What Has Carbamazepine Taught Crystal Engineers?

The antiepilepsy drug carbamazepine is one of the most studied pharmaceuticals in the world. The rich story of its solid forms, cocrystals, and formulation is a microcosm of the topical world of pharmaceutical materials. Understanding carbamazepine has required time, money, and dedication from numerous researchers and pharmaceutical companies worldwide. This wealth of knowledge provides the opportunity to reflect on progress within the crystal engineering field in general. This Perspective covers the extensive solid form landscape of carbamazepine and applies these examples to discuss and answer fundamental questions in the discipline. The story encompasses screening methods, computational solid form discovery, the power and influence of crystal engineering in understanding and controlling crystals and the amorphous state, and the environmental legacy of modern pharmaceuticals. This broad but in-depth analysis of carbamazepine is a vehicle into modern crystal engineering, not only in its own right but across the spectrum of organic materials science and pharmaceutical formulation. Discoveries of carbamazepine demonstrate the potential richness in the materials chemistry of every drug

Evaluation of Ceftaroline Activity against Heteroresistant Vancomycin-Intermediate Staphylococcus aureus and Vancomycin-Intermediate Methicillin-Resistant S. aureus Strains in an In Vitro Pharmacokinetic/Pharmacodynamic Model: Exploring the “Seesaw Effect”

A “seesaw effect” in methicillin-resistant Staphylococcus aureus (MRSA) has been demonstrated, whereby susceptibility to β-lactam antimicrobials increases as glyco- and lipopeptide susceptibility decreases. We investigated this effect by evaluating the activity of the anti-MRSA cephalosporin ceftaroline against isogenic pairs of MRSA strains with various susceptibilities to vancomycin in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activities of ceftaroline at 600 mg every 12 h (q12h) (targeted free maximum concentration of drug in serum [fCmax], 15.2 μg/ml; half-life [t1/2], 2.3 h) and vancomycin at 1 g q12h (targeted fCmax, 18 μg/ml; t1/2, 6 h) were evaluated against 3 pairs of isogenic clinical strains of MRSA that developed increased MICs to vancomycin in patients while on therapy using a two-compartment hollow-fiber PK/PD model with a starting inoculum of ∼107 CFU/ml over a 96-h period. Bacterial killing and development of resistance were evaluated. Expression of penicillin-binding proteins (PBPs) 2 and 4 was evaluated by reverse transcription (RT)-PCR. The achieved pharmacokinetic parameters were 98 to 119% of the targeted values. Ceftaroline and vancomycin were bactericidal against 5/6 and 1/6 strains, respectively, at 96 h. Ceftaroline was more active against the mutant strains than the parent strains, with this difference being statistically significant for 2/3 strain pairs at 96 h. The level of PBP2 expression was 4.4× higher in the vancomycin-intermediate S. aureus (VISA) strain in 1/3 pairs. The levels of PBP2 and PBP4 expression were otherwise similar between the parent and mutant strains. These data support the seesaw hypothesis that ceftaroline, like traditional β-lactams, is more active against strains that are less susceptible to vancomycin even when the ceftaroline MICs are identical. Further research to explore these unique findings is warranted.This work was funded by an investigator-initiated grant from Forest Laboratories. M.J.R. is funded in part by NIH R21A1092055-01. We thank Abbott Laboratories for the use of the fluorescence polarization immunoassay analyzer for determination of vancomycin concentrations. We also thank Alexander Tomasz (The Rockefeller University, New York, NY) for providing strains JH-1 and JH-9. M.J.R. has received grant support, consulted for, or provided lectures for Astellas, Cubist, Forest, Pfizer, Novartis, and Rib-X. B.J.W., M.E.S., and G.W.K. have no potential conflicts of interest to declare

Analysis of the magnetic coupling in binuclear complexes. I. Physics of the coupling

Accurate estimates of the magnetic coupling in binuclear complexes can be obtained from ab initio configuration interaction ~CI! calculations using the difference dedicated CI technique. The present paper shows that the same technique also provides a way to analyze the various physical contributions to the coupling and performs numerical analysis of their respective roles on four binuclear complexes of Cu (d9) ions. The bare valence-only description ~including direct and kinetic exchange! does not result in meaningful values. The spin-polarization phenomenon cannot be neglected, its sign and amplitude depend on the system. The two leading dynamical correlation effects have an antiferromagnetic character. The first one goes through the dynamical polarization of the environment in the ionic valence bond forms ~i.e., the M1¯M2 structures!. The second one is due to the double excitations involving simultaneously single excitations between the bridging ligand and the magnetic orbitals and single excitations of the environment. This dispersive effect results in an increase of the effective hopping integral between the magnetic orbitals. Moreover, it is demonstrated to be responsible for the previously observed larger metal-ligand delocalization occurring in natural orbitals with respect to the Hartree–Fock one

Potassium binding adjacent to cationic transition metal fragments: unusual heterobimetallic adducts of a calix[4]arene-based thione ligand

