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Controlled
Release
A Technical Review
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Many years of commercial experience
indicate that the physical properties
and drug release of controlled-release
(CR) tablets containing METHOCEL™
cellulose ethers have excellent
long-term stability. Several studies
conducted by Dow Wolff Cellulosics
have confirmed this observation.
Study 1: Effects of storage time and elevated
temperatures on drug degradation and
dissolution
One study examined the effect of storage time at elevated
temperature on tablets containing mixtures of diclofenac
sodium and METHOCELTM USP 2910 combined with 1%
silicon dioxide and 0.5% magnesium stearate. The mixtures
were:
• 50/50 diclofenac sodium/4000 mPa˙s METHOCELTM
• 50/37.5/12.5 diclofenac sodium/4000 mPa˙s
METHOCELTM/ 50 mPa˙s METHOCELTM
• 50/25/25 diclofenac sodium/4000 mPa˙s METHOCELTM/
50 mPa˙s METHOCELTM
• 50/12.5/37.5 diclofenac sodium/4000 mPa˙s
METHOCELTM/ 50 mPa˙s METHOCELTM
• 50/50 diclofenac sodium/50 mPa˙s METHOCELTM
Tablets were prepared using wet granulation; target tablet
weight was 750 mg. Tablets were stored in amber bottles.
No further details were given on containers used or number
of tablets per container. Storage conditions were 1, 2, and 3
months at ambient temperature, 31, 37, and 43°C. Humidity
was 75% for all temperature conditions except ambient.
The authors found that none of the five formulations showed
a significant effect of storage time or temperature on drug
degradation or dissolution.
01 Controlled Release
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Controlled Release 02
STUDY 2: Impact of storage time,
temperature and humidity on drug
degradation and dissolution
Another study investigated the effect of storage time,
temperature, and humidity on drug degradation and
dissolution of matrix tablets containing alprazolam and
either METHOCELTM K100 LV or METHOCELTM K4M. The
formulation containing METHOCELTM K100 LV included
45% METHOCELTM K100 LV, 2.5% alprazolam, 20%
microcrystalline cellulose, 31.5% lactose, 0.5% silicon
dioxide, and 0.5% magnesium stearate. The formulation
containing METHOCELTM K4M included 37% METHOCELTM
K4M, 2.5% alprazolam, 20% microcrystalline cellulose, 39.5%
lactose, 0.5% silicon dioxide, and 0.5% magnesium stearate.
Tablets were prepared by direct compression; target tablet
weight was 400 mg. The tablets were placed in 60-mL, white,
high-density polypropylene (HDPE) bottles. Each bottle
contained 80 tablets. Storage conditions were 25°C at 60%
RH and 40°C at 75% RH.
Tables 1 and 2 show the effects of up to 12 months storage
on drug assay and hardness. As shown by similarity factors
greater than 50, there was no significant effect of storage
time or conditions on assay.
Figures 1 and 2 provide the results from drug dissolution
testing for up to 12 months of storage.
Storage time and conditions did not appear to affect drug
dissolution in these formulations. This study examined
the effects of storage time and humidity on the physical
properties and drug release of hydrophilic matrix tablets
containing the model drug hydrochlorothiazide and
either METHOCEL™ K4MP or METHOCEL™ K100MP. The
formulation included 87% METHOCEL™ K4MP or K100MP,
12.5% hydrochlorothiazide, and 0.5% magnesium stearate.
Tablets were prepared using direct compression; tablet
weight was adjusted to 200 mg. Tablets were stored for 1,
3, and 6 months at 20°C in air-tight boxes. According to
the authors, the boxes contained reservoirs of sulfuric acid
at the dilution required to establish relative humidity such
that the equilibrium moisture content of the METHOCEL™
product was 5% or 8%. The lower humidity corresponded to
the prestorage equilibrium moisture content of the cellulose
ethers. The actual relative humidity was interpreted to be
roughly 35-40% and 50-55%, respectively.
Figure 3 provides the representative data.
The results for METHOCEL™ K4MP and K100MP were
similar. Drug release was not significantly affected by storage
time and storage at the lower relative humidity had no
significant effects on tablet properties. However, storage
at the higher humidity resulted in reductions in crushing
strength, and increases in total porosity and mean pore
diameter. Most changes occurred within 1 month of storage.
The authors concluded that storage of METHOCEL™based tablets for 6 months at 20°C had no significant effect
on physical properties unless storage humidity was high
enough to allow the tablets to absorb a significant amount of
water. Drug release, as measured by the fraction of the area
under the dissolution curve between 0 and 8 h relative to the
total area under the curve, was not significantly affected by
storage time or humidity.
