Controlled release from triple layer,donut-shaped tablets with enteric polymers

The purpose of this research was to evaluate triple layer, donut-shaped tablets (TLDSTs) for extended release dosage forms. TLDSTs were prepared by layering 3 powders sequentially after pressing them with a punch. The core tablet consisted of enteric polymers, mainly hydroxypropyl methylcellulose acetate succinate, and the bottom and top layers were made of a water-insoluble polymer, ethyl cellulose. Drug release kinetics were dependent on the pH of the dissolution medium and the drug properties, such as solubility, salt forms of weak acid and weak base drugs, and drug loading. At a 10% drug loading level, all drugs, regardless of their type or solubility, yielded the same release profiles within an acceptable level of experimental error. As drug loading increased from 10% to 30%, the drug release rate of neutral drugs increased for all except sulfathiazole, which retained the same kinetics as at 10% loading. HCl salts of weak base drugs had much slower release rates than did those of neutral drugs (eg, theophylline) as drug loading increased. The release of labetalol HCl retarded as drug loading increased from 10% to 30%. On the other hand, Na salts of weak acid drugs had much higher release rates than did those of neutral drugs (eg, theophylline). Drug release kinetics were governed by the ionization/erosion process with slight drug diffusion, observing no perfect straight line. A mathematical expression for drug release kinetics (erosion-controlled system) of TLDSTs is presented. In summary, a TLDST is a good design to obtain zero-order or nearly zero-order release kinetics for a wide range of drug solubilities.     

Nickel(II)-, cobalt(II)-, copper(II)-, and zinc(II)-phthalate and 1-methylimidazole coordination compounds: synthesis, crystal structures and magnetic properties

Three new coordination polymers [M(Pht)(1-MeIm)₂]_n (where M=Cu (1), Zn (2), Co (3); Pht²⁻=dianion of o-phthalic acid; 1-MeIm=1-methylimidazole) and two compounds [M(1-MeIm)₆](HPht)₂ · 2H₂O (M=Co (4), Ni (5)) have been synthesized and characterized by X-ray crystallography. The structures of 1-3 (2 is isostructural to 3) consist of [M(1-MeIm)₂] building units connected by 1,6-bridging phthalate ions to form infinite chains. In complex 1, each copper(II) center adopts a square coordination mode of N₂O₂ type by two O atoms from different phthalate ions and two N atoms of 1-MeIm, whereas in 3 two independent metal atoms are tetrahedrally (N₂O₂) coordinated to a pair of Pht ligands and a pair of 1-MeIm molecules. There are only van der Waals interactions between the chains in 1, while the three-dimensional network in 3 is assembled by C-H?O contacts. In contrast to polymers 1-3 the structures of 4 and 5 (complexes are also isostructural) are made up of the [M(1-MeIm)₆]²⁺ cation, two hydrogen phthalate anions (HPht⁻) and two H₂O solvate molecules. The coordination around each metal(II) atom is octahedral with six nitrogen atoms of 1-MeIm. Extended hydrogen bonding networks embracing the solvate water molecules and a phthalate residue as well as the weak C-H?O interactions stabilize the three-dimensional structures. Magnetic studies clearly show that the magnetic ions do not interact with each other. Furthermore, in compound 4 we have another example of a highly anisotropic Co²⁺ ion with a rhombic g-tensor and large zero-field-splitting. The complexes were also characterized by IR and ¹H NMR spectroscopy, thermogravimetric analysis, and all data are discussed in the terms of known structures.     

Syntheses and crystal structures of cyano-bridged cluster-metal layered coordination polymers [Cu(dien)]3[W4Te4(CN)12] · 9H2O and [Ni(en)(NH3)]3[W4Se4(CN)12] · 7.5H2O

Two new tetrahedral tungsten cyanide cluster compounds, [Cu(dien)]₃[W₄Te₄(CN)₁₂] · 9H₂O (1) (dien=diethylenetriamine) and [Ni(en)(NH₃)]₃[W₄Se₄(CN)₁₂] · 7.5H₂O (2) (en=ethylenediamine), were synthesized by treating aqueous solutions of the saltlike cluster compound K₆[W₄Te₄(CN)₁₂] · 5H₂O/K₆[W₄Se₄(CN)₁₂] · 6H₂O with copper(II)/nickel(II) chloride in aqueous ammonia containing dien/en. The cyano-bridged layered coordination polymeric compounds were characterized by single-crystal X-ray diffraction analysis: monoclinic, space group P2₁ for 1; trigonal, space group for 2. Structures of 1 and 2 consist of infinite neutral layers of cluster components {W₄Te₄(CN)₁₂}/{W₄Se₄(CN)₁₂} connected, one another by {Cu(dien)} or {Ni(en)(NH₃)} fragments, respectively.     

