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A WORLD OF POSSIBILITIES

LIES JUST BELOW THE SURFACE

Protanal. Protacid.Protanal Ester

ALGINATES
FORMULA

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

Functionality
Viscosity .................................................... 06
Gel formation .............................................. 08
Film formation .......................................... 11

Working with Protanal Alginates


Mixing and dissolving .............................. 12
Preservation in a formulation .................... 12
Stability and sterilization ........................... 14
Regulatory ............................................... 14
Products and main applications ............... 14

The following are trademarks or service marks of FMC Corporation or its subsidiaries, which may be Registered U.S. Patent & Trademark
Office and in other countries: FMC Logo, Protacid, Protanal, NovaMatrix, The Science of Formulation and The Science of Formulation mark.
01

ALGINATES
A world of possibilities
lies just below the surface

For over 60 years, we have built But as much as weve learned


partnerships. We have pioneered about alginates, we know that
new thinking. And we have created weve penetrated only the first layers
solutions. We look back on this legacy of discovery. Applying our scientific
with pride, but we must also continue expertise and our passion for leaving
to look ahead. Now were exploring no problem unsolved, we seek to
a new generation of possibilities develop the full potential of this material,
for an established technology, working alongside our partners and
giving researchers and formulators customers to turn ideas into practical,
another problem-solving toolset to profitable reality.
enhance the patient experience
and improve healthcare. We challenge you to think beyond
whats been done and imagine what
Alginates personify the possibility could be. We invite you to join us
of science. Extracted from brown as we redefine the potential of one
seaweeds that grow rich and plentiful of natures building blocks. Together,
in consistently cold, clear waters, we can push new boundaries and
alginates have already proven discover whats really possible for
themselves in numerous applications. alginates and the human condition.
02

What are What can alginates


alginates? do for you?
Alginates are hydrocolloids, water-soluble As formulators who are familiar with alginates
biopolymers extracted from brown seaweed. have already learned, this hydrocolloid
They were first researched in the late 19th has many attributes which naturally lend
century by British chemist E.C. Stanford, to a variety of applications. They possess
although it was another 50 years before unique, valuable functionality in esophageal
they were produced commercially. Since anti-reflux suspensions and tablets, and
that time, scientists have discovered much have demonstrated promise in the area of
about this versatile material. Not just new controlled release medications. They also
knowledge of its multiple properties (such offer benefits as viscosifiers and disintegrants,
as gelling, film-forming, thickening and and can be customized so that their
stabilizing characteristics)but also how gel-forming characteristics facilitate
to adjust harvesting and processing matrix and structural building properties.
methods to enhance those properties. Alginates wide range of gel strengths have
made them a mainstay of the dental
While alginates are natural products derived impression and denture adhesive markets
from a natural origin, FMC BioPolymer for decades. And in the areas of wound
has refined its harvesting and processing care and dermatology, their ability to
techniques for maximizing yield and create films, foams and fibers offers a
ensuring batch-to-batch consistency. wide range of potential uses. Regardless
of this history of success, we believe that
the best is yet to come for alginates.

Regardless of this history of success, we believe


that the best is yet to come for alginates.
03

Unique structure.
Precision harvesting
The primary brown seaweed utilized Using a proprietary process employing
by FMC BioPolymer for the extraction of specially designed trawlers and mechanical
alginates is Laminaria hyperborea, which harvesting equipment, FMC harvests
is harvested off the west coast of Norway. seaweed in a way that sustains regrowth,
in accordance with advice provided by the
At these latitudes the waters are Norwegian Marine Research Institute and
clear and clean, resulting in a healthy, the Directorate of Fisheries. This responsible
sustainable, renewable crop which grows resource management solidifies our position
just below the surface. Water temperature as a long-term provider of a consistent,
also plays an important role, and the reliable supply of highly functional, cost-
consistently cold water found in this effective alginates to customers in the
region results in plants containing pharmaceutical and medical industries.
alginates with a molecular structure
that accentuates their useful properties. In order to supply alginates with different
functionalities, FMC BioPolymer also
utilizes other sources of brown seaweed,
which are harvested off the Chilean coast
(figure 1).

