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The Role of Polymer Excipients in Hot Melt Extrusion – A Continuous Manufacturing Process

Nigel LangleyExcipientFest May 1, 2018

Principle of HME

Hot-Melt Extrusion – A Continuous Manufacturing Process

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Hot-Melt Extrusion Technology

A poorly soluble crystalline API and an amorphous polymer are transferred into a solid dispersion with thermal and mechanicalenergy

Hot Melt Extrusion is one key technology for the preparation of solid dispersions

Extruder

∆EHot Melt Extrusion

Solid dispersionAPI in polymer

poorly soluble crystalline API

Amorphouspolymersolvent

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Biopharmaceutical Classification System BCS

The BCS classifies APIs by their solubility and permeability for cell membranes. There is a trend for recent API candidates to fall in the low solubility class II (or IV).

Source: G.L. Amidon, H. Lennermäs, V.P. Shah, J.R. Crison, Pharm. Res. 12 (1995), 413-420

High Solubility Low Solubility

High Permeability Class I Class II

Low Permeability Class III Class IV

Relevant Types of Solid Dispersions

Drug:dissolved

crystalline amorphous molecularly

Polymer: amorphous amorphous amorphous

Thermo-dynamic almost stable unstable stable (drug belowstabilitysolubility)

(kinetically controlled) saturation

Solid Solutions and Solid Dispersions

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Relevant Polymer Characteristics

Targeted release profileLong term

stability

Hygros-copicity

Physico-chemical

properties of active

Thermo-stability of

drug & polymer

Solution &solubilizingcapability

Melt viscosity

Drug + Polymer

Glass transition tempera-

ture

Parameters to Consider

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Basic Requirements for Polymers

Thermoplastic behavior

Suitable Tg

High thermal stability

Low hygroscopicity

No toxicity

High or no solubilization capability

deformability is essential

50 – 180°C

50 – 180°C

prevents crystallization

application of large amounts

thermodynamically stable formulation

Polymer Properties

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Polymers for Different Release Profiles

EntericIR

9

SR

Kollidon® VA 64 Kollidon® K17, K30, K90

Kollicoat® IR Soluplus®

Kolliphor P 188 / 407HPMCHPCEudragit® EPEGPolyvinyl alcohol

Kollicoat® MAE 100- 55Kollicoat MAE 100 PEudragit® L 100-55 HPMCAPHPMCAS

Kollidon® SR Polyvinyl acetate Ethyl celluloseEudragit® RS

Polymers for Hot Melt Extrusion

Matrix polymers for solid dispersions

Kollidon® 12 PF, 17 PF(Povidone)

**

NO

n

**

N

n

O O O

m

Kollidon® VA 64(Copovidone)

Kollicoat® IR,Kollicoat®

Protect

OHO

OO

*

*

N

O

O

Oo o

o

Soluplus® Kollicoat® MAE 100P

Kollidon® SR(PVAc)

**

O O

n

OHO

m

**

O O

n

Hydrophilicity / Polarity

Lipophilicity / Hydrophobicity

(enteric release)

(modified release)

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dried polymer film

Preparation of filmswith 10% to 50% drug content

Observation of film stability drug must not recrystallize

Goal:stable solid solution with 50% drug load

Active in solvent

Polymer in solvent

1:1

Film Test for Solid Solution Capacity

Solvent Screening Procedure

> 50< 25

> 5033 - 5033 - 50

< 25< 25< 25

< 25< 25

< 25< 25

> 5033 - 5025 – 33

> 50< 25< 25

> 50< 25< 25

33 - 5025 – 33< 25

33 - 5025 – 3325 – 33

> 5033 - 5025 – 33

Polymer

Drug content[% dissolved in polymer]

Fenofibrate Carbamazepine Itraconazole

Kollidon VA 64 25 – 33 33 - 50 > 50

Soluplus 33 - 50 33 - 50 > 50

Kollidon 12 PF 25 – 33 25 – 33 33 - 50

Kollidon 17 PF < 25 25 – 33 33 - 50

Kollidon 30* < 25 < 25 > 50

Kollidon 90 F** < 25 < 25 > 50

Kollidon SR 25 – 33 33 - 50 > 50

Kollicoat MAE 100P* < 25 > 50 n.d.

