critical material properties for pharmaceutical dosage forms - industry perspective tony hlinak...

Critical Material Properties for Pharmaceutical Dosage Forms- Industry Perspective

Tony HlinakAbbott LaboratoriesNorth Chicago, IL

Phys Props of Pharm PowdersApril, 2006

2Company Confidential© 2006 Abbott

Real World – Case 1

0

10

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100

A A A A A A B B B B B B B C C C C C C C D D E E E E E E E E E F F F F F F G G G G G G G G G H H H H

Lot Designation

Crit

ica

l Qu

alit

y A

ttrib

ute

Spec Limits

Spec Limits ?



Real World – Case 2

0

10

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Am

ps

Plant 1 Ave +/- 3

Plant 2 API

?



Drug Product Manufacturing

FormulaComponents

ManufacturingProcess

ProcessParameters

DrugProduct

PhysicalProcess

MaterialProperties

ProcessModel

QualityAttributes

ModelParameters

Model-BasedProcess



Material Properties Require Attention

• Affect processing behavior and final dose performance

• Can compromise an otherwise robust process

– Reduce Reliability

– Make Less Predictable

• Minimum Costs

– Excessive waste, chronic rework, increased cycle times, uneven utilization of resources, and increased compliance risk

• Worst Case– Disrupt supply chain, exhaust technical and management resources,

threaten relationship with regulatory agencies, weaken competitive position, and ultimately lose customers



Material Property Effects - Realities

• Complex, Broad, Interrelated

• Many Characteristics Not True “Properties” in Thermodynamic Sense

• Relevant Property Information Not Available for Many Materials Even Those That are Widely Used in our Industry

• Many Properties of Interest Not Measurable Using Conventional Analytical Tools

• Variability in Some Methods are High and/or Highly Technique Dependent

• Property Impacts May Change with Processing Scale

• Property Impacts Depend on Both Amount Present in Formula and Other Components Present



Property Example – Handbook of Excipients (2000)

Compression characteristics of dibasic calcium phosphate anhydrous. Tablet weight: 750 mg

Handbook of Pharmaceutical Excipients, First Edition

Reprinted with permission from Marcel Dekker, Inc., to be published in Compaction of Pharmaceutical Excipients by Metin Celik, in press, 1999)

: Microcrystalline cellulose, Emcocel 90M (Lot # 1037X. Mendell) at V = 100 mm/s

: Microcrystalline cellulose, Emcocel 90M (Lot # 1037X. Mendell) at V = 300 mm/s



Microcrystalline Cellulose

Mechanical properties(a)

Compression pressure: 9.84 kN/cm2

Tensile strength: 0.8711 kN/cm2

Permanent deformation pressure: 15.3

Brittle fracture index: 0.0821

Bonding index: 0.0571

Reduced modulus of elasticity: 1472

Flowability: 1.41 g/s for Emcocel 90M.(9)

Calcium Phosphate

Flowability: 18.9 g/s for A-TAB

Property Example – Handbook of Excipients (2000)



The Current State

1) Little or no information concerning relevant properties may be available on a particular component even those that are widely used within the industry

2) The properties of interest may not be measurable using conventional analytical tools or the results obtained are very technique dependent

3) Reliable mixing rules that allow estimates of mixture properties to be generated from the known properties of the components don’t generally exist

4) Physical models that link the output properties to the input properties are currently insufficient for most pharmaceutical unit operations

5) The impact of a particular property may change as the pharmaceutical manufacturing process is scaled or optimized, and will likely depend on both the amount of the component present in the formula as well as the type and amount of other components present



The Flow Property Group

Particle Size Distribution

Particle Shape Distribution

Bulk Density

Surface Area

Surface Energy

Cohesiveness

Surface Structure

Static Charge

Hygroscopicity

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

Diameter (mm)