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

Figure 1. Industrially
utilized brown seaweed.

Laminaria hyperborea

Laminaria digitata

Laminaria japonica

Ascophyllum nodosum

Ecklonia

Lessonia

Macrocystis pyrifera

Durvillaea
04

From seaweed
to functionality
Alginate occurs naturally in seaweed mainly What does this mean for you? It means Alginate is a block copolymer composed
in the form of calcium, magnesium and that FMCs alginate products are among of longer homopolymeric regions of M
sodium salts. To transform seaweed into the most reliable in the industry. It means or G, potentially separated by regions
products like Protanal alginates and Protacid that you can introduce alginates into the of alternating structure (MG) (figure 4).
alginic acid, FMC has developed a process formulation process with the highest The proportion, distribution and length
that extracts alginate while thoroughly degree of confidence. And it means that of these blocks determine the chemical
removing all other biological and inorganic were able to provide the versatility you and physical properties of the alginate
impurities (figure 2). This stringently need to ensure success in a wide range molecules. While G-blocks provide
controlled process ensures that our of formulations. gel-forming capacity, MM and MG
alginates are of a consistently high quality. units provide flexibility to the uronic
acid chains, with flexibility increasing
Whether your needs call for excipient
grade, active pharmaceutical or ultrapure
The science behind in the order GG<MM<MG.

grade alginates, you can be sure that FMC


employs and adheres to the highest relevant
the product The chemical composition of alginate
varies according to seaweed species
standards to ensure purity and consistency. Alginates are polysaccharides (carbohydrate and structure. FMC BioPolymer has the
polymers) with building blocks comprised experience and expertise to select the
We offer an array of over 100 alginate of two uronate sugars, the salts of appropriate seaweeds (or combinations
productsincluding alginic acid and its mannuronic and guluronic acid. When of seaweeds), and process them in
salts (sodium, triethanolamine, potassium, extracting alginates from harvested a way that assures consistency over
ammonium, magnesium, calcium) and material, the uronic acids are converted a wide range of functionalities.
varying grades of esterified alginate in the into the salt forms mannuronate (M)
form of propylene glycol alginatemaking and guluronate (G) through a neutralization
us one of the worlds largest and broadest step (figure 3).
suppliers of alginate-based materials.

Figure 2. Simplified production process.


Seaweed
Water & acid Washing
Grinding
Water & alkali Alginate extraction
Screening / flotation

Filter aid Filtration

Water & acid Precipitation


Na-Alginate
Alginic acid
K-Alginate

NH4 -Alginate
Neutralization / Incorporation
Mg-Alginate
Ca-Alginate
Drying
Propylene Glycol Alginate
Milling
Blending
Packaging
Figure 3. The monomers of alginate.

(1,4) - D - mannuronate

(1,4) - L - guluronate

Figure 4. Alginate block types.


06

FUNCTIONALITY

Viscosity

Careful selection and management of This property is known as pseudoplasticity,


our resources, highly developed harvesting or non-Newtonian flow. Temperature will
techniques and stringent processing give influence viscosity as well, with increasing
us the ability to control alginate properties, temperature resulting in decreased
such as gel strength, particle size and viscosity (figure 7).
viscosity. You provide the targetwe have the
raw material and the technology to meet it. Standard grades of alginate form gels
in acidic conditions. The pKa values for
Complete hydration of alginates is necessary mannuronic and guluronic acid are 3.38
to obtain full functionality of the polymer. and 3.65, respectively. However, propylene
The viscosity of an alginate solution depends glycol alginate (PGA) is soluble in acid.
on the alginate concentration and length PGA is produced by reacting the free
of the alginate molecules, or the number carboxylic group of the alginic acid with
of monomer units in the chains (i.e., average propylene oxide (figure 8).
molecular weight), with longer chains resulting
in higher viscosities at similar concentrations
(figure 5). Aqueous solutions of alginates
have shear-thinning characteristics, meaning
that viscosity decreases as the shear rate,
or stirrer speed, increases (figure 6).

