Drug-polymer inclusion complex as a new pharmaceutical solid form

Drug-polymer crystalline inclusion complex is a new structure for the drug-polymer 2-component system, and also is a new drug solid form providing more options to optimize the drug pharmaceutical profile.     

Novel drug delivery systems based on the complexes of block ionomers and surfactants of opposite charge

In this paper we have evaluated a novel family of polymer-surfactant complexes formed between block ionomers and oppositely charged surfactants. Complexes between cationic copolymer poly(ethylene oxide)-g-polyethyleneimine (PEO-g-PEI) and sodium salt of oleic acid, natural nontoxic surfactant, are prepared and characterized. These systems self-assemble in aqueous solutions into particles with average size of 50–60 nm, which can solubilize hydrophobic dyes (Yellow OB) and drug molecules (paclitaxel). The use of the biologically active surfactants as components of block ionomer complexes is demonstrated for the complexes from PEO-g-PEI and all-trans-retinoic acid. Binding of relatively soluble drugs with block ionomers is illustrated using PEO-b-poly(sodium methacrylate) and doxorubicin. Overall these studies suggest that block ionomer complexes can be used to prepare a variety of soluble and stable formulations of biologically active compounds, and have potential application as drug delivery systems     

Photocrosslinkable polynorbornene-based block copolymers with enhanced dielectric and thermal properties

Block copolymers poly(endo-N-3,5-bis(trifluoromethyl)biphenyl-norbornene-pyrrolidine)-block-poly(exo-N-(cinnamoyloxyethyl)-7-oxanorborn-5-ene-2,3-dicarboximide) (endo-PTNP-b-exo-PCONBI) and poly(exo-N-3,5-bis(trifluoromethyl)biphenyl-norbornene-pyrrolidine)-block-poly(exo-N-(cinnamoyloxyethyl)-7-oxanorborn-5-ene-2,3-dicarboximide) (exo-PTNP-b-exo-PCONBI) were synthesized by ring-opening metathesis polymerization. The endo- or exo-PTNP served as the high dielectric functional chain, and exo-PCONBI acted as the crosslinking segment. The endo-PTNP-b-exo-PCONBI, in which endo-PTNP has a high content of trans double bond and adopts isotactic configuration, shows a dielectric constant (ε) of 15.5, whereas exo-PTNP-b-exo-PCONBI, in which exo-PTNP has 67% trans double bonds and atactic microstructure, displays relatively low ε of 7.1. The cinnamate groups in exo-PCONBI were crosslinked to form three-dimensional network by cycloaddition reaction under UV irradiation. Exposed to UV-light for 10 min, the cinnamate group in polymer films has a crosslinking conversion of 36%, as determined by UV-Vis absorption measurements. By photocrosslinking, the polymer film has an increased ε of 16.6, a dielectric loss of 0.03, an elevated glass-transition temperature of 137 °C, and an enhanced decomposition temperature of 405 °C, compared to those of polymer films without irradiation.     

Relationships between the stability,circular dichroism spectrum and type of substitution in inclusion complexes formed between phenophthalein and different cyclodextrins

The perturbation of the three-site interaction of phenolphthalein on complexation with different cyclodextrins (CDs) has been investigated as a function of the type and degree of substitution of the CD. The UV visible spectra are practically identical, while the circular dichroism spectra change dramatically both in intensities and signs. Parallel to this, the stability constants are influenced not only by the size of the cavity but also by the substitution of its rims, particularly by that of the primary hydroxyls. The two phenomena can be related to allow conclusions concerning the mode of inclusion.     

Super-nucleation in nanocomposites and confinement effects on the crystallizable components within block copolymers, miktoarm star copolymers and nanocomposites

