The Schiff base N,N'-ethylenebis(pyridoxylideneiminato) (H 2 pyr 2 en, 1) was synthesized by reaction of pyridoxal with ethylenediamine; reduction of H 2 pyr 2 en with NaBH 4 yielded the reduced Schiff base N,N'-ethylenebis-(pyridoxylaminato) (H 2 Rpyr 2 en, 2); their crystal structures were determined by X-ray diffraction. The totally protonated forms of 1 and 2 correspond to H 6 L 4 + , and all protonation constants were determined by pH-potentiometric and Supporting information for this article is available on the WWW under http://www.chemeurj.org/ or from the author. Some additional X-ray data for 1, 2, 4, and 9 (SI-1); further discussion of IR spectra (

A new polymorph of 4′-hydroxyacetophenone (form I, monoclinic, P21/c, Z′ = 1) was isolated and characterized. The structural differences between this phase and the previously known one (form II, orthorhombic, P212121, Z′ = 2) were investigated by X-ray diffraction. The two polymorphs exhibit distinct packing features and, at the molecular level, they seem to differ by the relative conformations of the OH and C(O)CH3 groups. The stability domains of the two phases from 298.15 K to the fusion temperature were also studied by a variety of thermodynamic methods and by density functional theory calculations. On the basis of the obtained results, p−T and Δf G m o−T phase diagrams for 4′-hydroxyacetophenone were defined. Differential scanning calorimetry experiments indicated that the system is enantiotropic, with form II first transforming into form I at 351.2 ± 2.7 K, followed by fusion of form I at 381.9 ± 0.1 K. Solution calorimetry demonstrated that form II is more stable than form I at 298.15 K, with Δtrs H m o(II→I) = 0.49 ± 0.13 kJ mol−1. Despite this small enthalpy difference compared to the thermal energy at 298.15 K (RT = 2.5 kJ mol−1), a sample of form I could be stored at ambient temperature, for at least 1 year, without change. Results of B3LYP/6–31G(d,p) calculations indicated that the most stable conformation of the isolated molecule is also that corresponding to the most stable polymorph of 4′-hydroxyacetophenone at ambient temperature (form II). The computations further suggest that the occurrence of the II → I transition through a simple rotation of the OH group is unlikely. Finally, the fact that the more stable form II has a greater Z′ than the less stable form I contrasts with the recent proposal that high Z′ polymorphs are metastable precursors of lower Z′ forms along the crystallization pathway.

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Objectives In a short approach, we want to present the improvements that have recently been done in the world of new solid forms of known active pharmaceutical ingredients (APIs). The different strategies will be addressed, and successful examples will be given. Key findings This overview presents a possible step to overcome the 10-15 years of hard work involved in launching a new drug in the market: the use of new forms of well-known APIs, and improve their efficiency by enhancing their bioavailability and pharmacokinetics. It discusses some of the latest progresses. Summary We want to present, in a brief overview, what recently has been done to improve the discovery of innovative methods of using well-known APIs, and improve their efficiency. Multicomponent crystal forms have shown to be the most promising achievements to accomplish these aims, by altering API physicochemical properties, such as solubility, thermal stability, shelf life, dissolution rate and compressibility. API-ionic liquids (ILs) and their advantages will be briefly referred. An outline of what has recently been achieved in metal drug coordination and in drug storage and delivery using bio-inspired metal-organic frameworks (BioMOFs) will also be addressed. PreambleIn the last decade, several approaches to attain multicomponent pharmaceutical forms have been used and different kinds have been obtained. The most notorious cases are undoubtedly co-crystals and molecular salts [1] and their design, using crystal engineering principles, strategic and synthetic approaches have been the subject of different reviews.[2-5] Also, their characterization and implications for regulatory control and intellectual property protection have been presented and discussed. Here, we go one step forward and taking into account the recent definition of pharmaceutical co-crystal; from the published outcome of the Indo-US bilateral meeting in 2012 [6] and the FDA guidance draft for co-crystals, [7] which classifies co-crystals as 'dissociable API-excipient molecular complexes' where the co-former is the excipient, we call pharmaceutical companies' attention to the fact that following FDA rules, co-crystals can be treated as drug product intermediate, offering the potential of abbreviated new drug application rather than the full new drug application. This can be looked upon as not only a prompt process involving fewer risks, but also a less cost-effective process. Different steps have also been given to enhance drug properties through API metal coordination, generating metallodrugs and metallopharmaceuticals and more recently bio-inspired metal-organic frameworks (BioMOFs) for drug storage and controlled delivery. Here, we briefly present and discuss some of the recent published work, giving examples where the proposed routes proved to be beneficial.