Figure 5. Viscosity as a function of Figure 6. Viscosity as


concentration of Protanal alginate. a function of shear rate.

32000 100000
30000
28000
26000 High viscosity 10000
24000 Medium viscosity
Apparent Viscosity (mPa*s)

22000 Low viscosity


Viscosity (mPa*s)

20000 1000
18000
16000
14000
100
12000
10000
8000 2.5%
10 1.5%
6000
0.5%
4000
2000

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 01 10 100 1000 10000
Concentration (%) Shear Rate (s-1)
07
Figure 7. Viscosity of three 1% Protanal Figure 8. Propylene glycol alginate: Alginic acid chain with some acid
alginate solutions at different temperatures. residues esterified (R indicates ester group, H indicates acid group).

800 High viscosity


Apparent Viscosity (mPa*s)

Medium viscosity
700
Low viscosity
600
500
400
300
200
100

10 20 30 40 50 60
Temperature (C)
M G M
08

Gel formation

Gel formation is another area in which To fully appreciate the potential of alginates
alginates have shown great promise. gel-forming properties, it helps to understand
An alginates ability to form a gel is the chemistry behind gel formation. Regions
determined by the proportion and length of guluronate monomers, or G-blocks, in
of G-blocks in its molecular structure, one alginate molecule can be linked to a
a position of strength for FMCs alginates similar region in another alginate molecule
due to several factors (table 1). First, by means of calcium ions or other multivalent
we use Laminaria hyperborea, which has cations (figure 9). The divalent calcium
one of the highest G-block contents of cation, Ca2+, fits into the guluronate block
any species. Because the stems of structure like eggs in an egg box (figure 10).
Laminaria hyperborea possess the highest This binds the alginate polymers together
concentrations of guluronate monomers by forming junction zones, resulting
we process these stems separately, resulting in gelation of the solution.
in alginates with superior gel-forming
capabilities. Second, our choice of harvesting
locationcold, rough watersfacilitates
higher G-block content. And finally, proprietary
processing refinements enable us to
extract alginates that form stronger
gelling networks.

Table 1. Typical M- and G-block profiles for different seaweeds


as measured by nuclear magnetic resonance spectroscopy (NMR).

Type of %MM %MG & GM %GG


seaweed

Laminaria hyperborea (stem) 17 26 57


Available from FMC

Laminaria hyperborea (leaf) 36 38 26

Lessonia nigrescens 40 38 22

Lessonia trabeculata 25 26 49

Durvillaea antarctica 56 26 18

Laminaria digitata 43 32 25

Ecklonia maxima 38 24 28

Macrocystis pyrifera 38 46 16

Ascophyllum nodosum 44 40 16

Laminaria japonica 48 36 16
09

Once formed, an alginate gel may be grades and adjusting formulations,


considered part solid and part solution. alginate gels can be developed into
Water and other molecules are physically a range of structure types, from
trapped within the alginate matrix by firm and brittle to soft and pliable.
capillary forces, yet remain free to migrate
by diffusion, depending on size. This property There are three main components in a
makes alginate gels ideal for multiple typical alginate gelling systemalginate,
applications, including cell immobilization calcium salt and sequestrant. Alginate type
and/or encapsulation. Another area where and counter-ion, calcium source and the
this property plays a role is in wound sequestering agent control the gelling
treatment where the gel network is system structure and the rate at which the
rehydrated through the absorption of gel forms. Hydration and uniform distribution
exudates from wounds into alginate of the alginate are essential to optimize
wound dressings. Also, in the treatment of gel formation. The grade of alginate, calci-
anti-reflux diseases, alginates react in situ um source and sequestering agents must
with acid and calcium carbonate, creating be matched with the process and overall
a protective, floating gel raft, due to the formulation to develop the final product
trapped bubbles of carbon dioxide. (figure 11). This is an area where our 60
years of experience yields huge dividends
Another valuable property of alginates is for our customers.
that they are soluble in cold water and do
not need a heating and cooling cycle to
form gels, as is the case with most other
gelling biopolymers. By selecting alginate

Figure 9. Calcium Figure 10. Egg box model Figure 11. Factors influencing
binding site in G-blocks. for alginate gel formation. gel formation and properties.

