phenomenon involved in this processdepends on solute type mobile phase and stationary phase[1] For enantiomeric separation the adsorption mechanismis related to the chiral recognition According to informationfrom Figure 6 the adsorption is controlled by entropy(|119879 sdot ΔΔ119878| gt |ΔΔ119867|) because entropy contribution is more
Chromatography Research International 5
relevant than enthalpy contribution for the ibuprofen re-tention mechanism in cellulose tris(35-dimethylphenylcar-bamate)
However the separation will not be driven by entropy forall temperature ranges this happens due to 119879iso it is a bound-ary temperature for driven forces in this case This becomesevident when the conditions for 119879iso are applied in Gibbs-Helmholtz equation and the result is zero for energy change(Δ119866) For this case adsorption phenomenon at temperaturesbelow 119879iso 23738 K will be driven by entropy on the otherhand temperatures above 119879iso will be driven by enthalpy It iscommon that the adsorption phenomenon is exothermic andit occurs above 119879iso [18 20ndash23] Probably the elution order ofcompounds could be inverted in temperature lower than119879isoMoreover the phenomenon would be controlled by enthalpychange the selectivity would decrease as temperature risesand the adsorption would be exothermic if ibuprofen wereseparated below 119879iso [20 22 23]
4 Conclusions
Racemic ibuprofen can be separated using a chiral stationaryphase based on cellulose tris(35-dimethylphenylcarbamate)and a high nonpolar mobile phase The mobile phase com-posed of hexane (99) and isopropyl alcohol (1)was chosento separate the mixture Trichloroacetic acid at 01 wasemployed as an additive on this configuration of mobilephase and stationary phase the S-(+)-ibuprofen is the mostretained enantiomer
Thermodynamic parameters obtained from Figure 4demonstrated that the adsorption is physical and the separa-tion phenomenon is endothermic It shows that high temper-atures favored the separation Furthermore the parametersfrom Figure 5 show that phenomenon of separation is con-trolled by entropy (|119879 sdotΔΔ119878| gt |ΔΔ119867|) at temperatures above119879iso
Nomenclature
Symbols
ΔΔ119867 Variation of enthalpy change betweenmore and less retained compound (Jmol)
ΔΔ119878 Variation of entropy change between moreand less retained compound (JKsdotmol)
Δ119867 Standard enthalpy change (Jmol)Δ119866 Standard Gibbs free energy change (Jmol)Δ119878 Standard entropy change (JKsdotmol)119896119894 Retention factor of the least retained
compound119896119895 Retention factor of the most retained
compound119871 Column length (cm)119873119894 Number of plates of the least retained
compound119873119895 Number of plates of the most retained
compound119877 Universal gas constant (83144 JmolsdotK)119877119878 Resolution
119879 Absolute temperature (K)1199050 Column dead time (min)119879iso Isoenantioselective temperature (K)119905119877119894 Retention time of the least retainedcompound plus dead time (min)
119905119877119895 Retention time of the most retainedcompound plus dead time (min)
119908119894 Peak width at half-height of the least
retained compound119908119895 Peak width at half-height of the mostretained compound
Greek Letters
120572 Selectivity120576 Porosity] Superficial velocity (cmmin)
Competing Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The financial support of this research by CNPq (Brazil) isgratefully acknowledged
References
[1] M Lammerhofer ldquoChiral recognition by enantioselective liquidchromatography mechanisms and modern chiral stationaryphasesrdquo Journal of Chromatography A vol 1217 no 6 pp 814ndash856 2010
[2] I Ali S D Alam Z A Al-Othman and J A Farooqi ldquoRecentadvances in SPE-chiral-HPLC methods for enantiomeric sep-aration of chiral drugs in biological samplesrdquo Journal of Chro-matographic Science vol 51 no 7 pp 645ndash654 2013
