Engineering of drug nanoparticles by HGCP for pharmaceutical applications

This paper reviews our work on the fundamental principles of high gravity controlled precipitation (HGCP) technology, and its applications in the production of drug nenoparticles, which was carded out in a rotating packed bed (RPB). Several kinds of drug nanoparticles with narrow particle size distributions (PSDs) were successfully prepared via HGCP, including the 300-nm Cefuroxirne Axetil (CFA) particles, 200-400-nm cephradine particles, 500-nm salbutamol sulfate (SS) particles (100 nm in width), end 850-nm beclomethasone dipropionate (BDP) particles, etc. Compared to drugs available in the current market, all the drug nanoparticles produced by HGCP exhibited advantages in both formulation end drug delivery, thus improving the bioavailability of drugs. HGCP is essentially a platform technology for the preparation of poorly water-soluble drug nanoparticles for oral and injection delivery, and of inhalable drugs for pulmonary delivery. Consequently, HGCP offers potential applications in the pharmaceutical industry due to its cost-effectiveness, efficient processing end the ease of scaling-up.     

Rheological characterization of carbon nanotubes/poly(ethylene oxide) composites

Rheological properties of poly(ethylene oxide) nanocomposites embedded with carbon nanotubes (CNTs) were investigated in the present study. It was found that the CNT nanocomposites had a higher effective filler volume fraction than the real filler volume fraction, which yielded a drastic enhancement of shear viscosity. As the CNT loading in the nancomposites increases, non-Newtonian behavior was observed at the low-shear-rate region in the steady shear experiments. Oscillatory dynamic shear experiments showed that more addition of the CNTs led to stronger solidlike and nonterminal behaviors. To identify a dispersion state of the CNTs, field emission scanning electron spectroscopy and transmission electron microscopy were adopted and thermal analysis was also performed by using differential scanning calorimetry. The existence of percolated network structures of the CNTs even at a low CNT loading was verified by rheological properties and electrical conductivities.     

Size-dependent cellular uptake and sustained drug release of PLGA particles

Poly (lactic-co-glycolic) acid (PLGA) particles have become a commonly used drug delivery strategy in the pharmaceutical industry. In this work, we aim to investigate the size-dependent cellular internalization of PLGA particles and its effects on sustained drug release. We prepared three different-sized particles using PLGA (200, 500 and 2000 nm) ranging from submicrometer to micrometer. Dexamethasone (DEX) with excellent anti-inflammatory properties was used as a model drug to prepare DEX-loaded PLGA particles (DPs). We comprehensively investigated the encapsulation efficiency, cellular uptake and in vitro drug release profile. Pharmacodynamic assessment revealed that, in the lipopolysaccharide (LPS)-induced RAW 264.7 cells model, 500 nm DPs showed sustained anti-inflammatory efficacy. This work provides important information for designing PLGA-based drug delivery systems for biomedical applications.     

An experimental study for impact of a drop onto a particle in mid-air: The influence of particle wettability

Drop impact onto a particle in mid-air is a fundamental physical phenomena relevant to many applications involving a fluidized bed, for example, refining of heavy oil or coating of drug particles for pharmaceutical industry. A literature analysis shows that previous studies were focused on collisions of drops with static particles of either spherical or non-spherical shapes. This paper reports on experiments conducted at similar impact conditions with water drops and particles made of hydrophobic (polystyrene) and hydrophilic (soda-lime glass) materials. It was observed that at similar Weber numbers, wettability of the particle plays a key role in transition between collision outcomes with formation of a liquid lamella and ligaments. Present investigation is one of the first which reveals quantitative aspects for dynamics of the lamella and liquid ligaments in a particular case of mid-air collisions.     