Calcium

pH
Solubility
Temperature

Alginate Sequestrant
10

While alginates naturally lend themselves One example of using diffusion setting is In an internal setting process, calcium is
to multiple gelling methods, the two most in manufacturing calcium alginate fibers released within the product under controlled
frequently used are diffusion setting and for wound dressings. In this case, alginate conditions. This method employs the
internal setting. solution is extruded into a calcium bath combination of alginate, a slowly soluble
through fine nozzles and the fibers gel by calcium salt and a suitable calcium
In a diffusion setting system at neutral pH, calcium diffusion into the fine threads. This sequestrant, such as a phosphate or
an alginate solution, or a mixture containing principle is also used when encapsulating citrate. A sequestrant is needed to bind
alginate, is gelled by being dipped into, cells or materials in alginate beads. free calcium and prevent pregelation of
or sprayed with, a calcium salt solution the alginate during the time the product
(calcium chloride is the most commonly The diffusion setting system can also be is mixed (prior to being cast into the
used). The calcium ions diffuse into the triggered by lowering pH. To accomplish desired shape). The shorter the mixing time,
solution and react with the alginate molecules, this, a calcium salt that is insoluble at neutral the lower the level of sequestrant needed.
forming a calcium alginate gel. This process pH is mixed with the alginate. When the
is especially suitable for relatively thin or acid comes into contact with the surface The internal setting method may be
small dimension materials, or when trying of this mass, the calcium salt is solubilized. performed at neutral or acidic pH and
to provide a thin coating on a product The solubilized calcium will then react with acidity may be achieved through the
surface. The rate of diffusion can be the alginate, triggering the gelation process. addition of an acidifier, which will
increased by raising the concentration One example of this application is anti- accelerate the solubility of the calcium
of calcium in the setting bath or spray reflux medicines, where alginate forms salts. This method is commonly used
and by using a strongly calcium-reactive a protective raft in the stomach. for dental impression materials.
alginate, such as an alginate with a high
proportion of G-blocks.
11

Film formation

Another attribute of alginates which presents We see several possibilities to leverage


exciting possibilities is its film-forming the inherent flexibility and other unique
capability. While several biopolymers can properties of alginates. For example,
be used for film formation, alginates inherent alginate's film-forming capabilities
properties give it some distinct advantages. could provide potential new platforms
Films formed using alginates in combination for the innovative drug delivery
with a plasticizer are generally strong and systems of the future.
flexible, and also provide a strong oxygen
barrier. Alginate films also offer excellent
transparency and can be either soluble or
insoluble. Soluble films of sodium alginate
are made by casting and drying, while
insoluble or gelled alginate films are
produced by applying a layer of alginate
solution followed by cross-linking with
calcium salt and then drying.

Alginates film-forming capabilities could provide potential new


platforms for the innovative drug delivery systems of the future.
12
WORKING WITH
PROTANAL ALGINATES
When working with alginates, its important
to follow a few simple guidelines

Mixing and Preservation in


dissolving a formulation
During the dissolving process, it is crucial Although naturally derived alginates are
that the water be vigorously stirred while less susceptible to microbial attack than
powder is being added. Protanal alginates many other carbohydrates, preservatives
should be introduced slowly into the vortex are recommended for use in systems with
created by the water to avoid lumping and high moisture or suspensions. When on
stirred until complete hydration occurs the lookout for the presence of microbial
(5 to 20 minutes, depending on the grade growth, one clear indicator is a reduction
of Protanal alginate and equipment used). in viscosity. Preservatives like sorbic acid,
Premixing with another powder or in potassium sorbate, benzoic acid, sodium
a liquid that does not dissolve alginate benzoate or esters of hydroxybenzoic acid
(such as alcohol, PEG or oil) will enhance can all be safely employed when trying to
dispersion and subsequent dissolution. prevent growth. The amount required
will depend on the type of preservative,
the composition of the product and the
storage conditions.
NATURE
HUMANS
SCIENCE
14

