Eutectics as improved pharmaceutical materials: design, properties and characterization

Abstract

Eutectics are a long known class of multi-component solids with important and useful applications in daily life. In comparison to other multi-component crystalline solids, such as salts, solid solutions, molecular complexes and cocrystals, eutectics are less studied in terms of molecular structure organization and bonding interactions. Classically, a eutectic is defined based on its low melting point compared to the individual components. In this article, we attempt to define eutectics not just based on thermal methods but from a structural organization view point, and discuss their microstructures and properties as organic materials vis-a-vis solid solutions and cocrystals. The X-ray crystal structure of a cocrystal is different from that of the individual components whereas the unit cell of a solid solution is similar to that of one of the components. Eutectics are closer to the latter species in that their crystalline arrangement is similar to the parent components but they are different with respect to the structural integrity. A solid solution possesses structural homogeneity throughout the structure (single phase) but a eutectic is a heterogeneous ensemble of individual components whose crystal structures are like discontinuous solid solutions (phase separated). Thus, a eutectic may be better defined as a conglomerate of solid solutions. A structural analysis of cocrystals, solid solutions and eutectics has led to an understanding that materials with strong adhesive (hetero) interactions between the unlike components will lead to cocrystals whereas those having stronger cohesive (homo/self) interactions will more often give rise to solid solutions (for similar structures of components) and eutectics (for different structures of components). We demonstrate that the same crystal engineering principles which have been profitably utilized for cocrystal design in the past decade can now be applied to make eutectics as novel composite materials, illustrated by stable eutectics of the hygroscopic salt of the anti-tuberculosis drug ethambutol as a case study. A current gap in the characterization of eutectic microstructure may be fulfilled through pair distribution function (PDF) analysis of X-ray diffraction data, which could be a rapid signature technique to differentiate eutectics from their components.

Co-crystals of diflunisal and isomeric pyridinecarboxamides – a thermodynamics and crystal engineering contribution

“…For this kind of drugs, besides cocrystals, binary eutectic mixtures, for instance, are also relevant [23][24][25][26] due to their increased surface area and the potential for increasing dissolution rate. Therefore, the establishment of the binary solid-liquid phase diagrams of the API and the potential co-former is of considerable interest as it gives comprehensive information of the solid binary mixtures behavior.…”

Polymorphism in Molecular Crystals and Cocrystals

“…A solid solution is a variable stoichiometry multicomponent crystalline solid formed by substitutional incorporation of a component in the lattice of another component Multicomponent crystals such as solvates, hydrates, salts, and cocrystals can also exist in polymorphic forms (Adapted from Ref. [8] with permission from The Royal Society of Chemistry) [7]. Eutectics are conglomerates of solid solutions or conglomerates of lattice structures of different materials [8].…”

“…[8] with permission from The Royal Society of Chemistry) [7]. Eutectics are conglomerates of solid solutions or conglomerates of lattice structures of different materials [8]. Amorphous materials are distinct from the abovementioned solids, which lack long-range molecular order and relatively high energy materials compared to their crystalline counterparts [9].…”

Multicomponent Adducts of Pyridoxine: An Evaluation of the Formation of Eutectics and Molecular Salts

“…5 Cocrystallization studies serve as an important methodology to probe the physical and supramolecular compatibility of a given combination, particularly multi-nutrient/drug combinations, and achieve an optimal formulation for the combination. [6][7][8][9][10][11][12][13][14][15][16][17][18][19] Friščić et al emphasized the biological and pharmaceutical significance of cocrystallization through their studies on steroid hormones. 20,21 In their recent review, Sinha et al 6 noted that in spite of the importance of cocrystallization studies on vitamins, they were found to be least explored.…”