Ibuprofen production

Fazlena, H., Kamaruddin, A.H. and ZulkaU, M.M.D., Dynamic kinetic resolution alternative approach in optimizing 5-ibuprofen production. Bioprocess Biosyst. Eng., 2006, 28, 227-233. 

Performing the S-ibuprofen production process with an ultrafiltration unit, 6 of the 11 unit production steps shown in Figure 6 could be skipped The entire process scheme was reduced to the one given in Figure 8. 

In 1992, BASF opened a 35 000 tons per year ibuprofen production plant in Bishop, Texas. This plant was the result of the elegant green chemistry route developed by the BHC consortium. The clean synthesis of ibuprofen is an excellent example of how combining catalysis and green chemistry can yield both commercial success and environmental benefits. Ibuprofen is a nonsteroidal, anti-inflammatory painkiller. It is a popular over-the-counter drug against headache, toothache, and muscular pains. You may know it better as Advil , Motrin , or Nurofen. 

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. 

Non-steroidal Antiinflammatory Drugs (NSAIDs). In some cases, a patient may unknowingly be taking several different products that contain the same NSAID. An arthritic patient whose condition has been managed with ibuprofen obtained via prescription (often at dosage levels at or near the recommended maximum) may purchase a non-prescription ibuprofen product for pain/discomfort not associated with the arthritis. The patient may not know that the two products contain the same drug and that there is an increased risk of adverse effects. 

Preparation of (S)-ibuprofen by enzyme-catalyzed enantioselective hydrolysis of racemic ibuprofen esters has been investigated by several companies such as Sepracor [50,51], Rhone-Poulenc [52,53], Gist-Brocades [54,55], and the Wisconsin Alumni Research Foundation [56]. These processes are usually performed under mild reaction conditions, yield highly optically pure product, and can be readily scaled up for industrial production. The disadvantage of these processes for (S)-ibuprofen production is the extra step needed to produce the corresponding ester of racemic ibuprofen, as well as the cost of producing the enzyme and microorganism catalysts. 

To illustrate the benefits of atom economy, consider the synthesis of ibuprofen, mentioned earlier, which won the Presidential Green Chemistry Challenge Award in 1997. In the former process, developed in the 1960s, only 40% of the reactant atoms were incorporated into the desired ibuprofen product the remaining 60% of the reactant atoms found their way into unwanted by-products or wastes that required disposal. The new method requires fewer reaction steps and recovers 77% of the reactant atoms in the desired product. This "green" process eliminates millions of pounds of waste chemical by-products every year, and it reduces by millions of pounds the amount of reactants needed to prepare this widely used analgesic. 

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. 

This strategy, for the production of (5 )-ibuprofen, is illustrated in Fig. 7-19. Ibuprofen is derivatized to the corresponding sulphonmethyl ester, but only one enantiomer of this compound is converted by a protease to (5 )-ibuprofen [33]. The resulting (5 )-ibuprofen and the unreacted ibuprofen sulphonmethyl ester can be sep-... 

Jessop and co-workers studied asymmetric hydrogenation reactions with the catalyst complex Ru(OAc)2(tolBINAP) dissolved in [BMIM][PFg]. In both reactions under investigation - the hydrogenation of tiglic acid (Scheme 5.2.10) and the hydrogenation of the precursor of the anti-inflammatory dmg ibuprofen (Scheme 5.2.11) - no CO2 was present during the catalytic transformation. However, SCCO2 was used in both cases to extract the reaction products from the reaction mixture when the reaction was complete. 

Scheme 5.2-11 Ru-catalyzed asymmetric hydrogenation of isobutylatropic acid, followed by extraction of the product ibuprofen with SCCO2.

In a similar manner, the asymmetric hydrogenation of isobutylatropic acid to afford the anti-inflammatory dmg ibuprofen has been carried out (Scheme 5.4-2). Here, the reaction was carried out in a [BMIM][PFg]/MeOH mixture, again followed by product extraction with SCCO2 (see Section 5.2.4.1 for more details on these hydrogenation reactions). 

