Mechanochemical Synthesis of New Praziquantel Cocrystals: Solid-State Characterization and Solubility.

New cocrystals of praziquantel with suberic, 3-hydroxybenzoic, benzene-1,2,4,5-tetracarboxylic, trimesic, and 5-hydroxyisophthalic acids were obtained through ball milling experiments. The optimal conditions for the milling process were chosen by changing the solvent volume and the mechanical action time. Supramolecular interactions in the new cocrystals are detailed based on single-crystal X-ray diffraction analysis, confirming the expected formation of hydrogen bonds between the praziquantel carbonyl group and the carboxyl (or hydroxyl) moieties of the coformers. Different structural characterization techniques were performed for all samples, but the praziquantel:suberic acid cocrystal includes a wider range of investigations such as thermal analysis, infrared and X-ray photoelectron spectroscopies, and SEM microscopy. The stability for up to five months was established by keeping it under extreme conditions of temperature and humidity. Solubility studies were carried out for all the new forms disclosed herein and compared with the promising cocrystals previously reported with salicylic, 4-aminosalicylic, vanillic, and oxalic acids. HPLC analyses revealed a higher solubility for most of the new cocrystal forms, as compared to pure praziquantel.

Five Novel Polymorphs of Cardarine/GW501516 and Their Characterization by X-ray Diffraction, Computational Methods, Thermal Analysis and a Pharmaceutical Perspective.

GW501516, also known by the name of cardarine, is a synthetic peroxisome-proliferator-activated receptor delta (PPR-δ) agonist agent developed for applications in the treatment of metabolic disorders and cardiovascular diseases. A broad polymorph screening in various solvents and mixtures was completed in order to explore its capabilities to grow polymorphs. The crystal structures of four polymorphs were elucidated using single-crystal X-ray diffraction, while one structure was solved via a powder X-ray diffraction method. The solid state features (nature of intermolecular interactions) were investigated by computational methods. The polymorphs were further investigated by thermal DSC analysis and X-ray diffraction on powders. From a pharmaceutical perspective, the stability and solubility of the polymorphs were analyzed as well.

Crystal Structure and Intermolecular Energy for Some Nandrolone Esters.

Nandrolone (Estr-4-en-17ß-ol-3-one) is a derivative of testosterone and a naturally occurring anabolic-androgenic agent which belongs to the steroid group. Crystal structures of four short, medium and long esterified forms of nandrolone, including propionate, phenylpropionate, cypionate and undecanoate were determined using single-crystal X-ray diffraction. Crystal packing, supramolecular features and intermolecular interactions were described based on a quantitative and qualitative Hirshfeld surfaces analysis accompanied by evaluation of crystal energies and intermolecular interactions computation. Also, the solubility of the esters was investigated from a pharmaceutical perspective.

In Vitro Degradation of Mg-Doped ZrO2 Bioceramics at the Interface with Xerostom® Saliva Substitute Gel.

Zirconia-based bioceramics, one of the most important materials used for dental applications, have been intensively studied in recent years due to their excellent mechanical resistance and chemical inertness in the mouth. In this work, the structural, morphological and dissolution properties of the Zr1-xMgxO2 (x = 0.05, 0.1, 0.15, 0.2, 0.25, and 0.3) system, prepared by the conventional ceramic method, were evaluated before and after immersion in saliva substitute gel (Xerostom®, Biocosmetics Laboratories, Madrid, Spain), one of the most common topical dry mouth products used in dentistry. The X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDS) techniques were employed to investigate the phase transformations and morphology of the ceramics during the degradation process in Xerostom®. In vitro analyses showed overall good stability in the Xerostom® environment, except for the x = 0.05 composition, where significant t- to m-ZrO2 transformation occurred. In addition, the strong interconnection of the grains was maintained after immersion, which could allow a high mechanical strength of the ceramics to be obtained.

Solid forms and ß-cyclodextrin complexation of turinabol.

4-Chloro-17ß-hydroxy-17α-methylandrosta-1,4-dien-3-one (C20H27ClO2), known as turinabol, is a synthetic anabolic-androgenic agent which belongs to the steroid class. Recrystallization from various solvents was performed and the following new solid forms of turinabol were obtained: the hemihydrate (C20H27ClO2·0.5H2O), the anhydrous form (C20H27ClO2), the multicomponent acetic acid hydrate (2C20H27ClO2·C2H4O2·H2O) and the 2,2,2-trifluoroethanol hemisolvate (C20H27ClO2·0.5C2H3F3O). The absolute structures were determined by single-crystal X-ray diffraction. The starting hemihydrate form contains one turinabol molecule in the asymmetric unit, while the others contain two molecules in the asymmetric unit. Structural features were investigated in terms of the conformational analysis of the steroid skeleton rings and intermolecular interactions. The magnitudes, the nature of the crystal structure energies and the intermolecular interactions were also evaluated. Complexation with ß-cyclodextrin was performed and the obtained complex was investigated using powder X-ray diffraction, Fourier-transform infrared (FT-IR) spectroscopy and differential thermal analysis/thermogravimetric analysis (DTA/TGA).

Co-Crystals of Etravirine by Mechanochemical Activation.

