Melt Extrusion and Granulation-11 2011 (Abu S).pdf
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Transcript of Melt Extrusion and Granulation-11 2011 (Abu S).pdf
Abu T. M. Serajuddin, Ph.D.St. John‟s University, Queens, New York
E-mail: [email protected]; Phone: 718-990-7822
MELT EXTRUSION AND
MELT GRANULATION
PROCESSES
IN DEVELOPMENT OF DRUG PRODUCTS
2
General Understanding : Hot melt extrusion is a single-
step process suitable to manufacture high-energy
solids (e.g., solid dispersion)
Homogeneous mixture of active, polymer
plasticizer, surfactant
Hot Melt Extrusion Technology
Extrusion Detail – Melting & Mixing
Ref: Adapted from Scott Martin (ThermoFisher
Scientific ) presentation
Basic Screw Elements
Conveying Elements
Feeding Sections
Blending
Melt Exchange (longitudinal mixing)
Pumping, Pressurization
Degassing / Venting
Mixing Elements
Blending
Intense Shear Introduction
Dispersive Mixing
Distributive Mixing
Ref: Adapted from Scott Martin (ThermoFisher
Scientific ) presentation
Extrusion System – Length-to-Diameter Ratio
25:1 l/d
40:1 l/d
Ref: Adapted from Scott Martin (ThermoFisher
Scientific ) presentation
6
High-energy Solid
and
Solid Dispersion
Application of Melt extrusion
7Temperature
Heat
co
nte
nt
(en
thalp
y, H
)
Tg (drug)
liquid
Crystal
Tmelting
Heat of
fusion
High-energy
state
Low energy
state
Formation of High-energy Solid
8
Sto
rag
e tem
pera
ture
Tg (mixture)
Drug - polymer
miscible blend
(solid dispersion)
Temperature
He
at
co
nte
nt
(en
thalp
y, H
)
Tg (drug)
Drug only
Conversion to Solid Dispersion
Elevated Tg
What is Solid Dispersion ?
Complete miscibilityNo miscibility
Carrier
(amorphous)
Partial miscibility
Drug
(crystalline) +
“the dispersion of one or more active ingredients in an inert carrier or matrix,
where the active ingredients could exist in finely crystalline, solubilized or
amorphous state” - Chiou and Riegelman, J Pharm Sci 1971, 60, 1281-1302
10
Application of Melt Extrusion
Solid Dispersion
11
Homogeneous mixture of active, polymer
plasticizer, surfactant
Solid Dispersion by Hot Melt Extrusion
Advantages of Melt Extrusion
Continuous Process
Complete conversion to amorphous state, reproducible and no local melting (unlike co-milling or co-melting)
Solid dispersion without solvents
Avoids solvent toxicity
Reduced cost/environment impact
No drying issues/residual solvents
Sustained-release capabilities
High potency capabilities (closed system)
13
Feed port
Motor
Die
Heated barrel with temperature zones
Conveying zoneMixing
zone
Feed port
Motor
Die
Heated barrel with temperature zones
Conveying zoneMixing
zone
• Temperature must be higher than the melting temperature (at
least 20°C higher) for complete conversion to amorphous form
and ease of processing (reduce viscosity)
• Risk associated with chemical stability – thermo-labile
compounds
• High Tg of commonly used polymers (150-160 °C) – need
suitable plasticizers; temperature must be > Tg
• Lack of miscibility between drug and polymer
Challenges with Melt Extrusion
Why So Few Solid Dispersion Products?
Most Significant Impediments
Lack of appropriate carriers/polymers
Immiscibility with drugs leads to phase separation
Incomplete drug release
Difficulty in predicting physical stability
Solid dispersions are usually amorphous
Crystallization of drug, carrier or both leads to physical
instability
15
Polymer Trade Name Tg
Poly(ethylene oxide) Polyox WSR -67
Polyethylene glycol Carbowax -20
Poly (vinyl pyrrolidone) Kollidon 168
Poly (lactide-co-glycolide) PLGA 40-60
Polyvinyl alcohol Elvanol 85
Ethyl cellulose Ethocel 133
Hydroxypropyl cellulose Klucel 130
Hydroxypropylmethyl cellulose Methocel 175
Aminomethacrylate colpolymer Eudragit RS/RL 64
Poly(dimethlyaminoethylmethacryl
ate-co-methacrylic ester)
Eudragit E 50
Poly methcyrlic acid-co-
methylmethacrylate)
Eudragit S 160
Some Common Polymers
Solid Miscibility
– Drug-carrier miscibility may lead to single-phase solid dispersion systems
– Drug-carrier „solid miscibility‟ is the first step in identifying a suitable carrier for a drug candidate
Carrier Screening
Partial miscibility Full miscibility
What is Drug-Carrier Miscibility ?
