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We are DFE PharmaGlobal leader in excipient solutions

March 10, 2014St John’s University

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A century long heritage

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With roots in dairy producing companies

Our heritage

1900 – HMS (Dutch Milk Sugar Factory) founded

1926 – Six Dutch dairy producers form DMV

1946 – First lactose plant built in Kapuni NZ

1960 – DOMO starts producing pharmaceutical grade lactose

1985 – Start inhalation grade lactose by DOMO in Borculo

2003 – Superdisintegrants acquired from Avebe

2006 – DMV-Fonterra Excipients created from DMV & LNZ

2010 – DOMO-pharma integrated

2011 – Acquisition Brahmar Cellulose India

2011 – Launch new corporate brand name DFE Pharma

2013 – Global launch of MCC by DFE Pharma

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DFE Pharma – a joint venture between 2 leading global dairy cooperatives

Sales Marketing QA R&D F&A Operations

50% 50%

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HR

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International dairy cooperative

Registered head office in

Amersfoort (the Netherlands)

Turnover USD12.5 billion

19,000 employees

14,400 member dairy farmers

International dairy cooperative

Registered head office in

Auckland (New Zealand)

Turnover USD 16.8 billion

17,300 employees

10,600 share holder farmers

Our parent companies

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We want to grow from a lactose supplier to an excipient expert.

DFE Pharma Strategy

Our ambition

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Lactose supplierWide range supplier

Excipient expert

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Quality is guaranteed

Production:cGMP production standardsICH Q7A Guidelines (API)Pharmacopoeial standards: USP/ NF ,Ph. Eur., JPEDrug Master FilesISO 9001:2008 certified production facilities, FDA inspected

Shelf life guaranteed:MCC: 4 yearsMilled & sieved lactose: 3 yearsDirect compression lactose: 2-3 years (vary by grade)Starches: 2-4 yearsSuperdisintegrants: 5 years

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DFE Pharma production facilities

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FoxholThe Netherlands

BorculoThe Netherlands

Nörten HardenbergGermany

KapuniNew Zealand

VeghelThe Netherlands

CuddaloreIndia

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Responsiveness with global presence

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Offices, production facilities & global distributor network

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Sales Office Japan

Sales Office Singapore

Production New Zealand

3 Production The Netherlands

Sales Office US

Production Germany

Main Office Germany

Sales Office India

Production India

Global distributors

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DFE Pharma excipients

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We supply you with one of the broadest ranges of excipients on the market

Almost half the tablets manufactured each year worldwide use DFE Pharmaexcipients that are sourced from a variety of top quality raw materials

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DFE Pharma excipients

% of formulations in the most prescribed drugs in the USA (OSDF type), source: RXList 201012

We supply you with one of the broadest ranges of excipients on the market

Almost half the tablets manufactured each year worldwide use DFE Pharmaexcipients that are sourced from a variety of top quality raw materials

Disintegrant

Sodium starch glycolate

• Primojel®

Croscarmellose sodium

• Primellose®

Native Potato Starch

• Solani Amylum

Partly pregelatinised maize starch

• SuperStarch® 200

Diluent

Milled lactose

• Lactochem® Powders (6 grades)

• Pharmatose® 130M-450M (5 grades)

Microcrystalline cellulose

• Pharmacel® 101

Filler-binder

Sieved lactose

• Lactochem® crystals (4 grades)

• Pharmatose® 50M-125M (8 grades)

Milled lactose

• Lactochem® Powders (6 grades)

• Pharmatose® 130M-450M (5 grades)

Spray-dried lactose

• Lactopress® Spray Dried (3 grades)

• SuperTab® 11SD and 14SD

Granulated lactose

• Lactopress® Granulated

• SuperTab® 30GR and 24AN

Anhydrous lactose

• Lactopress® Anhydrous (4 grades)

• SuperTab® 21AN, 22AN and 24AN

Micronised lactose

• Lactochem® Microfine

• Lactopress® Anhydrous Microfine

Customised lactose

Microcrystalline cellulose

• Pharmacel® 101

• Pharmacel® 102

Partly pregelatinised maize starch

• SuperStarch® 200

Fully pregelatinised potato starch

• Prejel® PA5 PH

51%Lactose 60%

MCC30% Starch

16% SSG

23% CCS

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Effects of Excipients on the Performance of Bilayer Tablets

