Racemization of ibuprofen

The polymers were also able to resolve racemic naproxen, but not the racemates of ibuprofen and ketoprofen (Fig. 17.9). Even though direct comparisons of the two chromatograms cannot be done because of differing flow rates, it is not obvious that the chromatographic efficiency was better with the uniformly sized beads (Fig. 17.9b) than with the irregular particles (Fig. 17.9a). This may be due to the detrimental influence of water on the stability of the monomer-print molecule complex... 

Ibuprofen is an analgesic sold under various names including Advil, Motrin, and Nuprin. The material is sole as a racemic mixture, but only one enantiomer acts as ar analgesic. The other enantiomer is inactive. Assign R oi S forms to the two enantiomers of ibuprofen. 

The reaction under investigation is the enzymatic hydrolysis of racemic ethoxyethyl-ibuprofen ester. The (R)-ester is not active in the above reaction,1-3, thus simplifying the reaction mechanism, as shown in Figure 5.13. Because both enantiomers are converted according to fust-order kinetics, the conversion of one enantiomer is independent of the conversion of the other.4... 

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]. 

Dynamic kinetic resolution (DKR) is a process in which the resolution process is coupled with in situ racemization of unreacted substrate. This has been shown to be a potential and feasible method to produce 100 % theoretical yield. We have developed a chemo-enzymatic DKR to obtain higher desired yield for (5)-ibuprofen. The combined base catalyst with lipase has resulted in high conversion and excellent ee of the product. 

Ibuprofen is a popular analgesic and anti-inflammatory drug. There are two stereoisomeric forms of ibuprofen. This drug can exist as (S)- and (/ )-stereoisomers (enantiomers). Only the (5)-form is active. The (/ )-form is completely inactive, although it is slowly converted in the body to the active (5)-form. The drug marketed under the trade names, commercially known as Advil , Anadin , Arthrofen , Brufen , Nurofen , Nuprin , Motrin etc., is a racemic mixture of (/ )- and (5)-ibuprofen. 

Scheme 33 Racemic resolution of ibuprofen with hydrolase (Sepracor Process).

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. 

An HPLC method to determine racemic etodolac and its major metabolites in urine using a reverse-phase column has been developed [13]. Determination of etodolac in urine involved acidifying the diluted urine before extraction with cyclohexane-ethyl acetate (95 5, v/v). The organic layer was separated, evaporated, and reconstituted in solution of ibuprofen in acetonitrile (internal standard). The samples were injected onto a LiChrosper 100 RP-18 25 cm x 4 mm i.d., (5 pm particle size) column. 

Manufacture of optically pure (5)-(+)-ibuprofen (13), an NSAID similar to naproxen, is another example demonstrating the role of resolution in production of chiral fine chemicals, although from a somewhat different angle. Unlike naproxen, ibuprofen (14) was introduced to the market as a racemate almost 30 years ago.30 31 At the time of the introduction, it was thought that both R- and 5-isomers of ibuprofen had the same in vivo activity.32 It has been demonstrated that the R-isomer is converted to the 5-isomer in vivo29 by a unique enzyme system called invertase.34 Based on these data, ibuprofen has since been marketed as a racemate and has achieved sales of more than a billion... 

Taking advantage of the ready availability of racemic ibuprofen, the resolution approach for production of (S)-(+)-ibuprofen becomes an attractive alternative. Merck s resolution process involves the formation of a diastereomeric salt of ibuprofen with (S)-lysine, an inexpensive and readily available natural amino acid.45 The racemic ibuprofen is mixed with 1.0 equivalent of (5)-lysine in aqueous ethanol. The slurry is agitated to allow full dissolution. The supernatant, which is a supersaturated solution of ibuprofen-lysine salt, is separated from the solid and seeded with (.S )-ibuprofcn-(.S )-lysine to induce crystallization. The precipitated solid is collected by filtration, and the mother liquor is recycled to the slurry of racemic ibuprofen and (S)-lysine. This process is continued until essentially all (S)-ibuprofen in the original slurry is recovered, resulting in the... 

