High viscosity Medium viscosity

AWORLDOFPOSSIBILITIES LIES JUSTBELOWTHESURFACE

Protanal.Protacid.Protanal Ester

ALGINATES

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Alginates What are alginates?.................................... 02What can alginates do for you? ................ 02Unique structure. Precision harvesting ...... 03From seaweed to functionality ................. 04The science behind the product ............... 04

FunctionalityViscosity .................................................... 06Gel formation .............................................. 08Film formation ..........................................11

Working with Protanal AlginatesMixing and dissolving .............................. 12Preservation in a formulation .................... 12Stability and sterilization ........................... 14Regulatory ............................................... 14Products and main applications ............... 14

FORMULA

For over 60 years, we have built partnerships. We have pioneered new thinking. And we have createdsolutions. We look back on this legacywith pride, but we must also continueto look ahead. Now we’re exploringa new generation of possibilities for an established technology,giving researchers and formulatorsanother problem-solving toolset toenhance the patient experienceand improve healthcare.

Alginates personify the possibility of science. Extracted from brown seaweeds that grow rich and plentifulin consistently cold, clear waters, alginates have already proventhemselves in numerous applications.

But as much as we’ve learned about alginates, we know that we’ve penetrated only the first layers of discovery. Applying our scientificexpertise and our passion for leavingno problem unsolved, we seek todevelop the full potential of this material,working alongside our partners andcustomers to turn ideas into practical,profitable reality.

We challenge you to think beyondwhat’s been done and imagine whatcould be. We invite you to join us as we redefine the potential of one of nature’s building blocks. Together,we can push new boundaries and discover what’s really possible for alginates and the human condition.

ALGINATESA world of possibilities lies just below the surface

01

What are alginates?

What can alginates do for you?

Alginates are hydrocolloids, water-solublebiopolymers extracted from brown seaweed.They were first researched in the late 19thcentury by British chemist E.C. Stanford,although it was another 50 years beforethey were produced commercially. Sincethat time, scientists have discovered muchabout this versatile material. Not just newknowledge of its multiple properties (suchas gelling, film-forming, thickening andstabilizing characteristics)—but also howto adjust harvesting and processing methods to enhance those properties.

While alginates are natural products derivedfrom a natural origin, FMC BioPolymer has refined its harvesting and processing techniques for maximizing yield and ensuring batch-to-batch consistency.

As formulators who are familiar with alginates have already learned, this hydrocolloid has many attributes which naturally lend to a variety of applications. They possessunique, valuable functionality in esophagealanti-reflux suspensions and tablets, andhave demonstrated promise in the area ofcontrolled release medications. They alsooffer benefits as viscosifiers and disintegrants,and can be customized so that their gel-forming characteristics facilitate matrix and structural building properties.Alginates’ wide range of gel strengths havemade them a mainstay of the dentalimpression and denture adhesive marketsfor decades. And in the areas of woundcare and dermatology, their ability to create films, foams and fibers offers a wide range of potential uses. Regardlessof this history of success, we believe thatthe best is yet to come for alginates.

02

Regardless of this history of success, we believe that the best is yet to come for alginates.

Laminaria hyperborea

Laminaria digitata

Laminaria japonica

Ascophyllum nodosum

Ecklonia

Lessonia

Macrocystis pyrifera

Durvillaea

The primary brown seaweed utilized by FMC BioPolymer for the extraction of alginates is Laminaria hyperborea, which is harvested off the west coast of Norway.

At these latitudes the waters are clear and clean, resulting in a healthy, sustainable, renewable crop which growsjust below the surface. Water temperaturealso plays an important role, and the consistently cold water found in this region results in plants containing alginates with a molecular structure that accentuates their useful properties.

Using a proprietary process employingspecially designed trawlers and mechanicalharvesting equipment, FMC harvests seaweed in a way that sustains regrowth,in accordance with advice provided by theNorwegian Marine Research Institute andthe Directorate of Fisheries. This responsibleresource management solidifies our positionas a long-term provider of a consistent, reliable supply of highly functional, cost-effective alginates to customers in thepharmaceutical and medical industries.

