Ibuprofen preparation

Fig. 4 shows the plasma profiles obtained after oral administration of two plain tablets of 300 mg of ibuprofen prepared with two different batches of active principle, having differing particle size distributions dv= 1.5 pm and 5 pm), compared with a conventional marketed ibuprofen tablet. The plasma levels are strongly dependent on the specific surface area of the ibuprofen powder. 

In a previous paper [5] the conversion of sec-butylbenzene (sBB) was studied under atmospheric pressure over some acidic zeolite catalysts. The reaction turned out to be rather complex, involving many parallel and/or successive steps. Among the reaction products, the iso-butylbenzene is the most interesting one, being an important intermediate for die Ibuprofen preparation [6]. Those results showed that the overall conversion decreased for all the catalysts, with different deactivation rates. Dealkylation was the prevailing reaction and the isomerization product, the iso-butylbenzene was formed in a larger amount on the HY catalyst. 

Considerable advances in asymmetric hydroformylation, a process which, among other things, provides a potential route to enantiomericaHy pure biologically active compounds, have occurred. Of particular interest are preparations of nonsteroidal antiinflammatory (NSAI) pharmaceuticals such as Naproxen (8) and Ibuprofen (9), where the represents a chiral center. 

From 1981 to 1995 other dmgs switched to OTC were the antifiingal preparations containing micona2ole nitrate [22832-87-7] (7) and clotrima2ole [23593-75-1] (8) the antiinflammatory agent ibuprofen [15687-27-1] (9) and the histamine H2-receptor antagonists famotidine [76824-35-6] (10) and cimetidine [51481-61-9] (11). 

Lipase-catalyzed kinetic resolutions are often practical for the preparation of optically active pharmaceuticals (61). For example, suprofen [40828-46-4] (45), which is a nonsteroidal antiinflamatory dmg, can be resolved by Candida glindracea]i 2Lse in >95% ee at 49% conversion (61). Moreover, hpase-based processes for the resolution of naproxen [22204-53-1] and ibuprofen [15687-27-1] (61) have also been developed. 

Recently, Picciola et al. (81FES1037) prepared some 2iT-indazole derivatives containing a phenylalkanoic acid residue with potential antiinflammatory activity (693). M.G. 18755 (R = CHMeC02H, R = R = R = H) and its lysine salt, M.G. 18334, showed greater activity than ibuprofen, and the homologous butyric acid derivative M.G. 18860 showed good activity as a platelet aggregation inhibitor. 

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. 

To get around this problem, pharmaceutical companies attempt to devise methods of enantioselective synthesis, which allow them to prepare only a single enantiomer rather than a racemic mixture. Viable methods have already been developed for the preparation of (5)-ibuprofen, which is now being marketed in Europe. We ll look further into enantioselective synthesis in the Chapter 19 Focus On. 

Show how ou might prepare the anti-inflammatory agent ibuprofen starting from isobutylbenzene. More than one step is needed. 

Solid super bases, prepared by successive treatment of y-alumina with alkali metal hydroxide and alkali metal, are highly active catalysts for reactions involving reactive carbanions, and have been commercialised by Sumitomo (Suzukamo et al, 1997). For example, t.vobutylbenzene, the. starting material for ibuprofen (see earlier) is produced by side-chain alkylation of toluene with propylene over a K/KOH/AI2O3 catalyst (Eqn. (14)). 

Y Kawashima, T Iwamoto, T Niwa, H Takeuchi. Preparation and characterization of a new controlled release ibuprofen suspension for improving suspend-ability. Int J Pharm 75 25-36, 1991. 

How much of a crystallizable material X can I blend uniformly into a polymer until it starts to form crystals A series of blends with increasing amount of X is prepared. The samples are studied by WAXS (cf. Sect. 8.2) using laboratory equipment. Crystalline reflections of X are observed, as X starts to crystallize. Peak areas can be plotted vs. the known concentration in order to determine the saturation limit. Think of X being Ibuprofen and Y a polystyrene-(7 )-polyisoprene copolymer, and you have an anti-rheumatism plaster. 

