1Photo-Acoustics Research Laboratory

Compaction Simulator Forum 2012Vertex PharmaceuticalsCambridge, Massachusetts 9:40–10:20, November 13, 2012

Real-time/In-die Monitoring of Tablet Compaction

Çetin ÇetinkayaDept. of Mechanical and Aeronautical Engineering

Clarkson UniversityPotsdam, New York 13699-5725

cetin@clarkson.edu (315) 268-6514

2Photo-Acoustics Research Laboratory

Presentation Outline

• Seminar ObjectivesPersonalized Medicine and Individual Dosing: the Future of the Tablet?Real-time/In-die/wireless monitoringQuestion: How can we manufacture more predictable solid dosage products?

• Motivations and Mega-Trends

• Ultrasonic MonitoringOverview: Contact and air-coupled methodsIn-die characterization and monitoringWireless monitoringCharacterization and macro/micro-mechanics of tablets

• Future Research Directions and AreasPersonalized Medicine and Individual Dosing Hardware challengesCan we monitor the inter-granular coupling properties?

3Photo-Acoustics Research Laboratory

Motivations

• Status Today the drug tablet is the most popular drug delivery deviceProduction: 100+B tablets/yearMegatrend: Personalized Medicine, Individual Dosing, Targeted Drug DeliveryGlobal Spending: $880B in 2011 (prescription drugs)Research Expenditure: $68B in 2010 (U.S. R&D Total: $280B in 2012)

• Key Challenges and OpportunitiesExpiring Patents/IP How will the tablet adopt to the Personalized Medicine/Individual Dosing paradigm?Trial-and-error manufacturing techniques versus Quality-by-Design Predictable/dial-in/modifiable performance of the tablet for Personalized MedicineEmergence of biopharmaceuticals and delivery techniques

• Pushes/PullsMarket Pull: Novel and cost-effective drugs, needs for delivery methodsRegulatory Push: Process predictability, quality assurance (FDA’s PAT/QbD initiatives)Technology Push: Wireless, IT and nano/micro-manufacturing

4Photo-Acoustics Research Laboratory

Personalized Medicine and Individual Dosing

www.HelpofOthers.com

Research Question: How can we make the performance of the tablet more predictable and its delivery/dosage more tunable? • The drug tablet is the most popular drug delivery device• Megatrends: Personalized Medicine, Individual Dosing and Targeted Delivery• Expiring Patents/IP

5Photo-Acoustics Research Laboratory

Monitoring Tablet Production and Enterprise IT System

BlendingRoller Compaction Granulation Tablet

Compaction Coating TestingRelease

PAT Unit Operation Level

PAT Manufacturing Level

Process Analytical Technology (PAT) – A Framework by the FDA• Supports innovation/efficiency in pharmaceutical development, manufacturing, and quality assurance

• Founded on process understanding to facilitate innovation/risk-based regulatory decisions

6Photo-Acoustics Research Laboratory

Principle: The speeds of pressure and shear waves in materials depend on their mechanical properties (Young’s moduli, Poisson’s ratio, and mass density). By measuring these speeds, two of these three properties can be extracted for a known sample size.

Key Features:• Penetration Depth: Layer and Full Body• Contact/Damage• Resolution: High axial 1-5 m

(with ns time resolution) • Poor radial resolution (diffraction limit)• Fast and low costPrimary Uses:• Young’s modulus, Poisson’s ratio• Mass density • Coat thickness• Integrity/Defect detection

Pulser/ReceiverUnit

Digitizing Oscilloscope

Computer/SignalProcessing

T

Contact Ultrasound

A

C

Delay Line

Backing Layer

To Signal Processing

B

PZT

J. Liu and C. Cetinkaya, Mechanical and GeometricProperty Characterization of Dry-coated Tablets withContact Ultrasonic Techniques, the International Journalof Pharmaceutics, 392, 1-2, 148-155, 2010.

I. Akseli, D. Becker, and C. Cetinkaya, UltrasonicDetermination of Young’s Moduli of the Coat and CoreMaterials of a Drug Tablet, the International Journal ofPharmaceutics, Vol. 370, 2009.

