Pharma & Food Solutions

ETHOCEL Ethylcellulose
A Technical Review

ETHOCEL Ethylcellulose - Technical Bulletin | 10-2013

A Portfolio of Versatile Solutions

to Help Address a Variety of Formulation and Processing Needs
ETHOCEL Premium Polymers are essentially tasteless, colorless, odorless, non-caloric
and very inert physiologically. Dow Pharma &Food Solutions, a business unit of The Dow
Chemical Company, offers nine different ETHOCEL Polymers for pharmaceutical
applications. These include a variety of molecular weights, which translate into a range of
viscosities.

Comparison of ETHOCELTM Grades

ETHOCEL
Standard Grade

4
Premium

7
7 FP
10
10 FP
20
Premium Premium Premium Premium Premium

45
100
premium Premium

100 FP
Premium

Viscosity (mPa.s)

3 - 5.5

6-8

6-8

9 - 11

9 - 11

6-8

6-8

90 - 110

90 - 110

Ethoxyl Content
(% wt)

48 - 49.5

48 - 49.5

48 - 49.5

48 - 49.5

48 - 49.5

4 - 49.5

48 - 49.5 48 - 49.5

48 - 49.5

Loss on Drying
(% wt)

2 Max

2 Max

2 Max

2 Max

2 Max

2 Max

2 Max

2 Max

2 Max

Particle Size
(microns)

N/A

N/A

140 Max,
5 - 15
Mean

N/A

100 Max,
3 - 15
Mean

N/A

N/A

N/A

150 Max,
30 - 60
Mean

Ethanol, Acetone, Isopropanol, Methanol, and Combinations of All

Solvent Solubility
(These are typical properties, not to be construed as specifications.)
By selecting among these variables, it is possible for ETHOCELTM to be used in a variety
of pharmaceutical functions including: barrier coatings for modified / controlled release,
granulation and direct compression aides, and extrudate for hot melt extrusion processes.

pg 2

ETHOCEL Ethylcellulose - Technical Bulletin | 10-2013

Barrier Coating for Modified/Controlled Release

This investigation explored different dissolution rates of

multiparticulate beads which have been coated with ETHOCELTM
to form barrier membranes. Variables that significantly impact
properties of coatings made with ETHOCELTM include the
molecular weight, solvent system, additives, and the amount of
ETHOCELTM applied.
In all experiments, barrier coatings were applied to non-pareils
(30 35 mesh) which had been coated with Diphenhydramine
HCl using a mini-fluid bed coater. Tri-ethyl citrate (TEC) and dibutyl
sebacate (DBS) were the plasticizers used while hydroxypropyl
methyl cellulose (HPMC) was used as the pore-former. ETHOCELTM
Std. 4, 7, 10, 20, 45, and 100 Premium were used to determine
the influence of molecular weight on drug release rate. Lastly, a
comparison of 7% weight gain vs. 13% weight gain was used to
determine the influence of film thickness.
In Figure 1, ETHOCEL Std. 10 Premium was combined with
either 1 or 3% TEC or DBS to measure the effect of plasticizer
choice or combined with 1% HPMC to measure how water soluble
pore-former additives influence drug release rates. As illustrated
by Figure 1, all dissolution profiles were similar for plasticizer
choice or pore-former additive. Pore-formers are commonly used
in barrier coatings of multiparticulates since pure films made
with ETHOCELTM demonstrate drug dissolution rates too slow for
pharmaceutical needs. In this experiment only a 1% addition of
HPMC was used, a larger percentage of the total formulation could
significantly increase drug dissolution rate.

Figure 1: Influence of Plasticizer Choice or Pore-Former (1)

Diphenhydramine HCl dissolved , %

ETHOCELTM Polymers have a long history in film and bead coating

for controlled release applications. ETHOCELTM forms a strong film
with good adhesion. These polymers can offer a versatile diffusion
barrier whose properties can be modified by film thickness (weight
gain), level of water soluble pore-forming additives (such as
METHOCELTM), plasticizer choice, solvent(s) used, or the viscosity
(molecular weight) of ETHOCELTM.