The co-crystals formation of etravirine with three carboxylic acids was investigated. New co-crystals of etravirine with adipic acid, benzoic acid, and 4-hydroxybenzoic acid have been synthesized by wet milling of ingredients for 120 min. The novelty of these solid forms was first evidenced by powder X-ray diffraction. Their different morphology was evidenced by SEM microscopy. Spectroscopic analyses (FT-IR, MAS-NMR, and XPS) highlighted the hydrogen bonds between etravirine and co-formers, as a result of the solid-state reaction of the ingredients by wet milling. Thermal analyses pointed out that the milling process caused in co-crystals a reduction in the fusion enthalpy and the melting temperature, compared to the values obtained for etravirine. These co-crystals are stable up to four months on storage under extreme conditions, excepting the co-crystal with benzoic acid which begins to transform into a polymorph of etravirine after 30 days. The UV absorption spectra of the samples tested in three simulated physiological media with pH values of 6, 6.3, and 7 have evidenced the conformation change of etravirine due to hydrogen bonds between etravirine and carboxylic acids.

New solvates and a salt of the anti-HIV compound etravirine.

Four new solvates of the anti-HIV compound etravirine [systematic name: 4-({6-amino-5-bromo-2-[(4-cyanophenyl)amino]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile, C20H15BrN6O] with dimethyl sulfoxide (C2H6OS, two distinct monosolvates), 1,4-dioxane (C4H8O2, the 0.75-solvate) and N,N-dimethylacetamide (C4H9NO, the monosolvate), which exhibit conversion to the same anhydrous etravirine phase upon desolvation, and a stable etravirinium oxalate salt {6-amino-5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]pyrimidin-1-ium hemioxalate, C20H16BrN6O+·0.5C2O42-} were obtained. The crystal structures were solved by single-crystal X-ray diffraction and analyzed by powder X-ray diffraction, and the intermolecular interactions were explored by Hirshfeld surface analysis. Lattice energies were evaluated using the atom-atom force field Coulomb-London-Pauli (AA CLP) approximation, which distributes the total energy as four separate contributions: Coulombic, polarization, dispersion and repulsion. The formation of the solvates and the oxalate salt was further characterized by thermal analysis and IR spectroscopy.

Bioactive glass-biopolymers­gold nanoparticle based composites for tissue engineering applications.

Biomaterials based on bioactive glass with gold nanoparticle composites have many applications in tissue engineering due to their tissue regeneration and angiogenesis capacities. The objectives of the study were to develop new composites using bioactive glass with gold nanospheres (BGAuSP) and gold nanocages (BGAuIND), individually introduced in alginate-pullulan (Alg-Pll) polymer, to evaluate their biocompatibility potential, and to compare the obtained results with those achieved when ß-tricalcium phosphate-hydroxyapatite (ßTCP/HA) replaced the BG. The novel composites underwent structural and morphological characterization followed by in vitro viability testing on fibroblast and osteoblast cell lines. Additionally, the biomaterials were subcutaneously implanted in Sprague Dawley rats, for in vivo biocompatibility assessment during 3 separate time frames (14, 30 and 60 days). The biological effects were evaluated by histopathology and immunohistochemistry. The physical characterization revealed the cross-linking between polymers and glasses/ceramics and demonstrated a suitable thermal stability for sterilization processes. The in vitro assays demonstrated adequate form, pore size of composites ranging from few micrometers up to 100 µm, while the self-assembled apatite layer formed after simulated body fluid immersion confirmed the composites' bioactivity. Viability assays have highlighted optimal cellular proliferation and in vitro biocompatibility for all tested composites. Furthermore, based on the in vivo subcutaneous analyses the polymer composites with BGAuNP have shown excellent biocompatibility at 14, 30 and 60 days, exhibiting marked angiogenesis while, tissue proliferation was confirmed by high number of Vimentin positive cells, in comparison with the polymer composite that contains ßTCP/HA, which induced an inflammatory response represented by a foreign body reaction. The obtained results suggest promising, innovative, and biocompatible composites with bioactive properties for future soft tissue and bone engineering endeavours.

Crystal structure and physicochemical characterization of ambazone monohydrate, anhydrous, and acetate salt solvate.

The crystal structures of the monohydrate and anhydrous forms of ambazone were determined by single-crystal X-ray diffraction (SC-XRD). Ambazone monohydrate is characterized by an infinite three-dimensional network involving the water molecules, whereas anhydrous ambazone forms a two-dimensional network via hydrogen bonds. The reversible transformation between the monohydrate and anhydrous forms of ambazone was evidenced by thermal analysis, temperature-dependent X-ray powder diffraction and accelerated stability at elevated temperature, and relative humidity (RH). Additionally, a novel ambazone acetate salt solvate form was obtained and its nature was elucidated by SC-XRD. Powder dissolution measurements revealed a substantial solubility and dissolution rate improvement of acetate salt solvated form in water and physiological media compared with ambazone forms. Also, the acetate salt solvate displayed good thermal and solution stability but it transformed to the monohydrate on storage at elevated temperature and RH. Our study shows that despite the requirement for controlled storage conditions, the acetate salt solvated form could be an alternative to ambazone when solubility and bioavailability improvement is critical for the clinical efficacy of the drug product.