Paul A. Cox

A zeolite family with expanding structural complexity and embedded isoreticular structures

The prediction and synthesis of new crystal structures enable the targeted preparation of materials with desired properties. Among porous solids, this has been achieved for metal–organic frameworks, but not for the more widely applicable zeolites, where new materials are usually discovered using exploratory synthesis. Although millions of hypothetical zeolite structures have been proposed, not enough is known about their synthesis mechanism to allow any given structure to be prepared. Here we present an approach that combines structure solution with structure prediction, and inspires the targeted synthesis of new super-complex zeolites. We used electron diffraction to identify a family of related structures and to discover the structural ‘coding’ within them. This allowed us to determine the complex, and previously unknown, structure of zeolite ZSM-25 (ref. 8), which has the largest unit-cell volume of all known zeolites (91,554 cubic ångströms) and demonstrates selective CO2 adsorption. By extending our method, we were able to predict other members of a family of increasingly complex, but structurally related, zeolites and to synthesize two more-complex zeolites in the family, PST-20 and PST-25, with much larger cell volumes (166,988 and 275,178 cubic ångströms, respectively) and similar selective adsorption properties. Members of this family have the same symmetry, but an expanding unit cell, and are related by hitherto unrecognized structural principles; we call these family members embedded isoreticular zeolite structures.

Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH–Rate Profiles, Autocatalysis, and Disproportionation

pH-rate profiles for aqueous-organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model containing five general pathways (k1-k5) has been developed, and together with input of [B]tot, KW, Ka, and KaH, the protodeboronation kinetics can be correlated as a function of pH (1-13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3- and 4-pyridyl boronic acids (t0.5 > 1 week, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t0.5 ≈ 25-50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two additional processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pKa ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.

Design, synthesis and characterization of captopril prodrugs for enhanced percutaneous absorption

Most drugs are designed primarily for oral administration, but the activity and stability profiles desirable for this route often make them unsuitable for transdermal delivery. We were therefore interested in designing analogues of captopril, a model drug with poor percutaneous penetration, for which the sustained steady‐state blood plasma level associated with transdermal delivery (and which is unattainable orally) would be particularly beneficial. Quantitative structure—permeability relationships (QSPRs) predicted that ester and thiol prodrug derivatives of captopril would have lower maximal transdermal flux (Jm) than the parent drug, since the increases in permeability coefficient (kp) of prodrugs would be outweighed by the reductions in aqueous solubility. Therefore, the aim of this study was to synthesize a series of prodrugs of captopril and to determine if a QSPR model could be used to design therapeutically viable prodrugs. Molecules with the highest predicted kp values were synthesized and characterized, and Jm measured in Franz diffusion cells from saturated aqueous donor across porcine skin (fresh and frozen). In‐vitro metabolism was also measured. Captopril and the prodrugs crossed the skin relatively freely, with Jm being highest for ethyl to butyl esters. Substantial first‐order metabolism of the prodrugs was observed, suggesting that their enhanced percutaneous absorption was complemented by their metabolic performance. The results suggested that QSPR models provided excellent enhancements in drug delivery. This was not seen at higher lipophilicities, suggesting that issues of solubility need to be considered in conjunction with any such use of a QSPR model.

In vitro and in silico investigations of drug delivery via zeolite BEA

A combination of experiment and theory has been used to assess the potential use of the zeolite BEA as a drug delivery agent. Molecular dynamics (MD) has been used to examine the diffusion of two different drug molecules, salbutamol and theophylline, inside the zeolite BEA. MD shows that the two molecules display different diffusion behaviour, with the salbutamol molecule able to diffuse more freely than theophylline within the internal channel system of the zeolite. Several experimental techniques have been used to investigate the loading and release of the drug molecules from the BEA host. The results obtained support the observations from the modelling and suggest that modelling has an important role to play in screening zeolite–drug combinations prior to experimental investigation.

Controlled release of 5-fluorouracil from microporous zeolites.

UNLABELLED Zeolite particles with different pore diameter and particle size were loaded with the model anticancer drug 5-fluorouracil. The loaded zeolites were characterized by means of SEM, XRD, DSC, XPS, N2 physisorption and FT-IR. Higher loading of 5-FU was observed for NaX-FAU than BEA. Release studies were carried out in HCl 0.1N. Release of 5-FU from NaX-FAU showed exponential-type behaviour with the drug fully released within 10 min. In the case of BEA, the kinetics of 5-FU shows a multi-step profile with prolonged release over time. Molecular dynamics simulations showed that diffusion of the drug molecule through the BEA framework is lower than for NaX-FAU due to increased van der Waals interaction between the drug and the framework. The effect of zeolitic particles on the viability of Caco-2 monolayers showed that the NaX-FAU particles cause a reduction of cell viability in a more pronounced way compared with the BEA particles. FROM THE CLINICAL EDITOR This article describes zeolite-based nanoparticles in generating time-controlled release of 5-FU from zeolite preparations for anti-cancer therapy.

