Section 16

Alginate
By Dr. Rolf Myrvold and Dr. Edvar Onsyen

Table of Contents
Alginate ..........................................................................................................................................1 Table of contents........................................................................................................................1 Current FMC BioPolymer Products ...............................................................................................3 Protacid F 120 NM ...................................................................................................................3 Protanal LFR 5/60.....................................................................................................................3 Protanal LFMG 5/60 .................................................................................................................3 Protanal LF 120 M ....................................................................................................................3 Protanal LF 240 D.....................................................................................................................3 Protanal LF 10/60 .....................................................................................................................3 Protanal LF 10/60 LS................................................................................................................3 Protanal HF 120 RBS ...............................................................................................................3 Protanal LF 200 S.....................................................................................................................3 Protanal LF 200 DL...................................................................................................................4 Protanal KF 200 S ....................................................................................................................4 Protanal KF 200 ........................................................................................................................4 Protanal KF 200 RBS................................................................................................................4 Protanal TA 250 ........................................................................................................................4 Propylene Glycol Alginate, PGA ................................................................................................4 General Introduction ......................................................................................................................5 History ...........................................................................................................................................5 Alginate Source ..............................................................................................................................5 Processing......................................................................................................................................8 Molecular Structure........................................................................................................................9 Properties .....................................................................................................................................10 Solubility...................................................................................................................................10 Water ....................................................................................................................................10 Salt Solutions .......................................................................................................................10 Sugar Solutions....................................................................................................................11 Alcohols ...............................................................................................................................11 Acids ....................................................................................................................................11 Gelation ....................................................................................................................................11 Gel Strength .........................................................................................................................12 Gel Texture Modification ......................................................................................................12 Synergies with other Gums......................................................................................................12 Protein Reactivity .....................................................................................................................12 Effect of pH ..............................................................................................................................13 Rheology ..................................................................................................................................13
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Dispersion of Alginate ..............................................................................................................14 Applications..................................................................................................................................14 Esophageal/Oesophageal Reflux.............................................................................................14 Sustained/Controlled Release..................................................................................................14 Wound Healing Dressings........................................................................................................15 Dental Impression Materials ....................................................................................................16 Suspension, Emulsion and Foam Stabilizer ............................................................................16 Other Applications ...................................................................................................................16 Regulatory ....................................................................................................................................17 Regulatory Status for Pharmaceutical Use..............................................................................17 Regulatory Status for Use in Dietary Supplements .................................................................17 References ...................................................................................................................................18

Current FMC BioPolymer Products

Protacid F 120 NM
Protacid F 120 NM is based on alginic acid extracted from the stem of Laminaria hyperborea. With its pKa value of approximately 3.5 it is not soluble in water, but dissolves in alkali. Normally Protacid F 120 NM is used in solid dry formulations, either as a disintegrant or as the active ingredient in esophageal reflux formulations. extracted from both Durvillea antartica and Lessonia nigrescens. Gel forming capability is relatively poor due to the high mannuronate content. This product is mostly used in oral solid dosage sustained release/controlled release formulations. Compared to Protanal LF 120 M, this product is more effective in retarding the release of the active due to higher acid solubility of the alginate.

Protanal LF 10/60 Protanal LFR 5/60

Protanal LFR 5/60 is a low molecular weight (low viscosity) sodium alginate extracted from the stem of Laminaria hyperborea. It is cold soluble, and forms relatively weak gels when gelled with calcium. Protanal LFR 5/60 has widest application in liquid esophageal reflux formulations.

Protanal LF 10/60 is based on alginate extracted from the stem of Laminaria hyperborea. This product may be used to spin fibers by extrusion into a calcium bath. These fibers are used in the production of alginate wound healing dressings. The fibers made with this product are brittle and absorb many times their own weight of liquid.

Protanal LF 10/60 LS Protanal LFMg 5/60

Protanal LFMg 5/60 is a low molecular weight magnesium alginate manufactured from extract of Laminaria hyperborea stem. It is cold soluble, and forms relatively weak gels when gelled with calcium. Protanal LFMg 5/60 is mostly used in infant liquid esophageal reflux formulations because of sodium intolerance due to the fact that infant kidneys are not fully developed. Protanal LF 10/60 LS is based on alginate extracted from Lessonia nigrescens. This product may be used to spin fibers by extrusion into a calcium bath. These fibers are used in the production of alginate wound healing dressings. The fibers made with this product are less brittle and absorb less liquid than the fibers made with Protanal LF 10/60.

