influence of binder critical material attributes on ...
Transcript of influence of binder critical material attributes on ...
——influence of binder critical material attributes on granule and tablet properties
introducing Klucel™ EXF Ultra HPC
Dr. Christian Mühlenfeldhead of pharma R&D, Europe
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—today’s presenter
Christian Mühlenfeld
Dr. Christian Mühlenfeld leads the European research and development and technicalservices team for Pharmaceuticals at Ashland, based in Düsseldorf, Germany. Hiscurrent role involves support for Ashland’s highly functional materials and ingredientsthat enable overcoming active delivery challenges such as bioavailabilityenhancement, drug stabilization and controlled drug delivery as well as processtechnologies to achieve advanced drug delivery and continuous manufacturing.
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—agenda
o considerations for binder selection
o case study: binder selection for wet granulation
o new ultra-fine binder
o case study: influence of binder critical material attributes in high-shear granulation
o summary
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—common ingredients for tablets
tablet
tablet binder = material that is able under compression to hold the particles of the compressed powder together. Binders ensure that powders and granules can be formed with required mechanical strength to tablets
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—role of binders in tablet development
the role of binders during compaction1
contribute to the plastic deformation during the consolidation of powders or granules
generate or enhance inter-particulate surface sites where bonding can take place
contribute to the plastic deformation during decompaction
withstand shear stresses & strains that can cause crack propagation & structural failure during post compactional stages of tablet production
1Reference: Symecko and Rhodes, Drug Dev Ind Pharm 21 (9) (1995)
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—Ashland's binder portfolio
exceptional range of binders to find the right one for your formulation and process
Klucel™ HPC
Plasdone™ povidone
Plasdone™S-630
copovidone
Aqualon™ EC
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—considerations for rational binder selection
○ mechanical properties of the polymer○ type of solvent and solids level○ tablet disintegration and dissolution time ○ binder use levels○ manufacturing process
– in dry processing, finer particle size provides the best binding performance
– in wet granulation, wetting and binder–drug surface interaction, i.e., relationship between drug hydrophobicity (logP) and binder surface tension, improve binding
○ stability and incompatibility with APIs and other excipients○ regulatory acceptance and supplier reliability
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case study: binder selection for wet granulation
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—critical binder attributes for wet granulation
o mechanical properties of the polymer– toughness and plasticity are important in wet and dry processing
o viscosity1
– for some binders, this may preclude pre-dissolving and solution addition can also affect spreadabiltiy
o particle size– for dry addition and granulation with pure solvent, not relevant if binder is pre-dissolved– distribution in interstitial spaces– smaller particles are inherently more plastic/less brittle
o surface interaction between binder solution and API– surface wetting and spreadability are critical
1in water (or other granulation liquids used) and the dissolution medium
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—wet granulation process and composition
○ comparison of binders with metformin, albendazole, and efavirenz○ these APIs vary in mechanical properties and hydrophobicity (logP)
structure
compound Metformin Albendazole Efavirenz
solubility in water1
>300 g/L 2.28 mg/L 0.86 mg/L
hydrophobicity (logP)1
-0.5 2.7 4.6
flowability poor poor poor
compactability poor good poor
plasticity poor good poor
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—wet granulation process and composition
Binders used for wet granulation processes
2Measured by laser diffraction 3BET method
Property Klucel™ EXF HPC
E15 HPMC
Plasdone™ S-630 PVP/VA
Plasdone™ K-29/32
PVP
Surface tension(mN/m) 40 45.9 49.5 53.6
Mean particlesize (µm)2 50 90 76 107
Relative toughness
Superior Low High Medium
Surface area(m²/cm³)3 0.32 0.15 0.21 0.37
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10
100
1000
0 5 10 15 20
visc
osit
y (m
Pa∙s
)
