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.

Two polymorphs of the well-known diuretic drug Lasix, generic name furosemide, are characterized by single crystal X-ray diffraction to give a trimorphic cluster of polymorphs: known form 1 in P1 space group, and novel forms 2 and 3 in P2 1 /n and P1 space groups. The conformationally flexible molecule 4-chloro-2-[(2-furanylmethyl)amino]-5-sulfamoylbenzoic acid has variable torsions at the sulfonamide and furyl ring portions in conformers which lie in a 6 kcal mol -1 energy window. A conformer surface map was calculated to show that the two conformations in crystal form 1 are ∼4.5 kcal mol -1 less stable than conformers present in forms 2 and 3 (0.7, 0.0 kcal mol -1 ). The stabilization of molecular conformations is analyzed in terms of attractive intramolecular N-H 3 3 3 Cl hydrogen bonds and minimization of repulsive SdO 3 3 3 Cl interactions. Phase stability relationships confirm the thermodynamic nature of form 1 in grinding and slurry experiments by X-ray powder diffraction and infrared spectroscopy. Despite the large difference in molecular conformer energies, crystal lattice energies of polymorphs 1-3 are very close (-41.65, -41.78, -41.53 kcal mol -1 ). These results show that the thermodynamic stability of polymorph 1 of furosemide concluded in crystallization experiments is not possible to predict through computations. Moreover, the presence of metastable conformers in the stable crystal structure reemphasizes that there is no substitute for experimental validation in polymorphic systems. The greater stability of polymorph 1 is ascribed to its more efficient crystal packing, higher density, and the presence of R 4 2 (8) sulfonamide N-H 3 3 3 O dimer synthon. Because of the differences in torsion angles and hydrogen bonding in polymorphs 1-3, they are more appropriately classified as conformational and synthon polymorphs.

The phenomenon of cocrystallization, which encompasses the art of making multicomponent organic solids such as cocrystals, solid solutions, eutectics, etc. for novel applications, has been less studied in terms of reliably and specifically obtaining a desired cocrystallization product and the issues that govern their formation. Further, the design, structural, and functional aspects of organic eutectics have been relatively unexplored as compared to solid solutions and cocrystals well-established by crystal engineering principles. Recently, eutectics were proposed to be designable materials on par with cocrystals, and herein we have devised a systematic approach, based on the same crystal engineering principles, to specifically and desirably make both eutectics and cocrystals for a given system. The propensity for strong homomolecular synthons over weak heteromolecular synthons and vice versa during supramolecular growth was successfully utilized to selectively obtain eutectics and cocrystals, respectively, in two model systems and in two drug systems. A molecular level understanding of the formation of eutectics and cocrystals and their structural interrelationships which is significant from both fundamental and application viewpoints is discussed. On the other hand, the obscurity in establishing a low melting combination as a eutectic or a cocrystal is resolved through phase diagrams.

The stability of four polymorphs of pyrazinamide, R, β, γ, and δ, was studied under solvent-mediated crystallization, neat and liquid-assisted grinding, polymorph seeding, and ambient storage conditions. In contrast to a recent report that the δ polymorph is the most stable modification (Castro et al. Cryst. Growth Des. 2010, 10, 274), we find that the R polymorph is the thermodynamic form. β, γ, and δ transform to the R phase in the above-mentioned conditions as monitored by infrared, near-infrared, and Raman spectroscopy, differential scanning calorimetry, and X-ray powder diffraction. Transformation to the high temperature γ phase is monitored by thermogravimetric analysis-infrared (TG-IR) spectrometry. A semischematic energy-temperature diagram consistent with phase transformation experiments, thermal measurements, and crystal structure data gives the order R < δ < γ < β at 25°C (R is the most stable form), whereas at 160°C γ < R < δ < β (γ stable modification), but at absolute zero δ < R < β < γ (δ stable modification). Even though the δ polymorph has the lowest free energy at absolute zero temperature, the R polymorph is the thermodynamic form under the ambient conditions regime more relevant to crystallization and handling of pharmaceuticals. The intrinsic dissolution rate of the γ form is faster than R and δ polymorphs, but R is the preferred polymorph of pyrazinamide considering both stability and bioavailability criteria. We also report high quality X-ray crystal structures of all the four polymorphs of pyrazinamide (R = 0.0387, 0.0340, 0.0392, and 0.0372 for R, β, γ, and δ).

Co-crystallization is the supramolecular phenomenon of aggregation of two or more different chemical entities in a crystalline lattice through non-covalent interactions. It encompasses the study of the manifestation of multi-component crystalline solids as well as their design. The chemistry community and the literature suggest cocrystals with reference to co-crystallization products and multi-component crystalline solids. Over the last decade cocrystals have become very popular as a potential new/alternate solid form of pharmaceuticals. However, there is no consensus on what exactly a cocrystal means and what it constitutes across academia, industry and regulatory bodies. On the other hand, cocrystals have been endorsed to the extent that the following facts have been obscured: (1) cocrystals are only one of the putative outcomes of co-crystallization, if at all, and (2) their application goes way beyond pharmaceuticals. Solvates, solid solutions, eutectics, salts, ionic liquids, solid dispersions, supramolecular gelators etc. are among the multifarious products of co-crystallization. The manifestation of these supramolecular/non-covalent crystalline adducts is controlled by the inherent nature of the system (the components involved) besides the surroundings (temperature, solvent, pH etc.); in effect it is a thermodynamic outcome. Each of these adducts, including cocrystals, are unique, exhibit varied physicochemical properties and are amenable to design and therefore have, and potentially find, manifold applications in diverse fields such as organic synthesis & separation, green chemistry, energy storage, solar cells, electronics, luminescent and smart materials, apart from pharmaceuticals. This article highlights the diversity of crystal forms and the utility of small molecule supramolecular combinations.