excipientfest americas 2008
TRANSCRIPT
1
Improving of compactibility and friability in high dose tablets using
novel microcrystalline cellulose CeolusTM KG-1000
16th April 2008KAZUHIRO OBAE, Ph.D.
Asahi Kasei Chemicals CorporationE-mail: [email protected]
ExcipientFest Americas 2008
2
Contents
Back ground
Properties of KG-1000
Mechanism of high compactibility of KG-1000
Performance of KG-1000 in key applications
Conclusions
3
Back ground
Tableting
Tablet is the most preferred solid dosage form due to its high productivity and easy swallowing.
Tableting problems often occur because of lowcompactibility of APIs.
Epecially in case of high dose tablets with limitedexcipient volume of excipient, it is hard to preventtableting problems.
4
KG-1000 development
Investigated the effects of MCC particle properties intablet compaction to solve those tableting problems.
It found L/D value of MCC is one of most importantfactors dominating tablet hardness of MCC 1), 2).
KG-1000 is designed especially to improvecompactibility and friability with small portion of MCC.
1) K. Obae, H. Iijima and K. Imada, Int. J. Pharm., 182, 155-164(1999).2) K.Obae, H. Iijima and K. Imada, Kobunshi Ronbunshu, Vol.56, No.3, 141-150(1999).
Introduction
5
Properties of Ceolus™ KG-1000
NF/EP/JP compatible MCC
superior compactibility due to its unique
particle morphology (Bigger the L/D ratio,
higher the compactibility)
High oil absorbing capacity
6
Repose Angle [deg]
Bulk Density[g/cm³]
Av. ParticleSize [µm]
Oil absorbingCapacity[wt%]
KG-1000 0.12 50 57 270
KG-802 0.21 50 49 200
PH-F20JP 0.23 20 >60 180
PH-101 0.29 50 45 190
PH-102 0.30 90 42 180
PH-301 0.41 50 41 120
PH-302 0.42 90 38 120
PH-200 0.35 170 36 130
Powder properties of Ceolus™ grades
Tocopherol Acetate was used as oil.
7
Physical properties of Ceolus™ grades
Flowability
High
Low
Low
High
DisintegrationSlow
Fast
PH-F20JP
PH-101PH-102
PH-301
PH-302
PH-200
KG-802
KG-1000
Compactibility
8
Particle morphology of Ceolus™ grades
PH-101 PH-102
KG-1000 KG-802
9
Average particle size and L/D ratio of Ceolus™ grades
10
Mechanism of high compactibility of KG-1000
MCC particle’s orientation inside tablets
Plastic deformation of large L/D particle
11
Impact of L/D ratio on compactibility
40
60
80
100
120
140
1.5 2.0 2.5 3.0 3.5L/D [-] : measured by classifying in 38-20µm
Har
dnes
s of
MC
Cpl
ain
tabl
et [
N]
KG-1000
KG-802
PH-102
4.0
160
12
b) L/D=1.59; 75-150µm
0
20
40
60
10 30 50 70 90
a) L/D=1.58; 0-38µm
0
20
40
60
10 30 50 70 90
Orientation angle [deg]
Freq
uenc
y [%
]
c) L/D=1.83; 45-75µm
010 30 50 70 90
20
40
60d) L/D=1.90; 38-45µm
0
20
40
60
10 30 50 70 90
h) L/D=2.51; 45-75µm
10 30 50 70 900
20
40
60g) L/D=2.26; 38-45µm
10 30 50 70 900
20
40
60f) L/D=1.74; 0-38µm
10 30 50 70 900
20
40
60e) L/D=1.70; 75-150µm
10 30 50 70 900
20
40
60
Freq
uenc
y [%
]
KG
-802
PH
-101
In the result of image analysis from previous photos, MCC particles tend to arrange at smaller angle, as L/D ratio increases.
Orientationangle
MCC particle
Distribution of MCC particle’s orientation inside tablets
13
Particle aggregation and L/D ratio
Cross section-D Cross section-L
Large
L/D
Small L/D particle has aggregated particles which prevents free deformation of particles.Large L/D particle keeps fibrous structure facilitating particle deformation.
