Viscosity Of Concentrated Solutions Research Articles

Towards an improved prediction of concentrated antibody solution viscosity using the Huggins coefficient

The viscosity of a monoclonal antibody solution must be monitored and controlled as it can adversely affect product processing, packaging and administration. Engineering low viscosity mAb formulations is challenging as prohibitive amounts of material are required for concentrated solution analysis, and it is difficult to predict viscosity from parameters obtained through low-volume, high-throughput measurements such as the interaction parameter, kD, and the second osmotic virial coefficient, B22. As a measure encompassing the effect of intermolecular interactions on dilute solution viscosity, the Huggins coefficient, kh, is a promising candidate as a parameter measureable at low concentrations, but indicative of concentrated solution viscosity. In this study, a differential viscometry technique is developed to measure the intrinsic viscosity, [η], and the Huggins coefficient, kh, of protein solutions. To understand the effect of colloidal protein–protein interactions on the viscosity of concentrated protein formulations, the viscometric parameters are compared to kD and B22 of two mAbs, tuning the contributions of repulsive and attractive forces to the net protein–protein interaction by adjusting solution pH and ionic strength. We find a strong correlation between the concentrated protein solution viscosity and the kh but this was not observed for the kD or the b22, which have been previously used as indicators of high concentration viscosity. Trends observed in [η] and kh values as a function of pH and ionic strength are rationalised in terms of protein–protein interactions.

The peculiar elongational viscosity of concentrated solutions of monodisperse PMMA in oligomeric MMA

Concentrated solutions of nearly monodisperse poly(methyl methacrylate), PMMA-270k and PMMA-86k, in oligo(methyl methacrylate), MMA o-4k and MMA o-2k, investigated by Wingstrand et al. (Phys Rev Lett 115:078302, 2015) and Wingstrand (2015) do not follow the linear-viscoelastic scaling relations of monodisperse polystyrenes (PS) dissolved in oligomeric styrene (Wagner in Rheol Acta 53:765–777, 2014a, in Non-Newtonian Fluid Mech 222:121–131, 2014b; Wagner et al. in J Rheol 59:1113–1130, 2015). Rather, PMMA-270k shows an attractive interaction with MMA, in contrast to the interaction of PMMA-86k and MMA. This different behavior can be traced back to different tacticities of the two polymers. The attractive interaction of PMMA-270k with o-4k creates pseudo entanglements, which increase the interchain tube pressure, and therefore, the solution PMMA-270k/o-4k shows, as reported by Wingstrand et al. (Phys Rev Lett 115:078302, 2015), qualitatively a similar scaling of the elongational viscosity with $$ {\left(\dot{\varepsilon}{\tau}_R\right)}^{-1/2} $$ as observed for polystyrene melts. For the solution PMMA-270/o-2k, this effect is only seen at the highest elongation rates investigated. The elongational viscosity of PMMA-86k dissolved in oligomeric MMA is determined by the Rouse time of the melt, as in the case of polystyrene solutions.

The shear rate and concentration dependence of viscosity in concentrated solutions of PVP and Bovine Mucin

Purpose: Mucin is a component in natural tears which serve a number of functions in the eye, including lubrication. Polyvinylpyrrolidone (PVP) is a key component in contact lenses with water-holding capability, thus resembling one function of mucin. Because blinking is associated with a shearing process between eyelid and cornea, it is relevant to investigate the solution viscosity behavior of mucin and PVP solutions as a function of shear rate.

Cluster Size and Quinary Structure Determine the Rheological Effects of Antibody Self-Association at High Concentrations.

The question of how nonspecific reversible intermolecular protein interactions affect solution rheology at high concentrations is fundamentally rooted in the translation of nanometer-scale interactions into macroscopic properties. Well-defined solutions of purified monoclonal antibodies (mAbs) provide a useful system with which to investigate the manifold intricacies of weak protein interactions at high concentrations. Recently, characterization of self-associating IgG1 antibody (mAb2) solutions has established the direct role of protein clusters on concentrated mAb rheology. Expanding on our earlier work with three additional mAbs (mAb1, mAb3, and mAb4), the observed concentration-dependent static light scattering and rheological data present a substantially more complex relationship between protein interactions and solution viscosity at high concentrations. The four mAb systems exhibited divergent correlations between cluster formation (size) and concentrated solution viscosities dependent on mAb primary sequence and solution conditions. To address this challenge, well-established features of colloidal cluster phenomena could be applied as a framework for interpreting our observations. The initial stages of mAb cluster formation were investigated with small-angle X-ray scattering (SAXS) and ensemble-optimized fit methods, to uncover shifts in the dimer structure populations which are produced by changes in mAb interaction modes and association valence under the different solution conditions. Analysis of mAb average cluster number and effective hydrodynamic radii at high concentrations revealed cluster architectures can have a wide range of fractal dimensions. Collectively, the static light scattering, SAXS, and rheological characterization demonstrate that nonspecific and anisotropic attractive intermolecular interactions produce antibody clusters with different quinary structures to regulate the rheological properties of concentrated mAb solutions.

