Rapid Base-Catalyzed Racemization of (R)-Ibuprofen Ester in

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Rapid Base-Catalyzed Racemization of (R)‑Ibuprofen Ester in Isooctane−Dimethyl Sulfoxide Medium with Improved Kinetic Model Fadzil Noor Gonawan,† Lau Sie Yon,‡ Azlina Harun Kamaruddin,† and Mohamad Hekarl Uzir*,† †

School of Chemical Engineering, Engineering Campus, Universiti Sains Malaysia, Seri Ampangan, 14300 Nibong Tebal, Seberang Prai Selatan, Pulau Pinang, Malaysia ‡ Department of Chemical Engineering, Curtin University, Sarawak Campus CDT 250, 98009 Miri, Sarawak, Malaysia ABSTRACT: The synthesis of chiral compounds through dynamic kinetic resolution has shown improved results with the presence of racemization. Integrating the reaction media for biocatalytic kinetic resolution and base-catalyzed racemization pose challenges in chiral separation due to its alkaline environment. Base-catalyzed racemization of (R)-ibuprofen ester has been separately studied in isooctane, isooctane−water, and isooctane−DMSO media. A rapid racemization rate of (R)-ibuprofen ester was obtained in isooctane-DMSO medium as compared with the other two media with racemization rate constants (krac) of 0.292 and 0.001 h−1, respectively. An investigation carried out on sodium hydroxide and Amberlyst A26 (OH− resin) as base catalysts has shown that Amberlyst A26 gave a better performance compared to that of sodium hydroxide. Additionally, the rate of racemization increases at higher reaction temperatures, but shows otherwise at a higher concentration of substrate. The kinetic model of the base-catalyzed racemization was developed and experimentally validated. The model incorporates two main contributing factors in the racemization reaction: a base catalyst and initial substrate concentrations. Base-catalyzed racemization was conducted in the proposed packed-bed reactor, where the racemization rate was faster with an increased velocity of feed flow rate. The absolute rate constants of racemization (kabs) obtained were 0.112 and 0.275 h−1 for feed flow rates of 0.6 and 1.2 mL· min−1, respectively. The packed-bed reactor was then proposed to be coupled with a membrane reactor as an integrated dynamic kinetic resolution reactor of chiral compounds.

1.0. INTRODUCTION Racemization is a reaction where a single enantiomer is restored to its racemic form in a mixture where more than one enantiomer exist. In racemic form, both enantiomers are in equal composition. The racemization of the unwanted isomer is important in the resolution of a chiral constituent so that it exceeds the theoretical yield of 50% in an enantioselective synthesis. This would be an added advantage in the production of optically pure active pharmaceutical ingredients, (APIs) because of the high purification cost incurred. The choice of biocatalyst and chemical catalyst has been highlighted to be based on the balance between resolution and racemization reactions.1 Hence, a detailed understanding on the behavior of both reactions is necessary. The racemization of asymmetric carbon atoms has been reviewed in depth, and the reactions were mostly catalyzed by a strong base and acid at elevated temperatures.2 Base-catalyzed racemization has been widely used in the pharmaceutical industry for the production of optically active organic compounds bearing an acidic hydrogen at the chiral center or an α-carbon with low pKa value. For instance, a low cost base, such as sodium hydroxide has been employed for the racemization of unreacted enantiomeric ibuprofen ester in the dynamic kinetic resolution (DKR) process in order to achieve 100% theoretical yield of the active compound.3,4 Moreover, a racemization of ibuprofen acid catalyzed by sodium hydroxide has also been carried out, and the kinetic mechanism of the reaction was carefully described.5 According to Yuchun and co-workers, the variation of enantiomeric excess during racemization is highly dependent on the base concentration rather than that of the substrate. © 2013 American Chemical Society

