Degradation of poly-L-lactide. Part2 : increased temperature accelerated degradation

Poly-L-lactide (PLLA) is one of the most significant members of a group of polymers regarded as bioresorbable. The degradation of PLLA proceeds through hydrolysis of the ester linkages in the polymer's backbone; however, the time for the complete resorption of orthopaedic devices manufactured from PLLA is known to be in excess of five years in a normal physiological environment. To evaluate the degradation of PLLA in an accelerated time period, PLLA pellets were processed by compression moulding into tensile test specimens, prior to being sterilized by ethylene oxide gas (EtO) and degraded in a phosphate-buffered solution (PBS) at both 50°C and 70°C. On retrieval, at predetermined time intervals, procedures were used to evaluate the material's molecular weight, crystallinity, mechanical strength, and thermal properties. The results from this study suggest that at both 50°C and 70°C, degradation proceeds by a very similar mechanism to that observed at 37°C in vitro and in vivo. The degradation models developed also confirmed the dependence of mass loss, melting temperature, and glass transition temperature (Tg) on the polymer's molecular weight throughout degradation. Although increased temperature appears to be a suitable method for accelerating the degradation of PLLA, relative to its physiological degradation rate, concerns still remain over the validity of testing above the polymer's Tg and the significance of autocatalysis at increased temperatures.

On thin ice: surface order and disorder during pre-melting

The effect of temperature on the structure of the ice Ih (0001) surface is considered through a series of molecular dynamics simulations on an ice slab. At relatively low temperatures (200K) a small fraction of surface self-interstitials (i.e. admolecules) appear that are formed exclusively from molecules leaving the outermost bilayer. At higher temperatures (ca. 250 K), vacancies start to appear in the inner part of the outermost bilayer exposing the underlying bilayer and providing sites with a high concentration of the dangling hydrogen bonds. Around 250-260 K aggregates of molecules formed on top of the outermost bilayer from self-interstitials become more mobile and have diffusivities approaching that of liquid water. At similar to 270-280 K the inner bilayer of one surface noticeably destructures and it appears that at above 285 K both surfaces are melting. The observed disparity in the onset of melting between the two sides of the slab is rationalised by considering the relationship between surface energy and the spatial distribution of protons at the surface; thermodynamic stability is conferred on the surface by maximising separations between dangling protons at the crystal exterior. Local hotspots associated with a high dangling proton density are suggested to be susceptible to pre-melting and may be more efficient at trapping species at the external surface than regions with low concentrations of protons thus potentially helping ice particles to catalyse reactions. A preliminary conclusion of this work is that only about 10-20 K below the melting temperature of the particular water potential employed is major disruption of the crystalline lattice noted which could be interpreted as being "liquid", the thickness of this film being about a nanometre.

Effect of high temperature, biaxial stretching on the thermal and mechanical properties of HDPE/MWCNT sheet

High density polyethylene (HDPE)/multi-walled carbon nanotube (MWCNT) composites containing 4 wt% MWCNTs were prepared by melt mixing followed by compression moulding into sheet. Compression moulded sheets were heated to just below the melting temperature and biaxially stretched at ratios (SRs) of 2, 2.5 and 3.0. The effect of stretching on the thermal and mechanical properties of the sheet was studied by differential scanning calorimetry (DSC) and tensile testing. DSC results show that the crystallinity of all the stretched samples increases by approximately 13% due to strain induced crystallization. The melting temperature of the biaxially stretched samples increases only slightly while crystallization temperature is not affected. Tensile test results indicate that at a SR of 2.5 the elastic modulus of the stretched composites increases by 17.6% relative to the virgin HDPE, but the breaking strength decreases by 33%. While the elastic modulus and breaking strength of the HDPE/MWCNT samples continue to increase as SR increases they drop off after a SR of 2.5 for the virgin HDPE. This is probably due to the constraining influence of the nanotubes preventing the relaxation of polymer chains caused by adiabatic heating at high SRs. The addition of MWCNTs results in significant strain hardening during deformation. While this will lead to increased energy requirement in forming it will also result in a more stable process and the ability to produce deep draw containers with more uniform wall thickness

Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings

The in vitro release characteristics of eight low-molecular-weight drugs (clindamycin, 17beta-estradiol, 17beta-estradiol-3-acetate, 17beta-estradiol diacetate, metronidazole, norethisterone, norethisterone acetate and oxybutynin) from silicone matrixtype intravaginal rings of various drug loadings have been evaluated under sink conditions. Through modelling of the release data using the Higuchi equation, and determination of the silicone solubility of the drugs, the apparent silicone elastomer diffusion coefficients of the drugs have been calculated. Furthermore, in an attempt to develop a quantitative model for predicting release rates of new drug substances from these vaginal ring devices, it has been observed that linear relationships exist between the log of the silicone solubility of the drug (mg ml(-1)) and the reciprocal of its melting point (K-1) (y = 3.558x - 9.620, R = 0.77), and also between the log of the diffusion coefficient (cm(2) s(-1)) and the molecular weight of the drug molecule (g mol(-1)) (y = - 0.0068x - 4.0738, R = 0.95). Given that the silicone solubility and silicone diffusion coefficient are the major parameters influencing the permeation of drugs through silicone elastomers, it is now possible to predict through use of the appropriate mathematical equations both matrix-type and reservoir-type intravaginal ring release rates simply from a knowledge of drug melting temperature and molecular weight. (C) 2003 Elsevier Science B.V. All rights reserved.

High speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a solid or semi-solid matrix

Conventional differential scanning calorimetry (DSC) techniques are commonly used to quantify the solubility of drugs within polymeric-controlled delivery systems. However, the nature of the DSC experiment, and in particular the relatively slow heating rates employed, limit its use to the measurement of drug solubility at the drug's melting temperature. Here, we describe the application of hyper-DSC (HDSC), a variant of DSC involving extremely rapid heating rates, to the calculation of the solubility of a model drug, metronidazole, in silicone elastomer, and demonstrate that the faster heating rates permit the solubility to be calculated under non-equilibrium conditions such that the solubility better approximates that at the temperature of use. At a heating rate of 400 degrees C/min (HDSC), metronidazole solubility was calculated to be 2.16 mg/g compared with 6.16 mg/g at 20 degrees C/min. (C) 2005 Elsevier B.V. All rights reserved.

Structure-Property Relationships in Biaxially Deformed Polypropylene Nanocomposites

Semi-solid forming processes such as thermoforming and injection blow moulding are used to make much of today’s packaging. As for most packaging there is a drive to reduce product weight and improve properties such as barrier performance. Polymer nanocomposites offer the possibility of increased modulus
(and hence potential product light weighting) as well as improved barrier properties and are the subject of much research attention. In this particular study, polypropylene–clay nanocomposite sheets produced via biaxial deformation are investigated and the structure of the nanocomposites is quantitatively determined in order to gain a better understanding of the influence of the composite structure on mechanical properties. Compression moulded sheets of polypropylene and polypropylene/Cloisite 15A nanocomposite (5 wt.%) were biaxially stretched to different stretching ratios, and then the structure of
the nanocomposite was examined using XRD and TEM techniques. Different stretching ratios produced different degrees of exfoliation and orientation of the clay tactoids. The sheet properties were then investigated using DSC, DMTA, and tensile tests .It was found that regardless of the degree of exfoliation or
orientation, the addition of clay has no effect on percentage crystallinity or melting temperature, but it has an effect on the crystallization temperature and on the crystal size distribution. DMTA and tensile tests show that both the degree of exfoliation and the degree of orientation positively correlate with the dynamic mechanical properties and the tensile properties of the sheet.

