Towards understanding the energetics in polymorphs through charge density studies

The detailed study of the structure and electron density distributions of polymorphic and phase transition materials is presented. Understanding and predicting the appearance of polymorphism and phase transitions in organic and organometallic materials is of considerable interest in fields such as pharmaceutical science, solid-state chemistry, and materials science. However, the small lattice energy difference between the different molecular conformations and packing between these materials are often particularly challenging in this area. Consequently, obtaining the most accurate description of the atomic positions and the electronic distributions plays an extremely important role in obtaining the best estimation of the lattice energies. In the present work,high-resolution X-ray diffraction as well as neutron diffraction tehniques have been used in reaching these aims. For minimizing the data collection times, synchrotron sources were also used for obtaining X-ray diffraction data, including Diamond, I19 beam line and Soleil, CRYSTAL beam line. Molecular complexes of lutidine isomers and chloranilic acid are also studied, in both 1:1 and 2:1 ratios, in order to investigate their relative stabilities through hydrogen bond contributions towards stabilising stoichiometrically different ‘compositional polymorphs’. The energy stability rankings in small organic molecules and transition metal complexes which exhibit polymorphism or displacive phase transitions are calculated using experimental charge density and fully theoretical approaches. The effect of the hydrogen bonds in the rank stabilities is also investigated. The pharmaceutical sulfathiazole and piracetam compounds are identified to have very small lattice energy differences between the polymorphs studied and the ranking stability orders are not maintained in the approaches used. Studies of the coordination complex [Ni(en)3]2+(NO3-)2 show that, contrary to expectation, the higher temperature phase is calculated to be the most stable one, showing the strongest intermolecular interaction energies. Overall, the presented studies show that current methodologies for estimating solid state lattice energies, even using high quality diffraction data and complex modeling of the electron density, are not sufficiently accurate to allow reliable estimation of polymorph energy differences. The results obtained for all studied polymorphic and phase transition materials using the experimental charge density approach show a high dependence of the lattice energies on the multipole model used

Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease

Introduction: CAD106 is designed to stimulate amyloid-β (Aβ)-specific antibody responses while avoiding T-cell autoimmune responses. The CAD106 first-in-human study demonstrated a favorable safety profile and promising antibody response. We investigated long-term safety, tolerability and antibody response after repeated CAD106 injections. Methods: Two phase IIa, 52-week, multicenter, randomized, double-blind, placebo-controlled core studies (2201; 2202) and two 66-week open-label extension studies (2201E; 2202E) were conducted in patients with mild Alzheimer’s disease (AD) aged 40 to 85 years. Patients were randomized to receive 150μg CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 μg CAD106; subcutaneous, 2201E1; intramuscular, 2202E1). Our primary objective was to evaluate the safety and tolerability of repeated injections, including monitoring cerebral magnetic resonance imaging scans, adverse events (AEs) and serious AEs (SAEs). Further objectives were to assess Aβ-specific antibody response in serum and Aβ-specific T-cell response (core only). Comparable Aβ-immunoglobulin G (IgG) exposure across studies supported pooled immune response assessments. Results: Fifty-eight patients were randomized (CAD106, n = 47; placebo, n = 11). Baseline demographics and characteristics were balanced. Forty-five patients entered extension studies. AEs occurred in 74.5% of CAD106-treated patients versus 63.6% of placebo-treated patients (core), and 82.2% experienced AEs during extension studies. Most AEs were mild to moderate in severity, were not study medication-related and did not require discontinuation. SAEs occurred in 19.1% of CAD106-treated patients and 36.4% of placebo-treated patients (core). One patient (CAD106-treated; 2201) reported a possibly study drug-related SAE of intracerebral hemorrhage. Four patients met criteria for amyloid-related imaging abnormalities (ARIA) corresponding to microhemorrhages: one was CAD106-treated (2201), one placebo-treated (2202) and two open-label CAD106-treated. No ARIA corresponded to vasogenic edema. Two patients discontinued extension studies because of SAEs (rectal neoplasm and rapid AD progression, respectively). Thirty CAD106-treated patients (63.8%) were serological responders. Sustained Aβ-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Aβ1–6 nor Aβ1–42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier. Conclusions: No unexpected safety findings or Aβ-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Aβ-specific antibody titers and prolonged time to decline indicate antibody exposure may increase with additional injections. CAD106 may be a valuable therapeutic option in AD

The Equilibria of Lipid–K+ Ions in Monolayer at the Air/Water Interface

The effect of K+ ion interaction with monolayers of phosphatidylcholine (lecithin, PC) or cholesterol (Ch) was investigated at the air/water interface. We present surface tension measurements of lipid monolayers obtained using a Langmuir method as a function of K+ ion concentration. Measurements were carried out at 22°C using a Teflon trough and a Nima 9000 tensiometer. Interactions between lecithin and K+ ions or Ch and K+ ions result in significant deviations from the additivity rule. An equilibrium theory to describe the behavior of monolayer components at the air/water interface was developed in order to obtain the stability constants and area occupied by one molecule of lipid–K+ ion complex (LK+). The stability constants for lecithin–K+ ion (PCK+) complex, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$K_{{{\text{PCK}}^{ + } }} = { 3}. 2 6\times 10^{ 2} {\text{dm}}^{ 3} \,{\text{mol}}^{ - 1}$$\end{document}, and for cholesterol–K+ ion (ChK+) complex, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$K_{{{\text{ChK}}^{ + } }} = { 1}.00 \times 10^{ 3} {\text{dm}}^{ 3} \,{\text{mol}}^{ - 1}$$\end{document}, were calculated by inserting the experimental data. The value of area occupied by one PCK+ complex is 60 Å2 molecule−1, while the area occupied by one ChK+ complex is 40.9 Å2 molecule−1. The complex formation energy (Gibbs free energy) values for the PCK+ and ChK+ complexes are −14.18 ± 0.71 and −16.92 ± 0.85 kJ mol−1, respectively