However, in the present work, substrate concentration gives a significant effect on the racemization of (R)-ibuprofen ester. Hence, the kinetic model of the existing base-catalyzed racemization will be revised and discussed accordingly. Generally, the racemization rate of reaction determines the time required for a reaction to reach completion. A low racemization rate slows down the total DKR rate and reduces the chiral product formation. Therefore, this limiting factor has to be further investigated and optimized. The rate of racemization depends closely on temperature, and high temperature is sometimes required in order to achieve a fast reaction rate. However, an ideal racemization reaction should be conducted at the highest rate possible with a minimal usage of energy. Ebber and co-workers have reported that, besides temperature and substrate concentration, the solvent used as a medium for the reaction also gave a significant effect, in which an aprotic polar solvent has resulted in a faster racemization rate.2 Recently, an in situ racemization has been carried out in a lipase-catalyzed hydrolysis of ibuprofen methyl ester, and it was found that dimethyl sulfoxide (DMSO) is an important solvent for the dynamic kinetic resolution of ibuprofen methyl ester.4 In the present work, base-catalyzed racemization of (R)-2ethoxyethyl ibuprofen ester was carried out in three different media in order to compare the racemization rates and consequently determine the appropriate medium, which Received: Revised: Accepted: Published: 635

September 16, 2013 December 3, 2013 December 15, 2013 December 16, 2013 dx.doi.org/10.1021/ie403070u | Ind. Eng. Chem. Res. 2014, 53, 635−642

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Figure 1. Interconversion of (R)- and (S)-substrate in racemization reaction.

(Barnstead, UK) set at 150 rpm agitation speed and reaction temperature of 35 °C. After 24 h of reaction, the aqueous layer was carefully removed. The substrate, (R)-2-ethoxyethyl ibuprofen ester in isooctane medium was neutralized using sodium hydroxide solution and further washed with deionized water. The residual substrate was further purified using a microdistillation unit in order to remove the remaining solvent and other impurities. The remaining (R)-2-ethoxyethyl ibuprofen ester was again diluted, and a sample from the solution was used for further analysis. 2.3. Racemization of (R)-Ibuprofen Ester. The racemization of substrate was investigated in three different media, namely; isooctane, isooctane−water (1:1 v/v) and isooctane− DMSO (1:1 v/v) in order to determine the reactivity of the base catalyst. NaOH and OH− resin were chosen as the catalysts, which were varied in the range of 0.4−2.0 g and 0.5− 2.0 g, respectively. The condition of the media was fixed at 50 °C and 160 rpm agitation speed. 2.4. Analytical Method. All samples collected from the reaction were analyzed using high performance liquid chromatography (HPLC) (Shimadzu, Japan) equipped with (R,R)-Whelk-O1 Chiral column (Regis-Pirkle, US) and a UV detector. The wavelength of the detector and the environment of the column oven were set up at 254 nm and 40 °C, respectively, during the quantification. The composition of the mobile phase consists of hexane−isopropyl alcohol−acetic acid with the ratio of 98:2:0.5 (v/v).6 The concentration of (R)- and (S)-ibuprofen ester was monitored periodically, and the ee of the substrate was calculated using eq 1.

would then give the highest rate of product formation. In the present work, the performance of sodium hydroxide and Amberlyst A26 will be investigated as the source of base catalysts for racemization. Furthermore, the studies were also carried out at varying concentrations and temperatures in order to investigate the effect of those parameters toward the rate of racemization.