High pressures generated by laser driven shocks: applications to planetary physics

High power lasers are a tool that can be used to determine important parameters in the context of Warm Dense Matter, i.e. at the convergence of low-temperature plasma physics and finite-temperature condensed matter physics. Recent results concerning planet inner core materials such as water and iron are presented. We determined the equation of state, temperature and index of refraction of water for pressures up to 7 Mbar. The release state of iron in a LiF window allowed us to investigate the melting temperature near the inner core boundary conditions. Finally, the first application of proton radiography to the study of shocked material is also discussed.

Triose phosphate isomerase from the blood fluke Schistosoma mansoni:Biochemical characterisation of a potential drug and vaccine target

The glycolytic enzyme triose phosphate isomerase from Schistosoma mansoni is a potential target for drugs and vaccines. Molecular modelling of the enzyme predicted that a Ser-Ala-Asp motif which is believed to be a helminth-specific epitope is exposed. The enzyme is dimeric (as judged by gel filtration and cross-linking), resistant to proteolysis and highly stable to thermal denaturation (melting temperature of 82.0°C). The steady-state kinetic parameters are high (Km for dihydroxyacetone phosphate is 0.51mM; Km for glyceraldehyde 3-phosphate is 1.1mM; kcat for dihydroxyacetone phosphate is 7800s(-1) and kcat for glyceraldehyde 3-phosphate is 6.9s(-1)).

Biochemical characterisation of triose phosphate isomerase from the liver fluke Fasciola hepatica

Triose phosphate isomerase (TPI) catalyses the interconversion of dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, a reaction in the glycolytic pathway. TPI from the common liver fluke, Fasciola hepatica, has been cloned, sequenced and recombinantly expressed in Escherichia coli. The protein has a monomeric molecular mass of approximately 28 kDa. Crosslinking and gel filtration experiments demonstrated that the enzyme exists predominantly as a dimer in solution. F. hepatica TPI is predicted to have a ß-barrel structure and key active site residues (Lys-14, His-95 and Glu-165) are conserved. The enzyme shows remarkable stability to both proteolytic degradation and thermal denaturation. The melting temperature, estimated by thermal scanning fluorimetry, was 67 °C and this temperature was increased in the presence of either dihydroxyacetone phosphate or glyceraldehyde 3-phosphate. Kinetic studies showed that F. hepatica TPI demonstrates Michaelis-Menten kinetics in both directions, with Km values for dihydroxyacetone phosphate and glyceraldehyde 3-phosphate of 2.3 mM and 0.66 mM respectively. Turnover numbers were estimated at 25,000 s(-1) for the conversion of dihydroxyacetone phosphate and 1900 s(-1) for the conversion of glyceraldehyde 3-phosphate. Phosphoenolpyruvate acts as a weak inhibitor of the enzyme. F. hepatica TPI has many features in common with mammalian TPI enzymes (e.g. ß-barrel structure, homodimeric nature, high stability and rapid kinetic turnover). Nevertheless, recent successful identification of specific inhibitors of TPI from other parasites, suggests that small differences in structure and biochemical properties could be exploited in the development of novel, species-specific inhibitors.

Microstructure evolution of 6061 O Al alloy during ultrasonic consolidation:An insight from electron backscatter diffraction

6061 O Al alloy foils were welded to form monolithic and SiC fibre-embedded samples using the ultrasonic consolidation (UC) process. Contact pressures of 135, 155 and 175 MPa were investigated at 20 kHz frequency, 50% of the oscillation amplitude, 34.5 mm s sonotrode velocity and 20 °C. Deformed microstructures were analysed using electron backscatter diffraction (EBSD). At all contact pressures deformation occurs by non-steady state dislocation glide. Dynamic recovery is active in the upper and lower foils. Friction at the welding interface, instantaneous internal temperatures (0.5-0.8 of the melting temperature, T), contact pressure and fast strain rates result in transient microstructures and grain size reduction by continuous dynamic recrystallization (CDRX) within the bonding zone. Bonding occurs by local grain boundary migration, which allows diffusion and atom interlocking across the contact between two clean surfaces. Textures weaken with increasing contact pressure due to increased strain hardening and different grain rotation rates. High contact pressures enhance dynamic recovery and CDRX. Deformation around the fibre is intense within 50 μm and extends to 450 μm from it. © 2009 Acta Materialia Inc.