Protanal HF 120 RBS Protanal LF 120 M

Protanal LF 120 M is based on sodium alginate extracted from Lessonia nigrescens. It is cold soluble and forms medium strength gels with high freeze/thaw stability when gelled with calcium. As the alginate concentration increases the strength of the resultant gel will become stronger. This product is mostly used in oral solid dosage sustained release/controlled release formulations. Protanal HF 120 RBS is a high viscosity sodium alginate extracted from the leaves of Laminaria hyperborea. The gel strength of this product is comparable with corresponding alginates extracted from Lessonia nigrescens. The product is mostly used as a viscosity modulator in dental impression materials.

Protanal LF 200 S
Protanal LF 200 S is a medium viscosity sodium alginate extracted from the stem of Laminaria hyperborea. The resultant gel made with this alginate has superior gel strength, and is one

Protanal LF 240 D

Protanal LF 240 D is based on sodium alginate

of the highest gel strength products on the market. The product is mostly used in different dental impression material products where material strength is an important parameter.

Protanal TA 250
Protanal TA 250 is a medium viscosity sodium/triethanolamine alginate extracted from the stem of Laminaria hyperborea. The resultant gel made with this alginate has superior gel strength, and is one of the highest gel strength products on the market. The product is mostly used in different dental impression material products where it finds its application in special formulations where texture and smoothness of the impression material are important parameters.

Protanal LF 200 DL
Protanal LF 200 DL is a medium viscosity sodium alginate based on a mixture of extracts from Laminaria hyperborea and Lessonia trabreculata. The resultant gel made with this alginate has medium to high gel strength. The product is mostly used in different dental impression material products where material strength and flexibility are important parameters.

Propylene Glycol Alginate, PGA

PGA is a propylene glycol ester of alginic acid. It is prepared by reacting the carboxyl groups of the alginic acid with propylene oxide. PGA finds its main application as a suspension, emulsion and foam stabilizer. FMC BioPolymer offers several grades of PGA for different applications.

Protanal KF 200 S
Protanal KF 200 S is a medium viscosity potassium alginate extracted from the stem of Laminaria hyperborea. The resultant gel made with this alginate has superior gel strength, and is one of the highest gel strength products on the market. The product is mostly used in different dental impression material products where material strength is an important parameter.

Protanal KF 200
Protanal KF 200 is a medium viscosity potassium alginate extracted from the stem of Laminaria hyperborea. The resultant gel made with this alginate has superior gel strength, and is one of the highest gel strength products on the market. The product is mostly used in different dental impression material products where material strength is an important parameter.

Protanal KF 200 RBS

Protanal KF 200 RBS is a medium viscosity potassium alginate extracted from the leaves of Laminaria hyperborea. The strength of the gel made from this product is medium. The product is mostly used in different dental impression material products where material strength and flexibility are important parameters.

General Introduction
Alginate and alginic acid are the generic terms applied to a natural occurring, commercially important family of hydrophilic polysaccharides extracted from a number of closely related species of brown seaweed. More specifically, alginate and alginic acids are the linear co-polymers comprised of 1-4 linked -D-mannuronic and -L-guluronic acid as the monomeric building blocks (salts; mannuronate and guluronate). The two monomers occur in block, alternating or random sequences. The pKa value of mannuronic and guluronic acid is 3.4 and 3.7 respectively, which limits the solubility of polymannuronic and polyguluronic acid in water at low pH. Alginates with alternating mannuronic and guluronic acid residues (MG) have the highest acid solubility. However, salts of alginic acid are soluble in water and form viscous solutions. PGA is a slightly hydrophobic modified alginic acid where the carboxyl groups of the alginic acid are esterified with propylene oxide. The modification results in that the intrinsic property of the carboxyl group is screened, i.e. the polymer becomes acid soluble. In addition the divalent cation reactivity is reduced and the polymer hydrophobic modification leads to bulk associative properties and surface activity.

substance could be extracted from seaweed ash. Iodine factories were built and up to 6000 metric tons of seaweed ash were exported annually. The British chemist, E.E.C. Stanford, who was engaged in the production of iodine, discovered alginic acid in 1883 when he successfully extracted it from seaweed [1]. Alginic acid makes up about thirty percent of the organic constituents in seaweed or roughly three to six percent of the weight of the raw plant. Rapidly Stanford identified several commercial applications for alginic acid and he built a factory to produce alginate i.e. salts of alginic acid. However, this was not a commercial success and it was not until 1930 that purified alginates and alginic acid were available in commercial volumes.