Stability and Regulatory


sterilization
Time, temperature and humidity influence As with most carbohydrates, alginates Protacid alginic acid and Protanal
the stability of alginate systems. The are susceptible to hydrolysis or degradation sodium alginate meet the requirements
stability of Protanal alginates and Protacid in acid and alkali, especially when exposed of the monographs in the National
alginic acid is well established and has to high temperatures over extended periods. Formulary (NF) and European
been documented through FMCs alginate To limit this possibility, apply high heat Pharmacopoeia (Ph.Eur.). Protanal Ester
stability program. FMC has developed only when needed and for as short a time propylene glycol alginate meets the
packaging and distribution techniques as possible. If use of high heat is undesirable, requirements of the monograph in the NF.
that help ensure stability, allowing customers sterilization can also be achieved through A Type IV Drug Master File is on file with
to take delivery of product shipments with filtration via an appropriate submicron filter. the U.S. Food and Drug Administration for
a high degree of confidence. FMC has Protanal sodium alginate. No compendial
also optimized product logistics to ensure Sterile alginates have achieved monographs currently exist for magnesium
reliable delivery and maintain product great success in encapsulation of alginate, potassium alginate or
quality and integrity during shipment. living cells that release biologically triethanolamine alginate.
Once customers receive Protanal alginate active substances to treat conditions
shipments, it is recommended that they such as diabetes and brain tumors.
be stored cool (8-15 C) and dry, while Sterile and ultrapure alginates can
Protacid alginic acid, which is less stable be obtained through our NovaMatrix
than sodium and potassium alginate, should business unit.
be stored cold (less than 5 C) and dry.

Nature, Humans, Science photography shot on location by:


Jake Chessum. Alex Williams/JDK Photostudio.

Products and main applications


Type of alginate Brand name Main applications

Alginic acid Protacid Anti-reflux tablets, natural disintegrant

Sodium alginate Protanal Anti-reflux suspensions, controlled release tablets, wound


dressings, dental impression material, denture fixatives,
viscosifier, encapsulation, films, foams

Magnesium alginate Protanal Anti-reflux suspensions for infants

Potassium alginate Protanal Dental impression material

Triethanolamine alginate Protanal Dental impression material

Propylene glycol alginate Protanal Ester Suspending agent/stabilizer, plastisizer, binder, emulsifier
A WORLD OF POSSIBILITIES
LIES JUST BELOW THE SURFACE
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Patents: Warranty: Technical Service:


FMC Corporation does not warrant against Because of the numerous factors affecting The information contained in this bulletin is
infringement of patents of third parties by results, FMC BioPolymer ingredients are sold intended to be general in nature. Techniques
reason of any uses made of the product on the understanding that purchasers will and data pertaining to specific uses for FMC
in combination with other material or in the make their own tests to determine suitability BioPolymer products and new developments
operation of any process, and purchasers of these products for their particular purpose. will be published periodically in the form of
assume all risks of patent infringement The several uses suggested by FMC supplemental application bulletins. Our
by reason of any such use, combination BioPolymer are presented only to assist our technical staff is ready to offer assistance
or operation. customers in exploring possible applications. in the use of FMC BioPolymer products.
All information and data presented are
The products, processes and uses thereof believed to be accurate and reliable, but Copyright 2003 FMC Corporation.
described herein are covered by one or are presented without the assumption of All rights reserved.
more patent applications or patents. any liability by FMC BioPolymer.

www.fmcbiopolymer.com

ALG.01.01 Printed in the USA

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