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New ruthenium(II) and iron(II) organometallic compounds of general formula [(η(5)-C5H5)M(PP)Lc][PF6], bearing carbohydrate derivative ligands (Lc), were prepared and fully characterized and the crystal structures of five of those compounds were determined by X-ray diffraction studies. Cell viability of colon cancer HCT116 cell line was determined for a total of 23 organometallic compounds and SAR's data analysis within this library showed an interesting dependency of the cytotoxic activity on the carbohydrate moiety, linker, phosphane coligands, and metal center. More importantly, two compounds, 14Ru and 18Ru, matched oxaliplatin IC50 (0.45 μM), the standard metallodrug used in CC chemotherapeutics, and our leading compound 14Ru was shown to be significantly more cytotoxic than oxaliplatin to HCT116 cells, triggering higher levels of caspase-3 and -7 activity and apoptosis in a dose-dependent manner.

The relationship between energetics and structure in 2-, 4-, 5-, and 6-hydroxynicotinic and 5-chloro-6-hydroxynicotinic acids (2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA, respectively) was investigated in the solid and gaseous phases by means of a variety of experimental and computational chemistry techniques. The molecular and crystal structures of the 2HNA, 4HNA, 6HNA, and 5Cl6HNA solid forms used in this study were determined by single crystal X-ray diffraction at 293 +/- 2 K. The 2HNA, 4HNA, and 5Cl6HNA samples were monoclinic (space groups: P2(1)/n for 2HNA and P2(1)/c for 4HNA and 5Cl6HNA), and that of 6HNA was found to be triclinic (space group: P1). The 2HNA sample investigated corresponds to a new polymorphic form of this compound. The 2HNA, 4HNA, 6HNA, and 5Cl6HNA molecules crystallize as oxo tautomers exhibiting N-H and Cring=O bonds. This is also supported by the observation of bands typical of N-H and Cring=O stretching frequencies in the corresponding FT-IR spectra. The absence of these bands in the spectrum of 5HNA indicates that a hydroxy tautomer with an unprotonated N heteroatom and a Cring-OH bond is likely to be present in this case. Results of theoretical calculations carried out at the G3MP2 and CBS-QB3 levels of theory suggest that in the ideal gas phase, at 298.15 K, 2HNA favors the oxo form, 4HNA prefers the hydroxy form, and no strong dominance of one of the two tautomers exists in the case of 6HNA and 5Cl6HNA. The standard molar enthalpies of formation of 2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA in the crystalline state, at 298.15 K, Delta(f)H(m)(o)(cr), were determined by micro combustion calorimetry. The corresponding enthalpies of sublimation, Delta(sub)H(m)(o), were also derived from vapor pressure versus temperature measurements by the Knudsen effusion method. The obtained Delta(f)H(m)(o)(cr) and Delta(sub)H(m)(o) values led to the enthalpies of formation of 2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA in the gaseous phase. These were discussed together with the corresponding predictions by the B3LYP/cc-pVTZ, B3LYP/aug-cc-pVTZ, G3MP2, and CBS-QB3 methods on the basis of isodesmic or atomization reactions. The experimental "stability" order (more stable meaning a more negative Delta(f)H(m)(o)(g) value) found was 5Cl6HNA > 2HNA > 6HNA > 4HNA > 5HNA, and it was accurately captured by the CBS-QB3 and G3MP2 methods, which give 5Cl6HNA > 2HNA approximately 6HNA > 4HNA > 5HNA, irrespective of the use of isodesmic or atomization reactions. In contrast, only when well-balanced isodesmic reactions were considered did the DFT results agree with the experimental ones. The picture that emerged from the structural and energetic studies carried out in this work was also discussed in light of that typical of hydroxypyridines, which are generally regarded as the archetype systems for the study of the hydroxy <--> oxo tautomerization in N-heterocyclic compounds.