Twin-screw melt granulation of a thermally labile drugFENG ZHANG

UNIVERSITY OF TEXAS AT AUSTIN

8 TH AMERICAN DRUG DELIVERY AND FORMULATION SUMMIT

SAN FRANCISCO, SEPTEMBER 10, 2018

1

ObjectivesTwin-screw melt granulation offers many advantages over continuous wet granulation and roller compaction.

To investigate the effect of formulation and process variables on the physicochemical properties of granules• Formulation variables: binder type• Process variables: screw profile, barrel temp, screw speed and feed rate

To understand the mechanisms and physicochemical changes during granulation

2

Presentation outline1. Introduction of melt granulation and gabapentin (GABA), a

thermally labile drug with poor compaction property

2. Selection of thermal binder and effect of thermal binder on the properties of GABA granules

3. Effect of processing conditions on the properties of GABA granules

4. Conclusions and future studies

3

Twin-Screw Melt Granulation

Granulation by TSE

Wet granulation

Melt granulation

• Continuous manufacturing• On-line and real time monitoring of product quality• Short granulation time and wider processing window• Reduction in binder (solution) level• Uniform distribution of formulation components• Less undesired physicochemical changes

• Use low-melting or thermoplastic materials as binders

• Energetic materials/explosives; powder metallurgy

• Improved flow and flow properties than roller-compacted granules

4

Nucleation mechanism of melt granulation: Depend on particle size and viscosity of binder

Distribution• Binder with low melt-viscosity• Molten binder is distributed onto the

surfaces of solid particles• Nuclei are formed by collision between

the wetted particle

Immersion• Thermoplastic binder with high melt

viscosity• Adhesion of solid particles onto the

surface of molten binder particles

James S, et al. Handbook of Pharmaceuitcal Granulation Technology. Taylor & Francis group LLC. 2005. 390-392. 5

Gabapentin (GABA) as a “Model drug”Goal of the study

• Identify formulation and process to (1) Improve compactability of gabapentin and (2) minimize processing-induced chemical degradation of gabapentin

Gabapentin as a “model drug” for melt granulation• High-dose, poorly compressible drug• Poor thermal stability• Current commercial process: fluidized-wet or high-shear wet granulation.

Gradual increase in the impurity content during the shelf life has been an real issue.

• During wet granulation, GABA is solubilized in binder solution. The presence of polymeric binders prevent GABA from recrystallize during drying. The solubilized GABA undergoes significant degradation during the storage.

6

Properties of GabapentinProperties

Indication Anti epileptic

Description White to off-white, crystalline solidForm II, the most stable form, is used in this study

MW 171.24 g/mol

Melting point 162-166°CpKa 3.7 (carboxylate), 10.7 (amine)

BCS class BCS class III (high solubility and low permeability)

Solubility pH-dependent solubility; soluble in water (100 mg/mL)

Particle size 6.1 μm (d10), 55.24 μm (d50), 215.64 μm (d90)

Others Crystalize rapidly, amorphous GABA could not be prepared

USP39 NF34 Gabapentinhttps://pubchem.ncbi.nlm.nih.gov/compound/gabapentin#section=Top

7

Degradation pathway in solution & solid state: lactamization (GABA-L)

• Gabapentin degrades to a cyclic lactam via an intramolecular cyclization reaction triggered by a nucleophilic attack of the COOH group by the N of the amino group, followed by a dehydration reaction

• The degradation reaction is irreversible• USP specification of Gaba-lactam: NMT 0.4%

Zhizin Z, et al. The stabilizing effect of moisture on the solid-state degradation of gabapentin. AAPS PharmSciTech. 2011. 12(3):924-931. 8

GABA undergoes lactamization upon melting

Tm ~ 174°C-40

-30

-20

-10

0

0

20

40

60

80

100

50 100 150 200 250 300 350 400

% w

eigh

t

Temperature (°C)

Heat flow (W

/g)

Dehydration due to degradation (~10.5%w/w)

Overlap between melting and degradation

9

The experiment from DSC and Hot stage PLM confirm that Gabapentin is immiscible with binders

Preliminary study: binder selectionMiscibility between GABA and binders

Hydrophilic binder

PEG 8000

Hydrophobic binder

Glycerol behenate (Compritol)

Thermoplastic polymer

HPC ELF (Klucel)

10

wt% hydroxypropyl groups: 53-81

Too good miscibility of GABA and binders is not desired!