03 Controlled Release
TABLE1: EFFECT OF STORAGE TIME AND CONDITIONS ON DRUG
DEGRADATION OF HYDROPHILIC MATRIX TABLETS CONTAINING
ALPRAZOLAM AND METHOCELTM K4MP.
(37% METHOCELTM K4MP, 2.5% alprazolam, 20% microcrystalline
cellulose, 39.5% lactose, 0.5% silicon dioxide, and 0.5% magnesium
stearate)
STABILITY SAMPLE
(TIME, CONDITION)
COMPOSITE ASSAY
(MG)
SIMILIRATY FACTOR
(F2)
Initial
105.58
ref
AMBIENT (25°C/60%RH)
3 months
6 months
12 months
102.01
103.15
105.09
84
96
81
AMBIENT (40°C/75%RH)
1 months
2 months
3 months
6 months
105.56
101.35
102.14
102.58
FIGURE 1: EFFECT OF STORAGE TIME, TEMPERATURE
AND HUMIDITY ON DRUG DISSOLUTION OF HYDROPHILIC MATRIX
TABLETS CONTAINING ALPRAZOLAM AND METHOCELTM K100P LV
(45% METHOCELTM K100P LV, 2.5% alprazolam, 20% microcrystalline
cellulose, 31.5% lactose, 0.5% silicon dioxide, 0.5% magnesium
stearate)
Drug released, % // Time, H
FIGURE 3: EFFECT OF STORAGE TIME AND HUMIDITY ON SELECTED
PHYSICAL PROPERTIES AND DRUG DISSOLUTION OR HYDROPHILIC
MATRIX TABLETS CONTAINING HYDROCHIOROTHIAZIDE
AND METHOCELTM K4MP.
87% METHOCELTM K4MP, 12.5% hydrochlorothiazide, 0.5% magnesium stearate)
Crushing strength, N // Time, months
120
120
100
100
80
80
60
40
91
75
81
81
60
20
0
0
TABLE2: EFFECT OF STORAGE TIME AND CONDITIONS ON DRUG
DEGRADATION OF HYDROPHILIC MATRIX TABLETS CONTAINING
ALPRAZOLAM AND METHOCELTM K100P LV.
(45% METHOCELTM K100P LV, 2.5% alprazolam, 20% microcrystalline
cellulose, 31.5% lactose, 0.5% silicon dioxide, and 0.5% magnesium
stearate)
STABILITY SAMPLE
(TIME, CONDITION)
COMPOSITE ASSAY
(MG)
SIMILIRATY FACTOR
(F2)
Initial
101.04
ref
Initial
26°C, 80%RH, 3mo.
2
4
6
26°C, 80%RH, 6mo.
26°C, 80%RH, 12mo.
8
10
12
40°C, 80%RH, 1mo.
40°C, 80%RH, 2mo.
14
16
40°C, 80%RH, 3mo.
40°C, 80%RH, 6mo.
1
2
3
4
5
6
6% moisture
8% moisture
0-8 h Dissolution efficiency // Time, months
FIGURE 2: EFFECT OF STORAGE TIME, TEMPERATURE,
AND HUMIDITY ON DRUG DISSOLUTION OF HYDROPHILIC MATRIX
TABLETS CONTAINING ALPRAZOLAM AND METHOCELTM K4MP.
(37% METHOCELTM K4MP, 2.5% alprazolam, 20% microcrystalline
cellulose, 31.5% lactose, 0.5 silicon dioxide, 0.5% magnesium
stearate)
Drug released, % // Time, H
0,35
0,30
AMBIENT (25°C/60%RH)
3 months
6 months
12 months
100.15
102.75
100.21
83
94
85
100.11
100.35
101.10
103.57
0,25
100
0,20
80
AMBIENT (40°C/75%RH)
1 months
2 months
3 months
6 months
120
93
88
89
84
60
0,15
40
0
20
2
4
6
6% moisture
8% moisture
0
Initial
26°C, 80%RH, 3mo.
2
4
6
26°C, 80%RH, 6mo.
26°C, 80%RH, 12mo.
8
10
12
40°C, 80%RH, 1mo.
40°C, 80%RH, 2mo.
14
16
40°C, 80%RH, 3mo.
40°C, 80%RH, 6mo.
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Controlled Release 04
Study 3: Effects of scale-up,
storage time and temperature
on drug stability and release
A study involving CR tablets containing theophylline as
the model drug and METHOCELTM K4MP CR cellulose
ether examined the effects of process scale-up, storage
time, temperature, and humidity on the stability of physical
properties and drug release. The formulation included 30%
METHOCELTM K4MP CR, 50% theophylline, 19.75% lactose,
and 0.25% magnesium stearate. Tablets were prepared from
laboratory, pilot-plant, and full-scale granulations using roll
compaction. Target tablet weight was 400 mg. Tablets were
stored in 60-mL, opaque, polypropylene (PP) bottles, 60
tablets per bottle. Stability was evaluated under ambient
conditions (21°C/50% relative humidity) and accelerated
conditions (40°C/75% relative humidity). The testing intervals
were 1, 2, 3, 6, 9, and 12 months.