Bulky Polar Additives That Greatly Reduce the Viscosity of Concentrated Solutions of Therapeutic Monoclonal Antibodies

The viscosity of concentrated aqueous solutions of 3 clinical monoclonal antibodies (mAbs), Erbitux®, Herceptin®, and Rituxan®, has been reduced up to over 10-fold by adding certain bulky polar additives instead of saline at isotonic levels. Because these additives are also found not to compromise mAbs’ stability against aggregation induced by stresses, a drug-delivery modality switch from intravenous infusions to more convenient and inexpensive parenteral options like subcutaneous injections may become possible.

Grafting of Butadiene–Acrylonitrile Copolymer onto High Vinyl Polybutadiene by Copolymerization

AbstractHigh vinyl polybutadiene‐graft‐(hydroxyl‐terminated butadiene–acrylonitrile copolymer) (HVPBR‐g‐HTBN) was successfully synthesized through the copolymerization of butadiene and HTBN using a molybdenum (Mo)‐based catalyst. The results indicated that the grafting coefficient of the product was <1 and the nitrogen content of the product was higher than that of linear HVPBR, demonstrating the grafting during the copolymerization by the Mo‐based catalyst. Upon grafting, the intrinsic viscosity of the product's solution was lower, while the molecular weight was higher than that of linear HVPBR. Moreover, the apparent viscosities of concentrated solutions of grafted products were lower than the linear counterpart, despite their higher molecular weight.

Radiopaque iodinated ethers of poly(vinyl iodobenzyl ether)s: Synthesis and evaluation for endovascular embolization

ABSTRACTLeachable‐free radiopaque iodinated polymers were designed as long‐lived embolization materials visible by X‐ray tomography. This is a definite improvement over liquid embolics incorporating either radiopaque inorganic particles or iodinated polymers having hydrolysable ester bonds. Grafting 4‐iodobenzyl or 2,3,5‐triiodobenzyl groups to poly(vinyl alcohol) (PVAL) yields iodobenzyl ethers of PVAL having iodine contents in the range 40–70 wt %. Their solubility in solvents accepted for medical devices (DMSO and NMP), viscosity of concentrated solutions, precipitation behavior, radiopacity, and stability with respect to sterilization and hydrolysis were assessed. The solvent NMP allows the preparation of concentrated solutions of suitable viscosity for their application as liquid embolics. Precipitation in water yields a cohesive mass of material that can plug vascular malformations. A rationale to the properties is given in terms of the Hansen contributions to the Hildebrand solubility parameters. Iodobenzyl ethers of PVA resist hydrolysis whereas their corresponding iodobenzoyl esters leach iodinated fragments. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41791.

Comparative properties of hyaluronan and chitosan in aqueous environment

In this paper, our objective is to compare the physico-chemical properties of chitosan (CHIT) and hyaluronic acid (HA), two important polysaccharides often used in biomedical or cosmetic applications. Polymer-polymer interactions as well as polymer-solvent interactions, studied by experiments and by molecular modeling, are discussed for the two biopolymers in presence of aqueous environments. HA and CHIT have similar non-freezing water content, although HA retains more water than CHIT at large degree of relative humidity (RH). Thermal degradation is larger for HA. The specific viscosity at zero shear rate of CHIT deviates from the master curve, whereas that of HA superimposed nicely. The solution viscosity of concentrated solutions of CHIT continuously decreases in the shear rate range between 0.5 up to 100 s−1, whereas HA shows a Newtonian plateau at low shear rates. Dynamic rheology of semi-diluted solutions of HA shows storage modulus G′ lower than the loss modulus G″ up to 30 g/L but that of CHIT at 20 g/L shows G′ > G″ at nearly the same overlap parameter. The viscosity of CHIT solution is less influenced by temperature than that of HA. These results clearly underline the importance of interchain interactions for CHIT in a good solvent. Molecular modelling is used to provide insights on both the aggregated state and solution state of the two polysaccharides. Interchain interactions in the organized models were predicted larger for CHIT than for HA whereas the interaction between the polysaccharide and the solvent molecules are larger for HA than for CHIT. This approach rationalizes the experimental observations: the higher solvation of HA and the higher ability to aggregate for CHIT.