Small
PH-101
KG-1000
14
Fisher Instrument Co., Ltd.Fisher Scope H-100
Condition：100mN/10s（load）－10 s（creep）－0.4mN/10 s（without load）
Indenter ： flat indenter （50um s.q.）Sample ：MCC ParticleSampling scale ：10 samples each were spread on slide glass and measured
Plastic deformation of Ceolus grades
Pressure test of MCC particle Elastic recovery
0
0.1
0.2
0.3
0.4
0.5
0.6
Wor
k of
ela
stic
def
orm
atio
n [m
N・
nm]
L/DSmall Large1.8
PH-101 KG-802 KG-1000
Particles with large L/D have smaller elastic recovery and contribute to enhance larger plastic deformation.
3.52.8
Disp. [nm]
Forc
e [m
N]
Work of plasticdeformation
Work of elasticdeformation
Straingauge
Particle
15
Mechanism of compactibility of high L/D particle
Compression force High
Smal
lL/
D
1.6
2.3
Larg
e
Large elasticity⇒low-dense structure
(many voids)
Small elasticity⇒high-dense structure
(few voids)
LowC
ompr
essi
on
Plastic deformation and filling of small voids
Particles re-arrangementand filling of large voids
PH-101
KG-802
16
Improves compactibility and friability with only 5% addition as an extra granular additionContributes in preventing tableting problems such as sticking and capping
High Oil Adsorbing Capacity
High Compactibility
Makes the tableting of liquid or oily APIspossible due to restraint of API bleeding whiletableting
Key Features of Ceolus™ KG-1000
17
1. Direct compression of lactose tablet
2. High shear granulation/ tableting, Extra-granular
addition of MCC (MCC addition rate: 5%)
3. Direct compression for Vitamin C 80% formulation
4. Roller compaction for large dose drug
5. Direct compression for Vitamin E formulation
Application data of Ceolus™ KG-1000
18
70~90 10~30
0.5
Evaluation
Mixing
Mixing
Tableting
Mg-St
ø8mm
12R
200mg
for 3 min in PE bag
for 30 s on PE bag
Rotary press12 punches56rpmgravity feeder
Tablet hardness
Ceolus™ KG-1000, 802PH-102 (Asahi)
Lactose MCC
Direct compressionof lactose based formulations
The 1st experimental example
19
Hardness of lactose base tablet
0
50
100
150
200
250
300
5 10 15 20 25Compression force [kN]
Har
dnes
s [N
]
0
Lactose : MCC = 70~90 : 30~10
KG-1000/30%
KG-1000/20%KG-802/30%
PH-102/30%KG-1000/10%
content 2/3
content 1/3
20
Issues:Low compactible drugs tend to show a capping tendency at high compression force, therefore, tablets of these drugs may show insufficient tablethardness and friability.
High shear granulation/ tableting extra granular addition of MCC MCC addition rate: 5%
Small addition of KG-1000 was effective to improve hardness and friability, it is very useful for making low compactible drugs tablets. Small addition of KG-1000 was effective to improve hardness and friability, it is very useful for making low compactible drugs tablets.
The 2nd experimental example
21
MCC
APAP Corn Starch CCS*
6% HPC-L aq.
Ceolus™ PH-102 KG-1000, 802 (Asahi)
Mg-St
0.5wt%(against granule)
Granule
90 wt% 7 wt% 3 wt%
0.85wt%(against mixing powder)
* CCS: Croscarmellose Sodium
Impeller： 280rpm, cross screw： 3000rpmgranulation time： 6 min.
5wt%
Rotary tableting machine53rpm, 180mg, ø 8mm, 12 punchesCompression force ; 4, 8, 12kN
95wt%
Sieved by 1410mm screen
Mixing
Granulation
Mixing (1)Mixing (2)
Tableting
Experimental procedure
22
Tablet Weight Variance Tablet Hardness
Tablet properties
0
0.2
0.4
0.6
0.8
1.0
Tabl
et w
eigh
t R
SD [
%]
No MCCPH-102
KG-802KG-1000
0
10
20
30
40
50
60
5 10 15Compression force [kN]
Har
dnes
s [N
] KG-802
PH-102
no MCC
Required practical level
KG-1000
0
23
Tablet Friability
KG-1000 is excellent MCC in avoiding capping at high compression force.
