Co-crystal is a crystalline entity formed by two or more different molecular entities. The individual components are interconnected via non-covalent intermolecular interactions like hydrogen bonding, halogen bonding and π-π stacking, Van der Waals interactions rather than by ion pairing. The analysis of co-crystal structures in the Cambridge Structural Database (CSD) shows that hydrogen bonds are the predominant form of interaction between co-crystal components. The chemical and physical properties of the co-crystals undergo drastic changes upon co-crystallization in comparison to the starting materials and this is a consequence of alterations in the formation of new intermolecular interactions . A co-crystal is only expected to form if it is thermodynamically more stable than the crystals of its components. This report gives a brief review of co-crystallization and also highlights the various methods of preparing co-crystals and their characterization as well as their applications.

Crystallization Methods

There are many synthetic strategies that are available to prepare co-crystals depending on the chemical properties (air sensitivity, moisture sensitivity, ability for hydrogen bonding or any other interactions and reactivity with certain solvents) of the compounds. Some common methods like Slow evaporation, Vapour diffusion, Grindin method, Anti-solvent method, Solution method, Slow cooling are standard for co-crystallization.

"Patience is the major thing that one needs to remember to get ideal co-crystals!!"

Nucleation and Crystal Growth

Nucleation is formation of new thermodynamic phase or new structure via self assembly of atoms, ions or molecules. The nucleus is microscopic and thus too small to be directly observed. Crystal growth is subsequent growth of the nuclei that succeed in achieving the critical cluster size. The nucleation and rates of crystal growth depends on time and temperature. Once the super-saturation is exhausted, the solid–liquid system reaches equilibrium along with a ceasing in nucleation and the crystallization is complete. Experimentally synthesized Co-crystals usually π-conjugated organic molecule consisting of electron rich or electron poor substituent have the tendency to co-crystallize through π-π stacking interactions in two different packing motifs, namely, segregated stacking and mixed stacking.

"Grinding is where the materials are mixed, pressed and crushed in a mortar and pestle or in mill. In case of co-crystallization this have proved to be a viable method for solid-state grinding along with the liquid grinding. In liquid state grinding the solvent added is in very minute quantity which when added cats as a catalyst but does not form a part of the end product. Their advantage lie in its increased performance in the ability to control the production of polymorphs, and in the improved crystallinity of the product"

Characterizations

Several methods have been applied for the characterization of co-crystals and the elucidation of intermolecular interactions. Characterization of co-crystals involves both structure (infrared spectroscopy, single crystal x-ray crystallography and powder x-ray diffraction) and physical properties (e.g. melting point apparatus, Differential Scanning Calorimetry, Thermogravimetric Analysis).

"Solvent evaporation is the most conventional method in case of crystallization. In this technique the material is mixed with the common solvent and evaporation slowly. In evaporation stage the solution of molecules are expected to undergo various hydrogen bonding reactions."

Applications

Co-crystal engineering plays a vital role in production of energetic materials, pharmaceuticals, and other compounds. The most widely studied and used application is in drug development and more specifically the formation, design, and implementation of active pharmaceutical ingredients or API’s. Changing the structure and composition of the API can greatly influence the bioavailability of a drug. Co-crystal structures have also become a staple for drug discovery. Structure-based virtual screening methods, such as docking, make use of co-crystal structures of known proteins or receptors to elucidate new ligand-receptor binding conformations.

The crystal structure of co- crystal (a) Phenanthrene (PHEN) + tetrafluoro-1,4- benzoquinone (TFQ) has been found to adopt the mixed stacking arrangement, where the constituent molecules are co-facially over each other.

Conclusions

Several methods are available for the formation of co crystal and physicochemical characterization. Many efforts are being made at developing theoretical as well as empirical methods for the prediction of co-crystal formation; attempts that have been hindered, so far, by the lack of sufficient understanding of mechanism of co-crystal formation.

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