Synthesis, structure and thermal transformations of aluminophosphates containing the nickel complex [Ni(diethylenetriamine)2]2+ as a structure directing agent

Abstract [Ni(diethylenetriamine)2]2+, (Ni(deta)2), acts as a structure directing agent for aluminophosphates and metalloaluminophosphates with the CHA and AFI framework topologies. In the presence of ammonium fluoride, triclinic Ni(deta)2-UT-6; P 1 , a=9.289(1) A, b=9.095(1) A, c=9.356(1) A, α=88.35(1)°, β=78.91(1)°, γ=89.21(1)°, with the CHA topology and orthorhombic Ni(deta)2-AlPO(F)-5; Ccc2, a=13.8603(5) A, b=23.1285(5) A, c=8.5420(4) A with the AFI topology are prepared, the latter being favoured by higher water contents in the synthesis gel. Upon heating in nitrogen or oxygen at temperatures of 500 °C and above, Ni(deta)2-UT-6 is transformed reconstructively to an aluminophosphate with the AFI topology whereas heating at lower temperatures followed by heating in oxygen at 600 °C removes the organic and gives a solid with the CHA topology. Calcination of all samples prepared in the absence of fluoride leaves the original frameworks intact. Ni K-edge X-ray spectroscopy of Ni(deta)2-UT-6 calcined in oxygen at 600 °C reveals the formation of nanoparticulate NiO.

Azamacrocycles and the azaoxacryptand 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosaneas structure-directing agents in the synthesis of microporous metalloaluminophosphates

Hydrothermal syntheses of aluminophosphates have been performed in the presence of Mg2+, Cr3+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+ and Zn2+ cations using the macrocycles 1,4,7-trimethyl-1,4,7-triazacyclononane (tmtacn), 1,4,8,11-tetraazacyclotetradecane (cyclam), 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane (tmtact) and 1,4,7,10,13,16-hexamethyl-1,4,7,10,13,16-hexaazacyclooctadecane (hmhaco), and the cryptand 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (K222) as structure directing agents. Tmtacn is found to template MAPO-18, K222 to template MAPO-42 and tmtact to template STA-6 or STA-7; the solids formed using tmtact depend on the metal cation present. Use of cyclam with a cobalt aluminophosphate gel results in a new solid, CoII(C10N4H24)Al(PO4)PO3(OH), which consists of aluminophosphate chains of stoichiometry AlP2O8H linked via cobalt–cyclam complexes. Bonding between the cobalt–cyclam complexes and the aluminophosphate chains is through direct Co–O bonds and a complex hydrogen-bonding network—quite different from that between the three-dimensionally connected frameworks and the tertiary amine-containing templates. An isostructural solid is formed via the substitution of cobalt by nickel in the aluminophosphate gel. The role of divalent cations in structure direction, in the presence of tertiary amine-containing macrocycles, has been further investigated. Adding Co2+ or Zn2+, in particular, enhances the amines’ ability to act as templates for STA-7 and MAPO-42, yet single crystal and powder diffraction using synchrotron radiation indicates that the divalent cations do not remain within the macrocycles after crystallisation.

Molecular Modelling Studies of Zeolite Synthesis

Abstract A number of molecular modelling methods have been used to investigate the relationship between zeolite structures and the organic molecules used in their synthesis. The results reveal the remarkable correlation that exists between the shape of the organic molecule and that of the zeolites pore channel system. These techniques greatly enhance our understanding of zeolite formation, and have clear benefits for directing novel synthesis programmes.

Molecular-modelling studies of the polypropylene catalyst

Polypropylene is formed using a catalyst typically consisting of TiCl4 supported on a MgCl2 substrate. A combination of molecular-modelling methods has been used to investigate the catalyst at the atomic level. Molecular graphics and static lattice calculations show that MgCl2 exhibits stable surfaces in which surface Mg ions are four, five and six coordinated. Density functional theory calculations show that TiCl4 binds to MgCl2via a ‘triply bound’ model. This results in one of the Cl–Ti–Cl bond angles opening up to 135°, an event that clearly facilitates cis insertion of the monomer unit at this position. These calculations also demonstrate the stability of this TiCl4/MgCl2 cluster with a propene monomer unit.

Formulation and characterization of a captopril ethyl ester drug-in-adhesive-type patch for percutaneous absorption

Background: The ethyl ester of captopril has been shown to exhibit enhanced permeation across human skin compared to the parent drug. A drug-in-adhesive patch formulation of a captopril ethyl ester was therefore developed for optimum drug release. Method: A wide range of transdermal patches were prepared using two commercially available bioadhesive polymers. Investigational screening was conducted on the patches using microscopy, texture profile analysis, and infrared spectroscopy. Drug release profiles of suitable patches were obtained using both polydimethylsiloxane (Silastic™) and porcine skin in vitro. Results: Diffusion results across Silastic™ showed a gradual plateau in flux with increased drug loading that may be attributable to intramolecular interactions while flux across porcine skin was seen to increase with increasing patch thickness and attained a therapeutic level. Conclusions: This study demonstrated that adhesion and drug loading are significant factors in optimizing a topical patch formulation for the delivery of a captopril prodrug.