solution concentration %
Klucel™ EXF HPC
Plasdone S-630 PVP/VA
Plasdone™ K-29/32 PVP
MC A15LV
HPMC E15
Plasdone™ S-630 PVP/VA
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—wet granulation process and composition
Material % mg/tablet
API 80 400
Lactose monohydrate 200 mesh 11 55
Binder 5 25
Polyplasdone™ XL crospovidone 3 15
Magnesium stearate 1 5
TOTAL 100 500
mix API, lactose and binder in high shear mixer
granulate with DI water, dry, then pass through conical mill (1.0 mm screen)
blend with Polyplasdone™ XL crospovidone
blend with magnesium stearate
compress 500 mg tablets using a rotary press and 11 mm round tooling
hypothesis:• in wet binder optimization, surface interaction is important alongside
mechanical properties• surface interaction may be simplistically predicted for aqueous systems on
the basis of API logP and binder surface tension
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—compactability profiles
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350
0 5 10 15 20
tab
let
bre
aki
ng
forc
e (
N)
compaction force (kN)
Klucel™ HPC EXFPlasdone™ PVP K-29/32HPMC E15Plasdone™ PVPVA S-630
Metformin HCl (log P –0.5)
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50
100
150
200
250
300
0 5 10 15
tab
let
bre
aki
ng
forc
e (
N)
compaction force (kN)
Plasdone™ PVPVA S-630Klucel™ HPC EXFHPMC E15Plasdone™ PVP K29-32
Albendazole (log P 2.7) Efavirenz (log P 4.6)
0
50
100
150
200
250
0 10 20 30
tab
let
bre
aki
ng
forc
e (
N)
compaction force (kN)
Plasdone™ PVPVA S-630Plasdone™ PVP K-29/32Klucel™ HPC EXFHPMC E15
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—conclusion
○ in wet binder optimization, it is important to understand the correlation between the API logP and the surface tension of the binder solution: – hydrophilic APIs (low log P):
higher surface tension (hydrophilic) binders like Plasdone™ K-29/32 PVP generate granules that bring about result in better tablet compactibility.
– moderate hydrophobicity APIs (medium log P): binder surface tension is not critical and most binders will work, but differences in binder performance will be seen based on their mechanical properties
– highly hydrophobic APIs (high log P):lower surface tension binders such as Klucel™ HPC will result in the strongest tablets due to better surface energetics/wetting and excellent mechanical properties.
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NEW ultra-fine binder
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—
3 binder in wet granulation
2 binder in dry granulation
1 binder in direct compression
Klucel™ hydroxypropylcellulose (HPC) is a non-ionic water soluble cellulose ether with a unique combination of properties.
Klucel™ hydroxypropylcellulose (HPC)
Klucel™ EXF Ultra HPC
standardgrades
(regular grind)
d50 regular grind: 230 – 510 μmd50 fine (X) grind: 45 – 90 μmd50 ultra fine grind: 15 – 30 μm
X-grinds
Klucel™ HPC
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—Klucel™ hydroxypropylcellulose (HPC)
○ product designation is a combination of viscosity type (e.g. E) followed by particle size○ Klucel™ E HPC viscosity-type differences in particle size:
0
20
40
60
80
100
1 10 100 1000 10000
cu
mu
lativ
e
dist
ribu
tion
(%
)
particle size [µm]
Klucel™ EXF Ultra HPC
Klucel™ EXF HPC
Klucel™ EF HPC0
50
100
150
200
250
1 10 100 1000 10000
dist
ribu
tion
(q
3lo
g)
particle size [µm]
Klucel™ EXF Ultra HPC
Klucel™ EF HPC
Klucel™ EXF HPC
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—mechanical properties of binders
○ to assess mechanical properties ofbinders, 400 mg 11.28 mm flat-faced pure polymer tablets were prepared on a STYLCAM compaction simulator
250
300
350
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450
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550
600
650
5 10 15 20 25 30
tab
let
bre
aki
ng
forc
e (
N)
compaction force (kN)
competitive HPC 2 (fine)
competitive HPC 1
MCC
Klucel™ EXF Ultra HPC
Klucel™ EXF HPC
binder d10 (µm)
d50(µm)
d90(µm)
Klucel™ EXF Ultra HPC 6 23 55
Klucel™ EXF HPC 23 68 200
competitive HPC 1 17 64 121
competitive HPC 2 (fine) 8 20 50
MCC 35 110 225
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—mechanical properties of binders: plasticity and toughness
0
200
400
600
800
1000
1200
0 2 4 6 8
forc
e (
N)
displacement (mm)
Microcrystalline cellulosePovidoneCompetitive HPC 1Competitive HPC 2Klucel™ EXF HPCKlucel™ EXF Ultra HPC
Klucel™ EXF Ultra HPC exhibits excellent plasticity and toughness
area under the force-distancecurve = toughness (work of failure) pure polymer tablets subjected to diametral compression
testing until breaking. Example: Klucel™ EXF Ultra HPC.