Another classic resolution process developed by Ethyl Corp. for (S)-ibuprofen production uses (S)-(-)-a-methylbenzylamine (MAB) as the chiral base for diastereomeric salt formation 49 The difference in solubility between (S)- and (ft)-ibuprofen MAB salts is so substantial that only half an equivalent of MAB is used for each mole of racemic ibuprofen, and no seeding is needed. The process can also be performed in a wide range of solvents, and the unwanted (ft)-ibuprofen can be recycled conveniently by heating the mother liquor in sodium hydroxide or hydrochloric acid. Other designer amines have been developed for resolution of ibuprofen with good stereoselectivities,50 but these chiral amines were prepared specifically for ibuprofen resolution and are thus unlikely to be economical for industrial production. 

Both naproxen and ibuprofen are chiral but, while both enantiomers of ibuprofen are effective painkillers, and the drug is sold as a racemic mixture (and anyway racemizes in the body) only the (S) enantiomer of naproxen has anti-inflammatory activity. When the American pharmaceutical company Syntex first marketed the drug they needed a way of resolving the racemic naproxen they synthesized in the laboratory,... 

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... 

To illustrate how a racemate system can be turned into a conglomerate system, and to demonstrate how one may recognize the existence of a conglomerate system, we will consider the example of ibuprofen, or 2-(4-isobutylphenyl)propanoic acid. The single crystal structures of enantio-merically pure [44] and racemic [45] ibuprofen have been published, and the powder diffraction patterns of the enantiomerically pure and racemic forms are shown in Fig. 9.3. The existence of a conglomerate system is indicated if the diffraction patterns of enantiomerically pure and racemic... 

In contrast to drugs from natural sources, those drugs that are made entirely in the laboratory are either achiral or, if cliiial, are often produced and sold as racemic mixtures. Ibuprofen, for example, has one chirality center and is sold commercially under such trade names as Advil, Nuprin, and Motrin as a racemic mixture of R and 5. It turns out, however, that only the 5 enantiomer is active as an analgesic and anti-inflammatory agent. The R enantiomer of ibuprofen is inactive, although it is slowly converted in the body to the active S form. 

In the case of ibuprofen, an analgesic drug used as a racemate, solely... 

The relative concentration of the pharmacologically active S enantiomer of ibuprofen (S R ratio) increases with prolongation of the gastrointestinal transit time of racemic formulations due to a corresponding increase in chiral inversion of the R to S enantiomer in the gut (25). Administration of S-ibuprofen, therefore, reduces the formulation-dependent variability in the concentration of the active enantiomer in the body. 

From physicochemical viewpoints, enantiomers and racemates are often very different from one another. For example, it has been shown that individual enantiomers of ibuprofen have greater water solubility and faster dissolution than their racemates (30). A formulation of S-ibuprofen, therefore, may have more rapid absorption and consequently a shorter onset of analgesia. This is important, as evidence exists in the literature in support of a meaningful relationship between ibuprofen serum concentrations and its analgesic effects (31). Hence, a more rapidly absorbed formulation may provide shorter onset of action, Therefore, as a pain reliever, stereochemically pure NSAIDs may be preferable to their respective race-mates. Furthermore, one may take advantage of the single enantiomer s greater solubility to prepare various soluble formulations of NSAIDs and products with an accelerated dissolution rate. 

An unique example of stereoisomer selective tissue uptake of stereoisomers is noted with NSAIDs. The R enantiomer of ibuprofen shows preferential uptake into fat following the administration of the racemate and individual isomersJ However, this apparent difference in fat distribution is probably a consequence of the selective metabolic uptake and formation of the coenzyme A thioester of the R isomer, which does not occur with the S isomer. 

Mustillo and CiurczakP" presented a paper discussing the spectral effect of optically active solvents on enantiomer mixes. This information was used as a technique to screen for polar modifiers in normal-phase chromatography of racemic mixtures. In 2000, the enantiomeric composition of ibuprofen in solid-state mixtures was performed by Agatonovic-Kurstrin, Beresford, Razzak. ... 

In this method, an internal standard is added, and its weight fraction is maintained constant in all the mixtures. This method was used to simultaneously quantify the S(+)-enantiomer and the racemic compound of ibuprofen. ... 

---