Preclinical Assessment of a Zwitterionic Tantalum Oxide Nanoparticle X-ray Contrast Agent

Tantalum oxide nanoparticles show great potential as the next generation of X-ray contrast media. Recently, we reported advances in tantalum oxide nanoparticles and identified improvements that were required for such particles to progress further. Namely, the viscosity of concentrated particles, the amount of retention in reticuloendothelial (RES) tissues, and the effect of large quantities of particles on the kidneys after administration were all identified as critical factors which needed further study, understanding, and development. Here, we report on a zwitterionic siloxane polymer nanoparticle coating that reduced the viscosity of concentrated solutions of particles by a factor of 5, decreased tissue retention of injected particles by a factor of 10, and, importantly, did not induce pathological responses in the kidneys.

Hydrophobic salts markedly diminish viscosity of concentrated protein solutions

Reducing viscosities of concentrated solutions of therapeutic proteins is important for their subcutaneous and intravenous delivery. Although inorganic salts and optimizing the pH were previously reported to dramatically lower the viscosity of a monoclonal antibody solution, herein we have determined these effects not to be general. Separately, we have found that hydrophobic ionic excipients, both anionic and cationic, substantially decrease the viscosity of concentrated (300-400 mg/mL) aqueous solutions of bovine serum albumin and γ-globulin. The more hydrophobic the excipient, the greater its viscosity-lowering effect is. With cationic ones, the concomitant contribution of the counter-ion broadly follows the chaotropic order. The most potent excipients lower the viscosity over fourfold to levels far below the 50 cP threshold for subcutaneous injections. The observed viscosity reductions are rationalized in terms of three-dimensional transient protein networks formed in concentrated solutions due to hydrophobic and, to a lesser extent, ionic interactions. These reversible protein aggregates are responsible for strong resistance to flow in concentrated protein solutions and hence their high viscosity; hydrophobic ions apparently effectively compete for these interprotein interactions, thereby giving rise to less viscous solutions.

Effect of a solvent on the solution behavior of Teflon-42 and the structure of related films

The viscosity characteristics of dilute and concentrated solutions of Teflon-42 in acetone, DMF, DMAA, N-methylpyrrolidone, and trimethyl phosphate have been studied. Films based on Teflon-42 prepared by precipitation from concentrated aqueous solutions are investigated by IR spectroscopy and X-ray analysis. The analysis of intrinsic viscosity and viscosity of concentrated solutions shows that, with respect to Teflon-42, solvent quality changes in the following order: acetone > DMF > DMAA > trimethyl phosphate ≥ N-methylpyrrolidone. Films prepared from polymer solutions in various solvents are characterized by a highly crystalline structure (the degree of crystallinity is ∼70%) that involves three polymorphic modifications.

Viscosity of concentrated solutions of polystyrene and poly(vinyl acetate) (empirical equations)

The viscosity of solutions of polystyrene with Mw from 2.8 × 104 to 7.8 × 105 in toluene and of poly(vinyl acetate) with Mw from 2 × 104 to 1.4 × 105 in butyl acetate at 30–80°C is measured. The dependence of the activation energy of the viscous flow of the solutions on the molecular weight of the polymers and solution concentration is examined. This dependence is approximated by a cubic polynomial for polystyrene solutions and by a quadratic polynomial for poly(vinyl acetate) solutions. The dependences of the solution viscosity on the concentration, molecular weight, and temperature are approximated by exponential equations in which the exponents are sums of polynomials. The coefficients of the polynomials are determined.

The Nonequilibrium Phase and Glass Transition Behavior of β-Lactoglobulin

Concentrated solutions of bovine β-lactoglobulin were studied using osmotic stress and rheological techniques. At pH 6.0 and 8.0, the osmotic pressure was largely independent of NaCl concentration and could be described by a hard sphere equation of state. At pH 5.1, close to the isoelectric point, the osmotic pressure was lower at the lower NaCl concentrations (0 mM, 100 mM) and was fitted by an adhesive hard sphere model. Liquid-liquid phase separation was observed at pH 5.1 at ionic strengths of 13 mM and below. Comparison of the liquid-liquid and literature solid-liquid coexistence curves showed these solutions to be supersaturated and the phase separation to be nonequilibrium in nature. In steady shear, the zero shear viscosity of concentrated solutions at pH 5.1 was observed at shear rates above 50 s −1. With increasing concentration, the solution viscosity showed a progressive increase, a behavior interpreted as the approach to a colloidlike glass transition at ∼60% w/w. In oscillatory shear experiments, the storage modulus crossed the loss modulus at concentrations of 54% w/w, an indication of the approaching glass transition. Comparison of the viscous behavior with predictions from the Krieger-Dougherty equation indicates the hydrodynamic size of the protein decreases with increasing concentration, resulting in a slower approach to the glass transition than a hard sphere system.

