Biocatalytic Insights for The Synthesis of New Potential Prodrugs: Design of two Ibuprofen Derivatives  
[PERSON]  
1 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara,  
Via [PERSON], 46-41421 Ferrara, Italy; [EMAIL_ADDRESS] (F.P. ); [EMAIL_ADDRESS] (L.A.L. ); [EMAIL_ADDRESS] (P.G. ); cts  
contra-indications, including damage to the gastric mucosa, such as stomach ulcers, bleeding, and perforation. These disadvantages are mostly due to the limited bioavailability of ibuprofen, which is the result of its very low solubility in water (only 21 mg/L) [3] and results in serious adverse effects when it is administered at high doses in the currently available solid dosage forms. Due to this aspect, ibuprofen ranks among the poorly water-soluble drugs, characterized by dissolution-limited oral bioavailability [4]. In particular, the carboxylic acid group of ibuprofen limits its solubility in acidic media (such as in the stomach) [5]. The contact of ibuprofen's carboxylic group with the gastric mucosa leads to damage (through a combination of local irritation and the inhibition of the cytoprotective function of prostaglandandandins) [6]. To overcome these limitations, we planned to design ibuprofen prodrugs masking the carboxylic acid of ibuprofen and enhancing its water solubility. A prodrug is a derivative of an active pharmaceutical ingredient obtained through modifications, sometimes chemical, involving the covalent attachment of molecules that, as in the case of this article, may lead to the increased water solubility of the native active compound. Among the generally reported characteristics of prodrugs, they should readily revert to the native drug form once inside the body. For this reason, prodrugs listed as \"ester prodrugs\" find significant utility, given the abundant presence of lipases and esterases in our bodies [7]. In this regard, the literature reports studies on the esterification of racemic ibuprofen with glycerol. [PERSON] et al. published a study on the diffusion of ibuprofen into the active site of _Candida antarctica_ lipase type B (CalB) [8], as well as investigations into the esterification at the molecular level through concentration-modulated infrared spectroscopy [9]. [PERSON] et al. reported the kinetic model of the esterification of racemic ibuprofen with CalB in _solventless_[10] and biphasic [11] systems, both for immobilized [12] and free [13] biocatalysts. Moving from viscous glycerol towards more hydrophilic polyols, [PERSON] et al. reported the enzymatic esterification of _rac_-ibuprofen with sorbitol [14] and xylitol [2]. The esterification of ibuprofen masks its carboxylic functional group, limiting the side effects of the active ingredient. In this study, we report the study of the esterification of ibuprofen with erythritol. Erythritol is a highly water-soluble polyol and noncariogenic sweetener that has been used safely in many countries due to its inability to be metabolized by cariogenic organisms. Erythritol has been a component of the human diet for millennia, occurring naturally in various fruits, like pears, melons, and grapes, as well as in mushrooms and foods produced via fermentation, such as cheese, soy sauce, and wine. Erythritol is widely used in the food and beverage industry as a sweetener and to enhance taste and texture. It functions as a flavor enhancer, humectant, formulation aid, nutritive sweetener, stabilizer, thickener, sequestrant, and texturizer. Compared to other polyols, it is preferred due to its minimal or absent glycemic response, making it a safe choice for diabetics. Indeed, erythroid is primarily used as a bulk sweetener in various food products, including confectioneries, chewing gum, bakery items, and beverages, due to its non-impact on glucose and insulin levels. Its molecular structure bears similarities to mannitol, a well-established antioxidant.