Table 3 shows the results of 12-month stability testing on
the physical properties of production-scale samples. Tablets
stored under ambient conditions showed little change in
tablet crushing strength, tablet thickness, and tablet weight
over the 12-month period. Tablets stored under accelerated
conditions showed a slight lowering of tablet crushing
strength values during the same 12-month period. However,
tablet thickness and tablet weight values showed only
minor differences. No correlation was observed between
slight reductions in tablet crushing strength values under
accelerated conditions and tablet thickness and tablet
weight.
TABLE 3: EFFECT OF STORAGE TIME AND CONDITIONS ON PHYSICAL
PROPERTIES OF HYDROPHILIC MATRIX TABLETS CONTAINING
THEOPHYLINE AND METHOCELTM K4MP CR (PRODUCTION SCALE).
(30% METHOCELTM K4MP CR, 50% Theophyline, 19,75% lactose,
and 0.25% magnesium stearate)
STABILITY SAMPLE
(TIME, CONDITION)
Initial
AVE. TABLET
CRUSHING
STRENGH
(SCU, SD)
AVE. TABLET
CRUSHING
STRENGH
(SCU, SD)
AVE. TABLET
WEIGHT
(MG, 5D)
30.6, 1.4
5.7
401,2
AMBIENT
(25°C/60%RH)
1 months
2 months
3 months
6 months
9 months
12 months
29.1, 3.0
27.1, 2.5
25.9, 1.4
23.8, 1.4
27.1. 1.8
26.5, 1.5
5.7
5.8
5.9
5.8
5.9
5.7
400,9
400,5
403,4
403,4
401,5
403,5
26.2, 2.1
24.4, 1.5
24.4, 1.2
23.1, 1.2
15.9, 1.1
18.8, 1.2
5.7
5.9
5.9
5.8
6.0
6.0
405,7
404,4
400,4
402,4
404,6
413,6
FIGURE 5: EFFECT OF STORAGE TIME AT 40°C/75% RH ON DRUG
DISSOLUTION OF HYDROPHILIC MATRIX TABLETS CONTAINING
THEOPHYLLINE AND METHOCELTM K4MP CR (PRODUCTION SCALE).
(30% METHOCELTM K4MP CR, 50% theophylline, 19.75% lactose,
0.25% magnesium stearate)
Drug released, % // Time, H
100
100
80
80
60
60
40
40
20
20
0
AMBIENT
(40°C/75%RH)
1 months
2 months
3 months
6 months
9 months
12 months
FIGURE 4: EFFECT OF STORAGE TIME AT 21°C/50% RH ON DRUG
DISSOLUTION OF HYDROPHILIC MATRIX TABLETS CONTAINING
THEOPHYLLINE AND METHOCELTM K4MP CR (PRODUCTION SCALE).
(30% METHOCELTM K4MP CR, 50% theophylline, 19.75% lactose,
0.25% magnesium stearate)
Drug released, % // Time, H
Initial
1 mo.
5
2 mo.
6 mo.
10
15
9 mo.
12 mo.
20
0
Initial
1mo.
5
10
2mo.
3mo.
15
6mo.
9mo.
20
12mo.
Similar results were noted for both laboratory and pilot-plant
samples. Drug-release profiles from ambient and accelerated
conditions were essentially unchanged (Figures 4 and 5).
Values for ƒ2 metric on drug release for the ambient samples
were greater than 88, indicating similarity between profiles.
Values for ƒ2 metric on drug release for the accelerated
samples were greater than 75, also indicating similarity
between profiles.
05 Controlled Release
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Controlled Release 06
STUDY 4: Effects of storage time,
temperature and humidity on drug release,
degradation and hardness
A study involving dihydroergotoxine mesylate investigated
the effect of storage time, temperature, and humidity on
drug release, assay, degradation products, and tablet
hardness. One formulation included 39.8% METHOCELTM
E4MP CR, 6.4% dihydroergotoxine mesylate, 45.7% lactose,
0.3% sodium lauryl sulfate, 5.2% microcrystalline cellulose,
and 2.7% polyvinylpyrrolidone. Tablets were prepared using
fluid bed granulation; target tablet weight was not specified.
Tablets were placed in glass containers for stability testing.
No further details on containers or number of tablets per
container were given. Storage times were 32, 91, 186, and
375 days; storage conditions were 2-8°C, 25°C/NMT60% RH,
30°C, 37°C, 45°C, and 25°C/80% RH.