7Photo-Acoustics Research Laboratory

Multiple Reflection Ray Tracing and E vs. Porosity

)()2(

)1(

)()3(

)1()4( )()(...)(tf

BAr

tf

ABt

BAt

CBr tfCttfCCCtf )()()( )2()4()3( tftftf

)()()( )1(*

)4()3(* tfCtftf BA

r AB

tBA

tCB

r CCCttf

tf

..)(

)(

)1(

*)3(

LcZ .1

2

12

12

ZZZZCt1

1

12

12

ZZZZCr

J. D. Stephens, B. R. Kowalczyk, B. C. Hancock, G. Kaul, M. V. Lakshmaiah, C. Cetinkaya, Porosity Testing/Characterization/Determination of Drug Tablet Materials, In Preparation for publication in the International Journal of Pharmaceutics, 2012.

8Photo-Acoustics Research Laboratory

Principle: The vibrational motion of a tablet is excited by an acoustic field generated by an air-coupled transducer. A set of vibrational resonance frequencies are used to extract mechanical and geometric properties of the tablet.

Key Features• Penetration depth: Full body• Resolution: Limited by the sensitivity analysis• Relatively low costPrimary Uses:• Tablet integrity/defect detection• Mechanical property determination• Coat thickness• Mass density

Non-contact Methods: Air-coupled Acoustics

0 100 200 300 400 500 600 700 800 900 1000-2.5

-2-1.5

-1-0.5

00.5

11.5

22.5

t (s)

Dis

plac

emen

t (nm

)

9 5 1 0 0 1 0 5 1 1 0 1 1 5 1 2 0 1 2 5 1 3 0 1 3 5 1 4 0 1 4 5 1 5 0 1 5 5 1 6 0- 1 1 5

- 1 1 0

- 1 0 5

- 1 0 0

- 9 5

- 9 0

- 8 5

- 8 0

- 7 5

- 7 0

F r e q u e n c y ( k H z )

Am

plitu

de (d

B)

Mode 5 (75.9 kHz)

I. Akseli, C. Cetinkaya, Air-Coupled Non-contact Mechanical Property Determination of Drug Tablets, the Int. J of Pharmaceutics, Vol. 359, Issues 1-2, pp. 25-34, 2008

Collaborators: Dr. D. Ventura and Dr. D. Becker.

9Photo-Acoustics Research Laboratory

Non-contact Techniques: Air-coupled Acoustics

95 100 105 110 115 120 125 130 135 140 145 150 155 160-115

-110

-105

-100

-95

-90

-85

-80

-75

-70

-65

Frequency (kHz)

Am

plitu

de (d

B)

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800-12-10

-8-6-4-202468

1012

Time (sec)

Dis

plac

emen

t (nm

)

0 50 100 150 200 250 300 350-70-60-50-40-30-20-10

01020304050607070

Time (sec)

Dis

plac

emen

t (nm

)

95 100 105 110 115 120 125 130 135 140 145 150 155 160-85

-80

-75

-70

-65

-60

-55

Frequency (kHz)

Am

plitu

de (d

B)

I. Akseli, C. Cetinkaya, Drug Tablet Thickness Estimations using Air-coupled Acoustics, the International Journal of Pharmaceutics, Vol. 351, No. 1-2, 165-173, 2008.I. Akseli, D. Dey and C. Cetinkaya, Mechanical Property Characterization of Bilayered Tablets using Nondestructive Air-Coupled Acoustics, 11, 1, 90-102, AAPSPharmSciTech, 2010.

10Photo-Acoustics Research LaboratoryI. Akseli, C. Cetinkaya, Drug Tablet Thickness Estimations using Air-coupled Acoustics, the International Journal of Pharmaceutics, Vol. 351, No. 1-2, 165-173, 2008.

The first noncontact characterization technique for drug tablets

11Photo-Acoustics Research Laboratory

Upper Punch

Lower Punch

Die

Real-time/In-die Compaction Monitoring

Dwell time: 10s msecForce: 10s kNRate: 0.5M tablets/hour

Objective: Determine the defect state and the critical performance/mechanical properties of a tablet core as it is being compacted.

C.-Y. Wu, et. Al, Modelling the mechanical behaviour of pharmaceutical powders during compaction, Powder Technology, Vol. 152, 2005, pp. 107–117.