2.0. MATERIALS AND METHODS 2.1. Materials. (R,S)-Ibuprofen acid was purchased from Shasun Company, India. Candida rugosa lipase (CRL) (EC 3.1.1.3), sulphuric acid, Amberlyst A26 hydroxide form (OH− resin) and sodium hydroxide (NaOH) were obtained from Sigma-Aldrich, Germany. Solvents used for media preparation, such as isooctane and DMSO were purchased from Merck, Germany. Meanwhile, the analytical reagent, such as n-hexane, isopropyl alcohol, and acetic acid were supplied by Fisher Chemical (UK). 2.2. Preparation of (R)-Ibuprofen Ester. The substrate, (R)-2-ethoxyethyl ibuprofen ester, was synthesized by CRLcatalyzed hydrolytic reaction of (R,S)-2-ethoxyethyl ibuprofen ester to give >90% enantiomeric excess (ee). Initially, the (R,S)ibuprofen acid (20 g) was reacted with 2-ethoxyethanol (19.5 mL), catalyzed by ρ-toluene sulfonic acid (0.5 g) in 100 mL of isooctane to give (R,S)-2-ethoxyethyl ibuprofen ester. The resultant solution was neutralized using 25 mL of aqueous sodium hydroxide (0.5 M) and washed with 25 mL of deionized water to remove the remaining residue. The organic phase, rich in (R,S)-2-ethoxyethyl ibuprofen ester was collected and further purified using a microdistillation unit in order to obtain a pure (R,S)-2-ethoxyethyl ibuprofen ester. The purified (R,S)-ester was then diluted into a desired concentration using isooctane as a solvent. A 50 mL portion of the (R,S)-2-ethoxyethyl ibuprofen ester solution was mixed with 50 mL of deionized water and 2 g of CRL for the hydrolysis reaction in a biphasic isooctane−water medium. The reaction was conducted in an incubator shaker

eeS =

[R ] − [S] [R ] + [S]

(1)

2.5. Kinetic Model of Base-Catalyzed Racemization. The kinetic model of the base-catalyzed racemization has been the point of interest for a number of researchers in order to describe the performance of a particular reaction system.2 The stereomutation of optically pure enantiomer to a racemate can 636

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be described by a reversible reaction. The reversible transformation of (R)-ibuprofen ester into its isomer is clearly depicted in Figure 1. In a solution, the chiral molecule will eventually reach equilibrium with an equimolar proportion of each enantiomer, which is known as a racemate. It was suggested that, in an equimolar racemic solution, the interconversion difference between the two enantiomers is negligible, and it can therefore be assumed that k1 = k−1. By solving the differential equation (eq 2) with conditions given by [R]o = [S]t + [R]t and [S]o = [R]t + [S]t − [R]o, the resulting equation is given by eq 3. d[R ] = k −1[S] − k1[R ] dt

(2)

eeS = eeSoe−k intt

(3)

where, kint is defined as the interconversion constant. The equation follows the initial condition, given that, at t = 0; eeS = eeSo. From eq 3, it is apparent that the enantiomeric excess varies exponentially with the reaction time of a particular racemization process. Experimental data analyses indicated that the eeS gradually decreased exponentially over the reaction period as depicted in Figure 2.

Figure 2. The exponential variation of enantiomeric excess of substrate (eeS) with the reaction time in the base-catalyzed racemization of (R)ibuprofen ester. Figure 3. Schematic diagram of packed-bed reactor used in the racemization of (R)-ibuprofen ester.

In the previous investigation of a similar system, it was reported that, the racemization rate was directly proportional to the concentration of the base catalyst and eq 3 was further refined, which resulted into eq 4 which is similar to that reported by Yuchun and co-workers;5 eeS = eeSoe

−k int[OH]t

0.6 − 1.2 mL.min−1. The samples were taken periodically from the outlet of the reactor for 6 h of reaction time.

3.0. RESULTS AND DISCUSSION 3.1. Effect of Reaction Medium. The first investigation on the importance of solvent in a racemization reaction conducted by Yuchun and co-workers was used as a basis for the racemization of (R)-ibuprofen ester.5 The results clearly confirmed that DMSO has played an important role in the racemization of (R)-ibuprofen ester, which are also backed up by other previous reports.4,5 In this study, OH− resin was employed as a base catalyst. As expected, in pure isooctane and isooctane−water (1:1 v/v) media, the racemization of substrate gave no positive results as tabulated in Table 1. This indicates that the racemization process is significantly affected by the reaction medium. In a base-catalyzed reaction, the OH− ion is apparently bound to the carrier, and it remains intact with the carrier in the organic (isooctane) medium. Because of this reason, there would be less contact between the OH− ion and the substrate within the organic phase for the formation of

(4)