Jian-Xin Li, Ph.D.Tel: 732-585-0608jian-xin.li@dfepharma.com

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Pharma industry is conservative – slow evolution– Tablets remain the preferred dosage form, will not disappear in 2050– Innovators still prefer WG, rather than DC– More IR ANDA filing than MR ANDA filing

NDAs: slow growth– NCEs are poorly soluble, challenging technically– Life Cycle Management (LCM) is important due to lean NCE pipeline

ANDAs: key driver for future global growth– Forced to file ANDA based on QbD starting in 2013– Big generic players focused on MR– Active R&D and filing in US, manufacturing oversea

Market Insight: North America

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Chemical compatibility

High compactability

Good flowability

Good blending properties

No (drug) segregation

Physical and chemical stability

DC Excipients for Tablet ProductionMost important requirements for DC filler/binders

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Particle rearrangement

Particle deformation

Particle fragmentation

Bonding

Tablet relaxation

CompactabilityWhat happens during compression?

Compression

De-compression

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MCC/Lactose SynergyParticle deformation and fragmentation

MCC

Lactose

BEFORE COMPRESSION

DURINGCOMPRESSION

AFTERCOMPRESSION

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Why are Lactose and MCC commonly used (together)

Lactose– Wide range of types for all applications– Good flow and die filling properties– Good tableting properties

MCC– Plastic deformation for strong tablets– Nothing tablets better!

– Tablets can be made to disintegrate quickly

Together– It’s possible to balance lactose & MCC to optimise formulations easily

– For ease and robustness of production– For optimal tablet properties

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Examples

plastic COMPACTION brittle

excellent TABLET STRENGTH good

good FLOW excellent

lower DENSITY / DIEFILL higher

low COMPACTION FORCE medium

low EJECTION FORCE medium

faster TABLET DISINTEGRATION slower

Pharmacel

MCC

SuperTab & Lactopress

Lactose

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Is there an ideal DC material?

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Is there an ideal DC material?

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How do DC lactose and Pharmacel shape up?

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Particle Size & ShapeFavours Spray dried and granulated lactose

D10(>30)

D50(>80)

D90(<1000)

Shape

LactoPress Spray Dried 250 70 156 249SuperTab 11SD EU 48 125 233SuperTab 11SD NZ 33 119 231SuperTab 21AN 10 159 335LactoPress Anhydrous 250 20 136 330SuperTab 22AN 63 211 373SuperTab 24AN 33 123 265LactoPress Granulated 56 155 291SuperTab 30GR 40 144 297

Pharmacel 101 19 67 135

Pharmacel 102 31 97 197

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Pharmacel® is Spray Dried MCC

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Direct compression lactoseSummary of production routes

Crystals of pharmaceutical grade α-lactose monohydrate

Spray-drying Roller drying Granulated

Lactopress® Spray Dried 250SuperTab® 11SD or 14 SD

Lactopress® Anhdyrous 250SuperTab® 22AN or 24 AN

Lactopress® GranulatedSuperTab® 30GR

24

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What lactose type should I use?

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Use DC-lactose (spray, anhydrous or granulated)

Tablets Other solid dosage forms

Lactose types Wet Granulation Dry GranulationDirect

CompressionCapsules Sachets Spheres

Milled lactose +++ + o + o +++

Sieved lactose o o + +++ +++ o

Spray-dried lactose

+ o +++ + ++ +

Granulated lactose

+ o +++ +++ ++ +

Anhydrous lactose

+ +++ +++ +++ + +

+++ Highly recommended++ Recommended+ Possible but not recommendedo Not advised

Dry granulation in this overview includes roller compaction and slugging. Spheres in this overview are made by extrusion-spheronisation.