Tablet

Controlling Microstructure Porosity Dissolution profile Bioavailability

12Photo-Acoustics Research Laboratory

Real-time In-Die Monitoring: Experimental Set-up

1

2

3

(b)

1

2

3

I. Akseli, C. Libordi, C. Cetinkaya, Real-Time Acoustic Elastic Property Monitoring of Drug Tablet Cores during Compaction, J. of Pharma. Innovation, Vol. 3(2), 2008.J. D. Stephens, B. R. Kowalczyk, B. C. Hancock, G. Kaul, C. Cetinkaya, Real-Time In-Die Monitoring of Tablet Compaction, Accepted for publication in the International Journal of Pharmaceutics, April 4, 2012.

Collaborator: B. Hancock, Pfizer

13Photo-Acoustics Research Laboratory

Calcium Carbonate h= 9mm 3.1 mm,D = 12.68 mmρ = 528 kg/m3 (powder)Transducer: 10 MHzV=400 V (spike)

J. D. Stephens, B. R. Kowalczyk, B. C. Hancock, G. Kaul, C. Cetinkaya, Real-Time In-Die Monitoring of Tablet Compaction, Accepted for publication in the International Journal of Pharmaceutics, April 4, 2012.

Instrumented Upper Punch for In-Die Monitoring

14Photo-Acoustics Research Laboratory

Wireless In-Die Monitoring

J. Stephens, M. V. Lakshmaiah, B. Hancock, C. Cetinkaya, Wireless Electromagnetic Transmission of Ultrasonic Waveforms for Monitor Drug Tablet Properties, Accepted for publication in the International Journal of Pharmaceutics, April 5, 2012.

The first wireless in-die technique for compaction

15Photo-Acoustics Research Laboratory

Tablet Micro-structure: Pharmaceutical Excipient Powders

Ascorbic Acid20m

Microcrystalline Cellulose100m

-Lactose Monohydrate100m

Aspartame

50m

SEM: 3000× Magnification

16Photo-Acoustics Research Laboratory

Granular Structures of Tablet Compacts

100 µm

Lactose to MCC ratio: 1:1

Excipient: Destab Calcium CarbonateX-Ray contrast agent: Tungsten particles (1-5um)

200 µm200 µm

17Photo-Acoustics Research Laboratory

( ( ) )( , ) ( ) i x tx t G e d

{ ( , )}{ ( 0, )}

1( ) ( ) ( ) ln xi ti x th

h

FF

Dispersion of Ultrasonic Waves in Granular Media

( ( ) )

( 0, ) ( )

( , ) ( )

i t

i h t

x t G e d

x h t G e d

( ) ( )p gdc cd

2 ( )2 ( )s s

s

dd

Kramers-Kronig (K-K) relation

Objectives:• Dispersion: scattering + viscoelasticity• Viscoelastic properties characterization• Grain-matrix elastic mismatch• Grain sizing

h

x = 0

x = h

x

x = 0 x = h

18Photo-Acoustics Research Laboratory

3 4( , ) rf D c D f

4 30

0

( ) ( )s rc N qf f dD DD

Scattering of Ultrasonic Waves: Attenuation Coefficient• Dispersion: Scattering + Viscoelasticity• For long waves λ>>D (i.e. λ/D>>1), attenuation is due

mainly to Rayleigh scattering

/2 2212

D

q D e

0

,s N D D dD

2

22

0

2, 2 1 sinmm

D mD

1 1

1 1

1tan

1m m

mm m

m j m jmn m n

22

2

tansin

tan 1

μ=π D/λ

Rayleigh Scattering

19Photo-Acoustics Research Laboratory

1 22 2 222 1 1 1

2 2 2 21 1

1 1( )2 1 1v

p p qE q q

1 22 2 222 1 1 1

2 2 2 21 1

1 1( )2 1 1v

p p qE q q

1 1

i in mxx xx

xx xxi

i ii ii

p Et t

q

) ( ( ) )( ( ) ()( , ) ( ) ( ) v vx i x ti x to ou x t u e u e e

Viscoelasticity: Standard Linear Solid (Zener) Model 2

2xxu

t x

Viscoelastic Attenuation αv(ω): v(ω) = βv(ω) + i αv(ω)