1500-50
Temperature
-100
Rev
Hea
t F
low
(W
/g)
50 100Exo Up
-0.0045250200
-0.0040
-0.0035
-0.0030
-0.0025
-0.0020
-0.55
109.13
162.35
1500-50
Temperature
-100
Rev
Hea
t F
low
(W
/g)
50 100Exo Up
-0.0045250200
-0.0040
-0.0035
-0.0030
-0.0025
-0.0020
-0.55
109.13
162.35
1500-50
Temperature
-100
Rev
Hea
t F
low
(W
/g)
50 100Exo Up
250200-0.0040
-0.0035
-0.0030
-0.0025
-0.0020
101.42
-0.0015
1500-50
Temperature
-100
Rev
Hea
t F
low
(W
/g)
50 100Exo Up
250200-0.0040
-0.0035
-0.0030
-0.0025
-0.0020
101.42
-0.0015
Tg of drug
Tg of solid
dispersion
Tg of polymer
Tg of solid
dispersion
Carrier Screening
Solid Miscibility versus Solid Solubility
Solid miscibility, however, does not guarantee physical stability
„Solid solubility‟ is a better predictor of physical stability
Ref: Vasanthavada et al., Phase Behavior of Amorphous Molecular Dispersions:
Determination of the Degree and Mechanism of Solid Miscibility, Pharm. Res., 2004, 21:1598
& 2005, 22:440
Tg of pure
polymerTgeq
Heat F
low
(W
/g)
Temperature
Fresh SD
Pure polymer
SD @ stability conditionsTg of
drugTg of drug + polymer
Tg of fresh SD
dissolved drug plasticizes the polymer
Ref: Vasanthavada et al., Phase Behavior of Amorphous Molecular Dispersions: Determination
of the Degree and Mechanism of Solid Miscibility, Pharm. Res., 2004, 21:1598 & 2005, 22:440
Effect of Storage Condition Drug-Carrier Miscibility
20
Case Study
Solid Dispersion by Melt Extrusion
21
Molecular weight 573.70
Melting point 180°C
Glass transition [Tg] ~120°C
Chemical form Weak base
pKa 10.03; 2.91
Solubility in water (RT) pH 1: 0.03 mg/mLpH 3 - 9: <0.003 mg/mL
15% degradation during melt extrusion of crystalline form with PVP or HPMC
Lower Temperature Melt Extrusion –A Case Study
Compound A
22
Crystalline drug subs.
Polymer
+High
temperature
melt extrusion
Drug
degradation
Am
orp
h.e
xtr
ud
ate
Amorphous drug subs.
+Polymer
Lower
temperature
melt extrusion
Stable product
Lower Temperature Melt Extrusion – A Novel Strategy
Ref: Lakshman & Serajuddin et al., Molecular Pharmaceutics, 5:994-
1002, 2008
23
Amorphous Form* of Compound A Used for Melt Extrusion
Nature of amorphous form as a function of temperature
25 C 120 C 126 C 140 C
Miscibility of amorphous form with PVP K-30
120 C 140 C 155 C 170 C*Amorphous form prepared separately by solvent evaporation
24
Melt extruded with PVP K-30 at 20 and 40% w/v drug load
using sorbitol as plasticizer (30% and lower drug load). No
significant drug degradation.
