Ibuprofen Ethanol

Carbonylation of IBPE and other 2-arylethanols with various organosoluble Pd-catalysts was studied in detail with special emphasis on the role of the promoters p-toluenesulfonic acid and LiCl [55], Some of the catalytic species, such as [PdCl(PPh3)2] formed from [Pd(PPh3)4] or from Pd(II) precursors in aqueous methylethylketone (MEK) under reaction conditions (54 bar CO, 105 °C) were identified by P NMR spectroscopy. Ibuprofen was obtained in a fast reaction (TOP = 850 h" ) with 96% yield (3-IPPA 3.9 %), while the carbonylation of l-(6-methoxynaphtyl)ethanol gave 2-(6-methoxynaphtyl)propionic acid (Naproxen) with high selectivity (97.2 %) but with moderate reaction rates (TOP = 215 h" ). 

D) Confusion and ataxia these CNS toxicities of ibuprofen are additive with those of ethanol... 

Carbonylation of Alcohols - Pd(tppts)3 catalyses the carbonylation of benzylic alcohols to the corresponding phenylacetic acids, in the presence of a Bronsted acid cocatalyst such as H2S04 or p-CH3C6H4S03H in biphasic aqueous/organic media (no organic solvent).305,451 For example, benzyl alcohol was converted to phenylacetic acid (Equation 6) and l-(4-isobutylphenyl)ethanol (IBPE) to ibuprofen (Figure 9). 

The effect of various SFC parameters on chiral resolution were also studied. Modifiers can provide control over both retention and selectivity and, therefore, certain modifiers were used to optimize the separation in sub-FC and SFC. The effect of the enantioselectivity of carbon dioxide on acidic drugs (benzoxaprofen, temazepam, and mephobarbital), profen, and barbiturate derivatives was carried out on Chiralcel OJ, with acetonitrile or methanol as organic modifier [140]. Acetonitrile proved to be a good alternative to methanol, especially for the profen compounds that were not well resolved when methanol was used. Wilson [143] studied the effects of methanol, ethanol, and 2-propanol as organic modifiers on the chiral resolution of ibuprofen on Chiralpak AD CSPs. Methanol was found to be the best organic modifier. 

FIGURE 28 Chromatograms of the chiral resolution of ibuprofen by SFC on Chiralpak AD column, with (a) methanol, (b) ethanol, and (c) 2-propanol as the organic modifiers. (From Ref. 143.)... 

Overmeyer et al. (1999) Batch Esterification of 1-phenyl ethanol and ibuprofen Novozym-435... 

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... 

Anandamide is rapidly hydrolysed enzymatically to arachidonic acid and ethanol-amine by a fatty acid amide hydrolase (FAAH) [50], The molecular characterization, cloning and expression of FAAH have been reported in a recent study [51]. FAAH can be blocked with either the general serine protease inhibitor phenyl methy(sulphonyl fluoride [38] or with the highly efficient methyl arachidonyl fluorophsphonate [52], The non-steroidal antiinflammatory ibuprofen in therapeutic doses, but not aspirin, sulindac or acetaminophen, also inhibits anandamide metabolism [53], This observation may have therapeutic implications. 

The salt production can be circumvented by performing the selective Pd/ tppts-catalysed carbonylation of benzyl alcohol in an acidic aqueous biphasic system (Fig. 1.36) [106]. This methodology was also applied to the synthesis of ibuprofen (see earlier) by biphasic carbonylation of l-(4-isobutylphenyl)ethanol [107] and to the biphasic hydrocarboxylation of olefins [108]. 

PdCl2(PPh3)2 catalyzed homogeneous carbonylation of l-(4 -isobutylphenyl) ethanol, in which some of the isomeric linear acid, 4- -Bu-C6H4CH2CH2C02H, is also formed typical yields are 92% of ibuprofen and 6% of the linear acid (see also Section 4.3.1). The carbonylation is performed at 50 bar, 130°C, in an acidic aqueous medium containing chloride ions, a ketone (such as methyl ethyl ketone) as solvent, and at least 10% of water [V. Elango et al., US Patent 4 981 995 (1991)]. A convenient ratio of substrate palladium catalyst is 10 1. A 3.5kt/a plant in Bishop, Texas has been operated by BHC since 1992. The palladium catalyst can be precipitated from the organic phase of the carbonylation reaction and re-used without further treatment. 