Key synthesis of magnetic Janus nanoparticles using a modified facile method

Inorganic/organic poly（methylmethacrylate-acrylic acid-divinylbenzene） iron oxide Janus magnetic nanoparticles（P（MMA-AA-DVB）/Fe3O4） with strong magnetic domains and unique surface functionalities were prepared using a solvothermal process.The P（MMA-AA-DVB） nanoparticles were prepared via soapfree emulsion polymerization and used as a precursor for preparing Janus nanoparticles.The morphology and magnetic properties of the magnetic Janus nanoparticles formed were characterized using a laser particle size analyzer,transmission electron microscopy,Fourier transform infrared spectroscopy,vibrating sample magnetometry,and thermogravimetric analysis.The synthesized P（MMA-AA-DVB）/Fe3O4 magnetic Janus nanoparticles were characterized by a Janus structure and possessed a stable asymmetric morphology after being dually functionalized.The particle size,magnetic content,and magnetic domain of the P（MMA-AA-DVB）/Fe3O4 magnetic Janus nanoparticles were 200 nm,40%,and 25 emu/g,respectively.The formation mechanism of the Janus nanoparticles was also investigated,and the results revealed that the reduction of Fe3＋ ions and growth of Fe3O4 took place on the surface of the P（MMA-AA-DVB） polymeric precursor particles.The size of the Janus particles could be controlled by narrowing the size distribution of the P（MMA-AA-DVB） precursor nanoparticles.     

ADVANCES IN MICROEMULSION PHASE ON SELF-ASSEMBLY AND MICELLE EXTRACTION WITH BLOCK COPOLYMERS

In this paper we review our work on self-assembly of the system, poly（ethylene oxide）-poly（propylene oxide）-poly（elhylene oxide） （PEO-PPO-PEO） block copolymers, which is a kind of macromolecular complex fluids. The control of self-assembly could be obtained by adding inorganic salts or aliphatic alcohols. By self-assembly of amphiphilic block copelymers a microemulsion phase is formed which could be applied in micelle extraction, such as hollow-fiber membrane micelle extraction, magnetic micelle extraction and immobilized micelle extraction.     

Glial Model for Traumatic Brain Injury: Network Strain Field and Inflammation Induced by Repeated Mechanical Impacts <Emphasis Type="Italic">In Vitro</Emphasis>

Traumatic brain injury (TBI) is a form of acquired brain trauma in which sudden external mechanical insults damage brain structures and cells. With a wide range of severities, TBI induces inflammatory responses with neurodegeneration and dysfunction. To develop new treatments, reproducible models of implementation are needed. Moreover, these models need to exhibit high biological and mechanical fidelity to the injurious event that they are trying to mimic. Here, the Highly Automated Mechanical Impactor (HAMr) is used to deliver 64 controlled pressure-pulses of known magnitude and duration to mixed glia cultures as a model for repetitive TBI. The mechanical response of those glial networks was quantified in terms of induced strain histories using Digital Image Correlation (DIC) under high-speed microscopic imaging. Four hours post-impact, glial network shearing and gene expression increases of TNFα and IL-1α were observed. However, select microglia and astrocyte markers were unchanged. These findings validate HAMr as a tool that enables quantification of the cell-substrate strain history during impact loading while reproducibly inducing inflammation and damaging glial network integrity, which are both common consequences of TBI.     

Shear-thickening behavior of high molecular weight poly(ethylene oxide) solutions

Simple shear rheological properties of solutions of a high molecular weight (8 × 10⁶ g/mol) poly(ethylene oxide) (PEO) and its mixtures with sodium dodecyl sulfate (SDS) have been studied. Shear-thickening effects set in at a critical shear rate for PEO solutions. This particular behavior has not been reported for aqueous solutions of PEO, to our knowledge. The effect is attributed to PEO flow-induced self-aggregation. The experiments were performed in different operation modes (strain rate and stress controlled) and with different geometries (double wall Couette and Couette) and identical viscosities were obtained, which rules out flow instabilities as possible cause for the shear-thickening effect. Shear thickening was observed in the temperature range 15–50°C. Flow-induced PEO degradation occurs for shear rates in the shear-thickening regime, which indicates substantial chain deformation and accumulated stresses in the molecule when shear thickening occurs. Addition of SDS to the PEO solutions induces the formation of surfactant polymer complexes that preserve the characteristic shear-thickening effect.     

