0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 1

Average Relative Density-( )

0

50

100

150

200

250

300

Aver

age

Mai

n Co

mpr

essio

n Pr

essu

re[M

Pa]-P

• Consolidateandcompactpowders(tableting)• Achievecontinuouscontrolofpharmaceuticalsolidproducts’CQAs

(e.g.,tensilestrength,weight,disintegrationtime)• ModelforQualitybyDesign(QbD)andforProcessAnalyticalTechnology

(PAT)• Utilizemulti-scaleresultsinvolvingvaryinglengthandtimescalesto

characterizethematerialsusedintabletmanufacturing• Usesimulationtoolstoverifyandvalidatethereducedordermodels

• Predictiveconstitutivemodelsofinter-particleinteractionsforavarietyofphysicalmechanisms+Predictabilityathighlevelsofconfinementremainsanopenproblem

• Concurrentandefficientmulti-scalestrategieswhicharefully-descriptiveatthegranularscale+Basedonaparticlemechanicsdescription

MULTI-SCALERESULTS

Multi-scalecharacterizationofpowdercompactionspanningsingleparticle,singletabletfabricationandindustrialrotarytabletpress

PARTICLECHARACTERIZATION

Goals:• Assistthedevelopmentofconstitutivemodelsofinter-particleinteractions

withdirectexperimentaltestingofindividualparticlesathighlevelsofdeformationandconfinement.

• Createaprotocolformeasuringmechano-chemicalpropertiesattheparticlescale.

• Createaprotocolforpredictingtableting(oranotherunitoperation)basedonsingleparticlemeasurements.

• Adapttheprotocolfornon-sphericalparticles(chasetowardstheactualshapeofpharmaceuticalpowders).

Approach:• Singleparticleundercontrolledloadingpatterns.• Imageacquisitionofdeformedconfigurationsandprocessingto

reconstructdeformationfields.• Initialfocus:ExcipientsandAPIsusedincontinuouslineFromparticlebehaviortotableproperties:Bydevelopingmechanisticpredictivemodelsattheparticlescaleandnumericalmulti-scaletechniquesatthepowder/tabletscale(R&Deffort!)

ShimadzuMCT-510

PMMAsphericalparticles

Sidecamera recordstheshapeofaparticledeformed

underdiametricalcompression

Capabilities:+particlediameter:1-500μm+displacement range:0-100μm+displacement increment:1nm+loading/unloading cyclesChallenges:+Toposition theparticleandfocusthe camera

REDUCEDORDERMODELING INCONTINUOUSLINE

PARTICLEMECHANICSSTRATEGIESPOWDERBLENDCHARACTERIZATION

Dominantmechanisms:- Elasticdeformations- Plasticdeformations- Bonding- Strain-ratemechanisms- Frictionandfracture

- Waterintakeandswelling

cp3 NationalScienceFoundationwww.nsf.gov

CenterforStructuredOrganicParticulateSystemswww.csops.org

U.S.FoodandDrugAdministrationwww.fda.gov

CenterforParticulateProductsandProcessesengineering.purdue.edu/CP3

YasasviBommireddy,Prof.Marcial Gonzalez MechanicalEngineering

§ TestModes• Targetthickness• Targetpeakcompactionforce• Fracturetest

§ Measurements• Compactionprofile• Detachmentforce• Ejectionforce• Breakingforce

PILOTPLANTEXPERIMENTS§ UpstreamMaterial

Properties• Particlesizedistribution

(PSD)• Truedensityofblend• Massflowrate

§ VariableParametersinTabletPress• Productionrate• Fillingheightofpowder

blendindies

§ MeasurableCriticalQualityAttributes(CQAs)ofTabletsbyAT4• Weight• Thickness• Diameter• BreakingForce

CONCLUSION

- Fillingdepthandgapheight- Main&Pre-compressionForce- Ejection&TakeoffForce- Tablet&CompartmentTemp.- CompartmentHumidity- TableWeight(Mass), thickness,diameter

- Tablethardness

Powdercharacterization Microcompressiontesting Continuousmanufacturingline:tabletpressandAT4

Input DatawithUncertainty Calibration/Training ofBayesianModels Processcontrol &optimizationProduct design

CosteffectiveScience-driven

Natoli BLP-16Press

ReducedOrderModelswithuncertainty

quantificationandbuilt-indimensionalityreduction

Particle Number

F m [

N]

10 20 30 40660

670

680

690

700

710

720

730

740

Particle Number

FWH

M [

Dia

met

er]

10 20 30 402.02

2.04

2.06

2.08

2.1

2.12

2.14

2.16

680 690 700 710 720 730650

660

670

680

690

700

710

720

730

740

F m [N]

V s

[m/s

ec]

F mU:+/−5%E − F m

0%E [N]

Prob

abilit

y

−40 −20 0 20 40

0

0.01

0.02

0.03

0.04

0.05

TOFU:+/−5%E − TOF0%E [µsec]

Prob

abilit

y

−20 −10 0 10 20

0

0.05

0.1

0.15

0.2

0.25

FWHMU:+/−5%E [Diameter]

Prob

abilit

y

2.05 2.1 2.15

0

10

20

30

40

50

Particle Number

F m [

N]

10 20 30 40

680

690

700

710

720

Particle Number

FWH

M [

Dia

met

er]

10 20 30 402.02

2.04

2.06

2.08

2.1

2.12

2.14

690 700 710 720

670

680

690

700

710

720

730

F m [N]