Type I CSPs have also been used with aqueous mobile phases. Pirkle et al. (32) have reported on the resolution of N-(3,5-dinitrobenzoyl) derivatives of M-amino adds and 2-aminophosphonic adds on an (l )-N-(2-naphthyl)-alanine-derived CSP using a mobile phase composed of methanol-aqueous phosphate buffer. The utility of achiral alkyltrimethylammoruum ion-pairing reagents was also investigated. Other examples include the following (1) The recently commercialized ot-Burke 1 CSP resolves the enantiomers of a number of underivatized p-blockers using an ethanol-dichlorornethane-ammonium acetate mobile phase (33) (2) an (R)-l-naphthylethylurea CSP was used to resolve N-(3,5-dinitrobenzoyI)-substituted amino adds and 3,5-dinitrobenzoyl amide derivatives of ibuprofen, naproxen, and fenoprofen with acetonitrile-sodium acetate mobile phases (34). 

ASA = aspirin NSAIDs = non-steroidal anti-inflammatory drugs, such as ibuprofen, naproxen, and diclofenac CNS stimulants include drugs such as pseudoephedrine, dextroamphetamine, theophylline, and caffeine MAO = monoamine oxidase CNS depressants include drugs such as benzodiazepines, barbiturates, and ethanol SSRIs = selective serotonin reuptake inhibitors, such as fluoxetine, sertraline, and paroxetine. Antidiabetic agents include drugs such as insulin, glipizide, glyburide, and metformin. 

The nature of solvent has been found to have a profound effect on crystal habit of ibuprofen. Ibuprofen crystals precipitated from ethanol and acetone (solvents having high surface tension, dielectric constant, and less specific gravity) were thin, platy, and nearly circular-shaped, whereas those obtained from propylene... 

It is important to note that unlike in precipitation method, both polar solvent, such as acetone, and nonpolar solvents, such as diethyl ether and hexane, produced needlelike crystals of ibuprofen when saturated solutions were cooled to 5°C over 120 min. Dichloromethane produced cubic, whereas acetonitrile produced spherical agglomerated crystals by this method. Solvent evaporation of ethanol gave platy... 

A 37-year-old man with a history of ethanol abuse presented with hepatic failure and non-cardiogenic pulmonary edema after an overdose of paracetamol, codeine, ibuprofen, and diazepam. He received two... 

Solvated crystals are also common in the chemical and pharmaceutical industries. Figure 2-18 shows the room temperamre solubility curve of ibuprofen-lysinate as a function of water content in ethanol. As shown in the figure, the crossover point between anhydrous solid and monohydrate is < 5% water. At room temperamre, ibuprofen-lysinate remains anhydrous when the water content is below 5% and transforms into monohydrate when the water content is above 5%. In this example, solvate and anhydrous materials also have different crystal habits, as shown in Fig. 2-19. 

For adsorption of impurities, the suiTounding phase of interest is typically the liquid phase. The adsorption isotherm can be built by determining the impurity levels in the solution before and after adding the solid (as adsorbent). Based upon the change of impurity levels in the solution, the adsorption isotherm can then be determined. Figiue 2-24 shows a Langmuir-type adsorption isotherm of R-ibuprofen S-lysinate on S-ibuprofen S-lysinate crystals in an ethanol/water solvent mixture. As shown in the figure, a trace amount of impurities can be adsorbed onto the crystal surface even when the impurity concentration in the solution is well below its solubility limit. 

The stable anhydrous ibuprofen lysinate can be produced by the combination of lysine in water and ibuprofen in ethanol at room temperature such that the final water level in the solvent mixture is below 5 weight %. If the weight % of water is greater than 5%, a monohydrate of ibuprofen lysinate is obtained. The monohydrate converts to anhydrous ibuprofen lysinate if water is flushed out by the anhydrous ethanol. 