2.6. Packed-Bed Reactor Operation. The experiment was conducted in a recirculated packed-bed reactor with the presence of OH− resin-mediated DMSO solution as shown in Figure 3. The reactor consists of a jacketed Pyrex-glass column, 1.2 cm internal diameter and 24 cm height. The resin bed height is approximately 15 cm. The column was filled with 2 − 8 g of OH− resin and DMSO solution. The reactor was heated up to 50 °C by circulating hot water through the jacketed column prior to use. Once the desired operating temperature was reached, the substrate solution in isooctane was continuously fed from the bottom of the column by means of peristaltic pump. The temperature of the packed-bed reactor was controlled by manipulating the feed flow rate of hot water. The flow rate of substrate was controlled in the range between 637

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Table 1. Effect of Media on the Racemization of (R)-Ibuprofen Ester in the Presence of 0.045 (mmol/mL H2O) OH−, at 50 °C of Reaction Temperature and 100 mM of Initial Substrate Concentration eeS (%) medium

t=0h

t=6h

t = 24 h

kint (h−1) ± (0.000−0.030)

isooctane isooctane−water (1:1 v/v) isooctane−DMSO (1:1 v/v)

49 50 50

49 49 16

48 49 0

2%) in the outlet stream, which could later affect the subsequent hydrolysis processing unit. Hence, in this present investigation, the optimum inlet flow rate was determined at 1.2 mL·min−1, where no significant loss of DMSO was found from the packed-bed column, giving a faster racemization rate. The incorporation of simultaneous hydrolysis and racemization into a single process has been the main interest in chiral resolution. However, the process could only be achieved in the presence of metal catalyst which requires a high cost for catalyst preparation, where lipase activity was preserved for a long period of time.8,9 From the investigation, it is rather feasible to conduct both the hydrolysis and racemization in series with a low cost catalyst such as OH− ion originating from sodium hydroxide without affecting the activity of the biocatalyst employed. From the previous investigation, the batch reactor and hollow-fiber membrane reactor have been utilized to carry out the dynamic kinetic resolution of ibuprofen ester.3,10 Since the OH− ion is able to racemize the (S)-ibuprofen acid,5 a hollow-fiber membrane reactor is the best option in coupling together with the proposed packed-bed reactor system. This is due to the fact that the product (S)-ibuprofen acid could be continuously extracted from the substrate solution, which could then avoid product accumulation within the reaction medium and consequently product inhibition.

easily regenerated by incubation in sodium hydroxide solution. As a conclusion, the racemization rate depends entirely on the reaction temperature and substrate concentration, in which a better performance was obtained at a higher temperature range with low substrate concentrations. A new kinetic model of basecatalyzed racemization was introduced by incorporating the effect of base and initial substrate concentrations simultaneously. The newly developed kinetic model was validated and later used to predict the variation of enantiomeric excess of the substrate during the racemization reaction in any system close to that obtained from the experimental work. Meanwhile, the investigation also found that it is rather feasible to carry out the base-catalyzed racemization in the packed-bed reactor, and therefore, a system of coupled racemization−separation was proposed for the dynamic kinetic resolution of a chiral compound. The finding from this current work is expected to give a better insight in designing a new dynamic kinetic resolution system for any immobilized enzyme-catalyzed reactions.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: 604-5996464. Fax: 6045941013. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to acknowledge Universiti Sains Malaysia for funding the current study through the Research University Grant Scheme (1001/PJKIMIA/814114). The financial support from the Research University Postgraduate Research Grant Scheme (USM-RU-PGRS 1001/PJKIMIA/ 8033032) and the research facilities provided by Universiti Sains Malaysia are also duly acknowledged. F.N.G. and M.H.U. would also like to thank Dr. Subhash Bhatia for his constant help and advice throughout this research work as well as during the development of the entire (S)-ibuprofen pilot plant. We wish him the very best for his retirement years.

