Influence of benzylamine on the resolution of ibuprofen with (+)-(R)-phenylethylamine via...

Influence of Benzylamine on the Resolution of Ibuprofen with(1)-(R)-Phenylethylamine via Supercritical Fluid ExtractionPETER MOLNAR,1 PETRA BOMBICZ,2 CSABA VARGA,1 LAURA BERECZKI,3 EDIT SZEKELY,1* GYORGY POKOL,3

ELEMER FOGASSY,4 AND BELA SIMANDI1

1Department of Chemical and Environmental Process Engineering, Budapest University of Technology and Economics,Budapest, Hungary

2Institute of Structural Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary3Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Budapest, Hungary4Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary

ABSTRACT The resolution of racemic ibuprofen was studied by partial diaster-eomer salt formation. The resolution was performed via two methods: resolution with(1)-(R)-phenylethylamine as chiral agent and resolution with a mixture of (1)-(R)-phe-nylethylamine and benzylamine. The diastereomers and unreacted enantiomers wereseparated by supercritical fluid extraction with carbon dioxide at 15 MPa and 338C. Theinfluence of the achiral benzylamine on the resolution efficiency was studied by varyingthe concentrations of the structurally related amines in their mixtures, keeping the summolar ratio of the amines to racemic ibuprofen constant at 0.55 6 0.02. The presence ofbenzylamine positively influenced the resolution efficiency at certain concentrations.The crystal structure of the salts of (1)-(R)-phenylethylamine with (2)-(R)-ibuprofenand (1)-(S)-ibuprofen, respectively, as well as the cocrystal of the benzylamine—ibupro-fen salt with neutral ibuprofen molecules are presented. These structures were deter-mined by single crystal X-ray diffraction, proving the significantly different stoichiome-try of the related amines with the chiral acid, in accordance with mass balance calcula-tions. Chirality 21:628–636, 2009. VVC 2008 Wiley-Liss, Inc.

KEY WORDS: achiral additive; resolution; supercritical fluid extraction; ibuprofen;(1)-(R)-phenylethylamine; benzylamine

INTRODUCTION

Research and development of resolution processes forenantiomer purification has been the focus of many groupssince the time of Pasteur. The primary goal is to achieve amore efficient and less time-consuming method of separa-tion, with minimal waste. Investigations into new aspectsof already existing model resolutions also play importantrole.

The resolution of ibuprofen, generally used as nonste-roidal antiinflammatory drug, is the topic of many publica-tions, including classical resolutions,1–5 enzyme-aided res-olutions and synthesis,6–8 or asymmetric synthesis reac-tions.9–11 Several new approaches adopting the use ofionic liquids also can be found in the literature.12–14 Sincethe introduction of supercritical fluid extraction (SFE) asan alternative green technology for optical isomer separa-tion,15 numerous trials have been made in the search fordifferent resolution systems. Valentine described a logicalsupercritical carbon dioxide- (scCO2) soluble resolutionagent design, as well as solubility determination and an insitu resolution of ibuprofen in scCO2.

16

One of the most interesting examples influencing a reso-lution, with the purpose of enhancing the separation effi-ciency using different additives, was discovered a decade

ago. The ‘‘Dutch Resolution’’ technique proved the impor-tance of the chiral and structurally similar additives to theoriginal resolving agent, which were incorporated in theprecipitated salts.17

Addition of achiral agents to the resolution systems wasfirst used only to keep one of the diastereomers in solutionaccording to Pope and Peachey.18 Some results verify thepossible positive effects of the achiral compounds. The re-solution of rac-phenylethylamine by its glutaric acid deriva-tive was outstandingly enhanced when achiral additiveswere present in 1:0.5:0.5 molar ratio of racemic compound:resolving agent:achiral additive, respectively.19 The influ-ence of achiral compounds is also discussed in severalpublications using achiral phase chromatography.20,21

‘‘Enantiomer self-disproportionation’’ is thought to be re-

*Correspondence to: Edit Szekely, Budafoki str. 8, Building F, BudapestH-1521, Hungary. E-mail: [email protected]

Contract grant sponsor: National Office for Research and Technology;Contract grant number: MU-00338/2003; Contract grant sponsor: Hungar-ian Research Grant (OTKA); Contract grant number: K72861.

Received for publication 19 March 2008; Accepted 16 July 2008DOI: 10.1002/chir.20655Published online 6 October 2008 in Wiley InterScience(www.interscience.wiley.com).