Table 7-2 Solubility of the R/S-Ibuprofen-S-Line in an Ethanol/Water 97/3 Solvent Mixture (23°C)...

The apparent acid dissociation constants (p s)Ka) of two water-insoluble drugs, ibuprofen and quinine, were determined pH-metrically in ACN water, dimethyl-formamide water, DMSO water, 1,4-dioxane-water, ethanol water, ethylene glycol-water, methanol water, and tetrahydrofuran water mixtures. A glass electrode calibration procedure based on a four-parameter equation (pH = alpha-i- SpcH -i-jH[H+] -i-jOH[OH ]) was used to obtain pH readings based on the concentration scale (pcH). We have called this four-parameter method the Four-Plus technique. The Yasuda Shedlovsky extrapolation p s)K a + log [H2O] = A/epsllon -1- B) was used to derive acid dissociation constants in aqueous solution (pKa). It has been demonstrated that the pK a values extrapolated from such solvent-water mixtures are consistent with each other and with previously reported measurements. The suggested method has also been applied with success to determine the pKa values of two pyridine derivatives of pharmaceutical Interest. Spectrometric, ultraviolet (UV) ... 

Nonsteroidal anti-inflammatory drugs (naproxen and ibuprofen) Penicillins Phenylbutazone Probenecid Salicylates Sulfonamides Barbitu rates Phenytoin Probenecid Retinoids Salicylates Sulfonamides Sulfonylureas Tetracycline Ethanol Retinoids Dipyridamole... 

Arylpropionicacids such as ibuprofen 105 are important NS AIs (non-steroidal anti-inflammatories). Only one enantiomer is active and some are administered as enantiomerically pure compounds through there is a problem with racemisation in the body by enolisation. This can be turned to advantage in deracemisation . Weak bases are enough to convert the acid chloride 106 into an enolate that eliminates 107 to form the achiral ketene 108. Addition of, say, ethanol then gives racemic esters 109 R = Et of ibuprofen. 

If a compound is poorly soluble in water, the pKa may be difficult to measure. One way around this problem is to measure the apparent pKa of the compound in solvent and water mixtures and then extrapolate the data back to a purely aqueous medium using a Yasuda-Shedlovsky plot. The organic solvents most frequently used are methanol, ethanol, propanol, dimethylsulphoxide (DMSO), dimethyl formamide (DMFA), acetone and tetrahydrofuran (THF). However, methanol is by far the most popular because its properties are closest to water. A validation study in water-methanol mixtures has been reported by Takacs-Novdk et al. (1997) and the determination of the pfCas of ibuprofen and quinine in a range of organic solvent-water mixtures has been reported by Avdeef et al. (1999). 

On the other hand, SEPA (2-n-nonyl-l,3-dioxolane) has been shown to be a more versatile penetration enhancer in terms of its ease of formulation, chemical stability and its ability to enhance the skin penetration of a wide variety of compounds of varying physicochemical characteristics. Permeants that have been evaluated include indomethacin, ibuprofen, minoxidil, acyclovir, caffeine, econazole, papaverine, progesterone and estradiol. The degree of skin penetration enhancement using SEPA is dependent on the physicochemical characteristics of the permeant. For example, following application of indomethacin in a simple ethanol-propylene glycol vehicle to human skin in vitro, cumulative absorption over 24 h amounted to 0.7 percent of the applied dose. The addition of 2 percent SEPA to the vehicle increased the 24 h absorption value to 23 percent of the applied dose (Marty et al. 1989). Furthermore, in comparative studies between SEPA and Azone, SEPA was shown to be a more effective human skin permeation enhancer for indomethacin (Figure 14.6, Marty et al. 1989). 

Ethinylestradiol Ethanedisulfonic acid Caramiphen edisylate Ethanol Alibenol Benoxinate HCI Bufexa mac Clobazam Clofibrate Dicyclomine HCI Ethionamide Ethoheptazine Etiroxate Exalamide Feprazone Floredil HCI Flurbiprofen Gramicidin Heptabarbitol Ibuprofen Ibuproxam Insulin Ketoprofen Lofexidine HCI Mebeverine HCI Meperidine HCI Methitural... 

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