Ibuprofen Manufacture

Celanese process for the manufacture of ibuprofen on a 3500-ton scale has been operating since 1992. In this process isobutyl benzene is acylated and then hydrogenated over a heterogeneous catalyst to give the appropriate precursor alcohol. This alcohol is then carbonylated. The overall synthetic scheme is shown by reaction 4.14. The conventional process for ibuprofen manufacture was based on six synthetic steps and generated a large amount of salt as a solid waste. 

The BHC Company is a joint venture of the Hoechst Celanese Corporation and the Boots Company. BASF purchased the Boots Company and Celanese sold its interest in the BHC Company to BASF. Celanese operates the new ibuprofen manufacturing facility in Bishop, Texas, for BASF. Ibuprofen manufactured via the BHC process is marketed under the brand names Advil and Motrin. The industrial-scale facility created in Bishop, Texas, in 1992 is the world s largest ibuprofen manufacturing plant, is operated by the Celanese Corporation for BASF, and currently produces approximately 20-25 % (more than 7 million pounds) of the world s yearly supply of ibuprofen. 

An early example of Raman mapping by Breitenbach et al. [52] showed that when crystalline ibuprofen is formulated in a hot melt extrudate the API changes to the amorphous form. Ibuprofen is a sparingly water-soluble compound, so this formulation provides a route to better bioavailability via the more soluble amorphous form. Using confocal Raman mapping the form of the API was determined at the time of manufacture and under stress conditions and was used to assess the stability of the amorphous form. These studies also showed that the API was homogeneously distributed throughout the formulation based on the relative band intensities of the amorphous API and a formulation excipient, polyvinylpyrrolidone (PVP). 

One of the basic unit operations is dry mixing that is used in most manufacturing schemes. In Fig. 10.6, an example of the use of Raman monitoring for blend control is shown. In this case the blending procedure is very fast and the mixture is well blended within the 5 min used. De Beer et al. used an in situ Raman immersion probe setup to study an ibuprofen-xanthan gum... 

In 1992 BHC (Boots Hoechst-Celanese) Company commercialized a new synthetic process to manufacture ibuprofen in BHC s 3500 metric-ton-per-year facility in Bishop/TX, USA, which was cited as an industry model of environmental excellence in chemical processing technology. For its innovation, BHC was the recipient of the 1997 Alternative Synthetic Pathways Award of the Presidential Green Chemistry Challenge. 

The BHC ibuprofen process is an innovative, efficient technology that revolutionized bulk pharmaceutical manufacturing. The new technology with its three catalytic steps achieves approximately 80% atom utilization, which is increased to almost 99% if recovery of the by-product acetic acid is included. It replaces a pro-... 

The Boots patent on ibuprofen expired in the 1980s, and other manufacturers became able to manufacture and sell ibuprofen. In 1991, the Boots and Hoechst Celanese... 

Cauwenberg V, Vergossen P, Stankiewicz A, Kierkels H. Integration of reaction and separation in manufacturing of pharmaceuticals membrane-mediated production of S-ibuprofen. Chem Eng Sci 1999 54 1473-1477. 

The BHC ibuprofen process is an innovative, efficient technology that has revolutionized bulk pharmaceutical manufacture. The process provides an elegant solution to a prevalent problem encountered in bulk pharmaceutical synthesis It avoids the large quantities of solvents and waste (especially aqueous salt waste... 

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... 

Other asymmetric synthetic processes used for the manufacturing of (S)-(+)-naproxen can also be applied to the production of (S)-(+)-ibuprofen these include the Rh-phosphite catalyzed hydro-formylation,37 hydrocyanation,25 and hydrocarboxylation reactions.24... 

Because ibuprofen has been a successful drug on the market for almost 30 years with no patent protection since 1985, there is a widespread competition for commercial production of this product throughout the world. As a result, several practical and economical industrial processes for the manufacture of racemic ibuprofen (14) have been developed and are in operation on commercial scales.38 Most of these processes start with isobutylbenzene (15) and go through an isobutylstyrene3 4 or an acetophenone intermediate.42 The most efficient route is believed to be the Boots-Hoechst-Celanese process, which involves 3 steps from isobutylbenzene, all catalytic, and is 100% atom-efficient (Scheme 6.1).43 44... 

The ultimate goal in most industrial research is to develop economically attractive processes or products. The technology of asymmetric hydrogenation of 2-arylacrylic acids is probably most useful for the production of naproxen and S-ibuprofen. Naproxen is currently one of the top ten prescription drugs in the world S-ibuprofen is the active isomer in the popular anti-inflammatory drug ibuprofen. Figures 5 and 6 summarize two commercially feasible processes for the manufacturing of these products. 

In this chapter we discuss the mechanistic and other details of a few industrial carbonylation processes. These are carbonylation of methanol to acetic acid, methyl acetate to acetic anhydride, propyne to methyl methacrylate, and benzyl chloride to phenyl acetic acid. Both Monsanto and BASF manufacture acetic acid by methanol carbonylation, Reaction 4.1. The BASF process is older than the Monsanto process. The catalysts and the reaction conditions for the two processes are also different and are compared in the next section. Carbonylation of methyl acetate to acetic anhydride, according to reaction 4.2, is a successful industrial process that has been developed by Eastman Kodak. The carbonylation of propyne (methyl acetylene) in methanol to give methyl methacrylate has recently been commercialized by Shell. The Montedison carbonylation process for the manufacture of phenyl acetic acid from benzyl chloride is noteworthy for the clever combination of phase-transfer and organometallic catalyses. Hoechst has recently reported a novel carbonylation process for the drug ibuprofen. 

The main large-scale metal catalyzed reactions involving addition of CO (rather than CO + H2) to an organic substrate are the manufacture of acetic acid from methanol and the related production of acetic anhydride from methyl acetate. The syntheses of some other carboxylic acids and the conversion of a substituted benzyl alcohol to ibuprofen involve similar reactions. 

Carbonylation of Benzyl Alcohol to Phenylacetic Acid Manufacture of Ibuprofen... 

S)-Naproxen, 18, and S-ibuprofen, 19, are important and widely used analgesics with annual sales of about US 1.4 billion and a production volume of about 8000 tons. A technical feasible use of R,R-tartaric acid as chiral auxiliary was demonstrated in the Zambon Process for S-naproxen manufacture [3]. The diastereoselective bromination is followed by bromine hydrogenolysis and hydrolysis to produce S-naproxen in 75 percent overall yield. 

All the clinical trials that have been performed on glucosamine have shown it to be safe. However, there are allegations that the trials have been liable to bias, as some of the trials to date have had sponsorship from companies that manufacture glucosamine supplements. An additional concern is that most trials have been carried out using less than maximal daily dose of ibuprofen as control, and none compared glucosamine with paracetamol, both of which are widely used NSAIDs. 

---