formulating

elegant liquid
and semisolid
drug products
—
natrosol 250
™

hydroxyethylcellulose (HEC)
contents
introduction...................................................................... 3 synergistic effect with sodium
carboxymethylcellulose............................................... 18
polymer chemistry.......................................................... 4
tolerance for inorganic salts.........................................19
grades and specifications............................................. 5
compatibility with other materials.............................. 20
products available.......................................................... 5
application examples for
pharmacopeial specifications...................................... 6
natrosol™ 250 pharm HEC............................................ 21
polymer properties......................................................... 7
natrosol™ 250 pharm HEC as a viscosity
typical properties............................................................. 7 modifier in pharmaceutical oral liquids..................... 21

solubility in water and case study: sugar-free ambroxol syrup......................22

organic solvents............................................................... 7
case study: taste-masked loratadine syrup..............23
moisture absorption........................................................ 8
case study: syrup for poorly soluble
dissolving natrosol™ 250 pharm HEC in water............. 9 paracetamol...................................................................24

microbial limits................................................................ 10 natrosol™ 250 pharm HEC as rheology

modifier and structured vehicle promoter
properties of solutions and gels of
for semi-solid formulations............................................ 25
natrosol™ 250 pharm HEC.............................................11
case study: diclofenac gel...........................................26
viscosity ............................................................................11
case study: aluminum hydroxide oral gel..................27
effect of concentration................................................. 11
ophthalmic solutions using
effect of shear rate......................................................... 11
natrosol™ 250 pharm HEC............................................................................. 29
effects of temperature.................................................. 14
packaging and storage............................................... 31
effect of pH...................................................................... 15
product safety and
mechanical properties of handling precautions................................................... 31
natrosol™ 250 pharm HEC gels..................................... 16
toxicological studies ................................................... 31
antimicrobial preservatives...........................................17

heat sterilization and

sterile filtration..................................................................17

heat sterilization.............................................................. 17

sterile filtration................................................................. 17

2
introduction

Natrosol™ 250 Pharm hydroxyethylcellulose (HEC) is This brochure describes the properties of Natrosol™
a nonionic, water-soluble polymer widely used in 250 Pharm HEC and its solutions. Natrosol™ 250 Pharm
pharmaceutical formulations. Like Aqualon™ and HEC is a versatile pharmaceutical excipient with many
Blanose™ sodium carboxymethylcellulose (CMC), it applications including as a tablet binder, a modified-
is a cellulose ether, but it differs in that it is nonionic release matrix former, a film-coating agent, and a
and its solutions are unaffected by cations and, thus, viscosity modifier. In this brochure we describe the
less affected by pH changes and more tolerant of properties and applications of Natrosol™ 250 Pharm HEC
the presence of anions and organic co-solvents. in semi-solid and liquid pharmaceutical formulations.
It also differs from other cellulose ethers, such as
Klucel™ hydroxypropylcellulose (HPC) and Benecel™
hydroxypropylmethylcellulose (HPMC), in that it is soluble
in both cold and hot water and does not precipitate
from aqueous solutions at elevated temperatures.
polymer chemistry
The Natrosol™ 250 Pharm HEC polymer is a partially In reacting ethylene oxide with cellulose to form the
substituted poly(hydroxyethyl) ether of cellulose. hydroxyethyl ether of cellulose, solubility in water is
The base of the HEC molecule is formed by the achieved as the degree of substitution is increased. By
polysaccharide cellulose and its β (1→4)–linked selecting appropriate reaction conditions and moles
D-glucose units. The structure of the cellulose molecule of substituent, complete and quick solubility in water is
can be visualized as a polymer chain composed of obtained. Natrosol™ 250 Pharm HEC, which has optimum
repeating cellobiose units. These, in turn, are composed solubility in water, has a MS of 2.5. An idealized structure
of two anhydroglucose units (β-glucopyranose residues). of Natrosol™ 250 Pharm HEC is shown in figure 2. This
Each anhydroglucose unit contains three hydroxyls example has a MS of 2.5 (10 ethylene oxide groups/4
capable of reaction, shown in light blue in figure 1. anhydroglucose units) and a DS of 1.5 (6 hydroxyls
substituted/4 anhydroglucose units).
figure 1: Structure of cellulose in chair form notation.
figure 2: Idealized structure of Natrosol™ 250 Pharm
HEC. This example has a MS of 2.5 (10 ethylene oxide
OH OH groups/4 anhydroglucose units) and a DS of 1.5
OH
6 (6 hydroxyls substituted/4 anhydroglucose units).
3 OH
HO O HO 2
O
HO O O O OH
O HO 2 O HO OH HO
3 6
OH OH
OH OH
n O O
6
OH 3 OH
HO O HO 2
O
The number of hydroxyl groups substituted per HO O O O OH
O HO 2 O HO
anhydroglucose unit in any reaction is known as the
3
O 6 O
O n
degree of substitution, or DS. Theoretically, all three O
OH
O
hydroxyls can be substituted. If all three hydroxyls O

are replaced, the maximum theoretical D.S. of 3.0 O

O HO
OH
(impossible in practice) would result. By treating cellulose HO
with sodium hydroxide and reacting with ethylene
oxide, hydroxyethyl groups are introduced to yield a
hydroxyethyl ether. The reaction product is purified and
ground to a white to light tan, free-flowing powder.
Substitution can also occur when ethylene oxide reacts
at previously substituted hydroxyls, and polymerizes to
form a side chain (branching). The average number
of moles of ethylene oxide that become attached to
each anhydroglucose unit in cellulose, in the two ways
described, are called total molar substitution, or MS.

4
grades and specifications
products available measured in aqueous solutions. Additionally,
different particle sizes are available to optimize the
performance in specific applications, such as the
Natrosol™ 250 Pharm hydroxyethyl cellulose (HEC) is
use as matrix former for modified release tablets
available in several grades as given in table 1. The
Natrosol™ 250 Pharm HEC uses a maximum of 1%
available grades differ principally in their weight
phosphates as a pH stabilizer.
average molecular weight, and thus, in their viscosities

table 1: Different grades of Natrosol™ 250 Pharm HEC grades. (X = fine grade and W = superfine grade).
Brookfield viscosity *

weight average Brookfield LVF viscosity solution EP viscosity label** at 10 s−1 and 25 °C
grade molecular weight (Da) at 25 °C, mPa·s concentration (mPa·s in 2% solution)
natrosol™ 250 L pharm 90,000 75–150 5% 9.5 (at 100 s−1)
natrosol 250 G pharm
™
300,000 250–400 2% 295
natrosol™ 250 M pharm 720,000 4,500–6,500 2% 4,400
natrosol™ 250 H pharm 1,000,000 1,500–2,500 1% 8,500
natrosol 250 HX pharm
™
1,000,000 1,500–2,500 1% 8,500
natrosol™ 250 HHX pharm 1,300,000 3,500–5,500 1% 14,500
natrosol™ 250 HHW pharm 1,300,000 3,500–5,500 1% 14,500

*
Brookfield LV viscosity at 25 °C, mPa·s, according to the Ashland method
**
EP label viscosity based on the EP viscosity method. EP viscosity range 75–140% of the value stated on the label (NF viscosity range 50–150% of the value stated on the label).
pharmacopeial specifications
Excipient grades of Natrosol™ 250 Pharm HEC meet the specifications are listed in table 2. For pH stabilization
monograph requirements as set forth in the current of Natrosol™ 250 Pharm HEC a certain amount of
editions of the United States National Formulary (NF) phosphate is added. Added phosphate quantity is
and the European Pharmacopoeia (Ph. Eur.) The printed on the bag label.
pharmacopeial specifications and Ashland’s product

table 2: Pharmacopeial specifications for hydroxyethylcellulose and compendial compliance of Natrosol™ 250 Pharm HEC.
test Ph. Eur. 9.0 USP40-NF35 Ashland specification
residue on ignition (calculated as Na2SO4, %)
• natrosol™ 250 G pharm and natrosol™ 250 L pharm* HEC 4.0 max 5.0 max 4.0 max
• all other grades 4.0 max — 1.0 max
pH, 1% solution 5.5–8.5 6.0–8.5 6.0–8.5
loss on drying, % 10.0 max 10.0 max 5.0 max
nitrate, %
• natrosol™ 250 G pharm and natrosol™ 250 L pharm* HEC 3.0 max — 3.0 max
• all other grades 0.2 max — 0.2 max
chlorides, % 1.0 max — 0.2 max
heavy metals (as lead), ppm 20 max 20 max 10 max
lead, ppm — 10 max 0.5 max
arsenic, ppm — — 3 max
glyoxal, ppm 20 max — 20 max
ethylene oxide, ppm 1 max — 1 max
2-chloroethanol, ppm 10 max — 10 max
*
Low molecular weight HEC with an apparent viscosity of 1000 mPa·s (2% w/v) or less.