DSC Analysis of Melt Extrudates
40% w/w drug
30% w/w drug
20% w/w drug
15% w/w drug
25
Pooled data from two PK dog studies
0
10
20
30
40
50
60
70
80
0 2 4 6 8
Time (hrs)
Pla
sma
con
c. (
ng
/ml)
20% TKA & Poloxamer triturate, capsule
20% Melt extrusion, capsule
20% melt extrusion & surfactant,capsule
20% spray drying, tablet
20% spray granulation, tablet
old 20% melt extrusion
20% rotavap, tablet
Mean PK profiles of Compound A in dogs at Mean PK profiles of Compound A in dogs at a constant drug load
20% drug A & Poloxamer triturate, capsule
20% melt extrusion, K90, capsule
20% melt extrusion, K90 w/SLS, capsule
20% spray drying, tablet
20% spray granulation, tablet
20% melt extrusion, K30, capsule
20% rotavap, tablet
0
10
20
30
40
50
60
70
80
0 2 4 6 8
Time (hrs)
Pla
sma
con
c. (
ng
/ml)
20% TKA & Poloxamer triturate, capsule
20% Melt extrusion, capsule
20% melt extrusion & surfactant,capsule
20% spray drying, tablet
20% spray granulation, tablet
old 20% melt extrusion
20% rotavap, tablet
Mean PK profiles of Compound A in dogs at Mean PK profiles of Compound A in dogs at a constant drug load
20% drug A & Poloxamer triturate, capsule
20% melt extrusion, K90, capsule
20% melt extrusion, K90 w/SLS, capsule
20% spray drying, tablet
20% spray granulation, tablet
20% melt extrusion, K30, capsule
20% rotavap, tablet
Relative Bioavailability of Melt Extruded Solid Dispersion (Compound A)
Recent Breakthrough in
Granulation Technology
- Use of Twin-screw Extruders
Melt Granulation Technology –
Traditional
Melt granulation is a process by which pharmaceutical
powders are efficiently agglomerated by the use of a
binder which melts during the process
Melt Granulation
High-shear granulation
Heat transfer is a major issue
Relatively high temperature cannot be used
Melt Granulation – Traditional Methods
Traditional Methods
High-shear melt granulation
Fluidized bed melt granulation
Tumbling melt granulation
Melt Granulation – Traditional Methods
Granulating Agents Used
(Melting Points: 45 – 85° C)
Poloxamers
Polyethylene glycols
Carnauba wax
Beeswax
Paraffin wax
Stearic acid
Hydrogenated castor oil
Use of Twin-Screw Extruders
32
Feed port
Motor
Die
Heated barrel with temperature zones
Conveying zoneMixing
zone
Feed port
Motor
Die
Heated barrel with temperature zones
Conveying zoneMixing
zone
• Relatively short dwell time in the heated barrel
• Temperature maintained below the melting
temperature of drug substance but above the glass
transition (or melting) temperature of polymer used
• Unlike older, traditional methods, temperature can be
raised as high as 200⁰C, making the use of a wide
range of polymeric materials possible
• A continuous process
Melt Granulation Using Twin-Screw Extruder
33
Polymer Trade Name Tg
Poly(ethylene oxide) Polyox WSR -67
Polyethylene glycol Carbowax -20
Poly (vinyl pyrrolidone) Kollidon 168
Poly (lactide-co-glycolide) PLGA 40-60
Polyvinyl alcohol Elvanol 85
Ethyl cellulose Ethocel 133
Hydroxypropyl cellulose Klucel 130
Hydroxypropylmethyl cellulose Methocel 175
Aminomethacrylate colpolymer Eudragit RS/RL 64
Poly(dimethlyaminoethylmethacryl
ate-co-methacrylic ester)
Eudragit E 50
Poly methcyrlic acid-co-
methylmethacrylate)
Eudragit S 160
Much Wider Range of Polymers May be Used
Ref: M. Vasanthavada, Y. Wang, J. P. Lakshman, W. Tong, Y. M. Joshi, A. T. M. Serajuddin. Application of Melt
Granulation Technology Using Twin-screw Extruder in the Development of Modified-release Oral Formulation for
a High-dose Drug Product. J. Pharm. Sci. 100, 1923–1934 (2011)
Development of High Dose Tablet-
Case Study
Development of High-Dose Modified
Release Tablet – A Case Study
Immediate release 400-mg marketed tablet weighs
~775 mg
What will be the weight of a 800-mg tablet?
