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Cosolvent
In chemistry, cosolvents are substances added to a primary solvent in small amounts to increase the solubility of a poorly-soluble compound. Their use is most prevalent in chemical and biological research relating to pharmaceuticals and food science, where alcohols are frequently used as cosolvents in water (often less than 5% by volume) to dissolve hydrophobic molecules during extraction, screening, and formulation. Cosolvents find applications also in environmental chemistry and are known as effective countermeasures against pollutant non-aqueous phase liquids, as well as in the production of functional energy materials and synthesis of biodiesel.
The topic of cosolvency has attracted attention from many theorists and practicing researchers who seek to predict the solubility of compounds using cosolvent systems, and it is the subject of considerable research in scientific literature. Studies exist to propose and review methods of modeling cosolvency using calculation, to describe empirical correlations of cosolvents and observed solvation phenomena, and to report the utility of cosolvent systems in various fields.
Long-standing challenges in pharmaceutical chemistry include overcoming the inherent hydrophobicity/lipophilicity of certain molecules for treatment and finding effective synthesis procedures for complex molecules. Cosolvents are able to aid researchers in both the trials of formulation and synthesis.
In pharmaceutical chemistry, numerous methods exist to help solubilize poorly water-soluble drugs for use in treatment. These methods include cosolvency, hydrotropism, complexation, ionization, and using surface active agents. The most pervasive is the application of non-toxic cosolvents with water to produce formulations that can dissolve hydrophobic molecules while maintaining cohesion with biological systems. Common cosolvents for this purpose are ethanol, propylene glycol, glycerine, glycofural, and polyethylene glycols. The effect of cosolvency on drug solubilization can be great, as evidenced by a 2009 study in which researchers from Panjab University showed the solubility of various anti-diabetic drugs increase by more than 500 times by use of a cosolvent.
Cosolvents prove useful in synthetic applications as well as in formulation. Cosolvent systems are commonly specific to the synthetic target being studied, so reviewed here are the generalized findings of several publications that exemplify important points on the subject:
In a 2017 project, researchers at Cornell University studied the effect of cosolvency in oxazolidinone enolizations mediated by lithium hexamethyldisilazide (LiHMDS). This reaction pathway was exemplified by the group in the synthesis of filibuvir, a drug used for the treatment of hepatitis C that is produced on plant-scale by Pfizer. The researchers focus primarily on polymer formation in systems of tetrahydrofuran with hydrocarbon cosolvents, and find that the rate is strongly sensitive to the cosolvent utilized. Among other results, the study concludes that cosolvent choice is of acute importance in the pharmaceutical industry where percent yield, trace impurities, and processing techniques are chemically, financially, and toxicologically relevant. However, the researchers take care to mention that the mechanisms that bring about these empirical differences in cosolvent systems are not yet well-understood.
A 2016 paper from researchers at Hokkaido University describes a cosolvent-promoted mechanism for benzylating hydroxyl groups in the synthesis of sucrose derivatives. The group reports a method by which the benzylation reaction, empirically low yielding and with significant formation of byproducts due to the generally low reactivity of the target 1’-hydroxyl group in sucrose, was carried out to up to 95% yields with excellent selectivity for the synthetic molecule. They accomplished this yield by utilizing a cosolvent system of hexanes and methylene chloride, and extrapolated the method to include a number of benzyl halide substrates, as well as alcohols, glucose, and ribose derivatives. This study is one of many where reaction yields in organic synthesis can be optimized by application of polar/non-polar cosolvent systems.
Cosolvents also play a role in the biochemical subdiscipline: a 2012 study from researchers at the South China University of Technology reports how cosolvent parameters can be optimized to obtain higher yields in enzyme-catalyzed reactions. Specifically, the group looked at the prune seed meal-catalyzed synthesis of bioactive anti-depressant salidroside, and found that using ethylene glycol diacetate in conjunction with an ionic liquid cosolvent afforded up to a 50% increase in product yield. The use of ionic liquids as cosolvents in this study and many similar demonstrates the variability of this methodology, where cosolvent systems can extend beyond standard conventions of polar and non-polar solvents to affect change on a mechanistic level.
