PHARMACEUTICAL BULLETIN

Pharmaceutical Bulletin 32
Edition: October 29, 2008
Previous Edition: October 28, 2004 / April 28, 2006
For further i nformation, please visit www.pharma.lubrizol.com
Lubrizol Advanced Materials, Inc. / 9911 Brecksville Road, Cleveland, Ohio 44141-3247 / TEL: 800.379.5389 or 216.447.5000
The information contained herein is believed to be
reliable, but no representations, guarantees or
warranties of any kind are made as to its accuracy,
suitability for particular applications or the results to be
obtained therefrom. The information is based on
laboratory work with small-scale equipment and does
not necessarily indicate end product performance.
Because of the variations in methods, conditions and
equipment used commercially in processing these
materials, no warranties or guarantees are made as to
the suitability of the products for the application
disclosed. Full-scale testing and end product
performance are the responsibility of the user. Lubrizol
Advanced Materials, Inc. shall not be liable for and the
customer assumes all risk and liability of any use of
handling of any material beyond Lubrizol Advanced
Materials, Inc.s direct control. THE SELLER MAKES NO
WARRANTIES, EXPRESS OR IMPLIED, INCLUDING,
BUT NOT LIMITED TO, THE IMPLIED WARRANTIES
OF MERCHANTABILITY AND FITNESS FOR A
PARTICULAR PURPOSE. Nothing contained herein is
to be considered as permission, recommendation, nor
as an inducement to practice any patented invention
without permission of the patent owner.

For further i nformation, please visit www.pharma.lubrizol.com
Lubrizol Advanced Materials, Inc. / 9911 Brecksville Road, Cleveland, Ohio 44141-3247 / TEL: 800.379.5389 or 216.447.5000
The information contained herein is believed to be
reliable, but no representations, guarantees or
warranties of any kind are made as to its accuracy,
suitability for particular applications or the results to be
obtained therefrom. The information is based on
laboratory work with small-scale equipment and does
not necessarily indicate end product performance.
Because of the variations in methods, conditions and
equipment used commercially in processing these
materials, no warranties or guarantees are made as to
the suitability of the products for the application
disclosed. Full-scale testing and end product
performance are the responsibility of the user. Lubrizol
Advanced Materials, Inc. shall not be liable for and the
customer assumes all risk and liability of any use of
handling of any material beyond Lubrizol Advanced
Materials, Inc.s direct control. THE SELLER MAKES NO
WARRANTIES, EXPRESS OR IMPLIED, INCLUDING,
BUT NOT LIMITED TO, THE IMPLIED WARRANTIES
OF MERCHANTABILITY AND FITNESS FOR A
PARTICULAR PURPOSE. Nothing contained herein is
to be considered as permission, recommendation, nor
as an inducement to practice any patented invention
without permission of the patent owner.

Lubrizol Advanced Materials, Inc. is a wholly owned subsidiary of The Lubrizol Corporation
* Trademark owned by The Lubrizol Corporation
Copyright 2008 / The Lubrizol Corporation
A Ap pp pl l i i c ca at t i i o on n o of f C Ca ar rb bo op po ol l

* * 7 71 1G G N NF F P Po ol l y ym me er r i i n n
C Co on nt t r ro ol l l l e ed d R Re el l e ea as se e T Ta ab bl l e et ts s
Carbopol

71G NF Polymer Development and Properties

Carbopol

polymers have demonstrated good performance in tablet applications. When used at low levels
(0.5 - 3%) as binders, they improve the hardness and friability of the tablets and enable target properties to
be achieved at low compression forces. At higher levels (3 - 30%), they provide controlled release of the
drugs.

Powder Carbopol

polymers (971P NF, 974P NF) have very fine particle size and static charge, thus they do
not flow freely and at high inclusion levels, are not ideal candidates for direct compression.

Carbopol

71G NF polymer is a granular form of Carbopol

971P NF polymer, designed to have improved

flow properties and be suitable for direct compression process. It is chemically the same polymer, with no
additives.


Carbopol

71G NF Polymer Carbopol

971P NF Polymer
(Granular Form) (Powder Form)
PHARMACEUTICAL BULLETIN 32
APPLICATIONS OF CARBOPOL

71G NF POLYMER IN CONTROLLED RELEASE TABLETS

Page 2 of 9

Carbopol

71G NF polymer is manufactured by roller compaction of Carbopol

971P NF polymer. The

process consists of the following steps and it is schematically presented in Figure 1:

delivering a fine polymer powder to the compaction device;
compacting into larger agglomerates and/or aggregates;
fracturing of agglomerates and/or aggregates into smaller granules (grinding);
screening the granules to obtain the desired particle size range and recycling the oversized and/or
undersized granules.

Figure 1 Schematic representation of the manufacture of Carbopol

71G NF Polymer
















Process variables such as the compaction pressure, roll speeds, attrition device, operation speed, and
screening parameters are used to control the densification and particle size distribution.