800 mg drug substance in its salt form weighs ~960 mg
Is the development of a single-unit tablet formulation
feasible?
Active pharmaceutical ingredient (API) in a tablet is often
<50%
Major tabletting issues with higher drug load
The formulation development becomes very difficult, if not
impossible, if at least 25% of the weight of a tablet is not
excipient
It becomes even more challenging for a modified release
tablet, where at least 30-40% of the weight must be a
release-controlling polymer, in addition to other excipients
The maximum acceptable tablet size is 1000-1200 mg
For 750-1000 mg API, tablet size becomes unacceptably
high of 1500-2000 mg
Challenges in Development of High-Dose
Tablets
37
Formula-
tion No.
API*
[%w/w]
Polymer %w/w Tablet
weight
[mg]
MR1 94 Hydroxypropyl cellulose (Klucel HF) 5 1017
MR2 89 Hydroxypropyl cellulose (Klucel HF) 10 1074
MR3 89 Ethyl cellulose 100cP 10 1074
MR4 89 Hydroxypropylmethyl cellulose
K100M + Ethyl cellulose 100cP
5 + 5 1074
* Drug load in the final tablet, since all formulations contained 1% w/w
magnesium stearate as lubricant to aid in tabletting.
Compositions of High Dose Tablets (960
mg Salt Equivalent per Tablet)
A 16 mm co-rotating twin screw melt extruder (Thermo Fischer Scientific Inc., Germany) with a length-to-diameter ratio of 40-to-1 was used.
The extruder barrel was divided into 6 temperature zones: 50°, 110°, 130°, 170° and 185°C, with the cooler zone positioned towards the feeder and the warmer one towards the exit.
The maximum processing temperature of 185°C was below the melting temperature of 212°C for the API
A volumetric feeder (Brabender Technologie, Germany) with a unique pulsating mechanism and single horizontal feed screw was used to feed the powder.
The pre-mix was fed directly into the extruder at a constant volumetric rate equivalent to 20 g/min.38
Melt Granulation Process Used
39
Processing Conditions
40
Drug Release from Tablets (960 mg
mesylate salt, 800 mg free base
equivalent per tablet)
MR 1MR 1MR2
MR 4
MR 3
HPC 5%
HPC 10%
EC 10%
HPMC 5% + EC 5%
41
50µmoverlay
50µmAPI 50µmHPC 50µmMg Stearate
Confocal Raman Microscopic Study –Hydroxypropyl Cellulose Polymer
42
50µmm04s08184
Tablet Surface – MR 1
Development of High Dose Tablet-
Metformin HCl Case Study
J. P. Lakshman, J. Kowalski, M. Vasanthavada, W. Q. Tong, Y. M. Joshi, A. T. M. Serajuddin.
Application of melt granulation technology to enhance tabletting properties of poorly
compactible drug substance at high dose. J. Pharm. Sci. 100, 1553–1565 (2011).
Metformin hydrochloride exhibits minimal moisture sorption;
however, the small amount of moisture sorbed is enough to
dissolve large amounts of the drug.
Moisture desorption leaves behind metformin hydrochloride
particles with solid bridges.
In worst cases, extensive formation of solid bridges could result
in free flowing powder transforming overnight into a solid block.
With wet granulation or solvent granulation, this ability of
metformin leads to changing granulation flow, density, tablet
hardness, disintegration/ drug release that is difficult to control.
Further, poor tablet compaction and process robustness become
key concerns because of the need for high drug load in the
formulation.
44
Challenges in Development of Metformin HCl Tablet
Ingredients Amount/tablet (mg) %w/w
Metformin hydrochloride 1000.0 91%
Hydroxypropylcellulose 98.9 9%
Purified water q.s. n/a
(or ethanol: isopropanol 95:5)
Second drug substance 25.0/50.0 2.2%*
Magnesium stearate 10.2 0.9%
Total core weight 1134/1159
*dry mix with granules
Composition of Metformin HCl Tablet
Moist granulation was carried out using a high shear Collete-Gral® granulator. About 2.2 to 2.5% w/w water was sprayed over 4 min and granution was continued for 4 more min at ‘high’ plough speed. No drying was employed.