Alginate Source
In nature alginate is mainly limited to the marine brown algae, Phaeophyta [2], although extracellular polymeric material resembling alginate from brown algae are also produced by soil bacteria such as Azotobacter vinelandii and several species of Pseudomonas [3, 4]. Alginate exist in the brown algae, as the most abundant polysaccharide comprising up to 40% of the dry matter, and 2-7% of the weight of the wet seaweed [5]. It is located in the intercellular matrix as a gel containing sodium, calcium, magnesium and other multivalent cations [6]. Its main function is structural giving both strength and flexibility to the algal tissue [2]. Because of its ability to retain water, and its gelling, viscosifying and stabilizing properties, alginate is widely used industrially. The technical applications of alginate form the basis of the exploitation of brown seaweeds in the Western Hemisphere [7]. The most commercially important alginate bearing seaweeds are shown in Figure 1. Brown algae mainly grow in relatively low temperature water below approximately 20C. This is illustrated in Figure 2, where the major harvesting regions are indicated.

History
In Iceland back in the days of the sagas, sl, a species of dried red seaweed was eaten as a snack. In Norway seaweed has literally been a life-saver. A description of life in Lofoten and Vesterlen in the northern part of Norway written by a bailiff named Schnnebl, reported that most nourishing foods eaten by the poor folk of Andenes were mountain cranberries, mussels and rockweed. However, animals were the greatest consumers of seaweed. In his Physical and economic description of the Sndmrs judicial district (1762-1769), author Hans Strm mentions another use of seaweed, namely as fertilizer for soil improvement. Seaweed was also used to manufacture soda ash that was used in the production of glass. Iodine was discovered in 1811, and quickly it became clear that this new

Figure 1: Commercial important Alginate bearing seaweeds.

Class:

Phaeophyta (Brown Algea)

Genus:

Laminaria

Lessonia

Durvillea

Ascophyllum

Macrocystis

Species:

hyperborea digitata saccharina japonica

nugrescens trabeculata

antartica potatorum

nodosum

pyrifiera

Figure 2: Geographic regions where Brown Algeas grow. Note that the Regions are located to relatively colder waters. Below 20C.

Alginate is a natural product, and the amount, and properties of the alginate will vary based on the species, growing conditions and plant reproductive cycle. Due to its functionality in the plant, to provide strength and flexibility, plants growing in rough waters will provide

alginate richer in guluronic acid compared to plants of the same species from calmer waters as illustrated in Figure 3.

Figure 3: The chemical structure of alginate from the same specie is determined by the environmental conditions at the geographic location where the plants grow.

Poly-Guluronate G-block

Poly-Mannuronate M-block

Four species of brown seaweed make up the predominant amount of commercial alginate used by FMC BioPolymer. Laminaria hyperborea, harvested from the western coast of Norway, is a relatively large plant, approximately 1.5-2 meters in height when it is harvested. Lessonia

nigrescens, Lessonia trabeculata and Durvillea antarctica are harvested off the coast of Chile, milled and dried before shipping to Norway for processing. Table 1 summarizes the alginate raw materials utilized by FMC BioPolymer.

Table 1: Alginate seaweed raw materials utilized by FMC BioPolymer. Brown Seaweed Species Laminaria hyperborea-stem Laminaria hyperborea-leaf Lessonia trabeculata Lessonia nigrescens Durvillea antarica Harvest Location Norway Norway Chile Chile Chile Alginate Type High G Medium G Medium/HIgh G Medium G Low G Gel-Strength High Medium Medium/High Medium Low

The seaweed imported from Chile is harvested by manual and relatively labor-intensive procedures. The seaweed harvested off the Norwegian

coast is harvested in a more automated manner as depicted in Figure 4.

The exposed coast-line, a suitable habitat for Laminaia Hyperborea.

Figure 4: Automated harvesting of Laminaria Hyperborea by specially designed trawlers.

Figure 5: Schematic illustration of the alginate extration and purification process.