In order to supply alginates with differentfunctionalities, FMC BioPolymer also utilizes other sources of brown seaweed,which are harvested off the Chilean coast(figure 1).

Unique structure.Precision harvesting

Figure 1. Industrially utilized brown seaweed.

03

At these latitudes the waters are clear and clean, resulting in a healthy, sustainable, renewable crop which grows just below the surface.

04

Water & acid

Water & alkali

Filter aid

Water & acid

Washing

Seaweed

Grinding

Alginate extraction

Filtration

Precipitation

Alginic acid

Milling

Blending

Packaging

Screening / flotation

Neutralization / Incorporation

Drying

Na-Alginate

K-Alginate

NH4-Alginate

Mg-Alginate

Ca-Alginate

Propylene Glycol Alginate

Alginate occurs naturally in seaweed mainlyin the form of calcium, magnesium andsodium salts. To transform seaweed intoproducts like Protanal alginates and Protacidalginic acid, FMC has developed a processthat extracts alginate while thoroughlyremoving all other biological and inorganicimpurities (figure 2). This stringently controlled process ensures that our alginates are of a consistently high quality.

Whether your needs call for excipient grade, active pharmaceutical or ultrapuregrade alginates, you can be sure that FMCemploys and adheres to the highest relevantstandards to ensure purity and consistency.

We offer an array of over 100 alginateproducts—including alginic acid and itssalts (sodium, triethanolamine, potassium,ammonium, magnesium, calcium) andvarying grades of esterified alginate in theform of propylene glycol alginate—makingus one of the world’s largest and broadestsuppliers of alginate-based materials.

What does this mean for you? It meansthat FMC’s alginate products are amongthe most reliable in the industry. It meansthat you can introduce alginates into theformulation process with the highestdegree of confidence. And it means thatwe’re able to provide the versatility youneed to ensure success in a wide range of formulations.

The science behindthe productAlginates are polysaccharides (carbohydrate polymers) with building blocks comprisedof two uronate sugars, the salts ofmannuronic and guluronic acid. Whenextracting alginates from harvested material, the uronic acids are convertedinto the salt forms mannuronate (M) and guluronate (G) through a neutralizationstep (figure 3).

Alginate is a block copolymer composedof longer homopolymeric regions of M or G, potentially separated by regions of alternating structure (MG) (figure 4). The proportion, distribution and length of these blocks determine the chemicaland physical properties of the alginatemolecules. While G-blocks provide gel-forming capacity, MM and MG units provide flexibility to the uronic acid chains, with flexibility increasing in the order GG<MM<MG.

The chemical composition of alginatevaries according to seaweed species and structure. FMC BioPolymer has theexperience and expertise to select theappropriate seaweeds (or combinations of seaweeds), and process them in a way that assures consistency over a wide range of functionalities.

Figure 2. Simplified production process.

From seaweed to functionality

(1,4) - D - mannuronate

(1,4) - L - guluronate

Figure 3. The monomers of alginate.

Figure 4. Alginate block types.

FUNCTIONALITY

Viscosity

Ap

par

ent V

isco

sity

(mP

a*s)

Vis

cosi

ty (m

Pa*

s)

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

4000

8000

12000

16000

20000

24000

28000

32000

30000

26000

22000

18000

14000

10000

6000

2000

Concentration (%)

High viscosityMedium viscosityLow viscosity

01 10 100 1000 10000

10

100

1000

10000

100000

Shear Rate (s-1)

2.5%1.5%0.5%

Figure 5. Viscosity as a function of concentration of Protanal alginate.

Figure 6. Viscosity as a function of shear rate.

06

Careful selection and management of our resources, highly developed harvestingtechniques and stringent processing giveus the ability to control alginate properties,such as gel strength, particle size and viscosity. You provide the target—we have theraw material and the technology to meet it.

