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1 Alston, Purdue University
Inves4ga4on of Mechanical Property Variability in Lactose
Products Kris4ne Alston and Carl Wassgren School of Mechanical Engineering
Purdue University
In associa4on with Steve Hoag and Ting Wang University of Maryland
Ann Chris4ne Catlin, Sumudinie Fernando, and Sudheera Fernando Purdue University
2 Alston, Purdue University
Overview
• Importance of understanding excipient proper4es
• Proper4es of interest • Background • Proper4es measured and test methods • Materials • Results • Conclusions
3 Alston, Purdue University
Importance of Measuring Excipient Proper4es
• Component proper4es have significant impact on drug product performance and manufacturability – Create a database of proper4es for use in models, correla4ons and quality control
• Derived from natural sources; varia4on may occur due to – Geographic origin – Seasonal climate varia4ons – Storage and processing
• Formula4ons and manufacturing processes regulated by FDA – Variable input + constant process = variable output
4 Alston, Purdue University
Some Proper4es of Interest
Par$cle Power Compact size distribu4on Hausner ra4o elas4c modulus
shape compressibility yield strength true density flow func4on fracture strength
apparent density effec4ve angle of internal fric4on indenta4on hardness specific surface area poured and tapped bulk density cri4cal stress intensity factor elas4c modulus Poisson's ra4o yield strength
fracture strength adhesion
Par$cle Powder Compact size distribu4on Hausner ra4o elas4c modulus
shape compressibility yield strength true density flow func4on fracture strength
apparent density effec4ve angle of internal fric4on indenta4on hardness specific surface area poured and tapped bulk density cri4cal stress intensity factor elas4c modulus Poisson's ra4o yield strength
fracture strength adhesion
5 Alston, Purdue University
Background • Literature survey
– Large sca]er in the data – Range of test methods used – Details of tes4ng condi4ons and procedures are rarely reported
• Difficult to determine the source of discrepancies • Few studies have been performed on the variability of lactose
(Gamble et al., 2010; Kushner et al., 2011; Whiteman et al., 1990) – Common excipient – Purpose: diluent, filler-‐binder
• Objec4ve: study the variability in par4cle, powder, and compact level proper4es of lactose – Though a wide range of lactose grades were studied, only select
results are presented here.
6 Alston, Purdue University
Materials Tested • Crystalline milled α-‐lactose monohydrate • “Equivalent” products
– 85 – 100 µm nominal par4cle size • Lactose Monohydrate 310 (Foremost Farms, USA) • Pharmatose 130M (DMV – Fonterra Excipients)
– 40 – 50 µm nominal par4cle size • Lactose Monohydrate 312 (Foremost Farms, USA) • Pharmatose 130M (DMV – Fonterra Excipients)
Product Name From Manufacturing Site Lot no.