Seaweed Alginic Acid

Milling

Neutralization

Water + Acid

Washing

Na-Alginate

Na2CO3

K-Alginate Water + Alkali Alginate Extration NH4-Alginate Clarification Mg-Alginate

K2CO3 NH4HCO3 MgCO2

harvested, it must be dried and baled for shipment to Norway. The seaweed harvested off the Norwegian coastline is not dried, but used fresh. Once the seaweed arrives at the extraction plant it is milled down and washed. The extraction process starts with alkali, and after a number of different processing steps pure alginic acid is produced. The alginic acid serves as the raw material for the different alginate salts and ester as illustrated in Figure 5. In order to extract the alginate from the rest of the biomass the pH is lowered below the pKa of the acid residues. This enables the removal of Ca2+ from the polymer. At this stage the alginate is in the insoluble acid stage. By increasing pH with alkali, the alginic acid is re-dissolved to form sodium alginate followed by filtration. Subsequently the sodium alginate is precipitated as Ca-alginate. This is followed by an acid wash to convert the water insoluble Ca-alginate to alginic acid. The resultant alginic acid is used as the starting material for preparation of the different alginate salts, and also for the covalently modified propylene glycol ester. After the alginic acid has been neutralized, the alginate salt is dried and milled to the desired meshgrade. This material is then shipped to the blending facility for dry blending to meet the customer specification. 8

Filter Aid

Filtration

Ca-Alginate Propylene Glycol Alginate Drying

CaCO3 Propylene oxide

CaCl2

Precipitation

Calcium Alginate Milling Water + Acid Washing Packing Alginic Acid

Blending

Packing

Shipping

Processing
Alginate processing consists of many important steps where the harvesting of the seaweed is the initial one. In Chile, once the seaweed is

Molecular Structure
In molecular terms alginate is a family of linear binary copolymers of 1-4 linked b-D-mannuronic acid (M) and a-L-guluronic acid (G), of widely varying composition and sequential structure. The monomeric units M and G are depicted in Figure 6.

have made it possible to determine the monomer frequencies FG, and FM, the four dimer frequencies, FGG, FMG, FGM, and FMM, and the eight possible trimer frequencies, FGGG, FMGG, FMGM, FMMM, FMMG, FGMM and FGMG. A typical NMR spectrum is shown in Figure 7.

Figure 6: The monomeric units of alginate. The monomers can be linked in varying sequences, as blocks, alternating or random sequences.

Figure 7: A typical NMR Spectrum of Alginate extracted from the Stem of Laminaria Hyperborea.
400 - MHz, H1 -n.m.r. Spectrum of Alginate (Stipe of Laminaria Hyperborea**)
FG 0.74 FM 0.26 FGG 0.65 Total G FMG 0.09 FMM 0.17 FGGG 0.61 FGGM 0.04 FMMG 0.05 G-G-G

M-M M-G M-G-M G-G-M

**)Grasdalen, H.: (1983) High-field 1H-NMR spectroscopy of alginate. Sequential structure and linkage confirmations. Carbohydr. Res., 118, 255-260.

Knowledge of these frequencies enables the calculation of the average G and M-block lengths as given in the two equations below: Alginate was believed to be a homopolymer mannuronan until 1958 when Fisher and Drfel showed that hydrolysates of both commercially and laboratory produced alginates contained L-guluronic acid in addition to D-mannuronic acid [8]. It is now well established that except for some bacterial alginate [9], alginates contain L-guluronic acid in various proportions depending on the organism and tissue it is isolated from [10]. In determining the structure of alginate, both 1H and 13C NMR spectroscopy are probably the most valuable methods known today [11-13]. These very powerful techniques _ F FMGM Average G-block length: NG>1 = G FGGM

_ F FGMG Average M-block length: NM>1 = M FMMG Both sequential and block structure varies in alginate extracted from different types of brown algae as shown in Table 2.

