MELT EXTRUSION AND
MELT GRANULATION
PROCESSES
IN DEVELOPMENT OF DRUG PRODUCTS
Abu T. M. Serajuddin, Ph.D.
St. John‟s University, Queens, New York
E-mail: [email protected]; Phone: 718-990-7822
Hot Melt Extrusion Technology
General Understanding : Hot melt extrusion is a singlestep process suitable to manufacture high-energy
solids (e.g., solid dispersion)
Homogeneous mixture of active, polymer
plasticizer, surfactant
2
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
Application of Melt extrusion
High-energy Solid
and
Solid Dispersion
6
Formation of High-energy Solid
(enthalpy, H)
Heat content
liquid
High-energy
state
Heat of
fusion
Crystal
Low energy
state
7
Tg (drug)
Temperature
Tmelting
Storage temperature
(enthalpy, H)
Heat content
Conversion to Solid Dispersion
Drug only
Drug - polymer
miscible blend
(solid dispersion)
Elevated Tg
Tg (drug)
8
Temperature
Tg (mixture)
What is Solid Dispersion ?
“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
Drug
(crystalline)
No miscibility
Carrier
+
Partial miscibility
(amorphous)
Complete miscibility
Solid Dispersion
Application of Melt Extrusion
10
Solid Dispersion by Hot Melt Extrusion
Homogeneous mixture of active, polymer
plasticizer, surfactant
11
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)
Challenges with Melt Extrusion
Feed port
Heated barrel with
temperature zones
Motor
Conveying zone
Mixing
zone
Die
• 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
13
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
Some Common Polymers
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
Eudragit E
50
Eudragit S
160
ate-co-methacrylic ester)
Poly methcyrlic acid-co15
methylmethacrylate)
Carrier Screening
Solid Miscibility
–
Drug-carrier miscibility may lead to singlephase solid dispersion systems
–
Drug-carrier „solid miscibility‟ is the first step
in identifying a suitable carrier for a drug
candidate
-0.0020
-0.0015
-0.0025
-0.0020
-0.55
Rev Heat Flow (W/g)
Rev Heat Flow (W/g)
What is Drug-Carrier Miscibility ?
Tg of drug
-0.0030
109.13
Tg of solid
-0.0035
dispersion
-0.0040
162.35
-50
0
50
100
150
101.42
-0.0030
Tg of solid
dispersion
-0.0035
Tg of polymer
-0.0045
-100
Exo Up
-0.0025
200
Temperature
Partial miscibility
250
-0.0040
-100
Exo Up
-50
0
50
100
150
200
Temperature
Full miscibility
250
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
Effect of Storage Condition Drug-Carrier
Miscibility
Tg of pure
Tgeq
polymer
Heat Flow (W/g)
Pure polymer
Fresh SD
Tg of fresh SD
Tg of
drug
SD @ stability conditions
Tg of drug + polymer
Temperature
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
Solid Dispersion by Melt Extrusion
Case Study
20
Lower Temperature Melt Extrusion –
A Case Study
Compound A
Molecular weight
Melting point
Glass transition [Tg]
Chemical form
pKa
Solubility in water (RT)
21
15% degradation
during melt
extrusion of
crystalline form with
PVP or HPMC
573.70
180°C
~120°C
Weak base
10.03; 2.91
pH 1: 0.03 mg/mL
pH 3 - 9: <0.003 mg/mL
Crystalline drug subs.
+
Polymer
Amorphous drug subs.
+
Polymer
High
temperature
melt extrusion
Lower
temperature
melt extrusion
Amorph. extrudate
Lower Temperature Melt Extrusion – A
Novel Strategy
Drug
degradation
Stable product
Ref: Lakshman & Serajuddin et al., Molecular Pharmaceutics, 5:9941002, 2008
22
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
23
140 C
155 C
*Amorphous form prepared separately by solvent evaporation
170 C
DSC Analysis of Melt Extrudates
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.
40% w/w drug
30% w/w drug
20% w/w drug
15% w/w drug
24
Relative Bioavailability of Melt Extruded
Solid Dispersion (Compound A)
Plasma conc. (ng/ml)
Mean PK profiles of Compound A in dogs at a constant drug load
80
20%
TKAA&&Poloxamer
triturate,
capsule
20% drug
Poloxamer triturate,
capsule
70
20%
Meltextrusion,
extrusion,
capsule
20% melt
K90,
capsule
60
20%
meltextrusion,
extrusion
& surfactant,capsule
20% melt
K90
w/SLS, capsule
20%
spraydrying,
drying,
tablet
20% spray
tablet
50
20%
spraygranulation,
granulation,
tablet
20% spray
tablet
40
old
extrusion
20%20%
melt melt
extrusion,
K30, capsule
30
20%
rotavap,tablet
tablet
20% rotavap,
20
10
0
0
2
4
Time (hrs)
Pooled data from two PK dog studies
25
6
8
Recent Breakthrough in
Granulation Technology
- Use of Twin-screw Extruders
Melt Granulation Technology –
Traditional
Melt Granulation
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 – Traditional Methods
Traditional Methods
 High-shear melt granulation
 Fluidized bed melt granulation
 Tumbling melt granulation
High-shear granulation
 Heat transfer is a major
issue
 Relatively high
temperature cannot be
used
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
Melt Granulation Using Twin-Screw
Extruder
Feed port
Heated barrel with
temperature zones
Motor
Conveying zone
Mixing
zone
Die
• 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
32
Much Wider Range of Polymers May be
Used
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
Eudragit E
50
Eudragit S
160
ate-co-methacrylic ester)
Poly methcyrlic acid-co33
methylmethacrylate)
Development of High Dose TabletCase Study
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 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?