Melt granulation was performed using a 16-mm ThermoPrism® Melt Extruder. A maximum process temperature of 140-180°C together with an extruder screw speed of 120-300 rpm and feed rate of 1.2-2.7 kg/hr was used. All tablet compressions were performed using a ManestyBetapress® or Korsch® press after lubrication with magnesium stearate.
46
Granulation Processes for Metformin HCl Tablet
47
Moist Granulation – Effect of Moisture Content and Drying on Tablet Hardness
40
50
60
70
80
90
5 10 15 20 25
120
150
180
210
240
5 10 15 20 25
Compaction Force [kN]
a
b
Ta
ble
t H
ard
ne
ss [N
] . Measured
(a)immediately following
tablet compaction and
(b)after tray-drying the
tablets for 24 hours at 50⁰C.
Initial moisture levels:
1.45%; 1.54%; 1.60%;
1.67%; 1.77%; 1.80%;
2.08%; 2.12%; x 2.21%.
48
Moist Granulation – Effect of Moisture Content and Drying on Tablet Friability
0%
2%
4%
6%
8%
5 10 15 20 25
0%
2%
4%
6%
8%
5 10 15 20 25
Compaction Force [kN]
A B C D E F G H I
Fri
ab
ilit
y, 500 d
rop
s [
%]
b
a
0%
2%
4%
6%
8%
5 10 15 20 25
0%
2%
4%
6%
8%
5 10 15 20 25
Compaction Force [kN]
A B C D E F G H I
Fri
ab
ilit
y, 500 d
rop
s [
%]
b
a
Measured
(a) immediate following tablet
compaction and
(b) after tray-drying the tablets
for 24 hours at 50⁰C.
Initial moisture levels:
1.45%; 1.54%; 1.60%;
1.67%; 1.77%; 1.80%;
2.08%; 2.12%; x 2.21%.
Melt Granulation – Effect of Processing Condition on Tablet Hardness
0
50
100
150
200
250
300
350
400
450
0 10 20 30
Compaction Force (kN)
Ta
ble
t H
ard
ne
ss (
N)
Temperature, feed rate, screw speed and
magnesium stearate level :
: 180ºC, 40 g/min , 120 rpm and 0.75%;
: 140ºC, 40g/min, 120 rpm and 0.75%;
: 140ºC, 40 g/min 120 rpm and 1.25%; :
180ºC, 40 g/min, 120 rpm and 1.25%;
: 160ºC, 30 g/min, 210 rpm and 1.00%;
: 160ºC, 30 g/min, 210 rpm and 1.00%;
+: 180ºC, 20 g/min, 300 rpm and 0.75%;
x: 140ºC, 20 g/min, 300 rpm and 1.25%;
: 140ºC, 20 g/min, 300 rpm and 0.75%.
Melt Extrusion – Effect of Processing Condition on Tablet Friability
0
0.2
0.4
0.6
0.8
1
1.2
1.4
100 150 200 250 300 350 400
Hardness (N)
% F
riab
ilit
y (
500 d
rop
s)
180°C 40g/min 120rpm 0.75%
180°C 20g/min 300rpm 1.25%
180°C 40g/min 120rpm 1.25%
140°C 40g/min 120rpm 1.25%
140°C 40g/min 120rpm 0.75%
51
Melt Granulation: Application in Continuous Processing
Powder Feeding
Powder Mixing
Melt GranulationC
oolin
g
Sizing/Sieving
Tabletting/Spray
Lubrication
Coating
Packaging
Sieving (optional)
More drug in a tablet leads to smaller tablet size!!
Over 90% drug per tablet
Conclusions - Melt Extrusion Technology
Conv. technology
Melt granulation technologySame dose
Creating a safer
environment
with no organic
solvents
Reducing cost with
fewer
manufacturing
steps &
IP protectionA Continuous Manufacturing Process
Ref: Andreas Gryczke, RÖHM GmbH & Co. KG, Darmstadt Specialty Acrylics / Pharma
Polymers. 2005-10-03
Drug + Polymer+Melt Granulates
[Drug Product]
Melt granulation –
A promising technology