Hold at 80°CHold at 100°C

Hold at 140°C

PEG (Tm ~60°C) Compritol (Tm ~70°C)

HPC (Tg ~0°C, soften at 100-140°C)

11

Binders Zone 1 Zone 2 Zone 3

GB-PEG8000 80°C 80°C 40°C

GB-Compritol 90°C 90°C 60°CGB-HPC ELF 120°C 120°C 70°C

GB-PEG8000 GB-Compritol 888 ATO GB-HPC ELF

80% GAGB and 20% binder; Feed rate 10 g/min, Screw speed 100 rpm

Leistritz nano 16Open-end discharge

12

SEM Images of Granules

GAGB+HPC/1000 X

13

GABA+Compritol/1000 XGABA+PEG/1000 X

• Mill the granule and collect the granule between 20-60 mesh (250-850 μm) mix with 1% Mg stearate compress into tablet

0.0

1.0

2.0

3.0

4.0

5.0

0.0 50.0 100.0 150.0

Tens

ile st

reng

th (M

Pa)

Compression pressure (MPa)

Melt granulation(20%HPC ELF+GB)Direct compression(20%HPC ELF+GB)

0.0

1.0

2.0

3.0

4.0

5.0

0.0 50.0 100.0 150.0

Tens

ile st

reng

th (M

Pa)

Compression pressure (MPa)

Melt granulation(20%PEG 8000+GB)Direct compression(20%PEG8000+GB)

0.0

1.0

2.0

3.0

4.0

5.0

0.0 50.0 100.0 150.0

Tens

ile st

reng

th (M

Pa)

Compression pressure (MPa)

Melt granulation(20%Compritol+GB)Direct compression(20%Compritol+GB)

Melt granulation significantly improves compaction properties.HPC is the most effective.

14

Degradation of GABA granules upon storage USP specification for GABA-L: NMT 0.4%

Induction-sealed HDPE bottles, desiccated

15

0.000

0.010

0.020

0.030

0.040

0.050

0.060

85 90 95 100 105 110

%Im

purit

y

Barrel temperature (°C)

20%HPC ELF+GB20%PEG8000+GB20%Compritol+GB

Degradation of gabapentin USP specification for GABA-L: NMT 0.4%

• Higher barrel temperature led to higher level of degradant

• At the same temperature : HPC ELF-based granule shown higher % GABA-lactam than Compritol and PEG 8000-based granules

16

Particle size reduction during melt granulation

0.00.1

0.2

0.3

0.4

0.50.6

0.7

0.8

0.9

1.0

1.11.2

1.3

1.4

1.5

1.6

1.7

Den

sity

dis

tribu

tion

q3*

0.4 0.6 0.8 1.0 2 4 6 8 10 20 40 60 80 100

particle size / µm

x(10 %)µm21.727.574.691.57

x(50 %)µm63.1242.8821.4110.45

x(90 %)µm116.1396.4949.0641.90

Param. 3

Opt. concentration%33.4725.6926.5130.75

Gabapentin drug substance

Compritol-GABA granules

HPC-GABA granules

PEG8000-GABA granules

GABA in HPC ELF based formulation has the smallest particle size high mechanical stress resulted in breakage of drug crystals and amorphization highest impurity

Acetone

Chloroform

17

Development of granule structure during the granulation along screw profile20% HPC EXF + Gabapentin

70°C120°C120°C

18

Change in gabapentin particle size along screw (EXF2-4)

• Sample the granules from each zone• Disperse in acetone in order to dissolve HPC • Measure the particle size of gabapentin

120°C 120°C 70°C

Feeding zone

Zone 1

Zone 2

Zone 3

Granules

Feeding zone Zone 1 Zone 2 Zone 3

Gradual decrease in GABA particle size

19

PM Z1

Z2 Z3

PM

Z1

Z2

Z3

Total CH2N- C2H3O-

20

Binder Distribution on the surface of granules: Time-of-Flight Secondary Ion Mass Spectrometry (TOF-SIMS)

Melt rheology of binders

• Melt viscosity of HPC ELF (pseudoplastic) >> melt viscosity of PEG 8000 and Compritol (Newtonian fluid).