4.0. CONCLUSION The racemization of (R)-ibuprofen ester can readily take place in the presence of base catalyst. The racemization rate increased significantly when 50% (v/v) DMSO was introduced in the reaction medium. In the presence of water, the racemization process progresses fairly slowly due to the electrostatic interaction between the OH− ion and water molecules. Meanwhile, in the isooctane−DMSO (1:1 v/v) mixture, the OH− ion is less affected by the electrostatic interaction due to the partial negative charge of DMSO that dominates in the media, thus, resulting in a rapid rate of racemization. An investigation on the NaOH and Amberlyst A26 as base catalysts has shown that the OH− ion from Amberlyst A26 is more reactive because the OH− ion is freely available on the surface of the support, while the OH− ion from the aqueous NaOH on the other hand, may still be bound to the cation Na+ rather than moving freely in the solution mixture. Furthermore, the OH− attached on the surface of the Amberlyst A26 resin could be

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NOMENCLATURE eeS = enantiomeric excess of substrate (%) eeSo = initial enantiomeric excess of substrate (%) k1 = interconversion rate constant of (R)-substrate (h−1) k−1 = interconversion rate constant of (S)-substrate (h−1) kabs = absolute rate constant of racemization (h−1) kB = Boltzmann constant (J·K−1) dx.doi.org/10.1021/ie403070u | Ind. Eng. Chem. Res. 2014, 53, 635−642

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ke = equilibrium constant (dimensionless) h = Planck’s constant (J·s) kint = interconversion constant (h−1) [OH] = concentration of OH− ion (mmol/mL in H2O) [SA] = concentration of (S)-substrate (mM) [SB] = concentration of (R)-substrate (mM) [SA]o = initial concentration of (S)-substrate (mM) [SB]o = initial concentration of (R)-substrate (mM)

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REFERENCES

(1) Kamaruddin, A. H.; Uzir, M. H.; Aboul-Enein, H. Y.; Halim, H. N. A. Chemoenzymatic and microbial dynamic kinetic resolutions. Chirality 2009, 21, 449. (2) Ebbers, E. J.; Ariaans, G. J. A.; Houbiers, J. P. M.; Bruggink, A.; Zwanenburg, B. Controlled racemization of optically active organic compounds: Prospects for asymmetric transformation. Tetrahedron 1997, 53, 9417. (3) Fazlena, H.; Kamaruddin, A. H.; Zulkali, M. M. D. Dynamic kinetic resolution: Alternative approach in optimizing S-ibuprofen production. Bioprocess Biosyst. Eng. 2006, 28, 227. (4) Chavez-Flores, D.; Salvador, J. M. Facile conversion of racemic ibuprofen to (S)-ibuprofen. Tetrahedron: Asymmetry 2012, 23, 237. (5) Yuchun, X.; Huizhou, L.; Jiayong, C. Kinetics of base catalyzed racemization of ibuprofen enantiomers. Int. J. Pharm. 2000, 196, 21. (6) Gonawan, F. N.; Yon, L. S.; Kamaruddin, A. H.; Uzir, M. H. Effect of co-solvent addition on the reaction kinetics of the lipasecatalyzed resolution of ibuprofen ester. J. Chem. Technol. Biotechnol. 2013, 88, 672. (7) Lin, H.-Y.; Lay, E.; Wen, W.-Y.; Dewi, H.; Cheng, Y.-C.; Tsai, S.W. Racemization and hydrolysis of (S)-naproxen 2,2,2-trifluoroethyl ester in non-polar solvents by strong neutral bases: Implication for ionpair kinetic basicity and hydrolysis. J. Phys. Org. Chem. 2004, 17, 387. (8) Martín-Matute, B.; Bäckvall, J.-E. Dynamic kinetic resolution catalyzed by enzymes and metals. Curr. Opin. Chem. Biol. 2007, 11, 226. (9) Wieczorek, B.; Träff, A.; Krumlinde, P.; Dijkstra, H. P.; Egmond, M. R.; van Koten, G.; Bäckvall, J.-E.; Klein Gebbink, R. J. M. Covalent anchoring of a racemization catalyst to CALB-beads: Towards dual immobilization of DKR catalysts. Tetrahedron Lett. 2011, 52, 1601. (10) Lau, S. Y.; Uzir, M. H.; Kamaruddin, A. H.; Bhatia, S. Lipasecatalyzed dynamic kinetic resolution of racemic ibuprofen ester via hollow fiber membrane reactor: Modeling and simulation. J. Membr. Sci. 2010, 357, 109.

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