100
90
80
70
60
50
40
30
20
10
0
0

200

400

600

800

1000

1200

Timen, min.
3% Dibutyl sebacate

1% Dibutyl sebacate

1% Tri-ethyl citrate

3% Tri-ethyl citrate

1% Hydroxypropyl methyl
cellulose

Dissolution results are for Diphenhydramine HCl coated on nonpareil seeds followed by 13% weight gain coating of ETHOCELTM
Std. 10 Premium with either TEC, DBS, or HPMC.

(1)
The properties shown are typical but not to be construed as specifications,
data is based on results from internal studies

pg 3

ETHOCEL Ethylcellulose - Technical Bulletin | 10-2013

Figure 3 demonstrates ETHOCEL Std. 10 Premium at 13%

weight gain has a slower drug release rate than ETHOCELTM Std.
10 Premium at 7% weight gain. For slowing drug release rate,
it is generally more efficient to increase weight gain of ETHOCEL
than to increase viscosity grade use in a coating solution.
TM

Barrier coatings made with ETHOCEL from organic solutions

are also stable over time. Stability is a critical component to the
pharmaceutical industry since final product performance must
remain consistent even at longer shelf storage times. Figure 4
shows 0, 1, 3, and 6 month stability profiles of non-pareils with
Diphenhydramine HCL coated with ETHOCEL Std. 10 Premium
and DBS. Samples were either left in ambient conditions or placed
in accelerated storage conditions (40C & 75% relative humidity).
In both accelerated and ambient conditions, the performance of
barrier membranes made with ETHOCEL remained stable.

100
90
80
70
60
50
40
30
20

100
90
80
70
60
50
40
30
20
10
0
0

200

400

600

800

1000

1200

Timen, min.
ETHOCELTM Std. 4 Prem

ETHOCELTM Std. 10 Prem

Std. 7 Prem

ETHOCELTM Std. 20 Prem

Std. 45 Prem

ETHOCELTM Std. 100 Prem

ETHOCEL

TM

ETHOCEL

TM

Dissolution results are for Diphenhydramine HCl coated on

non-pareil seeds followed by 13% weight gain coating of
ETHOCELTM Std 4, 7, 10, 20, 45, or 100 Premium with DBS.

Figure 4: Influence of Storage Conditions (1)

Diphenhydramine HCl dissolved, %

Diphenhydramine HCl dissolved, %

Figure 3: Influence of Film Thickness on Dissolution Rates (1)

Figure 2: Influence of Molecular Weight on Dissolution Rates (1)

Diphenhydramine HCl dissolved, %

In Figure 2, ETHOCELTM Std. 4, 7, 10, 45, and 100 Premium were

used to coat the Diphenhydramine HCl coated non-pareils to a
13% weight gain. Dissolution rates decreased as a function of
increasing viscosity grade. Viscosity grades are determined by the
molecular weight of the ethylcellulose polymer chain.
A higher molecular weight film is going to form a greater number of
entanglements resulting in a film with fewer defects and reduced
free volume causing drug transport to decrease through the
polymer layer. Another way to decrease drug release rates is by
increasing film thickness (weight gain).

100
90
80
70
60
50
40
30
20
10

10

200

400

600

20

40

60

800

80 100 120 140 160 180 200

Timen, min.

Timen, min.
7% weight gain

Zero

1 month amb

3 months amb

1 month acc

3 months acc

6 months acc

6 months amb

13% weight gain

Dissolution results are for Diphenhydramine HCl coated on

non-pareil seeds followed by either 7% or 13% weight gain
coating of ETHOCELTM Std. 10 Premium with DBS.
The properties shown are typical but not to be construed as specifications,
data is based on results from internal studies

(1)

pg 4

Dissolution results are for Diphenhydramine HCl coated on

non-pareil seeds followed by 7% weight gain coating of
ETHOCELTM Std 10 Premium with DBS. Samples were taken at 0, 1,
3, and 6 months at ambient (amb) and accelerated (acc) conditions.