The resulting granules are free flowable, have increased bulk density, and contain minimal amounts of very
small particles that can cause dusting and/or static adherence compared to the powder polymer.

Roller compaction has been used to granulate Carbopol

polymers as it avoids processing with water or

flammable solvents. The polymers swell rapidly in water, thus the wet granulation process might be difficult.

The particle size distribution of Carbopol

971P NF and 71G NF polymers (Micron AirJ et Sieve) are shown

in Figures 2 and 3. Carbopol

971P NF polymer has very fine particles, while the granular grade has most
of the particles in the 40-100 mesh range.
PHARMACEUTICAL BULLETIN 32
APPLICATIONS OF CARBOPOL

71G NF POLYMER IN CONTROLLED RELEASE TABLETS

Page 3 of 9


Figure 2 Typical particle size distribution of Carbopol

971P NF polymer

0
5
10
15
20
25
30
35
40
45
50
>40 40 - 60 60 - 80 80 - 100 100 - 140 140 - 200 200 - 325 325 - 500 <500
mesh
%

r
e
t
a
i
n
e
d






















Figure 3 Typical particle size distribution of Carbopol

71G NF polymer

0
5
10
15
20
25
30
35
40
45
50
>40 40 - 60 60 - 80 80 - 100 100 - 140 140 - 200 200 - 325 <325
mesh
%

r
e
t
a
i
n
e
d
PHARMACEUTICAL BULLETIN 32
APPLICATIONS OF CARBOPOL

71G NF POLYMER IN CONTROLLED RELEASE TABLETS

Page 4 of 9

Figures 4 & 5 show the scanning electron micrographs of Carbopol

971P NF and 71G NF polymers.

Figure 4 SEM of Carbopol

971P NF polymer


Figure 4 SEM of Carbopol

971P NF polymer

Figure 5 SEM of Carbopol

71G NF polymer




Carbopol

71G NF polymer has the following typical properties (not specifications):

Property Value Range
Bulk density (kg/m
3
) 325 - 400
Tap density (kg/m
3
) 400 - 465
BET surface area (m
2
/g) 10 - 12
PHARMACEUTICAL BULLETIN 32
APPLICATIONS OF CARBOPOL

71G NF POLYMER IN CONTROLLED RELEASE TABLETS

Page 5 of 9

Recommended usage levels for Carbopol

71G NF polymer are 10 - 30% of the tablet weight. Granular

and powder Carbopol

polymer grades can be combined in direct compression and wet granulation

formulations to reduce the total polymer level and drug release variability. Carbopol

71G NF polymer is
added extragranularly to the formulation while the powder grades can be added either intra or
extragranuarly. For example, Metoprolol tablets were formulated with Carbopol

71G NF polymer (24%)

and Carbopol

971P NF polymer (6 or 8%) and had release profiles that met U.S. Pharmacopeial
requirements Figure 6.

Figure 6 - Metoprolol tablets formulated with Carbopol

71G NF and Carbopol

971P NF polymers

0
10
20
30
40
50
60
70
80
90
100
110
120
0 2 4 6 8 10 12 14 16 18 20 22 24
ti me (h)
%

r
e
l
e
a
s
e
d
USP min
USP max
24% 71G NF & 6% 971P NF
24% 71G NF & 8% 971P NF
commercial product


Performance of Carbopol

71G Polymer in Tablets

Intra-Lot Reproducibility
Theophylline tablets manufactured with Carbopol

71G NF polymer (Table 1) were very uniform and no

segregation was observed during the compression run.

Table 1
Theophylline Tablets with Carbopol 71G NF Polymer

Formulation
Ingredient %
Process Flow Blend Properties
Theophylline 32.9 Flow rate (g/sec) 3.67
Carbopol

71G NF polymer 25.0 Bulk density (g/cc) 0.533

Anhydrous lactose 20.8 Tap density (g/cc) 0.673
Dibasic calcium phosphate 20.8 Hausner ratio 1.263
Magnesium stearate 0.5
Blend all ingredients except the
lubricant for 25 min. in V-blender
Add the lubricant and mix for additional
2 min.
Compress on Korsch PH101 tablet
press (target weight 303 mg, hardness
10 kP)
Batch size: 1.5 kg


PHARMACEUTICAL BULLETIN 32
APPLICATIONS OF CARBOPOL

71G NF POLYMER IN CONTROLLED RELEASE TABLETS

Page 6 of 9

Tablets collected at the beginning and end of the compression run had similar physical properties and drug
release Table 2, Figures 7 & 8.
Table 2
Properties of Theophylline Tablets with Carbopol

71G NF Polymer - Intra-Lot Variability

Tablet property First 20% Last 20%
Weight (mg) 302 0.6 303 0.6
Hardness (kP) 10.6 0.5 10.4 0.5
Friability (%) 0.14 0.10