In this paper we reexamine recent results obtained by our group on the crystallization of nanocomposites and linear and miktoarm star copolymers in order to obtain some general features of their crystallization properties. Different nanocomposites have been prepared where a close interaction between the polymer matrix and the nano-filler has been achieved: in situ polymerized high density polyethylene (HDPE) on carbon nanotubes (CNT); and polycaprolactone (PCL) and poly(ethylene oxide) (PEO) covalently bonded to carbon nanotubes. In all these nanocomposites a “super-nucleation” effect was detected where the CNTs perform a more efficient nucleating action than the self-nuclei of the polymer matrix. It is believed that such a super-nucleation effect stems from the fact that the polymer chains are tethered to the surface of the CNT and can easily form nuclei. For polystyrene (PS) and PCL block copolymers, miktoarm star copolymers (with two arms of PS and two arms of PCL) were found to display more compact morphologies for equivalent compositions than linear PS-b-PCL diblock copolymers. As a consequence, the crystallization of the PCL component always experienced much higher confinement in the miktoarm stars case than in the linear diblock copolymer case. The consequences of the topological confinement of the chains in block copolymers and nanocomposites on the crystallization were the same even though the origin of the effect is different in each case. For nanocomposites a competition between super-nucleation and confinement was detected and the behavior was dominated by one or the other depending on the nano-filler content. At low contents the super-nucleation effect dominates. In both cases, the confinement increases as the nano-filler content increases or the second block content increases (in this case a non-crystallizable block such as PS). The consequences of confinement are: a reduction of both crystallization and melting temperatures, a strong reduction of the crystallinity degree, an increase in the supercooling needed for isothermal crystallization, a depression of the overall crystallization rate and a decrease in the Avrami index until values of one or lower are achieved indicating a nucleation control on the overall crystallization kinetics.     

A novel approach to biodegradable block copolymers of epsilon-caprolactone and delta-valerolactone catalyzed by new aluminum metal complexes

The chemical preparation of structurally well-defined biodegradable amphiphilic block copolymers is now of great interest for biomedical applications and the fundamental mimetic study of biomacromolecule self-assembly. For this purpose, in this study, (R,R)-N,N'-bis(3-tert-butylsalicylidene)-1,2-cyclohexanediamine 2 as a ligand was first synthesized from 1,2-cyclohexanediamine (DACH) and was allowed to further react with AlMe3, leading to a precursor compound 3. Then, the novel five-coordinated aluminum metal complexes 4-6 and 7-8 were prepared with good yields of 80-90%, bearing various molar mass monofunctional methoxy-poly(ethylene glycol) MPEG and difunctional poly(ethylene glycol) PEG as the alkoxy moieties, respectively. By means of nuclear magnetic resonance spectrometry (NMR), mass spectrometry (MALDI-FTMS) and Fourier Transform infrared spectrometry (FT-IR), new metal aluminum complexes 4-8 were characterized as having distinct chemical structures. Utilizing the synthesized metal complexes 4-8 as novel coordination polymerization catalytic templates, biodegradable amphiphilic MPEG-b-PCL, MPEG-b-PVL, PCL-b-PEG-b-PCL and PVL-b-PEG-b-PVL were synthesized with good control of the molecular weight distribution via the ring opening polymerization of epsilon-caprolactone and delta-valerolactone monomers at 100 degrees C in toluene. In addition, the chemical and crystalline structures and the thermal properties of these block biodegradable copolymers were analyzed by means of NMR, gel permeation chromatography (GPC), wide-angle X-ray diffraction (WAXD), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). It was found that the melting points and crystallinities of the block copolymers synthesized strongly depended on the molecular structures of the polyether and polyester building blocks. Only one glass transition stage was detected, indicating good chain/segmental miscibility between the hydrophilic MPEG/PEG and hydrophobic PCL/PVL blocks in the non-crystalline regions. Moreover, TGA analysis exhibited typical two-step decomposition profiles with the weight-loss percentages in good agreement with block compositions from NMR calculations.     

Synthesis and characterization of random and block copolymers with pendant rhenium diimine complexes by controlled radical polymerization

We report the polymerization of rhenium‐containing methacrylates by atom transfer radical polymerization. The structure of the monomer was confirmed by X‐ray crystallography, which showed the bulkiness of the metal‐complex moiety. The rhenium complexes were polymerized in the presence of copper(I) bromide, 1,1,4,7,7‐pentamethyldiethylenetriamine, and methyl 2‐bromopropionate. They were copolymerized with methyl methacrylate in different monomer ratios. An ABA triblock copolymer was also synthesized with poly(methyl methacrylate) as the macroinitiator. When 2,2′‐bipyridine was used as the ligand for the copper catalyst in the polymerizations, it underwent a ligand exchange process with the iminopyridine ligand in the monomer. The neutral rhenium complex in the homopolymers and copolymers could be converted into ionic forms by the replacement of the chloride with an imidazole ligand, and the solubility of the resulting ionic polymers was greatly enhanced. The photosensitizing properties of the doped and undoped polymer films were investigated by the measurement of the photocurrent response under an externally applied electric field. The photoconductivities of the polymers were approximately 10^?12–10^?13 Ω^?1 cm^?1. The experimental quantum efficiencies were simulated with Onsager's theory, and they showed that the initial quantum yield and thermalization distance were 10^?3 and 1.7 nm, respectively. Transmission electron microscopy showed that the rhenium complexes aggregated to form domains with dimensions of approximately 20–30 nm. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 1292–1308, 2005     

