influence of binder critical material attributes on

——influence of binder critical material attributes on granule and tablet properties

introducing Klucel™ EXF Ultra HPC

Dr. Christian Mühlenfeldhead of pharma R&D, Europe

2

—today’s presenter

Christian Mühlenfeld

Dr. Christian Mühlenfeld leads the European research and development and technicalservices team for Pharmaceuticals at Ashland, based in Düsseldorf, Germany. Hiscurrent role involves support for Ashland’s highly functional materials and ingredientsthat enable overcoming active delivery challenges such as bioavailabilityenhancement, drug stabilization and controlled drug delivery as well as processtechnologies to achieve advanced drug delivery and continuous manufacturing.

3

—agenda

o considerations for binder selection

o case study: binder selection for wet granulation

o new ultra-fine binder

o case study: influence of binder critical material attributes in high-shear granulation

o summary

4

—common ingredients for tablets

tablet

tablet binder = material that is able under compression to hold the particles of the compressed powder together. Binders ensure that powders and granules can be formed with required mechanical strength to tablets

5

—role of binders in tablet development

the role of binders during compaction1

contribute to the plastic deformation during the consolidation of powders or granules

generate or enhance inter-particulate surface sites where bonding can take place

contribute to the plastic deformation during decompaction

withstand shear stresses & strains that can cause crack propagation & structural failure during post compactional stages of tablet production

1Reference: Symecko and Rhodes, Drug Dev Ind Pharm 21 (9) (1995)

1 2 3 4

6

—Ashland's binder portfolio

exceptional range of binders to find the right one for your formulation and process

Klucel™ HPC

Plasdone™ povidone

Plasdone™S-630

copovidone

Aqualon™ EC

7

—considerations for rational binder selection

○ mechanical properties of the polymer○ type of solvent and solids level○ tablet disintegration and dissolution time ○ binder use levels○ manufacturing process

– in dry processing, finer particle size provides the best binding performance

– in wet granulation, wetting and binder–drug surface interaction, i.e., relationship between drug hydrophobicity (logP) and binder surface tension, improve binding

○ stability and incompatibility with APIs and other excipients○ regulatory acceptance and supplier reliability

8

case study: binder selection for wet granulation

9

—critical binder attributes for wet granulation

o mechanical properties of the polymer– toughness and plasticity are important in wet and dry processing

o viscosity1

– for some binders, this may preclude pre-dissolving and solution addition can also affect spreadabiltiy

o particle size– for dry addition and granulation with pure solvent, not relevant if binder is pre-dissolved– distribution in interstitial spaces– smaller particles are inherently more plastic/less brittle

o surface interaction between binder solution and API– surface wetting and spreadability are critical

1in water (or other granulation liquids used) and the dissolution medium

10

—wet granulation process and composition

○ comparison of binders with metformin, albendazole, and efavirenz○ these APIs vary in mechanical properties and hydrophobicity (logP)

structure

compound Metformin Albendazole Efavirenz

solubility in water1

>300 g/L 2.28 mg/L 0.86 mg/L

hydrophobicity (logP)1

-0.5 2.7 4.6

flowability poor poor poor

compactability poor good poor

plasticity poor good poor

11


Binders used for wet granulation processes

2Measured by laser diffraction 3BET method

Property Klucel™ EXF HPC

E15 HPMC

Plasdone™ S-630 PVP/VA

Plasdone™ K-29/32

PVP

Surface tension(mN/m) 40 45.9 49.5 53.6

Mean particlesize (µm)2 50 90 76 107

Relative toughness

Superior Low High Medium

Surface area(m²/cm³)3 0.32 0.15 0.21 0.37

1

10

100

1000

0 5 10 15 20

visc

osit

y (m

Pa∙s

)

solution concentration %

Klucel™ EXF HPC

Plasdone S-630 PVP/VA

Plasdone™ K-29/32 PVP

MC A15LV

HPMC E15

Plasdone™ S-630 PVP/VA

12


Material % mg/tablet

API 80 400

Lactose monohydrate 200 mesh 11 55

Binder 5 25

Polyplasdone™ XL crospovidone 3 15

Magnesium stearate 1 5

TOTAL 100 500

mix API, lactose and binder in high shear mixer

granulate with DI water, dry, then pass through conical mill (1.0 mm screen)

blend with Polyplasdone™ XL crospovidone

blend with magnesium stearate

compress 500 mg tablets using a rotary press and 11 mm round tooling

hypothesis:• in wet binder optimization, surface interaction is important alongside

mechanical properties• surface interaction may be simplistically predicted for aqueous systems on

the basis of API logP and binder surface tension

13

—compactability profiles

0

50

100

150

200

250

300

350

0 5 10 15 20

tab

let

bre

aki

ng

forc

e (

N)

compaction force (kN)