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—diametral compression test (tablet fracture test)failure mode of polymers
Klucel™ EXF Ultra HPC competitive HPC 2 MCC
Pure polymer tablets of Klucel™ EXF Ultra never break, just deform
400 mg pure polymer tablets (STYLCAM compaction simulator, 11.28 mm flat-faced) subjected to diametral compression testing until breaking (Instron universal testing machine); cross head speed 0.5 inch/min.
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—summary: Klucel™ EXF Ultra HPC
○ ultra fine particle size – significantly lower typical particle size, to enhance
performance○ exceptional plasticity
– enables higher binder efficiency—leading to enhanced tablet strength and low friability at lower usage levels
○ outstanding compressibility– excellent plasticity and toughness results in
outstanding compressibility– unlike other binders, Klucel™ HPC tablets never
actually break, they just deform. Klucel™ EXF Ultra HPC withstands significantly greater breaking forces
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influence of binder critical material attributes in high-shear granulation
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—aim of the study
○ in wet granulation granule and tablet properties depend mainly on following critical material attributes (CMAs)– particle size distribution– viscosity of binder
○ variability of the starting/raw materials may be manifested in the final product properties but also can cause processing difficulties
○ aim of this study is to understand how variation of the binder (within its specification range) interacts with high-shear mixer process parameters for their impact on granulate and tablet properties
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—critical material attributes evaluated
○ variation of particle size distribution by using different grades of Klucel™ hydroxypropylcellulose:
○ variation of viscosity by lot selection:
Viscosity Product Viscosity (mPas)
low Klucel™ EXF HPC 386
medium Klucel™ EXF HPC 425
high Klucel™ EXF HPC 475
Particle Size Product d50 [µm]
low Klucel™ EXF Ultra HPC 15 – 30
medium Klucel™ EXF HPC 45 – 90
high Klucel™ EF HPC 230 – 510
EXF Ultra
EXF
EF
-1 +1
+1
-1
0Viscosity
Pa
rtic
leSi
ze
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—formulation and process
water
granule calibration1.6mmdiameter =10 mm
weight = 300 mg
blend withexternal phase
70 °C15 minphase component weight
(%)weight (mg)
internalparacetamol 93 279
binder 3 9
external
Polyplasdone™ XL crospovidone
3 9
magnesium stearate 1 3
total 100 300
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—granule PSD & friability
○ for binders at same viscosity, increasing binder particle size:– lower span of granule PSD– less fines (highest fines at EXF
Ultra)○ EXF with increasing viscosity:
– more oversized granules– lower span
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
10 100 1000
de
nsit
y d
istrib
utio
n, q
3
minimum feret diameter (µm)
Klucel™ EXF Ultra HPC
Klucel™ EXF 'low' HPC
Klucel™ EXF 'medium' HPC
Klucel™ EXF 'high' HPC
Klucel™ EF HPC
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—
0
5
10
15
20
25
30
Klucel™ EXF Ultra
HPC
Klucel™ EXF 'low'
HPC
Klucel™ EXF
'medium' HPC
Klucel™ EXF 'high'
HPC
Klucel™ EF
HPC
gra
nu
le f
riab
ility
[%
]
granule friability1 & densitiesgranules containing EXF Ultra with slightly lower BD & TDdecreasing friability with PSD increase EXF Ultra > EXF > EF
higher friability with increasing viscosity ’low’ < ’medium’ < ‘high’
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Klucel™ EXF Ultra
HPC
Klucel™ EXF 'low'
HPC
Klucel™ EXF
'medium' HPC
Klucel™ EXF 'high'
HPC
Klucel™ EF HPC
gra
nu
le d
en
sity
[g/m
l] bulk density tapped density
1friability of the granules during sieving through an air-jet sieve was used as surrogate parameter to estimate granule strength. Thus, friability and granule strength are inversely proportional.
