Ibuprofen displacement

The reasons for this reaction are not known, but the authors of the report postulate that the ibuprofen displaced the ciprofibrate from its binding sites, thereby turning a safe dose into a toxic one. However, it should be said that this mechanism of interaction is rarely important on its own, so it seems likely that some other factors may have contributed to what happened. 

Ghosh [548] used cellulose nitrate microporous filters (500 pm thick) as scaffold material to deposit octanol into the pores and then under controlled pressure conditions, displace some of the oil in the pores with water, creating a membrane with parallel oil and water pathways. This was thought to serve as a possible model for some of the properties of the outermost layer of skin, the stratum comeum. The relative proportions of the two types of channel could be controlled, and the properties of 5-10% water pore content were studied. Ibuprofen (lipophilic) and antipyr-ine (hydrophilic) were model drugs used. When the filter was filled entirely with water, the measured permeability of antipyrine was 69 (in 10 6 cm/s) when 90% of the pores were filled with octanol, the permeability decreased to 33 95% octanol content further decreased permeability to 23, and fully octanol-filled filters indicated 0.9 as the permeability. 

Figure 3.4 The synthesis of ibuprofen is initiated by a Friedel-Crafts acylation of an aUcyl-substituted benzene ring. The resulting ketone is then reduced to an alcohol with sodium boro-hydride. The alcohol functionality then undergoes a functional group interchange by conversion to a bromide. In turn, this permits the introduction of an additional carbon atom in the form of a nitrile introduced via an 8, 2 nucleophilic displacement. This is then hydrolyzed to give the target molecule.

Acute renal insufficiency occurred in one patient taking ciprofibrate 100 mg/day and ibuprofen 400 mg/day (84). Both drugs are highly protein-bound and contain propionic acid groups. Thus, ibuprofen may displace ciprofibrate. 

For exanple, it can be seen in Fig. 3, that the highest possible k values for the phenolic solutes are lower than desirable, even in pure water as eluent. The solubility of these phenolic compounds is also low in pure water. Therefore, as a oenpremise between the opposing requirements of sufficient retention and high solubility, a carrier solution oenpositien of 10 % methanol water was selected for the further studies. Similarly, it can be seen from Fig. 5, that the k values of the Ibuprofen enantiomers are around 10 in the 30 % acetonitrile buffer eluent, therefore this conposition was selected for the carrier solution for the displacement chromatographic studies. 

Aromatic phenols and alcohols were also found to act as good displacers on cyclodextrin-silica columns (67,69). Since the retention studies discussed above indicate that p-nitrophenol is more retained (Fig. 2) than the chloroaniline isomers (Fig. 3), and 4-t-butyl cyclohexanol is more retained than the Ibuprofen enantiomers (Fig. 4), p-nitrophenol and 4-t-butylcyclohexanol were selected as possible displacers for the separations discussed below. 

Since the chloroanilines are sufficiently retained (k >5) in a 10 % v/v methanol water eluent, and the Ibuprofen enantiomers are sufficiently retained in a 30 % v/v acetonitrile buffer eluent, these solvents were selected as carrier solvents for the displacement chromatographic separations. Also, these solvents were used to determine the adsorption isotherms of p-nitrophenol and 4-t-butylcyclohexanol on beta-cyclodextrin silica. The isotherms were determined from frontal chromatographic measurements as described in (56). The isotherms are shown in Figs. 7 and 8. Since both isotherms are downwardly convex, p-nitrophenol and 4-t-butylcyclohexanol might prove useful displacers for our test solutes, provided that they are more strongly adsorbed that the solutes. 

Many trial-and-error experiments can be avoided during the development of a displacement chromatographic separation, when the isotherm of at least the most strongly adsorbed sample component is known. Therefore, as the next step, the adsorption isotherms of the most retained iscmers of chloroaniline and Ibuprofen, the examples discussed above, were determined as shown in Figs. 8 and 9. It can be seen by cxnparing the isotherms of the solute and prospective displacer pairs that indeed p-nitrophenol can be used as a displacer for the separation of the chloroaniline iscmers. The situation is more complicated with Ibuprofen and 4-t-butylcyclchexanol because their isotherms cross each other at 1.5 irM. This indicates that successful separations can be expected only below this concentration level. Other examples of crossing isotherms were also reported (69). 

Displacement chromatogram of a racemic mixture of 0.5 umol Ibuprofen. Conditions 50 cm x 4.6 mm ID beta-cyclodextrin-silica column, carrier solvent 30 % v/v acetonitrile water, 5 mM triethylamine adjusted to pH 6.0 by acetic acid displacer 1 mM 4-t-butyl-cyclohexanol dissolved in the carrier solvent displacer flow-rate 0.2 mL/min column temperature 30 C. 

Ibuprofen Phenytoin Interaction probably of little or no clinical significance Displacement from plasma protein binding sites... 

Parkas, G, LH Irgens, G Quintero, MD Beeson, A Al-Saeed and G Vigh (1993). Displacement chromatograpy on cyclodextrin silicas, IV. Separation of the Enantiomers of Ibuprofen. Journal of Chromatography, 645,67-74. 

G. Farkas, L.H. Irgens, G. Quintero, M.D. Beeson, A. Al-Saeed and G. Vigh, Displacement Chromatography on Cyclodextrin Silicas, IV. Separation of the Enantiomers of Ibuprofen, J. 

Meclofenamic acid, indomethacin, ibuprofen and acetylsallcylic acid inhibit platelet aggregation. Phenylbutazone is less active in this re-speot o The anti-rheumatic action of aoetylsalicylic acid, phenylbutazone and indomethacin may not be associated with the displacement of... 

Carboxylic acids can he prepared from nitriles by heating with aqueous acid or base by a mechanism that we ll see in Section 15.7. Since nitriles themselves are easily made by Sn2 reaction of a primary or secondary alkyl halide with CN , the two-step sequence of cyanide displacement followed by nitrile hydrolysis is a good way to make a carboxylic acid from an alkyl halide (RBr RC=N RCO2H). Note that the product acid has one more carbon than the starting alkyl halide. An example occurs in one commercial route for the synthesis of the nonsteroidal anti-inflammatory drug ibuprofen. 

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