CHIRALITY 21:628–636 (2009)

VVC 2008 Wiley-Liss, Inc.

sponsible for the observed amplifications of the enantio-meric excess values in the case of enantiomer associa-tions.22 The use of achiral hydrochloric acid23 as well asan achiral support24 in the resolution of rac-tetramisole bySFE resulted in a significant improvement of the enan-tiomer separation.

The resolution of ibuprofen (1) with mixture of (1)-(R)-phenylethylamine (2) and benzylamine (3) was comparedwith the results obtained without achiral additive. Singlecrystal X-ray studies were performed on the salts of (1)-(R)-phenylethylamine crystallized with (2)-(R)-ibuprofen(4) and (1)-(S)-ibuprofen (5). The cocrystal resulted fromthe crystallization of the racemic ibuprofen with the achiralbenzylamine (6) has also been prepared for X-ray analysis.Our aim was to study the influence of different concentra-tions of the structurally related achiral amine on resolutionefficiency (FS).

MATERIALS AND METHODSMaterials

Racemic ibuprofen (2-(4-isobutylphenyl)-propionic acid)(1) and benzylamine (3) were purchased from Sigma-Aldrich Corp. (Budapest, Hungary). (1)-(R)-Phenylethyl-amine (2) was bought from Merck (Hohenbrunn, Ger-many). Carbon dioxide (99.5 w/w% pure) was supplied byLinde Ltd. (Budapest, Hungary). Ethanol and dichlorome-thane were delivered by Reanal Ltd. (Budapest, Hungary).Support, Perfil 250TM (expanded and milled perlite for use

as a filtering aid, specific surface area is 2.89 m2/g) waskindly given by Baumit Co. (Budapest, Hungary).

Single Crystal X-Ray Diffraction

The (1)-(R)-phenylethylamine (2)-(R)-(2-(4-isobutyl-phenyl)-propionate (4), (1)-(R)-phenylethylamine (1)-(S)-(2-(4-isobutylphenyl)-propionate (5), and benzylamine-(2-(4-isobutylphenyl)-propionate) (2-(4-isobutylphenyl)-propi-onic acid cocrystal (6) were crystallized from ethanol. Allwere colorless columns. Despite the slow and careful crys-tallization, the quality of the crystals was poor. Compound6 showed bad crystal quality, making it impossible torefine the structure to a low R value in the lack of reflec-tions in the high y region.

The crystals were mounted on a MiTeGen loop with par-athon oil. Cell parameters were determined by leastsquares of all reflections in the whole measured y range.Intensity data were collected on a RIGAKU RAXIS-RAPIDdiffractometer (graphite monochromator; Mo-Ka radiation,k 5 0.71073 A). Empirical absorption corrections wereapplied to the data. The structures were solved by directmethods.25 Anisotropic full-matrix least-squares refine-ments26,27 on F2 for all nonhydrogen atoms were per-formed. Neutral atomic scattering factors are taken fromthe International Tables for X-ray Crystallography.28 Crys-tallographic data, parameters of data collection, further-more the structure solution and refinement can be foundin Table 1.

TABLE 1. Summary of crystallographic data, data collections, structure determination, and refinement for (4), (5) and (6)

Salt (4) (5) (6)

Formula C13H17O2,C8H12N1 C13H17O2, C8H12N1 C13H18O2, C13H17O2, C7H10N1

Formula weight 327.45 327.45 519.70Crystal system Orthorhombic Orthorhombic TriclinicSpace group P212121 P212121 P-1a, b, c [A] a, b, g [8] 5.887(1) 6.884(1) 6.048(1)

15.257(4) 12.400(3) 13.193(1)22.235(6) 23.491(5) 19.243(1)

90.98(1)98.85(1)98.22(1)

V [A3] 1997.2(9) 2005.2(8) 1500.29(15)Z 4 4 2D(calc) [g cm23] 1.089 1.085 1.150l (MoKa) [mm21] 0.069 0.069 0.074F(000) 712 712 564Crystal size [mm] 0.25, 0.25, 0.50 0.25, 0.25, 0.75 0.12, 0.12, 0.50Temperature (K) 115 111 113Radiation [A] MoKa, 0.71073 MoKa, 0.71073 MoKa, 0.71073y Min–max [8] 3.1, 27.5 3.1, 27.5 2.1, 19.4Dataset 27:7; 219:19; 228:28 28:8; 216:16; 230:30 25:5; 212:12; 217:17Tot., uniq. data, R(int) 57854, 4572, 0.062 75017, 4572, 0.108 23691, 2561, 0.060Observed data [I > 2.0 r(I)] 2111 3068 2517Nref, Npar 4572, 226 4572, 223 2561, 354R, wR2, Goof 0.0464, 0.1073, 1.28 0.0743, 0.1931, 1.05 0.1328, 0.3673, 1.12Max. and Av. shift/error 0.03, 0.00 0.00, 0.00 0.00, 0.00Min. and max. resd. dens. [e A23] 20.65, 0.66 20.20, 0.27 20.35, 0.61