V s

[m/s

ec]

F mU:+/−5%E − F m

0%E [N]

Prob

abilit

y

−20 −10 0 10 20−0.01

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

TOFU:+/−5%E − TOF0%E [µsec]

Prob

abilit

y

−20 −10 0 10 20

0

0.05

0.1

0.15

0.2

0.25

FWHMU:+/−5%E [Diameter]

Prob

abilit

y

2.08 2.1 2.12 2.14

0

10

20

30

40

50

60

Particle Number

F m [

N]

10 20 30 40660

670

680

690

700

710

720

730

740

Particle Number

FWH

M [

Dia

met

er]

10 20 30 402.02

2.04

2.06

2.08

2.1

2.12

2.14

2.16

680 690 700 710 720 730650

660

670

680

690

700

710

720

730

740

F m [N]

V s

[m/s

ec]

F mU:+/−5%E − F m

0%E [N]

Prob

abilit

y

−40 −20 0 20 40

0

0.01

0.02

0.03

0.04

0.05

TOFU:+/−5%E − TOF0%E [µsec]

Prob

abilit

y

−20 −10 0 10 20

0

0.05

0.1

0.15

0.2

0.25

FWHMU:+/−5%E [Diameter]

Prob

abilit

y

2.05 2.1 2.15

0

10

20

30

40

50

Particle Number

F m [

N]

10 20 30 40660

670

680

690

700

710

720

730

740

Particle Number

FWH

M [

Dia

met

er]

10 20 30 402.02

2.04

2.06

2.08

2.1

2.12

2.14

2.16

680 690 700 710 720 730650

660

670

680

690

700

710

720

730

740

F m [N]

V s

[m/s

ec]

F mU:+/−5%E − F m

0%E [N]

Prob

abilit

y

−40 −20 0 20 40

0

0.01

0.02

0.03

0.04

0.05

TOFU:+/−5%E − TOF0%E [µsec]

Prob

abilit

y

−20 −10 0 10 20

0

0.05

0.1

0.15

0.2

0.25

FWHMU:+/−5%E [Diameter]

Prob

abilit

y

2.05 2.1 2.15

0

10

20

30

40

50

Particle Number

F m [

N]

10 20 30 40660

670

680

690

700

710

720

730

740

Particle Number

FWH

M [

Dia

met

er]

10 20 30 402.02

2.04

2.06

2.08

2.1

2.12

2.14

2.16

680 690 700 710 720 730650

660

670

680

690

700

710

720

730

740

F m [N]

V s

[m/s

ec]

F mU:+/−5%E − F m

0%E [N]

Prob

abilit

y

−40 −20 0 20 40

0

0.01

0.02

0.03

0.04

0.05

TOFU:+/−5%E − TOF0%E [µsec]

Prob

abilit

y

−20 −10 0 10 20

0

0.05

0.1

0.15

0.2

0.25

FWHMU:+/−5%E [Diameter]

Prob

abilit

y

2.05 2.1 2.15

0

10

20

30

40

50

TabletstrengthDissolutionprofile,etc.

In-linemeasurementsModel-formuncertaintyMaterialproperties,etc.

Goal:• Developmentoffirst-principlespredictivemodelsto

understandtheattributesofpowderblendsandsubsequentcompacts

Leuenberger→ 𝝈𝒕,𝒑 = 𝝈𝒎𝒂𝒙 𝟏 −𝟏 − 𝝆𝟏 − 𝝆𝒄,𝝈

𝐞 𝝆/𝝆𝒄,𝝈

Goals:• ControlofCQAsoftabletsusingpredictive

modelstoachieveQbD ofthecontinuousline• DevelopmentofreliabilitystrategiesusingPAT

toolstohavearobustcontroloftheentireplant

Kawakita→ 𝐶𝐹1 − 𝜌4 𝜌⁄ =

𝐶𝐹𝑎 +

𝜋𝐷; 4⁄ 𝑎𝑏

WeightPredictionin-line→ 𝑊? = 𝜌@ABCD

E𝐷𝑃(1 −cTS)

MCTcanbeusedtocharacterizeonlyoneparticlewhilethecompactionsimulatorcanproduceonlyonetabletatatimewhilethetabletpressgenerateshundredsoftabletspermin.Hencethemodelsdescribingeachstagewouldbedifferentandofvaryingorders.

0.55 0.6 0.65 0.7 0.75 0.8 0.85 0.9 0.95 1

Relative Density

0

20

40

60

80

100

120

Com

pacti

on P

ress

ure[

MPa

]

0 ms300 ms600 ms900 ms1200 ms

• At a time only a single partcan be compacted

• The particle size is only inmicro-meters

• The time of compaction islonger

• The size of particles andtheir uniformity play a rolein the characterization ofparticle

• At a time only a singletablet can be fabricated

• The time required can bechanged by changing thepunch speeds from veryslow to very high

• Different compositions ofblend can be changedquite easily and hencevarying ranges ofproperties can be observed

• Hundreds of tablets can beused within a minute, hencethe time required to produceone tablet is very low

• The composition of the blendcannot be changedfrequently as segregationand mixing could take placein various stages of the press

• The models would need tobe scaled up and reduced inorder to be predictive forreal time control

Sizeofcom

pacted

unit

CompactionTime

MOTIVATION

Powderblendcharacterization

Note:PilotplantislocatedatPurdueUniversity

GamlenDSeriesCompactionSimulator