Novel cup-like helical coordination polymers: synthesis, crystal structures and thermal properties

By the design of ligand 1,1^′-(1,5-pentamethylene)bis-1H-benzimidazole (pbbm), we have synthesized polymers {[Co(NO₃)(pbbm)₂]NO₃ · 1/2H₂O}_n (1), {[CdCl(pbbm)₂]Cl · CH₃OH}_n (2) and {[Cu(Ac)₂(pbbm)] · CH₃OH}_n (3), and characterized their structures by single crystal X-ray diffraction as well as thermoanalysis. In polymers 1 and 2, one of the anions coordinates to the central ion, the other is located in the environment. Two pbbm ligands coordinate simultaneously to two metal centers generating one-dimensional cup-like helical chains. To our best knowledge, this cup-like structure has never been observed in the reported polymers. In polymer 3, each Cu atom is five-coordinate by two nitrogen atoms from two pbbm ligands, and three oxygen atoms from one monodentate acetate anion and one chelating acetate anion leading to one-dimensional wave-like linear chain. In addition, the DTA and TG results of the three polymers are in agreement with the crystal structures.     

Exploring the Linkage Dependence of Polyubiquitin Conformations Using Molecular Modeling

Posttranslational modification of proteins by covalent attachment of a small protein ubiquitin (Ub) or a polymeric chain of Ub molecules (called polyubiquitin) is involved in controlling a vast variety of processes in eukaryotic cells. The question of how different polyubiquitin signals are recognized is central to understanding the specificity of various types of polyubiquitination. In polyubiquitin, monomers are linked to each other via an isopeptide bond between the C-terminal glycine of one Ub and a lysine of the other. The functional outcome of polyubiquitination depends on the particular lysine involved in chain formation and appears to rely on linkage-dependent conformation of polyubiquitin. Thus, K48-linked chains, a universal signal for proteasomal degradation, under physiological conditions adopt a closed conformation where functionally important residues L8, I44, and V70 are sequestered at the interface between two adjacent Ub monomers. By contrast, K63-linked chains, which act as a nonproteolytic regulatory signal, adopt an extended conformation that lacks hydrophobic interubiquitin contact. Little is known about the functional roles of the so-called “noncanonical” chains (linked via K6, K11, K27, K29, or K33, or linked head-to-tail), and no structural information on these chains is available, except for information on the crystal structure of the head-to-tail-linked diubiquitin (Ub₂). In this study, we use molecular modeling to examine whether any of the noncanonical chains can adopt a closed conformation similar to that in K48-linked polyubiquitin. Our results show that the eight possible Ub₂ chains can be divided into two groups: chains linked via K6, K11, K27, or K48 are predicted to form a closed conformation, whereas chains linked via K29, K33, or K63, or linked head-to-tail are unable to form such a contact due to steric occlusion. These predictions are validated by the known structures of K48-, K63-, and head-to-tail-linked chains. Our study also predicts structural models for Ub₂ chains linked via K6, K11, or K27. The implications of these findings for linkage-selective recognition of noncanonical polyubiquitin signals by various receptors are discussed.     

One-dimensional Cu(I) camphor hydrazone polymers: Structure and catalytic properties

Complexes of general formula [{CuX}₂(YNC₁₀H₁₄O)] (X = Cl; Y = NHMe, NH₂ or X = Br; Y = NH₂) were synthesised from camphor hydrazone ligands (YNC₁₀H₁₄O) by reaction with the suitable copper(I) halide. Structural analysis by X-rays performed on a red crystal of [{CuCl}₂(Me₂NNC₁₀H₁₄O)] revealed that the complex is a one-dimensional copper polymer formed by two rather different copper units bridged by chloride. One of the copper units displays a tetrahedral geometry while the other is linear. Although the geometries and neighbourhoods of the two copper units are very different the oxidation state of the metal is the same, i.e. Cu(I) as corroborated by magnetic and electrochemical measurements.The ability of [{CuCl}₂(Me₂NNC₁₀H₁₄O)] to promote the activation of 4-pentyn-1-ol towards cyclization was studied under homogeneous or heterogeneous experimental conditions. The best results were obtained under homogeneous conditions at 40 °C.     

