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Oyster shell wastes from the fishing industry represent a major environmental problem, as 7 million Tm/year are produced with no efficient recycling [1]. They are composed of Mgcalcite embedded in an organic matrix formed of proteins and polysaccharides. On the other hand, nanocrystalline apatites (NAp), which are structural and compositional analogues to the major inorganic component of human bones, exhibit excellent bioactivity and biocompatibility, and present a broad range of applications in hard tissue engineering, biomedicine, drug-delivery system and even in analytical sciences [2]. In this work, biogenic calcite from oyster shells was used to obtain apatite NPs by a ¿one-pot¿ hydrothermal process. Eu3+ and Tb3+ ions were added to the formulation to obtain Eu3+- and Tb3+-doped apatite NPs with luminescent properties. Solid-state characterization of the nanoparticles was performed by powder X-ray diffraction (PXRD), FT-IR and Raman spectroscopy, SEM and TEM microscopy, dynamic light scattering (DLS) and inductively coupled plasma (ICP) spectrometry, while luminescence properties were evaluated by luminescent spectroscopy. Finally, the biological behaviour of the NPs was evaluated by cytotoxicity and osteogenic differentiation assays, in murine mesenchymal (M17.1) and murine endothelial (MS-1) cells. Results demonstrated the efficiency of this novel ¿one pot¿ hydrothermal process to obtain nanoparticles of apatite with improved luminescent properties, while, in vitro assays demonstrated the excellent cytocompatibility and the impact of the metal-doping over the osteogenic differentiation capacity of the nanoparticles. Acknowledgment: This work was supported by project PCI2020-112108 funded by MCI/AEI/10.13039/501100011033 (Spain) and the European Union ¿NextGenerationEU¿/PRTR¿. PCI2020-112108 is part of the CASEAWA project of the ERA-NET Cofund BlueBio Programme, supported by the European Union (H2020).

Pharmaceutical multicomponent solids have proved to efficiently modulate the physicochemical properties of active pharmaceutical ingredients. In this context, polyphenols are interesting coformers for designing pharmaceutical cocrystals due to their wide safety profile and interesting antioxidant properties. The novel 6-propyl-2-thiouracil multicomponent solids have been obtained by mechanochemical synthesis and fully characterized by powder and single-crystal X-ray diffraction methods. The analysis of supramolecular synthons has been further performed with computational methods, with both results revealing a robust supramolecular organization influenced by the different positions of the hydroxyl groups within the polyphenolic coformers. All novel 6-propyl-2-thiouracil cocrystals show an enhanced solubility profile, but unfortunately, their thermodynamic stability in aqueous media is limited to 24 h.

According to the World Health Organization, more than 422 million people worldwide have diabetes. The most common oral treatment for type 2 diabetes is the drug metformin (MTF), which is usually formulated as a hydrochloride to achieve higher water solubility. However, this drug is also highly hygroscopic, thus showing stability problems. Another kind of worldwide prescribed drug is the non-steroidal anti-inflammatory drug (NSAID). These latter, on the contrary, show a low solubility profile; therefore, they must be administered at high doses, which increases the probability of secondary effects. In this work, novel drug-drug pharmaceutical solids combining MTF-NSAIDs have been synthesized in solution or by mechanochemical methods. The aim of this concomitant treatment is to improve the physicochemical properties of the parent active pharmaceutical ingredients. After a careful solid-state characterization along with solubility and stability studies, it can be concluded that the new molecular salt formulations enhance not only the stability of MTF but also the solubility of NSAIDs, thus giving promising results regarding the development of these novel pharmaceutical multicomponent solids.

The pharmaceutical cocrystal landscape of ethenzamide has been addressed during the past years with the aim of improving its physicochemical properties, mainly solubility and dissolution rate. Herein four novel ethenzamide cocrystals have been isolated by mechanochemical synthesis and thoroughly characterized by powder and single-crystal X-ray diffraction. Polyphenols have been selected as coformers based on ethenzamide synthon preference as well as their safety profile and antioxidant character. Besides crystallographic analysis, theoretical calculations have been made to evaluate the strength of intermolecular interactions and their role in crystal packing. The results evidence differences in the supramolecular architecture depending on the different polyphenolic isomers used as coformers. Finally, the physicochemical properties of the novel compounds were assessed and compared to those of ethenzamide alone. Although the solubility profile is significantly enhanced, the thermodynamic stability of the novel cocrystals in aqueous medium is restricted to 24 hours. These findings have been correlated with the crystal structure.