CommercialGranulated

Sugar Blend

Before GranulationBlend

After Granulation



The Uniformity Property Group


Particle Shape Distribution

Surface Area

Surface Energy

Cohesiveness

Surface Structure

Static Charge

Hygroscopicity

i

i

Si p

p

m

drsd

)1(

6100

3

2 ,275 m

0

10

20

30

40

50

60

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90

100

0 100 200 300 400 500 600 700 800 900 1000

Screen Opening (um)

Cum

mul

ativ

e M

ass

% G

reat

er T

han

Sie

ve O

peni

ng

Unmilled - Control

Milled - No. 16

Milled - No. 20

Milled - No. 30

rsd = 11.0%

rsd = 2.7%

rsd = 0.7%

rsd = 1.3%

Lot 95K002-G1A



The Wetting Property Group


Bulk Density

Pore Size Distribution

Surface Area

Surface Energy

Cohesiveness

Surface Structure

Static Charge

airm

airm

inT

outT

in

out

OHm2

LT

fg

outinairpinout h

TTc ,

OHfgoutinairpair mhTTcm2,

SV

LV

SLSV

LV

SL

x

y

z Cantilever Probe

PiezoelectricPositioner

Laser

Sample

MirrorDiode A

Diode B



The Drying Property Group


True Density


Surface Area

Hygroscopicitymair

m

mair

H O2

Qloss

Tin

Tout

HeatSource

Coolant

Blower

FiltersAir Flow Lines

TWB

wet core

Ti

Ts

l

L

boundrylayer

V

dry layer

T

q

wet core

Ti

Ts

l

L

boundrylayer

V

dry layer

T

q0.00

0.05

0.10

0.15

0.20

0.25

0.0 0.2 0.4 0.6 0.8 1.0

p/p0

Mo

istu

re C

on

ten

t(g

H2O

/ g

dry

so

lids)

Silica gel (Kontny, 1988)

orbofiban 25 C (David, 1998)



Silica gelwm = 0.256cg = 10.3K = 0.387

orbofibanwm = 0.0299cg = 55.7K = 0.087



The Mechanical Property Group


True Density

Bulk Density

Cohesiveness

Elastic Modulus

Compactibility

Brittleness

12

Effective Yield Locus

’

’

’

12

Effective Yield Locus

’

’

’

D

P0

s

Slip Region

h

Nip Regionx

D

P0

s

Slip Region

h

Nip Regionx

-5 0

-3 0

-1 0

1 0

3 0

5 0

7 0

9 0

1 1 0

1 3 0

1 5 0

-2 5 .0 -2 0 . 0 -1 5 . 0 - 1 0 .0 -5 .0 0 . 0

( ° )

(

MP

a)

= 4 0 ° D = 8 in c h e s 4 5 ° s /D = 0 .0 2 9K = 1 0 P 0 = 0 .1 p s i

h = 4 5 ° 0 = 0 .2 8 p s i

w = 4 i n c h e s = 1 1 .5 °

C a lc u la te dJ o h a n s o n

C a lc u la te d S c h ö n e r t = 0 .3

= 4 0 ° D = 8 in c h e s 4 5 ° s /D = 0 .0 2 9K = 1 0 P 0 = 0 .1 p s i

h = 4 5 ° 0 = 0 .2 8 p s i

w = 4 i n c h e s = 1 1 .5 °

C a lc u la te dJ o h a n s o n

C a lc u la te d S c h ö n e r t = 0 .3

log

log

1

2

K1lo

g

log

1

2

K1



The Dissolution Property Group



Surface Area

Wetting Propensity

Amorphous Content

c s a t

R 0R 0

R tR tR t

md V

d tD A

c

r r R

c

t

D

r rr

c

r

2

2

satt cRrc

crc

0

c

t

D

r rr

c

r

2

2

satt cRrc

crc

0

r

Elapsed Time (minutes)