Jet Cooking of Waxy Maize Starch: Solution Rheology and Molecular Weight Degradation of Amylopectin

ABSTRACTThe effect of processing conditions in an excess steam jet cooker on the degradation of waxy maize starch was studied. The temperature of the steam, the flow rate of the starch slurry, and the concentration of starch were determined to influence the extent of degradation. The viscosity of concentrated solutions of the jet‐cooked product and the intrinsic viscosity of dilute solutions were used as measures of the extent of molecular degradation. The viscosity decreased at higher reaction temperatures, and at higher team‐to‐starch ratios. Multiple passes through the jet cooker decreased the viscosity dramatically for the first two passes, but little additional change was observed for further passes. The results show that mechanical and thermal degradation effects are both important in the jet cooking of waxy maize starch, although the primary effect is due to mechanical degradation.

Improvement of the water purification capability of poly(acrylonitrile) ultrafiltration membranes

Ultrafiltration membranes used for drinking water treatment need to have high rejection for microbial species. The effect of various inorganic halides added to a casting solution of poly(acrylonitrile) in N, N-dimethyl formamide was examined by measuring changes in the intrinsic viscosity, concentrated solution viscosity and the ternary phase boundary. Both mono- and divalent salts decreased polymer–solvent affinity; the higher viscosity in the case of polymer solutions containing multivalent salts was attributed to increased interaction between polymer chains. The resulting membrane structure was characterized by scanning electron microscopy and bubble point measurements. The addition of di- and trivalent salts resulted in membranes with a mode pore size similar to the membrane prepared without any additive; but significantly fewer number of large pores/defects and consequently higher rejection for E. coli.

Association in anionic polymerization. Its effect on the polymerization mechanism

A critical analysis is presented of the measurement and interpretation of association phenomena in anionic polymerization in non-polar solvents. In chain initiation, measured differences in reaction order arise because of differences in the way the process is defined. Some also may be caused by the extreme sensitivity of these systems to traces of polar impurities. In chain propagation, differences in measured association numbers of the active centers exist in diene polymerization. These can be caused by problems in the experimental technique. This is illustrated by data on concentrated solution viscosity measurements on linear and regular four-star polystyrenes and polyisoprenes as models for dimeric and tetrameric association.

Association in anionic polymerization. Its effect on the polymerization mechanism

A critical analysis is presented of the measurement and interpretation of association phenomena in anionic polymerization in non-polar solvents. In chain initiation, measured differences in reaction order arise because of differences in the way the process is defined. Some also may be caused by the extreme sensitivity of these systems to traces of polar impurities. In chain propagation, differences in measured association numbers of the active centers exist in diene polymerization. These can be caused by problems in the experimental technique. This is illustrated by data on concentrated solution viscosity measurements on linear and regular four-star polystyrenes and polyisoprenes as models for dimeric and tetrameric association.

Recrystallization in Aqueous Fructose Solutions as Affected by Locust Bean Gum

ABSTRACTRates of ice recrystallization were measured in aqueous fructose solutions containing locust bean gum (LBG). The effects of temperature, ice phase volume and LBG concentration were determined. Decreasing temperature reduced the recrystallization rate: the dependency followed Williams Landell Ferry kinetics. An increase in ice phase volume resulted in an increase in the recrystallization rate. Addition of LBG reduced the recrystallization rate up to a concentration of 0.3% (w/w); further addition resulted in no further decrease. The hypothesized mechanism of action of LBG is via weak adsorption of the polysaccharide to the ice crystal. Freeze concentrated solution viscosity did not correlate with observed recrystallization rates.

Concentrated solutions of perfluoro polyoxyalkylene oligomers—I. The influence of solvent

Glass transition temperatures, specific volumes and viscosities of concentrated solutions of two diolic (functionalized) perfluoropolyoxyalkylene oligomers in various solvents are reported. It is shown that polar solvents, generally considered poor or non-solvents of perfluorinated macromolecules, are particularly effective in determining strong decreases of η and T g and positive mixing volumes. The experimental results are referred to the copolymer end effect on the examined properties, due to the fact that the cohesive state of such oligomers is ruled mainly by end units interactions. Accordingly, a classification of solvents on the basis of the different solubility features is proposed.

Evaluation of viscosities of amorphous phases in partially frozen systems by WLF kinetics and glass transition temperatures

The viscosities of concentrated solutions of glucose, fructose, sorbitol and xylitiol were measured by a falling sphere method. The measured viscosities were compared with those predicted by WLF kinetics from glass transition temperatures. Discrepancies between measured and predicted viscosities were found to be within an order of magnitude of 0.3 on log ϵ. Experimental data on sucrose solutions obtained from literature sources were also compared with WLF predicted values. The viscosities of the amorphous phases in frozen or partially frozen sucrose-, glucose-, fructose-, citric acid-, dimethyl sulfoxide-, polyvinylpyrrolidone- and glycerol-water systems were estimated by WLF kinetics and freezing temperatures. At equal sub-freezing temperature, the viscosities increased with the increasing of molecular weight. In addition, viscosity changes during devitrification and recrystallization of 60–70% sucrose solutions, which do not freeze upon cooling, were evaluated.