ETHOCEL Ethylcellulose - Technical Bulletin | 10-2013

The following conclusions were drawn:

Plasticizer selection between TEC and DBS at these levels did not make a
big difference; however, the use of plasticizer is critical to apply a flexible,
relaxed barrier coating to give consistent performance results
Increasing the viscosity grade (molecular weight) of ETHOCEL used at
the same weight gain will give decreased drug release rate
ETHOCEL barrier coatings from organic solutions will give stable
performance results in accelerated and ambient storage conditions

pg 5

ETHOCEL Ethylcellulose - Technical Bulletin | 10-2013

Direct Compression
For Matrix Tablets
This investigation involved the use of ETHOCELTM in a dry system
by directly compressing unmilled and milled ETHOCEL TM Polymer
into tablets. These tablets form a matrix from which the drug
can be released over time. Typically using ETHOCELTM involves
hydrating the ethylcellulose polymer in an organic solvent and
applying the solution to a substrate. However, this investigation
is a completely different method of controlled drug release using
ethylcellulose polymers because it does not use the polymer in the
hydrated state.
Drug dissolution and tablet physical testing were completed
on milled and unmilled ETHOCELTM Std 7 Premium samples.
ETHOCELTM Std. 7 Prem. (unmilled 313 m), ETHOCELTM Std. 7
Prem. (milled - 12.8 m), and ETHOCELTM Std. 7 Prem. (milled 4.8 m) will be used as sample identifier, where 313, 12.8 and 4.8
m refer to the median particle size.
The tablet formulation used throughout the study was limited to
the following ETHOCELTM and drug ratio (Diphenhydramine HCL):
25% ETHOCELTM: 75% drug, 50% ETHOCELTM: 50% drug, and
75% ETHOCELTM : 25% drug. 300 mg tablets were formed using
a Carver (model C) laboratory press equipped with 13/32 in flatfaced-bevel-edged tolling using a compression force of 8,000 lb
and a dwell time of 5 sec.
Table 1 shows the effects of milling and increased ethylcellulose
content on tablet crushing strength. Tablet crushing strength
values for tablets using a 25% level ETHOCELTM Std. 7 Prem
(unmilled 313 m) ranged from 7 to 13 kN. ETHOCELTM Std. 7
Prem. (unmilled 313 m) and EC Std 7. Prem. (milled 12.8 m)
had similar crushing strength values even with the large difference
in their median particle sizes. Tablets using ETHOCELTM Std 7.
Prem (unmilled 4.8 m) had the highest value at 13 kN. Tablets
manufactured with 75% ETHOCELTM Std. 7 Prem. (unmilled
313 m) had crushing strength values of 18 to 22 kN. Increasing
polymer weight content had a significant impact on the strength of
the tablets.

Table 1: Results of Tablet Physical Testing

Sample
ETHOCELTM Std. 7 Prem.:
Drug Ratio

Tablet Crushing
Strength (kN, sd)

ETHOCELTM Std 7 Prem.

(unmilled)
25%: 75%

7.8, 0.94

75% : 25%

22.0, 0.59

ETHOCELTM Std 7 Prem.

(milled 12.8 m)
25%: 75%

7.6, 1.59

75% : 25%

22.2, 1.36

ETHOCELTM Std 7 Prem.

(milled 4.8 m)
25%: 75%

13.3, 1.53

75% : 25%

17.9, 1.32

Figures 5 8 show drug release from tablets containing unmilled

and milled ETHOCELTM Std. 7 Premium at concentrations of 25%
(Figure 6), 50% (Figure 5), and 75% (Figure 7).
It was observed that as polymer particle size decreased, drug
release decreased (Figure 5 7); furthermore, as polymer
concentration increased drug release decreased (Figure 8).
A secondary study utilizing the same methods was completed
with milled and unmilled ETHOCELTM Std. 100 Premium. This
study demonstrated the same trends in respect to polymer
concentration and particle size. However, when comparing
ETHOCELTM Std 7 Prem. to ETHOCELTM Std. 100 Prem. polymer
viscosity had little effect on drug release times.

The following conclusions were drawn:

Polymer particle size had a significant effect on drug release
times. The finely ground (milled) ETHOCEL samples
extended the release of the model drug compound several
times longer than the unmilled ETHOCEL samples
Polymer viscosity grade (molecular weight) had a minor effect
on drug release because the ethylcellulose was not in a
hydrated state during drug dissolution

pg 6

Tablet crushing strengths were higher in tablets containing

finely ground ETHOCEL than those containing unmilled
ETHOCEL.

