Towards Diastereomeric Pure Salts with Antisolvent Methods

Chiral molecules, especially enantiomers and diastereomers of purity > 99 %, present a significant market share within the chemical, pharmaceutical, and flavor industries. Antisolvent precipitations, both batch and semicontinuous operations to serve the current trends in flow chemistry were demonstrated to be environmentally benign and efficient tools in achieving high optical purities. Although salts are known to be insoluble in supercritical CO₂, instabilities of the nascent salts were detected and applied for increasing efficiency. Diastereomeric excess values of the crystalline products exceeded 99 % in maximum of three consecutive steps both by repeated resolution with half molar equivalent of the amine to the acid and by direct recrystallization of the salts.     

Manipulation of mental models of anatomy in interventional radiology and its consequences for design of human–computer interaction

Interventional radiology procedures require extensive cognitive processing from the physician. A set of these cognitive functions are aimed to be replaced by technology in order to reduce the cognitive load. However, limited knowledge is available regarding mental processes in interventional radiology. This research focuses on identifying mental model–related processes, in particular during percutaneous procedures, useful to improve image guidance during interventions. Ethnographic studies and a prototype-based study were conducted in order to perform a task analysis and to identify working strategies and cognitive processes. Data were compared to theories from visual imagery. The results indicate a high level of complexity of mental model construction and manipulation, in particular when mentally comparing mental model knowledge with radiology images on screen (e.g., to steer a needle correctly). Regarding current interface support, most difficult is the interpretation and selection of oblique views. New interface principles are needed to bring cognitive demands within reasonable human range, and also accompanying cognitive work strategies should be developed.     

Effective Oral Administration of an Antitumorigenic Nanoformulated Titanium Complex

Abstract : Orally administered anticancer drugs facilitate treatment, but the acidic conditions in the stomach often challenge their availability. PhenolaTi is a Ti^IV-based nontoxic anticancer drug with marked in-vivo efficacy. We report that nanoformulation protects phenolaTi from decomposition in stomach-like conditions. This is evidenced by similar NMR characteristics and similar in-vitro cytotoxicity toward murine (CT-26) and human (HT-29) colon cancer cells before and after incubation of nanoformulated phenolaTi (phenolaTi-F) at pH 2, unlike results with the unformulated form of the complex. Furthermore, administration of phenolaTi-F in animal drinking water revealed a notable inhibition of tumor growth in Balb/c and immune-deficient (Nude) mice inoculated with CT-26 and HT-29 cells, respectively. In-vivo efficacy was at least similar to that of the corresponding intraperitoneal treatment with phenolaTi-F and the clinically employed oral drug, capecitabine. No body weight loss or clinical signs of toxicity were evident in the phenolaTi-F-treated animals. These findings demonstrate a new convenient mode of cancer treatment through oral administration by safe titanium-based drugs.     

Raft crystals of poly(isoprene)-block-poly(ferrocenyldimethylsilane) and their surface wetting behavior during melting as observed by AFM and NanoTA

We report on the morphology evolution during heating and melting of lamellar poly(isoprene)-block-poly(ferrocenyldimethylsilane) (PI₇₆-b-PFDMS₇₆) raft crystals deposited at the native oxide surface of silicon (SiO₂) or at a highly ordered pyrolytic graphite (HOPG) surface, studied by in situ temperature controlled atomic force microscopy. Crystals deposited on hydrophilic SiO₂ surfaces revealed an irreversible decrease in length at temperatures of up to tens of degrees above their expected melting temperature, while maintaining their platelet-like structure. Crystals deposited on hydrophobic HOPG surfaces initially decreased in length below their expected melting temperature, while at 120 °C and above a typical molten morphology was observed. In addition, the irreversible formation of a PI₇₆-b-PFDMS₇₆ wetting layer around the crystals was observed upon increasing the temperature. These observations in the morphological behavior upon heating emphasize the role of interfacial energy between a surface deposited block copolymer based macromolecular nanostructure and its supporting substrate.     

Interactions and Chemical Transformations of Coronene Inside and Outside Carbon Nanotubes

By exposing flat and curved carbon surfaces to coronene, a variety of van der Waals hybrid heterostructures are prepared, including coronene encapsulated in carbon nanotubes, and coronene and dicoronylene adsorbed on nanotubes or graphite via π–π interactions. The structure of the final product is determined by the temperature of the experiment and the curvature of the carbon surface. While at temperatures below and close to the sublimation point of coronene, nanotubes with suitable diameters are filled with single coronene molecules, at higher temperatures additional dimerization and oligomerization of coronene occurs on the surface of carbon nanotubes. The fact that dicoronylene and possible higher oligomers are formed at lower temperatures than expected for vapor‐phase polymerization indicates the active role of the carbon surface used primarily as template. Removal of adsorbed species from the nanotube surface is of utmost importance for reliable characterization of encapsulated molecules: it is demonstrated that the green fluorescence attributed previously to encapsulated coronene is instead caused by dicoronylene adsorbed on the surface which can be solubilized and removed using surfactants. After removing most of the adsorbed layer, a combination of Raman spectroscopy and transmission electron microscopy was employed to follow the transformation dynamics of coronene molecules inside nanotubes.     

