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.

The design of new multicomponent pharmaceutical materials that involve different active pharmaceutical ingredients (APIs), e.g., drug-drug cocrystals, is a novel and interesting approach to address new therapeutic challenges. In this work, the hydrochlorothiazide-caffeine (HCT–CAF) codrug and its methanol solvate have been synthesized by mechanochemical methods and thoroughly characterized in the solid state by powder and single crystal X-ray diffraction, respectively, as well as differential scanning calorimetry, thermogravimetric analyses and infrared spectroscopy. In addition, solubility and stability studies have also been performed looking for improved physicochemical properties of the codrug. Interestingly, the two reported structures show great similarity, which allows conversion between them. The desolvated HCT–CAF cocrystal shows great stability at 24 h and an enhancement of solubility with respect to the reference HCT API. Furthermore, the contribution of intermolecular forces on the improved physicochemical properties was evaluated by computational methods showing strong and diverse H-bond and π–π stacking interactions.

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.

This work explores the preparation of luminescent and biomimetic Tb3+-doped citrate-functionalized carbonated apatite nanoparticles. These nanoparticles were synthesized employing a citrate-based thermal decomplexing precipitation method, testing a nominal Tb3+ 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 Tb3+ concentrations were (i) ≤ 0.005 M at all maturation times or (ii) = 0.010 M with 4 h of maturation. At higher Tb3+ concentrations, amorphous TbPO4·nH2O formed at short maturation times, while materials consisting of a mixture of carbonated apatite prisms, TbPO4·H2O (rhabdophane) nanocrystals, and an amorphous phase formed at longer times. The Tb3+ content of the samples reached a maximum of 21.71 wt%. The relative luminescence intensity revealed an almost linear dependence with Tb3+ 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 Tb3+-doped citrate-functionalized apatite nanoparticles are excellent candidates for bioimaging applications.

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.

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.

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 P21/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.