Natrosol™ 250 HEC Pharm grades meet the monograph requirements

of the United States National Formulary (NF) and the European
Pharmacopoeia (Ph. Eur.).

6
polymer properties
typical properties
table 3: Typical properties for Natrosol™ 250 Pharm hydroxyethylcellulose.
property value
acidity/alkalinity pH 6.0 – 8.5 for a 1% w/v aqueous solution

density (bulk) 0.4 – 0.6 g/cm³

density (tap) 0.6 – 0.7 g/cm³

moisture content ≤ 5% (w/w) of water

particle size distribution standard grind, retained on #40 mesh (420 µm; max 10%)
X-grind, retained on #60 mesh (250 µm; max 0.5%)
type HHW, retained on #80 mesh (177 µm; max 0.5%)

table 4: Surface tension of different Natrosol™ 250 Pharm HEC grades at varying concentrations and temperatures.
surface tension (dyne/cm or mN/m) at

0.001% (w/v) solution 0.01% (w/v) solution 0.1% (w/v) solution

grade at 20 °C at 25 °C at 20 °C at 25 °C at 20 °C at 25 °C
natrosol™ 250 L pharm HEC 68.7 70.1 68.2 67.9 65.5 66.5
natrosol™ 250 G pharm HEC 69.2 72.1 67.3 70.7 65.9 70.9
natrosol 250 M pharm HEC
™
69.7 69.6 67 68.9 67.9 70.7
natrosol™ 250 H pharm HEC 67.7 71.1 67.1 69.7 68.1 72.2
natrosol™ 250 HX pharm HEC 67.7 71.1 67.1 69.7 68.1 72.2
natrosol™ 250 HHX pharm HEC 67.8 72.7 67.4 71.8 68.7 73.9

solubility in water and

organic solvents
The most important uses of
Natrosol™ 250 Pharm HEC dissolves quickly in cold or hot
water to form clear and smooth solutions; furthermore, Natrosol™ 250 Pharm HEC
it does not gel or precipitate even when heated to
the boiling point of water. Natrosol™ 250 Pharm HEC is
involve its aqueous solutions
essentially insoluble in organic solvents. It is, however, — it is soluble in both hot
partly soluble in some solvents, usually those that are
miscible with water (e.g., ethanol: water mixtures), or and cold water.
that contain polar groups (e.g., glycerin and propylene
glycol at temperatures around 55 °C to 60 °C).
moisture absorption figure 3a: Equilibrium moisture content of different
grades of Natrosol™ HEC at 25 °C. The bold lines
indicate sorption and dotted lines indicate
Natrosol™ 250 Pharm HEC can absorb moisture from the
desorption behavior.
atmosphere, as do other hygroscopic or finely divided
materials. The amount of moisture absorbed depends 50 a
on the initial moisture content of Natrosol™ 250 Pharm
natrosol™ 250 L pharm HEC
HEC and on the relative humidity of the surrounding air. natrosol™ 250 G pharm HEC

Opened bags not totally used may experience natrosol™ 250 M pharm HEC
natrosol™ 250 H pharm HEC
moisture uptake. natrosol™ 250 HX pharm HEC
natrosol™ 250 HHX pharm HEC

The moisture content of Natrosol™ 250 Pharm HEC, when

40
packed by Ashland, does not exceed 5% by weight.
During prolonged storage, the moisture content of
Natrosol™ 250 Pharm HEC reaches an equilibrium level
that varies with temperature and the humidity of the
surrounding atmosphere, particularly after the bag equilibrium moisture at 25 °C (%)
is opened. 30

equilibrium moisture content of Natrosol™ 250 Pharm

HEC at 25 °C:

at 50% relative humidity 8.7 ± 0.1% (w/w)

at 90% relative humidity 50.0 ± 2.0% (w/w)

20

equilibrium moisture content of Natrosol™ 250 Pharm

HEC at 40 °C:

at 50% relative humidity 7.8 ± 0.3% (w/w)

at 90% relative humidity 41.0 ± 1.5% (w/w)

10
To maintain its original moisture content, Natrosol™ 250
Pharm HEC should be stored in tightly closed containers
in a dry atmosphere. If stored in open containers, the
moisture content will change to an equilibrium value
determined by the relative humidity of the environment.
The effects of relative humidity on equilibrium moisture 0
0 20 40 60 80 100
contents of different grades of Natrosol™ 250 Pharm HEC
at 25 °C (left) and 40 °C are shown in figure 3. relative humidity, %

8
figure 3b: Equilibrium moisture content of different
grades of Natrosol™ HEC at 40°C. The bold lines
dissolving natrosol™ 250
indicate sorption and dotted lines indicate
desorption behavior.
pharm HEC in water
Natrosol™ 250 Pharm HEC is readily soluble in either
50 b
hot or cold water. However, as with most water-soluble
natrosol™ 250 L pharm HEC
natrosol™ 250 G pharm HEC
thickeners, the particles tend to agglomerate, or lump,
natrosol™ 250 M pharm HEC when first wetted with water. Thus, the time required
natrosol™ 250 H pharm HEC
natrosol™ 250 HX pharm HEC to achieve complete solution of Natrosol™ 250 Pharm
natrosol™ 250 HHX pharm HEC
HEC is usually governed by the degree of lumping that
40 can develop during the solution process. In general,
the low-viscosity grades are more easily dissolved than
the high-viscosity grades. Employing these methods will
facilitate the quick preparation of solutions of Natrosol™
250 Pharm HEC:
equilibrium moisture at 40 °C (%)

30
method 1: stirring

Natrosol™ 250 Pharm HEC is sifted slowly into the vortex

of vigorously agitated water. The rate of addition should
be slow enough for the particles to separate without
lump formation, but not so slow that the solution thickens
appreciably before all the solids are added. Agitation
20
should be continued until all the swollen or gelatinized
particles are dissolved to yield a smooth solution.

method 2: use of water miscible organic solvent

Excellent solution rates can be obtained by prewetting

10
Natrosol™ 250 Pharm HEC with a water-miscible organic
liquid before the powder is added to water. Anhydrous
ethyl alcohol is suitable for this use, as are other organic
liquids such as propylene glycol and glycerin.

method 3: blending with other water

insoluble materials
0
0 20 40 60 80 100
Improved solution rates can be obtained by dry-
relative humidity, % blending Natrosol™ 250 Pharm HEC with other dry
components (preferably water insoluble) contained
in the formulation prior to dispersing in water. This
technique effectively separates particles of Natrosol™
250 Pharm HEC so that no lumping is experienced when
the dry mix is added to water.
microbial limits
Natrosol™ 250 Pharm HEC grades are routinely
sampled and subjected to microbiological testing by
an independent laboratory to ensure compliance
with good manufacturing practices. This testing is
not done on a lot-by-lot basis, and Ashland does not
make microbiological specifications for this product.
Although the data generated are not intended to
provide product specifications, typical results obtained
using our standard protocols are as shown.

aerobic plate count, cfu/g <100

mold, cfu/g <100

yeast, cfu/g <100

coliforms, MPN/g <30

Escherichia coli/10 g negative

Staphylococcus aureus/10 g negative

Salmonella spp./25 g negative

Pseudomonas aeruginosa/10 g negative

Ashland uses officially approved methods to test

products but recommends that users of Natrosol 250
Pharm HEC assure themselves of compliance with any
microbiological specification that the user may have
by testing each lot.