Table 2: Structural parameters obtained with high resolution 1H NMR for alginate extracted from different types of brown algeas. The number given in the table are typical average numbers. Brown Algea Laminara hyperborea (stem) Laminara hyperborea (leaf) Macrocystis pyrifeira Asophylllum nodosum Lessonia nigrescens Laminaria japonica Laminaria digitala FG 0.70 FM 0.30 FGG 0.57 FMG+GM 0.26 FMM 0.17 FGGG 0.52 FMGM 0.041 FGGM 0.04 NG>! 17

0.55

0.45

0.26

0.38

0.36

0.29

0.12

0.05

0.39

0.61

0.16

0.46

0.38

0.12

0.20

0.03

0.36 0.40 0.34 0.41

0.64 0.60 0.66 0.59

0.16 0.22 0.16 0.25

0.40 0.38 0.36 0.32

0.44 0.40 0.48 0.43 Solubility

0.12 0.20 0.13 0.20

0.15 0.14 0.15 0.11

0.15 0.04 0.03 0.05

4 7 6 6

Properties
Alginate tend to be a white to pale yellowishbrown powder. The powder structure is short fibrous or compact particles with relatively irregular shape. Normally 95% of the powder will pass through a mesh as indicated as the mesh grade for that particular product. For instance for Protanal LF 200 S, not more than 5% of the material should be retained on a 200-mesh (75 micron) screen. The density of the powders varies with mesh grade and particle size distribution. On average the powder density will range between 0.5-1 g/cm3. Alginate and PGA are polydisperse biopolymers with average polydispersity index of about 2-2.5. The average molecular weight varies between the different products, and ranges from 30000-40000 g/mol for Protanal LFR 5/60 up to 375000-425000 g/mol for Protanal HF 120 RBS.

In general, when hydrating hydrocolloids, the hydration should be done under relatively high stirring rates, sprinkling the powder into the vortex. Stirring for 10-20 minutes at high stirring speeds will usually give a homogeneous solution.

Water
Sodium, potassium and magnesium alginates and PGA are soluble in water but care has to be taken to avoid lump formation. Calcium alginate and alginic acid are not soluble, but swell slowly in water.

Salt Solutions
Sodium and potassium alginate and PGA are soluble in saline up to molar ionic strength. Calcium alginate is slowly soluble in saline solutions if the sodium concentration is more

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than twenty times higher than the calcium concentration. In higher ionic strength solutions the salts of alginic acid are not soluble. PGA is less sensitive to ionic strength compared to alginate. Alginic acid is soluble in alkaline media, forming the corresponding salt.

Gelation
In general all alginates gel or form three-dimensional structures when they react with multivalent ions. The selectivity for binding of cations and the gel-forming properties vary widely depending on composition [14] and sequence [15, 16]. Divalent cations such as calcium bind preferentially to G-blocks in a highly cooperative manner [17, 18]. It is this selective binding of cations to alginate which accounts for its capacity to form ionotropic gels. As there are only minor differences in the affinity of the two monomers for divalent cations, the large difference in ion-binding between poly(mannuronan) and poly(guluronan) is a phenomenon of the polymer primary structure. Guluronic and mannuronic acid residues will adopt axial and equatorial configurations respectively [19]. The di-axially-linked G-residues form cavities that function as binding sites for ions as demonstrated in Figure 9. Sequences of such sites form bonds via multivalent ions to similar sequences in other polymer chains giving rise to the junction zones as illustrated in Figure 10 (the so called egg-box model). Thus the average length of G-blocks is the main structural feature contributing to gel formation [21]. PGA does not form gels or precipitates with divalent metal ions and is insensitive to acidic medias.

Sugar Solutions
Sodium and potassium alginate and PGA are soluble in up to 70-80% sugar solutions. Certain water activities levels are required for hydration of alginate dependent on the type and concentration of sugar.

Alcohols
Sodium and potassium alginate and PGA are soluble in hydroalcoholic mixtures up to a certain level. The solubility depends on the type of alcohol, and for ethanol concentrations above 20%, the alginate will not dissolve. Alginate will be soluble in glycerol solutions up to over 90%.

Acids
Sodium and potassium alginates are soluble in weak acids with pKa values above that of the alginate. In stronger acids the solubility of alginate depends strongly on the primary structure of the polymer as illustrated in Figure 8. PGA is completely soluble in acids.

Figure 8: The acid solubility of alginate fragments (A, B and C) as function of pH.
A: Mainly MG(65%M), B: Mainly M(92%M), C: Mainly G(13%M)
120
Solubility % in 0.02 N KCI

Figure 9: Binding of Ca2+ to -L-GulUA(1-4)-L-GulUA unit in alginate [20]. The main attractive interaction is of an electrostatic nature represented by an attraction between the cation and partial negatively charged oxygen atoms.