629INFLUENCE OF BENZYLAMINE ON RESOLUTION OF IBUPROFEN

Chirality DOI 10.1002/chir

There are no strong anomalous scattering centers in theinvestigated diastereomer salts (4 and 5), thus the deter-mination of the absolute configuration29 by single crystalX-ray diffraction is not reliable (Flack x is 0.3(17)) in 4and 0.5(23) in 5. As one or both of the starting materialswere enantiomerically pure, the absolute configurations ofthe salts are known. In spite of the bad crystal qualities,the hydrogen atomic positions could be located in the dif-ference maps. Hydrogen atoms were included in structurefactor calculations, but they were not refined. The iso-tropic displacement parameters of the hydrogen atomswere approximated from the U(eq) value of the atom theywere bonded.

Crystallographic data (excluding structure factors) forthe above crystal structures have been deposited with theCambridge Crystallographic Data Centre as supplemen-tary publication number CCDC 680215, CCDC 680216,and CCDC 680217.

General Resolution Process

The reaction scheme is shown in Figure 1.Calculated amounts of rac-1, (1)-(R)-2, and 3 were dis-

solved separately in 10 ml of ethanol, each. These solu-tions were combined and 1.5 g of Perfil 100TM, as inertsupport, was added to the clear solution. The organic sol-vent was evaporated at 408C in 100 mbar vacuum. Thesolid sample then was left at room temperature in a Petridish overnight. The next day the sample was loaded intothe extractor of a lab scale supercritical extraction unit.Approximately 600 g CO2/g rac-1 was used for the extrac-tion of unreacted enantiomers at 15 MPa and 338C (opti-mized in a previous work30). The average CO2 mass flowrate was 0.6–0.8 g CO2/s. The dissolved enantiomers((1)-(S)-1 rich mixture) were collected in a separator at 4MPa pressure and 408C. The internal volumes of the ex-tractor and separator were 25 ml, each. The remainingsalts were separated from the Perfil and were decomposedwith hydrochloric acid solution. The raffinate enantiomericmixture ((2)-(R)-1 rich mixture) was retrieved by classicalliquid–liquid extraction. The enantiomeric excess values ofthe extract and raffinate ibuprofen enantiomers weredetermined according to prior calibration of optical rota-tion data measured by a Perkin-Elmer 241 polarimeter,([a20

RD] 5 608, c 5 1 MeOH). Enantiomeric excess values(ee %) and yields (Y %) in the extracts (subscript Extr) andraffinates (subscript Raff), as well as the resolution effi-

ciency (FS) were calculated according to the followingterms:

eeExtr ¼ S � R

S þ R3 100 in the extract; ð1aÞ

eeRaff ¼ R � S

S þ R3 100 in the raffinate ð1bÞ

YExtr ¼ mExtr

mrac�IBU3 100 in the extract; ð2aÞ

YRaff ¼ mRaff

mrac�IBU3 100 in the raffinate ð2bÞ

FS ¼ YExtreeExtr þ YRaffeeRaff ð3Þ

where, S and R are the masses of the single enantiomers,mExtr and mRaff are the masses of enantiomeric mixtures inthe extracts and raffinates, mrac-IBU is the mass of the race-mic ibuprofen in the extractor, respectively. The concen-trations of the compounds in the solid sample wereexpressed by the terms of molar ratios (mrPhEA, mrBA,mrBASE), as follows:

mrPhEA ¼ nPhEAnrac�IBU

ð4Þ

mrBA ¼ nBAnrac�IBU

ð5Þ

mrBASE ¼ mrPhEA þmrBA; ð6Þ

where n is the molar amount of the compounds, subscriptsPhEA and BA regard to the (+)-(R)-phenylethylamine andbenzylamine respectively.

RESULTS AND DISCUSSIONStructural Study of the Ibuprofen Salts

The salts of ibuprofen with (1)-(R)-phenylethylamineand with benzylamine were crystallized from ethanol.