[3] J S Yoon D-C Jeong J-W Oh et al ldquoThe effects and safetyof dexibuprofen compared with ibuprofen in febrile childrencaused by upper respiratory tract infectionrdquo British Journal ofClinical Pharmacology vol 66 no 6 pp 854ndash860 2008
[4] M Venu Madhav and C B Ching ldquoStudy on the enzymatichydrolysis of racemic methyl ibuprofen esterrdquo Journal of Chem-ical Technology and Biotechnology vol 76 no 9 pp 941ndash9482001
[5] M Yousefi M Mohammadi and Z Habibi ldquoEnantioselectiveresolution of racemic ibuprofen esters using different lipasesimmobilized on octyl sepharoserdquo Journal of Molecular CatalysisB Enzymatic vol 104 pp 87ndash94 2014
[6] H Li X Jiang W Xu Y Chen W Yu and J Xu ldquoNumer-ical determination of non-Langmuirian adsorption isothermsof ibuprofen enantiomers on Chiralcel OD column usingultraviolet-circular dichroism dual detectorrdquo Journal of Chro-matography A vol 1435 pp 92ndash99 2016
[7] Z Pataj I Ilisz A Aranyi et al ldquoLC separation of 120574-amino acidenantiomersrdquo Chromatographia vol 71 no 1 pp S13ndashS19 2010
[8] A Cavazzini L Pasti A Massi N Marchetti and F DondildquoRecent applications in chiral high performance liquid chro-matography a reviewrdquo Analytica Chimica Acta vol 706 no 2pp 205ndash222 2011
6 Chromatography Research International
[9] I Ilisz N Grecso M Palko F Fulop W Lindner and A PeterldquoStructural and temperature effects on enantiomer separationsof bicyclo[222]octane-based 3-amino-2-carboxylic acids oncinchona alkaloid-based zwitterionic chiral stationary phasesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 98 pp130ndash139 2014
[10] M A Cremasco B J Hritzko Y Xie and N H L WangldquoParameters estimation for amino acids adsorption in a fixedbed by moment analysisrdquo Brazilian Journal of Chemical Engi-neering vol 18 no 2 pp 181ndash194 2001
[11] A Seidel-MorgensternM Schulte andA Epping ldquoFundamen-tals and general terminologyrdquo in Preparative Chromatographypp 7ndash46 2nd edition 2012
[12] C H Collins G L Braga and P S Bonato Fundamentos deCromatografia Unicamp 2006
[13] A L Myers and J M Prausnitz ldquoThermodynamics of mixed-gas adsorptionrdquo AIChE Journal vol 11 no 1 pp 121ndash127 1965
[14] D M Ruthven Principles of Adsorption and Adsorption Pro-cesses John Wiley amp Sons 1984
[15] G Guiochon A Felinger and D G Shirazi Fundamentals ofPreparative and Nonlinear Chromatography Academic Press2006
[16] ADucretM Trani P Pepin andR Lortie ldquoComparison of twoHPLC techniques for monitoring enantioselective reactions forthe resolution of (RS)-ibuprofen chiral HPLC vs achiral HPLClinked to an optical rotation detectorrdquoBiotechnology Techniquesvol 9 no 8 pp 591ndash596 1995
[17] P S Bonato M P F M Del Lama and R de Carvalho ldquoEnan-tioselective determination of ibuprofen in plasma by high-performance liquid chromatography-electrospray mass spec-trometryrdquo Journal of Chromatography B Analytical Technologiesin the Biomedical and Life Sciences vol 796 no 2 pp 413ndash4202003
[18] W M Ferrari and M A Cremasco ldquoThermodynamic studyof the separation of racemic ibuprofen by chiral liquid chro-matographrdquo in Anais do XX Congresso Brasileiro de EngenhariaQuımicamdashCOBEQ 2014 vol 1 Blucher Sao Paulo Brazil 2015
[19] V R Meyer Practical High-Performance Liquid Chromatogra-phy John Wiley amp Sons 2013
[20] T D Booth and I W Wainer ldquoMechanistic investigationinto the enantioselective separation of mexiletine and relatedcompounds chromatographed on an amylose tris(35-dimeth-ylphenylcarbamate) chiral stationary phaserdquo Journal of Chro-matography A vol 741 no 2 pp 205ndash211 1996
[21] C B Castells and P W Carr ldquoA study of the thermodynam-ics and influence of temperature on chiral high-performanceliquid chromatographic separations using cellulose tris(35-dimethylphenylcarbamate) coated zirconia stationary phasesrdquoChromatographia vol 52 no 9-10 pp 535ndash542 2000