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—
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0 5 10 15 20 25
tab
let
bre
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ng
forc
e (
N)
compaction force (kN)
Klucel™ EXF Ultra HPCKlucel™ EXF 'low' HPCKlucel™ EXF 'medium' HPCKlucel™ EXF 'high' HPCKlucel™ EF HPC
tablet compaction
○ for binders at same viscosity(Klucel™ EF, EXF & EXF Ultra HPC)– highest breaking force for EXF
Ultra at all compaction forces – EF shows capping tendencies at
high compaction forces○ for binders at ‘same’ particle size
(Klucel™ EXF ‘low’, ‘medium’ & ‘high’ HPC)– with increasing viscosity slightly
lower breaking force at highest compaction force
*
*capping tendency
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—tablet disintegration and friability
EXF Ultra: low disintegration time at all compaction forcesNo distinguishable impact of other HPC grades or viscosity
All tablets are well below a friability threshold of 1%
0102030405060708090
100
5 10 15 20
disi
nte
gra
tion
tim
e (
s)
compaction force (kN)
Klucel™ EXF Ultra HPCKlucel™ EXF 'low' HPCKlucel™ EXF 'medium' HPCKlucel™ EXF 'high' HPCKlucel™ EF HPC
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
5 10 15 20
fria
bilit
y (%
)
compaction force (kN)
Klucel™ EXF Ultra HPCKlucel™ EXF 'low' HPCKlucel™ EXF 'medium' HPCKlucel™ EXF 'high' HPCKlucel™ EF HPC
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—case study: summary
○ variations in starting material properties showed to have no influence on processability of raw materials, indicating that the physical variability (PSD, viscosity) of hydroxypropyl cellulose (HPC) does not negatively affect the processability at all
○ an improvement was observed in mechanical properties of granules and tablets, without significantly influencing disintegration times, when using Klucel™ EXF Ultra HPC– the use of Klucel™ EXF Ultra HPC resulted in finer granules and yielded tablets with
stronger mechanical properties, possibly due to the higher dry binding efficiency of smaller binder particles associated with a higher specific surface area
○ A better understanding about Klucel™ HPC material attribute variation (PSD, viscosity) was gained, which can optimally be used to manage the variability in the production process in order to obtain end-products with similar properties
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—Ashland's binder portfolio
exceptional range of binders to find the right one for your formulation and process
Klucel™ HPC
Plasdone™ povidone
Plasdone™S-630
copovidone
Aqualon™ EC
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—Ashland’s binder selection decision tree
Klucel™ EXF or EF hydroxypropylcellulose
Klucel™ EXF Ultra hydroxypropylcellulose
Klucel™ EXF hydroxypropylcellulose
what type of process will be used?
wet processing
low (hydrophilic)
Plasdone™ K-29/32 povidone
Plasdone™ S-630 copovidone
medium
Klucel™ EXF hydroxypropylcellulose
Plasdone™ K-29/32 povidone
Plasdone™ S-630 copovidone
high (hydrophobic)
what is the logP of the API? (how wettable is it?)
dry processing
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