Granulationpharmaceutical applications

08.05.2018

Maximilian Eggersdorfer

1

Agenda

• Personal & Novartis Introduction

• Particle Engineering in Drug Development

• Granulation Introduction

• Adhesion forces between particles

• Types of granulation• Dry granulation

• Wet granulation

• Spray Drying

• Summary

2

Max Eggersdorfer• PhD at Particle Technology Laboratory, ETH Zürich, Zürich, Switzerland

Agglomerate breakage in shear flows

Sintering/coalescence of particles

3

Max Eggersdorfer• Postdoc at Weitz lab, Harvard University, Cambridge, MA, USA

• Particle Engineer at Novartis, Basel, Switzerland

Double emulsions by step emulsification

4

Agenda

• Personal & Novartis Introduction

• Particle Engineering in Drug Development

• Granulation Introduction

• Adhesion forces between particles

• Types of granulation• Dry granulation

• Wet granulation

• Spray Drying

• Summary

5

Active Pharmaceutical Ingredient (API)

6

Composition: Ibuprofen ► Active

Pharmaceutical Ingredient (API) Croscarmellose sodium Silicon dioxide Magnesium stearate Croscarmellose sodium Cellulose Talc …

Drug formulationcontains:

ActivePharmaceuticalIngredient (API)

Additional components• Filler• Disintegrant• Binder• Lubricant• Glidant• Stabilizers

Synthesis Scheme of an Active Pharmaceutical Ingredient (API) & Responsibility

A1 A2 A3

A4A5

A7

A6

A8 A9 A10 A11

API-SM

IP API = DS

millingCrystallization

Chemistry Particle Engineering

Principle Set-up:

Last solid forming step +

homogenization

(saltformation)

7

Crystallization Filtration Drying= Mechanical Solid / Liquid

Separation= Thermal Solid / Liquid

Separation

Solids are a Challenge for Scale-up !

= Solids Formation

8

Drug Substance Finishing TechnologiesWhat determines final DS properties?

9

Example of tray drying – Industrial Hygiene

10

Formulation of Drug Product

11

Objectives for Particle Engineering• Critical Material Attributes Drug Substance vs Drug Product

Bioavailability (Dissolution)Drug ContentStability

Particle Size & (Shape)

FlowabilityStickinessBulk DensityCompressibilityElectrostatics

PurityPolymorphSalt StoichiometryYieldCostsRobustnessDS Stability

Drug Substance Drug Product

Powder Properties

DP Manufacturing Process

Tailor Made Particle Properties

= f (Dose, Target PK Profile, Throughput)

12

s1 = consolidation stresssc = unconfined yield strengthrb = bulk density

1c

C

ffs

s

Powder Flow - uniaxial compression test

Flow function

Agenda

• Personal & Novartis Introduction

• Particle Engineering in Drug Development

• Granulation Introduction

• Adhesion forces between particles

• Types of granulation• Dry granulation

• Wet granulation

• Spray Drying

• Summary

13

Granulation…is the process in which dry primary powder particles are treated toadhere to form larger multi-particle entities called granules

• «Granulated» is derived from the Latin word «granulatum» meaninggrained

• hand rolling medicinal powder into a pill using honey or sugar hasbeen used for centuries

14

granulation

Typical size range 0.2 to 4 mm

Why granulate powders?

•Prevent segregation of constituents of powdermixture• Improve• flow properties• compaction characteristics of the mixture

e.g. bulk density

•Produce• Uniform mixtures• Dust free formulations

15

segregation

Agenda

• Personal & Novartis Introduction

• Particle Engineering in Drug Development

• Granulation Introduction

• Adhesion forces between particles

• Types of granulation• Dry granulation

• Wet granulation

• Spray Drying

• Summary

16

Adhesion forces between particles

17

Surface and field forces at contact Material bridges at contact

Shape dependent bonding

Comparison between different adhesion forcesdisregarding the solid bonds

18

Smooth surface – smooth plateLiquid bridge is dominant adhesion force

31crita V

|

2

ovdW

RF

a

|oconductor

RF

a

| 2oisolatorF R

3|

2

ogravity

RF

a

Electrostatic precipitatorRemoval of non-conductive/charged particles in an electric field