[22] K Fulde and A W Frahm ldquoTemperature-induced inversion ofelution order in the enantioseparation of sotalol on a cellobio-hydrolase I-based stationary phaserdquo Journal of ChromatographyA vol 858 no 1 pp 33ndash43 1999
[23] B Yao F Zhan G Yu et al ldquoTemperature-induced inversion ofelution order in the chromatographic enantioseparation of 111015840-bi-2-naphthol on an immobilized polysaccharide-based chiralstationary phaserdquo Journal of Chromatography A vol 1216 no28 pp 5429ndash5435 2009
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
Chromatography Research International 5
relevant than enthalpy contribution for the ibuprofen re-tention mechanism in cellulose tris(35-dimethylphenylcar-bamate)
However the separation will not be driven by entropy forall temperature ranges this happens due to 119879iso it is a bound-ary temperature for driven forces in this case This becomesevident when the conditions for 119879iso are applied in Gibbs-Helmholtz equation and the result is zero for energy change(Δ119866) For this case adsorption phenomenon at temperaturesbelow 119879iso 23738 K will be driven by entropy on the otherhand temperatures above 119879iso will be driven by enthalpy It iscommon that the adsorption phenomenon is exothermic andit occurs above 119879iso [18 20ndash23] Probably the elution order ofcompounds could be inverted in temperature lower than119879isoMoreover the phenomenon would be controlled by enthalpychange the selectivity would decrease as temperature risesand the adsorption would be exothermic if ibuprofen wereseparated below 119879iso [20 22 23]
4 Conclusions
Racemic ibuprofen can be separated using a chiral stationaryphase based on cellulose tris(35-dimethylphenylcarbamate)and a high nonpolar mobile phase The mobile phase com-posed of hexane (99) and isopropyl alcohol (1)was chosento separate the mixture Trichloroacetic acid at 01 wasemployed as an additive on this configuration of mobilephase and stationary phase the S-(+)-ibuprofen is the mostretained enantiomer
Thermodynamic parameters obtained from Figure 4demonstrated that the adsorption is physical and the separa-tion phenomenon is endothermic It shows that high temper-atures favored the separation Furthermore the parametersfrom Figure 5 show that phenomenon of separation is con-trolled by entropy (|119879 sdotΔΔ119878| gt |ΔΔ119867|) at temperatures above119879iso
Nomenclature
Symbols
ΔΔ119867 Variation of enthalpy change betweenmore and less retained compound (Jmol)
ΔΔ119878 Variation of entropy change between moreand less retained compound (JKsdotmol)
Δ119867 Standard enthalpy change (Jmol)Δ119866 Standard Gibbs free energy change (Jmol)Δ119878 Standard entropy change (JKsdotmol)119896119894 Retention factor of the least retained
compound119896119895 Retention factor of the most retained
compound119871 Column length (cm)119873119894 Number of plates of the least retained
compound119873119895 Number of plates of the most retained
compound119877 Universal gas constant (83144 JmolsdotK)119877119878 Resolution
119879 Absolute temperature (K)1199050 Column dead time (min)119879iso Isoenantioselective temperature (K)119905119877119894 Retention time of the least retainedcompound plus dead time (min)
119905119877119895 Retention time of the most retainedcompound plus dead time (min)
119908119894 Peak width at half-height of the least
retained compound119908119895 Peak width at half-height of the mostretained compound
Greek Letters
120572 Selectivity120576 Porosity] Superficial velocity (cmmin)
Competing Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The financial support of this research by CNPq (Brazil) isgratefully acknowledged
References
[1] M Lammerhofer ldquoChiral recognition by enantioselective liquidchromatography mechanisms and modern chiral stationaryphasesrdquo Journal of Chromatography A vol 1217 no 6 pp 814ndash856 2010
