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Chemical and Physical Properties Chemical Structure Alginate is a non-branched binary co-polymer composed of two 14 glycosidically linked monomers:

-D-mannuronic acid (M) and -L-guluronic acid (G). The relative amounts of M and G, as well as their sequential arrangement along the polymer chain, is not fixed and varies greatly with the origin of the alginate, age of the algae, and the method of extraction. For example, in two common sources of alginate, Macrocystis pyrifera and Laminaria hyperborean, the M/G ratio varies from 1.6 to 0.45, respectivelyOX6. In younger algae, the concentration of M is much higher than the concentration of G. In older plants, this is reversed, as enzyme C5 epimerase converts M monomers to G monomersMX1. The arrangement of M and G monomers is limited, however, to three types of blocks: homopolymeric M block, homopolymeric G block, and heteropolymeric alternating M/G block. M blocks are linear because they bind using the equatorial position and G block appear buckled because they bind using the axial position. The M blocks are considered flexible, as only the G blocks are involved in crosslinking, containing binding sites for cations. The M blocks determine the elasticity of the alginate, compared to the G blocks which influence rigidityMX1. The number and distribution of subunits present in the alginate determines the physical properties of that particular alginate. Molecular Weight Commercial alginates are polydisperse with respect to molecular weight. The natural alginate polymer length is rather long, yet is decreased by the manufacturing

process. Commerical alginate is usually sold with a molecular weight (Mn) of 500,000 g/mol or lower, with a degree polymerization of 2500.OZ1 The most common method to calculate molecular weight is based upon intrinsic viscosity which can only give an estimate of the molecular weight. Most producers blend alginates to target a given viscosity specification product with the same intrinsic viscosity which may have different molecular weight populations. Therefore, in biomedical applications, equivalent products may have different molecular weight populations and therefore have differing biomaterial interactions.OZ1 Glass Transition Temperature The glass transition temperature is defined as the approximate midpoint of the temperature range at which a non-crystalline (amorphous) polymer changes from brittle, glass state to a rubbery, soft state. In Roger et al., powder samples of alginate exhibit Tg ranging from 95C to 136C.AZ6 In the same experiment, no significant effect on Tg was observed for different molecular weight samples.AZ6 There was, however, an increase in Tg with increase G content. AZ6 This effect can be explained by the presence of residual Ca2+ ions in the alginate powder, crosslinking oligomeric G-rich chains. AZ6 Roger et al. also determined the Tg of sodium alginate films to be 158C. They mentioned that it was higher than glass transition temperatures mentioned previously in literature for sodium alginate films ranging from 95C to 110C. AZ6 The source of this discrepancy is hypothesized to be residual Ca2+ content in the alginate sources used experimentally, highlighting the importance of source variability in determining the mechanical and thermal properties of alginates. Experimentally, substituting sodium with calcium in alginate films increases Tg concurrent with the theory that divalent cations have strong binding effects at junction

points between chains. AZ6 Tg of alginate films also varies according to the crosslinking cation. Experimentally, the Tg of alginate films having various cations decreased in the order A13+ > Ca2+ > Fe2+ > Cu2+ > Na+.AZ7

Figure The relationship between Tg, ionic radius of crosslinking cation, and heat capacity in alginate films (Cp)(Nakumura et al., 1995). Figure above demonstrates the relationship between Tg, ionic radius of crosslinking cation, and heat capacity in alginate films.AZ7 The data demonstrates Tg of alginate film decreases and the heat capacity increases with increasing ionic radius of the cross-linking agent. Properties in Solutions Solubility The solubility of alginate is related to the rate of dissociation of the alginate molecule. At low pH (pH<3), M-structures and G-structures will precipitate as alginic acid, while alternating M,G structures will remain in solution despite being fully protonated. This pH dependent physical property of alginates is used in pharmaceutical applications as an antireflux remedy which, when swallowed, forms an alginic acid raft on top of stomach contents (Mandel et al., 2000).