Aspirin and other NSAIDs function by blocking the cyclooxygenase (COX) enzymes that carry out the body s synthesis of prostaglandins (Sections 7.11 and 27.4). There are two forms of the enzyme, COX-1, which carries out the normal physiological production of prostaglandins, and COX-2, which mediates the body s response to arthritis and other inflammatory conditions. Unfortunately, both COX-1 and COX-2 enzymes are blocked by aspirin, ibuprofen, and other NSAIDs, thereby shutting down not only tire response to inflammation but also various protective functions, including the control mechanism for production of acid in the stomach. 

Certain drugs, both prescription and over-the-counter, contain organic acids. Two of the most popular products of this type are the analgesics aspirin and ibuprofen (Advil, Nuprin, and so on). 

In this case study, an enzymatic hydrolysis reaction, the racemic ibuprofen ester, i.e. (R)-and (S)-ibuprofen esters in equimolar mixture, undergoes a kinetic resolution in a biphasic enzymatic membrane reactor (EMR). In kinetic resolution, the two enantiomers react at different rates lipase originated from Candida rugosa shows a greater stereopreference towards the (S)-enantiomer. The membrane module consisted of multiple bundles of polymeric hydrophilic hollow fibre. The membrane separated the two immiscible phases, i.e. organic in the shell side and aqueous in the lumen. Racemic substrate in the organic phase reacted with immobilised enzyme on the membrane where the hydrolysis reaction took place, and the product (S)-ibuprofen acid was extracted into the aqueous phase. 

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. 

The 2-ethoxyethanol was a by-product, as shown in Figure 5.13. The formation rate of 2-ethoxyethanol was the same as the conversion rate of the (S)- or (R)-ibuprofen ester one mole of 2-ethoxyethanol was formed when one mole of ester was catalysed. A known concentration of 2-ethoxyethanol was added in the organic phase before the start of the reaction for product inhibition. The plots of the kinetics for the free lipase system are presented in Figure 5.17 and immobilised enzyme (EMR) in Figure 5.18, respectively. The Kw value was 337.94 mmoFl 1 for the free lipase batch system and 354.20 mmoll 1 for immobilised... 

Enzyme reaction kinetics were modelled on the basis of rapid equilibrium assumption. Rapid equilibrium condition (also known as quasi-equilibrium) assumes that only the early components of the reaction are at equilibrium.8-10 In rapid equilibrium conditions, the enzyme (E), substrate (S) and enzyme-substrate (ES), the central complex equilibrate rapidly compared with the dissociation rate of ES into E and product (P ). The combined inhibition effects by 2-ethoxyethanol as a non-competitive inhibitor and (S)-ibuprofen ester as an uncompetitive inhibition resulted in an overall mechanism, shown in Figure 5.20. 

There are several hundred reported NF-kB inhibitors (see www.nf-kb.org for a complete and updated list). These inhibitors include natural products, chemicals, metabolites, and synthetic compounds. A large majority of these products, in particular commonly used antiinflammatory drugs such as corticosteroids and the nonsteroidal antiinflammatory drugs (NSADDs) aspirin, sulindac, ibuprofen and sulphasalazine, have the ability to partially inhibit NF-kB activity in cell culture. However, the precise mechanism of action and the specific molecular targets of most of these inhibitors remain unclear. 

Quite a few NSAlDs are available as OTC products. OTCformulations such as ibuprofen (Advil, Motrin, and Nuprin), ketoprofen (Orudis), and naproxen sodium (Aleve) are available to any consumer. The potential for misuse and abuse is high, especially when one is confronted by the large number of advertisements on television and in print heralding the wonderful benefits of these products. 

Yamamoto K, Y Ueno, K Otsubo, K Kawakami, K-I Komatsu (1990) production of 5-(+)-ibuprofen from a nitrile compound by Acinetobacter sp. strain AK 226. Appl Environ Microbiol 56 3125-3129. 

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