[2] I Ali S D Alam Z A Al-Othman and J A Farooqi ldquoRecentadvances in SPE-chiral-HPLC methods for enantiomeric sep-aration of chiral drugs in biological samplesrdquo Journal of Chro-matographic Science vol 51 no 7 pp 645ndash654 2013
[3] J S Yoon D-C Jeong J-W Oh et al ldquoThe effects and safetyof dexibuprofen compared with ibuprofen in febrile childrencaused by upper respiratory tract infectionrdquo British Journal ofClinical Pharmacology vol 66 no 6 pp 854ndash860 2008
[4] M Venu Madhav and C B Ching ldquoStudy on the enzymatichydrolysis of racemic methyl ibuprofen esterrdquo Journal of Chem-ical Technology and Biotechnology vol 76 no 9 pp 941ndash9482001
[5] M Yousefi M Mohammadi and Z Habibi ldquoEnantioselectiveresolution of racemic ibuprofen esters using different lipasesimmobilized on octyl sepharoserdquo Journal of Molecular CatalysisB Enzymatic vol 104 pp 87ndash94 2014
[6] H Li X Jiang W Xu Y Chen W Yu and J Xu ldquoNumer-ical determination of non-Langmuirian adsorption isothermsof ibuprofen enantiomers on Chiralcel OD column usingultraviolet-circular dichroism dual detectorrdquo Journal of Chro-matography A vol 1435 pp 92ndash99 2016
[7] Z Pataj I Ilisz A Aranyi et al ldquoLC separation of 120574-amino acidenantiomersrdquo Chromatographia vol 71 no 1 pp S13ndashS19 2010
[8] A Cavazzini L Pasti A Massi N Marchetti and F DondildquoRecent applications in chiral high performance liquid chro-matography a reviewrdquo Analytica Chimica Acta vol 706 no 2pp 205ndash222 2011
6 Chromatography Research International
[9] I Ilisz N Grecso M Palko F Fulop W Lindner and A PeterldquoStructural and temperature effects on enantiomer separationsof bicyclo[222]octane-based 3-amino-2-carboxylic acids oncinchona alkaloid-based zwitterionic chiral stationary phasesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 98 pp130ndash139 2014
[10] M A Cremasco B J Hritzko Y Xie and N H L WangldquoParameters estimation for amino acids adsorption in a fixedbed by moment analysisrdquo Brazilian Journal of Chemical Engi-neering vol 18 no 2 pp 181ndash194 2001
[11] A Seidel-MorgensternM Schulte andA Epping ldquoFundamen-tals and general terminologyrdquo in Preparative Chromatographypp 7ndash46 2nd edition 2012
[12] C H Collins G L Braga and P S Bonato Fundamentos deCromatografia Unicamp 2006
[13] A L Myers and J M Prausnitz ldquoThermodynamics of mixed-gas adsorptionrdquo AIChE Journal vol 11 no 1 pp 121ndash127 1965
[14] D M Ruthven Principles of Adsorption and Adsorption Pro-cesses John Wiley amp Sons 1984
[15] G Guiochon A Felinger and D G Shirazi Fundamentals ofPreparative and Nonlinear Chromatography Academic Press2006
[16] ADucretM Trani P Pepin andR Lortie ldquoComparison of twoHPLC techniques for monitoring enantioselective reactions forthe resolution of (RS)-ibuprofen chiral HPLC vs achiral HPLClinked to an optical rotation detectorrdquoBiotechnology Techniquesvol 9 no 8 pp 591ndash596 1995
[17] P S Bonato M P F M Del Lama and R de Carvalho ldquoEnan-tioselective determination of ibuprofen in plasma by high-performance liquid chromatography-electrospray mass spec-trometryrdquo Journal of Chromatography B Analytical Technologiesin the Biomedical and Life Sciences vol 796 no 2 pp 413ndash4202003
[18] W M Ferrari and M A Cremasco ldquoThermodynamic studyof the separation of racemic ibuprofen by chiral liquid chro-matographrdquo in Anais do XX Congresso Brasileiro de EngenhariaQuımicamdashCOBEQ 2014 vol 1 Blucher Sao Paulo Brazil 2015
[19] V R Meyer Practical High-Performance Liquid Chromatogra-phy John Wiley amp Sons 2013
[20] T D Booth and I W Wainer ldquoMechanistic investigationinto the enantioselective separation of mexiletine and relatedcompounds chromatographed on an amylose tris(35-dimeth-ylphenylcarbamate) chiral stationary phaserdquo Journal of Chro-matography A vol 741 no 2 pp 205ndash211 1996