• The high viscosity of HPC melt during granulation resulted in high shear stress that led to significant particle size reduction.

21

0.01

0.1

1

10

100

10 100 1000 10000

Ln (m

elt V

iscos

ity) (

Pa.s

)

Shear rate (1/s)

HPC ELF at 120°CPEG8000 at 80°CCompritol at 90°C

0.00

0.01

0.01

0.02

0.02

1 2 3 4

%G

ABA-

L

WEEK

40C, 10%RH40C, 30%RH40C, 75%RH

When granules were stored in open containers, slower degradation at higher humidity – due to crystallization of amorphous GABA

0.10

0.15

0.20

0.25

0.30

0 1 2 3 4

%G

ABA-

L

WEEK

40°C, 10%RH40°C, 30%RH40°C, 75%RH

GABA drug substanceGB-HPC ELF Granules

22

“The stabilizing effect of moisture on the solid-state degradation of gabapentin”, Z. Zong, AAPS PharmSciTech, 12(3) 925-31 (2011)

Effect of processing variables: screw speed, feed rate, and screw profile

70°C 110°C 110°C

• Move kneading element further down stream • Remove some narrow pitch conveying element to lower the torque

vent

23

5 g/min

7.5 g/min

10 g/min

100 rpm 150 rpm 200 rpm 300 rpm

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The effect of screw speed and feed rate on GABA extrudate size

Effect of screw speed and feed rate on the level of GABA-L

• Degradant content increases with increasing feed rate and decreasing the screw speed (increasing specific rate)

0.000

0.020

0.040

0.060

0.080

0.100

0.120

0.140

100 150 200 250 300 350

% G

ABA-

L

SCREW SPEED (RPM)

10 g/min7.5 g/min5 g/min

25

Impurity increases as degree of fill of conveying elements prior to kneading elements increases

y = 0.0042x + 0.0263R² = 0.7966

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.00 5.00 10.00 15.00 20.00 25.00

%GA

BA-L

%DEGREE OF FILL OF CONVEYING ELEMENTS

IMPURITY VS DEGREE OF FILL

10 g/min7.5 g/min5 g/min

𝐾𝐾𝐾𝐾 (𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎) =𝐾𝐾𝐾𝐾 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑚𝑚𝑎𝑎𝑚𝑚𝑎𝑎𝑟𝑟𝑟𝑟 𝑥𝑥 %𝑚𝑚𝑚𝑚𝑚𝑚𝑡𝑡𝑡𝑡𝑎𝑎 𝑥𝑥 𝑚𝑚𝑎𝑎𝑚𝑚 𝑥𝑥 0.97

𝑀𝑀𝑎𝑎𝑥𝑥. 𝑚𝑚𝑎𝑎𝑚𝑚

𝑆𝑆𝑎𝑎𝑎𝑎𝑆𝑆𝑎𝑎𝑆𝑆𝑎𝑎𝑆𝑆 𝑎𝑎𝑟𝑟𝑎𝑎𝑚𝑚𝑟𝑟𝑒𝑒 =𝐾𝐾𝐾𝐾 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎

𝐹𝐹𝑎𝑎𝑎𝑎𝑎𝑎 𝑚𝑚𝑎𝑎𝑚𝑚𝑎𝑎 (𝑘𝑘𝑟𝑟ℎ𝑚𝑚)

%𝐹𝐹𝑎𝑎𝑎𝑎𝑎𝑎 =𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭 𝒓𝒓𝒓𝒓𝒓𝒓𝑭𝑭 𝑥𝑥 100