The authors found the formulation to be stable at elevated
humidity conditions (Table 4).
At elevated temperature conditions, degradation products
of the drug increased. However, the tablet hardness and
dissolution profile (data not shown) were not affected by
either storage time or storage conditions.
Similar dissolution results were found in a study involving
pseudoephedrine HCl.
The formulation contained 61% METHOCELTM
K4MP, 13% pseudoephedrine HCl, and 26% sodium
carboxymethylcellulose (NaCMC). Tablets were prepared by
direct compression; target tablet weight was not specified.
Tablets were placed in amber glass bottles.
No further details on containers or number of tablets per
container were given. Storage conditions included 37°C,
45°C, and 37°C/80% RH for 3 months.
Drug dissolution was very similar under all three conditions.
The authors concluded that the release integrity of the
tablets under these accelerated conditions indicated good
stability. Stark et al.1 studied the effect of accelerated stability
conditions on tablet crushing strength, in vitro dissolution,
and in vivo performance of tablets containing a Class I drug
and 60% METHOCEL™. No information was given on tablet
preparation. Tablets were stored in 100-mL, white, HPDE
bottles, 100 tablets per bottle. Two conditions were used:
25°C/60% RH (nonstressed) and 40°C/75% RH (stressed).
Crushing strength and in vitro drug dissolution were
determined over 6 months. In vivo evaluations involving
Cmax and AUC parameters were performed on stressed and
nonstressed tablets stored for 3 months. This study is unusual
in that it included in vivo as well as in vitro evaluation.
Stark, P., Kinahan, A., Cunningham, S., Farrell, C., Butler, J., Reilly, M.,
and Devane, J., “In Vivo-In Vitro Evaluation of the Impact of Accelerated
Stability Conditions on a Hydrophilic Matrix Tablet,” In:Young et al. (ed.) In
Vitro-In Vivo Correlations, Plenum Press, New York, 221-224, (1997).
TABLE 4: EFFECT OF STORAGE TIME AND CONDITIONS ON PHYSICAL PROPERTIES OF HYDROPHILIC MATRIX TABLETS
CONTAINING THEOPHYLINE AND METHOCELTM K4MP CR (PRODUCTION SCALE).
(30% METHOCELTM K4MP CR, 50% Theophyline, 19,75% lactose, and 0.25% magnesium stearate)
2-8°C
25°C/NMT60% RH
30°C
37°C
45°C
25°C/80% RH
0
-
104.4
-
-
-
-
32
91
186
375
103.3
104.1
102.7
101.8
104.1
104.1
104.1
101.6
103.3
103.3
102.3
102.4
103.1
103.1
104.4
101.4
102.7
102.0
103.2
100.3
102.7
103.8
107.7
102.6
0.41
0.55
0.55
0.40
0.41
0.55
0.55
0.53
0.55
0.60
0.90
0.95
0.85
1.20
1.60
1.45
0.40
0.70
0.70
25.6, 38.7
37.7, 45.8
32.6, 35.6
33.6, 42.8
32.6-54.0
35.6-41.2
38.7-50.9
32.6-44.8
24.4-40.7
35.6-36.5
47.9-58.1
22.4-39.7
28.5-35.6
33.1-45.3
30.1-44.4
33.6-43.8
30.5-34.6
41.7-44.78
37.6-56.2
35.6-44.4
44.8-64.2
34.6-37.8
32.6-48.8
43.8-56.0
32.6-38.7
TIME
(DAYS)
ASSAY (%)
DEGRADATION
PRODUCTS (%)
0
32
91
186
TABLET HARDNESS (N)
0
32
91
186
375
1
07 Controlled Release
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Controlled Release 08
STUDY 4: Effects of storage time,
temperature and humidity
on drug release, degradation
and hardness
TABLE 5: EFFECT OF STORAGE TIME AND CONDITIONS ON
CRUSHING STRENGH OF HYDROPHILIC MATRIX TABLETS
CONTAINING A CLASS I DRUG AND 60% HYPROMELLOSE.
CRUSHING STRENGH (N)
NONSTRESSED
(25°C/60%RH)
TIME
(MONTHS)
RANGE
0
1
2
3
4
6
249-283
N/E
N/E
260-288
N/E
256-277
N/E : NOT EXAMINED
STRESSED
(40°C/75%RH)
MEAN
269
N/E
N/E
276
N/E
268
RANGE
249-283
208-241
166-199
159-186
163-180
158-183
MEAN
269
226
186
173
173
172
Table 5 shows the effect of storage time and conditions on
tablet crushing strength.