Compression force [kN]
0
1
2
3
4
5 10 15
Fria
bilit
y [%
]
KG-1000
KG-802
PH-102no MCC
0
24
Stability after stored under 40℃75%RH in sealed container
Fria
bilit
y [%
]0
2
4
6
8
10
12
0 30 60 90
KG-1000
KG-802
PH-102
Retention periods [d]
0
20
40
60
Har
dnes
s [N
]
KG-1000
KG-802
PH-102
0 30 60 90Retention periods [d]
25
Issues:Tableting problems such as sticking and capping may occur as the content of low compactible drug increases. Furthermore, tablet hardness and friability decrease as a turn table speed increases.
Effectiveness of KG-1000 on preventing tableting problems was observed.And also, it was observed KG-1000 contributed to improve tablet hardness and friability at faster a turn table speed.
Effectiveness of KG-1000 on preventing tableting problems was observed.And also, it was observed KG-1000 contributed to improve tablet hardness and friability at faster a turn table speed.
The 3rd experimental example
Direct compression for Vitamin C 80% formulation
26
MCC 15 wt%CCS** 2
Mg-St
Ascorbic acid* 80 wt%Calcium silicate 3
MCC：CeolusTM KG-1000 (Asahi)
KG-802 (Asahi)
PH-102 (Asahi)ProsolvTM SMCC90 (JRS)
for 5 min. in tumbler type mixer
for 25 min. in tumbler type mixer
** CCS: Croscarmellose Sodium
for 5 min. in tumbler type mixer
3 wt% (against mixing powder)
*milled crystalline powderAv.particle size： 170μm
Rotary tableting machine LIBRA2 (Kikusui)12 punches, 30 or 50 rpm600mg (ø12mm), using gravity feeder Compression force : 10-20 kN
Mixing
Mixing
Mixing
Tableting
Tablet weight, Hardness, Friability, Disintegration timeEvaluation
Experimental procedure
27
Powder properties
0.5070.516
0.4940.487
0.46
0.48
0.50
0.52
no MCCPH-102
KG-802KG-1000
Bu
lk d
ensi
ty [
g/cm
3 ]
no MCCPH-102
KG-802KG-1000
Rep
ose
angl
e [
deg]
40
45
50
55
60
65
70
44.0
58.0
44.5 45.0
Bulk density Repose angle
0.480
SMCC90
43.5
SMCC90
28
Tablet Weight Variance
0
1.0
2.0
3.0
30 50
Tabl
et w
eigh
t RSD
[%
] *a
vera
ge v
alue
PH-102
SMCC90
KG-802KG-1000
Rotating speed [rpm]
29
Tablet Hardness
Rotating speed: 30 rpm Rotating speed: 50 rpm
0
20
40
60
80
10 15 20
Har
dnes
s [N
]
Compression force [kN]
PH-102
SMCC90
KG-802
KG-1000
0
20
40
60
80
Har
dnes
s [N
]10 15 20Compression force [kN]
PH-102SMCC90KG-802
KG-1000
30
Influence of rotating speed on tablet hardness
30 50
Rotating speed [rpm]
0
20
40
60
80
Har
dnes
s [N
]
PH-102
SMCC90
KG-802
KG-1000
Compression force 20kN
31
Rotating speed: 50 rpm
Tablet Friability
Rotating speed: 30 rpm
15 20Compression force [kN]
0
2
4
6
8
10
12
Fria
bilit
y [%
]0
2
4
6
8
10
12
Fria
bilit
y [%
]
15 20Compression force [kN]
PH-102
SMCC90KG-802KG-1000
KG-802
KG-1000
PH-102
SMCC90
32
Tableting problems
KG-1000 is effective in preventing tabeting problems.
10
30
50
70
90
0 5 10 15 20 25Conpression force [kN]
Stic
king
rat
e [%
]
Rotating speed 50rpm
5
10
15
20
25
0 10 30 50Rotating speed [rpm]
Capp
ing
rate
[%
]
Compression force 20kN
KG-802KG-1000
PH-102
SMCC90
KG-802KG-1000
PH-102
SMCC90
Sticking rate Capping rate
33
Disintegration properties
0
20
40
60
80
100
120
0 20 40 60 80Hardness [N]
PH-102SMCC90
KG-802KG-1000
Dis
inte
grat
ion
tim
e [s
ec]
34
Issues:In roller compaction method, tablet hardness and friability are often insufficient due to the decrease of compactibility of MCC after milling of rollercompaction sheet.