(𝐶𝐶𝑚𝑚𝑚𝑚𝐶𝐶𝐶𝐶 𝐶𝐶𝑎𝑎𝑆𝑆𝑚𝑚𝑎𝑎𝑚𝑚𝑟𝑟 𝑎𝑎𝑚𝑚𝑎𝑎𝑎𝑎 𝑥𝑥 𝑃𝑃𝑎𝑎𝑚𝑚𝑆𝑆ℎ 𝑎𝑎𝑎𝑎𝑟𝑟𝑟𝑟𝑚𝑚ℎ 𝑥𝑥 𝒓𝒓𝒓𝒓𝒓𝒓 𝑥𝑥 𝐷𝐷𝑎𝑎𝑟𝑟𝐶𝐶𝑎𝑎𝑚𝑚𝑒𝑒)/2

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.10 0.11 0.12 0.13 0.14 0.15 0.16 0.17 0.18

%G

ABA-

L

SPECIFIC MECHANICAL ENERGY (KW)

IMPURITY VS SPECIFIC MECHANICAL ENERGY10 g/min7.5 g/min5 g/min

26

GABA particle size of GABA in extrudates: highest vs. lowest degree of fill

Granule, 5 g/min, 300 rpm

Granule, 10 g/min, 100 rpm

GABA drug substance

High degree of fill

Low degree of fill

27

Effect of shear stress on %GABA-L

GABA-L

Shear stress

Relation between %GABA-L (A) and shear stress (B) generated along the screw profile during melt granulation

(A)

(B)

28

0.00

0.10

0.20

0.30

%G

ABA-

L

10 g/min, 100 rpm

5 g/min, 300 rpm

0

20

40

60

80

100

%br

eaki

ng

DSC and ATR-FTIR of melt granules processed at different degrees of fill

Physical mixture

5 g/min, 300 rpm

10 g/min, 100 rpm

Amorphous GABA(Spray dry GABA+60%HPC)

Physical mixture

5 g/min, 300 rpm

10 g/min, 100 rpm

GABA

HPC

• Decreasing in Tm and ∆H• No recrystallization signal detected • No FT-IR peak shift

ATR-FTIRDSC

ATR-FTIR spectra of melt granules processed at different degree of fill compared with physical mixture, GABA, and HPC

DSC profiles of GABA granules processed at different degree of fill compared with physical mixture and Amorphous GABA

C=O stretchNH stretch

29

Polymorphic transformation of GABA when processed with a more aggressive screw design

30°KB

60°KB10 g/min, 100 rpm (30°KB)

10 g/min, 100 rpm (60°KB)

GABA

• GB Form II transformed to GABA Form III with an aggressive screw design

Torque ~700 G.m

Torque ~1300 G.m

FTIR spectra of GABA granules compared with GABAXRD patterns of GABA granules compared with physical mixtures

10 g/min, 100 rpm (60°KB)

10 g/min, 100 rpm (30°KB)

Physical mixture

30

More compressible GABA granules at higher degree of fill

Compressibility of the granules processed at different degree of fill

0.0

1.0

2.0

3.0

4.0

0.00 5.00 10.00 15.00 20.00 25.00 30.00

Tens

ile st

reng

th (M

Pa)

% Degree of fill

5 g/min

7.5 g/min

10 g/min

0.0

1.0

2.0

3.0

4.0

0 20 40 60 80 100 120 140

Tens

ile st

reng

th (M

Pa)

Compression pressure (MPa)

10 g/min at 100 rpm

5 g/min at 300 rpm

Physical mixture

Correlation between tensile strength of the tablet compressed at 100 MPa, as a function of degree of fill

31

More degradation

Ongoing studies

32

1. Evaluate split feeding to minimize drug degradation while improving the compaction properties of GABA granules

2. Quantify the thermal and mechanical stress during melt extrusion

3. More advanced technique to characterize binder distribution

Conclusions• From improving the compaction properties perspective, hydroxypropyl

cellulose, a thermoplastic polymer, is more effective than low melting point waxes such as PEG 8000 and Compritol.