Poly(1,3,4-oxadiazole-ether-imide)s and their polydimethylsiloxane-containing copolymers

Poly(1,3,4-oxadiazole-ether-imide)s were prepared by thermal imidization of poly(amic-acid) intermediates resulting from the solution polycondensation reaction of a bis(ether-anhydride), namely 2,2′-bis-[(3,4-dicarboxyphenoxy)phenyl]-1,4-phenylenediisopropylidene dianhydride, with different aromatic diamines containing 1,3,4-oxadiazole ring, such as 2,5-bis(p-aminophenyl)-1,3,4-oxadiazole, 2,5-bis[p-(4-aminophenoxy)phenyl]-1,3,4-oxadiazole, 2-(4-dimethylaminophenyl)-5-(3,5-diaminophenyl)-1,3,4-oxadiazole. Poly(1,3,4-oxadiazole-ether-imide)-polydimethylsiloxane copolymers were prepared by polycondensation reaction of the same bis(ether-anhydride) with equimolar quantities of an aromatic diamine having 1,3,4-oxadiazole ring and a bis(aminopropyl)polydimethylsiloxane oligomer of controlled molecular weight. A solution imidization procedure was used to convert quantitatively the poly(amic-acid) intermediates to the corresponding polyimides. All the polymers were easily soluble in polar organic solvents such as N-methylpyrrolidone and N,N-dimethylacetamide. The polymers showed good thermal stability with decomposition temperature being above 400 °C. Solutions of some polymers in N-methylpyrrolidone exhibited blue fluorescence, having maximum emission wavelength in the range of 370-412 nm.     

Sertaconazole-HPβCD-pluronic F127 solid inclusion complexes: characterization and effect on drug solubility

The influence of Pluronic^® F127 (PF127) on hydroxypropyl-β-cyclodextrin (HP-βCD) complexation in solid state with sertaconazole, a highly active but poorly soluble antifungal drug, and its repercussion on drug solubilization and release rate were evaluated. Solid ternary systems comprising sertaconazole: HP-βCD:PF127 were obtained by (i) kneading of blends wetted with methanol:phosphate buffer; (ii) freeze-drying of filtered suspensions; and (iii) cast of films of filtered suspensions in an oven at 37°C. Two levels of PF127 concentrations were evaluated, one below (0.1%) and other above (5%) the critical micellar concentration (CMC). Physical mixtures were used as references. Differential scanning calorimetry, Raman spectroscopy and X-ray difractometry showed that PF127 did not significantly interfere in the complexation process, as confirmed by the total amount of sertaconazole nitrate (SN) dissolved. Nevertheless, the presence of 5% PF127 significantly delayed the release owing to its ability to form a gel layer. These ternary systems are potentially useful to combine drug solubilization ability with control of drug release.     

Calorimetry and thermogravimetry as tools for the assessment of the thermal stability of polyoxide-based nonionic surfactants

Differential scanning calorimetry (DSC) and thermogravimetry (TGA) have been used to evaluate the thermal stability of nonionic surfactants. We have studied monofunctional diblock copolymers of poly(ethylene oxide-propylene oxide) (R-PEO–PPO–OH, where R length is linear C₄ or C_12–14) as nonionic surfactants. It was observed that the thermal stability was dependent on the copolymer structure. Moreover, the higher the EO/PO ratio in the copolymers the higher the oxidative thermal stability. The autoxidation exhibits exothermic behaviour and the enthalpy related to the process depends on the EO/PO ratio. The initial temperatures of degradation obtained from DSC and TGA were in agreement.     