ETHOCEL Ethylcellulose - Technical Bulletin | 10-2013

Figure 7: Drug Dissolution from Tablets Containing

ETHOCELTM (1)
Std. 7 Prem. at 75% and Diphenydramine HCI at 25%

100

100

90

90

Diphenhydramine Release, %

Diphenhydramine Release, %

Figure 5: Drug Dissolution from Tablets Containing

ETHOCELTM (1)
Std. 7 Prem. at 50% and Diphenydramine HCI at 50%

80
70
60
50
40
30

80
70
60
50
40
30

20

20

10

10

0
0 100 200

300 400 500 600 700

800

0 100 200

900

ETHOCEL Std. 7 Prem

(unmilled - 313 m)

ETHOCELTM Std. 7 Prem

(unmilled - 313 m)

ETHOCELTM Std. 7 Prem

(milled - 12.8 m)

900

ETHOCELTM Std. 7 Prem

(milled - 12.8 m)

ETHOCELTM Std. 7 Prem

(milled - 4.8 m)

ETHOCELTM Std. 7 Prem

(milled - 4.8 m)

Figure 6: Drug Dissolution from Tablets Containing

ETHOCELTM (1)
Std. 7 Prem. at 25% and Diphenydramine HCI at 75%

Figure 8: Drug Dissolution from Tablets Containing

ETHOCELTM (1)
Std. 7 Prem. and Diphenydramine HCI

100

100

90

Diphenhydramine Release, %

Diphenhydramine Release, %

800

Timen, min.

Timen, min.
TM

300 400 500 600 700

80
70
60
50
40
30
20
10

90
80
70
60
50
40
30
20
10

0
0 100 200

300 400 500 600 700

800

900

Timen, min.
ETHOCELTM Std. 7 Prem
(unmilled - 313 m)

50

100

150

200

250

Timen, min.

ETHOCELTM Std. 7 Prem

(milled - 12.8 m)

25% ETHOCELTM
(unmilled), 75% Drug

ETHOCEL Std. 7 Prem

(milled - 4.8 m)
TM

75% ETHOCELTM
(unmilled), 25% Drug

50% ETHOCELTM
(unmilled), 50% Drug

The properties shown are typical but not to be construed as specifications,

data is based on results from internal studies

(1)

pg 7

ETHOCEL Ethylcellulose - Technical Bulletin | 10-2013

Hot Melt Extrusion

ETHOCELTM possesses excellent thermoplasticity and softens
between 135 C to 160 C making it a versatile and powerful
tool in pharma hot melt extrusion (HME). Pharmaceutical
companies can obtain specific release profiles while shaping their
formulations into a wide variety of final dosage forms including
tablets, multiparticulates and core-sheath systems. Another driver
for hot melt extrusion is improved bioavailability of poorly soluble
drugs (PSD). The desired result from HME of a PSD is the formation
of a solid solution, wherein the drug remains in its amorphous form
within the polymer matrix.

ETHOCELTM Std. 10 Prem. was combined with ketoprofen (USP

classified Very Slightly Soluble 0.14 mg/ml) and water soluble
additives of either POLYOX WSR N-10 (PEO), POLYOXTM WSR 301,
or METHOCELTM E5 Prem. LV (HPMC) to form extrudate for drug
dissolution. Some extrudate was further milled to aid in dissolution
properties.
Table 2 gives the experimental formulations and process
conditions for hot melt extrusion from a conical twin screw.

ETHOCELTM possesses distinctive polymer attributes to add in

keeping poorly soluble drugs in the amorphous state, but these
same attributes cause very slow drug dissolution. The objective of
this study was to explore additives that improved drug dissolution
rates.
Table 2: Experimental Formulations and Process Conditions

Sample ID

Polymer

Water Soluble
Additive

Dissolution
Ketoprofen (%) Process Temp (C)
Promoter (%)

45 - 1

EC Std. 10

35

HPMC E5

45

20

150

45 - 10

EC Std. 10

35

PEO N-10

45

20

150

45 - 11

EC Std. 10

35

PEO 301

45

20

150

45 - 13

EC Std. 10

35

MC A15

45

20

150

All samples formed excellent extrudate with amorphous ketoprofen distributed throughout (Table 3).
All samples except for EC Std. 10 Prem containing METHOCELTM A15 demonstrated improved dissolution rates (Figure 9; table 3).
Further milling of the extrudate resulted in increased ketoprofen solubility (Figure 10)
Table 3: Ketoprofen Extrudate Quality and Dissolution