Ultrapermeable membranes based on connected cluster of hollow polydimethylsiloxane nanoparticles for gas separation

Mixed matrix membranes (MMMs) with the performance between the matrix and the filler is a promising strategy for membranes with excellent gas permeability-selectivity. In this study, the hollow polydimethylsiloxane nanoparticles were synthesized and then incorporated with the poly(oxide ethylene) monomer and tri-functional cross-linker to form mixed matrix membranes by in situ polymerization. The hollow nanoparticles formed the independent closed nanocavities in membranes, which enhanced the gas permeability contributed by both the improved diffusivity and solubility. At high loading, the hollow polydimethylsiloxane nanoparticle was converted into the continuous phase with the cross-linked poly(oxide ethylene) as the dispersed phase. Gases preferred to permeate through the connected cluster of hollow polydimethylsiloxane nanoparticles, finally leading to ultrahigh gas permeabilities far going beyond the instinct values of polydimethylsiloxane and the cross-linked poly(oxide ethylene). The optimized membrane with 34 wt% hollow nanoparticles loadings exhibited ultrahigh permeabilities with the values of 44186 Barrer for CO₂ and 11506 Barrer for O₂, accompanied with a CO₂/N₂ selectivity of 9.9 and an O₂/N₂ selectivity of 2.6, which exceeded the 2008 Robeson upper bound for O₂/N₂ and located at the 2008 Robeson upper bound for CO₂/N₂.     

Relaxation dynamics of selected polymer chain segments and comparison with theoretical models

Simultaneous measurement of infrared dichroism and birefringence is used to study selected polymer segment dynamics in isotopically labeled block copolymers. Two different polymers were studied: polybutadiene and poly (ethylene propylene). The first type consisted of a triblock with a short middle block labeled and a diblock with a short end block labeled, while the second type consisted of a triblock with three equal blocks and the end blocks labeled. Results of step strain experiments at –10°C for polybutadiene and at room temperature for poly(ethylene propylene) indicated that segments located at chain ends relax faster than segments located at chain centers. These experimental data were compared to the predictions of two molecular models: the bead-spring model of Rouse and the tube model of Doi and Edwards, and it was found that both models correctly predict the qualitative features of segmental relaxation. However, the tube-model predictions were closer to the experimental results. In addition, when the effects of orientational coupling interactions between segments in the melt were incorporated into this model, its predictions quantitatively agreed with the experimental results. The orientational coupling coefficient for poly(ethylene propylene) was 0.45 as measured from previous work, and for polybutadiene it was found to be 0.4.Delivered as a Keynote Lecture at the Golden Jubilee Conference of the British Society of Rheology and Third European Rheology Conference, Edinburgh, 3–7 September, 1990.Dedicated to Prof. R.S. Stein, University of Massachussets at Amherst, USA, on the occasion of his 65th birthday.     

Nonlinear rheological properties and stability of dibenzylidene sorbitol fiber networks in poly(propylene oxide)

Dibenzylidene sorbitol (DBS) is known to gel organic liquids and polymers such as poly(propylene oxide) (PPO) by forming long fibers and fiber networks. Potential applications of these networks depend on their ability to withstand large deformations without significant morphological changes. Therefore, we studied the nonlinear rheological properties of the DBS fiber network in PPO for different DBS concentrations. We found that the concentration dependence of critical deformation (transition from linear to nonlinear viscoelastic region) and gel strength (G′ plateau in the linear region) can be explained on the basis of a model for densely cross-linked fiber gels (MacKintosh et al., Phys Rev Lett 75:4425–4428, 1995). Performing periodic strain sweeps, we found that the decrease in gel strength during the deformation cycles can be ascribed to reversible fiber coarsening. Additionally, start-up experiments showed a strong shear thinning behavior, which is in quantitative agreement with the SGM model (Sollich, Phys Rev E 58:738–759, 1998).     