Kollicoat IR* < 25 < 25 n.d.

Kollicoat Protect* < 25 < 25 n.d.

Lutrol F 127 < 25 < 25 < 25

* with 10 % PEG 1500 ** with 20 % PEG 1500

Solid Solution Capacity

API Drug load – model drugs

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Glass Transition Temperatures of matrix polymersTe

mpe

ratu

re [

°C]

70

90

149 156

39

114 118130

186

101

0

20

40

60

80

100

120

140

160

180

200

Soluplus Kollidon12PF

Kollidon90F

KollicoatMAE

HPC

152

Usually, extrusion requires temperatures of min. 20 - 30 °C > Tg

Polymers for HME

**

N

n

O O O

m

Soluplus®

Innovative matrix andsolubilizer in one

taylored for HME use

increases solubilityand bioavailability

Solid Dispersions / Solid Solutions

Matrix Formers Solubilizers

Plasticizers

SoluplusKollidon VA 64Kollidon VA 64 FineKollidon 12 PFKollidon 17 PFKollidon 25 / 30Kollidon 90Kollidon SRKollicoat IRKollicoat ProtectKollicoat MAE 100P

Kolliphor P 188 Kolliphor P 188 micro

Kolliphor P 407Kolliphor P 407 micro

Kollisolv GTAKolliwax GMS IKolliwax SAKollisolv PEG E 300 Kollisolv PEG E 400Kollisolv PEG 1450

Kolliphor HS 15Kolliphor RH 40Kolliphor EL/ ELPKolliphor PS 20 Kolliphor PS 60Kolliphor PS 80Kolliphor SLS / FineKolliphor P 188Kolliphor P 407Soluplus

Kollidon® VA 64

Established matrixformer especially in hot melt extrusion

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Melt Viscosity as a Function of Temperature

Shear stress controlled rotational rheometer (Rheometrics SR5), plate to plategeometry, angular frequency: 16 rad/s

100

10

1000

10000

100000

1000000

120 140 220 240160 180 200

Temperature [°C]

Vis

cosi

ty*

[Pa*

s]Kollidon VA 64 SoluplusKollidon 12 PFKollidon 17 PFKollidon 30Kollidon 90 F Kollidon SRKollicoat MAE 100PKollicoat IRKollicoat Protect

Optimal melt viscosity range for HME

Melt Viscosities

Influence of Plasticizers on Extrusion Temperatures

The addition of 10% plasticizer significantly decreases processing temperatures

Pure Polymer

+ 10 %Kolliphor® P 188

Temperature [°C]

Kollidon® VA 64

Kollidon® 12 PF

Soluplus®

Kollidon® 17 PF

Kollicoat® IR

Kollidon® SR

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Appearance of polymer extrudates at specific extrusion temperatures

Kollidon® VA 64(160 °C)

Soluplus® (145 °C)

Kollidon® 12 PF (100 °C)

Kollidon® 17 PF(175 °C)

Kollicoat® Protect(160 °C)

Kollicoat® IR(160 °C)

Kolliphor™ P407(60 °C)

Kollidon® SR(180 °C)

0,00

0,10

0,20

0,30

0,40

0,50

0,60

0,70

0,80

0,90

1.000 10.000 100.000 1.000.000 10.000.000

w(l

og

(M))

M/Da

Kollidon VA 64 LOT 76964875L0extruded 160°C

Kollidon VA 64 LOT 76964875L0

Kollidon® VA 64 extrudates prepared at different temperatures

Kollidon® VA 64 can be extruded up to 220°C without degradation

160 °C 180 °C

220 °C 240 °C

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Soluplus® - The Solid Solution

Soluplus® combines the benefits of asolid solution and an excellent solubilizer

PEG 6000/ vinylcaprolactam/ vinyl acetate grafted copolymer 13/57/30

Tg: ~ 70 °C

soluble in water, acetone, ethanol

Soluplus®

Saturation solubility in phosphate buffer pH 7.0 [g/100 ml]

Soluplus® strongly increases the solubility for APIs with different chemical structures

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

~0.

001

~0.

001

~0.

001

~0.

0001

~0.

0001

~0.

0001

~0.