Challenges in Development of High-Dose
Tablets
 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
Compositions of High Dose Tablets (960
mg Salt Equivalent per Tablet)
Formula-
API*
tion No.
[%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
5+5
1074
K100M + Ethyl cellulose 100cP
* Drug load in the final tablet, since all formulations contained 1% w/w
magnesium stearate as lubricant to aid in tabletting.
37
Melt Granulation Process Used
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
Processing Conditions
39
Drug Release from Tablets (960 mg
mesylate salt, 800 mg free base
equivalent per tablet)
HPC 5%
MR 1
HPC 10%
MR2
MR 3
EC 10%
MR 4
HPMC 5%
+ EC 5%
40
Confocal Raman Microscopic Study –
Hydroxypropyl Cellulose Polymer
overlay
41
API
50µm
50µm
HPC
50µm
Mg Stearate
50µm
Tablet Surface – MR 1
s08184
42
m04
50µm
Development of High Dose TabletMetformin 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).
Challenges in Development of
Metformin HCl Tablet
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
Composition of Metformin HCl Tablet
Ingredients
Amount/tablet (mg) %w/w
Metformin hydrochloride
1000.0
91%
Hydroxypropylcellulose
98.9
9%
Purified water
(or ethanol: isopropanol 95:5)
q.s.
n/a
Second drug substance
25.0/50.0
2.2%*
Magnesium stearate
10.2
0.9%
Total core weight
1134/1159
*dry mix with granules
Granulation Processes for 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 Manesty
Betapress® or Korsch® press after lubrication
with magnesium stearate.
46
Moist Granulation – Effect of Moisture
Content and Drying on Tablet Hardness
a
90
.
70
Measured
Tablet Hardness [N]
80
60
(a)immediately following
50
tablet compaction and
40
5
10
15
20
(b)after tray-drying the
tablets for 24 hours at 50⁰C.
b
240
210
Initial moisture levels:
180
 1.45%;  1.54%;  1.60%;
150
 1.67%;  1.77%;  1.80%;
120
 2.08%;  2.12%; x 2.21%.
5
10
15
20
Compaction Force [kN]
47
25
25
Moist Granulation – Effect of Moisture
Content and Drying on Tablet Friability
a
8%
Measured
Friability, 500 drops [%]
6%
(a) immediate following tablet
4%
compaction and
2%
(b) after tray-drying the tablets
0%
5
10
15
20
for 24 hours at 50⁰C.
b
8%
Initial moisture levels:
6%
4%
 1.45%;  1.54%;  1.60%;
2%
 1.67%;  1.77%;  1.80%;
0%
 2.08%;  2.12%; x 2.21%.
5
10
15
20
Compaction Force [kN]
48
25
25
Melt Granulation – Effect of Processing
Condition on Tablet Hardness
450
Temperature, feed rate, screw speed and
400
magnesium stearate level :
Tablet Hardness (N)
350
: 180ºC, 40 g/min , 120 rpm and 0.75%;
300
: 140ºC, 40g/min, 120 rpm and 0.75%;
250
: 140ºC, 40 g/min 120 rpm and 1.25%; :
180ºC, 40 g/min, 120 rpm and 1.25%;
200
150
: 160ºC, 30 g/min, 210 rpm and 1.00%;
100
: 160ºC, 30 g/min, 210 rpm and 1.00%;
+: 180ºC, 20 g/min, 300 rpm and 0.75%;
50
0
0
10
20
Compaction Force (kN)
30
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
1.4
180°C 40g/min 120rpm 0.75%
180°C 20g/min 300rpm 1.25%
1.2
180°C 40g/min 120rpm 1.25%
140°C 40g/min 120rpm 1.25%
% Friability (500 drops)
1
140°C 40g/min 120rpm 0.75%
0.8
0.6
0.4
0.2
0
100
150
200
250
Hardness (N)
300
350
400
Melt Granulation:
Application in Continuous Processing
Powder Feeding
Sizing/Sieving
Powder Mixing
Tabletting/Spray
Lubrication
Cooling
Sieving (optional)
Coating
Melt Granulation
Packaging
51
Conclusions - Melt Extrusion Technology
More drug in a tablet leads to smaller tablet size!!
Over 90% drug per tablet
Conv. technology
Same dose
Melt granulation technology
Drug+ + Polymer
Melt Granulates
[Drug Product]
Reducing cost with
fewer
manufacturing
Ref: Andreas Gryczke, RÖHM GmbH & Co. KG, Darmstadt Specialty Acrylics / Pharma
Polymers. 2005-10-03
Creating a safer
A Continuous Manufacturing Process
environment
with no organic
Melt granulation –
solvents
A promising technology
steps &
IP protection