Klucel™ HPC EXFPlasdone™ PVP K-29/32HPMC E15Plasdone™ PVPVA S-630

Metformin HCl (log P –0.5)

0

50

100

150

200

250

300

0 5 10 15

tab

let

bre

aki

ng

forc

e (

N)


Plasdone™ PVPVA S-630Klucel™ HPC EXFHPMC E15Plasdone™ PVP K29-32

Albendazole (log P 2.7) Efavirenz (log P 4.6)

0

50

100

150

200

250

0 10 20 30

tab

let

bre

aki

ng

forc

e (

N)


Plasdone™ PVPVA S-630Plasdone™ PVP K-29/32Klucel™ HPC EXFHPMC E15

14

—conclusion

○ in wet binder optimization, it is important to understand the correlation between the API logP and the surface tension of the binder solution: – hydrophilic APIs (low log P):

higher surface tension (hydrophilic) binders like Plasdone™ K-29/32 PVP generate granules that bring about result in better tablet compactibility.

– moderate hydrophobicity APIs (medium log P): binder surface tension is not critical and most binders will work, but differences in binder performance will be seen based on their mechanical properties

– highly hydrophobic APIs (high log P):lower surface tension binders such as Klucel™ HPC will result in the strongest tablets due to better surface energetics/wetting and excellent mechanical properties.

15

NEW ultra-fine binder

16

—

3 binder in wet granulation

2 binder in dry granulation

1 binder in direct compression

Klucel™ hydroxypropylcellulose (HPC) is a non-ionic water soluble cellulose ether with a unique combination of properties.

Klucel™ hydroxypropylcellulose (HPC)

Klucel™ EXF Ultra HPC

standardgrades

(regular grind)

d50 regular grind: 230 – 510 μmd50 fine (X) grind: 45 – 90 μmd50 ultra fine grind: 15 – 30 μm

X-grinds

Klucel™ HPC

17

—Klucel™ hydroxypropylcellulose (HPC)

○ product designation is a combination of viscosity type (e.g. E) followed by particle size○ Klucel™ E HPC viscosity-type differences in particle size:

0

20

40

60

80

100

1 10 100 1000 10000

cu

mu

lativ

e

dist

ribu

tion

(%

)

particle size [µm]


Klucel™ EXF HPC

Klucel™ EF HPC0

50

100

150

200

250

1 10 100 1000 10000

dist

ribu

tion

(q

3lo

g)

particle size [µm]


Klucel™ EF HPC

Klucel™ EXF HPC

18

—mechanical properties of binders

○ to assess mechanical properties ofbinders, 400 mg 11.28 mm flat-faced pure polymer tablets were prepared on a STYLCAM compaction simulator

250

300

350

400

450

500

550

600

650

5 10 15 20 25 30

tab

let

bre

aki

ng

forc

e (

N)


competitive HPC 2 (fine)

competitive HPC 1

MCC


Klucel™ EXF HPC

binder d10 (µm)

d50(µm)

d90(µm)

Klucel™ EXF Ultra HPC 6 23 55

Klucel™ EXF HPC 23 68 200

competitive HPC 1 17 64 121

competitive HPC 2 (fine) 8 20 50

MCC 35 110 225

19

—mechanical properties of binders: plasticity and toughness

0

200

400

600

800

1000

1200

0 2 4 6 8

forc

e (

N)

displacement (mm)

Microcrystalline cellulosePovidoneCompetitive HPC 1Competitive HPC 2Klucel™ EXF HPCKlucel™ EXF Ultra HPC

Klucel™ EXF Ultra HPC exhibits excellent plasticity and toughness

area under the force-distancecurve = toughness (work of failure) pure polymer tablets subjected to diametral compression

testing until breaking. Example: Klucel™ EXF Ultra HPC.