19

| 2oisolatorF R

Comparison between different adhesion forcesdisregarding the solid bonds

20

rough sphere (hemisphericalroughness) – smooth plate

Example: force between two sphericalparticles by capillary bridge

21

Derjaguin approximation:

2 ( )effF H R U H

With U(H) being the specific (per unit area) energy of interaction of two flat plates

Specific energy U in contact: 2 cosU = surface tension

1 1 11 2effR R R With:

For sphere – plate: effR R

2effR RFor sphere – sphere:

0 4 cosF H R

0 2 cosF H R

Agenda

• Personal & Novartis Introduction

• Particle Engineering in Drug Development

• Granulation Introduction

• Adhesion forces between particles

• Types of granulation• Dry granulation

• Wet granulation

• Spray Drying

• Summary

22

Types of granulation - Dry

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• Direct compression/slugging• Roller compaction

• Agglomeration of primary powder particles by high pressure• Used for drugs which

• Are sensitive to moisture and/or heat• Do not compress well after wet granulation

Dry GranulationMilling andsieving

Tablets (mainly) orhard gelatine capsules

Granules are typically only an intermediate product!

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a) Filling big pores by randomizing the grain position.

b) Filling small pores by bridging processes.

c) Filling smaller pores by plastic deformation.

Reduce distance between particlesIncrease contact area

Dry Granulation

Direct Compression - Slugging

25

Many pharmaceutical materialssuffer from work hardening -> poor recompaction in final tablet

Conventional tableting machine25 mm by 10-15 mm thick slugs

Roller compaction

26

API powder

Compacted API blend

Milled and blended compacts

Pressed tablets

Alexanderwerk

Through-puts: 10 – 2000 kg/hCompaction forces: 16 – 64 kN/cm

roller geometries

Alternative, gentler method compared to slugging

Types of granulation - Wet

27

• Agglomeration of primary powder particles by granulating fluid: • non-toxic, volatile: e.g. water, ethanol and isopropanol• often contains binder

Wet GranulationSieving andscreening

Tablets (mainly) orhard gelatine capsules

• Low/high-shear granulators• High-speed mixer granulators• Fluidized-bed granulator• Extrusion-spheronization• Spray drying

Drying

States of water distribution between particles

28

Important forspray drying

Solid bridges form betweenparticles upon drying by:• Partial melting (dry granulation)• Hardening binders• Crystallization of dissolved

substances

approx. threefold increase in adhesion force

Stages of Wet Granulation

• Nucleation and wetting

• Consolidation and growth

• Attrition and breakage

29

Wetting

30

< 90°: mostly (partial) wetting < 90°: mostly (partial) wetting

Water on polymethylmethacrylate Water on silanized silicon wafer

Wet Granulators

31Source: Glatt

High-speed mixer Dry powder blending

Granulating liquid addition

Wet massing

Wet sieving

drying

Dry sievingExtensively used for pharmaceutical granulationMixing and granulation in same equipment

Wet Granulators

32

Fluidized-bed granulatorsSee Dr. Wegners lecture for details: Lecture Fixed and Fluidized Beds

Rotorgranulation

Source: Freund Vector Spherical Granulator

• Powder is blended in different equipment

• Drying in granulatingequipment

• Subsequent coatingpossible

Extrusion/Spheronization

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Dry powder blending

Granulating liquid addition

Wet massing

Extrusion

Spheronization

Drying

Screening

Spheronizer plate

Source: Caleva

• Typically used forcontrolled drug releaseby applying different coatings

• Major advantage: incorporate high levelsof API without producingexcessively large particles