Fig. 1. The resolution of ibuprofen (1) with the mixture of (1)-(R)-phenylethylamine (2) and benzylamine (3).

630 MOLNAR ET AL.


In the crystallization experiments containing the chiralamine, both rac-1 and (1)-(S)-1 were used as startingmaterials to form crystals with (1)-(R)-2. In the absenceof strong anomalous scattering centers, the determinationof the absolute configuration by single crystal X-ray diffrac-tion is hardly reliable. However, as the amine starting ma-terial was enantiomerically pure in the crystallization withracemic 1, we can conclude that both of the chiral centers(C2 and C21) of the two components in 4 have the (R)configuration (Fig. 2a). Both the reacted amine and acidwere enantiomerically pure in the crystallization with (S)-1, thus the C21 chiral center has (R) configuration in thephenylethylamine and (S) configuration of the C2 chiralcenter in the ibuprofen in 5 (Fig. 2b). One ibuprofen anionand one (1)-(R)-2 cation crystallizes in the asymmetricunit of the crystals in the chiral space group P212121 (No.19.), orthorhombic crystal system. The unit cell dimen-sions are significantly different (Table 1) and at the sametime the cell volumes are similar, (1997.2(9) and 2005.2(8)A3) having the same chemical content. The calculated den-sities are also similar (1.089 and 1.085 g cm23), thus some-what closer packing is realized in the crystal of the (R,R)salt.

When the racemic mixture of ibuprofen was crystallizedwith achiral benzylamine, a cocrystal was formed (6). Itcontains the benzylamine—ibuprofen salt and a neutralibuprofen molecule (Fig. 2c). The crystal system is tri-clinic, the space group is P-1. The (R)- and (S)-1 anions,and (R) and (S) neutral ibuprofen molecules, as well as

the benzylamine cations are arranged around inversioncenters in the unit cell.

There is a one-dimensional infinite hydrogen bondednetwork running along the a crystallographic axis inall three crystals (Fig. 3). In the crystals of 4 and 5,the periodic unit is formed by two cations and twoanions (Figs. 3a–3d.). The columns of molecules havea core of strong hydrogen bonds (Table 2), whereasthe aromatic groups form an apolar coat around thehydrogen-bonded chain. Despite the configurationaldifference of the ibuprofen in the two crystal struc-tures, the N��H. . .O hydrogen bond system is thesame. The hydrogen bond loop can be described bygraph set analysis33 as R3

4 (10) (Figs. 4a–4b.). Besidethe three strong N��H. . .O type interactions, a weakC��H. . .O contact contributes to the forces keepingthe column together in the (R,R) crystal (4), whereasit is missing in the salt with mixed ionic configurations(5). Fitting of the (1)-(R)-phenylethylamine from bothstructures enhances the differences in the placementand conformation of the anions with different configu-ration (Fig. 5a).

In the cocrystal (6), six molecules form a turn of thecolumn: two benzylamine cations, two ibuprofen anions,and two neutral ibuprofen molecules with opposite con-figuration each (Figs. 3e and 3f). Alternating ionic andapolar layers can be found along the c crystallographicaxis. The ionic components form two different alternat-ing hydrogen bonded loops of N��H. . .O interactions.

Fig. 2. ORTEP diagrams31 of the salts. (a) Salt of (1)-(R)-phenylethylamine with (2)-(R)-ibuprofen (4), represented at 50% probability level,heteroatoms are shaded. (b) Salt of (1)-(R)-phenylethylamine with (1)-(S)-ibuprofen (5), represented at 50% probability level, heteroatoms areshaded. (c) ORTEP diagram of the cocrystal (6), benzylamine–ibuprofen salt with the neutral ibuprofen at 30% probability level, heteroatoms areshaded.



Fig. 3. Packing diagrams32 of the salts, 4, 5, and 6. (a) (R,R) salt (4). View from the a crystallographic axis. The columns are perpendicular to the sheet.(b) (R,R) salt (4). View from the b crystallographic axis showing the parallel columns. (c) (R,S) salt (5). View from the a crystallographic axis. (d) (R,S) salt(5). View from the b crystallographic axis showing the parallel columns. (e) Packing diagram of the cocrystal (6) with neutral ibuprofen. View from the acrystallographic axis. The columns are perpendicular to the sheet. (f) Packing diagram of the cocrystal (6) with neutral ibuprofen. View from the b crystallo-graphic axis showing the parallel columns. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Their descriptions by graph set analysis33 are R24 (8)

and R44 (12), respectively (Fig. 4c). The neutral ibupro-

fens are linked to the column by O. . .H��O interactionslike side end groups having more freedom of motion(Fig. 2c). The conformational comparison of the ionic

and neutral ibuprofen in the crystal is shown by super-imposing them (Fig. 5b).

