Pharma & Food Solutions
ETHOCEL™ Ethylcellulose
A Technical Review
ETHOCEL™ Ethylcellulose - Technical Bulletin | 02-2016
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
18 - 22
41 - 49
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 | 02-2016
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 | 02-2016
Figure 3 demonstrates ETHOCELTM 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.
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 (40°C & 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
0
0
0
0
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 | 02-2016
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 | 02-2016
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 µm), ETHOCELTM Std. 7
Prem. (milled - 12.8 µm), and ETHOCELTM Std. 7 Prem. (milled 4.8 µm) will be used as sample identifier, where 313, 12.8 and 4.8
µm 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 µm) ranged from 7 to 13 kN. ETHOCELTM Std. 7
Prem. (unmilled – 313 µm) and EC Std 7. Prem. (milled – 12.8 µm)
had similar crushing strength values even with the large difference
in their median particle sizes. Tablets using ETHOCELTM Std 7.
Prem (unmilled 4.8 µm) had the highest value at 13 kN. Tablets
manufactured with 75% ETHOCELTM Std. 7 Prem. (unmilled –
313 µm) 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 µm)
25%: 75%
7.6, 1.59
75% : 25%
22.2, 1.36
ETHOCELTM Std 7 Prem.
(milled – 4.8 µm)
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 | 02-2016
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
0 100 200
300 400 500 600 700
800
0 100 200
900
ETHOCEL Std. 7 Prem
(unmilled - 313 µm)
ETHOCELTM Std. 7 Prem
(unmilled - 313 µm)
ETHOCELTM Std. 7 Prem
(milled - 12.8 µm)
900
ETHOCELTM Std. 7 Prem
(milled - 12.8 µm)
ETHOCELTM Std. 7 Prem
(milled - 4.8 µm)
ETHOCELTM Std. 7 Prem
(milled - 4.8 µm)
Figure 8: Drug Dissolution from Tablets Containing
ETHOCELTM (1)
Std. 7 Prem. and Diphenydramine HCI
Figure 6: Drug Dissolution from Tablets Containing
ETHOCELTM (1)
Std. 7 Prem. at 25% and Diphenydramine HCI at 75%
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
0
900
0
Timen, min.
ETHOCELTM Std. 7 Prem
(unmilled - 313 µm)
50
100
150
200
250
Timen, min.
ETHOCELTM Std. 7 Prem
(milled - 12.8 µm)
25% ETHOCELTM
(unmilled), 75% Drug
ETHOCEL Std. 7 Prem
(milled - 4.8 µm)
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 | 02-2016
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 | 02-2016
pg 9
ETHOCEL™ Ethylcellulose - Technical Bulletin | 02-2016
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
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