10
properties of solutions and gels of
natrosol™ 250 pharm HEC
viscosity figure 4: Effect of concentration on viscosity of aqueous
solutions of Natrosol™ 250 Pharm HEC.
All polymer solutions and many pharmaceutical
100000
formulations such as syrups, dispersions, emulsions, gels HH-type

solution viscosity at 25 °C (mPa•s)

and creams are examples of non-Newtonian fluids. This H-type
G-type

means that their viscosities are not fixed, but rather are 10000
M-type
dependent upon the degree of shear to which they
are exposed. By far the most common form of non-
1000
Newtonian behavior is shear-thinning or pseudoplastic L-type
flow, where the viscosity decreases with increasing
shear rate. Solutions of Natrosol™ 250 Pharm HEC are 100

examples of shear-thinning materials. Thus, if a solution

of high-viscosity Natrosol™ 250 Pharm HEC appears to 10
be a viscous liquid as it is poured from a bottle, it can 0 1 2 3 4 5 6 7

behave as a runny liquid when applied as a lotion to natrosol™ 250 pharm HEC in solution (% w/w)

the skin, and yet when high stress is removed, it will

quickly revert to its original high viscosity. Because of
this behavior, Natrosol™ 250 Pharm HEC is extensively
used to modify the viscosity of solutions, dispersions, and
emulsions. Depending on the selected grade and the
Any desired thickening
concentration used, a wide variety of viscosities can be efficiency can be achieved
achieved with Natrosol™ 250 Pharm HEC. Thus, solution
viscosity is dependent on several factors, which will be with the wide variety of
discussed in detail.
Natrosol™ 250 Pharm HEC
effect of concentration
grades available.
When Natrosol™ 250 Pharm HEC is dissolved in water,
the viscosity of the aqueous solution increases with
increasing concentration and molecular weight, as
shown in figure 4.
effect of shear rate
A formulation encounters different levels and kinds of
shear during production, packaging, storing over its
shelf life and during application. These shear forces differ
depending upon the type of formulation, container-
closure system and the type of application.

Shear thinning properties of Natrosol™ 250 Pharm HEC

solutions can contribute different required attributes
to a product, such as formulation stability or ease
of application/pouring when a stress is applied.
Understanding the impact of these shear forces on
solution rheology provides formulators with perspective
on formulation development to maintain functionality
and stability under varying shear forces.
For non-Newtonian products, measuring viscosity at a By increasing the concentration of Natrosol™ 250
single shear rate does not provide the full picture. A flow Pharm HEC in water, the dissolved polymer particles
curve of viscosity across a range of shear rates, from form a three-dimensional network, which produces
which a viscosity value at a shear rate relevant to the solid-like properties. These polymer gels possess both
process or product use conditions can be determined, elastic (solid-like) and viscous (liquid-like) properties,
is far more meaningful. which means they are viscoelastic. The data shown
in figure 6 illustrate the viscoelastic properties of
As shown in figure 5, most tested grades of Natrosol™
aqueous gels containing Natrosol™ 250 Pharm HEC
250 Pharm HEC will behave similarly in terms of flow
at different concentrations and molecular weights,
behavior, but to varying degrees, and eventually, the
measured in an oscillating disc rheometer at
lower the molecular weight, the lower the change in
increasing frequencies. Typically, the complex viscosity
viscosity that occurs under varied stress conditions (as
of HEC gels is high at low frequencies and decreases
shown in the typical ranges at the top of figure 5).
monotonically as the frequency is increased, which is a
figure 5: Effect of shear rate on viscosity for characteristic of viscoelastic systems.
solutions containing different grades of Natrosol™ 250
figure 6: Eeffect of polymer grade, concentration, and
Pharm HEC grades.
oscillatory frequency on the viscosity of Natrosol™ 250
Pharm HEC gels.
1000
storage in a container pouring mixing and stirring
swallowing
100 10000
complex viscosity η* (Pa•s)
viscosity (Pa•s)

10 1000

1
100

0.1
10
0.01

1
0.001
0.01 0.1 1 10 100 1000
shear rate (1/s) 0.1
0.1 1 10 100
natrosol™ 250 HHX pharm HEC 1% natrosol™ 250 G pharm HEC 1%
natrosol 250 H pharm HEC 1%
™
natrosol 250 L pharm HEC 2%
™ frequency (Hz)
natrosol™ 250 M pharm HEC 1% natrosol™ 250 HHX pharm HEC 5% natrosol™ 250 HHX pharm HEC 2%
natrosol™ 250 HX pharm HEC 5% natrosol™ 250 HX pharm HEC 2%
natrosol™ 250 M pharm HEC 5% natrosol™ 250 M pharm HEC 2%
natrosol™ 250 G pharm HEC 5% natrosol™ 250 G pharm HEC 2%

12
Spreadability of pharmaceutical gels and other The ratio of viscous modulus (G’’) to elastic modulus
semisolids is the result of a combination of rheological (G’) is commonly employed to characterize the
behaviors, of which viscosity is just one. In addition, relationship between these two parameters. This
structural and viscoelastic characteristics that describe parameter is called the loss tangent (tan δ), a
the rigidity, strength and relative contributions of dimensionless parameter that provides a comparative
the elastic and viscous behaviors of a material play measure of both the elastic and viscous contributions
important roles in spreadability. The usual way to (figure 8). While both loss and storage moduli increased
quantify viscoelastic properties is to measure the as a function of frequency, the decrease in tan δ
elastic or storage modulus (G’) and viscous or loss indicates greater elastic character of the aqueous
modulus (G”) of the material. The storage modulus is polymeric gels. The smaller the tan δ, the more rubbery
proportional to the extent of elastic component (the or elastomeric is the behavior.
solid-like component, contributed by crosslinking,
entanglement, and/or aggregation) of the system, while figure 8: The effects of polymer grade and oscillatory
the loss modulus is proportional to the extent of viscous frequency on the loss tangent (tan δ) of gels containing
component (contributed by the liquid-like portion) of Natrosol™ 250 Pharm HEC.
the system. Gels (and creams) cannot relax quickly and
10
are highly elastic at similar frequency ranges, and thus,
the elastic modulus (G’) tends to be considerably higher
than the viscous modulus (G’’), as shown in figure 7.
loss tangent (tan δ)

figure 7: Effect of polymer grade and oscillatory

1
frequency on viscoelastic properties of gels containing
Natrosol™ 250 Pharm HEC.