The lack of the methyl moiety in benzylamine in struc-ture 6 compared with the (1)-(R)-phenylethylamine mole-cule in structures 4 and 5 results a sterically favorable

TABLE 2. Intermolecular interactions in the crystal structure of the salts of both (R )- and (S )-ibuprofen with(1)-(R )-phenylethylamine (4 and 5) and the cocrystal of ibuprofen with benzylamine (6)

D-H. . .A D-H [A] H. . .A [A] D. . .A [A] D-H. . .A [A] Symmetry operation

(1)-(R)-(1-phenylethyl)ammonium-[(2)-(R)-2-(4-isobutylphenyl)propanoate] (4)

N1-H1N. . .O1 0.9100 1.8300 2.730(3) 168.00 –N1-H2N. . .O1 0.9100 1.8800 2.787(3) 176.00 21/2 1 x,1/2 2 y,1 2 zN1-H3N. . .O2 0.9100 1.8000 2.707(3) 171.00 21 1 x, y, zC5-H5. . .O2 0.9500 2.4800 3.379(3) 158.00 21 1 x, y, z

(1)-(R)-(1-phenylethyl)ammonium-[(1)-(S)-2-(4-isobutylphenyl)propanoate] (5)N1-H1N. . .O1 0.9100 1.8100 2.696(3) 164.00 21/2 1 x,1/2 2 y,2zN1-H2N. . .O1 0.9100 1.9300 2.762(3) 152.00 –N1-H3N. . .O2 0.9100 1.9000 2.809(3) 176.00 21 1 x,y,z

benzylammonium-[rac-2-(4-isobutylphenyl)propanoate][rac-2-(4-isobutylphenyl)propionic acid] co-crystal (6)N1-H1A. . .O1 0.9100 1.9000 2.794(11) 169.00 –N1-H1B. . .O1 0.9100 1.9300 2.819(10) 164.00 12x, 2y, 2zN1-H1C. . .O2 0.9100 1.8400 2.749(11) 176.00 1 1 x,y,zO31-H31. . .O2 0.8400 1.8500 2.665(11) 162.00 2x,1 2 y, 2zC24-H24. . .O1 0.9500 2.5900 3.440(13) 149.00 1 1 x, y, z

Fig. 4. The one-dimensional infinite hydrogen bonded chain running along the a crystallographic axis in all three crystal structures. The carbonatoms of the phenyl rings as well as the alkyl substituent of 1 are omitted for clarity. (a) Compound 4, (b) Compound 5, and (c) Compound 6. [Colorfigure can be viewed in the online issue, which is available at www.interscience.wiley.com.]



closer packing, higher crystal density. There is enoughspace in crystal 6 close to the ladder-like hydrogen bondcolumn to bond a neutral ibuprofen molecule as end groupin the low acidity medium.

Resolution of Ibuprofen with the Mixture of StructurallyRelated Amines

Our aim was to compare the resolutions of ibuprofenwith (1)-(R)-phenylethylamine (conventional method) andby mixtures of (1)-(R)-phenylethylamine and benzyl-amine. The mixture of amines contains structurally similar

molecules, thus it can be regarded as a ‘‘Dutch Resolu-tion’’—like method. As the resolving agent:racemic com-pound 5 1:2 molar ratio gives the best resolution, in ac-cordance with the Pope–Peachey technique,18 the summolar ratio of the amines was set to a constant value(mrBASE 5 0.55 6 0.02) in the experiments. The enantio-meric excess values of extracts and raffinates, and the FSparameters of these two methods, as the function ofmrPhEA, are shown in Figs. 6–8., respectively.

When the amine mixture was used (l), the enantio-meric purities in the extracts (eeExtr) significantly exceedthe results of the conventional method (o) at low to me-dium mrPhEA ratios (0.1 < mrPhEA < 0.35 and 0.20 < mrBA< 0.45), however, the results of both methods are similarat higher mrPhEA values. The eeRaff values show dissimilarcharacter, the curves of the two methods have an intersec-tion at mrPhEA 5 0.48. Low-resolution efficiencies wereobtained when the amine mixture was used at low-chiralamine concentrations, showing the negative effect of ben-

Fig. 8. Comparison of the resolution efficiency parameters with andwithout the achiral amine. mrBA 5 0 (*), mrBASE 5 mrBA1 mrPhEA 50.55 6 0.02 (l).