20

—diametral compression test (tablet fracture test)failure mode of polymers

Klucel™ EXF Ultra HPC competitive HPC 2 MCC

Pure polymer tablets of Klucel™ EXF Ultra never break, just deform

400 mg pure polymer tablets (STYLCAM compaction simulator, 11.28 mm flat-faced) subjected to diametral compression testing until breaking (Instron universal testing machine); cross head speed 0.5 inch/min.

21

—summary: Klucel™ EXF Ultra HPC

○ ultra fine particle size – significantly lower typical particle size, to enhance

performance○ exceptional plasticity

– enables higher binder efficiency—leading to enhanced tablet strength and low friability at lower usage levels

○ outstanding compressibility– excellent plasticity and toughness results in

outstanding compressibility– unlike other binders, Klucel™ HPC tablets never

actually break, they just deform. Klucel™ EXF Ultra HPC withstands significantly greater breaking forces

22

influence of binder critical material attributes in high-shear granulation

23

—aim of the study

○ in wet granulation granule and tablet properties depend mainly on following critical material attributes (CMAs)– particle size distribution– viscosity of binder

○ variability of the starting/raw materials may be manifested in the final product properties but also can cause processing difficulties

○ aim of this study is to understand how variation of the binder (within its specification range) interacts with high-shear mixer process parameters for their impact on granulate and tablet properties

24

—critical material attributes evaluated

○ variation of particle size distribution by using different grades of Klucel™ hydroxypropylcellulose:

○ variation of viscosity by lot selection:

Viscosity Product Viscosity (mPas)

low Klucel™ EXF HPC 386

medium Klucel™ EXF HPC 425

high Klucel™ EXF HPC 475

Particle Size Product d50 [µm]

low Klucel™ EXF Ultra HPC 15 – 30

medium Klucel™ EXF HPC 45 – 90

high Klucel™ EF HPC 230 – 510

EXF Ultra

EXF

EF

-1 +1

+1

-1

0Viscosity

Pa

rtic

leSi

ze

25

—formulation and process

water

granule calibration1.6mmdiameter =10 mm

weight = 300 mg

blend withexternal phase

70 °C15 minphase component weight

(%)weight (mg)

internalparacetamol 93 279

binder 3 9

external

Polyplasdone™ XL crospovidone

3 9

magnesium stearate 1 3

total 100 300

26

—granule PSD & friability

○ for binders at same viscosity, increasing binder particle size:– lower span of granule PSD– less fines (highest fines at EXF

Ultra)○ EXF with increasing viscosity:

– more oversized granules– lower span

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

10 100 1000

de

nsit

y d

istrib

utio

n, q

3

minimum feret diameter (µm)


Klucel™ EXF 'low' HPC

Klucel™ EXF 'medium' HPC

Klucel™ EXF 'high' HPC

Klucel™ EF HPC

27

—

0

5

10

15

20

25

30

Klucel™ EXF Ultra

HPC

Klucel™ EXF 'low'

HPC

Klucel™ EXF

'medium' HPC

Klucel™ EXF 'high'

HPC

Klucel™ EF

HPC

gra

nu

le f

riab

ility

[%

]

granule friability1 & densitiesgranules containing EXF Ultra with slightly lower BD & TDdecreasing friability with PSD increase EXF Ultra > EXF > EF

higher friability with increasing viscosity ’low’ < ’medium’ < ‘high’

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Klucel™ EXF Ultra

HPC

Klucel™ EXF 'low'

HPC

Klucel™ EXF

'medium' HPC

Klucel™ EXF 'high'

HPC

Klucel™ EF HPC

gra

nu

le d

en

sity

[g/m

l] bulk density tapped density

1friability of the granules during sieving through an air-jet sieve was used as surrogate parameter to estimate granule strength. Thus, friability and granule strength are inversely proportional.