At 3 months, the crushing strength of the stressed tablets
was 37% lower than that of the nonstressed tablets, dropping
from 269 N to 173 N. Most of the decrease occurred in the
first two months. Storage at accelerated stability conditions
did not affect either in vitro dissolution profiles or in vivo
results, indicating that stressed and nonstressed tablets
were bioequivalent. Joly and Brossard1 studied the effect
of storage time, temperature, and humidity on the physical
properties and release characteristics of tablets containing
theophylline and METHOCEL™ K4M. The formulation
described in the article contained 20% METHOCEL™ K4M,
50% theophylline, 25% lactose, 4% polyvinylpyrrolidone,
and 1% magnesium stearate. However, stability testing
was described as conducted on tablets containing 25%
METHOCEL™ K4M, with no additional information on the
remainder of the formulation. Tablets were prepared by
wet granulation. Target tablet weight was 400 mg. Stability
conditioning was done on loose tablets with no packaging
or wrapping. Stability was studied over 5 months under three
conditions: ambient air, warm dry air (40°C), and warm moist
air (40°C/80% RH).
FIGURE 6: EFFECT OF STORAGE CONDITIONS AT 5 MONTHS
STORAGE ON WEIGHT OF HYDROPHILIC MATRIX TABLETS
CONTAINING THE OPHYLINE AND METHOCELTM K4MP
(25% METHOCELTM K4MP, balance not described)
Weight variation,% // Time, months
FIGURE 7: EFFECT OF STORAGE TIME AT ROOM TEMPERATURE
ON RELEASE OF PSEUDOEPHEDRINE HCL FROM HYDROPHILIC
MATRIX TABLETS CONTAINING METHOCELTM K4MP.
(26.6% METHOCELTM K4MP, 16.0% pseudoephedrine HCl, 56.7% lactose,
0.7% magnesium stearate)
Drug release, % // Time, months
120
100
80
60
40
20
0
Ambient air
Dry warm air
2
4
6
8
10
12
Immediately after production
After 28 months
Moist warm air
Figure 6 shows the effect of storage conditions on weight of
tablets containing 25% METHOCELTM K4M. The tablet weight
did not vary significantly from the first to the fifth month,
although there was a slight increase in weight variation in
warm air.
TABLE 6: EFFECT OF STORAGE CONDITIONS AT 5 MONTHS ON THE
RELEASE OF THEOPHYLINE FROM HYDROPHILIC MATRIX TABLETS
CONTAINING THEOPHYLINE AND METHOCELTM K4MP
(25% MethocelTM K4MP, balance not described)
AMOUNT DISSOLVED (MG)
NONSTRESSED
(25°C/60%RH)
Figure 7 shows the stability of METHOCEL™ K4M Premium
in hydrophilic matrix tablets containing pseudoephedrine
HCl. The formulation included 26.6% METHOCEL™ K4M
Premium, 16% pseudoephedrine HCl, 56.7% lactose, and
0.7% magnesium stearate. Tablets were prepared by direct
compression. No description of containers or number of
tablets per container was given. Tablet dissolution was
measured immediately after manufacture and again after 28
months storage at room temperature and humidity. Minimal
change in the in vitro dissolution resulted over this storage
interval.
STRESSED
(40°C/75%RH)
TIME
(MONTHS)
TIME 0
AMBIENT
WARM
DRY AIR
1
4
8
13
34
58
12
34
56
14
34
58
WARM
MOIST AIR
11
33
57
Table 6 shows the effect of storage conditions on drug
dissolution from tablets containing 25% METHOCELTM K4M.
The authors concluded that the release of theophylline was
independent of the storage conditions tested.
Joly, F., Brossard, C., “Development and Application of a Theophylline
Hydrophilic Matrix II. Industrial Development and Study of the Cleavability
and Stability Characteristics of the Tablets,” S.T.P. Pharma, 3 (11), 872-879
(1987).
1
09 Controlled Release
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Controlled Release 10
Study 5: Roller compaction
in the preparation of CR hydrophilic matrix
tablets containing METHOCELTM
Wet granulation is used to enhance material flow during the
manufacture of CR matrix formulations. However, hydrophilic
components can react with the aqueous system, making wet
granulation difficult. Roller compaction is a viable mechanical
process for enhancement of material flow in CR matrix tablet
formulations containing METHOCELTM and HPMC polymers.
TYPICAL DRY GRANULATION SYSTEM WITH RECYCLE
Original Mix
Feed Hopper
w/Screws
Compaction
Rolls
Pressured
applied
Compacted
Ribbon
Mill
Overs
Product
Fines
Recycle
system
combines
overs, fines
and original
powders
FIGURE 8: PARTICULES-SIZE DISTRIBUTION OF 18/80-MESH
GRANULATIONS CONTAINING METHOCELTM 2208 GENERATED
DURING THE FIRST ROLLER COMPACTION CYCLE.