) ) )( ( (s v

2 2

1 21 22 2 222 301 1 1

2 2 2 2 91 1

4

0

1 1(2 1 1 (2

))

Dr

Np p q c e DE q

Dq

d

Total Attenuation: Viscoelasticity + Scattering +

20Photo-Acoustics Research Laboratory

Extracting Scattering and Viscoelastic Model Parameters

A. S. Vahdat, J. D. Stephens, B. C. Hancock, C. Cetinkaya, Viscoelastic Characterization of Granular Pharmaceutical Compacts, In Preparation for publication in the Int. Journal of Pharmaceutics, 2012.

{ ( , )}{ ( 0, )}

1( ) ( ) ( ) ln xi ti x th

h

FF

+

2 2

1 21 22 2 222 301 1 1

2 2 2 2 91 1

4

0

1 1(2 1 1 (2

))

Dr

Np p q c e DE q

Dq

d

21Photo-Acoustics Research Laboratory

Nominal Diameter

(m)

Coating Nanoparticle Size

(nm)

Nanoparticle Surface Area

Coverage

Number of Particles Tested

Average Diameter

(m)

Average Pre-rolling Stiffness

(N/m)

Average Work-of-Adhesion(mJ/m2)

9.0 N/A N/A 9 9.1 1.1 0.37 0.19 20 10

6.0 N/A N/A 8 6.0 0.4 0.43 0.17 23 9.1

6.0 24 10% 11 7.3 0.6 0.75 0.68 40 366.0 24 10% 7 7.3 0.7 0.095 0.031 5.0 1.76.0 24 50% 8 6.0 0.3 0.075 0.070 4.0 3.76.0 24 100% 6 6.3 0.5 0.020 0.015 1.1 0.78

Hints: Adhesion Control of Toner with Nanoparticles 0%0% 10%10% 50%50% 100%100%

Substrate Substrate

Collaborators: Dr. K. Law andDr. S. Badesha, Xerox

22Photo-Acoustics Research Laboratory

• Personalized Medicine and Individual Dosing will impact ways the drugs aremanufactured and the production processes are monitored.

• Overview: Several methods have been developed for tablet mechanicalproperty characterization. Air-coupled technique requires no physical contactand is fast (microsecond). Suitable for rapid testing/evaluation of the defectstate, mechanical properties and coating layer thicknesses of tablets.

• A real-time compaction monitoring method for materials properties and coreintegrity has been introduced and discussed. Wireless transmission ofultrasonic signals is demonstrated.

• An approach for visco-elastic and scattering characterization of a compact isdetailed.

• Next Questions: How can we characterize and monitor the inter-granularproperties of a solid dose for satisfying the needs of Personalized Medicine andIndividual Dosing?

Conclusions and Remarks

23Photo-Acoustics Research Laboratory

Acknowledgements

Funding Sources:National Science Foundation PfizerWyeth Pharmaceuticals Consortium for the Advancement of

Manufacturing in Pharmaceuticals (CAMP)

OYSTAR Manesty USANYSERDA/NYSTARCenter for Advanced Materials

Processing (CAMP)Clarkson University

Special Thanks: B. Hancock of Pfizer, D. Ventura and D. Becker of Wyeth Pharma, Nancy Sever of Abbot Labs.

PAR Lab Co-Workers:James D. Stephens (M.S./Ph.D.)Armin S. Vahdat (Ph.D.)Brian R. Kowalczyk (M.S.)Dr. A. S. Reddy (Visiting Prof.)Dr. M. V. Lakshmaiah (Visiting Prof.)Saber Azizi (Visiting Research Fellow)Huan Zhang (M.S./Ph.D.)Prof. W. DingIlgaz Akseli (Ph.D., 2010)Jingfei Liu (M.S., 2009)M. D. Murthy Peri (Ph.D., 2008)Ivin Varghese (Ph.D., 2008)Ganesh Subramanian (M.S., 2006)Dr. G. N. Mani (Post-doc, 2006)Liang Ban (Ph.D., 2005)Chen Li (Ph.D., 2005)