Lactose Monohydrate 310Kerry Bioscience (Foremost
Farms, USA)Rothschild, WI 8510122310
Lactose Monohydrate 310Kerry Bioscience (Foremost
Farms, USA)Rothschild, WI 8511061010
Lactose Monohydrate 312Kerry Bioscience (Foremost
Farms, USA)Rothschild, WI 8510101512
Lactose Monohydrate 312Kerry Bioscience (Foremost
Farms, USA)Rothschild, WI 8510101712
Pharmatose 130M (NZ) DMV-‐Fonterra ExcipientsFonterra Limited, Kaponga, New
ZealandNZ000542
Pharmatose 130M (NZ) DMV-‐Fonterra ExcipientsFonterra Limited, Kaponga, New
ZealandNZ000570
Pharmatose 130M (NZ) DMV-‐Fonterra ExcipientsFonterra Limited, Kaponga, New
ZealandNZ000667
Pharmatose 150M DMV-‐Fonterra ExcipientsFrieslandCampina DMV BV, Veghel, The Netherlands
10498250
Pharmatose 150M DMV-‐Fonterra ExcipientsFrieslandCampina DMV BV, Veghel, The Netherlands
10544872
7 Alston, Purdue University
Proper4es and Test Methods Property Test Method Equipment Standard
Apparent Density Helium pycnometryAccupyc II 1340 Pycnometer
Helium gasASTM B923-‐10
Particle Size Distribution Laser diffraction
Malvern Mastersizer 2000 Particle Size AnalyzerHydro µP wet dispersion unit
Malvern Mastersizer 2000E Particle Size AnalyzerScirocco M dry powder feeder
ASTM B822-‐10
Poured Bulk Density -‐ Graduated cylinder ASTM D7481-‐09Tapped Bulk Density -‐ Agilent Technologies 350 Tapped Density Tester ASTM D7481-‐09Shear Cell Flowability Ring shear cell Schulze Ring Shear Tester RST-‐XS ASTM D6773-‐08
Elastic Modulus Three point bendingCarver Hydraulic Press
Instron ElectroPuls E1000Custom three point bend fixture
ASTM B925-‐08ASTM D790-‐07
Tensile Strength Three point bendingCarver Hydraulic Press
Instron ElectroPuls E1000Custom three point bend fixture
ASTM B925-‐08ASTM D790-‐07
Critical Stress Intensity Factor Three point bendingCarver Hydraulic Press
Instron ElectroPuls E1000Custom three point bend fixture
ASTM B925-‐08ASTM E399-‐09
8 Alston, Purdue University
1.50
1.51
1.52
1.53
1.54
1.55
1.56
1.57
1.58
Appa
rent Den
sity (g/cc)
Results – Apparent Density
85 – 100 µm lots 40 – 50 µm lots
Determined from 20 measurements ± 1 standard devia4on
True density of α-‐lactose monohydrate: 1.53 g/cc
9 Alston, Purdue University
0
2
4
6
8
10
12
0 200 400 600 800
Volume Pe
rcen
t (%)
Size (µm)
Foremost 310 Lot A Foremost 310 Lot B Pharmatose 130M Lot A Pharmatose 130M Lot B Pharmatose 130M Lot C
Results – Par4cle Size Distribu4on
85 – 100 µm lots
0
2
4
6
8
10
12
0 100 200 300 Vo
lume Pe
rcen
t (%)
Size (µm)
Foremost 312 Lot A
Foremost 312 Lot B
Pharmatose 150M Lot A
Pharmatose 150M Lot B
40 – 50 µm lots
10 Alston, Purdue University
Results – Par4cle Size Distribu4on
0
50
100
150
200
250
0 1 2 3 4 5 6
size [u
m]
d10 (F 310) d10 (P 130M) d50 (F 310) d50 (P 130M) d90 (F 310) d90 (P 130M) d3,2 (F 310) d3,2 (P 150M) d4,3 (F 310) d4,3 (P 150M)
0
20
40
60
80
100
120
140
0 1 2 3 4 5
size [u
m]
d10 (F 312)
d10 (P 150M)
d50 (F 312)
d50 (P 150M)
d90 (F 312)
d90 (P 150M)
d3,2 (F 312)
d3,2 (P 150M)