Influence of alkyl chain length and molecular weight on the surface functionalization via adsorption/entrapment with biocidal cationic block copolymers

Polysulfone (PSf) films were functionalized with block copolymers containing poly(n-butyl acrylate) (PBA) as anchor block which is able to firmly tether the biocidal quaternized poly(2-dimethylaminoethyl methacrylate) (PDMAEMAq) to the surface. Block copolymers were synthesized using sequential atom transfer radical polymerization (ATRP) and quaternization with methyl and/or octyl groups rendered the polymers biocidal. Upon reversible swelling of the PSf surface layer in the adsorption/entrapment process, incorporation of the block copolymer is anticipated to be stable; homopolymers, i.e., methyl- or octyl-quaternized PDMAEMAq, were investigated for comparison. The addition of salt to the functionalization solution containing the block copolymer induced a decrease in the critical micelle concentration and lead to higher functionalization efficiency. The impact of intra- or interchain interactions in these aggregates on adsorption and firm entrapment in PSf was determined by measuring contact angle, charge density and zeta potential.     

The use of the DPE radical polymerization method for the synthesis of chromophore-labelled polymers and block copolymers

Two analogues of diphenylethene carrying phenanthrene (1-(9-phenanthryl)-1-phenylethene (PPE)) and anthracene (1-(2-anthryl)-1-phenylethene (APE)) units were used in radical polymerization of styrene (St) and methyl methacrylate (MMA) at 80 °C using AIBN as initiator. Because of the nature of the polymerization, the resulting polymers possess the corresponding chromophoric groups. Using the methodology of a DPE system, these labelled polymers were further used for the synthesis of block copolymers. In this way poly(methyl methacrylate)-b-poly(styrene) and poly(methyl methacrylate)-b-poly(acrylonitrile) with molar masses of 60,000-90,000 g/mol were synthesized. Incorporation of the chromophoric groups into both homo- and block copolymers was confirmed by spectral measurements.     

New rod-coil block copolymers consisting of terfluorene segments and electron transporting units as the flexible blocks

A series of new rod-coil block copolymers having a well-defined terfluorene unit as the rigid segment with three different electron transporting moieties as the flexible part, such as side chain oxadiazole (TFPOXD), side chain quinoline (TFPQN) and a molecule containing two oxadiazole rings in the side chain (TFPDOXD), were synthesized using the atom transfer radical polymerization (ATRP) technique. All the synthesized copolymers were extensively examined with respect to their optical properties as pristine films, upon thermal annealing (200 °C for 30 min in air) and photo-oxidation treatment in air. Thermal annealing of the block copolymers resulted in stable blue light emission from TFPOXD and TFPDOXD while TFPQN showed the appearance of the undesired 520 nm emission band. In addition, TFPOXD does not exhibit the low-energy emission band at 520 nm after photo-oxidation under prolonged diffuse UV radiation at ambient atmosphere, despite the fluorenone formation on the terfluorene segment, in contrast to all the other copolymers.     

Influence of physical-chemical interactions on the thermal stability and surface properties of poly(vinyl chloride)-b-poly(hydroxypropyl acrylate)-b-poly(vinyl chloride) block copolymers

The synthesis of poly(vinyl chloride) (PVC) homopolymers and poly(vinyl chloride)-b-poly(hydroxypropyl acrylate)-b-poly(vinyl chloride) (PVC-b-PHPA-b-PVC) block copolymers via a single electron - degenerative transfer mediated living radical polymerisation was carried out on a pilot scale in industrial facilities. The thermal stability of the products was assessed conductimetrically. The block copolymers, that contained a low content of PHPA (below 12 wt.%), showed thermal stability that was approximately three times greater than that of conventional PVC. Inverse gas chromatography study of the copolymers surface showed that there was a decrease in the dispersive component and greater Lewis acidity and basicity constants were observed relative to those of PVC. The thermal stabilisation of PVC when in the presence of PHPA is explained by the interactions between its functional groups and the structures formed during the thermal degradation. The thermal stability and the surface properties of PVC-b-PHPA-b-PVC were strongly dependent on the molecular weight of the block copolymer. Lewis acid-base interaction parameters were determined and are interpreted as evidence of the PVC-b-PHPA-b-PVC compatibilising function in PVC-wood flour composites.     