Thickening The thickening properties of alginate are related to the molecular weight and conformation of the alginate molecule in solution. Alginates flow properties will be affected by interactions with other molecules as well as competition for water at high concentrations. Therefore, increasing alginate concentration corresponds to increased viscosity (Kong and Mooney, 2002). Cross-linking materials, such as calcium, present in even small concentrations will induce artificial viscosities higher than real ones. Solutions like these have thixothropic flow properties. Swelling Swellability is associated with the rate of hydration, and will strongly depend on the form of alginate. Cross-linked alginates will swell slower than pure sodium alginate. Swelling properties of alginates have been used in dietary products and sustained release tablets (Miyazaki et al., 200). Furthermore, swelling properties of partially neutralized alginic acid has a long tradition as a tablet disintegrant. Film-forming Properties The film forming properties of alginate are a result of entanglements of alginate molecules when water is removed. When cross-linked gels are dried, they exhibit this they exhibit this type of behavior. Therefore, the molecular weight of alginate needs to be above a lower limit to achieve film formation and avoid brittleness. In situ, alginate films can be formed by spraying alginate solution to a binding surface.

Cross-Linked Gel Properties

Dry alginate is usually sold in its sodium salt form, with a Na+ replacing the carboxylic acid hydrogen. Because the hydrogen from the carboxylic acid group can be easily removed, alginate is said to have a polyectronic nature, and is considered an anionic polymerOX11. Crosslinking of alginate occurs by the addition of divalent cations, which interact with the carboxylate groups on the guluronic acidOX7, most often replacing the sodium ionMX1, creating the egg box structuresOX8. Crosslinking is most often achieved with the addition of Ca2+, however, the addition of other divalent cations is also possible, with ion selectivity decreasing from barium, to calcium, and stroniumOX8. No gel forms after the addition of magnesium ionsOX8. This failure to crosslink is directly related to the radius of magnesium, which is too small to ensure the proper stacking of the G blocksOX12. Hydrogel Strength Gelling properties of alginate are related to both M/G composition and the sequential organization of M and G along the chain.OZ1 The binding of calcium to alginate is cooperative; the more monomers in a G block, the tighter the successive binding of calsium and the stronger the formed gel. Therefore, increases in G-content and molecular weight generally produce a stronger gel (Smidsrod and Skjak-Braek, 1990). Gel formation is reversible if the calcium is removedOX11. Crosslinking does not occur if the concentration of G blocks is less than 20%MX1. The gelling process is of particular importance to the gelling properties. Gelling can occur externally, through the diffusion of cross-linking agent from the outside, or internally, by homogeneously releasing a cross-linking agent from the inside. In internal gelling, ratio between the cross-linking agents and alginate is important in determination of gel strength. Furthermore, strength properties in high-G alginate is

much different than in high-M alginate at a particular cross-linking agent/alginate ratio. Evidence of this is seen in the experimental graph below:

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High-G alginates gels (G>60%) cross-linked with Ca2+, exhibit maximum gel strength, measured by the force needed (in grams) to rotate a metal plate immersed into the gel by 30, when the amount of calcium stoichiometrically matches the amount of calciumbinding guluronic acid blocks. As seen in the figure, when the alginate concentration in the gelling solution is higher than the optimal ratio, calcium will not bind available G-sites optimally, and will have lower gel strength. Contrarily, high-M alginate have shorter and fewer G-blocks and therefore show a continuous increase in gel strength for higher alginate concentrations. This is because the addition of high-M alginate does not present a surplus of G-sites, but a relative increase in calcium ion binding G-sites below threshold that facilitate increased gel strength. An important consideration when measuring gel strength is to differentiate between elastic and viscous moduli. In particular, the viscous modulus is often misinterpreted as gel strength in high viscosity solutions. Hydrogel Stiffness In general, the stiffness of alginate hydrogels can be enhanced by increasing alginate concentration (Kong and Mooney, 2002). However, this will also increase viscosity which may be unfavorable in particular processing applications. Therefore, to increase post-gel stiffness with minimal pre-gel viscosity increase, increasing quantities of low molecular weight (MW) alginate (Mn ~ 3.3x104 g/mol) can be incorporated into 1%