1000

0.1
1
viscous modulus G'' (Pa)

10 100
elastic modulus G' (Pa)

frequency (Hz)
100
natrosol™ 250 M pharm HEC 2% natrosol™ 250 G pharm HEC 2%

natrosol™ 250 HX pharm HEC 2% natrosol™ 250 HHX pharm HEC 2%

10

1
0.1 1 10
frequency (Hz)
100
Natrosol™ 250 Pharm HEC shows
G' natrosol™ 250 HHX pharm HEC 2%
G" natrosol™ 250 HHX pharm HEC 2%
G' natrosol™ 250 M pharm HEC 2%
G" natrosol™ 250 M pharm HEC 2%
a decreasing loss tangent with
increasing frequency, which
G' natrosol™ 250 HX pharm HEC 2% G' natrosol™ 250 G pharm HEC 2%
G" natrosol™ 250 HX pharm HEC 2% G" natrosol™ 250 G pharm HEC 2%

translates to excellent skin feel.

effect of temperature figure 10 presents a convenient nomograph that helps
The viscosities of aqueous solutions of Natrosol 250 ™ in estimating the viscosity of a solution of Natrosol™ 250
Pharm HEC change with temperature, increasing when Pharm HEC at different temperatures starting from a
cooled and decreasing when heated. The effect of known viscosity at a known temperature.
temperature on the viscosity of solutions of Natrosol™ For example, the viscosity of a solution is 100 mPa·s
250 Pharm HX HEC at 1% in aqueous solution is shown (shown on the center line in figure 10) at 25 °C. The
for example in figure 9. The effect on viscosity is the only unknown is the viscosity when the temperature is raised
influence temperature has on solutions of Natrosol™ 250 by 20 °C (shown on the right line in figure 10). By placing
Pharm HEC. In contrast to some other cellulose ethers, a straightedge at 20 °C on the right line and at 100 on
like methylcellulose, hydroxypropylmethylcellulose the center line, one can read the answer in the left
or hydroxypropylcellulose, Natrosol™ 250 Pharm HEC column, 52 mPa·s.
does not exhibit a cloud point (or gelation point), and
figure 10: Nomograph for estimating the viscosity of
solutions of HEC may be boiled without precipitation or
solutions of Natrosol™ 250 Pharm HEC at
gelling issues.
varying temperatures.
figure 9: Effect of temperature on natrosol™ 250 HX HEC.
viscosity at higher temperature, mPa•s

10 10,000
viscosity at lower temperature, mPa•s
complex viscosity η* (Pa•s)

100,000 difference in temperature, °C

1,000

10,000

1
70
100 1,000
60

50
100 40
10
30
10 example
0.1 20
1 10 100 10
frequency (Hz)

1% natrosol™ 250 HX pharm HEC at 10 °C 1% natrosol™ 250 HX pharm HEC at 40 °C

1% natrosol™ 250 HX pharm HEC at 25 °C 1% natrosol™ 250 HX pharm HEC at 55 °C

Natrosol™ 250 Pharm HEC

does not exhibit a cloud point
(gelation point) and viscosity of
solutions change reversibly
with temperature.

14
effect of pH figure 11: Polymer hydration/viscosity development of
The pH of a solution of Natrosol 250 Pharm HEC is
™ 1% Natrosol™ 250 Pharm HHX HEC solution. Hydration
time was taken as the time in minutes to achieve 90%
important for two reasons; first, because of the effect
of the final viscosity, where the final viscosity was
on hydrolytic breakdown, and second, because of
taken as the average of the last 10 minutes’ viscosity
the possible effect of pH on solution viscosity. Aqueous
during a 50 minute trial.
solutions of Natrosol™ 250 Pharm HEC are relatively
stable at pH 2 to 12, with the viscosity of the solutions
1200
being largely unaffected. However, solutions possess
the greatest viscosity stability in the pH range of 1000

6.5 to 8.0. Below pH 3, solutions are less stable and

viscosity (Pa•s)
800
may show some reduction in viscosity owing to acid
hydrolysis. This behavior is common with all water-
600
soluble polysaccharide polymers, and is accelerated by
high temperature and high acidity. At high pH (highly 400

alkaline conditions), some oxidative degradation may

200
occur, accelerated by heat and light, that will lower
the viscosity. 0
0 10 20 30 40 50
figure 11 illustrates polymer hydration and viscosity time (min)
development of aqueous 1% Natrosol™ 250 HHX Pharm 1% HHX; 0.1N HCl, 90% viscosity at 5.0 min 1% HHX; pH 6.8, 90% viscosity at 3.7 min

HEC solutions at different pH values. Polymer hydration 1% HHX; pH 4.0, 90% viscosity at 3.7 min 1% HHX; pH 7.5, 90% viscosity at 3.7 min
1% HHX; DI water [pH 6], 90% viscosity
and viscosity development are not affected by changes at 3.8 min

in pH.

Solutions of Natrosol™ 250

Pharm HEC are stable over
a broad pH range, with the
viscosity of the solutions being
largely unaffected.
mechanical properties of natrosol™ 250 in the weight average molecular weight and polymer
pharm HEC gels concentration. Increasing firmness indicates a stronger
gel due to higher resistance to deformation, and,
Textural properties should be considered in the design
eventually, the gel network would be more rigid with
of topical formulations, e.g., ease of removal from increasing molecular weight and/or concentration.
the tube, ease of application on skin, retention of Work of shear is a measurement of consistency and the
the product at the site of application and the feel inverse of spreadability. Higher values indicate a thicker
of the product after application. One method to consistency. The more negative the value for stickiness,
measure the mechanical and adhesive properties of the more sticky or cohesive is the sample. Topical
pharmaceutical gels containing Natrosol™ 250 Pharm preparations should exhibit mechanical characteristics
HEC is texture profile analysis. Typical results from this such as ease of removal from the product container,
kind of test are presented in table 5. as well as good spreadability on and adhesion to the
skin; however, a compromise must be made between
The grades evaluated in table 5 show a wide range product adhesiveness (stickiness on the skin), firmness
of mechanical and adhesive properties that are (ease of removal from container) and spreadability
significantly (and sequentially) affected by changes (ease of application on the skin).

table 5: Mechanical properties of Natrosol™ 250 Pharm HEC gels as determined using texture profile analysis
(n=3, average ± standard deviation).

weight average
grade molecular weight (da) conc. % (w/v) firmness/hardness (g) work of shear (g·s) stickiness (g)
2 15.53 7.55 −19.6
G 300,000 3.5 68 ± 2 30 ± 5 −91 ± 3
5 261 ± 4 120 ± 7 −349 ± 3
2 168 ± 8.67 86 ± 15.77 −145 ± 8
M 720,000 3.5 638 ± 16 423 ± 18 −523 ± 12
5 1761 ± 23 1374 ± 27 −1437 ± 35
2 258 ± 6 155 ± 18 −199 ± 9
HX 1,000,000 3.5 1049 ± 13 865 ± 7 −775 ± 14
5 2315 ± 113 2101 ± 123 −1676 ± 87
2 433 ± 25 315 ± 23 −323 ± 17
HHX 1,300,000 3.5 1371 ± 94 1132 ± 148 −964 ± 53
5 3168 ± 17 2918 ± 163 −2145 ± 22

Mechanical properties of pharmaceutical gels (such as hardness,

stickiness and spreadability) can be set precisely by varying grade
and concentration of Natrosol™ 250 Pharm HEC.

16
antimicrobial preservatives figure 12: Effect of moist heat sterilization on
rheological properties of solutions of various Natrosol™
250 Pharm HEC grades.
Aqueous solutions of Natrosol™ 250 Pharm HEC are
subject to enzymatic degradation, with consequent 100
loss in solution viscosity. Enzymes that catalyze this
degradation are produced by many bacteria and 10
fungi present in the environment. Therefore, it is

viscosity (Pa•s)
recommended that an antimicrobial preservative is 1

added when aqueous solutions are to be stored.