Synthesis, structures and luminescent properties of novel coordination polymers constructed by lanthanide salts and benzimidazole-5,6-dicarboxylic acid

Two three-dimensional (3D) novel lanthanide complexes with the H₂Lbenzimidazole-5,6-dicarboxylate [Ln₂L₃(H₂O)] [Ln = Eu (1), Tb (2)] and one two-dimensional (2D) novel lanthanide complex [Pr(L)(HL)H₂O]·H₂O (3) were synthesized by hydrothermal reaction at 180 °C and characterized by elemental analysis, infrared spectra and single-crystal X-ray diffraction. The result showed that complexes 1 and 2 are isostructural and build porous 3D networks by L²⁻ groups linking Ln(III) atoms via tetradentate (bridging and bridging) and pentadentate (bridging/chelating and bridging) coordination modes. Complex 3 is a eight-coordinated Pr(III) chain complex, exhibiting a 2D polymeric network with parallel Pr-carboxylate chains along the crystallographic c-axis. In addition, it is found that in these structures, coordination modes of L²⁻ and HL⁻ are versatile and can adopt different conformations according to distinct dimensions of polymeric structures. The photoluminescent properties of 1, 2 and thermogravimetric analyses of the three complexes were discussed in detail.     

Coordination polymers of Cu(II) and Cd(II) with bifunctional chelates of the type dipicolylamino-alkylcarboxylate, (NC5H4CH2)2N(CH2)nCO2H (n = 1, 2, 3 and 4)

A series of bifunctional chelates of the type dipicolylamino-alkylcarboxylate (NC₅H₄CH₂)₂N(CH₂)_nCO₂H (n = 1-4; HL¹-HL⁴, respectively) has been prepared. Reactions of the ligands in aqueous methanol/N,N-dimethylformamide with the appropriate Cu(II) salts yielded the compounds [CuL¹](NO₃)·H₂O (1·H₂O), [CuL²(H₂O)]BF₄·H₂O (2·H₂O), [Cu(HL³)(SO₄)]₂ (3) and [CuL⁴(NO₃)]·MeOH (4·MeOH). While compounds 1, 2 and 4 are one-dimensional, the detailed connectivities within the chains are quite distinct, depending on factors such as alkyl chain length and ligation of aqua ligands or anionic components. In contrast to 1, 2 and 4, the structure of 3 is molecular, a binuclear assembly of edge-sharing Cu(II) ‘4+2’ distorted octahedra. The Cd(II) species, [{CdL²}₂(SO₄)]·4H₂O (5·4H₂O), prepared from HL² and CdSO₄·nH₂O in aqueous methanol/N,N-dimethylformamide, is two-dimensional, with a network constructed from binuclear units of seven coordinate Cd(II), , linked through bridging SO₄²⁻ groups to produce an assembly of linked hexagonal rings [{CdL²}₂(SO₄)]₆.     

Syntheses, crystal structures and magnetic properties of 1D and 2D cobaltous coordination polymers with mixed ligands

Two new Co(II) coordination polymers with mixed ligands, {[Co(BTA)_0.5(DBI)₂]·DBI·H₂O}_n (1) and [Co(PDA)(DBI)(H₂O)]_n (2) (H₄BTA = benzene-1,2,4,5-tetracarboxylic acid; H₂PDA = 2,2′-(1,2-phenylene)diacetic acid; DBI = 5,6-dimethyl-1H-benzoimidazole) have been synthesized under hydrothermal conditions, respectively. Both of them are characterized by elemental analyses, powder X-ray diffraction, thermogravimetric analysis, single-crystal X-ray diffraction, and magnetic susceptibilities. In 1, the Co(II) ions are four-coordinated and lie in distorted tetrahedron coordination environment. 1D ladder-like chain structure is formed by the bridging BTA⁴⁻ ligand. In 2, the Co(II) ions are in slightly distorted octahedral coordination geometry, and linked by PDA²⁻ ligand exhibiting a 2D layer structure. Temperature-dependent magnetic susceptibility measurements of 1 and 2 revealed that there are antiferromagnetic interactions between Co(II) ions.