Ibuprofen, enantiomeric

A subfield in this area is using SCFs to control the stereoselectivity of biologically active chiral compounds. For example, supercritical CO2 has been used to do the lipase-catalyzed enantioselective esterification of ibuprofen. Enantiomeric purities exceeding 90% at an ibuprofen conversion of 25% have been reported [20]. 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

Substrate and product inhibitions analyses involved considerations of competitive, uncompetitive, non-competitive and mixed inhibition models. The kinetic studies of the enantiomeric hydrolysis reaction in the membrane reactor included inhibition effects by substrate (ibuprofen ester) and product (2-ethoxyethanol) while varying substrate concentration (5-50 mmol-I ). The initial reaction rate obtained from experimental data was used in the primary (Hanes-Woolf plot) and secondary plots (1/Vmax versus inhibitor concentration), which gave estimates of substrate inhibition (K[s) and product inhibition constants (A jp). The inhibitor constant (K[s or K[v) is a measure of enzyme-inhibitor affinity. It is the dissociation constant of the enzyme-inhibitor complex. 

FIGURE 2.20 Schematic presentation of the hydrogen-bonded cyclic dimers of enantiomeric antipodes of 2-phenylpropionic acid, Ibuprofen, and Naproxen (the latter two compounds are drugs from the group of profens). 

Since the separated enantiomers of a dissymmetric compound must crystallize in a different space group than does the racemic mixture, it should not be unanticipated that quantitative XRPD would be useful in the determination of enantiomeric composition. For instance, the differing XRPD characteristics of (S)-(+)-ibuprofen relative to the (-RS)-racemate have been exploited to develop a sound method for the determination of the enantiomeric purity of ibuprofen samples [53]. 

Most of the vanillic acid was reduced by E. coli containing Car in 2 h to vanillin (80 %) and vanillyl alcohol (20 %). Car does not reduce aldehydes to alcohols. However, E. coli s endogenous aldehyde reductase/dehydrogenase reduces vanillin to vanillyl alcohol. The broad substrate specificity of Car enables the wide application of this biocatalyst to other important applications, such as enantiomeric resolution of isomers such as ibuprofen and the reductions of many other natural and synthetic carboxylic acids. 

In a comparable system, (I ,S)-ibuprofen can be separated by a membrane reactor [83], see Fig. 13.10. The technique comprises a stereo-specific hydrolysis by an enzyme. Subsequently, the enantiomeric ester is extracted into the organic phase on the other side of the membrane. In the system developed by Sepracor Inc., (i )-ibuprofen is selectively hydrolyzed by proteases in a hollow-fiber unit and the (S)-ibuprofen ester can be isolated at 100% yield. This configuration also applies for enantioseparation of other acids such as naproxen and 2-chloropropionic acid. 

Others have investigated the influence of the presence of (i-cyclodextrin in the reaction medium on the electrochemical carboxylation of a-bromoethylbenzene and l-(4-isobutylphenyl)ethyl chloride [41], It has been reported that the preparative electrocarboxylahon of the inclusion complex (i-cyclodextrin-l-(4-isobutylphenyl) ethylchloride afforded the S-form of 2-(4-isobutylphenyl) propionic acid (S-ibuprofen) in a high enantiomeric excess (97%). 

Cheminor Drugs (part of Dr. Reddy s Group, Mumbai, India) have developed a process based on a chiral synthesis to (S)-ibuprofen. (S)-Ibuprofen is 160 times more active than the (R) form, so with an enantiomerically pure drug the dosage could be cut in half. As the human body has been reported to racemize (R)-ibuprofen partially into the (S) form and as (R)-ibuprofen is not harmful, nearly all the ibuprofen taken becomes active. The process discovered by Cheminor is therefore unlikely to have commercial significance. 

Pumera and coworkers [17] used nano-HPLC for enantiomeric resolution of ephedrine, pseudoephedrine, and ibuprofen by using (3-cyclodextrin as chiral... 

Pumera and coworkers [17] exploited (3-cylodextrin as chiral selector for the enantiomeric resolution of ephedrine, pseudoephedrine, and ibuprofen in NCEC. Male and Luong [23] described chiral analysis of three neurotransmitters (norepinephrine, epinephrine, and isoproterenol) by NCE using 25 mM... 

Arylpropionic acids are important class of non-steroidal anti-inflammatory drugs (NSAID). Their pharmacological activity is mainly in one of both enantiomers. Thus, efforts had been made to access to the enantiomerically pure substance. The kinetic resolution of racemic 2-(2-fluoro-4-biphenyl) propanoic acid 56 and 2(4-isobutylphenyl) propanoic acid 59 (Ibuprofen) was performed via enzymatic esterification and transesterification using an alcohol and vinyl acetate, respectively in a membrane reactor. The unreacted acid is obtained in highly enantiomerically enriched form. A consecutive approach consisting of the enzymatic hydrolysis of the resulted esters is needed to achieve the alcohol in optically pure form.77... 

Experimental work on resolution of ibuprofen and c/.v-chrysanthemic acid by supercritical fluid extraction using carbon dioxide was carried out. The effects of extraction temperature and pressure were investigated on the yield and enantiomeric excess of extracts and raffinates. An efficient extraction procedure was developed for production of (-)-c/s-chrysanthemic acid and (+)-c75-chrysanthemic acid resulting in 90 % enantiomeric excess. 

The mixtures of racemic acids and chiral bases were extracted with supercritical carbon dioxide. The extracts were collected as separate samples successively in time. Each of them was examined separately. The results of ibuprofen extraction are presented in Figure 3a. The extracts contained the (+)-enantiomer in 20-40 % optical purity while the raffinate was rich in (-)-enantiomer (enantiomeric excess= 44 7 %). Further purification of the extracts can be carried out by multiple extraction (Figure 3b). We have succeed to separate the cis-chrysanthemic acid mixture in a single extraction step with excellent enantiomeric excess for the (-)-enantiomer (greater than 95 %). The enantiomeric excess of the (+)-enantiomer was 90 % after three subsequent extraction. The resolution of ibuprofen was less efficient The... 

The pressure of the carbon dioxide (in the range of 90-150 bar) was found to have direct effect on the yield. Figure 4a shows the effect of the pressure on the extraction curves of ibuprofen. All four runs were performed at 38.5 °C. When the pressure was increased from 90 bar to 150 bar the carbon dioxide consumption was reduced to about 1/5 times. The enantiomeric excess of the extracts obtained from single extraction increased by 1.4 times for both acids (Figure 4b). 

Figure 4. Effect of the pressure on the extraction curve (pressure o 150 bar 120 bar 100 bar 90 bar) and b) on the enantiomeric excess ((x c/.v-chrysanthemic acid + ibuprofen)...

The effect of the temperature was investigated only in the supercritical range (32.5-50 °C). A rise in temperature at constant pressure led to an increase in extraction yield (Figure 5a). Similar temperature effects was observed for cv.s-chrysanthemic acid. The temperature dependency of enantiomeric excess of the extracts obtained from single extraction was different for the different acids. The enantiomeric excess of the cv.s-chrysanthemic acid extracts were 38 % and 75 % at temperatures 47 °C and 32 °C respectively. The enantiomeric excess of the ibuprofen was independent of the temperature (Figure 5b). 

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