0.1
Natrosol™ 250 Pharm HEC can be used with a wide
variety of water-soluble antimicrobial preservatives,
0.01
however it may decrease the antimicrobial activity of
various preservatives. Care should be taken in finding
0.001
an effective preservative concentration while ensuring 0.01 0.1 1 10 100 1000
that the concentration remains below an irritating/ shear rate (1/s)
toxic concentration. natrosol™ 250 HHX pharm HEC 1% natrosol™ 250 HHX pharm HEC 1% sterilized
natrosol™ 250 H pharm HEC 1% natrosol™ 250 H pharm HEC 1% sterilized
natrosol™ 250 M pharm HEC 1% natrosol™ 250 M pharm HEC 1% sterilized

heat sterilization and natrosol™ 250 G pharm HEC 1%

natrosol™ 250 L pharm HEC 2%
natrosol™ 250 G pharm HEC 2% sterilized
natrosol™ 250 L pharm HEC 2% sterilized

sterile filtration
As an alternative to adding antimicrobial sterile filtration
preservatives, some consideration might also be given Sterilizing filtration is the process of removing
to sterile filtration or heat sterilization. microorganisms from a fluid stream without adversely
affecting the product by heat or radiation. It is
heat sterilization
an aseptic process, typically using 0.2 µm-rated
Heat sterilization can alter molecular weight of
sterilizing grade filters, that is commonly employed
polymers like Natrosol™ 250 Pharm HEC. Exposure
in the preparation of biopharmaceuticals. Solutions
to high temperature and pressure may lead to
containing viscosity enhancers like Natrosol™ 250 Pharm
breakdown of long polymer chains, often leading to a
HEC can occasionally cause difficulties during sterile
drop in viscosity. The drop in viscosity does not occur
filtration, such as filter blockage. This would result in
to the same extent for all molecular weight grades,
frequent filter changeouts, increased processing time,
and thus, optimization of a formulation is necessary to
and product loss. The data shown in figure 13 illustrate
make sure that any viscosity drop is taken into account
the filterability of solutions of various grades of Natrosol™
in the final formulation. The data shown in figure 12
250 Pharm HEC tested at different concentrations to
illustrate the rheological behavior changes in solutions
achieve a viscosity of 5 mPa·s. A steeper curve shows
made with various Natrosol™ 250 Pharm HEC grades
superior filterability. Filter material for sterile filtration was
at different concentrations after moist heat sterilization
Supor ® EX grade ECV sterilizing grade filter (asymmetric
(autoclave: 121 °C; 20 min).
polyethersulfone [PES] / symmetric PES; Pall Life
Based on these data, a substantial decrease in Sciences, Basel, CH) with 47 mm diameter.
viscosity can be observed after sterilization. Therefore,
the grade of Natrosol™ 250 Pharm HEC should be
carefully selected when moist heat sterilization will be
applied to the product.
 figure 13: Filterability of various grades of Natrosol™ 250
Pharm HEC at an adjusted viscosity of 5 mPa•s.

350
Natrosol™ 250 Pharm HEC
grades can be either
throughput (g) (47 mm disc)

300

250
sterilized or sterile filtered,
200
depending on the other
150

100
formulation ingredients.
50

0
0 5 10 15 20 25 30
time (min)
natrosol™ 250 L pharm HEC 0.87%
natrosol™ 250 G pharm HEC 0.275%
natrosol™ 250 H pharm HEC 0.078%
natrosol™ 250 HHX pharm HEC 0.072%
synergistic effect
with sodium
natrosol™ 250 M pharm HEC 0.1%

By applying a short period of high shear forces to the

system, the filterability of all Natrosol™ 250 Pharm HEC
carboxymethylcellulose
grades can be significantly improved. This period of
Natrosol™ 250 Pharm HEC does not exhibit thixotropic
high shear mixing does not significantly impact the
behavior, per se. Therefore, it is seldom used for
viscosity and/or molecular weight of the solutions.
pharmaceutical suspensions alone. However,
By using this method of preparation, all Natrosol™
when a solution of non-ionic Natrosol™ 250 Pharm
250 Pharm HEC grades become viable options for
HEC is blended with a solution of anionic sodium
preparation of products via sterile filtration.
carboxymethylcellulose (Blanose™ or Aqualon™ CMC),
a synergistic effect on viscosity is typically observed.
figure 14: Filterability of various grades of Natrosol™ 250
CMC has been widely used in pharmaceutical
Pharm HEC at an adjusted viscosity of 5 mPa∙s using an
suspensions and shows varying degrees of thixotropy.
additional 2 min of 20000 RPM rotor stator stirring.
Such a polymer mixture produces solution viscosities
considerably higher than would ordinarily be expected
350
given the solution viscosities of both polymers alone,
throughput (g) (47mm disc)

300 and furthermore, this combination makes it possible

250 to incorporate thixotropic behavior into formulations
containing HEC as a suspending agent, which would
200
not otherwise be entirely suitable for pharmaceutical
150 suspensions. table 6 shows combinations of both
polymers, the resulting viscosities at a shear rate of 10s-1
100
of the mixtures, and the resulting viscosities of the pure
50 polymer grades at 1% use level, indicating the viscosity
0 without the synergistic effect.
0 5 10 15 20 25 30
time (min)
natrosol™ 250 L pharm HEC 0.87% + UT natrosol™ 250 H pharm HEC 0.078% + UT
natrosol™ 250 G pharm HEC 0.275% + UT natrosol™ 250 HHX pharm HEC 0.072% + UT
natrosol™250 M pharm HEC 0.1% + UT

18
table 6: Synergistic effect on viscosity of Natrosol™ 250
Pharm HEC with Blanose™ CMC.
tolerance for inorganic salts
viscosity at Because of its solubility and nonionic character,
polymers used concentration 10 s−1 (mPa·s)
Natrosol™ 250 Pharm HEC has good tolerance for
natrosol™ 250H HEC 1% 1780 dissolved electrolytes, although it may precipitate when
blanose 7H3SF CMC
™
1% 1490 mixed with high-salinity solutions. Data in table 7 show
natrosol 250H HEC +
™ that Natrosol™ 250 Pharm HEC is soluble in most 10% salt
0.5% each 2370
blanose™ 7H3SF CMC solutions, excluding disodium phosphate and sodium
natrosol 250M HEC
™
1% 850 sulfate, and some of the 50% (saturated) salt solutions.
blanose 7H3SF CMC
™
1% 1490
In obtaining these data, 1 ml of a solution of Natrosol™
250 Pharm HEC was added to 15 g of each of the salt
natrosol 250M HEC +
™
0.5% each 1850 solutions. The ratio of Natrosol™ 250 Pharm HEC to salt
blanose™ 7H3SF CMC

natrosol™ 250M HEC 1% 850 solids ranged from 1:150 to 1:750.

blanose 7H4XF CMC

™
1% 2740
table 7: compatibility of solutions of natrosol™ 250
natrosol 250M HEC +
™

blanose™ 7H4XF CMC 0.5% each 2530 50% salt

salt 10% salt Solution (saturated)
natrosol™ 250M HEC 1% 850
sodium tetraborate C C
blanose 7HF CMC
™
1% 1750 calcium chloride C C
natrosol 250M HEC +
™
0.5% each 1870 calcium sulfate C C
blanose™ 7HF CMC

natrosol™ 250M HEC 1% 850 disodium phosphate P P

blanose™ 7M31F CMC 1% 220 ferric sulfate C C

natrosol 250M HEC +

™
magnesium chloride C C
0.5% each 720
blanose™ 7M31F CMC
magnesium sulfate C P

sodium acetate C C

sodium chloride C C

The combination of Natrosol ™

sodium sulfate P P

250 Pharm HEC and Blanose™ trisodium phosphate C P

CMC provides a synergistic zinc sulfate C P

(C – compatible, P – precipitates)
effect on viscosity and
incorporates thixotropic
behavior into the formulation.
compatibility with
other materials Natrosol™ 250 Pharm HEC is
The nonionic nature of Natrosol™ 250 Pharm HEC makes
compatible in solutions with
it compatible with a broad range of water-soluble
materials, including other water-soluble polymers and many inorganic salts, as well
natural gums.
as with a broad range of other
Table 8 lists the viscosity and appearance of solutions of
Natrosol™ 250 Pharm HEC and some common additives materials such as surfactants,
in pharmaceutical formulations. The data were
obtained by adding a medium viscosity Natrosol™ 250 M solubilizers, and preservatives.
Pharm HEC grade to the respective additive (solution),
with moderate stirring to ensure that the Natrosol™ 250
Pharm HEC was completely dissolved.