001

Soluplus® Pure API

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

10% solubilizer solution, saturation solubility detected after 72h stirring

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Soluplus®

Saturation solubility in phosphate buffer pH 7.0 [g/100 ml]

With 4 out of 10 APIs Soluplus® shows the highest solubilization capacity!

10% solubilizer solution, saturation solubility detected after 72h stirring

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Soluplus® Kolliphor® PS 80

Kolliphor® P 407

Kolliphor® RH40

Kolliphor® HS15

Extrusion parameters• 120 – 260°C• 1 kg/h

At extrusion temperatures up to 160°C nearly colourless extrudates

Thermostability

Soluplus® Thermal Stability

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Polymer Stability During Extrusion - Soluplus®

No change in chemical and physicochemical parameters up to 180 °C

Test parameter PowderExtrudate Extrudate

[extruded at 140°C] [extruded at 180°C]

Identification (IR)

pH-value

Ester value [mg KOH/g]

Vinyl acetate [ppm]

Vinyl caprolactame [ppm]

Caprolactame [g/100g]

Ethylenglykole [ppm]

Acetic acid / Acetate [ppm]

Peroxide [ppm]

Molecular weight Mw [g/Mol]

conf.

4.1

197

<2

<10

0.3

<100

365

<20

118,000

conforms

3.9

196

<2

<10

0.3

60

399

<20

119,000

conforms

3.9

196

<2

<10

0.3

63

396

<20

116,000

Analytical Results

Extrusion lead to amorphous extrudates (XRD) in all cases

Extrusion Studies

Extrusion parameters

16mm ThermoFisher Polylab, 40D

200 rpm

1 kg/h

mean residence time ~1 min

PolymerItraconazole

(15 %API)Fenofibrate (20 %API)

Carbamazepine (15 %API)

Soluplus® 150 100 140

Extrusion temperature [°C]

Hot-Melt Extrusion Process Conditions

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Soluplus® Extrudates with Fenofibrate - Appearance dependent on drug load

The transparency of extrudates decreases with increasing Fenofibrate load

25% 30% 35% 40% 45% 50%

Soluplus® + Fenofibrate

Dissolution – Extrudates with 15% Itraconazole

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Different matrix polymers give different dissolution profiles for Itraconazole

USP apparatus 2, 50rpm, 700 ml HCL (0.1molar), granulated extrudates, 100mg API (n=3, mean±sd)0

20

40

60

80

100

0 30 60 90 120

t [min]

drug

rel

ease

[%]

SoluplusKollidon VA 64Kollidon 12 PFHPC

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5 15 25 45 5535

2 theta [°]

inte

nsity

[a.u

.]

crystalline itraconazole

solid solution itraconazole

Solid solution Soluplus & itraconazole (85/15)

XRD

No crystalline active

Soluplus® Amorphous Extrudate

Soluplus® Bioavailability Enhancement of Itraconazole

A Soluplus® solid solution significantly increases the bioavailability of Itraconazole

Itraconazole –Soluplus®

extrudate

Sempera®

Itraconazolecrystalline

Plasma level [ng/mL]

0

150

300

450

600

750

0 10 20 30 40 50 60 70 80Time [hours]

Bioavailability = area under the curve (AUC)

Bioavailability of Soluplus® extrudate: 26-fold compared to crystalline drug2.3-fold compared to Sempera®

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Strategy for Formulation Development

Keep the formulation (and process) as simple as possible

Choose the appropriate polymer

+

+

For improved processability

For improved drug contentand prevention of crystallization in gastric and intestinal fluid

Active + Polymer

Plasticizer

Solubilizer

Hot-Melt Extrusion Manufacturing Process

Melt extrusion is an excellent process to formulate poorly soluble drugs and to improvebioavailability

Advantages vs spray drying – continuous process

Choice of an appropriate polymer is crucial for the formulation and the process

Most important polymer features are

- Tg and melt viscosity

- Solubilization capacity

- Dissolution

- Stability

- Toxicity/regulatory status

Polymers show very different extrusion behavior and suitability

Interactions between the various ingredients strongly influence the formulation

Soluplus® is a highly promising excipient designed for solid solutions and hot-melt extrusion

SummarySummary

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