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Starting Formulation

Component Example Start at

API <1% to 20%

Filler�binder

Pharmacel PH 102

SuperTab 11SD

SuperTab 21AN

SuperTab 30GR

QS to 100%

Super�disintegrantPrimojel (SSG)

Primellose (CCS)3%

Lubricant Magnesium stearate 0.5%

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DC Formulation StrategiesHigh Dose API’s (greater than 50mg)

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Starting formulation & process

End

Flow OK

Hardness OK

Ejection OK

Friability OK

Dissolution OK

Uniformity OK

Add 0.1% � 0.3% glidant / Coarser API

Sticking: Increase lubricant / polish punches

Increase compaction / add 20% Pharmacel

Poor disintegration: Use Primellose / Increase disintegrant/ replace mg stearate

Improve mixing plan

Tablet Formulation Optimization Algorithm

N

Y

Use SuperTab AN or 14SD / reduce mag stearate / add 20% PharmacelN

Capping: Decrease pressure / increase SuperTab / add Pharmacel

Y

N

Y

N

YY

N

N

Poor intrinsic dissolution: mill API finer / add a wetting agent)

N

Y

Y

Granulation may be necessary if flow and compaction cannot be achieved

N

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Business/market driver: life cycle management

– Improve patient compliance

– Improve therapeutic outcomes

– Decrease adverse reactions

– Motivation by regulatory agencies

Need for bilayer or multi-layers of tablets

– Chemical incompatibility of APIs

– Different release profiles

– Core for osmotic pump

Bilayer or Multi-layer FDC Tablets

29 Adapted from Koo, 2013 AAPS Arden Conference

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Manufacture of single and bilayer tablets utilizing uniaxial compaction.

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A - Die filling, B - Compression, C - Decompression, D - lower punch removal and reapplication of load to the

upper punch, E - Tablet fully ejected. 1 refers to the final compaction conditions.

S.J. Inman , et. al. Powder Technology, Volume 188, Issue 3 , 2009 283 - 294

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Different stages occurring during bilayer tablet uniaxial compaction

31 S.J. Inman , et. al. Powder Technology, Volume 188, Issue 3 , 2009 283 - 294

A) Initial layer die filling and compaction. B) Initial layer compaction showing the predominant stress transmission profile. C) Density profile of initial layer before die filling of the final layer. D) Final layer die filling and compaction. E) Final layer compaction showing the predominant stress transmission profile. F) Density profile of bilayer tablet before ejection. G) Ejection of a bilayer tablet, dashed arrows show the postulated radial expansion due to energy dissipation.

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Delamination of bilayer tablets

X-ray micro-computed tomography cross-section images obtained after 2D reconstruction of the defective MCC–starch bilayer tablet compacted

32 Akseli , et al, Powder Technology 236 (2013) 30–36

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Temperature distribution throughout tablet at end of compaction

Klinzing et al. Computers and Chemical Engineering 34 (2010) 1082–109133

(a) internal view (b) external view

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Diametrical strain differential upon equilibration to different levels of relative humidity

Klinzing et al. Pharm Res, 2013 DOI 10.1007/s11095-012-0969-034

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Insufficient hardness

Inaccurate individual layer mass control

Cross contamination between the layers due to punch sticking

Elastic mismatch between adjacent layers

Delamination after compaction, during coating or storage

Damage during accelerated stability test

Formulation challenges for bilayer tablets

Adapted from Koo, 2013 AAPS Arden Conference

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Materials: brittle and plastically deforming materials

First-Layer Force: interfacial strength

Second-Layer Force: main compression force

Compaction Speed: dwell time

Layer Weight Ratio

Lubricant Level

Factors for bilayer tablet formulation/ process design

36 Adapted from Koo, 2013 AAPS Arden Conference

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Delamination occurs at a higher maximum compression force

37 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285–294

18 KN

9 KN

3 KN

Fracture patterns for crushed bilayer tablets 20%MCC+80%lactose (MCC 1st)

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Delamination occurs at a higher maximum compression force

38 C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285–294

Fracture patterns for crushed bilayer tablets 20%MCC+80%lactose (lactose 1st)

18 KN

9 KN

3 KN

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Interfacial strength test for bilayer tablets

39Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012

DOI: 10.1208/s12249-012-9845-9

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Bilayer tablet tensile tester

Akseli , et al, Powder Technology 236 (2013) 30–36

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Force–displacement curve during the fracture of an examined MCC-MCC bilayer tablet

(MCC (compressed to 8 kN)–MCC (compressed to 6 kN) bilayer tablet

Akseli , et al, Powder Technology 236 (2013) 30–36

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Effect of materials on the strength of bilayer tablets

(Ex1=material in layer 1; Ex2=material in layer 2)

=MCC

MCC

Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012DOI: 10.1208/s12249-012-9845-9

Total tablet weight 500 mg with each individual layer being 250 mg.