(w/w) alginate solutions composed of high MW alginate (Mn ~ 2.2x105 g/mol) (Kong and Mooney, 2002). The experimental results seen below are evidence of this method:

Fig - (Left)Effects of molecular weight distribution on stiffness of cross-linked hydrogels. (Right) The effects of molecular weight distribution on the viscosity of pre-gelled solution. (-- unary system, -o- binary system). Compositional Variations (M/G) and Effects on Properties The properties of alginate are dictated by polymer composition, sequential structure, molecular weight, and conformation. Specifically, functional properties of alginate are a direct result of the amount of crosslinking, and are thus dependent on the G content, average number of monomers in a G block, and molecular weight. Composition and sequential structure of alginate can be determined by high resolution 1H and

nuclear magnetic resonance spectroscopy. From this scan, the M/G ratio and average M and G block lengths can be calculated. NMR scans were also used to show that alginate does not have a regular repeating unit. The natural anginate polymer length is rather long, yet is decreased by the manufacturing process. Commercial alginate is usually sold with a molecular weight of 500,000 g/mol or lower, with a degree polymerization of 2500. (INSERT)

Alginate Production The primary source of algae is the Phaeophyta group of brown algae. From this group, the raw sources of algae include the following species: laminaria, alaria, ecklonia, eisenia, nereocystis, sargassum, cystoseiera, and fucus. Most of bulk production occurs by growing and harvesting Macrocystic pyrifera (giant kelp) and Ascopyyllum nodosum (Norwegian kelp). In brown algae, polyguluronic acid is present in the cell wall and polymannuronic acid is found in the extracellular spaceMX2. The main producers of alginate are China, United States, Norway and Scotland. China produces about 10,000 tons of alginate annually, from cultivated Laminaria japonica. The remaining countries combined produce about 15,000 tons of alginate annually, valued at approximately $120 million. Norway and Scotland use ascophyllum nodosum and laminaria hyperborean species to produce their alginate. Smaller alginate manufacturers include Japan, France and Chile. In brown algae, alginate is present in the cells wall as the sodium or calcium salt of alginic acid. The primary goal of the extraction process if to produce dry sodium alginate powder. Alginate is extracted based on the solubility of each different salt or form of alginate. Mainly, the fact that sodium alginate is soluble in water while calcium alginate is not. First, the algae is milled and sodium carbonate is added in order to draw the alginate into solution as sodium alginate. Next, the left over algae parts are removed, using flotation, centrifugation, sifting or filtration. The next steps involve the recover of the alginate from the aqueous solution. Then, acid is added to convert the sodium alginate back into alginic acid, in order to precipitate it from solution. Following, alcohol and sodium carbonate is added to the solution. Unlike in water, sodium alginate does not dissolve in alcohol, thus it can be separated from the mixture, dried and milled into the desired fine

powder. An extra step can be added in the beginning of the recovery procedure by adding calcium chloride. This forms insoluble calcium alginate fibers, which can be separated. This extra step adds another level of separation for the alginate, increases the purity. Major Algiante Producing Companies There are several major alginate-producing companies around the world. ISP Alginates Ltd, located in the United Kingdom, manufactures a broad range of products, including sodium, potassium, and ammonium alginate. FMC Biopolyer, based in Philadelphia, PA, manufactures alginate under the tradenames Protanal and ProtacidOX1. Another company is NovaMatrix, based in Olso, Norway, produce two main types of alginate G rich (65%+) Pronova LVG sodium alginate and M rich (50%+) Pronova LVM sodium alginate (LV = low viscosity, between 20 and 200 mPa). These companies sell bulk alginate products, and require individual quotes based on product, amount, and shipping, however, the general price for alginate is $10 per ounce. Individual alginate products can be purchased with ease, some even over the counter at drug stores. For example, Medline Industries cells a box of ten would dressings for $45 and CM3 Inc cells a box of 50 weight-loss capsules for $100.

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