The synthesis of cationic rhodium and iridium complexes of a bis(imidazol-2-thione) functionalised calix[4]arene ligand and their surprising capacity for potassium binding is described. In both cases uptake of the alkali metal into the calix[4]arene cavity occurs despite adverse electrostatic interactions associated with close proximity to the transition metal fragment (Rh+∙∙∙K+ = 3.715(1) Å, Ir+∙∙∙K+ = 3.690(1) Å). The formation and constituent bonding of these unusual heterobimetallic adducts has been interrogated through extensive solution and solid-state characterisation, examination of the host-guest chemistry of the ligand and its upper-rim unfunctionalised calix[4]arene analogue, and computationally using DFT-based energy decomposition analysis (EDA)

Scrolling in Supramolecular Gels: A Designer’s Guide

Gelation by small molecules is a topic of enormous importance in catalysis, nanomaterials, drug delivery, and pharmaceutical crystallization. The mechanism by which gelators self-organize into a fibrous gel network is poorly understood. Herein, we describe the crystal structures and gelation properties of a library of bis­(urea) compounds and show, via molecular dynamics simulations, how gelator aggregation progresses from a continuous pattern of supramolecular motifs to a homogeneous fiber network. Our model suggests that lamellae with asymmetric surfaces scroll into uniform unbranched fibrils, while sheets with symmetric surfaces undergo stacking to form crystals. The self-assembly of asymmetric lamellae is associated with specific molecular features, such as the presence of narrow and flexible end groups with high packing densities, and likely represents a general mechanism for the formation of small-molecule gels

Graz. Burgtor-Hofgasse

Blick durch das Burgtor in Richtung Hofgass

Reactions of ( q6-arene) (q6-[2.2] paracyclophane) ruthenium( 11) Complexes with Nucleophiles

Single addition of the nucleophiles X-= H-, CN-or OH-t o (q6-arene) (q6-[2.2]paracyclophane)-ruthenium(r1) tetrafluoroborate (arene = benzene, p-cymene, 1,4-diisopropylbenzene or hexamethylbenzene) and the osmium(1i) q6-C6H6 analogue produces the (q5-cyclohexadienyl) (q6-[2.2] paracyclophane)metal(it) complexes as the sole products. These compounds have been identified by l H NMR and by infrared spectroscopy. The expected isotope shift is observed when Na[BD,] is used in place of Na [BH,]. The steric factors influencing the site of nucleophilic attack are discussed and nucleophilic addition to [ R~( q~-C ,~t i~~) , ] [BF,], is also examined. Both single and double nucleophilic addition to co-ordinated arenes is of significant interest as a synthetic route to arene functionalisation and a single nucleophilic attack is a key initial step in the recently reported synthesis of ( f )-dihydroxyserrulatic acid.' While bis(arene)ruthenium complexes are expected ' to be around thirty times less electrophilic than their iron analogues they display a number of advantages which make them the more attractive alternative in this type of work. These advantages include (a) the ready availability, uiu the Bennett and Rybinskaya 5.6 syntheses, of unsymmetrical complexes and (6) the elimination of interfering electrontransfer reactions 7-9 which can occur on the addition of carbondonor nucleophiles and result in the formation and often rapid decomposition of unstable nineteen-and twenty-electron species. Use of the highly sterically hindered [2.2]paracyclophane ligand has recently been shown to direct nucleophilic attack onto less-hindered arenes co-ordinated to the same metal centre" to produce q4-diene complexes such as [Ru(q6-cyclohexa-1,4-diene). In addition, protonation of an q4-C2.2)paracyclophane compound gives a co-ordinated q '-cyclophane with the added hydrogen atom in the endo position." That reaction is believed to involve the initial formation of a metal hydride foliowed by proton transfer to the carbocyclic ring. We now report the use of the [2.2]paracyclophane ligand to direct singk nucleophilic attack onto a number of q6-arenes and examine the question of exo or endo addition by a study of the effects of deuterium isotopic substitution on solid-state infrared and solution 'H NMR spectra. A preliminary report ofpart of this work has been published. ' ' c 1 gH 1 6)(q4-C6Me6H2)](C6Me6H2 = 1,2,3,4,5,6-hexamethyI- spaced doublet resonance ('JHH = 13.5 Hz) is observed at 6 2.06 and is assigned to He,, Results and Discussio

Community pharmacy interventions for health promotion: effects on professional practice and health outcomes (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows: Primary objective To assess the effectiveness of health promotion interventions in community pharmacy practice settings on pharmacy workers and pharmacy clients (including diagnosed patients) when compared to i) No treatment controls ii) Usual treatment controls iii) Other active intervention Secondary objectives To assess whether there are differences in effectiveness of health promotion interventions in community pharmacy practice settings on i) Pharmacy worker ii) Client (patient) with regard to: i) Ethnicity of patients ii) Country income level (World Bank Group 2009) iii) Extent of adverse health behaviour (defined according to national guidelines where available) iv) Type of pharmacy worker delivering the intervention (e.g. pharmacist versus pharmacist technician) v) Theoretical constructs/components and behaviour change techniques employed in the intervention vi) Costs of health car