• High melt viscosity of HPC resulted in more chemical degradation during processing and upon storage.

• Both the size of the granules coming off the extruder and the impurity of GABA correlate better with the degree of fill (or specific rate) than the specific mechanical energy.

• Processing parameters (screw speed and feed rate) should be optimized to achieve the balance between improving GABA compressibility but also minimizing GABA degradation.

33

Acknowledgements

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Nada KittikunakornAbbe Haser

Charlie MartinAugie MachadoBrian Haight

Tony Listro

Backup slides

35

Melting and lactamization of GABA under hot-stage PLM

25°C 174°C 176°C (with bubble)

180°C 183°C 184°C

36

Studying HPC of different particle size

• HPC ELF : D50 ~ 160 μm

• HPC EXF : D50 ~ 50 μm• Spray-dried HPC : D50 ~ 10 μm

80% Gabapentin + 20% Binders

37

80% GAGB and 20% binder Feed rate 10 g/min, Screw speed 100 rpm

Effect of HPC particle size on GABA granule size

0.00

5.00

10.00

15.00

20.00

25.00

30.00

35.00

HPC ELF HPC EXF HPC SD

%w

/w

Granules size (μm)

>1180

850-1180

600-850

425-600

250-425

150-250

<150

38

Effect of HPC particle size on compaction profiles of granules

• Physical mixture : Small particle size of binder improve the compressibility of drug

• Melt granules : binder particle size does not have effect on the compressibility of drug

0.0

1.0

2.0

3.0

4.0

0 20 40 60 80 100 120 140

TEN

SILE

STR

ENGT

H (M

PA)

COMPRESSION PRESSURE (MPA)

90°C20% HPC ELF + GB (at 90°C)20% HPC EXF + GB (at 90°C)20% HPC SD + GB (at 90°C)

0.0

1.0

2.0

3.0

4.0

0 20 40 60 80 100 120 140

TEN

SILE

STR

ENGH

T (M

PA)

COMPRESSION PRESSURE (MPA)

100°C

20% HPC ELF + GB(at 100°C)

0.0

1.0

2.0

3.0

4.0

0 20 40 60 80 100 120 140

TEN

SILE

STR

ENGT

H (M

PA)

COMPRESSION PRESSURE (MPA)

110°C20% HPC ELF + GB(at 110°C)

0.0

1.0

2.0

3.0

4.0

0 20 40 60 80 100 120 140

TEN

SILE

STR

ENGT

H (M

PA)

COMPRESSION PRESSURE (MPA)

120°C

20% HPC ELF + GB (at120°C)

0.0

1.0

2.0

3.0

4.0

0 20 40 60 80 100 120 140

TEN

SILE

STR

ENGT

H (M

PA)

COMPRESSION PRESSURE (MPA)

PHYSICAL MIXTUREGABA-HPC ELF (PM)GABA-HPC EXF (PM)GABA-SD HPC (PM)

39

Effect of HPC particle size on the degradation of GABA

Smaller particle size of HPC more degradation

0.000

0.050

0.100

0.150

0.200

0.250

0.300

85 95 105 115 125

% G

ABA-

L

PROCESSING TEMPERATURE (°C)

GB+20%ELF granulesGB+20%EXF granulesGB+20%SD HPC granulesGabapentin

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0.4

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0.7

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1.3

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1.7

Den

sity

dis

tribu

tion

q3*

0.4 0.6 0.8 1.0 2 4 6 8 10 20 40 60 80 100

particle size / µm

x(10 %)µm21.721.571.461.34

x(50 %)µm63.1210.4510.778.83

x(90 %)µm116.1341.9043.7147.16

Param. 3

Opt. concentration%33.4730.7534.9529.85

Gabapentin

20% HPC ELF + GB

20% HPC SD + GB

20% HPC EXF + GB

No significant difference in particle size reduction after melt granulation

40