By Daniel Hernández
Esterification is a type of chemical reaction typical of carbonyl compounds. It occurs when a carbonyl compound (such as a carboxylic acid or a ketone) reacts with a nucleophile, such as an alcohol, under acidic or basic conditions to form an ester and release a water molecule. The esters produced are very important compounds in industry, as they are very stable compounds, so they are used as solvents, many exhibit pleasant odors, so they are used in fragrances, they are also used as varnishes, plastic coatings, herbicides, pesticides and others have wide application in the pharmaceutical industry as Active Pharmaceutical Ingredients (API)(Khan et al., 2021).
The esterification reaction can occur by three main mechanisms: 1) by reactions of alkyl halides, 2) reactions of alkenes and alkynes with epoxides and 3) Fischer reactions between acids and alcohols. The first two are widely used in the synthesis of drugs and other materials, while the third is commonly a secondary reaction in acidic compounds. For such a reaction to occur, all that is needed is an acidic compound, an alcohol and a relatively strong acidic or basic medium. Interestingly, this reaction is thermodynamically reversible, and relatively slow, so the reaction conditions are decisive for the formation of an ester (Lavis, 2008). For example, one way to accelerate the formation of an ester is by manipulating Le Châtelier's principle, either by adding an excess of a reactant such as alcohol or by removing a product, such as water, from the reaction through distillation or drying of the reaction sinus.
In relation to the pharmaceutical industry, esters play an important role in many drugs. There are many APIs that contain ester groups (e.g. benzocaine, lovaza, felbamate, valacyclovir, etc.) and others that function as prodrugs (e.g. enalapril, aspirin, ibuprofen, etc.), in which the ester group provides stability to the molecule, facilitates its absorption and produces a prolonged release by taking advantage of the reversibility of the ester bond (Abualhasan et al., 2020; Kalgutkar et al., 2000). There are also new drugs that study the capacity of the ester group in glycosylated molecules to focus and mark new molecular targets and thus better treat some ailments (Beaumont et al., 2003). However, there is also the case where ester formation is an undesired phenomenon. In many drugs, production requires the use of alcohols to sterilize surfaces, so that APIs, when they come into contact with an alcohol, undergo esterification, which changes the structure of the compound and potentially its biological effect. However, this may not always occur, as the reaction is very sensitive to pH conditions, amount of reagents, temperature, etc. To recognize that a drug is undergoing esterification, detailed analysis is necessary[DL1].
A very clear example of the degradation of an API by esterification reactions was presented in 2009 in the Journal of Pharmaceutical and Biomedical Analysis. In this study, 5 impurities of the drug Zafirlikast, a drug to treat asthma, were analyzed, all of which turned out to be products of the transesterification of the methanol used as solvent in the synthesis of the API and was catalyzed by traces of toluensulfonamide, an unreacted precursor in the synthesis. In this case, the transformation of the API did prove to be detrimental to the effectiveness of the drug reducing its effectiveness by more than 50% and in-depth analyses were necessary to recognize its degradation products and the correction of the synthesis process in order to avoid its degradation (Goverdhan et al., 2009).
In summary, esters are very important molecules for all industries, including the pharmaceutical industry. Although many times esterification can occur in drugs, it can be harmful, it is recommended to perform analysis to know the effects of this reaction on your drug.
Bibliography
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