Spectroscopic study and antioxidant properties of the inclusion complexes of rosmarinic acid with natural and derivative cyclodextrins

Measurement of total antioxidant activity/capacity of polyphenols in various solvent media necessitates the use of cyclodextrins to solubilize lipophilic antioxidants of poor aqueous solubility. The inclusion complexes of the slightly water soluble antioxidant, rosmarinic acid (RA), with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), 2-hydroxyethyl-β-cyclodextrin (HE-β-CD), and methyl-β-cyclodextrin (M-β-CD) were investigated for the first time. The effect of cyclodextrins (CDs) on the spectral features of RA was measured in aqueous medium using UV-vis and steady-state fluorescence techniques by varying the concentrations of CDs. The molar stoichiometry of RA-CD inclusion complexes was verified as 1:1, and the formation constants of the complexes were determined from Benesi-Hildebrand equation using fluorescence spectroscopic data. Among the CDs, maximum inclusion ability was measured in the case of M-β-CD followed by HP-β-CD, HE-β-CD, β-CD and α-CD. Solid inclusion complexes were prepared by freeze drying, and their functional groups were analyzed by IR spectroscopy. Antioxidant capacity of CD-complexed rosmarinic acid was measured to be higher than that of the lone hydroxycinnamic acid by the CUPric Reducing Antioxidant Capacity (CUPRAC) method. The mechanism of the TAC increase was interpreted as the stabilization of the 1-e oxidized o-catechol moiety of RA by enhanced intramolecular H-bonding in a hydrophobic environment provided by CDs, mostly by M-β-CD.     

UV-induced self-assembly of the inclusion complexes formed between a long-chain photochromic spiropyran and cyclodextrins

Photochromic spiropyran with a long chain alkyl substitute can form axial complexes with α-, β-, and γ-cyclodextrin, respectively. The complexes show normal photochromism. The novel property of the colored forms of the inclusion complexes is that they can assemble into dimers at relatively low concentration or J-aggregates at relatively high concentration. For α-, β-, and γ-cyclodextrin, λ_(max) of the J-aggregates appear at 700 650, and 630 nm, respectively. The sizes of the cavities of cyclodextrins have very little effect on the spectra and decoloration kinetics of the dimers, but have great effects on the spectra of the J-aggregates. Unlike the charge transfer complex of Krongauz, the decoloration process of the dimers or J-aggregates cannot be described by an exponential or a two-exponential kinetics, but obey half-order kinetics very well. Another result that can be deduced from the kinetic analysis is that unlike the dimers formed in apolar solvents or in polymers, which consist of a color     

Preparation and characterization of the crystalline inclusion complexes between cyclodextrins and poly(1,3-dioxolane)

The preparation and characterization of the crystalline inclusion complexes between a polymeric guest, poly(1,3-dioxolane) (PDXL), and small-molecular hosts, cyclodextrins (CDs) are reported. It is observed that the polymer guest can form crystalline inclusion complexes with three kinds of cyclodextrins, which may be attributed to the high oxygen atom density in PDXL chain. The crystalline inclusion complexes were characterized with FTIR , TGA, X-ray diffraction, SEM, 1H NMR and 13C CP/MAS NMR spectroscopes. It was found that the crystalline inclusion complexes have higher temperature stability than the pure CDs. The X-ray powder diffraction patterns of the crystalline inclusion complexes proved that they have columnar structures. 13C CP/MAS NMR spectra of the crystalline inclusion complexes indicate that CDs adopt a more symmetrical conformation in the complexes, while pure CDs assume a less symmetrical conformation in the crystal without a guest inside their cavities. The morphology of the crystal was     

Correlation between thermal and mass spectral techniques for the characterization of allenylidene and carbene complexes

The fragmentation pathways of allenylidene and carbene complexes have been studied using FAB mass spectrometry in comparison with thermal analyses (TGA, DrTG and DTA). Both the decomposition modes are investigated and the possible fragmentation pathways are suggested. The use of mass and thermal analyses (TGA and DTA) in the analyses of allenylidene and carbene complexes allowed the characterization of the fragmentation pathways in MS. The major pathway includes successive loss of carbon monoxide followed by fragmentation of the organic part of the allenylidene or carbene molecules. This is also confirmed by thermogravimetric analysis (TGA) where the first step involves the loss of carbon monoxide followed by the organic ligand. The nature of each step; exothermic or endothermic, is also studied using DTA technique. The kinetic parameters of the thermal decomposition are also studied using the Coates-Redfern method.     

Rise of photoluminescence in the photolysis of EuIII complexes with copolymers of acrylic acid and butyl methacrylate

The luminescence and photochemical properties of Eu^III complexes with copolymers of acrylic acid and butyl methacrylate have been studied by luminescence, IR spectroscopy, and EXAFS.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 958–959, May, 1994.