MCC-MCC

MCC-LactoseLactose-MCC

Lactose-Lactose

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Effect of storage condition and storage time on the strength of MCC-Lactose bilayer tablets

43 Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012DOI: 10.1208/s12249-012-9846-8

Total tablet weight 500 mg with each individual layer being 250 mg.

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Effect of storage condition and storage time on the strength of Lactose –MCC bilayer tablets

44 Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012DOI: 10.1208/s12249-012-9846-8

Total tablet weight 500 mg with each individual layer being 250 mg.

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Bilayer tablets made with brittle materials (lactose) in both layers are strongest.

For lactose–lactose tablets, an increase in adhesion between layers was observed, due to the formation of solid bridges upon storage.

More significant fracture is induced when MCC is the bottom layer (MCC 1st) than when it is compressed as the top layer (lactose 1st).

Interface was weakest for the compacts made with plastic materials (MCC) in both layers.

Spray dried lactose monohydrate was used in the study.

Lactose is good for bilayer tablets

45 Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012

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Anhydrous lactoseExcellent recompactability for roller compaction

Anhydrous lactose granules have essentially the same compaction profile as the original powder.

Hard tablets are formed irrespective of the first compaction implying robust formulations are achievable.

0

50

100

150

200

250

300

0 100 200 300

Tablet crushing strength (N)

Tableting pressure (MPa)

SuperTab 21AN powder

Densified granules

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Anhydrous lactoseLow lubricant sensitivity

0

50

100

150

200

250

0 5 10 15 20 25 30 35

Tablet hardness (N)

Compaction force (kN)

SuperTab 21AN unlubricated

SuperTab 21AN lubricated

SuperTab 22AN unlubricated

SuperTab 22AN lubricated

Compaction speed 300 mm/sLubrication with 0.5 % magnesium stearate

SuperTab 21AN and 22AN also have a low sensitivity to

speed of compaction : < 20 % reduction in tablet hardness from 3 mm/s to

300 mm/s(not shown here)

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SuperTab® 24ANProduct Properties - visualization

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Light Microscope

SEM

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Combines the key properties of granulated and anhydrous lactose

– High powder flowability (granulation)

– Quick disintegration time (granulation)

– Excellent mixing properties (granulation)

– High compactability (granulation of anhydrous material)

– Low moisture content below 1.0 % H2O (anhydrous material)

Product is an anhydrous lactose according to Pharmacopeia

SuperTab® 24ANDescription

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SuperTab® 24AN and 30GRComparative Compaction

250mg tablets9mm flat bevel edged toolingRoTab rotary tablet machine

0

50

100

150

200

250

9 10 11 12 13 14 15 16

SuperTab 24AN

SuperTab 30GR

SuperTab 21AN

Compaction Force (kN)

Tablet Hardness (N)

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Powder F low (DC-Grade E xcipients )

0

3

6

9

12

15

18

21

24

27

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RegularAnhydrousLactose

P-PGS MCC 102 S uperTab®24AN

GranulatedLactose-Monohydrate

S pray DriedLactose-Monohydrate

Flodex (flow through orifice)

SuperTab® 24ANProduct properties - flow

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Excellent flow: comparable to granulated/spray-dried lactose

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SuperTab® 24ANProduct properties – low moisture uptake

< 0.7% of water uptake up to 90% RH when measured by Dynamic Vapour Sorption (DVS)

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Free flowing, more re-compactable powder mixture selected as first layer– Better control of fill and weight for each layer– First layer undergoes 2 compressions

Optimization of individual layer composition for improved inter-layer adhesion– Lactose is good for bilayer tablets– Layers with similar compaction/relaxation properties– Layers with similar expansion (thermal or moisture driven)

Optimization of compaction pressure and tableting speed– Strength of the tablet and interfacial adhesion between layers

Principles and considerations guiding first layer selection and tableting

53 Adapted from Otilia Koo, 2013 AAPS Arden Conference

Impact Factors of Interfacial Bonding

Strength of Bilayer Tablets

S-Y. Chang1, J. Li2, and C.C. Sun1

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Methodologies

1 mm

Blade

Force

0.5 mm

Tablet

Holder

1. Shearing test 2. Pulling test

Force

Tablet

Holder

551. Bilayer tablet thickness: 5.8~6.0 mm

2. Weight: 210 mg for MCC layer; 200 mg for Lactose layer

3. Glue: Ethyl Cyanoacrylate, Hydroquinone

4. For shearing test, blade is padded with tape

Diametrical Tabletability (single layer)