Agenda

• Personal & Novartis Introduction

• Particle Engineering in Drug Development

• Granulation Introduction

• Adhesion forces between particles

• Types of granulation• Dry granulation

• Wet granulation

• Spray Drying

• Summary

34

35Source: ESTD

Solid gas separation by:• Cyclone • Electrostatic precipitationLink: Lecture Solid-Gas Separation

Spray Drying

Atomization

Drying

Particle collection

Spray Drying – Atomization

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Spray Drying - Droplet drying History

37

0 -> 1: no solvent evaporation1 -> 2: evaporation like pure solvent2 -> 3: solidification occurs

Spray Drying – Particle Formation

38

low Pe:

8 i

PeD

high Pe:

D = Diffusion coefficient liquid phase (m2/s) = evaporation rate (m2/s)

Peclet number:

Spray Drying – Particle Morphologies

Interplay between processparameters• Temperature

• flow rate of drying gas

and feedstock properties• solute diffusion coefficient

• solvent latent heat

determine final particlemorphology

39

Pe = 2.7 Pe =5.6 Pe = 16.8

8 i

PeD

Peclet number:D = Diffusion coefficientliquid phase (m2/s) = evaporation rate (m2/s)

Modeling the droplet drying history

40

Assumptions: • radial symmetry• const. Drying rate period• const. Temperature in droplet as heat

conduction within droplet much fasterthan heat convection at droplet surface

2

2

1 2

1 2i i i iC C C C

Pe rt Pe t r r r r

ii

CPe C

r

Diffusion eq.C = API concentration

Solidification for C ≥ Csat,crit

Agenda

• Personal & Novartis Introduction

• Particle Engineering in Drug Development

• Granulation Introduction

• Adhesion forces between particles

• Types of granulation• Dry granulation

• Wet granulation

• Spray Drying

• Summary

41

Summary Granulation

• Granulation is the process to form multi-particleagglomerates/granules consisting of primary particles

• Liquid bridges are the strongest adhesion forces(disregarding solid bonds)

• Granulation prevents segregation, improves flow propertiesand compaction to produce uniform mixtures and dust freeformulations

• Two main types: dry and wet granulation

42

References

• M.E. Aulton, K.M.G. Taylor «Aulton’s Pharmaceutics: The design and manufacture of medicines», Churchill Livingstone Elsevier, Edinburgh, 2013

• D.M. Parikh, «Handbook of Pharmaceutical Granulation Technology», CRC Press, New York, 2010

• D.H. am Ende «Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing», Wiley, New Jersey, 2011

• J. Tomas, «Mechanics of Particle Adhesion» 2006

• H. Rumpf, Chem. Ing. Techn. 46 (1974) 1-11

• G. Lian, C. Thornton and M.J. Adams, J. Colloid Inter. Sci. 161 (1993) 138-147

• R. Vehring, W.R. Foss, D. Lechuga-Ballesteros, J. Aerosol Sci. 38 (2007) 728-746

• R. Vehring, Pharm. Res. 25 (2008) 999-1022

• D. Huang, Novartis Pharmaceutical Company, European Drying Conference (2011)

• Y.I. Rabinovich, M.S. Esayanur, B.M. Moudgil, Langmuir 21 (2005) 10992-10997

• Franz, R.M., The Upjohn Company (1986) 338-338.

• A.B.D. Nandiyanto, K. Okuyama, Adv. Powder Technol. 22 (2011) 1-19.

43

Modeling of Granulation Processes

• Monte Carlo Methods

• Discrete Element Modeling

• Population Balance Equations

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1. 2.

3. 4.

5.

6.

Interparticle forces: 1. Adhesion (van der Waals attraction)2. Elasto-plastic repulsion3. Friction4. Rolling and5. Torsion resistance6. ....

