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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