Complete hydration of alginates is necessaryto obtain full functionality of the polymer.The viscosity of an alginate solution dependson the alginate concentration and length of the alginate molecules, or the number of monomer units in the chains (i.e., averagemolecular weight), with longer chains resultingin higher viscosities at similar concentrations(figure 5). Aqueous solutions of alginateshave shear-thinning characteristics, meaningthat viscosity decreases as the shear rate,or stirrer speed, increases (figure 6).

This property is known as pseudoplasticity,or non-Newtonian flow. Temperature willinfluence viscosity as well, with increasingtemperature resulting in decreasedviscosity (figure 7).

Standard grades of alginate form gels in acidic conditions. The pKa values formannuronic and guluronic acid are 3.38and 3.65, respectively. However, propyleneglycol alginate (PGA) is soluble in acid. PGA is produced by reacting the free carboxylic group of the alginic acid withpropylene oxide (figure 8).

10 20 30 40 50 60

200

400

600

800

100

300

500

700

Ap

par

ent V

isco

sity

(mP

a*s)

Temperature (°C)

High viscosityMedium viscosityLow viscosity

Figure 8. Propylene glycol alginate: Alginic acid chain with some acid residues esterified (R indicates ester group, H indicates acid group).

Figure 7. Viscosity of three 1% Protanal alginate solutions at different temperatures.

07

M G M

Gel formation

Gel formation is another area in which alginates have shown great promise. An alginate’s ability to form a gel is determined by the proportion and length of G-blocks in its molecular structure, a position of strength for FMC’s alginatesdue to several factors (table 1). First, we use Laminaria hyperborea, which has one of the highest G-block contents of any species. Because the stems ofLaminaria hyperborea possess the highestconcentrations of guluronate monomerswe process these stems separately, resultingin alginates with superior gel-forming capabilities. Second, our choice of harvestinglocation—cold, rough waters—facilitateshigher G-block content. And finally, proprietaryprocessing refinements enable us toextract alginates that form stronger gelling networks.

To fully appreciate the potential of alginate’sgel-forming properties, it helps to understandthe chemistry behind gel formation. Regionsof guluronate monomers, or G-blocks, inone alginate molecule can be linked to asimilar region in another alginate moleculeby means of calcium ions or other multivalentcations (figure 9). The divalent calciumcation, Ca2+, fits into the guluronate blockstructure like eggs in an egg box (figure 10). This binds the alginate polymers togetherby forming junction zones, resulting in gelation of the solution.

Type ofseaweed

Laminaria hyperborea (stem)

Laminaria hyperborea (leaf)

Lessonia nigrescens

Lessonia trabeculata

Durvillaea antarctica

17

36

40

25

56

26

38

38

26

26

57

26

22

49

18

Laminaria digitata

Ecklonia maxima

Macrocystis pyrifera

Ascophyllum nodosum

Laminaria japonica

43

38

38

44

48

32

24

46

40

36

25

28

16

16

16

%MM %MG & GM %GG

Ava

ilab

le f

rom

FM

C

Table 1. Typical M- and G-block profiles for different seaweedsas measured by nuclear magnetic resonance spectroscopy (NMR).

08

Once formed, an alginate gel may be considered part solid and part solution.Water and other molecules are physicallytrapped within the alginate matrix by capillary forces, yet remain free to migrateby diffusion, depending on size. This propertymakes alginate gels ideal for multipleapplications, including cell immobilizationand/or encapsulation. Another area wherethis property plays a role is in woundtreatment where the gel network is rehydrated through the absorption of exudates from wounds into alginatewound dressings. Also, in the treatment ofanti-reflux diseases, alginates react in situwith acid and calcium carbonate, creatinga protective, floating gel raft, due to thetrapped bubbles of carbon dioxide.

Another valuable property of alginates isthat they are soluble in cold water and donot need a heating and cooling cycle toform gels, as is the case with most othergelling biopolymers. By selecting alginate

grades and adjusting formulations, alginate gels can be developed into a range of structure types, from firm and brittle to soft and pliable.

