Ethanol as co-solvent

In this chapter, we have reviewed some of our own work on solvation properties in supercritical fluids using molecular dynamics computer simulations. We have presented the main aspects associated with the solvation structures of purine alkaloids in CO2 under different supercritical conditions and in the presence of ethanol as co-solvent, highlighting the phenomena of solvent density augmentation in the immediate neighborhood of the solute and the effects from the strong preferential solvation by the polar co-solvent. We have also presented a summary of our results for the structure and dynamics of supercritical water and ammonia, focusing on the dielectric behavior of supercritical water as functions of density and temperature and the behavior of excess solvated electrons in aqueous and non-aqueous associative environments. 

Result Extraction of dry nibs with pure CO2 seems to increase the concentration of the ingredients apparently. In reality the quantity is kept unaltered but gets higher because of the loss of cacao butter (this is contrary to the results of Li and Hartland). Independently to the pre-treatment and to the composition of the co-solvent the reduction of caffeine reaches about 90 %. Theobromine is reduced remarkably only with ethanol as co-solvent. Only with the knowledge of later tests the worse reduction of theobromine at a composition of the co-solvent of 1 2 waterethanol can be understood The concentration of ethanol in CO2 becomes too small. 

After water, ethanol is most commonly used in the formulation of oral liquids and is not without risk of acute overdose or chronic intoxication in children. There are still many extemporaneous and commercial preparations containing ethanol as co-solvents administered to children. Adverse effects to the central nervous system because of high blood-brain barrier permeability in children are reported, along with drug interactions linked with acute or chronic exposure. In the USA, the limits are set to a maximum of 10% alcohol in products for 12 year olds and over, a maximum of 5 % alcohol in products intended for children aged 6-12 years and less than 0.5% alcohol content in products intended for children under 6 years of age. Nevertheless, further longterm research is needed to evaluate safety when this excipient is present in the drug formulation. 

Figure 28. Pressure - composition (W2) plot for the system CO2 (l)/palmitic acid (2)/co-solvent (3) at 318 K for 3-methyl-1-butanol and ethanol as co-solvents at a range of co-solvent concentrations [36].

Mendes et al. [93] used ethanol as co-solvent (10 mol %) to increase the lipid yield during the SC extraction of Spirulina. The CO2 modified with ethanol gave lipid yields comparable with those of traditional organic solvents. Mendes et al. focussed their research on the extraction of Y-linoleinic acid but did also analyse the palmitic acid content of their samples. However, no comments regarding palmitic acid were given and too little information is presented to provide definitive conclusions. 

For lower hydrogen partial pressures the following rate expression was developed (hydroformylation of n-octene-1 with ethanol as co-solvent to increase the octene solubility [5]) ... 

Da Porto, C Decorti, D Natolino, A. Water and ethanol as co-solvent in supercritical fluid extraction of proanthoc anidins from grape marc A comparison and a proposal. J. of Supercritical Fluids 2014, 87, 1-8. 

In other studies of SFE of com germ oil using ethanol as co-solvent (Ronyai et al, 1998) a linear increase at the beginning of the process has been also observed. 

One of the drawbacks of pure CO2 as supercritical solvent is the low solubility of polar compounds which is attributed to lack of a strong permanent dipole moment in CO2. In order to improve solvation and extraction power, a highly polar or associative liquid is added to SC-CO2 in small quantities as co-solvent. Ethanol is the co-solvent of choice for a number of reasons, including its superior mixibility (compared to water, for instance) with CO2 and its wide acceptance in pharmaceutical and food-related supercritical extractions. 

The crushed seeds of Crotalaria spectabilis were first contacted with supercritical carbon dioxide and, as expected, the oils comprising the bulk of the seed material were preferentially extracted. The addition of ethanol and water as co-solvents in the fluid phase led to the appearance of monocrotaline in the extract. Monocrotaline contents as high as 24% of the total extract could be obtained with carbon dioxide-ethanol mixtures. 