Assessment of myometrial invasion in endometrial cancer by transvaginal ultrasonography

Transvaginal ultrasound was used in 52 women to characterise endometrial cancer with respect to myometrial invasion according to International Federation of Gynaecologist and Obstetricians (FIGO) recommendations for surgical staging of endometrial cancer. Endometrial cancer was diagnosed on the basis of dilatation and curettage and the degree of invasion was evaluated preoperatively by transvaginal ultrasound. The ultrasound data were compared to macroscopic finding of the uterine specimen and to histopathology. Evaluation with transvaginal sonography was accurate in 46 of 52 cases (accuracy 88%, sensitivity 86%, specificity 90%, positive predictive value 92%, negative predictive value 83%). Cervical tumor extension was correctly diagnosed in seven of ten women in which it was present. Transvaginal ultrasound seems to be a reliable method for assessing tumor invasion. This non-invasive method could be included as an important tool in te establishment of individualised treatment program in case of women with endometrial cancer.     

Stability test of novel combined formulated dry powder inhalation system containing antibiotic: physical characterization and in vitro–in silico lung deposition results

Objective: The aim was to study the stability of dry powder inhaler (DPI) formulations containing antibiotic with different preparation ways – carrier-based, carrier-free, and novel combined formulation – and thereby to compare their physicochemical and in vitro–in silico aerodynamical properties before and after storage. Presenting a novel combined technology in the field of DPI formulation including the carrier-based and carrier-free methods, it is the most important reason to introduce this stable formulation for the further development of DPIs.

Methods: The structure, the residual solvent content, the interparticle interactions, the particle size distribution and the morphology of the samples were studied. The aerodynamic values were determined based on the cascade impactor in vitro lung model. We tested the in silico behavior of the novel combined formulated samples before and during storage.

Results: The physical measurements showed that the novel combined formulated sample was the most favorable. It was found that thanks to the formulation technique and the use of magnesium stearate (MgSt) has a beneficial effect on the stability compared with the carrier-based formulation without MgSt and carrier-free formulations. The results of in vitro and in silico lung models were consistent with the physical results, so the highest deposition was found for the novel combined formulated sample during the storage.

Conclusions: It can be established that after the storage a novel combined formulated DPI contained amorphous drug to have around 2.5?μm mass median aerodynamic diameter and nearly 50% fine particle fraction predicted high lung deposition in silico also.     

Cytotoxic salan-titanium(IV) complexes: high activity toward a range of sensitive and drug-resistant cell lines, and mechanistic insights

The cytotoxicities of highly efficient salan-Ti(IV) complexes toward a range of cell lines, including drug-resistant cells, are reported along with preliminary mechanistic insights. Five salan-Ti(IV) complexes were investigated toward eight different human and murine cancer-derived cell lines, including colon, ovarian, lung, cervical, pancreatic, leukemic, skin, and breast. The salan complexes are more active toward the cells analyzed than cisplatin and the known titanium compound (bzac)(2) Ti(OiPr)(2) , and no cell line resistant to the salan complexes was identified. Moreover, the salan-Ti(IV) complexes are highly active toward both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780CisR) human ovarian cancer cell lines. Similarly, the salan complexes are cytotoxic toward multi-drug-resistant (ABCB1-expressing) mouse lymphoma cell lines HU-1 and HU-2. Importantly, minimal or no activity was observed toward primary murine cells (bone marrow, heart, liver, kidney, spleen, and lung), supporting selectivity for cancer cells. Additionally, the salan complexes maintain high cytotoxicity for up to 24 h following exposure to cell culture medium, whereas reference complexes (bzac)(2) Ti(OiPr)(2) and Cp(2) TiCl(2) rapidly lose much of their activity upon exposure to medium, within ~1 h. The upregulation of p53 followed by cell-cycle arrest in G(1) phase is likely one mechanism of action of the salan complexes. Taken together, the results indicate that these compounds are selectively toxic to cancer cells and are able to circumvent two independent mechanisms of drug resistance, thus expanding the scope of their potential medicinal utility.