Fig. 6. Comparison of the enantiomeric excess values in the extracts.mrBA 5 0 (*), mrBASE 5 mrBA1 mrPhEA 5 0.55 6 0.02 (l).

Fig. 7. Comparison of the enantiomeric excess values in the raffinates.mrBA 5 0 (*), mrBASE 5 mrBA1 mrPhEA 5 0.55 6 0.02 (l).

Fig. 5. (a) Structural overlay of the (1)-(R)-phenylethylamine from itsboth structures. Light color is 4, dark color is 5. (b) Structural overlay ofthe ionic and neutral ibuprofen from the cocrystal 6. Light color is ionicibuprofen, dark color is neutral ibuprofen. [Color figure can be viewed inthe online issue, which is available at www.interscience.wiley.com.]

634 MOLNAR ET AL.


zylamine. A further decrease of the achiral amine concen-tration, at constant mrBASE ratio, however, resulted in acrossing of the curves of the conventional and ‘‘amine mix-ture’’ methods. Furthermore, the FS parameters achievedby the amine mixtures even exceeded the efficiencies ofthe conventional method, in the range of 0.47 < mrPhEA <0.52. The maximum value of the FS curve is slightlyhigher at mrPhEA 5 0.55 than at the half equivalent ratio(mrPhEA 5 0.50), when 2 is the only amine in the salt. Inthe case of the amine mixtures, a relatively sharp maxi-mum was obtained at mrPhEA 5 0.51, mrBA 5 0.04. Theoptimal amount of benzylamine is �7% to (1)-(R)-phenyl-ethylamine at this point, which is comparable with theresults reported by Dalmolen et al.34 They found that 6%of the (1)-(R)-phenylbutylamine, as nucleation inhibitor,effectively enhanced the resolution of the racemic man-delic acid by the (1)-(R)-phenylethylamine and (1)-(R)-phenylbutylamine mixture, although the incorporation ofthe additive was not observed in the precipitated salts.

In a new series of the experiments, the molar ratio ofthe achiral amine was set to mrBA 5 0.04. The efficiencyparameters obtained with the amine mixture and from con-ventional resolutions are compared in Figure 9. In a rangeof amine:ibuprofen ratio (0.1 < mrPhEA < 0.7), the effi-ciency curve obtained with the mixtures of 2 and 3 runsdistinctly above the FS parameters of the conventionalmethod. Three repeated experiments were performed atmrPhEA 5 0.53 with (mrBA 5 0.04) and without benzyl-amine. A t test for independent samples confirmed the sig-nificant difference between the means of the two sets ofrepetitions.

Besides the X-ray analysis, the different stoichiometry ofthe structurally related amines to the chiral acid was alsoconfirmed by mass balance calculations. Brunner’s equa-tion,35 supplemented by a linear dependent term, is suita-ble to fit curves on the extraction data:

YExtr ¼ A 3 ½1� expð�B 3 COrel2 Þ� þ C 3 COrel

2 ; ð7Þ

where, COrel2 is the relative amount of the carbon dioxide

to the racemic ibuprofen. Among the equation constants(A, B, C), ‘‘A’’ indicates the maximum yield of unreactedibuprofen that can be extracted by scCO2. The yield of theibuprofen in the raffinates (Ycalc

Raff ) was calculated by sub-tracting ‘‘A’’ from the total mass of ibuprofen. Thus, theamine:acid molecule ratio was determined in the salt. Theresults are collected in Table 3.

According to the data in Table 3, the chiral amine bondsthe ibuprofen in 1:1 ratio, whereas the benzylamine reactswith two molecules of ibuprofen.

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TABLE 3. Calculation of the amine:ibuprofen moleculeratios in the raffinates

Run mrPhEA mrBA A (%) R2 YcalcRaff Amine:1 ratio

1 0.14 – 84.8 0.999 15.2 1.1:13 0.52 – 47.8 0.999 52.2 1.0:17 0.70 – 28.4 0.999 71.6 1.0:18 0.91 – 9.8 0.996 90.2 1.0:110 – 0.10 80.6 0.999 19.4 1.9:111 – 0.25 49.7 0.999 50.3 2.0:112 – 0.54 0.0 0.975 100.0 1.9:1

Fig. 9. Comparison of the resolution efficiencies with mrBA 5 0.04achiral content (l) and without benzylamine (*).



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