Reduction of derivatives of estradiol 3-methyl ether (I) and hydrolysis of the initially formed enol ether II provides an efficient route to 19-norsteroids (111) of considerable importance in hormone therapy. A. J. Birch, who introduced the method (1949), used sodium in liquid ammonia with ethanol as proton donor. A. L. Wilds and N.A. Nelson (1953) found that yields are improved by use of lithium in place of sodium and that lithium is effective in some cases where sodium is not. The Wilds-Nelson procedure, which became the standard one, employs ether as co-solvent and involves adding the ethanol lust terminal decomposition is done with water after evaporation of ammonia, Since this reaction is the key step in processes developed by O. D. Searleand Co. for the production of two I V-norsteroids... 

The use of supercritical CO2 to extract AR from cereal material was only recently presented (49). Pure supercritical CO2 was not able to extract AR even at pressures as high as 35 MPa and SS C. This result was attributed to the amphiphilic character of the AR and the non polar character of the supercritical CO2. With the addition of 10% of ethanol or methanol, it was possible to obtain extracts even at near the critical pressure (8 MPa). The optimal pressure was determined to be 3SMPa at S5°C when ethanol or methanol acted as co-solvent. The co-solvent was added as 10%wAv of the CO2. The CO2 flow was kept constant at Sg/min during the experiments. A comparison of the supercritical CO2 extraction with die addition of ethanol and classical extraction methods was made. For the classical method, pure acetone extraction at O.IMPa and 20°C was used. Between 15 and 30 MPa at 55°C, 8 to 80%w/w higher yields of AR crude extracts for the extraction with supercritical CO2 with co-solvents were obtained than for pure acetone extraction (refer to figure 2). However, the HPLC analysis of the extracts showed similar composition (49). 

In some investigations two methods have been employed simultaneously, e.g., Pankov and co-workers [30-34] studied the identification of higher pyridine bases in the products of the industrial synthesis of pyridines. Hydrogenation of double bonds in side-product hydrocarbon radicals [27—29] was carried out in ethanol as the solvent at room temperature under a hydrogen atmosphere on a 2% palladium catalyst on active carbon. The presence and the number of the double bonds were inferred from the change in the retention time of the components after hydrogenation. 

Other studies seem to indicate, however, that care must be exercised when such ternary systems include small, polar solutes. Low molecular weight, polar solvents, in particular alcohols, are used extensively as co-solvents in natural products and other extractions employing SCCO2 [18]. The polar solvent acts as a modifier of gas-phase polarity and enhances the solubility of polar species that would otherwise exhibit limited solubility in CO2. The effect of solvents such as ethanol and acetone was investigated [13,19] by measuring the solubility of [BMIM][PF6] in CO2 in the presence of these solvents (Figure 5). 

Figure 29. Palmitic acid (W2) - co-solvent (W3) concentration plot at 308 K and constant pressure for the system CO2 (l)/pahnitic acid (2)/co-solvent(3) for ethanol and octane as co-solvent [60].

Ethanol is used as co-solvent in a concentration up to 20 % in oral solutions. If present in a concentration of at least 15 %, it also serves as a preservative. 

Current interest in radiation sterilization of pharmaceuticals led Fletcher and Davies [142] to investigate the sensitivity of benzocaine to irradiation in aqueous solution. Cetrimide and polysorbate 80 protect the drug from the deleterious effects of a Co source at doses up to 0.3 M rad. However, ethanol, glycerol and polyoxyethylene glycol 200 when used as co-solvents at concentrations up to 40% were more effective [142] (Fig. 11.23) (equal concentrations of surfactant and co-solvent were not compared). These results emphasize the need to compare critically the different approaches to both solubilization and stabilization. High concentrations of surfactant, even non-ionic surfactant, are usually impracticable on the grounds of toxicity and thus the choice of solubilization technique cannot always be made on the basis of the physical chemistry of the competing methods. 

Addition of co-solvents can also change the co-miscibility characteristics of ionic liquids. As an example, the hydrophobic [BMIM][PFg] salt can be completely dissolved in an aqueous ethanol mixture containing between 0.5 and 0.9 mole fraction of ethanol, whereas the ionic liquid itself is only partially miscible with pure water or pure ethanol [13]. The mixing of different salts can also result in systems with modified properties (e.g., conductivity, melting point). 

We looked at a number of water soluble cosolvents (Table 28.3). In all cases aldehyde products were observed. 1,4-dioxane compares well with ethanol as a co-solvent. The data so far shows that 1,4-dioxane shows slightly lower olefin conversion after two hours than ethanol, but shghtly better selectivity. 

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