100 80 60 40 20 0 1.7 1.9 2.2 2.5 pH 2.75 3 3.4

A B C

Data from Acta Chem. Scand. 21 (1967) No. 3

11

Figure 10: Model for the alginate network formation, the Egg Box model [19]. The buckled part of the polymer represents the Di-Axially linked G-blocks.

Ca2+

The strength of an alginate gel will also depend on the concentration of the cross-linking multivalent cation. For a 1% alginate solution gelled with Ca2+, strength increases monotonically up to approximately 15 mM Ca2+ added. For Ca2+ levels above this, the gel becomes labile with a resulting dimensional instability. The strength of the gel appears to increase, but this is more a result of increasing alginate concentration due to syneresis.

Gel Texture Modification

Fine-tuning the amount of the cross-linking cation, the alginate concentration, the addition of sequestrant(s) and/or other gums to the system can modify the texture of the alginate gel. The amount of the different components for optimal performance will vary depending on the application.

Gel Strength
The amount of guluronate in the alginate polymer and the average G-block length are parameters of importance and will determine the strength of an alginate gel. In Figure 11, the strength of gels made from 1% alginate solutions are shown. The alginates used are extracted from different seaweed sources to cover the G range as indicated.

Synergies with Other Gums

The alginate/pectin synergism is one of very few known interactions for alginate with other hydrocolloids, and the only one of commercial value. When high-methoxyl (HM) pectins are used alone, they are only able to form gels at high sugar solids levels within a narrow pH range. When sodium alginate is included, gel formation takes place at low solids and a wider pH range. Rigid gels are formed with addition of high-methoxyl pectin and sodium alginate high in guluronic acid. Softer gels are formed by addition of high mannuronic alginate. A predominant characteristic of most alginates is the calcium reactivity, which determines their gel-forming capacity. When calcium ions are available in sufficient quantities these calcium interactions are usually so strong that they will dominate over weaker interactions between alginate and other hydrocolloids. As with alginate, PGA exhibits synergies with pectins and in addition with Xanthan gum.

Figure 11: The modulus of rigidity as function of the average length of the G-blocks. The modulus serves as a good illustration of how the gel-strength of alginate gels depends on the raw material the polymer is extracted from. Note that the gel-strength reaches a plateau as the average G-block size increases over approximately twelve guluronate residues.
10 9 8 7

E [N/cm2]

6 5 4 3 2 1 0 0 2 4 6 8 10 12 14 16 18

Protein Reactivity
In general alginate shows, no or little synergy with proteins with pKI-values on the acidic side.

N(G>1)

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However, for proteins and enzymes with pKIvalues on the basic side some synergies due to electrostatic interactions may be observed. As for alginate, PGA synergies with proteins originating from electrostatic interactions are observed. Synergies due to hydrophobic interactions may also occur.

describe what is known as the entanglement effect. Above a certain molecular weight the effect from separate chains entangling into each other becomes more pronounced with a resultant higher viscosity dependency.

Effect of pH
At pH values below or around the pKa of alginic acid (approximately 3.5 depending on the mannuronic/guluronic composition) alginates may show less functionality. As the pH decreases, alginate takes up protons and lose net negative charge. Eventually alginic acid starts to precipitate. Propylene glycol alginate (PGA), in contrast, possesses functionality even in low pH conditions. The presence of the lipophilic propylene glycol ester groups provides PGA with emulsifying power and makes it acid tolerant and less calcium reactive than the original sodium alginate. The remaining unesterified acid groups retain some negative charge even down to pH 2.75 and will participate in weak but significant cross-linking interactions with calcium or with proteins that, at this low pH, usually carry a net positive charge.