There are three main components in atypical alginate gelling system—alginate,calcium salt and sequestrant. Alginate typeand counter-ion, calcium source and thesequestering agent control the gelling system structure and the rate at which thegel forms. Hydration and uniform distributionof the alginate are essential to optimizegel formation. The grade of alginate, calci-um source and sequestering agents mustbe matched with the process and overall formulation to develop the final product(figure 11). This is an area where our 60years of experience yields huge dividendsfor our customers.

Alginate

pHSolubility

Temperature

Sequestrant

Calcium

Figure 9. Calcium binding site in G-blocks.

Figure 10. “Egg box” modelfor alginate gel formation.

Figure 11. Factors influencinggel formation and properties.

09

While alginates naturally lend themselves to multiple gelling methods, the two mostfrequently used are diffusion setting andinternal setting.

In a diffusion setting system at neutral pH,an alginate solution, or a mixture containingalginate, is gelled by being dipped into, or sprayed with, a calcium salt solution(calcium chloride is the most commonlyused). The calcium ions diffuse into thesolution and react with the alginate molecules,forming a calcium alginate gel. This processis especially suitable for relatively thin orsmall dimension materials, or when trying to provide a thin coating on a product surface. The rate of diffusion can beincreased by raising the concentration of calcium in the setting bath or spray and by using a strongly calcium-reactive alginate, such as an alginate with a highproportion of G-blocks.

One example of using diffusion setting is in manufacturing calcium alginate fibers for wound dressings. In this case, alginatesolution is extruded into a calcium baththrough fine nozzles and the fibers gel bycalcium diffusion into the fine threads. Thisprinciple is also used when encapsulatingcells or materials in alginate beads.

The diffusion setting system can also betriggered by lowering pH. To accomplishthis, a calcium salt that is insoluble at neutralpH is mixed with the alginate. When theacid comes into contact with the surface of this mass, the calcium salt is solubilized.The solubilized calcium will then react withthe alginate, triggering the gelation process.One example of this application is anti-reflux medicines, where alginate forms a protective raft in the stomach.

In an internal setting process, calcium isreleased within the product under controlledconditions. This method employs the combination of alginate, a slowly solublecalcium salt and a suitable calciumsequestrant, such as a phosphate or citrate. A sequestrant is needed to bind free calcium and prevent pregelation of the alginate during the time the product is mixed (prior to being cast into the desired shape). The shorter the mixing time,the lower the level of sequestrant needed.

The internal setting method may be performed at neutral or acidic pH and acidity may be achieved through the addition of an acidifier, which will accelerate the solubility of the calcium salts. This method is commonly used for dental impression materials.

10

Another attribute of alginates which presentsexciting possibilities is its film-formingcapability. While several biopolymers canbe used for film formation, alginate’s inherentproperties give it some distinct advantages.Films formed using alginates in combinationwith a plasticizer are generally strong andflexible, and also provide a strong oxygenbarrier. Alginate films also offer excellenttransparency and can be either soluble orinsoluble. Soluble films of sodium alginateare made by casting and drying, whileinsoluble or gelled alginate films are produced by applying a layer of alginatesolution followed by cross-linking with calcium salt and then drying.

We see several possibilities to leverage the inherent flexibility and other unique properties of alginates. For example, alginate's film-forming capabilities could provide potential new platforms for the innovative drug delivery systems of the future.

Film formation

11

Alginate’s film-forming capabilities could provide potential new platforms for the innovative drug delivery systems of the future.

During the dissolving process, it is crucialthat the water be vigorously stirred whilepowder is being added. Protanal alginatesshould be introduced slowly into the vortexcreated by the water to avoid lumping andstirred until complete hydration occurs (5 to 20 minutes, depending on the gradeof Protanal alginate and equipment used).Premixing with another powder or in a liquid that does not dissolve alginate (such as alcohol, PEG or oil) will enhancedispersion and subsequent dissolution.

