Introduction to Pharmaceutical Co-amorphous Systems Using a Green Co-milling Technique.

The concept of co-amorphous systems is introduced in an integrated laboratory experiment, designed for advanced chemistry students, using solvent-free, environmentally friendly mechanochemistry. The dual-drug naproxen-cimetidine co-amorphous system (NPX-CIM) is investigated as an example of the emergent field of medicinal mechanochemistry. Students are trained in solid-state characterization techniques including X-ray powder diffraction, Fourier-transform infrared spectroscopy, and thermal analysis by differential scanning calorimetry. This lab experiment also provides an opportunity to discuss the relevance of different solid forms of pharmaceutics, emphasizing particular properties of disordered materials. This experiment can easily fit the curriculum of any Chemistry or Pharmacy master level degree in courses dealing with instrumental analysis, solid state chemistry, or green chemistry, for classes of 6 to 18 students, in a 5-h lab session. Suggestions to adapt it to the use of a single characterization technique are provided.

Photoantibacterial Poly(vinyl)chloride Films Applying Curcumin Derivatives as Bio-Based Plasticizers and Photosensitizers.

Herein we describe the design of natural curcumin ester and ether derivatives and their application as potential bioplasticizers, to prepare photosensitive phthalate-free PVC-based materials. The preparation of PVC-based films incorporating several loadings of newly synthesized curcumin derivatives along with their standard solid-state characterization is also described. Remarkably, the plasticizing effect of the curcumin derivatives in the PVC material was found to be similar to that observed in previous PVC-phthalate materials. Finally, studies applying these new materials in the photoinactivation of S. aureus planktonic cultures revealed a strong structure/activity correlation, with the photosensitive materials reaching up to 6 log CFU reduction at low irradiation intensities.

Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening.

In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons.

Lamotrigine: Design and synthesis of new multicomponent solid forms.

In this work, a crystal engineering and thermodynamic based approach has been used aiming at contributing to a deeper knowledge of lamotrigine multicomponent solid forms. Two types of co-molecules have been chosen that can give rise to co-crystals with lamotrigine through different supramolecular heterosynthons: the xanthines, theophylline and caffeine, and the three isomeric pyridinecarboxamides. Association with diflunisal, which may result in a salt, was also investigated. Mechanochemistry, differential scanning calorimetry, thermogravimetry, X-ray powder and single crystal diffraction, infrared spectroscopy were the methods used. For all the systems, exploratory neat mechanochemistry experiments, carried out on lamotrigine + co-molecule binary mixtures of different compositions, were not successful in promoting association. From differential scanning calorimetry data and the binary solid-liquid phase diagrams, co-crystals/salts were identified as well as their respective stoichiometry, and a methodology of synthesis was established. For pyridinecarboxamides, molecular recognition is dependent on the position of the amide group in the pyridine ring: co-crystallization did not occur with picolinamide co-former. Both xanthines form co-crystals with lamotrigine, (1:1) with theophylline and (2:1) lamotrigine:caffeine. Additionally, the crystalline structure of a lamotrigine:theophylline 1:1 monohydrate was solved. The (1:1) lamotrigine:theophylline co-crystal converts to this monohydrate in accelerated stability tests. A (1:1) lamotrigine:diflunisal salt was identified, which proved to be stable in accelerated stability assays.

Levetiracetam+nonsteroidal anti-inflammatory drug binary systems: A contribution to the development of new solid dosage forms.

A study has been carried out of binary solid systems made up of the antiepileptic drug levetiracetam, LEV, and a nonsteroidal anti-inflammatory drug, NSAID, capable of managing the inflammation that accompanies epileptic activity. One aim of this research was to identify eutectic mixtures and co-crystals, which are able to impact positively on their biopharmaceutical properties. The NSAIDs studied are (S)- and (R,S)-ibuprofen, (S)- and (R,S)-naproxen, (R,S)-ketoprofen and (R,S)-flurbiprofen, all class II in the Biopharmaceutical Classification System. A green mechanochemical methodology has been used to prepare binary mixtures with different molar ratios, and the binary solid-liquid phase diagrams established. For LEV+(S)-ibuprofen, formation of a single (1:1) co-crystal was confirmed; this was found to melt incongruently. The co-crystal was found to be stable in accelerated stability tests. For the other systems, interesting eutectic mixtures were identified, which showed enhanced dissolution rates of the NSAID relative to the pure drug. For LEV+(R,S)-ibuprofen, LEV+(S)-naproxen and LEV+(R,S)-naproxen, the eutectic mixture compositions have the effective doses of both components. All the NSAIDs investigated are chiral, and their racemates are racemic compounds. Levetiracetam, the (S)-enantiomer of etiracetam, was not efficient in enantiomer discrimination, as all the racemic compound structures are present as the prepared solid mixtures.

Vibrational and Thermal Studies of Essential Oils Derived from Cistus ladanifer and Erica arborea Shrubs.

Essential oils from the two most representative shrub species from the Iberian Peninsula (namely Cistus ladanifer L. and Erica arborea L.) have been characterized by Fourier transform infrared spectroscopy (FTIR) and thermoanalytical techniques (TG/DTG and DSC). Vibrational spectra have been compared with those of components of the plants, and with those of oils, gums and resins from other species. The different content in terpenoids of C. ladanifer oil (mainly mono- and- sesquiterpenoids) and E. arborea oil (mainly triterpenoids) is reflected in the ATR-FTIR by the position of the bands at around 2873 cmf⁻¹, 1730 cm-⁻¹ and 1678 cm⁻¹ As regards their thermal behavior, C. ladanifer-derived oil evinced higher thermal stability than that of obtained from E arborea: the pyrolysis of the former was sensitized at 210°C, whereas for the later it occurred at 143°C. These temperatures are high enough to state that thermolabile constituents such as terpenoids are conserved in the hydrodistillation and that this extraction process ensures the recovery of the main constituents of both-essential oils.