table 8: Effect of formulation additives on properties of solutions of Natrosol™ 250 M Pharm HEC and water.
viscosity after appearance after
material additive % HEC % 48 hours (mPa·s) 48 hours
polymers
klucel™ HF HPC 1 1 22000 hazy
klucel HF HPC 0.5 1 13000 hazy
guar gum 0.5 1 7900 opaque
xanthan gum 0.5 1 6700 opaque
surfactants
sodium lauryl sulfate 1 1 580 clear
tween 60 1 1 1850 slightly hazy
tween 80 1 1 2500 clear
cetyl 1 1 1520 clear
trimethylammonium
bromide

triethanolamine 1 1 2950 clear

preservatives
sodium benzoate 0.5 1 2500 clear
methyl paraben 0.2 1 2100 clear

20
application examples for
natrosol™ 250 pharm HEC

natrosol™ 250 pharm HEC figure 15: Effect of shear on viscosity for various Natrosol™
250 Pharm HEC grades in relation to commercial syrups
as a viscosity modifier in (gray area).

pharmaceutical oral liquids 1000

storage in container pouring mixing and stirring

Oral solutions are liquid preparations in which the 100

swallowing

active pharmaceutical ingredient (API) and other

viscosity (Pa•s)
excipients are dissolved in a suitable solvent system, 10

consisting mainly of water. Because the API is

1
dissolved in the formulation, it is usually immediately
available for absorption. Oral solutions containing high 0.1
concentrations of sucrose or other sugars traditionally
0.01
have been defined as syrups. There is an increasing
trend to replace sucrose in whole or in part with
0.001
other substances because of its glycogenic and 0.01 0.1 1 10 100 1000

cariogenic properties. Cellulose ethers (e.g., Natrosol™ shear rate (1/s)

hydroxyethylcellulose) are non-glycogenic, because natrosol™ 250 HHX Pharm HEC 1% natrosol™ 250 G Pharm HEC 1%
natrosol™ 250 H Pharm HEC 1% natrosol™ 250 L Pharm HEC 2%
they are not hydrolyzed and absorbed into the blood natrosol™ 250 M Pharm HEC 1%

stream. Subsequently, when dissolved, they form a

syrup-like vehicle for medications intended for use
by diabetic patients and others whose diet must be
restricted to non-glycogenic substances. The viscosity
resulting from the use of these cellulose derivatives is Tested grades of Natrosol™
much like that of a sucrose syrup. The addition of one or
more artificial sweeteners usually produces an excellent 250 Pharm HEC are suitable to
imitation of a traditional syrup.
match typical viscosity profiles
The shaded portion of figure 15 represents the viscosity
ranges of 23 tested commercial syrup products. The of pharmaceutical syrups.
shear stress profiles indicate that different grades of
Natrosol™ 250 Pharm HEC with varying concentrations
are positioned across the entire range of rheological
profiles of analyzed, marketed syrup formulations.
The following case studies exemplify the use of the The rheological profiles shown in figure 17 indicate
different grades of Natrosol™ 250 Pharm HEC for that Natrosol™ 250 Pharm HEC helps the formulation
development of sugarless syrup formulations. achieve the desired rheological profile, which can’t be
achieved without the use of a viscosity modifier. The
case study: formulation without a viscosity modifier does not show
sugar-free ambroxol syrup the necessary behavior for most of the operations
Ambroxol stimulates mucus secretion and promotes exhibiting varying degrees of shear on the formulation.
a normalization of mucus viscosity for treatment of Its viscosity is comparable low at higher shear rates,
respiratory diseases. Formulation details are described in almost water like, making pouring the syrup onto
table 9. As seen in figure 16, all formulations are clear. a spoon challenging. The desired viscosity can be
adjusted by choosing the appropriate grade and
table 9: Formulation of ambroxol syrups using various concentration of Natrosol™ HEC.
Natrosol™ 250 Pharm HEC grades.
figure 17: Effect of shear on viscosity for various
ingredient content (%) functional use Natrosol™ 250 Pharm HEC grades used for an ambroxol
ambroxol HCl 0.6 active syrup at different concentrations.
pharmaceutical
ingredient
1000
benzoic acid 0.2 preservative storage in container pouring mixing and stirring
swallowing
propylene glycol 10 solvent 100

sorbitol 70% 5 sweetener

viscosity (Pa•s)

10

sucralose 0.5 sweetener

1
apricot flavor 0.1 flavor
0.1
natrosol™ 250 HEC 0.0–2.0 viscosity modifier
0.01
water, demineralized q.s. to 100 aqueous vehicle

0.001
0.01 0.1 1 10 100 1000
shear rate (s-1)
figure 16: Photographs of ambroxol formulations
HEC AXL #1 natrosol™ 250 M HEC 1% HEC AXL #5 natrosol™ 250 H HEC 0.5%
using varying amounts of different Natrosol™ 250 HEC AXL #4 natrosol™ 250 M HEC 0.75% HEC AXL #3 natrosol™ 250 L HEC 2%

Pharm HEC grades. HEC AXL #2 natrosol™ 250 G HEC 1% control: no HEC

22
case study: The same basic conclusions as those obtained for the
taste-masked loratadine syrup sugar-free ambroxol syrup can be drawn here. The
inconsistent shape of the curve without viscosifier,
Loratadine is used to alleviate allergy symptoms.
seen in figure 19, stems from the use of 2-hydroxypropyl
Formulation details are described in table 10. As can be
β-cyclodextrin in the formulation. This inconsistent
seen in figure 18, all formulations are clear.
rheological profile is controlled once a viscosifier is
table 10: Formulation of loratadine syrups using various introduced to the formulation. The desired viscosity
Natrosol™ 250 Pharm HEC grades. can be adjusted by choosing the right grade
and concentration.
ingredient content (%) functional Use
loratadine 0.1 active figure 19: Effect of shear on viscosity for various
pharmaceutical
ingredient Natrosol™ 250 Pharm HEC grades used for a loratadine
ethanol 96% 2.5 solvent for api syrup at different concentrations.
in preparation
(later mostly
evaporated)
1000
citric acid 0.05 solubilizer for api storage in container pouring mixing and stirring
swallowing
100
CAVASOL* W7 HP pharma 2.4 solubilizer and
2HP-β-Cyclodextrin taste masking
viscosity (Pa•s)

10
sorbic acid 0.1 preservative

natrosol™ 250 pharm HEC 0.0–2.0 viscosity modifier 1

water, demineralized q.s. to 100 aqueous vehicle 0.1

0.01

figure 18: Photographs of loratadine formulations 0.001

0.01 0.1 1 10 100 1000
using varying amounts of different Natrosol™ 250 shear rate (s-1)
Pharm HEC grades.
HEC LOR #1 natrosol™ 250 G HEC 2.5% HEC LOR #5 natrosol™ 250 H HEC 0.5%
control: no HEC HEC LOR #2 natrosol™ 250 G HEC 1%
HEC LOR #4 natrosol™ 250 M HEC 0.75% HEC LOR #3 natrosol™ 250 L HEC 2%
case study: The rheological profiles obtained (see figure 21)
syrup for poorly soluble paracetamol indicate that Natrosol™ 250 Pharm HEC effectively
enables the desired rheological behavior to be
Paracetamol is widely used as an analgesic
achieved. While the formulation without a viscosity
and antipyretic drug. It is well absorbed in the
modifier produces a rheological profile within the
gastrointestinal tract, showing a dose-dependent oral
range of investigated commercial syrup formulations, it
bioavailability. Formulation details are described in
does show a drop in viscosity at shear rates equivalent
table 11. As can be seen in figure 20, all formulations
to pouring the formulation out of its bottle, which is
are clear.
undesirable in a syrup formulation. This effect is not
table 11: Formulation of paracetamol syrups using observed for the formulations containing Natrosol™ 250
various Natrosol™ 250 Pharm HEC grades Pharm HEC, and the desired viscosity can be adjusted
by choosing the right grade and concentration.
ingredient content (%) functional use
paracetamol 5 active figure 21: Effect of shear on viscosity for various
pharmaceutical
ingredient Natrosol™ 250 Pharm HEC grades used for a
sodium benzoate 0.1 preservative paracetamol syrup at different concentrations.

