Ibuprofen salt formation

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. 

Another interesting example of combining diastereomeric salt formation and racemization was reported by Bhattacharya." In this work, selective crystallization of ibuprofen/lysinate from 1 mol of (/ ,5)-(racemic) ibuprofen and <0.5 mol of (5)-lysine in aqueous ethanol affords either (S)-(- -)-ibuprofen/(5)-lysinate or (/ )-ibuprofen/(5)-lysinate (in preponderance) depending on the crystallization conditions. Then, the unwanted enantiomeric ibuprofen could be recovered from the mother liquor and racemized by a simple, relatively waste-free thermal process. The combination of the thermal racemization process and the selective crystallization technology provides an efficient and environmentally friendly means to prepare (S)-(- -)-ibuprofen lysinate in an overall essentially quantitative yield (Figure 56.8). 

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... 

A reversed-phase HPLC post-column ion-pair extraction system was developed by Kim and Stewart [71, 72] for the analysis of carboxylic acid drugs and their salts (sodium formate, sodium acetate, 3-bromopropionic acid, 6-aminocaproic acid, 11-bromoundecanoic acid, 1-heptanesulfonic acid, / -n i t rophcny 1 acetic acid, sodium benzoate, sodium salicylate, valproic acid, probenecid, naproxen, ketoprofen, ibuprofen, mefenamic acid, flufenamic acid, and cefuroxime sodium) using a-(3,4-dimethoxy-phenyl)-4,-trimethylammoniummethylcinnamonitrile methosulfate... 

Tung et al. (1991) devised another approach to the problem of isolating S-ibuprofen. They determined that the formation of a diasteriomeric salt yielded favorable solubility characteristics. They reacted 5-lysine with racemic ibuprofen to form the (5,5) and (R, S) salts. This afforded a 50-50 mixture of the two salts, from... 

Further, the chiral discrimination model via the formation of ionic diastereomers, as proposed by Bhushan and Parshad [8] in Scheme 13.1, was viewed by Kowalska and coworkers [11] in terms of the energy difference for ion-pair formation (i.e., in the formation of the two diastereomeric salts). Ibuprofen is a carboxylic acid and, therefore, apt to dissociate (and form an organic anion) and the separation of the two enantiomers of ibuprofen can be achieved only because the thermodynamic equilibrium constants (K) for the ion-pair formation process for the two enantiomers (Ki and K2, respectively) have different numerical values. From the theory of adsorption liquid chromatography, it is well known [15] that the thermodynamic equilibrium constant of adsorption, K, can be defined as follows ... 

In another approach, optically pure (—)-brucine was mixed with ( )-ibuprofen while preparing the solution prior to its application onto TLC plates [16]. The premixing resulted in the formation of diastereomeric salts of the type (-1-)-ibuprofen-(—)-brucine and (—)-ibuprofen-(—)-brucine without resorting to any covalent linkage. It was the movement of these ionic diastereomers on TLC plates that resulted in separation. Chromatograms were developed at 28 2°C for 20 min in acetonitrile/methanol (5 1, v/v), and the spots were located with iodine vapors. 

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