Hydrodynamic interaction:7. Stokes drag force

Typical types of excipients in drug productformulation• Filler

• Disintegrant

• Binder

• Lubricant

• Glidant

45

Compaction Theory

1. Particle rearrangement

2. Particle deformation

3. Particle fragmentation

4. Particle bonding

46

Wet Granulators

47e.g. Collette UltimaGral mixer

High-speed mixer Dry powder blending

Granulating liquid addition

Wet massing

Wet sieving

drying

Dry sieving

Example: force between two sphericalparticles by capillary bridge

48

Total energy of liquid bridge (by Israelachvili):

2 22 cosW R

= surface tension

2( , ) 4 cosdW d

F H V RdH dH

De Laval nozzle – supersonic flow

5/7/2018 49Vitaly Koren, Master's Thesis – Final

Presentation

Primary liquid breakup in supersonic air

AIR

AIR

Liquid

Secondary dropletbreakup overshockfront

shock front

Ma < 1 Ma = 1 Ma > 1 pamb = 1 barp < 1 barMa =

𝐚𝐢𝐫 𝐯𝐞𝐥𝐨𝐜𝐢𝐭𝐲 [𝐦

𝐬]

𝐬𝐨𝐧𝐢𝐜 𝐬𝐩𝐞𝐞𝐝 (~𝟑𝟒𝟎𝐦

𝐬)

Device and Setup

5/7/2018 50

Epoxy made Tapered

glasscapillary

AirLiquidAir

Vitaly Koren, Master's Thesis – Final Presentation

3 mm

1: Air2: Liquid3: Air

0

5

10

15

20

25

0 20 40 60 80 100

Vo

lum

eflo

w [

L/m

in]

Pressuredrop [psi]

Device 1

Supersonic speed verification

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Vitaly Koren, Master's Thesis – Final Presentation

0

5

10

15

20

25

0 20 40 60 80 100

Vo

lum

eflo

w [

L/m

in]

Pressuredrop [psi]

Device 1

Theoretical subsonic conditions (Ma<1)

0

5

10

15

20

25

0 20 40 60 80 100

Vo

lum

eflo

w [

L/m

in]

Pressuredrop [psi]

Device 1

Theoretical subsonic conditions (Ma<1)

Theoretical sonic conditions (Ma=1)

𝑉 ~ ∆p

𝑉 ~ ∆p 1.85

Supersonic region

Sonic speed

0

1

2

3

4

5

6

0 5 10 15

Vo

lum

eflo

w [

L/m

in]

Pressuredrop [psi]

Messerschmid, M., Dissertation , Univ. Bonn, 2004

5/7/2018 52Vitaly Koren, Master's Thesis – Final

Presentation

Geometric mean diameter (GMD):

GMD = 𝑖𝑁𝑑𝑖

1

𝑁

Sauter Mean Diameter (SMD):

SMD = 𝑖 𝑑𝑖

3

𝑖 𝑑𝑖2

2 mm expander:

GMD and SMD minimal

Narrowest size distribution

Expander length optimization

Optimal performance due to:

High air velocity (primary

breakup)

Highest pressure gradient

(secondary breakup)1

Flow analysis

5/7/201853

Vitaly Koren, Master's Thesis – Final Presentation

𝑑 ≈ 1

𝑑𝑝

𝑑𝑥

𝑑 ≈ 1

𝑈𝑔

1 Messerschmid, M., Dissertation , Univ. Bonn, 2004

Specific surface area

5/7/2018 54Vitaly Koren, Master's Thesis – Final

Presentation

Raw Danazol coarse particles ~ 10s ofµm

Spray dried Danazol porous networkof submicron-particles

> 10fold increase in SSA

Increased wetting surface

Decrease in contact angle with water(66º ► 50º)

20 µm

20 µm

1 µm

Cristallinity

5/7/2018 55Vitaly Koren, Master's Thesis – Final

Presentation

Danazol cristallinity is preserved after spray drying

Stable dissolution kinetics over time1

1 Yushen, G.; Shalaev, E.; Smith, S., Trends in Analytical Chemistry 2013, 49, 137-144.

Powder performance - Dissolution test

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Presentation

> 95 % dissolved