Figure 12: The viscosity of a 1% alginate solution depends on the molecular weight of the polymer.
10000

(Brookfield) [mPa s]

1000

~ Mv 3,6

100

~ Mv 1,1
10

1 10000

100000

1000000

Mv [g/mol]

Rheology
In general, solutions of alginate and PGA (over 1% solution) display shear-thinning behavior. PGA solutions below 1% exhibit Newtonian flow at shear rates below 100s-1. Alginates with differences in primary structure do not display different rheological behaviors. If divalent ions are added to the system, the viscosity increases dramatically as the gel-point is approached. At limited concentrations of divalent cations thixotropic behavior can be observed. Viscosity of alginate solutions will vary according to concentration, temperature, ion strength and molecular weight. In Figure 12, the viscosity increase with molecular weight is shown. The figure displays the viscosity of 1% solutions as function of molecular weight and the observed variation is well in line with published results. The proportionalities as indicated in the figure

The impact microscopic conformational changes will have on the intrinsic viscosity, known as the Haugs triangle [22] is shown in Figure 13. The impact chain stiffness and extension have on the intrinsic viscosity is reflected through the Mark-Houwink-Sakurada equation as given in the figure. The semi-empiric equation explains how the intrinsic viscosity varies with molecular chain conformation where the exponent generally increases with increasing chain extension. Some measurements have been made on

Figure 13: The variations in intrinsic viscosity as function of molecular conformation [22].
Sphere: [] M0

Random coil: [] M0.5-0.8

Rod: [] M1.8

[] = K*Ma

13

alginate solutions yielding exponent values ranging from 0.73 1.31, depending on ionic strength and alginate composition [23-25]. By increasing the ionic strength, the alginate chain will change from a relatively stiff rod-like conformation to a random coil conformation. A further increase in ionic strength will lead to a further structural change in the chain before it collapses and precipitates.

a mechanical barrier against reflux of stomach contents into the esophagus/oesophagus. This is illustrated in Figure 14. As the intragastric pressure increases, the gel/foam is pushed upward into the lower esophagus/oesophagus coating and protecting the mucous membrane.

Dispersion of Alginate
Being able to properly disperse alginate or PGA is essential to deriving its optimal functionality in solutions. Alginate or PGA can be dispersed several different ways; first, dry alginate powder can be slowly sprinkled into the vortex of agitated water. Secondly, a dispersion aid such as sucrose or dextrose can be used. The dispersion aid helps to separate and prevent the alginate or PGA particles from forming clumps through agglomeration. Finally the alginate or PGA powder can be dispersed in glycerin or alcohols like propylene glycol. Alginate or PGA has limited solubility in polyols, which prevents clumping from occurring upon mixing with water. The order of addition may also be critical and optimally the alginate or PGA should be dispersed and completely hydrated prior to the addition of other formula ingredients. For alginate this is particularly important in high ionic strength formulas.

Figure 14: Illustration of the mechanical barrier provided by the buoyant alginate gel/foam protecting the esophagus/ oesophagus against the gastric acid.
Alginate raft acts as a physiochemical barrier against reflux.

Sustained/Controlled Release Hydrophilic matrix dosage forms essentially consist of a compressed blend of hydrophilic polymer and drug. In low pH gastric fluid, the surface of an alginate matrix is converted into insoluble alginic acid, which controls erosion and minimizes diffusion. In higher pH intestine fluids, alginic acid is neutralized to its corresponding salt, which forms highly viscous barriers. Surface hydration, Figure 15 Diffusion of gastric fluid from the surroundings into the polymer matrix. Gel layer formation, Figure 15 The gastric fluid promotes polymer chain relaxation and formation of a swollen gel layer presenting a highly viscous barrier to water penetration in and drug leaching out.

Applications
Esophageal/Oesophageal Reflux
When alginate reaches the stomach and interacts with gastric juice, it forms an acid gel, which remains in the stomach for up to three hours. If calcium carbonate and sodium bicarbonate are present in the formulation a calcium/acid gel is formed. In the acid environment, the carbonates will generate carbon dioxide, which will be entrapped in the gel, making the gel buoyant. The resulting raft floats on top of the gastric juices and provides

14

Figure 15: Illustration of the mode of action of alginate used as a matrix retarder.

Wound Healing Dressings

Extruding a solution of sodium alginate into a calcium chloride bath can generate calcium alginate fibers of various qualities. The properties of the gel and the rate at which it is formed differ from alginate product to alginate product. The properties are contingent on the source of the alginate raw material, method of production, and the ratio of sodium:calcium in the product. The calcium alginate fibers are subsequently applied in the manufacturing of alginate dressings of woven, non-woven, knitted and gauze types, Figure 16. Compared to other dressings, alginate dressings offer additional benefits, including; Higher absorption of wound exudate through hydrophilic gel formation keeps skin area moist and promotes healing. No adherence to exudating wounds Alginate fibers are easily removed from the wound with a saline wash Calcium alginate gel compatibility with other medicaments makes it an excellent drug carrier. Alginate high in guluronate create strong and brittle fibers which form highly absorbent gels Alginate high in mannuronate create softer fibers, which form less absorbent gels.