Retained % // Sieve size
Roller compaction uses bonding mechanisms such as particle
rearrangement, deformation, and fragmentation to form a
granule. The advantages of roller compaction include:
• Dry granulation system
• High-volume production of granules
• Good control of final particle bulk density and flow
properties
• Low consumption of energy
• Minimum labor requirements.
In a typical dry granulation system with product recycle, a
homogeneous mix is introduced into the top feed hopper,
which contains an auger. The auger helps deliver the powder
mix to the nip region of the compaction rolls. The rolls, while
under hydraulic pressure, compact the powder mixes into
ribbons. The ribbons are then milled and passed through a
series of screens that size the granules into acceptable product.
Granules that are either too large or too small are recycled and
combined with original powder mix and passed through the
compactor.
One study assessed roller compaction in the dry granulation
of a CR matrix formulation containing METHOCELTM
(methylcellulose or hydroxypropyl methylcellulose [HPMC]),
niacinamide, and magnesium stearate. Evaluation of 18/80mesh portions of the granulations showed a similar particlesize distribution. Granulations produced using 1 ton pressure
tended to generate smaller granules than those produced
using higher roller pressures. Product density increased as a
result of roller compaction, but only small differences in density
values were observed as a result of varying the compactor roll
pressures.
Tablet hardness values were consistently higher for material
compacted using the lowest roller pressure (1 ton). Inversely,
tablet friability values were lowest in granulations compacted
at 1 ton pressure. The effect of roller compaction pressure on
drug dissolution was minimal (T90% = 5.5- 7.0 h). Extensive
recycling of coarse and fine material had a negative impact on
the drug levels of some granulations. Elimination of product
recycling greatly improved drug-level uniformity.
• Particle-size distribution.
Granulations produced using the lowest compaction
pressure (1 ton) exhibited, on average, smaller diameter
granules than those produced using the higher
compaction pressures (3 and 6 tons). A similar trend was
observed during the second roller compaction of recycled
coarse and fine material. Higher roller compactor pressures
possibly generate a ribbon that is more resilient to the
milling process and thus may produce a coarser particlesize distribution. METHOCELTM 1828 generally produced
granules that were smaller than those of the other four
cellulosic polymers under similar conditions. The exception
was when METHOCELTM 1828 was initially compacted
at the high roller pressure. Figures 8-10 show the sieve
analysis results of the 18/80-mesh granules generated from
METHOCELTM 2208. These figures are representative of
the five cellulosic polymers used in Phase I. The majority of
the 3- and 6-ton roller compaction granules (23-40%) were
retained on the 20-mesh and 30- mesh screens. Based on
the level of applied roller compaction pressure, there was
a rank order of 6 tons > 3 tons > 1 ton in the percentage
of granulation retained on the 20- and 30-mesh screens.
The level of fines (<80 mesh) remaining on the pan was
1-5% for the 3- and 6-ton samples and 8-15% for the 1-ton
samples.
FIGURE 9: PARTICULES-SIZE DISTRIBUTION OF 18/80-MESH
GRANULATIONS CONTAINING METHOCELTM 2208 ROLLER
COMPACTED DURING THE RECYCLE PHASE USING
ONLY> 18-MESH GRANULES.
Retained % // Sieve size
FIGURE 10: PARTICULES-SIZE DISTRIBUTION OF 18/80-MESH
GRANULATIONS CONTAINING METHOCELTM 2208 ROLLER
COMPACTED DURING THE RECYCLE PHASE USING
ONLY< 80-MESH GRANULES.
Retained % // Sieve size
40
30
20
10
20
11 Controlled Release
30
40
60
80
Specific findings included:
• Density.
The granulations generated from roller compaction of the
original mixes demonstrated CI values ranging from 8%
to 26% (four granulations containing METHOCELTM were
>20%) and provided excellent flow characteristics during
tableting on a rotary tablet press. The level of applied roller
compaction force (1, 3, and 6 tons) used to generate the
compacted ribbons had little effect on CI or density values.
The lack of adequate product flow is one of the primary
reasons for using roller compaction technology. Tablet
compression machinery relies on the use of gravity to
efficiently and uniformly feed materials to the subsequent
punches and dies at high speeds. The data above indicate
that roller compaction is a viable mechanical process for
enhancement of material flow.
Pan
• Compaction efficiency.
Efficiency testing is an indication of granule strength. The
strength of the granule is related to its ability to withstand
the attrition processes during the milling of the compacted
ribbons and the aggressive mechanical activity of the RoTap sieve shaker during the sizing/separation operation.