40 – 50 µm lots
85 – 100 µm lots
11 Alston, Purdue University
Results – Par4cle Size Distribu4on
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 1 2 3 4 5 6
span
F 310
P 130M
F 312
P 150M
12 Alston, Purdue University
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Bulk Den
sity (g/cc)
Poured
Tapped
Results – Poured and Tapped Bulk Density
85 – 100 µm lots 40 – 50 µm lots
Determined from 3 measurements ± 1 standard devia4on
13 Alston, Purdue University
1.00 1.05 1.10 1.15 1.20 1.25 1.30 1.35 1.40 1.45 1.50
Hausne
r Ra$
o (-‐)
Results – Hausner Ra4o
Determined from 3 measurements ± 1 standard devia4on
HR=ρ↓tapped /ρ↓bulk Smaller HR = be]er flow
85 – 100 µm lots 40 – 50 µm lots
14 Alston, Purdue University
Results – Shear Cell Flowability
0
500
1000
1500
2000
2500
3000
3500
0 5000 10000 15000 Uncon
fined
Yield Stren
gth (Pa)
Consolida$on Stress (Pa)
85-‐100 µm Grades Foremost 310 Lot A Foremost 310 Lot B Pharmatose 130M Lot A Pharmatose 130M Lot B Pharmatose 130M Lot C
Grade Lot NumberFlow Factor at ~8000 Pa (-‐)
Foremost 310 A 3.69Foremost 310 B 4.67
Pharmatose 130M A 3.28Pharmatose 130M B 3.56Pharmatose 130M C 3.77
Larger flow factor => be]er flow
0
500
1000
1500
2000
2500
0 5000 10000 15000 Uncon
fined
Yield Stren
gth (Pa)
Consolida$on Stress (Pa)
Powder Flow Func$on for Foremost 310 Lot 8511061010
Run 1
Run 2
Run 3
15 Alston, Purdue University
Results – Shear Cell Flowability
0 500
1000 1500 2000 2500 3000 3500 4000
0 5000 10000 15000
Uncon
fined
Yield Stren
gth (Pa)
Consolida$on Stress (Pa)
40-‐50 µm Grades
Foremost 312 Lot A
Foremost 312 Lot B
Pharmatose 150M Lot A
Pharmatose 150M Lot B
Grade Lot NumberFlow Factor at ~8000 Pa (-‐)
Foremost 312 A 3.29Foremost 312 B 3.22
Pharmatose 150M A 3.15Pharmatose 150M B 2.93
Larger flow factor => be]er flow
16 Alston, Purdue University
Results – Elas4c Modulus
Sprigg’s Equa4on: E= E↓0 e↑−b&
0.0
0.5
1.0
1.5
2.0
2.5
0 0.05 0.1 0.15 0.2
Elas$c M
odulus (G
Pa)
Porosity (-‐)
85 -‐ 100 µm Grades
Foremost 310 Lot A
Foremost 310 Lot B
Pharmatose 130M Lot A
Pharmatose 130M Lot B
Pharmatose 130M Lot C
GradeLot
NumberE0 (GPa) b (-‐) R2
Foremost 310 A 4.3 11.6 0.98Foremost 310 B 5.1 13.3 0.98
Pharmatose 130M A 4.9 14.4 0.96Pharmatose 130M B 3.6 15.0 0.94Pharmatose 130M C 4.2 15.8 0.98
17 Alston, Purdue University
Results – Tensile Strength
Sprigg’s Equa4on: σ= σ↓0 e↑−b&
0
1
2
3
4
5
6
7
8
0 0.05 0.1 0.15 0.2
Tensile Stren
gth (M
Pa)
Porosity (-‐)
85 -‐ 100 µm Grades
Foremost 310 Lot A
Foremost 310 Lot B
Pharmatose 130M Lot A
Pharmatose 130M Lot B
Pharmatose 130M Lot C
GradeLot
Numberσ0 (MPa) b (-‐) R2
Foremost 310 A 21.8 15.1 0.98Foremost 310 B 20.6 14.3 0.98
Pharmatose 130M A 20.4 16.3 0.98Pharmatose 130M B 22.2 18.3 0.97Pharmatose 130M C 21.4 17.1 0.98
18 Alston, Purdue University
Results – Cri4cal Stress Intensity Factor
Sprigg’s Equa4on: K↓IC = K↓IC0 e↑−b&
0 0.02 0.04 0.06 0.08 0.1
0.12 0.14 0.16 0.18 0.2
0.00 0.05 0.10 0.15 0.20 Cri$cal Stress Inten