Scaling theory of adsorption-induced stresses in polymer brushes grafted onto compliant structures

The lateral forces exerted on a substrate by a layer of end-grafted polymer molecules are calculated on the basis of simple scaling arguments. The results are cast in terms of an equilibrium surface stress and an elastic constant, which describes the rate of change of the surface stress upon deformation of the substrate. This allows for straightforward integration of the present results into a continuum framework describing the response of a compliant structure, which facilitates device design and analysis. The results are illustrated with calculations for end-grafted poly(styrene) and poly(ethylene oxide), and the implications for building micromechanical devices based on adsorption-induced deformation are discussed.     

Shear-thickening and structure formation in polymer solutions

The phenomenon of shear-thickening has been investigated for solutions of several high molecular weight crystallizable polymers using capillary rheometry. The systems studied: polyethylene/xylene, polypropylene/tetralin, and poly(ethylene oxide)/ethanol have previously been investigated for their flow induced crystallization behavior. A shear-thickening pattern occurs in the relative viscosity vs. shear rate flow curves for the first two systems which, for the former of the two, also shows a strong molecular weight dependence. For the range of conditions studied, the poly(ethylene oxide)/ethanol system did not show shear-thickening, exhibiting instead a shear thinning pattern for the lower molecular weight sample studied and a constant viscosity high shear plateau for the higher MW system. The conclusion is reached that shear-thickening is due to molecular entanglements formed during flow and the implications of these results to the phenomenon of precursor phase separation in flow-induced fibrous crystallization are discussed.     

Symmetry-Breaking Bifurcations of Charged Drops

It has been observed experimentally that an electrically charged spherical drop of a conducting fluid becomes nonspherical (in fact, a spheroid) when a dimensionless number X inversely proportional to the surface tension coefficient is larger than some critical value (i.e., when <_c). In this paper we prove that bifurcation branches of nonspherical shapes originate from each of a sequence of surface-tension coefficients ), where ₂=_c. We further prove that the spherical drop is stable for any >₂, that is, the solution to the system of fluid equations coupled with the equation for the electrostatic potential created by the charged drop converges to the spherical solution as t provided the initial drop is nearly spherical. We finally show that the part of the bifurcation branch at =₂ which gives rise to oblate spheroids is linearly stable, whereas the part of the branch corresponding to prolate spheroids is linearly unstable.     

Rheological and diffusion properties of a dextran-con A polymer in the presence of Insulin and Magnesium

Previous work carried out in our laboratories has focused on the formation and investigation of a dextran and concanavalin A (con A) based gel, which has the ability to alter its conformational structure in the presence and absence of free and terminal glucoses such that a gel–sol phase transition occurs. Here we report the diffusion and rheological investigations in to the effects of the addition of insulin and varyingconcentrations of magnesium chloride hexahydrate (Mg₂Cl₂6H₂O) at 20 and 37 °C. Rheological examination of glucose-sensitive (dextran-con A) gels were conducted using a cone and plate viscometer used in continual rotation and oscillatory modes. The results are interpreted in terms of the structure of the gel network and suggest rheological assessment provides an effective method of assessing the properties of gel systems. The subsequent testing of such formulations in in-vitro diffusion experiments revealed a reduction in the rate of diffusivity in the insulin marker, poly R-478 dye. The performance of this self-regulating drug delivery system has been examined and the addition of insulin and magnesium chloride may alter the way in which the gel operates as a drug delivery device and in the delivery of insulin. This may have implications for other ligands.     