0

1

2

3

4

5

6

7

8

9

10

11

0 50 100 150 200 250 300 350 400

Te

ns

ile

str

en

gth

(M

Pa

)

Compaction pressure (MPa)

MCC Pharmacel with 0.5% MgSt

Lactose SuperTab 24 AN with 0.5% MgSt

Lactose SuperTab 11SD with 0.5% MgSt

Lactose SuperTab 30GR with 0.5% MgSt

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Tabletability: MCC >> 24AN >11SD>30GR

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Pulling test vs Shearing test

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0

1

2

3

Sh

ea

r/Te

nsi

le s

tre

ng

th (

MP

a)

Layer combination

Shearing Test at First layer(20MPa)/Second layer (200MPa)

Pulling Test at First layer(20MPa)/Second layer(200MPa)

MCC

MCC

11SD

MCC

24AN

MCC

MCC

11SD

11SD

11SD

24AN

11SD

MCC

24AN

11SD

24AN

24AN

24AN

Second

First

30GR

MCC

30GR

24AN

MCC

30GR

24AN

30GR

30GR

30GR

Pulling test vs Shearing test

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0.0

0.5

1.0

1.5

2.0

2.5

0.0 0.5 1.0 1.5 2.0

Sh

ea

rin

g t

est

at

20

MP

a/2

00

MP

a

Pulling test at 20MPa/200MPa

First layer inside

Second layer inside

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0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Sh

ea

r st

ren

gth

(M

Pa

)

Layer combination

Effect of Ejection direction

031-Chang-29 First (20MPa)/Second (200MPa) (n=3)

Breakage mode

First/Second Pushed from First Interface Second

11SD/11SDTop 1 2

Bottom 1 2

24AN/24ANTop 3

Bottom 3

30GR/30GR Top 3

Bottom 3

Ejection direction (pushed

out from) is indicated.

Ejection direction

affects breaking

strength

11SD/11SD 24AN/24AN 30GR/30GRFirst/Second

Top

Top

Top

Bottom

Bottom

Bottom

Ejection direction

affects breakage mode

Top

Bottom

Die

Punch

Punch

1st

2nd

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Axial T.S. of bilayer tablets of mixtures

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Complex but reproducible trend!

0.0

0.5

1.0

1.5

2.0

2.5

Ten

sile

str

en

gth

(M

Pa

)

Layer combination

20% MCC

80% 24AN

40% MCC

60% 24AN

60% MCC

40% 24AN

80% MCC

20% 24AN 24AN

diamonds: repeated data

squares: initial data

First (20MPa)/Second (200MPa)

MCC

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0

1

2

Ten

sile

str

en

gth

(M

Pa

)

Layer combination

Confirmation of the trend with 3 additional mixtures% of 24AN in

the mixture

Breakage mode (n=3 -5)

First Interface Second

100% 3/3

90% 3/3

80% 5/5

70% 3/3

60% 5/5

40% 5/5

20% 5/5

10% 3/3

0% 5/5

First (20MPa)/Second (200MPa)

24AN 10% MCC

90% 24AN 20% MCC

80% 24AN

30% MCC

70% 24AN

40% MCC

60% 24AN

60% MCC

40% 24AN 80% MCC

20% 24AN

90% MCC

10% 24AN MCC

Conclusions

1. There is a satisfactory correlation between data from shearing and

pulling tests. Tablet strength by shearing test is higher than that by

pulling test.

2. Interfacial bonding strength is sensitive to 1st layer pressure,

materials, and ejection direction

3. With 1st MCC layer compressed at 20 MPa, axial tensile strength

following the order of 24AN >> 30GR >≈ 11SD when they are used

as the 2nd layer materials (failures are always in lactose layer).

4. When 1st MCC layer is compressed at 100 MPa, no strong

interfacial bonding forms irrespective of the 2nd layer material.

5. First layer formulation rich in 24AN, less sensitive to 1st pressure,

therefore, more robust formulation for manufacturing.

6. 24AN is better than other grades of lactose (including Fast Flo) for

bilayer tablets

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