Predicting and tuning physicochemical properties in lead optimization: amine basicities

This review describes simple and useful concepts for predicting and tuning the pK(a) values of basic amine centers, a crucial step in the optimization of physical and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pK(a) values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chemistry. Next, the changes in pK(a) of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivatives are systematically analyzed, leading to the derivation of simple rules for pK(a) prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pK(a) predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.     

Physical,mechanical, and biological properties of electrophoretically deposited lithium-doped calcium phosphates

In the present work, the preparation of sintered lithium-doped tricalcium phosphates was studied, along with their physical, mechanical, and biological properties. Calcium phosphates were shaped via the use of electrophoretic deposition (EPD), using colloidally milled dispersions of hydroxyapatite (HAp) particles. The dispersions were stabilised with monochloroacetic acid. Lithium was incorporated into the structure via an addition of lithium chloride, which also served to optimise the deposition process. The dispersions were milled colloidally for periods of 0–48 h. The colloidal milling resulted in two effects: i) disintegration of the commercial HAp powder (10 µm) agglomerates, ii) unimodal distribution of the HAp particles (~ 170 nm). The fine particles of the milled HAp dispersions accelerated the deposition rate, and increased the mass of the deposit. The reduced size of the initial particles, owed to the milling, led to the superior arrangement of the particles during deposition and to reduced porosity after sintering (1050–1250 °C). The HAp decomposed into tricalcium phosphate phases during sintering. At a sintering temperature of 1250 °C, grain growth occurred, which consequently resulted in a slight degradation of the mechanical properties (reduction in hardness and Young's modulus). In contrast, the hardness and Young's modulus increased as the dispersion milling time increased (smaller grain size after sintering); however, the fracture toughness did not change. The results of the biological testing confirmed the bioactivity of the material through the growth of the apatite layer in the simulated body fluid (SBF), and the biodegradation of the prepared materials in the Tris-HCl solution. With regard to the preparation of compact lithium-doped tricalcium phosphates, the best results were obtained in the case of the sample that utilised the dispersion that was milled for 48 h, and was sintered at 1050 °C.     

High-voltage surge protection by a varistor-filled air gap

The electric discharge across a varistor granule filled air gap under a fast-rising voltage pulse was investigated for surge protection applications. The effects of temperature and pressure on the arc and the electrical conduction were analyzed by the characteristic changes in voltage waveforms triggered by a fast-rising high voltage pulse. In addition to the gap size, experimental results show that competing mechanisms among arc conduction, conduction through the varistor granule network, thermionic emission from Joule heating at granule-to-granule contact points, and the magnitude of the switching voltage dictate the maximum surge protection voltage for the filled air gap. Experimental evidence indicated that accumulated degradation was created at small contact points between varistor granules by repetitive assaults from longer duration, high voltage pulses. The uniqueness of using varistor over other dielectric granules in an air gap for surge protection is identified and discussed.     

Konzepte und Technologien für Mehrproduktanlagen

Multi-product plants are very flexible units which are finding increasing use in the chemical industry, e. g. for the production of fine chemicals, pharmaceutical active compounds and automotive paints. Various concepts have become established for multi-product plants, depending on the area of use and existing conditions. Technical equipment fitting in with these plant concepts is characterized by standardization, multi-product suitability and a particularly broad area of use. The paper describes four multi-product plant concepts and suggests criteria for selecting the suitable concept for a particular case.     

On the importance of specific interface area in clay nanocomposites of PMMA filled with synthetic nano-mica

In clay nanocomposites, the specific interface area is the key factor determining potential improvements of properties. Nevertheless, in most systematic studies of nanocomposites little emphasis is put on assuring and characterizing dispersion quality. To probe the influence of dispersion quality, we compare nanocomposites filled with two layered silicates which were made by melt compounding and solution blending, respectively. Poly(methyl methacrylate) (PMMA) is chosen here as a thermoplastic model matrix which was compounded with a synthetic nano-mica (O-hect) and commercial Bentone with typical diameters of 5–7 μm and <300 nm, respectively.     

A review of instance selection methods

In supervised learning, a training set providing previously known information is used to classify new instances. Commonly, several instances are stored in the training set but some of them are not useful for classifying therefore it is possible to get acceptable classification rates ignoring non useful cases; this process is known as instance selection. Through instance selection the training set is reduced which allows reducing runtimes in the classification and/or training stages of classifiers. This work is focused on presenting a survey of the main instance selection methods reported in the literature.     

Influence of a compatibilizer on the morphology development in polymer blends under elongation

Compatibilization is the modification of the interface in immiscible polymer blends in order to refine and stabilize their phase structure. The presence of a compatibilizer at the interface markedly affects the deformation behaviour of the dispersed droplets during and after cessation of flow. In this work the morphology development in blends of polystyrene and linear low-density polyethylene compatibilized with styrene-butadiene-styrene triblock copolymer during and after uniaxial elongation was investigated by means of electron microscopy and small-angle X-ray scattering. The incorporation of only 1 wt.-% of the compatibilizer led to a pronounced increase of the stationary elongational viscosity of the blend. It was found, that at moderate capillary number (Ca ≈ Ca_CR) the compatibilizer stabilises the droplets against break-ups during the flow. When Ca >> Ca_CR no differences in the deformation of uncompatibilized and compatibilized droplets were observed. After cessation of the flow, the presence of the compatibilizer prevented the droplet break-up and supported and accelerated the shape recovery of the elongated particles.     

Numerical optimal control of the wave equation: optimal boundary control of a string to rest in finite time

In many real-life applications of optimal control problems with constraints in form of partial differential equations (PDEs), hyperbolic equations are involved which typically describe transport processes. Since hyperbolic equations usually propagate discontinuities of initial or boundary conditions into the domain on which the solution lives or can develop discontinuities even in the presence of smooth data, problems of this type constitute a severe challenge for both theory and numerics of PDE constrained optimization.