Pre-clinical development of a combination microbicide vaginal ring containing dapivirine and darunavir

Objectives: Combination microbicide vaginal rings may be more effective than single microbicide rings at reducing/preventing sexual transmission of HIV. Here, we report the preclinical development and macaque pharmacokinetics of matrix-type silicone elastomer vaginal rings containing dapivirine and darunavir.

Methods: Macaque rings containing 25 mg dapivirine, 300 mg darunavir and 100 mg dapivirine, and 300 mg darunavir were manufactured and characterised by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28-day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values calculated.

Results: Darunavir caused a concentration-dependent reduction in the dapivirine melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present, and the release medium. In macaques, serum concentrations of both microbicides were maintained between 101–102 pg/mL. Vaginal fluid levels ranged between 103–104 ng/g and 104–105 ng/g for dapivirine and darunavir, respectively. Tissue concentrations ranges for each drug were: vagina (1.8×103–3.8×103 ng/g) > cervix (9.4×101–3.9×102 ng/g) > uterus (0–108 ng/g) > rectum (0–40 ng/g). Measured IC50 values were > 2 ng/mL for both compounds.

Conclusions: Based on these results, and in light of recent clinical progress of the 25mg dapivirine ring, a combination vaginal ring containing dapivirine and darunavir is a viable second-generation HIV microbicide candidate.

Thermal properties and eutectic behaviour of dapivirine in combination with steroid hormones and other antiretrovirals

Background: Combination drug products can display thermal behaviour that is more complex than for the corresponding single drug products. For example, the contraceptive vaginal ring (VR) Nuvaring contains a eutectic (lowest melting) composition of etonogestrel (ETN) and ethinyl estradiol. Here we report the predisposition of dapivirine (DPV) to form reduced melting/eutectic mixtures when combined with other contraceptive hormones and antiretrovirals, and discuss the implications for development of combination microbicide and multipurpose prevention technology (MPT) products.
Methods: Binary mixtures of DPV with darunavir (DRV), levonorgestrel (LNG), ETN or maraviroc (MVC) were prepared either by physical mixing or by solvent evaporation. Selected binary mixtures were also incorporated into silicone elastomer (SE) VR devices. Thermal behavior of the mixtures was analyzed using differential scanning calorimetry (DSC) operating in standard heating ramp mode (10 °C/min). DSC data were used to construct two component phase diagrams for each binary system.
Results: Drug mixtures typically showed reduced melting transitions for both drug components, with clear evidence for a eutectic mixture at a well-defined intermediate composition. Eutectic temperatures and compositions for the various mixtures were: 40% DPV / 60% ETN - 170°C; 25% DPV / 75% MVC - 172°C; 65% DPV / 35% LNG - 192°C. In each case, the eutectic composition was also detected when the drug mixtures were incorporated into SE VRs. For the DPV/DRV system, the thermal behaviour is complicated by desolvation from the darunavir ethanolate polymorph.
Conclusions: When DPV is combined with small molecular weight hydrophobic drugs, the melting temperature for both drugs is typically reduced to a degree dependent on the composition of the mixture. At specified compositions, a low melting eutectic system results. The formation of eutectic behavior in binary drug systems needs to be carefully characterised in order to define product performance and drug release.