28

—

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

tab

let

bre

aki

ng

forc

e (

N)


Klucel™ EXF Ultra HPCKlucel™ EXF 'low' HPCKlucel™ EXF 'medium' HPCKlucel™ EXF 'high' HPCKlucel™ EF HPC

tablet compaction

○ for binders at same viscosity(Klucel™ EF, EXF & EXF Ultra HPC)– highest breaking force for EXF

Ultra at all compaction forces – EF shows capping tendencies at

high compaction forces○ for binders at ‘same’ particle size

(Klucel™ EXF ‘low’, ‘medium’ & ‘high’ HPC)– with increasing viscosity slightly

lower breaking force at highest compaction force

*

*capping tendency

29

—tablet disintegration and friability

EXF Ultra: low disintegration time at all compaction forcesNo distinguishable impact of other HPC grades or viscosity

All tablets are well below a friability threshold of 1%

0102030405060708090

100

5 10 15 20

disi

nte

gra

tion

tim

e (

s)



0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

5 10 15 20

fria

bilit

y (%

)



30

—case study: summary

○ variations in starting material properties showed to have no influence on processability of raw materials, indicating that the physical variability (PSD, viscosity) of hydroxypropyl cellulose (HPC) does not negatively affect the processability at all

○ an improvement was observed in mechanical properties of granules and tablets, without significantly influencing disintegration times, when using Klucel™ EXF Ultra HPC– the use of Klucel™ EXF Ultra HPC resulted in finer granules and yielded tablets with

stronger mechanical properties, possibly due to the higher dry binding efficiency of smaller binder particles associated with a higher specific surface area

○ A better understanding about Klucel™ HPC material attribute variation (PSD, viscosity) was gained, which can optimally be used to manage the variability in the production process in order to obtain end-products with similar properties

31

—Ashland's binder portfolio

exceptional range of binders to find the right one for your formulation and process

Klucel™ HPC

Plasdone™ povidone

Plasdone™S-630

copovidone

Aqualon™ EC

32

—Ashland’s binder selection decision tree

Klucel™ EXF or EF hydroxypropylcellulose

Klucel™ EXF Ultra hydroxypropylcellulose

Klucel™ EXF hydroxypropylcellulose

what type of process will be used?

wet processing

low (hydrophilic)

Plasdone™ K-29/32 povidone

Plasdone™ S-630 copovidone

medium

Klucel™ EXF hydroxypropylcellulose

Plasdone™ K-29/32 povidone

Plasdone™ S-630 copovidone

high (hydrophobic)

what is the logP of the API? (how wettable is it?)

dry processing

34

disclaimerThe information contained in this presentation and the various products described are intended for use only by persons having technical skill and at their own discretion and risk after they have performed necessary technical investigations, tests and evaluations of the products and their uses. This material is for informational purposes only and describes the scientific support for the use of the products described herein as an ingredient intended to enhance performance of an end product. Certain end uses of these products may be regulated pursuant to rules governing medical devices or other regulations governing drug uses. It is the purchaser’s responsibility to determine the applicability of such regulations to its products. While the information herein is believed to be reliable, we do not guarantee its accuracy and a purchaser must make its own determination of a product’s suitability for purchaser’s use, for the protection of the environment, and for the health and safety of its employees and the purchasers of its products.

Neither Ashland nor its affiliates shall be responsible for the use of this information, or of any product, method, formulation, or apparatus described in this brochure. Nothing herein waives any of Ashland’s or its affiliates’ conditions of sale, and no statement, information and data is to be taken as a guarantee, an express warranty, or an implied warranty of merchantability or fitness for a particular purpose, or representation, express or implied, for which Ashland and its affiliates assume legal responsibility. We also make no warranty against infringement of any patents by reason of purchaser’s use of any information, product, method or apparatus described in this presentation.

The testing information (the “Testing Information”) has been gratuitously provided by Ashland. The Testing Information is based on many factors beyond Ashland’s control, including but not limited to, the conditions prevailing when the testing was conducted, and in some cases, is based on data generated with development samples of the Active Ingredient. Although it is intended to be accurate, ASHLAND DISCLAIMS ANY AND ALL LIABILITY, EITHER EXPRESS OR IMPLIED. The Testing Information is confidential or proprietary to Ashland, and may not, except as provided below, be disclosed to any third party. You may not make commercial use of the Testing Information, or make claims with respect to your products based the Testing Information, without the written agreement with Ashland covering such use.

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