Milled ribbons that have a higher percentage of granules
retained on the 18-mesh screen and less retained on the
pan (or fines material) are an indicator of higher granule
strength. The compaction efficiencies of methylcellulose,
METHOCELTM 2208, METHOCELTM 2910, and METHOCELTM
2906 were similar. Of these four polymers, METHOCELTM
2910, roller compacted at 1 ton, had the lowest >18-mesh
values and the highest <80-mesh values. METHOCELTM
1828 exhibited the lowest percentage of >18-mesh
material and the highest percentage of <80-mesh material,
indicating that METHOCELTM 1828 granules were low
in strength compared to the other materials. This was
especially apparent with METHOCELTM 1828 at 1-ton roller
compaction pressure, which left almost no material on the
18-mesh screen.
®TMTrademark of The Dow Chemical Company (“Dow”) or an affiliated company of Dow
Controlled Release 12
Study 5: Roller compaction
in the preparation of
CR hydrophilic matrix tablets
containing METHOCEL
The authors of this study have seen some correlation between
compaction efficiency results and tablet friability values. It
appears that very low compaction efficiency percentages for
>18- mesh material or high percentages for <80-mesh material
(fines) may be a predictor of low granule strength and high
tablet friability values.
Tablet physical testing.
It was generally observed (Figure 11) that as the compactor roll
pressure was increased from 1 ton through 6 tons, the tablet
hardness values decreased. The hardness values of tablets
formed using original mixes were consistently higher than
the hardness values of tablets generated from granulations
that were roller compacted at 3 and 6 tons of pressure.
However, those tablets generated from ribbons that were
roller compacted at 1 ton had hardness values comparable
to tablets from original mixes. Methylcellulose produced
the hardest tablets; METHOCELTM 1828 exhibited the lowest
hardness values. Lower hardness values in formulations
containing roller-compacted material are consistent with
findings from previous authors who investigated the reworking
of solid dosage forms as a means of retrieving or recycling
tablets that are out of specification. The tablet friability test is
an indicator of tablet brittleness. It measures how well tablets
will withstand the rigors of the tablet coating and packaging
processes without excessive wear and abrasion. The friability
value is a percent weight loss based upon 20 tablets tumbling
in a rotating cylinder over a 6-min period. Therefore, the lower
the friability value, the less the amount of tablet wear. As a rule,
6-min friability values of <1% usually equate to acceptable
tablet physical characteristics. Methylcellulose, METHOCELTM
2208, METHOCELTM 2910, and METHOCELTM 2906 had friability
values of <1%. These cellulosic products also tended to have
high compaction efficiency values for granules retained on the
18-mesh screen. METHOCELTM 1828 had the lowest percent
of coarse material (>18-mesh) and also demonstrated tablet
friability values >1% (1.61-3.06%).
Drug dissolution.
Figures 8-10 show the release of niacinamide from tablet
formulations used in Phase I. Figures 11-13 represent drug
dissolutions from Phase IIa-c. Because of the large volume
of experiments in this study, only specific figures have
been selected for discussion. The drug release from tablets
compressed from original (nonroller- compacted) mixes is
used in every figure as a point of reference for comparison. The
original-mix tablets are labeled as “direct compression” inthe
legend of each graph. Phase I drug dissolutions can be divided
into three categories based on the level of applied roller
compaction pressure (1, 3, and 6 tons).
The 1-ton drug dissolution is represented by Figure 12
(METHOCELTM 2906). Three of five polymers exhibited an 8% or
greater difference in niacinamide released from recycled and
nonrecycled granules. Perhaps at this low roller compaction
pressure, the drug and polymer do not bond sufficiently
to minimize their separation during product recycling.
This separation may cause nonuniform drug levels in the
granulations and final tablets.
Figure 13 (METHOCELTM 2208) and Figure 14 (METHOCELTM
2910) represent applied roller compaction pressures of 3 tons
and 6 tons, respectively. Only two of five polymers at 3 tons and
one of five polymers at 6 tons showed a >8% difference in the
final percentage of drug released. These results tend to confirm
that the higher roller compaction pressures bind the drug and
polymer more efficiently. The exception was methylcellulose,
USP, which exhibited differences in content uniformity at all
three compactor pressures.
13 Controlled Release
There was no apparent relationship between the level of
applied compactor pressure and drug dissolution nor between
tablet hardness and drug dissolution. This observation is
consistent with the findings of previous investigators, who
found that various applied compaction forces had little effect
on drug release from tablets containing METHOCELTM polymers
in a matrix system. Prior investigators addressed various tablet
press compression forces, and the authors of this study found a
similar comparison between various applied roller compactor
pressures and drug release from cellulose ether polymers in a
matrix system.
