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This article reports on the preparation and solid-state characterization of an indomethacin–caffeine drug–drug cocrystal (or codrug) in a 1:1 stoichiometry. These two active ingredients are frequently coadministered as part of a therapy against strong migraines, in a commercially available fixed dose combination formulation. The X-ray crystal structure of the codrug is characterized by a hydrogen bond interaction between the carboxylic moiety of indomethacin and the purinic nitrogen atom of caffeine. The combination of multinuclear and multidimensional solid-state NMR measurements (1H MAS, 13C and 15N CPMAS, 1H DQ MAS, 13C–1H HETCOR, 14N–1H J- and D-HMQC), as well as IR data, provided spectroscopic evidence about the hydrogen atom position along the hydrogen bond axis, thereby confirming the neutral nature of the cocrystal. Furthermore, dissolution kinetic tests revealed superior bioavailability of indomethacin in the codrug compared to indomethacin alone and to an indomethacin–caffeine physical mixture. On the other hand, the melting point of indomethacin was slightly lower in the cocrystal rather than in the pure drug.

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Solid-State Nuclear Magnetic Resonance (SSNMR) is a versatile characterization technique that can provide a plethora of information complementary to Single Crystal X-Ray Diffraction (SCXRD) analysis. However, the latter is still pivotal in assessing the halogen bond (XB) occurrence and having a rough estimation of its strength through the normalized distance parameter (RXB), obtained from experimental crystallographic data. Herein, we present an experimental and computational investigation of the relationship between the strength of an XB and the SSNMR chemical shifts of the nonquadrupolar nuclei either directly involved in the interaction ( 15 N) or covalently bonded to the halogen atom ( 13 C). We have prepared two series of X-bonded co-crystals based upon two different dipyridyl modules, and several halobenzenes and diiodoalkanes, as XB-donors. SCXRD structures of three novel co-crystals between 1,2-bis(4-pyridyl)ethane, and 1,4-diiodobenzene, 1,6-diiodododecafluorohexane, and 1,8-diiodohexadecafluorooctane are reported. For the first time, the change in the 15 N SSNMR chemical shifts upon XB formation is shown to experimentally correlate with the strength of the XB. The same overall trend is confirmed by density functional theory (DFT) calculations of the chemical shifts.13 C NQS experiments show a positive, linear correlation between the chemical shifts and the C-I elongation, which is an indirect probe of the strength of the XB. These correlations can be of general utility to estimate the strength of the XB occurring in diverse adducts by using affordable SSNMR analysis.In recent years, halogen bonding (XB) has been attracting increasing attention thanks to its applications in different fields, e.g., crystal engineering, materials chemistry, and biochemistry.1-3 The success of this specific noncovalent interaction derives from its unique physico-chemical properties, namely strength, selectivity, tunability, and directionality.4,5 XB spans an energy range similar to that of the more commonly used hydrogen bonding, i.e., 5-200 kJ/mol.6 By changing the XB-donor atom involved in the interaction or its covalently-bound substituents it is possible to fine-tune the final strength of the XB, an extremely useful feature for the design of new supramolecular species. 7 In addition, XB is strongly directional, 8,9 thus enabling the predictable alignment of molecular building blocks into crystalline architectures and functional materials, such as photoresponsive polymers, pharmaceutical co-crystals, porous materials, among others.10-14 XB plays also a key role in anion recognition and coordination both in solid state and in solution, 15,16 ability of relevant interest especially for biological systems. 17 The 2013 IUPAC XB definition states: "A halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity". 18 The counterintuitive electrophilic b...