Cocrystals Help Break the “Rules” of Isostructurality: Solid Solutions and Polymorphism in the Malic/Tartaric Acid System

Abstract

Crystalline solid solutions have the potential to afford tunable materials for pharmaceutical and technological applications. Unfortunately, these poorly understood phases are difficult to obtain and, hence, to study. In fact, commonly accepted empirical rules prescribe that only molecules of similar size and electron distribution are mutually soluble in the solid state. Here, despite the evident structural and electronic differences, the enantiomers of malic acid and tartaric acid are crystallized together in a variable stoichiometric ratio to produce both cocrystals and solid solutions. In some cases, physical mixtures are observed. The composition and polymorphism of the crystalline products are explained by DFT-d molecular substitution calculations for the cocrystallized molecules in different (known) structures. At the same time, from a crystal engineering perspective, the behavior of this complex system is rationalized thanks to the existence of intermediate cocrystal forms that merge the structural features of the pure molecular components.

Engineering Crystal Properties through Solid Solutions

“…For example, the recently reported solid solution of d - and l -malic acid could only be solved in the centrosymmetric C 2/ c space group despite simple geometrical considerations that impose a chiral structure (Figure ). For this reason the effects of chiral (and polar) enrichment has been interpreted as a “continuous loss of symmetry”, and it is observed in properties such as the intensity of the second harmonic. ,− …”

“…Recently, solid solutions have been prepared for pharmaceutical cocrystals . Neutral APIs can be crystallized with two or more similar coformers that can substitute for one another in a variable ratio. , Then, the use of mixed coformers can help increase structural and chemical variability as well as modify molecular solubility in the solid state. For instance, Zhang reported the phase diagrams of the ibuprofen enantiomers with 4,4′-bipyridine and suggested the potential use of that solid solution for enantiomeric separation …”

A Simple and Efficient Mechanochemical Route for the Synthesis of Salophen Ligands and of the Corresponding Zn, Ni, and Pd Complexes

“…The absence of solvent, or its use in a limited amount (liquid-assisted grinding, LAG, technique), makes mechanosynthesis a greener alternative to conventional synthetic methods. Recently, this strategy was extensively used to produce cocrystals [12,13,14], solid solutions, and polymorphs [15,16,17], as well as metal–organic frameworks [18].…”

Crystal engineering of nutraceutical phytosterols: new cocrystal solid solutions

“…[12][13] However, these solid forms are not well understood yet and are difficult to obtain. 14 Since the solid state of CSS is scarcely studied with respect to pharmaceutical and nutraceutical compounds not much is known about how the formation of CSS can impact the physicochemical properties of the crystal form. For instance, the difficulty to identify the number of molecules in the asymmetric unit, especially in chiral compounds, as a racemic solid solution of enantiomers [15][16][17] or a mixture of two diastereomers.…”