Drug–drug salts are a kind of pharmaceutical multicomponent solid in which the two co-existing components are active pharmaceutical ingredients (APIs) in their ionized forms. This novel approach has attracted great interest in the pharmaceutical industry since it not only allows concomitant formulations but also has proved potential to improve the pharmacokinetics of the involved APIs. This is especially interesting for those APIs that have relevant dose-dependent secondary effects, such as non-steroidal anti-inflammatory drugs (NSAIDs). In this work, six multidrug salts involving six different NSAIDs and the antibiotic ciprofloxacin are reported. The novel solids were synthesized using mechanochemical methods and comprehensively characterized in the solid state. Moreover, solubility and stability studies, as well as bacterial inhibition assays, were performed. Our results suggest that our drug–drug formulations enhanced the solubility of NSAIDs without affecting the antibiotic efficacy.

Nanocrystalline Apatites nanocomposites with graphene or graphene oxide nanoflakes, and with related carbonaceous materials, present promising applications in hard tissue engineering, biomedicine, or drug delivery. Different methodologies have been explored in the last years to prepare apatite-based nanocomposites. In this work, the sitting drop vapour diffusion method was used to induce the heterogeneous nucleation of biomimetic nanocrystalline apatites on the surface of graphene and graphene oxide flakes, creating nanocomposites with improved biological properties. Prior to the crystallization experiments, graphene flakes were obtained by sonication-assisted liquid-phase exfoliation of graphite using L-alanine as dispersing biomolecule, while a commercial aqueous graphene oxide dispersion was used for the nucleation essays in presence of the same biomolecule. A parallel set of nucleation experiments was performed in presence of Tb3+ ions, to endow the nanocomposites with luminescent properties. Characterization by X-ray diffraction, Fourier-transform infrared spectroscopy, and transmission electron microscopy demonstrated the heterogeneous nucleation of needle-shaped apatite nanocrystals on the surface of graphene and graphene oxide flakes. Fluorescence spectroscopy certified the presence of Tb3+ ions in the nanocomposites resulting in luminescent materials, which can be used in imaging or theranostic. Finally, in vitro tests with human mesenchymal stem cells revealed excellent cytocompatibility and cell proliferation in presence of the nanocomposites.

Multicomponent pharmaceutical materials offer new opportunities to address drug physicochemical issues and to obtain improved drug formulation, especially on oral administration drugs. This work reports three new multicomponent pharmaceutical crystals of the non-steroidal anti-inflammatory drug diclofenac and the nucleobases adenine, cytosine, and isocytosine. They have been synthesized by mechanochemical methods and been characterized in-depth in solid-state by powder and single crystal X-ray diffraction, as well as other techniques such as thermal analyses and infrared spectroscopy. Stability and solubility tests were also performed on these materials. This work aimed to evaluate the physicochemical properties of these solid forms, which revealed thermal stability improvement. Dissociation of the new phases was observed in water, though. This fact is consistent with the reported observed layered structures and BFDH morphology calculations.

Crystal engineering and, more specifically, the development of multicomponent materials has become an effective technique to rationally modify important physicochemical properties of solids, such as solubility and thermal stability. In this work, in order to overcome some of the problems that metformin has as a pharmaceutical, a new metformin base salt with citric acid (MTF–CIT) has been developed, which improves the thermal stability and solubility (two-fold) compared to metformin base (MTF). A complete characterization of the new crystalline form through PXRD, DSC, SCXRD, and FT–IR was conducted to ensure the purity of the new phase and provide a comprehensive view of its physicochemical behavior, thus correlating the improvement in stability and solubility with the crystal structure. The MTF–CIT salt crystallizes in the monoclinic P2/c1 spacegroup with z′ = 1. Intermolecular interactions found in MTF–CIT structure and simulated crystal morphology suggest a steric protection effect on the metformin ion that leads to the enhancement of stability in several orders of magnitude compared with MTF, as well as an improvement in solubility due to the exposition of polar groups in the biggest facets, making this new multicomponent salt a promising pharmaceutical solid.