When a preparation of ibuprofen was administered to a patient, the volume of distribution was found to be 5 L, and the half-life of elimination was 2 hours. What is the total clearance of ibuprofen ... 

The obtained results indicated that this procedure could be applied for the determination of ibuprofen, pseudoephedrine hydrochloride, chlorpheniramine maleate and nipagen in syrup preparations. 

Pharmaceutical grade ibuprofen, pseudoephedrine HCl, chlorpheniramine maleate, nipagen and syrup preparation were kindly supplied by Berko tlag Sanayi A. , Istanbul. 0.03 M H PO and KH PO solutions were prepared with analytical grade chemicals and milliQ water. HPLC grade acetoiutrile was used. 

Standard drag stock solutions (5,000 ppm for ibuprofen and 1,000 ppm for other drags) were prepared in water-acetoiutrile (50 50). 

The procedure shows that it is feasible to combine racemization with the kinetic resolution process (hence the DKR) of R,S)- ethoxyethyl ibuprofen ester. The chemical synthesis of the ester can be applied to any esters, as it is a common procedure. The immobilized lipase preparation procedure can also be used with any enzymes or support of choice. However, the enzyme loading will need to be optimized first. The procedures for the enzymatic kinetic resolution and DKR will need to be adjusted accordingly with different esters. Through this method, the enantiopurity of (5)-ibuprofen was found to be 99.4 % and the conversion was 85 %. It was demonstrated through our work that the synthesis of (5)-ibuprofen via DKR is highly dependent on the suitability of the reaction medium between enzymatic kinetic resolution and the racemization process. This is because the compatibility between both processes is crucial for the success of the DKR. The choice of base catalyst will vary from one reaction to another, but the basic procedures used in this work can be applied. DKRs of other profens have been reported by Lin and Tsai and Chen et al. ... 

Racemization via 1) HBr/AcOH and 2) KOH/MeOH Scheme 10.3 Two different preparations of (S)-ibuprofen by chemoenzymatic methods. 

The drugs like ibuprofen, flurbiprofen, ketoprofen etc. possess antiinflammatory property similar to aspirin but toxicity and adverse effects are fewer and of lesser intensity. These preparations alone and in combination with other NSAIDs are used for treatment of inflammatory disorders. 

The prototype for this class of compounds is ibufenac (42-3), developed by a group at Boots in the UK. This drug was to be quickly superseded by its a-methylated congener, ibuprofen, from the same laboratory [43]. The mechanistically very complex Wilgerodt reaction constitutes the key to the preparation of ibufenac. Thus, reaction of the acetylation product (42-1) from isobutyl benzene and acetyl chloride with sulfur and morpholine leads to the transposition of the oxidized function to the terminal carbon and formation of thiomorpholide (42-2). Hydrolysis of the thioamide... 

An intEiesting variant on the Wilgerodt reaction offers a simple three-step procedure that avoids the wastage involved in the schemes above, which require the incorporation of an extra carbon atom that must later be eliminated. The sequence starts with the acylation of isobutylbenzene (49-1) with propionyl chloride to give propiophenone (49-2). Reaction of that with thallium 111 nitrate and methyl ortho-formate in methanol leads in high yield to the methyl ester (49-3) of ibuprofen [50]. This would be the method of choice for preparing the dmg but for two unfortunate facts the extreme toxicity of thallium and the very high sensitivity of analytical methods for the detection of metals. It proved to be virtually impossible, in practice, to produce samples that showed zero residues of thallium. 

Therefore, we prepared and tested compressed three-layer tablets, covered on all surfaces, except for one part of the first dose, with an impermeable coating. We employed ibuprofen as a model drug, hydroxypropylmethylcelluloses as components of the control barrier and some superdisintegrants as the energy source [13]. 

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