Energetics of Glycine Cocrystal or Salt Formation with Two Regioisomers: Fumaric Acid and Maleic Acid

Abstract

Multicomponent crystals have received significant attention in recent years, given their considerable potential to develop new products or improve the properties of known ones. Many studies have examined the synthesis and structure of multicomponent (mostly binary) crystals. The thermodynamic aspects related to the driving force for their formation and stability are, however, still relatively unexplored. This work describes a structure–energetics study of binary crystals consisting of glycine (Gly) and fumaric acid (FA) or maleic acid (MA), two regioisomers with different proton transfer abilities. Single-crystal X-ray diffraction experiments showed that the mechanochemically synthesized materials corresponded to a new FA:Gly2 cocrystal and a MA:Gly salt that had been previously prepared by crystallization from solution. A packing analysis further suggested that the stoichiometry difference (1:2 vs 1:1) is possibly related to differences in hydrogen bonding ability between FA and MA. Calorimetric and solubility measurements indicated that: (i) The two binary crystals are stable relative to decomposition into their precursors under ambient conditions (298.15 K; 1 bar), since the process is endergonic (Δr G m° > 0) in both cases. (ii) The stability is of enthalpic nature because Δr H m° > 0 and Δr H m° > |TΔr S m°|. (iii) The formation of a salt, rather than a cocrystal, does not bring any notable stability advantage, since the obtained Δr G m° for MA:Gly exceeds that found for FA:Gly2 by ∼1.0 kJ·mol–1 only. (iv) The similarity appears to be originated by an enthalpy–entropy compensation effect: the Δr H m° contribution (reflecting lattice enthalpy differences between the binary crystals and their components) is approximately twice as large for MA:Gly than for FA:Gly2, but the difference is balanced, to a considerable extent, by a larger and opposing TΔr S m° contribution. (v) The number of classical hydrogen bonds established by a FA or MA molecule with Gly does not seem to be a reliable predictor of stability, as six of these bonds are present in FA:Gly2 and only four in MA:Gly. (vi) Finally, the results here obtained show that the formation of a binary crystal is not necessarily advantageous in terms of solubility enhancement. Indeed, while the solubility of FA from FA:Gly2 was found to be ∼4 times larger than that of pure FA, no analogous benefit was observed for the MA:Gly salt, which exhibited a ∼3 times lower MA solubility when compared with pure MA.

First and Second Dissociation Enthalpies in Bi-Component Crystals Consisting of Maleic Acid and L-Phenylalanine

“…The temperature and enthalpy of fusion of MA(cr I) in Table 2 ( T on = 410.7 ± 1.4 K, = 38.6 ± 0.6 kJ mol −1 ) were also in close agreement with the results of previous determinations for the same polymorph, namely, T fus = 411.9 K [ 45 ], T fus = 411.3 ± 0.4 K [ 27 ], and = 37.5 ± 0.1 kJ mol −1 (the latter value, which refers to the mean of three determinations with the sample melting at 411.3 ± 0.4 K, is only being reported in the present work).…”

“…The first observation is very common for bi-component crystals [ 44 ]. One related example is glycine maleate (MA:Gly), with T on = 417.6 ± 1.3 K [ 27 ] in the range of the fusion temperatures of maleic acid (MA form I polymorph; T fus = 411.3 ± 0.4 K) [ 27 ] and α -glycine ( T fus = 525.0 ± 0.6 K) [ 27 ]. The closer proximity of the thermal properties of MA:Phe 2 from those of pure L-phenylalanine parallels the trend noted for density in Table 1 .…”

“…This is supported by two wide-scope studies on the energetics of co-crystals, one based on periodic density functional theory (DFT) calculations [ 25 ] and the other on an empirical estimation scheme [ 24 ], suggesting a dominant enthalpy term in 70–95% of cases. This tendency is expected to be even more valid in the case of protic organic salts, where partial or complete proton transfer between the co-formers leads to the development of an enhanced coulombic contribution that is likely to reinforce the multi-component crystal lattice energy [ 27 ]. The generality of this hypothesis still needs, however, confirmation, given that the energetics of a dissociation process is not exclusively determined by the reactant considered but also depends on the products formed.…”

“…However, in contrast with the large body of available structural information [ 28 ], studies where the thermodynamic stability of multi-component crystals has been quantitatively assessed in terms of enthalpy or Gibbs energy changes are scarce. Representative examples include systems such as the already mentioned hydroquinone:quinhydrone [ 29 ] and, more recently, celecoxib:nicotinamide [ 30 ], flubendazole:maleic acid [ 31 ], fumaric acid:glycine [ 27 ], maleic acid:glycine [ 27 ], sulfamethazine:salicylic acid [ 32 , 33 ], itraconazole:4-aminobenzoic acid [ 34 ], and itraconazole:4-hydroxybenzamide [ 34 ].…”

Isonicotinamide-Based Compounds: From Cocrystal to Polymer

“…The average E lat value of each HPip and Isn coformers has been calculated, and the crystal E lat is computed considering the 2:1 (HPip:Isn) molar ratio. The crystal structure E lat value of 2 is −362.8 kJ·mol −1 , which is comparable to other reported energies of multicomponent cocrystals [44].…”