This work explores the preparation of luminescent and biomimetic Tb-doped citrate-functionalized carbonated apatite nanoparticles. These nanoparticles were synthesized employing a citrate-based thermal decomplexing precipitation method, testing a nominal Tb doping concentration between 0.001 M to 0.020 M, and a maturation time from 4 h to 7 days. This approach allowed to prepare apatite nanoparticles as a single hydroxyapatite phase when the used Tb concentrations were (i) ≤ 0.005 M at all maturation times or (ii) = 0.010 M with 4 h of matura-tion. At higher Tb concentrations, amorphous TbPO·nH O formed at short maturation times, while materials consisting of a mixture of carbonated apatite prisms, TbPO·H O (rhabdophane) nanocrystals, and an amorphous phase formed at longer times. The Tb content of the samples reached a maximum of 21.71 wt%. The relative luminescence intensity revealed an almost linear de-pendence with Tb up to a maximum of 850 units. Neither pH, nor ionic strength, nor temperature significantly affected the luminescence properties. All precipitates were cytocompatible against A375, MCF7, and HeLa carcinogenic cells, and also against healthy fibroblast cells. Moreover, the luminescence properties of these nanoparticles allowed to visualize their intracellular cytoplasmic uptake at 12 h of treatment through flow cytometry and fluorescence confocal microscopy (green fluorescence) when incubated with A375 cells. This demonstrates for the first time the potential of these materials as nanophosphors for living cell imaging compatible with flow cytometry and fluorescence confocal microscopy without the need to introduce an additional fluorescence dye. Overall, our results demonstrated that Tb-doped citrate-functionalized apatite nanoparticles are excellent candidates for bioimaging applications.

In this investigation, three new crystal forms of lidocaine, and another three of lidocaine hydrochloride with hydroquinone, resorcinol, and pyrogallol were synthetised. All the new forms were characterised using multiple techniques, PXRD, SC-XRD, DSC, and FTIR. The stability of the forms was studied, and, for the more stable forms, i.e., (lidhcl) forms, the solubility was determined through FTIR analysis. The new crystalline forms obtained with (lidhcl) and the three conformers showed an interesting steric stabilisation mechanism of the oxidation of hydroxybenzenes and showed good physicochemical properties with respect to (lidhcl), constituting a mechanism of modulation of the physicochemical properties.

The design of drug–drug multicomponent pharmaceutical solids is one the latest drug development approaches in the pharmaceutical industry. Its purpose is to modulate the physicochemical properties of active pharmaceutical ingredients (APIs), most of them already existing in the market, achieving improved bioavailability properties, especially on oral administration drugs. In this work, our efforts are focused on the mechanochemical synthesis and thorough solid-state characterization of two drug–drug cocrystals involving furosemide and two different non-steroidal anti-inflammatory drugs (NSAIDs) commonly prescribed together: ethenzamide and piroxicam. Besides powder and single crystal X-ray diffraction, infrared spectroscopy and thermal analysis, stability, and solubility tests were performed on the new solid materials. The aim of this work was evaluating the physicochemical properties of such APIs in the new formulation, which revealed a solubility improvement regarding the NSAIDs but not in furosemide. Further studies need to be carried out to evaluate the drug–drug interaction in the novel multicomponent solids, looking for potential novel therapeutic alternatives.

Any time the pharmaceutical industry develops a new drug, potential polymorphic events must be thoroughly described, because in a crystalline pharmaceutical solid, different arrangements of the same active pharmaceutical ingredient can yield to very different physicochemical properties that might be crucial for its efficacy, such as dissolution, solubility, or stability. Polymorphism in cocrystal formulation cannot be neglected, either. In this work, two different cocrystal polymorphs of the non-steroidal anti-inflammatory drug niflumic acid and caffeine are reported. They have been synthesized by mechanochemical methods and thoroughly characterized in solid-state by powder and single crystal X-ray diffraction respectively, as well as other techniques such as thermal analyses, infrared spectroscopy and computational methods. Both theoretical and experimental results are in agreement, confirming a conformational polymorphism. The polymorph NIF–CAF Form I exhibits improved solubility and dissolution rate compared to NIF–CAF Form II, although Form II is significantly more stable than Form I. The conditions needed to obtain these polymorphs and their transition have been carefully characterized, revealing an intricate system.

The preparation of graphene/apatite and graphene oxide/apatite hybrid nanocomposites has recently attracted great attention in the biomaterial community. The sitting drop vapor diffusion technique has been assessed as a preparative method for such nanocomposites in this work. The technique has been employed to induce heterogeneous nucleation and growth of calcium phosphate in the presence of exfoliated graphene and commercial graphene oxide flakes, both labeled with LAlanine. Exfoliated multilayered graphene flakes were produced by sonication-assisted liquidphase exfoliation of graphite. In both composites, the apatite nanocrystals displayed similar size and shape, but different labile and B-type carbonation contributions. Graphene and graphene oxide flakes also influenced the carbonation degree of the apatite, which was almost half that measured for the apatite blank, as well as the aggregation state of their composites. In this regard, those composites with graphene oxide formed larger aggregates because of their wider size distribution, with a high-volume percentage of nanosheets (of about 4 nm length). Overall, the method is very useful to prepare small amounts of nanocomposite with high reproducibility.