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Cosolvent
In chemistry, cosolvents are substances added to a primary solvent in small amounts to increase the solubility of a poorly-soluble compound. Their use is most prevalent in chemical and biological research relating to pharmaceuticals and food science, where alcohols are frequently used as cosolvents in water (often less than 5% by volume) to dissolve hydrophobic molecules during extraction, screening, and formulation. Cosolvents find applications also in environmental chemistry and are known as effective countermeasures against pollutant non-aqueous phase liquids, as well as in the production of functional energy materials and synthesis of biodiesel.
The topic of cosolvency has attracted attention from many theorists and practicing researchers who seek to predict the solubility of compounds using cosolvent systems, and it is the subject of considerable research in scientific literature. Studies exist to propose and review methods of modeling cosolvency using calculation, to describe empirical correlations of cosolvents and observed solvation phenomena, and to report the utility of cosolvent systems in various fields.
Long-standing challenges in pharmaceutical chemistry include overcoming the inherent hydrophobicity/lipophilicity of certain molecules for treatment and finding effective synthesis procedures for complex molecules. Cosolvents are able to aid researchers in both the trials of formulation and synthesis.
In pharmaceutical chemistry, numerous methods exist to help solubilize poorly water-soluble drugs for use in treatment. These methods include cosolvency, hydrotropism, complexation, ionization, and using surface active agents. The most pervasive is the application of non-toxic cosolvents with water to produce formulations that can dissolve hydrophobic molecules while maintaining cohesion with biological systems. Common cosolvents for this purpose are ethanol, propylene glycol, glycerine, glycofural, and polyethylene glycols. The effect of cosolvency on drug solubilization can be great, as evidenced by a 2009 study in which researchers from Panjab University showed the solubility of various anti-diabetic drugs increase by more than 500 times by use of a cosolvent.
Cosolvents prove useful in synthetic applications as well as in formulation. Cosolvent systems are commonly specific to the synthetic target being studied, so reviewed here are the generalized findings of several publications that exemplify important points on the subject:
In a 2017 project, researchers at Cornell University studied the effect of cosolvency in oxazolidinone enolizations mediated by lithium hexamethyldisilazide (LiHMDS). This reaction pathway was exemplified by the group in the synthesis of filibuvir, a drug used for the treatment of hepatitis C that is produced on plant-scale by Pfizer. The researchers focus primarily on polymer formation in systems of tetrahydrofuran with hydrocarbon cosolvents, and find that the rate is strongly sensitive to the cosolvent utilized. Among other results, the study concludes that cosolvent choice is of acute importance in the pharmaceutical industry where percent yield, trace impurities, and processing techniques are chemically, financially, and toxicologically relevant. However, the researchers take care to mention that the mechanisms that bring about these empirical differences in cosolvent systems are not yet well-understood.
A 2016 paper from researchers at Hokkaido University describes a cosolvent-promoted mechanism for benzylating hydroxyl groups in the synthesis of sucrose derivatives. The group reports a method by which the benzylation reaction, empirically low yielding and with significant formation of byproducts due to the generally low reactivity of the target 1’-hydroxyl group in sucrose, was carried out to up to 95% yields with excellent selectivity for the synthetic molecule. They accomplished this yield by utilizing a cosolvent system of hexanes and methylene chloride, and extrapolated the method to include a number of benzyl halide substrates, as well as alcohols, glucose, and ribose derivatives. This study is one of many where reaction yields in organic synthesis can be optimized by application of polar/non-polar cosolvent systems.
Cosolvents also play a role in the biochemical subdiscipline: a 2012 study from researchers at the South China University of Technology reports how cosolvent parameters can be optimized to obtain higher yields in enzyme-catalyzed reactions. Specifically, the group looked at the prune seed meal-catalyzed synthesis of bioactive anti-depressant salidroside, and found that using ethylene glycol diacetate in conjunction with an ionic liquid cosolvent afforded up to a 50% increase in product yield. The use of ionic liquids as cosolvents in this study and many similar demonstrates the variability of this methodology, where cosolvent systems can extend beyond standard conventions of polar and non-polar solvents to affect change on a mechanistic level.
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