Figure 7 Intra-lot variability of Theophylline release (USP apparatus 2, simulated gastric fluid) from
tablets with Carbopol

71G NF polymer


















Figure 8 Intra-lot variability of Theophylline release (USP apparatus 2, pH=7.5 simulated intestinal fluid)
from tablets with Carbopol

71G NF polymer



















PHARMACEUTICAL BULLETIN 32
APPLICATIONS OF CARBOPOL

71G NF POLYMER IN CONTROLLED RELEASE TABLETS

Page 7 of 9

Inter-Lot Reproducibility in Direct Compression Process
Theophylline tablets were manufactured by direct compression using five consecutive lots of Carbopol

71G
NF polymer (Table 3).
Table 3
Theophylline Tablets with Carbopol

71G NF Polymer Direct Compression

Formulation
Ingredient %
Process Flow
Theophylline 32.9
Carbopol

71G NF polymer 25.0

Anhydrous lactose 20.8
Dibasic calcium phosphate 20.8
Magnesium stearate 0.5
Blend all ingredients except the lubricant for 25 min. in V-blender
Add the lubricant and mix for additional 2 min.
Compress on Korsch PH101 tablet press (target weight 303 mg,
hardness 10 kP)

The properties of the polymer and tablets were very similar among the five lots (Table 4, Figure 9).

Table 4
Properties of Carbopol

71G NF Polymer and Resulting Theophylline Tablets Inter-Lot Variability

Properties / lot #47 #48 #49 #50 #51
Polymer
Bulk density(g/cc) 0.362 0.366 0.363 0.368 0.373
Tap density(g/cc) 0.426 0.428 0.428 0.433 0.437
Hausner ratio 1.175 1.169 1.178 1.178 1.172
Compressibility index 14.91 14.43 15.14 15.08 14.66
Tablets
Weight (mg) 303.00 2.71 303.13 2.04 303.98 2.08 303.26 2.43 304.37 1.91
Thickness (mm) 4.27 0.02 4.25 0.02 4.25 0.02 4.25 0.01 4.24 0.01
Hardness (kP) 10.31 0.62 10.24 0.90 10.93 0.57 10.42 0.68 10.80 0.3
Friability (%) 0.08 0.07 0.10 0.07 0.12

Figure 9 Particle size distribution of Carbopol

71G NF polymer inter-lot variability

0
5
10
15
20
25
30
35
40
45
50
>40 40 - 60 60 - 80 80 - 100 100 - 140 140 - 200 200 - 325 <325
mesh
%

r
e
t
a
i
n
e
d
#47
#48
#49
#50
#51















PHARMACEUTICAL BULLETIN 32
APPLICATIONS OF CARBOPOL

71G NF POLYMER IN CONTROLLED RELEASE TABLETS

Page 8 of 9

Drug release profiles demonstrated good inter-lot reproducibility (Figure 10).

Figure 10 Theophylline release (USP apparatus 2, pH=7.5 buffer) from tablets with
Carbopol

71G NF polymer - inter-lot reproducibility

0
10
20
30
40
50
60
70
80
90
100
110
0 1 2 3 4 5 6 7 8 9 10
time (h)
%

r
e
l
e
a
s
e
d
#47
#48
#49
#50
#51

Effect of Compression Force on Tablet Properties and Drug Release

Increasing the compression force in the case of Theophylline tablets (100 mg with 25% 71G NF) led to an
increase in the hardness (Figure 11). However, the release profiles were similar (Figure 12).



0
5
10
15
20
25
30
5 10 15 20 25 30 35 40
Compression force (kN)
H
a
r
d
n
e
s
s

(
k
P
)
Figure 11 Hardness of Theophylline direct compressible tablets with Carbopol

71G NF
polymer
PHARMACEUTICAL BULLETIN 32
APPLICATIONS OF CARBOPOL

71G NF POLYMER IN CONTROLLED RELEASE TABLETS

Page 9 of 9

Figure 12 Theophylline release (USP apparatus 2, pH=7.5 buffer) from tablets with Carbopol

71G NF polymer



Benefits of Carbopol

71G NF Polymer in Controlled Release Tablet Formulations

Good flow in high-speed equipment
Good compressibility
Direct compressible excipient
Minimal dust and static adherence
Controlled release performance in tablet
Can be combined with powder grade Carbopol

polymers or other controlled release excipients

to improve the flowability of the formulation and achieve flexibility in drug release performance
Reproducibility (intra- and inter-lot)
Global pharmacopeial status and U.S. and European Drug Master Files (DMFs)


0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10
time (h)
%

r
e
l
e
a
s
e
d
CF =10 kN
CF =15 kN
CF =20 kN
CF =25 kN
CF =30 kN
CF =35 kN
CF =40 kN