propylene glycol 45 solvent

1000
sorbitol 70% 5 sweetener storage in container pouring mixing and stirring
swallowing
sucralose 0.5 sweetener 100

apricot flavor 0.1 flavor

viscosity (Pa•s)

10

natrosol 250 pharm HEC

™
0.0–2.0 viscosity modifier
1

water, demineralized q.s. to 100 aqueous vehicle

0.1

0.01

figure 20: Photographs of paracetamol formulations 0.001

0.01 0.1 1
using varying amounts of different Natrosol™ 250 Pharm 10 100 1000

HEC grades. shear rate (1/s)

HEC PAR #1 natrosol™ 250 M HEC 1% HEC PAR #3 natrosol™ 250 L HEC 2%
HEC PAR #5 natrosol™ 250 H HEC 0.5% control: no HEC
HEC PAR #2 natrosol™ 250 G HEC 1% HEC PAR #4 natrosol™ 250 G HEC 0.75%

24
natrosol™ 250 pharm HEC figure 22: The effects of polymer grade, concentration,
and oscillatory frequency on the dynamic viscosity
as rheology modifier and of Natrosol™ 250 Pharm HEC hydrogels in relation to
commercial topical gels (gray area).
structured vehicle promoter
10000

for semi-solid formulations

complex viscosity η* (Pa•s)

1000
Gel-forming hydrophilic polymers are typically used to
prepare lipid-free semisolid dosage forms, including 100
dental, topical, nasal, ophthalmic, rectal and vaginal
gels. In the development of topical dosage forms, 10

several desirable attributes contribute to patient

acceptability and clinical efficacy. These attributes 1

include mechanical and rheological properties (e.g.,

viscosity, ease of removal of product from the container, 0.1
0.1 1 10 100
good spreadability on the skin, good adhesion to
frequency (Hz)
ensure retention), as well as the influence of the gel
natrosol™ 250 HHX pharm HEC 5% natrosol™ 250 HX pharm HEC 2%
former on drug release and drug absorption. natrosol™ 250 HX pharm HEC 5% natrosol™ 250 M pharm HEC 2%
natrosol™ 250 M pharm HEC 5% natrosol™ 250 G pharm HEC 5%
Products designed for topical administration will be natrosol™ 250 HHX pharm HEC 2% natrosol™ 250 G pharm HEC 2%

subjected to various shearing forces that occur on

removal of the product from its container, application
to the skin, and during flexing of the skin. figure 22
shows the complex viscosities of gels made from various
grades of Natrosol™ 250 Pharm HEC, measured using
oscillating rheometry. The shaded portion of figure
Higher molecular weight
22 represents the viscosity range of several tested, grades of Natrosol™ 250
commercial gel products. The rheological profiles
indicate that different grades and concentrations Pharm HEC (G, M, HX, and
of Natrosol™ 250 Pharm HEC cover a wide range
of rheological behaviors and viscosities to match HHX grades) are the preferred
marketed gel formulations.
pharmaceutical gel formers.
case study: figure 23: Viscosity (a) and tan δ (b) of
diclofenac gel diclofenac formulations.

Natrosol™ 250 Pharm HEC is a non-ionic polymer and,

1000 a
thus, more resistant to electrolytes and salts present in
topical formulations compared with ionic viscosifiers.

complex viscosity η* (Pa•s)

In this case study, the highest viscosity grade, Natrosol™ 100

250 HHX Pharm HEC was used. However, similar results

can be achieved by using other grades and
10
concentrations of Natrosol™ 250 Pharm HEC. table 12
illustrates the composition of a typical formulation.
1

table 12: Formulation composition of diclofenac gel.

ingredient content (%) functional use 0.1

0.1 1 10 100
diclofenac potassium 1 active
frequency (Hz)
co-solvent/
propylene glycol 30 natrosol™ 250 HX pharm HEC 2% diclofenac gel, marketed product
Solubilizer natrosol™ 250 HHX pharm HEC 1.5% natrosol™ 250 HX pharm HEC 1%

natrosol™ 250 HHX pharm HEC 1, 1.5 or 2 gelling agent

aqueous
water q.s. 100 vehicle 10 b

Formulations containing varying concentrations of

loss tangent (tan δ)

Natrosol™ 250 HHX Pharm (1, 1.5, and 2%, respectively)

were compared with a commercially available
diclofenac gel formulation. All gels were characterized 1

in terms of their rheological, mechanical and textural

properties. This information can be used to select
a suitable candidate formulation and to predict
the effects of physiological stresses on product
0.1
performance. The rheological behavior of the gels is 0.1 1 10 100
strictly related to polymer concentration. The elasticity frequency (Hz)
of the gels increased with increasing concentration from natrosol™ 250 HX pharm HEC 1% diclofenac gel, marketed product

1% to 2%, as illustrated by the decreasing values of tan δ. natrosol™ 250 HHX pharm HEC 1.5% natrosol™ 250 HX pharm HEC 2%

Viscosity decreased with increasing frequency, showing

a shear thinning behavior. Results from the rheological
profiling also reveal that the viscoelastic properties of a
formulation containing 1.5% Natrosol™ 250 HHX Pharm
HEC were very close to the viscoelastic properties of the
marketed product (figure 23).

26
As described in table 13, the concentration of case study:
Natrosol™ 250 Pharm HEC also has a significant effect on aluminum hydroxide oral gel
the mechanical properties of the gels. With increasing
Aluminum hydroxide (Al[OH]3) is an antacid commonly
concentrations of Natrosol™ 250 Pharm HEC, the gels
used to relieve symptoms of heartburn, stomach upset,
showed a greater resistance to deformation, as the
acid indigestion and sour stomach. Because liquid
values for hardness increased. Furthermore, a higher
antacids tend to work faster than tablets or capsules,
concentration of Natrosol™ 250 Pharm HEC results in
Natrosol™ 250 Pharm HEC was used to suspend and
a thicker consistency, as shown by an increase in the
stabilize aluminum hydroxide in an oral gel formulation.
work of shear. Finally, the stickiness of the gels is also
A marketed product containing aluminum hydroxide
directly related to the concentration, more ‘sticky’ or
in a gel formulation served as a benchmark. table
‘cohesive’ gels were obtained at higher concentrations
14 illustrates the composition of such an oral gel. The
of Natrosol™.
equivalent amount of aluminum hydroxide per single
dose is 320 mg per 5 ml.
table 13: Mechanical properties of gels containing
diclofenac as determined using texture profile analysis
table 14: Formulation of aluminum hydroxide oral gel.
(n=3, average ± standard deviation).
firmness/ work of stickiness ingredient content (%) functional use
formulation hardness (g) shear (g·s) (g)
aluminum hydroxide 9.14 active
diclofenac gel, (70% assay)
203 ± 3 152 ± 8 −142 ± 2
commercial reference
glycerin 4 humectant
formulation 1 containing 107 ± 17 81 ± 1 −84 ± 1
1% natrosol™ 250 HHX
sorbitol 7 sweetening agent
formulation 2 containing 286 ± 6 239 ± 67 −208 ± 69
1.5% natrosol™ 250 HHX polysorbate 80 1 surfactant
formulation 3 containing 487 ± 4 444 ± 21 −346 ± 1 anti-foaming
2% natrosol™ 250 HHX simethicone 0.1 agent

