On the Thermodynamic Thermal Properties of Quercetin and Similar Pharmaceuticals

Abstract

The thermodynamic properties of pharmaceuticals are of major importance since they are involved in drug design, processing, optimization and modelling. In this study, a long-standing confusion regarding the thermodynamic properties of flavonoids and similar pharmaceuticals is recognized and clarified. As a case study, the thermal behavior of quercetin is examined with various techniques. It is shown that quercetin does not exhibit glass transition nor a melting point, but on the contrary, it does exhibit various thermochemical transitions (structural relaxation occurring simultaneously with decomposition). Inevitably, the physical meaning of the reported experimental values of the thermodynamic properties, such as the heat of fusion and heat capacity, are questioned. The discussion for this behavior is focused on the weakening of the chemical bonds. The interpretations along with the literature data suggest that the thermochemical transition might be exhibited by various flavonoids and other similar pharmaceuticals, and is related to the difficulty in the prediction/modelling of their melting point.

Thermochemical Transition in Non-Hydrogen-Bonded Polymers and Theory of Latent Decomposition

“…Almost simultaneously with the above mentioned studies regarding polymers, the thermochemical transition was also reported to occur in some low molecular weight substances, namely two flavonoids (silybin [ 15 ] and quercetin [ 16 ]) and gallic acid [ 17 ]. It was reported [ 16 ] that the thermochemical transition is the “connection” among three different aspects [ 16 ].…”

“…Almost simultaneously with the above mentioned studies regarding polymers, the thermochemical transition was also reported to occur in some low molecular weight substances, namely two flavonoids (silybin [ 15 ] and quercetin [ 16 ]) and gallic acid [ 17 ]. It was reported [ 16 ] that the thermochemical transition is the “connection” among three different aspects [ 16 ]. These three aspects are: (1) the inconsistencies detectable in the literature regarding the experimental values of the thermal thermodynamic properties of such (pharmaceutical) substances [ 15 , 16 , 17 ]; (2) the reported difficulty and poor efficiency of predicting the melting point of pharmaceuticals [ 18 , 19 ]; (3) the fact that Bawn kinetics has been applied to study pharmaceuticals [ 2 ].…”

“…It was reported [ 16 ] that the thermochemical transition is the “connection” among three different aspects [ 16 ]. These three aspects are: (1) the inconsistencies detectable in the literature regarding the experimental values of the thermal thermodynamic properties of such (pharmaceutical) substances [ 15 , 16 , 17 ]; (2) the reported difficulty and poor efficiency of predicting the melting point of pharmaceuticals [ 18 , 19 ]; (3) the fact that Bawn kinetics has been applied to study pharmaceuticals [ 2 ].…”

“…In these recent studies of thermochemical transition, all of the substances (both polymers and low molecular weight substances) comprised molecules with increased hydrogen bond formation. It was recognized that the increased hydrogen bonding formation favors thermochemical transition through a double effect [ 10 , 11 , 15 , 16 , 17 ]: (1) hydrogen bonding hinders melting by keeping molecules close to each other by strong interaction and (2) it facilitates decomposition through the weakening of chemical bonds. For the O-H chemical bond, by FTIR spectroscopy it was found that in such substances, the free and strongly bounded hydroxyl groups may vary up to ~30% in their chemical bond strength [ 11 , 15 , 16 ].…”

“…It was recognized that the increased hydrogen bonding formation favors thermochemical transition through a double effect [ 10 , 11 , 15 , 16 , 17 ]: (1) hydrogen bonding hinders melting by keeping molecules close to each other by strong interaction and (2) it facilitates decomposition through the weakening of chemical bonds. For the O-H chemical bond, by FTIR spectroscopy it was found that in such substances, the free and strongly bounded hydroxyl groups may vary up to ~30% in their chemical bond strength [ 11 , 15 , 16 ]. This weakening of chemical bonds enables decomposition reactions, and for cellulose esters [ 9 , 10 , 11 ] and gallic acid [ 17 ] it was reported that the primary decomposition reaction is dehydration caused by esterification.…”