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We present a thought-provoking development in chiral resolution. Using a resolving agent of a given handedness, L-proline, we show that both R- and S-enantiomers of mandelic acid can be resolved from a racemic mixture simply by varying the stoichiometry. We are the first to report this specific feature, achieved by the existence of stoichiometrically diverse cocrystal systems between R- and S-mandelic acid and L-proline.

Combining different drugs into a single crystal form is one of the current challenges in crystal engineering, with the number of reported multi-drug solid forms remaining limited. This paper builds upon an efficient approach to combining Active Pharmaceutical Ingredients (APIs) containing carboxylic groups in their structure with APIs containing pyridine moieties. By transforming the former into their zinc salts, they can be successfully combined with the pyridine-containing APIs. This work highlights the successfulness of this approach, as well as the improvement in the physical properties of the obtained solid forms.

Combining active pharmaceutical ingredients (APIs) with sweeteners through crystal engineering is an attractive way to mask the bitter taste of drugs. However, traditional methods such as salt or cocrystal formation still suffer some major limitations. Herein, racetams, a series of normally bitter drugs, cannot be combined with the popular sweetener saccharin through either salt or cocrystal formation. We here, however, show how these compounds can be combined when zinc saccharinate is used rather than saccharin. The obtained complexes can either be identified starting from a binary target API/Zn saccharinate or a ternary API/ZnO/saccharin combination. This work opens up novel pathways to couple two compounds of interest through a crystal engineering approach.

We tap into an unexplored area of preferential crystallization, being the first to develop simultaneous chiral resolution of two racemic compounds by preferential cocrystallization. We highlight how the two racemic compounds RS-mandelic acid (MAN) and RS-etiracetam (ETI) can be combined together as enantiospecific R-MAN:R-ETI and S-Man:S-ETI cocrystals forming a stable conglomerate system and subsequently develop a cyclic preferential crystallization allowing to simultaneous resolve both compounds. The developed process leads to excellent enantiopurity both for etiracetam (ee>98%) and mandelic acid (ee~95%) enantiomers.

The coordination mode to lithium, magnesium, calcium and zinc cations of racemic vs. enantiopure amino acids and racetam APIs is analysed and its effect on chiral selection critically reviewed. It is shown that chiral resolution in the solid state can be obtained via cocrystallization of racemic compounds with an achiral inorganic salt coformer, such as LiX (X=Cl, Br, I) or ZnCl2, which favour tetrahedral coordination in the solid state. The chiral selection may take the form of conglomerate crystal formation or of selective homochiral aggregation in racemic crystals. When cocrystallization involves alkaline earth metal cations, such as Ca2+ and Mg2+, which favour octahedral coordination, heterochiral complexation is observed in most cases, with formation of racemic crystals.

A striking variety of anhydrous and hydrated ionic cocrystals (ICCs) of the enantiopure anti-epileptic drug (AED) levetiracetam and of its racemic intermediate etiracetam with the pharmaceutically acceptable salts CaCl2 and MgCl2 was synthesized and structurally characterized. The difference in the interaction of enantiopure and racemic compounds of interest with the inorganic salts was investigated. Variable temperature X-ray powder diffraction (VT XRPD) and calorimetric analyses (TGA and DSC) of all obtained ICCs showed a significant improvement in thermal stability with respect to pure racetams.

The concept of crystal engineering is making crystals with a purpose and it is an indisputable fact that multicomponent molecular solids such as co-crystals, metal-organic frameworks (MOFs), and solid solutions are at the forefront of crystal engineering research. Multicomponent crystalline systems are important targets in the quest for novel solid forms that can show improvement of physical and chemical properties (solubility, intrinsic dissolution rate, morphology, thermal and hydration stability, etc.) compared to those of the parent components. As a result, multicomponent solids can find application in a variety of industrial fields. The research activity performed in my PhD was mainly dedicated to the investigations of multicomponent crystalline assemblies, namely molecular and ionic co-crystals and molecular solid solutions. The project can be subdivided into the following topics: 1. Investigation of solid solutions consisting of organic molecules. 2. Co-crystallization as a tool to modify physicochemical properties of interest. 3. The effect of co-crystallization on chirality and its possible application for chiral resolution. The first two parts of the project were focused on the search for novel multicomponent crystalline assemblies capable of modifying the physicochemical properties of interest: thermostability for the obtained molecular solid solutions and enhancement of the solubility and intrinsic dissolution rate characteristics for the ionic co-crystals. The final chapter of this project was dedicated to the investigation of the influence of co-crystallization of chiral molecules of pharmaceutical interest with inorganic salts.

Chiral resolution of racemic etiracetam was achieved via co-crystallization with ZnCl2. Depending on the amount of ZnCl2 either a stable racemic compound or a stable conglomerate can be obtained. Excess ZnCl2 triggers the quantitative conversion of the racemate into the conglomerate solid; this unprecedented behaviour was investigated through a racetam/ZnCl2/solvent phase diagram.