% D

isso

lved

0

10

20

30

40

50

60

70

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90

100

0 10 20 30 40 50 60

As Received

Milled - 0 psig

Milled - 40 psig

% D

issol

ved

0

20

2 ccD

Rt

satf



The Stability Property Group


Surface Area

Amorphous Content

Hygroscopicity

EXTERNAL ENVIRONMENT

p T po, , , V

T p po, ,

HEAD SPACE

w w(i)m(i)

g(i) (i), , c , K

COMPONENTS

0.00

0.05

0.10

0.15

0.20

0.25

0.0 0.2 0.4 0.6 0.8 1.0

p/p0

Mo

istu

re C

on

ten

t(g

H2O

/ g

dry

so

lids)

Silica gel (Kontny, 1988)




Silica gelwm = 0.256cg = 10.3K = 0.387

orbofibanwm = 0.0299cg = 55.7K = 0.087

Acetominophen Suspension PDP-6, APDO-7 120 minutes X2Acetominophen Suspension PDP-6, APDO-7 100 minutes X2Acetominophen Suspension PDP-6, APDO-7 80 minutes X2Acetominophen Suspension PDP-6, APDO-7 60 minutes X2Acetominophen Suspension PDP-6, APDO-7 40 minutes X2

Acetominophen Suspension PDP-6, APDO-7 20 minutes (rerun) X2Acetominophen Suspension PDP-6, APDO-7 0 minutes X2

2.0 5.0 8.0 11.0 14.0 17.0 20.0 23.0 26.0 29.0 32.0 35.0 38.0Deg.

1424287141000128515711857214224282714300032853571385741424428471450005285CPS



Processing and Dosage Form Considerations

ProcessApproach

ProductKey

Operations

Capsule orSachet

MixingFilling

Tablet Above plusCompaction

Dry Granulation Capsule,Sachet, or Tablet

MixingFillingCompactionMilling

Capsule orSachet

MixingHigh-ShearGranulation DryingMillingBlendingFilling


Direct Dosing

Wet High-Shear Granulation

ProcessApproach

ProductKey

OperationsActives

Capsule orSachet

MixingFilling

FlowUniformityDissolutionStability


Above plus Mechanical



FlowUniformityMechanicalDissolutionStability

Capsule orSachet


UniformityWettingDryingMechanicalDissolutionStability


Same as Above

Direct Dosing


ProcessApproach

ProductKey

OperationsActives Fillers

Capsule orSachet

MixingFilling


FlowUniformity







FlowUniformityMechanical

Capsule orSachet



UniformityWettingDryingMechanical


Same as Above

Same as Above

Direct Dosing


ProcessApproach

ProductKey

OperationsActives Fillers Binders

Capsule orSachet

MixingFilling


FlowUniformity

FlowUniformity










Capsule orSachet






Same as Above

Same as Above

Same as Above

Direct Dosing


ProcessApproach

ProductKey

OperationsActives Fillers Binders Disintegrants Flow Aids

Capsule orSachet

MixingFilling


FlowUniformity

FlowUniformity


FlowUniformity














Capsule orSachet








Same as Above

Same as Above

Same as Above

Same as Above

Same as Above

Direct Dosing



18SPI - Bulk Properties Sub-ProcessCompany Confidential© 2006 Abbott

High Level Map SelectProperty

Particle Size

Bulk Density

Surface Area

Particle Shape

True Density

Pore Size

Surface Energy

Flow Property

Wetting

Cohesiveness

Surface Structure

Amorphous Content

Tensile Strength

Elastic Moduli

Compactibility

Brittleness

Static Charge

EvaluateProperty

PropertyCritical?

Select AnotherProperty

No

SelectControl

Yes

DemonstrateControl

PropertyDatabase



Recommendations1. Currently available models for common pharmaceutical unit

operations should be assessed and the relevant physical properties extracted

2. Available methods for quantifying the physical property list generated in the step above should be evaluated and the most promising approaches further developed specifically for pharmaceutical powders

3. As methods reach a sufficient state of maturity, the most commonly used pharmaceutical materials should be characterized and the results published in standardized tables. The results should include multiple vendors and include appropriate estimates of variation

4. The component results and the methods from the step above should be used to generate appropriate mixing rules for predicting the relevant properties of powder mixtures from the properties of the components

5. Iterate

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