A Combination Vaginal Ring Releasing Dapivirine and Darunavir

Background: Combination microbicide vaginal rings, containing two or more antiretrovirals targeting different steps in the HIV replicative process, may be more effective than single microbicide products at preventing sexual transmission of HIV. Here, we report the preclinical development, including in vitro release and macaque pharmacokinetics, of matrix-type silicone elastomer rings containing dapivirine (DPV; an experimental non-nucleoside reverse transcriptase inhibitor) and darunavir (DRV; a marketed protease inhibitor). Methods: Macaque rings containing 25 mg DPV, 300 mg DRV and 100 mg DPV, and 300 mg DRV were manufactured and characterised by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28-day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values calculated.
Results: DRV caused a concentration-dependent reduction in the DPV melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present, and the release medium. In macaques, serum concentrations of both
microbicides were maintained between 101-102 pg/mL. Vaginal fluid levels
ranged between 103-104 ng/g and 104-105 ng/g for DPV and DRV, respectively. Vaginal tissue concentrations decreased in rank order: vagina
(1.8×103-3.8×103 ng/g) > cervix (9.4×101-3.9×102 ng/g) > uterus (0-108 ng/g) > rectum (0-40 ng/g). Measured IC50 values (HIV-1 BaL) determined from macaque vaginal fluid samples were < 2 ng/mL for both compounds. Conclusions: Based on these results, and in light of the ongoing clinical progress of the 25mg DPV ring, a combination vaginal ring containing DPV and DRV is a viable second-generation HIV microbicide candidate.

Characterisation of melt processed nanocomposites of Polyamide 6 subjected to uniaxial-drawing

In this paper, the processing and characterization of Polyamide 6 (PA6) nanocomposites containing graphite nanoplatelets (GNPs) is reported. PA6 nanocomposites were prepared by melt-mixing using an industrial, co-rotating, intermeshing, twin-screw extruder. A bespoke screw configuration was used that was designed in-house to enhance nanoparticle dispersion into a polymer matrix. The effects of nano-filler type (xGnPTM M-5 and xGnPTM C-500), nano-filler content, and extruder screw speed on the bulk properties of the PA6 nanocomposites were investigated. The crystalline structures of PA6 nanocomposites are related to thermal treatment, stress history and the presence of moisture and nanofillers. DSC, Raman and XRD studies show an increase in crystallinity with increasing GNP content and a phase transformation between α-form to γ-form crystals as a result of the heterophase nucleation effect. The effect of uniaxial stretching on PA6 nanocomposites was investigated by drawing specimens heated at temperatures below the melting temperature. DSC and Raman studies on the drawn samples show an increase in yield stress as the GNP content increases due to the strain induced crystallization and γ—β transition during stretching. The rheological response of the nanocomposites resemble that of a ‘pseudo-solid’, rather than a molten liquid, and analysis of the rheological data indicates that a percolation threshold was reached at GNP contents of between 10–15wt%. An increase in tensile modulus of as much as 412% was observed for PA6/C-500 xGnPTM composites, at a filler content of 20wt%. The enhancement of Young’s modulus and yield stress can be attributed to the reinforcing effect of GNPs and their uniform dispersion in the PA6 matrix. The electrical conductivity of the composite also increased with increasing GNP content, with an addition of 15wt% GNP resulting in a 6 order-of-magnitude increase in conductivity. The effects of uniaxial-drawing and the inclusion of multiple nano-filler varieties on the electrical and mechanical properties are currently under investigation.

Solid-liquid interfacial free energy out of equilibrium

The properties of the interface between solid and melt are key to solidification and melting, as the interfacial free energy introduces a kinetic barrier to phase transitions. This makes solidification happen below the melting temperature, in out-of-equilibrium conditions at which the interfacial free energy is ill defined. Here we draw a connection between the atomistic description of a diffuse solid-liquid interface and its thermodynamic characterization. This framework resolves the ambiguities in defining the solid-liquid interfacial free energy above and below the melting temperature. In addition, we introduce a simulation protocol that allows solid-liquid interfaces to be reversibly created and destroyed at conditions relevant for experiments. We directly evaluate the value of the interfacial free energy away from the melting point for a simple but realistic atomic potential, and find a more complex temperature dependence than the constant positive slope that has been generally assumed based on phenomenological considerations and that has been used to interpret experiments. This methodology could be easily extended to the study of other phase transitions, from condensation to precipitation. Our analysis can help reconcile the textbook picture of classical nucleation theory with the growing body of atomistic studies and mesoscale models of solidification.