[21] C B Castells and P W Carr ldquoA study of the thermodynam-ics and influence of temperature on chiral high-performanceliquid chromatographic separations using cellulose tris(35-dimethylphenylcarbamate) coated zirconia stationary phasesrdquoChromatographia vol 52 no 9-10 pp 535ndash542 2000
[22] K Fulde and A W Frahm ldquoTemperature-induced inversion ofelution order in the enantioseparation of sotalol on a cellobio-hydrolase I-based stationary phaserdquo Journal of ChromatographyA vol 858 no 1 pp 33ndash43 1999
[23] B Yao F Zhan G Yu et al ldquoTemperature-induced inversion ofelution order in the chromatographic enantioseparation of 111015840-bi-2-naphthol on an immobilized polysaccharide-based chiralstationary phaserdquo Journal of Chromatography A vol 1216 no28 pp 5429ndash5435 2009
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
6 Chromatography Research International
[9] I Ilisz N Grecso M Palko F Fulop W Lindner and A PeterldquoStructural and temperature effects on enantiomer separationsof bicyclo[222]octane-based 3-amino-2-carboxylic acids oncinchona alkaloid-based zwitterionic chiral stationary phasesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 98 pp130ndash139 2014
[10] M A Cremasco B J Hritzko Y Xie and N H L WangldquoParameters estimation for amino acids adsorption in a fixedbed by moment analysisrdquo Brazilian Journal of Chemical Engi-neering vol 18 no 2 pp 181ndash194 2001
[11] A Seidel-MorgensternM Schulte andA Epping ldquoFundamen-tals and general terminologyrdquo in Preparative Chromatographypp 7ndash46 2nd edition 2012
[12] C H Collins G L Braga and P S Bonato Fundamentos deCromatografia Unicamp 2006
[13] A L Myers and J M Prausnitz ldquoThermodynamics of mixed-gas adsorptionrdquo AIChE Journal vol 11 no 1 pp 121ndash127 1965
[14] D M Ruthven Principles of Adsorption and Adsorption Pro-cesses John Wiley amp Sons 1984
[15] G Guiochon A Felinger and D G Shirazi Fundamentals ofPreparative and Nonlinear Chromatography Academic Press2006
[16] ADucretM Trani P Pepin andR Lortie ldquoComparison of twoHPLC techniques for monitoring enantioselective reactions forthe resolution of (RS)-ibuprofen chiral HPLC vs achiral HPLClinked to an optical rotation detectorrdquoBiotechnology Techniquesvol 9 no 8 pp 591ndash596 1995
[17] P S Bonato M P F M Del Lama and R de Carvalho ldquoEnan-tioselective determination of ibuprofen in plasma by high-performance liquid chromatography-electrospray mass spec-trometryrdquo Journal of Chromatography B Analytical Technologiesin the Biomedical and Life Sciences vol 796 no 2 pp 413ndash4202003
[18] W M Ferrari and M A Cremasco ldquoThermodynamic studyof the separation of racemic ibuprofen by chiral liquid chro-matographrdquo in Anais do XX Congresso Brasileiro de EngenhariaQuımicamdashCOBEQ 2014 vol 1 Blucher Sao Paulo Brazil 2015
[19] V R Meyer Practical High-Performance Liquid Chromatogra-phy John Wiley amp Sons 2013
[20] T D Booth and I W Wainer ldquoMechanistic investigationinto the enantioselective separation of mexiletine and relatedcompounds chromatographed on an amylose tris(35-dimeth-ylphenylcarbamate) chiral stationary phaserdquo Journal of Chro-matography A vol 741 no 2 pp 205ndash211 1996
[21] C B Castells and P W Carr ldquoA study of the thermodynam-ics and influence of temperature on chiral high-performanceliquid chromatographic separations using cellulose tris(35-dimethylphenylcarbamate) coated zirconia stationary phasesrdquoChromatographia vol 52 no 9-10 pp 535ndash542 2000
[22] K Fulde and A W Frahm ldquoTemperature-induced inversion ofelution order in the enantioseparation of sotalol on a cellobio-hydrolase I-based stationary phaserdquo Journal of ChromatographyA vol 858 no 1 pp 33ndash43 1999
[23] B Yao F Zhan G Yu et al ldquoTemperature-induced inversion ofelution order in the chromatographic enantioseparation of 111015840-bi-2-naphthol on an immobilized polysaccharide-based chiralstationary phaserdquo Journal of Chromatography A vol 1216 no28 pp 5429ndash5435 2009
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of