Sample ID

Melt Quality

Extrudate Ketoprofen
Morphology (X-RAY)

Dissolution Promoter
(%)

Ketoprofen (%)

45 - 1

Uniform Melt

Amorphous

Amorphous

50.6

45 - 10

Uniform Melt

Amorphous

Amorphous

63.8

45 - 11

Uniform Melt

Amorphous

Amorphous

66.8

45 - 13

Uniform Melt

Amorphous

Amorphous

37.4

(1)
The properties shown are typical but not to be construed as specifications data is based on results
from internal studies

pg 8

ETHOCEL Ethylcellulose - Technical Bulletin | 10-2013

pg 9

ETHOCEL Ethylcellulose - Technical Bulletin | 10-2013

Figure 9 also demonstrates the complete dissolution profile over a

24 hr period. The dissolution of ETHOCELTM Std. 10 with additives
HPMC or PEO are clearly faster than with METHOCELTM.

Figure 9 Ketoprofen Dissolution Results for Extruded

Tablets of Ethylcellulose Based Formulations Incorporating
PEO or HPMC (1)

The Following Conclusions were Drawn:

A broad assortment of water soluble additives can be
added to ETHOCELTM formulations to improve drug
dissolution through HME
Amorphous solid solutions of poorly soluble drugs
were obtained for all formulations studied through
the HME process.
POLYOXTM and METHOCELTM were the most effective
dissolution promoters

% diphenhydramine HCl dissolved

100
90
80
70
60
50
40
30
20
10
0
0

200

400

600

800

1000

1200

Time (min.)

Milling of extrudate further enhanced dissolution

rates.

ETHOCELTM Std. 10/HPMC E5/Ketoprofen (% = 35/45/20)

ETHOCELTM Std. 10/PEO 301/Ketoprofen (% = 35/45/20)
ETHOCELTM Std. 10/PEO N10/Ketoprofen (% = 35/45/20)

Figure 10 - Dissolution Profiles of Milled Extrudate in

Capsules Compared to HME Tablets for ETHOCELTM STD 10/
MC A15/Ketoprofen (25/55/20) (1)

Diphenhydramine Release, %

100
90
80
70
60
50
40
30
20
10
0
0 200

400

600

800 1000 1200 1400 1600

Timen, min.

HME Tablet
Milled Extrudate

The properties shown are typical but not to be construed as specifications,

data is based on results from internal studies

(1)

pg 10

North America
Europe, Middle East, Africa
Pacific


Latin America

+1 800 447 4369

+31 11 567 2626
+60 3 7965 5392
+55 11 5184 8722

www.dowpharmaandfood.com

TMTrademark of The Dow Chemical Company (Dow) or an affiliated company of Dow

Form No. 198-02293 - 10/13 EST

Dow requests that customers considering use of Dow products in medical applications notify Dow so that appropriate assessments may be conducted. Dow has a Corporate Medical Application
Policy in place that guides the use of Dow products in potential new pharmaceutical and medical device uses. Dow reviews all new applications/uses according to this Medical Application
Policy to determine if the use is appropriate for Dow materials. Dow does not endorse or claim suitability of its products for specific medical applications. It is the responsibility of the medical
device or pharmaceutical manufacturer to determine that the Dow product is safe, lawful, and technically suitable for the intended use. DOW MAKES NO WARRANTIES, EXPRESS OR IMPLIED,
CONCERNING THE SUITABILITY OF ANY DOW PRODUCT FOR USE IN MEDICAL APPLICATIONS.
NOTICE: No freedom from infringement of any patent owned by Dow or others is to be inferred. Because use conditions and applicable laws may differ from one location to another and
may change with time, Customer is responsible for determining whether products and the information in this document are appropriate for Customers use and for ensuring that Customers
workplace and disposal practices are in compliance with applicable laws and other government enactments. The product shown in this literature may not be available for sale and/or available
in all geographies where Dow is represented. The claims made may not have been approved for use in all countries. Dow assumes no obligation or liability for the information in this document.
References to Dow or the Company mean the Dow legal entity selling the products to Customer unless otherwise expressly noted. NO WARRANTIES ARE GIVEN; ALL IMPLIED WARRANTIES
OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE ARE EXPRESSLY EXCLUDED.