Figure 15 (Phase IIa) shows the drug release from the first of
three Phase II experiments. Assays of individual granulations
were used to determine drug content uniformity and were
compared with assays of the original mix tablets (direct
compression). Results show that the granulation assayed at
91% drug (niacinamide) level for the 1-ton samples, 95% for the
3-ton, and 94% for the 6-ton samples. The original mix assayed
at 100% of predicted drug level. This experiment helped to
confirm that there was a drug content uniformity concern in
many of the previous Phase I experiments, especially those
using a 1-ton applied roller compactor pressure. The second
experiment (Phase IIb, Figure 16) using one-third original mix,
one-third coarse material, and one-third fine material was also
assayed to evaluate drug content uniformity in the granulations.
Assays of the granulations revealed an 89% drug level in the
1-ton sample, 102% in the 3-ton, and 99% in the 6-ton samples.
This second experiment showed that increasing the percentage
of recycled material did not solve the drug uniformity problem.
The third experiment in Phase II (Figure 17) used a system in
which no product recycle was involved so that drug content
uniformity problems associated with excessive sieving and
processing would not be a significant factor. Compacted
ribbons were milled and only passed through a 16-mesh
screen. The quantity of coarse material was consistently <2%.
Assays of the granulations showed a 103% drug level for the
1- ton roller compacted samples, 101% for the 3-ton, and
100% for the 6-ton samples. Minimizing the amount of product
recycle during the roller compaction process appears to be an
important parameter in enhancing drug content uniformity in
the finished tablets.
FIGURE 11: EFFECT OF ROLLER COMPACTION PRESSURE
ON TABLET HARDNESS VALUES.
Tablet hardness, SCU (Strong-Cobb units) //
Roller compaction pressure, tons
FIGURE 13: TABLET DISSOLUTION WITH METHOCELTM 2208 USING
3 TONS ROLLER COMPACTION PRESSURE (PHASE I)
Niacinamide release, % // Time, H
FIGURE 12: TABLET DISSOLUTION WITH METHOCELTM 2906 USING
1 TON ROLLER COMPACTION PRESSURE (PHASE I)
Niacinamide release, % // Time, H
100
100
80
80
60
60
40
40
20
20
0
3
Direct compression
2nd roller compaction cycle
using only >18 mesh granules
6
9
12
15
1st roller compaction cycle
2nd roller compaction cycle
using only <80 mesh granules
FIGURE 14: TABLET DISSOLUTION WITH METHOCELTM 2910 USING
6 TONS ROLLER COMPACTION PRESSURE (PHASE I).
Niacinamide release, % // Time, H
100
100
80
80
60
60
40
40
20
20
0
3
Direct compression
2nd roller compaction cycle
using only >18 mesh granules
6
9
12
15
0
Direct compression
(mix assay = 100%)
1st roller compaction cycle
2nd roller compaction cycle
using only <80 mesh granules
100
100
10
80
80
60
60
40
40
20
20
2
OM*
METHOCELTM 2208, USP
METHOCELTM, USP
1
2
METHOCELTM 1828, USP
METHOCELTM 2906, USP
3
4
METHOCELTM 2910, USP
*Original mix (compressed on Carver press)
5
6
0
3
1 ton (granulation assay = 89%)
3 tons (granulation assay = 102%)
6 tons (granulation assay = 99%)
6
9
Direct compression
(mix assay = 100%)
12
6
9
12
15
1st roller compaction cycle
2nd roller compaction cycle
using only <80 mesh granules
3
6
1 ton (granulation assay = 91%)
3 tons (granulation assay = 95%)
9
12
15
6 tons (granulation assay = 94%)
FIGURE 17: TABLET DISSOLUTION WITH METHYLCELLULOSE USING
ALL GRANULATED MATERIAL PASSING THROUGH A 16-MESH
SCREEN AND NO PRODUCT RECYCLE AT 1, 3 AND 6 TON ROLLER
COMPACTION PRESSURE (PHASE IIC).
Niacinamide release, % // Time, H
14
6
3
FIGURE 15: TABLET DISSOLUTION WITH METHYLCELLULOSE USING
1, 3, AND 6 TON ROLLER COMPACTION PRESSURE (PHASE IIA).
Niacinamide release, % // Time, H
FIGURE 16: TABLET DISSOLUTION WITH METHYLCELLULOSE USING
1/3 ORIGINAL MIX, 1/3 COARSE (>18 MESH) GRANULES,
AND 1/3 FINE (<80 MESH) GRANULES AT 1, 3, AND 6 TON ROLLER
COMPACTION PRESSURE (PHASE IIB).
Niacinamide release, % // Time, H
18
0
Direct compression
2nd roller compaction cycle
using only >18 mesh granules
15
0
3
1 ton (granulation assay = 103%)
3 tons (granulation assay = 101%)
6 tons (granulation assay = 100%)
6
9
12
15
Direct compression
(mix assay = 100%)
®TMTrademark of The Dow Chemical Company (“Dow”) or an affiliated company of Dow
Controlled Release 14
Controlled
Release
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[email protected]
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•
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