Post on 10-May-2018
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?
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
23
• 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!
24
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
33
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 - 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
44
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
5/7/2018 51
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.