Unravelling the distinct crystallinity and thermal properties of suberin compounds from Quercus suber and Betula pendula outer barks.

The main purpose of this study was to investigate the potential of suberin (a naturally occurring aromatic-aliphatic polyester ubiquitous to the vegetable realm) as a renewable source of chemicals and, in particular, to assess their physical properties. A comparison between cork and birch suberin fragments obtained by conventional depolymerisation processes (hydrolysis or methanolysis) is provided, focusing essentially on their thermal and crystallinity properties. It was found that suberin fragments obtained by the hydrolysis depolymerisation of birch had a high degree of crystallinity, as indicated by their thermal analysis and corroborated by the corresponding XRD diffractions, as opposed to hydrolysis-depolymerised cork suberin counterparts, which were essentially amorphous.

Crystal structure of (R)-2'-benz-yloxy-[1,1'-binaphthalen]-2-yl tri-fluoro-methane-sulfonate.

In the title compound, C28H19F3O4S, a new 2'-benz-yloxy (R)-BINOL derivative containing a tri-fluoro-methane-sulfonate group in the 2-position, the planes of the two naphthyl ring systems (r.m.s. deviations = 0.012 and 0.019 Å) are at an angle of 73.36 (2)°, and the planes of the benzyl ring and the naphthyl ring system bound to the ether O atom are at an angle of 75.67 (4)°. In the crystal, mol-ecules are linked via C-H⋯F hydrogen bonds, forming chains propagating along [100]. The chains are linked via a weak C-F⋯π inter-action and weak π-π inter-actions [shortest inter-centroid distance = 3.9158 (12) Å], forming a three-dimensional structure. The absolute structure of the mol-ecule in the crystal was determined by resonant scattering [Flack parameter = 0.02 (6)].

A thermodynamic based approach on the investigation of a diflunisal pharmaceutical co-crystal with improved intrinsic dissolution rate.

A thermodynamic based approach is used to investigate diflunisal+nicotinamide binary and solution mixtures. A 2:1 co-crystal could be prepared by liquid assisted ball mill grinding and by solution crystallization from ethanol. The diflunisal+nicotinamide+ethanol ternary phase diagram points out conditions for co-crystal scaling-up. From the diflunisal+nicotinamide binary phase diagram, besides identification of the co-crystal stoichiometry, two additional useful binary compositions, eutectic mixtures, were characterized. From a solution enthalpy based approach, the enthalpic stabilization of the co-crystal relative to the pure solid components is quantified. Intrinsic dissolution rate, IDR, in test conditions consistent with USP requirements, including those referred in the diflunisal tablet monograph, were carried out, indicating that the co-crystal improves diflunisal IDR by about 20%. The systematic study of diflunisal+nicotinamide mixtures presented in this work is of particular interest due to the relevance of diflunisal, both as a non-steroidal anti-inflammatory drug and also due to the potentiality of orally administrated diflunisal in familial amyloid polyneuropathy.

Effect of postoperative xylazine administration on cardiopulmonary function and recovery quality after isoflurane anesthesia in horses.

OBJECTIVE: To evaluate equine cardiopulmonary function and recovery quality after administration of 0.25 or 0.50 mg/kg xylazine intravenously (IV) during recovery. STUDY DESIGN: Randomized, blinded, prospective, clinical study. ANIMALS: Horses (n = 20). METHODS: During recovery after 3 hours of isoflurane anesthesia for arthroscopic surgery, horses were administered either 0.25 mg/kg (G25, n = 10) or 0.50 mg/kg (G50, n = 10) xylazine intravenously. Vital signs and arterial blood samples were obtained during recovery before sedation (baseline), 5, 10, 20, 30, and 45 minutes after xylazine and 30 minutes after standing. The quality of recovery scores ranged from 10 to 72 (10 = best, 72 = worst). RESULTS: G25 horses recovered faster (mean ± SD, 33 ± 5 min) than G50 horses (50 ± 7 min, P < .0001). Mean maximal decrease in arterial oxygen tension was 55 ± 11 mmHg in G25 (at 10 minutes; P < .05) and 54 ± 7 mmHg in G50 (at 20 minutes; P < .01). G25 group had a total recovery score (23 [range 18-29]) and number of attempts to stand (4 ± 2) greater than the G50 group (18 [10-23] and 1 ± 1, respectively; P < .001). CONCLUSIONS: Both doses of xylazine promoted a moderate and transient hypoxemia during recovery; however, the 0.5 mg/kg dose produced a longer and improved quality of recovery from anesthesia.

5,10,15,20-Tetra-kis(4-acetyl-oxyphen-yl)porphyrin including an unknown solvate.

Mol-ecules of the title compound, C52H38N4O8, are located on an inversion center so that the asymmetric cell contains one half of the mol-ecule. The macrocycle exhibits a ruffled conformation with a maximum deviation of 0.16 Šfor the 24 macrocycle atoms: the dihedral angle between adjacent five-membered rings is 5.13 (19)°. The benzene rings are rotated by 70.25 (19)° with respect to their adjacent protonated five-membered rings, and by 65.56 (19)° with respect to the unprotonated rings. The porphyrin conformation is supported by bifurcated N-H⋯(N,N) hydrogen bonds. The structure contained poorly resolved solvent mol-ecules in voids of volume 217 Å(3) per unit cell. The latter were treated using the SQUEEZE routine in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148-155]. As the solvent could not be identified exactly, it was not included in the calculation of the overall formula weight, density and absorption coefficient.