Effect of polymer bridging on rheological properties of dispersions of charged silica particles in the presence of low-molecular-weight physically adsorbed poly(ethylene oxide)

 The effect of a low-molecular-weight physically adsorbed poly(ethylene oxide) on the rheological behavior of aqueous dispersions of silica particles (as a model system) has been investigated. Particular attention is given to the evolution of the rheological behavior with increasing polymer concentration in the system at different volume fractions of the particles. Experiments were performed in the absence of salt and just the pH of the dispersion was adjusted to 9.5, a condition at which the system is electrostatically stable and electrostatic repulsive forces are long range in nature. It was observed that the shear viscosity and the linear viscoelastic functions of the dispersion at 55 vol% increase initially through the addition of polymer, reach a maximum, and then decrease to a minimum with further addition of polymer to the system. At higher polymer concentrations, there may be an increase in the viscosity of the dispersion owing to an increase in the concentration of free polymer chains in the medium causing depletion flocculation in the system. The increase in the rheological behavior of the dispersion at low polymer coverage is attributed to polymer bridging flocculation caused by a low-molecular-weight poly(ethylene oxide) in the system. Comparison of the data given here with the results of earlier studies on the viscosity behavior of the system in the presence of salt (0.01 M) indicates that the range of the electrostatic repulsion has a significant role in the rheological behavior of the system. Received: 7 February 2001 Accepted: 18 October 2001     

Efficiency analysis of organic Rankine cycle with internal heat exchanger using neural network

In this study, artificial neural network (ANN) has been used for efficiency analysis of the organic Rankine cycle with internal heat exchanger (IHEORC) using refrigerants R410a, R407c which do not damage to ozone layer. It is well known that the evaporator temperature, condenser temperature, subcooling temperature and superheating temperature affect the thermal efficiency of IHEORC. In this study, thermal efficiency is estimated depending on the above temperatures. The results of ANN are compared with actual results. The coefficient of determination values obtained when the test set were used to the networks were 0.99946 and 0.999943 for the R410a and R407c respectively which is very satisfactory.     

Thermo-thickening during melting of dibenzylidene sorbitol fibre networks

Gels of dibenzylidene sorbitol (DBS) in poly(propylene oxide) (PPO) show an increase in viscosity in a certain temperature range during melting. This so-called thermo-thickening behaviour is quite uncommon. In the few already known cases, the thermo-thickening is caused by simple thermodynamic processes that result in the formation of structures. We show for the first time that, in the case of PPO-DBS gels, experimental parameters like sample volume and heating rate play an important role and indicate non-equilibrium behaviour. It turns out that the peculiar thermo-thickening is the result of a reformation of the fibre network structure, which was destroyed earlier due to a strong temperature gradient within the sample.     

Rubber-like behaviour of poly(ethylene oxide) solution in elongational flow

The behaviour of an aqueous poly(ethylene oxide) sucrose solution and of a suspension of glass beads in a similar solution has been examined in elongational flow using a spinline rheometer. Over the accessible strain-rate range of ca. 1 to 10 s^?1 these fluids behaved essentially as elastic materials whereas, at similar strain rates in shear, they show shear-thinning behaviour.     

Effect of Wetting on the Dynamics of Drainage in Porous Media

We examine the consequences of the wettability properties on the dynamics of gravity drainage in porous media. The relation between the wetting properties at the pore scale and the macroscale hydrodynamics is studied. Model porous media consisting of hydrophilic and hydrophobic glass beads or sand with well defined wetting properties, are prepared for this study. Gravity drainage experiments with air displacing water (two-phase flow), are performed for different Bond numbers, and using different techniques such as gamma-ray densitometry, magnetic resonance imaging (MRI) and weight measurements. The dynamics of drainage is found to be different for hydrophilic and hydrophobic porous media in the transition zone (funicular regime). Moreover, for hydrophilic (water-wet) porous media, MRI experiments reveal the importance of drainage through the continuous water film, which leads to an increase of the residual quantity of water in the transition zone with time.