Noncovalent Derivatives (NCDs): Harnessing the Power of Supramolecular Assembly

Dear Colleagues,

Noncovalent derivatives (NCDs) are materials formed when one coformer molecule or more is incorporated into the matrix of the target molecule by way of non-covalent forces [1,2]. These forces direct the supramolecular assembly of the NCD and can include ionic interactions, hydrogen bonding, and van der Waals forces, such as lipophilic-lipophilic and pi-pi interactions. In nature, supramolecular structures produce extraordinary materials, from DNA to organic crystals to enzymes. Non-covalent derivatization offers the opportunity to harness the power of supramolecular structures in the laboratory. NCDs show dramatic changes in advantageous material physical properties, such as solubility, melting point, optical properties, bioavailability, or stability when compared to their parent compounds.

NCDs encompass a variety of material forms, including cocrystals and eutectics [3]. A cocrystal is defined as a homogenous crystalline material made up of two or more molecules in definite stoichiometric amounts held together by non-covalent forces [4]. A cocrystal is distinguishable from a salt by the degree of proton sharing [5], and is also differentiated by the solid state of its starting materials. A eutectic is also formed from two solids, but the resulting NCD is a homogenous phase formed at the point at which the two solids become perfectly miscible, and is therefore recognizable as the minimum coherent point on the phase diagram both with respect to temperature and molar ratio.

Significant attention has been paid to the utility of cocrystals in the pharmaceutical industry and a number of review articles are in print on pharmaceutical NCD cocrystals [6–11]. More recently, pharmaceutical eutectics have been recognized as a useful means for altering active pharmaceutical ingredient properties [12]. However, the value of NCDs extends well beyond the pharmaceutical realm into areas as diverse as cosmetics, agrochemicals, chromophores, food additives, semi-conductors and chemical reagents. Because NCDs can be prepared from limited or no solvent and require no reagents or catalyst, their preparation is both environmentally and economically marketable.

In light of their aforementioned versatility and favorable manufacture, NCDs are a viable and powerful addition to traditional synthetic derivatization methodologies, particularly with respect to the development of greener chemistries [13]. This Special Issue explores advances in the preparation, analysis, and application of NCDs with an eye toward demonstrating the significant advantage of material design from a supramolecular perspective.

Dr. John C. Warner
Dr. Emily Stoler
Guest Editors

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3. Stoler, E.; Warner, J.C. Non-Covalent Derivatives: Cocrystals and Eutectics. Molecules 2015, 20, 14833–14848.
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8. Weyna, D.; Shattock, T.; Vishweshwar, P.; Zaworotko, M.J. Synthesis and Structural Characterization of Cocrystals and Pharmaceutical Cocrystals: Mechanochemistry vs Slow Evaporation from Solution. Cryst. Growth Des. 2009, 9, 1106–1123.
9. Aitipamula, S.; Chow, P.S.; Tan, R.B.H. Crystal Engineering of Tegafur Cocrystals: Structural Analysis and Physicochemical Properties. Cryst. Growth Des. 2014, 14, 6557–6569.
10. Thakuria, R.; Delori, A.; Jones, W.; Lipert, M.P.; Roy, L.; Rodríguez-Hornedo, N. Pharmaceutical Cocrystals and Poorly Soluble Drugs. Int. J. Pharm. 2013, 453, 101–125.
11. Perlovich, G.L.; Manin, A.N. Design of Pharmaceutical Cocrystals for Drug Solubility Improvement. Russ. J. Gen. Chem. 2014, 84, 407–414.
12. Cherukuvada, S.; Nangia, A. Eutectics as Improved Pharmaceutical Materials: Design, Properties and Characterization. Chem. Commun. (Camb). 2014, 50, 906–923.
13. Warner, J.C. Future Trends in Green Chemistry. Green Chemistry:Theory and Practice; Oxford University Press: Oxford, UK; 1998, p.119.

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• Noncovalent derivatives
• cocrystals, eutectics
• supramolecular structures
• supramolecular assembly
• green chemistry
• non-covalent forces