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

mailto:[email protected]

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



Extrusion System – Length-to-Diameter Ratio

25:1 l/d

40:1 l/d



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



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% 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



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 w/SLS, 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



zone

Feed port

Motor

Die



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


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


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

Documents

Melt Extrusion and Granulation-11 2011 (Abu S).pdf