Although naturally derived alginates areless susceptible to microbial attack thanmany other carbohydrates, preservativesare recommended for use in systems withhigh moisture or suspensions. When onthe lookout for the presence of microbialgrowth, one clear indicator is a reductionin viscosity. Preservatives like sorbic acid,potassium sorbate, benzoic acid, sodiumbenzoate or esters of hydroxybenzoic acidcan all be safely employed when trying toprevent growth. The amount required will depend on the type of preservative, the composition of the product and thestorage conditions.

WORKING WITH PROTANALALGINATES

Mixing and dissolving

Preservation in a formulation

12

When working with alginates, it’s important to follow a few simple guidelines

NATUREHUMANSSCIENCE

Type of alginate

Alginic acid

Magnesium alginate

Potassium alginate

Triethanolamine alginate

Propylene glycol alginate

Sodium alginate

Brand name

Protacid

Protanal

Protanal

Protanal

Protanal Ester

Protanal

Main applications

Anti-reflux tablets, natural disintegrant

Anti-reflux suspensions for infants

Dental impression material

Dental impression material

Suspending agent/stabilizer, plastisizer, binder, emulsifier

Anti-reflux suspensions, controlled release tablets, wound dressings, dental impression material, denture fixatives, viscosifier, encapsulation, films, foams

Stability and sterilization Time, temperature and humidity influencethe stability of alginate systems. The stability of Protanal alginates and Protacidalginic acid is well established and hasbeen documented through FMC’s alginatestability program. FMC has developedpackaging and distribution techniquesthat help ensure stability, allowing customersto take delivery of product shipments witha high degree of confidence. FMC hasalso optimized product logistics to ensurereliable delivery and maintain productquality and integrity during shipment.Once customers receive Protanal alginate shipments, it is recommended that they be stored cool (8-15° C) and dry, whileProtacid alginic acid, which is less stablethan sodium and potassium alginate, should be stored cold (less than 5° C) and dry.

As with most carbohydrates, alginates are susceptible to hydrolysis or degradation in acid and alkali, especially when exposedto high temperatures over extended periods.To limit this possibility, apply high heatonly when needed and for as short a timeas possible. If use of high heat is undesirable,sterilization can also be achieved throughfiltration via an appropriate submicron filter.

Sterile alginates have achieved great success in encapsulation of living cells that release biologically active substances to treat conditionssuch as diabetes and brain tumors. Sterile and ultrapure alginates can be obtained through our NovaMatrixbusiness unit.

Protacid alginic acid and Protanal sodium alginate meet the requirements of the monographs in the NationalFormulary (NF) and EuropeanPharmacopoeia (Ph.Eur.). Protanal Esterpropylene glycol alginate meets therequirements of the monograph in the NF.A Type IV Drug Master File is on file withthe U.S. Food and Drug Administration forProtanal sodium alginate. No compendialmonographs currently exist for magnesiumalginate, potassium alginate or triethanolamine alginate.

Nature, Humans, Science photography shot on location by: Jake Chessum. Alex Williams/JDK Photostudio.

Regulatory

14

Products and main applications

AWORLDOFPOSSIBILITIES LIES JUSTBELOWTHESURFACE

Patents:FMC Corporation does not warrant againstinfringement of patents of third parties by reason of any uses made of the product in combination with other material or in theoperation of any process, and purchasersassume all risks of patent infringement by reason of any such use, combination or operation.

The products, processes and uses thereofdescribed herein are covered by one or more patent applications or patents.

Warranty:Because of the numerous factors affectingresults, FMC BioPolymer ingredients are sold on the understanding that purchasers willmake their own tests to determine suitability of these products for their particular purpose.The several uses suggested by FMCBioPolymer are presented only to assist ourcustomers in exploring possible applications.All information and data presented arebelieved to be accurate and reliable, but are presented without the assumption of any liability by FMC BioPolymer.

Technical Service:The information contained in this bulletin isintended to be general in nature. Techniques and data pertaining to specific uses for FMCBioPolymer products and new developments will be published periodically in the form of supplemental application bulletins. Our technical staff is ready to offer assistance in the use of FMC BioPolymer products.

Copyright © 2003 FMC Corporation. All rights reserved.

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