sity Factor
(MPa
√m)
Porosity (-‐)
85 -‐ 100 µm Grades
Foremost 310 Lot A
Foremost 310 Lot B
Pharmatose 130M Lot A
Pharmatose 130M Lot B
Pharmatose 130M Lot C
GradeLot
NumberKIC0
(MPa√m)b (-‐) R2
Foremost 310 A 0.59 15.7 0.99Foremost 310 B 0.50 13.7 0.99
Pharmatose 130M A 0.57 16.8 0.98Pharmatose 130M B 0.50 15.7 0.99Pharmatose 130M C 0.61 16.5 0.96
19 Alston, Purdue University
Conclusions • Apparent density
– Larger than the true density; small variability • Par4cle size distribu4on
– Considerable lot-‐to-‐lot variability – Par4cle size distribu4on is more skewed for Foremost products – Median size distribu4ons quite different than stated by the manufacturer
• Bulk Density – 85-‐100 µm: Pharmatose poured and tapped density slightly larger than Foremost – More lot and vendor variability for 40-‐50 µm products – Both poured and tapped bulk densi4es smaller for 40-‐50 µm products – Hausner Ra4o smaller for smaller par4cle sizes
• Shear cell – Flow func4on: low variability between lots and products, except for Foremost 310 lot B – Flow factors suggest cohesive material, except for Foremost 310 lot B – Flow factor and Hausner Ra4o give conflic4ng results.
• Compact proper4es – Elas4c modulus , tensile strength, and cri4cal stress intensity factor follow Sprigg’s equa4on
quite well – Foremost gives consistently larger elas4c modulus, tensile strength, and cri4cal stress
intensity factor • However, the variability in data points is close to these differences
– Difficult to discern any differences between lots
• Data available at: pharmahub.org/excipientsexplore
20 Alston, Purdue University
Pharmahub Excipients Database
21 Alston, Purdue University
Ques4ons?
22 Alston, Purdue University
BACKUP SLIDES
23 Alston, Purdue University
Results – Elas4c Modulus
0
0.5
1
1.5
2
2.5
0 0.05 0.1 0.15 0.2 0.25
Elas$c M
odulus (G
Pa)
Porosity (-‐)
40 -‐ 50 µm Grades
Foremost 312 Lot A
Foremost 312 Lot B
Pharmatose 150M Lot A
Pharmatose 150M Lot B
GradeLot
NumberE0 (GPa) b (-‐) R2
Foremost 312 A 3.7 11.5 0.95Foremost 312 B 5.5 12.0 0.97
Pharmatose 150M A 4.9 15.1 0.89Pharmatose 150M B 4.5 13.6 0.94
24 Alston, Purdue University
Results – Tensile Strength
0
2
4
6
8
10
0 0.05 0.1 0.15 0.2 0.25
Tensile Stren
gth (M
Pa)
Porosity (-‐)
40 -‐ 50 µm Grades
Foremost 312 Lot A
Foremost 312 Lot B
Pharmatose 150M Lot A
Pharmatose 150M Lot B
GradeLot
Numberσ0 (MPa) b (-‐) R2
Foremost 312 A 20.4 13.1 0.97Foremost 312 B 25.1 14.2 0.98
Pharmatose 150M A 26.2 17.2 0.97Pharmatose 150M B 27.9 16.8 0.98
25 Alston, Purdue University
Results – Cri4cal Stress Intensity Factor
0.000
0.050
0.100
0.150
0.200
0.250
0.000 0.100 0.200 0.300
Cri$cal Stress Inten
sity Factor
(MPa
√m)
Porosity (-‐)
40 -‐ 50 µm Grades
Foremost 312 Lot A
Foremost 312 Lot B
Pharmatose 150M Lot A
Pharmatose 150M Lot B
GradeLot
NumberKIC0
(MPa√m)b (-‐) R2
Foremost 312 A 0.59 12.6 0.97Foremost 312 B 0.57 13.6 0.99
Pharmatose 150M A 0.63 16.2 0.90Pharmatose 150M B 0.62 15.1 0.97