natrosol™ 250 M pharm HEC 0.5/0.75 viscosity modifier

water q.s. to 100 aqueous vehicle

The oral gel antacid suspensions were evaluated for figure 25 illustrates the uniform dispersion of aluminum
composition and product quality. Natrosol™ 250 M hydroxide both in the marketed and the HEC-containing
Pharm HEC served as viscosity modifier to reduce formulation. There is a balance between particle size
settling of the suspended particles and to match the distribution, viscosity of the continuous phase and
rheological properties of the marketed product. The density differences between the dispersed phase
data in figure 24 illustrate how slight changes in the and that of the continuous phase. High shear mixing
content of Natrosol™ 250 M Pharm HEC result in different was used to achieve a better disaggregation of the
rheological profiles. Although it is possible to prevent Al(OH)3 particles, while the addition of Natrosol™ HEC,
settling of the particles simply by increasing the viscosity, polysorbate 80 and sorbitol helped in stabilizing the
there is a further important requirement that the suspension.
suspension should be sufficiently pourable for dosing,
e.g., out of the bottle into a measuring cup or spoon. figure 25: Photographs of aluminum hydroxide
Nevertheless, the use of Natrosol™ 250 M Pharm HEC to suspensions. (a) Marketed formulation; (b)
increase viscosity is an important part of formulation Formulation containing Natrosol™ 250 M Pharm HEC
as a viscosity modifier.
development, and allows for adjusting the rheological
properties of the formulation to prepare either a more
gel-like or a more liquid-like formulation. a b

figure 24: Viscosity of aluminum hydroxide formulations

10
complex Viscosity η* (Pa•s)

0.1

0.01
0.1 1 10 100
frequency (Hz)
inhouse natrosol™ 250 M HEC 0.75 % marketed product
inhouse natrosol™ 250 M HEC 0.5 %

28
ophthalmic solutions using figure 26: Aqueous solutions of low molecular weight
grades of Natrosol™ 250 Pharm HEC adjusted in their
natrosol™ 250 pharm HEC1 Brookfield viscosity to reflect the upper viscosity limit
of 25 mPa·s.
Many marketed ophthalmic solutions are formulated
with viscosifiers. Drug action from an ophthalmic
10
solution may be prolonged by increased corneal
retention or reduced drainage from the eye, when
1
viscosity is increased. The corneal contact time of

viscosity (Pa•s)
topical ophthalmic solutions typically increases with
0.1
viscosity of the formulations, up to 25 mPa·s. Further
increases result in reflex tearing and blinking to regain 0.01
the original viscosity of lacrimal fluid (1.07 – 5.97
mPa·s), setting 25 mPa·s as the upper viscosity limit for 0.001
eyedrop formulations.

The data shown in figure 26 suggest that lower 0.0001

0.01 0.1 1 10 100
molecular weight grades are the preferred choice shear rate (1/s)
when considering Natrosol™ 250 Pharm HEC in the
natrosol™ 250 G pharm HEC 0.5% natrosol™ 250 L pharm HEC 0.5%
development of ophthalmic solutions. The grey area
natrosol 250 M pharm HEC 0.2%
™

marks the typical formulation range of eyedrop

formulations. Depending on their concentration, low
molecular weight grades of Natrosol™ 250 Pharm HEC
exhibit different rheological behaviors, however, all
tested grades may be used in viscous
eyedrop formulations. Lower molecular weight
grades of Natrosol™ 250 HEC
(M, L, and G grades) are
recommended as viscosifiers
for ophthalmic solutions.1

1
Note that Natrosol™ 250 HEC pharmaceutical grades are excipient quality and manufactured
under excipient GMPs (USP <1078>; EXCiPACT). Ashland products are not sterile as supplied; further
sterilization is necessary.
Based on these results, it is possible to formulate eye the different formulations exhibit different viscosities,
drops with different viscosities for longer corneal coupled with other parameters that are close to those
contact times. table provides model formulations for of human tears, such as osmolality, pH, and
artificial tear solution. Based on the parameters tested, surface tension.

table 15: Eyedrop formulation for dry eye syndrome.

ingredient formulation 1 (% content) formulation 2 (% content) functional use

natrosol™ 250 L pharm HEC 0.5 1 viscosity modifier

benzalkonium chloride 0.005 0.005 preservative

aqualon™ 7L2P CMC 0.5 1 viscosity modifier

glycerin 0.2 0.2 lubricant

EDTA 0.03 0.03 chelating agent

boric acid 3 3 buffer/antibacterial agent

sodium borate 0.04 0.04 buffer

potassium chloride 0.35 0.35 tonicity adjuster

sodium chloride 0.4 0.4 tonicity adjuster

purified water q.s. 100% q.s. 100% aqueous vehicle

parameter

pH 7.26 7.28

osmolality (mOsmol/kg) 300 322

viscosity (mPa·s) 4.83 15.8

surface tension (mN/m) 38.25 38.92

30
packaging and storage
Natrosol™ 250 Pharm HEC is packaged in foil-lined, Natrosol™ 250 Pharm HEC is a non-perishable powder.
multiwall 25 kg bags, stretch-wrapped, capped, and It is recommended to use the product in rotation on a
palletized for handling convenience. It is supplied from first in, first out basis. The product should be stored under
the Ashland production facilities in Zwijndrecht, ambient conditions. The product is hygroscopic and
the Netherlands. water content of the packed product will/may increase
if not stored in tightly sealed bags under dry conditions.

product safety and

handling precautions
Please review our latest Safety Data Sheet (SDS) and dust generation should be avoided to minimize the
ensure that the use you intend can be accomplished risks of explosion. Hydroxyethylcellulose is combustible.
safely before using this product. Before handling any
other products mentioned in the text, you should CAS number and name
obtain available product safety information and take CAS number: 9004-62-0
necessary steps to ensure safety of use.
CAS name: cellulose, 2-hydroxyethyl ether
Hydroxyethylcellulose dust may be an irritant to the
eyes, and eye protection is recommended. Excessive

toxicological studies
Natrosol™ 250 Pharm HEC has found use in many on Natrosol™ 250 Pharm HEC in independent
pharmaceuticals and cosmetic preparations, however, laboratories. These are available by request only
Natrosol™ 250 Pharm HEC is not recommended for use in and can be shared after signing a confidentiality
preparations for parenteral injections. Animal toxicology agreement with Ashland.
and human dermatology studies have been conducted
regional centers The information contained in this brochure and
the various products described are intended for
North America — use only by persons having technical skill and
Covington, KY USA at their own discretion and risk after they have
Tel: +1 859 815 3333 performed necessary technical investigations,
tests and evaluations of the products and their
uses. Certain end uses of these products may
Europe — Switzerland be regulated pursuant to rules or regulations
Tel: +41 52 560 55 00 governing medical devices, drug uses, or
pesticidal or antimicrobial uses. It is the end
user’s responsibility to determine the applicability
India — Maharashtra of such regulations to its products.
Tel: +91 22 6148 4646
All statements, information, and data presented
herein are believed to be accurate and reliable,
Asia Pacific — Singapore but are not to be taken as a guarantee of fitness
Tel: +65 6775 5366 for a particular purpose, or representation,
express or implied, for which seller assumes
legal responsibility. No freedom to use any
Middle East, Africa — patent owned by Ashland, its subsidiaries, or its
Istanbul, Turkey suppliers is to be inferred.
Tel: +00 90 216 538 08 00

pharmaceutical@ashland.com

® Registered trademark, Ashland or its subsidiaries,

registered in various countries

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in various countries
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