Erosion/Diffusion, Figure 15 The polymer matrix erodes from the tablet surface into the gastro-intestinal fluid. Drug release from the surface occurs immediately followed by diffusion through, and/or erosion of, the transition layer. Relative proportions of drug released by diffusion/erosion are influenced by drug solubility, the physiochemical nature of the gel layer and the dissolution medium. Insoluble or poorly soluble drugs with transitlimited absorption/bio-availability are generally not good candidates for sustained release, because the proportion of the dose released after the absorption site will not be bio-available. The time profile of release may be tailored to customer requirements by use of different alginates, and by addition of complementary hydrocolloids and excipients.

15

Figure 16: An example of an alginate dressing.

Figure 17: Dental impression material based on alginate.

Dental Impression Materials

Alginate based dental impression materials as depicted in Figure 17, are tough, elastic, thermo-irreversible gels that are formed at room temperature by the reaction between alginate and a calcium salt. A range of Protanal alginate grades is available to give control in formulating the desired balance of strength and flexibility of the impression materials. Sodium alginate, potassium alginate or triethanolamine alginate are the main ingredients in the dental impression market. Categorized according to their different physiochemical properties as gelling alginates, the outcome will be impression material with different qualities. In addition to alginate, commercial dental impression materials contain a calcium source, such as calcium sulphate, a filler, such as diatomaceous earth, to increase rigidity and facilitate mixing, a reaction retarder, such as tetrasodium pyrophosphate, and pH modifiers, such as magnesium oxide (basic) and potassium fluortitanate (acidic), which act as setting aids.

Suspension, Emulsion and Foam Stabilizer

The propylene glycol group modification of alginic acid, PGA, provides the polymer with surface-active properties necessary for the stabilization of suspensions, emulsions and foams. The hydrophobic groups attract the polymer to interfaces between oil and water (emulsions), solid and liquid (suspensions), and water and air (foams) preventing the emulsion droplets to coalesce and the solid particles to flocculate through steric stabilization mechanisms. The foam stabilization mechanism is also due to the surface activity but associated with prevention of drainage and collapse of the film separating the air-bubbles.

Other Applications
The disintegrating action of alginic acid is caused by its excellent swelling properties. In contact with an acidic solution, alginic acid

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swells; this causes a rupture of the cohesive interactions between the different components in the tablet. Alginic acid is used as a tablet disintegrant in amounts varying from 2% to 15%. Sodium alginate can be used as a tablet binder in low concentrations. It can be used dry or pre-dissolved in the water for granulation. When sodium alginate is used in larger amounts, a high viscous hydrocolloid matrix is formed with a resulting sustained release effect on the active. Finer grade alginic acid or sodium alginates are used as tablet binders or binding agents, in contrast to the coarser particle size grades used to enhance dissolution without clumping in liquid applications.

Regulatory Status for Use in Dietary Supplements

Ammonium alginate: Calcium alginate: Potassium alginate: Sodium alginate: Propylene glycol alginate: (Propane-1,2, diol alginate) US GRAS, 21 CFR 184.1133 GRAS, 21 CFR 184.1187 GRAS, 21 CFR 184.1610 GRAS, 21 CFR 184.1724 21 CFR 172.858 EU E 403 E 404 E 402 E 401 E 405

Check the regulations for specific conditions to the use of these products.

Regulatory
Regulatory Status for Pharmaceutical Use
Alginic acid and sodium alginate products produced and marketed by FMC BioPolymer for use in pharmaceutical products are in compliance with the US Pharmacopoeia/National Formulary (USP/NF), the Eurpean Pharmacopoeia (Ph. Eur.), the British Pharmacopoeia (BP) and Japanese Pharmaceutical Excipeints (JPE). Protanal Ester propylene glycol alginate meets the requirements of the monograph in the NF. A Type IV Drug Master File is on file with the U.S. Food and Drug Administration for Protanal sodium alginate. No compendial monographs currently exist for magnesium alginate, potassium alginate or triethanolamine alginate.

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