It was observed KG-1000 contributed to improve tablet hardness and friability in roller compaction method.It was observed KG-1000 contributed to improve tablet hardness and friability in roller compaction method.
The 4th experimental example
Roller compaction for large dose drug
35
Acetaminophen 60 wt%Microcrystalline cellulose 20 %Lactose 20 %
Mg-St
Tablet weight, Hardness, Friability
Rotary tableting machine; CREANPRESS2(Kikusui) (12 punches, 54rpm, with gravity feeder, ø8mm/180mg)
for 3 min in PE bag
for 30 sec in PE bag
High-dense type
Ceolus™ KG-1000, KG-802, PH-101(Asahi)
Pharmatose 200M (DMV)
for 30 sec in PE bag
RCP-66K(Kurimoto)Roller compaction force: 15kN, sheet thickness: ca.1mm
Oscillator: QC-197S(Powrex)Screen: 1.14mm, Screw speed: 2400rpm
Mg-St SiO2
* Based on granules
Mixing
Mixing
Roller compaction
Milling
Mixing
Tableting
Evaluation
0.3 wt%*
0.2 wt%*
1.0%*
Experimental procedure
36
Granule properties
MCC
PH-101
KG-802
KG-1000
Bulkdencity[g/cm³]
0.51
0.51
0.46
AverageParticle size
[µm]202
228
250
Reposeangle[deg]
42
44
44
Granule propertiesRollerCompaction
Force[kN]
15
37
Tablet weight variance
Roller compaction force: 15kN
0
0.5
1.0
1.5
2.0
PH-101 KG-802 KG-1000
Tabl
et w
eigh
t C
V [
%, a
vera
ge]
38
Tablet properties
Roller compaction force: 15kN
0
20
40
60
80
0 5 10 15 20 25Compression force [kN]
KG-1000
KG-802
Har
dnes
s [N
]
Fria
bilit
y [%
]0
0.5
1.0
1.5
2.0
2.5
0 5 10 15 20 25Compression force [kN]
KG-1000
KG-802
PH-101
PH-101
Lowest practical level
Lowest practical level
39
Issues:Compaction after powderization of oily API causes decrease of the tablet hardness and friability due to bleeding of oily API from the powdery oily API.
It was observed KG-1000 restrained bleeding of oily API while tableting, and improved the tablet hardness, due to its compactibility and oil absorbing capacity.
It was observed KG-1000 restrained bleeding of oily API while tableting, and improved the tablet hardness, due to its compactibility and oil absorbing capacity.
The final experimental example
Direct compression for Vitamin E formulation
40
VE prep.* MCC SD lactose PC-10
Mg-St
Rotary tableting machine54rpm, 180mg, ø 8mm
1.5 wt%
* VE preparation (Commercial product)Tocopherol acetate 50wt%Light anhydrous silicic acid 50wt%
10 wt% 20 wt% 47 wt%
for 3 min in P.E. bag
for 30 sec. in P.E. bag
20 wt% 3 wt%
Tablet weight, Hardness, Friability
MCC: Ceolus™ PH-102KG-1000, 802 (Asahi)
MAS**
Mixing
Mixing
Tableting
Evaluation
** MAS: Magnesium Aluminometa Silicate
Experimental procedure
41
Compression force vs. Hardness Compression force vs. Friability
0
0.1
0.2
0.3
0.4
0.5
0.6
5 10 15 20 25Compression force [kN]
Fria
bilit
y [%
]
KG-1000
PH-102
KG-802
00
10
20
30
40
50
60
70
Har
dnes
s [N
]
KG-1000
KG-802
PH-102
5 10 15 20 25Compression force [kN]
0
Tablet properties
Lowest practical level
42
Stability after stored under 60ºC in sealed container
Using tablet compressed at 20kN
0
10
20
30
40
50
60
70
0 30 60 90Retention periods [d]
KG-1000
KG-802
PH-102
Har
dnes
s [N
] Lowest practical level
43
Conclusions
Superior compactibility due to its unique morphological properties
Designed especially for improving compactibility and friability with a small portion of MCC
High Oil absorbing capacity
An ideal MCC binder for challenging tablet formulations.