Effect of Magnesium Stearate
Lubricant Attributes on Product
Processibility and Quality
Stephen H. Wu, Ph.D
Technical Fellow, Pharmaceutical R/D
Covidien/Mallinckrodt
Presented in 2009 Land O’Lake Industrial Pharmacy Conference
MgSt is Used in > 2500 Pharmaceutical products.
The Most Used Excipient in Top 200 Rx Drugs1
Most Used Excipients
107
77
61
4945
4036
25 22 22 21 20 20 19 19
0
20
40
60
80
100
120
MgSt
Lactose
MC
CTiO
2
HPM
CPEG
PVPH
PC
XCM-N
a
Col
loid
al SiO
2
Pregel S
tarc
hTalc
X-Povid
one
Starc
h
Cel
lulo
se
Excipients
No
in T
op
200
Rx
Dru
gs
Series1
1. R. Dave, “Overview of pharmaceutical Excipients used in tablets
and capsules” in Drug Topic, Oct. 24, 2008
Functions
Anti-adherent
Gliding agent
Lubricant
Effects
Powder flow
Blend uniformity
Die wall lubrication
Process ease
Tablet quality
Tablet performance
When MgSt is used as a lubricant…
Insurgent Questions About Using
Magnesium Stearate
Used to hear:
“ …0.5 – 2 %, mix for 2 min…this is what we have being doing so far…”
“When it does not work right, we add more…”
Now…frequently hear:
Well-defined product composition and specifications – crystalline state, size/size distribution, specific surface area
Consistent quality – low Lot-to-lot variability
Process control and capability – Upper and lower limits
Samples with upper and lower specifications for DOE
Better understanding of lubrication mechanism
Problems Associated with MgSt
Polymorphs in Development and Scale-up
Inconsistent hydrate forms of MgSt were linked to variable sticking properties of the tablets.
Specifying the hydration state should be part of MgSt specifications.
Capping issues were observed in making tablets when MgSt contained a mixture of hydration states. No sticking issues when monohydrate was used and better distributed in the tablet matrix.
Sticking blends in roller compaction was linked to MgSt hydration state and material sources.
A study in Long Island University showed that pure MgSt monohydrate or dihydrate exhibited lower lubricity index and thus lower tendency to over-lubrication than a mixture of hydration forms.
What are considerations in selecting pharmaceutical lubricants?
Made with suitable vegetable source materials
Meet USP/NF monograph definition
Provide product quality attributes for regulatory filing needs (QbD)
Demonstrate manufacturing process control (Vendor)
Support product quality with validated analytical methods
Crystalline state specified and well defined
Demonstrate measurable benefits or equivalency, e.g.,
Powder flow
Blend uniformity
Tableting ease
Tablet quality
$$$, speed, problems free
Desirable MgSt Lubricant Attributes1
Bulk level (density, porosity, accessible surface area)
=> Absence of agglomerates
Particle level (size/size distribution, aggregation state)
=> Selected particle size,
=> Specific surface area value (?)
=> Plate-like crystal shape
Molecular level (fatty acid composition, hydration state)
=> Consistent composition and crystalline structure
=> Pure dihydrate desirable
1. K. Phanidhara Rao et. Al.
Pharmaceutical Development and Technology, Vol.10 (3), 2005 p. 423 - 437
Key Factors in Selecting
Pharmaceutical Lubricant
Outline
Chemistry and characterization of
Magnesium Stearate material properties
Not all MgSt are created equal
Effect of material attributes on
Powder flow, blending and blend uniformity
Tableting process ease
Tablet quality and performance
Effect of surface treatment of MgSt to
enhance disintegration and dissolution
MgSt Lubricants Evaluated
Multiple Lots of MgSt Products (Covidien)
Magnesium Stearate Monohydrate (2257, 5712)
Magnesium Stearate Dihydrate (1729)
Stear-O-WetTM (8577)
A co-processed surface-treated material of MgSt
monohydrate with sodium lauryl sulfate (94/6)
Multiple lots of commercial products from
various global sources: F, N, NK, P, T.
Methods Used
Powder X-Ray Diffraction
Thermal Analysis – TGA, DSC
NIR
Particle size analyzer (Malvern)
Scanning Electron Microscopy (SEM)
LIBS (PharmaLIBSTM 250, Pharma Laser)
Synthesis of Magnesium Stearate
C17 H35COOH* + NaOH
C17H35COONa + H2O
2C17H35COONa + MgSO47H2O
Mg(C17H35COO)2●nH2O
+ Na2SO4 + 6H2O
Depending on reaction conditions, highly pure monohydrate and dihydrate can be made.
*Stearic acid:palmitic acid = 2:1
Inter- conversion of MgSt Hydrates*
MgSt dihydrate* MgSt Trihydrate
Amorphous MgSt
Anhydrous MgSt
RH > 70%
Dry at 100 – 105 oC100 % RHDry at 100 – 105 oC
Hydration
100 – 105 oC
•The dihydrate is not an intermediate in the formation of trihydrate from anhydrous
form. [V. Swaminathan and D. Kilsig AAPS PharmSciTech 2001; 2 (4) article 28.]
MgSt Monohydrate
MgSt Monohydrate MgSt Dihydrate
MgSt TrihydrateAmorphous MgSt
Type IIType I Type IV
Type III
(?)
Dry 105 oC
RH 98 %
Dry 80
Dry 125 oC
RH 98 %
Dry 125 Dry 80
Dry 110 Dry 110 o C
RH 98 %
Inter-conversion of MgSt Hydrates
RH > 70 %
Our own study confirms MgSt dihydrate is a stable form.
Thermal Properties (TGA, DSC) of
Pure MgSt Monohydrate & Dihydrate
Powder X-Ray Diffraction and NIR of
MgSt Monohydrate & MgSt Dihydrate
-0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
400050006000700080009000
Frequency (cm-1)
NIR Re
flecta
nceMg Stearate Monohydrate
Mg Stearate Dihydrate
Not all MgSt are created equal!
Highly
crystalline
monohydate
and
di-hydrate
MgSt
(Covidien)
Some commercial
products (P) are
mixtures of mono- and
dihyrate and other
crystalline forms.
Highly pure
mono-hydrate and
dihydrate
magnesium stearate
Thermal Analysis (DSC)
0
0.5
1
1.5
2
2.5
0 0.5 1 1.5 2 2.5
Distance to Covidien Monohydrate
Dis
tan
ce t
o V
en
do
r P
Mate
ria
l
Covidien Monohydrate Vendor P Material
NIR Chemometric Data Analysis
Particle Size Distribution
Source C
Source P
MgSt monohydrate MgSt dihydrate
1000x 1000x
2500 x 2500 x
SEM
Commercial Lot F-a
F
Lot F-e Lot F-f
Lot F-g Lot F-h Lot F-i
SEM of 6 Commercial Lots1 of MgSt
1. Source F
SEM and Crystalline State of Stear-O-WetTM
A Proposed Mechanism of Lubrication
Wada and Matsubara, Powder Tech. 78 (1994) 109
Ertel and Carstensen, J.Pharm. Sci. 77 (1988) 625
• Highly pure dihydrate MgSt can provide
beneficial effects.
Hydrate
water
can
enhance
lubricity
MgSt Distribution in Powder is Important
Lubricant uniformity in a powder blend will influence its
flowability, density, compactability, wetting, dissolution…
0.00
5000.00
10000.00
15000.00
20000.00
25000.00
1 2 3 4 5
Run Cycles
Compression force at 50 mm/sec, g mm.
MgSt - M MgSt - D
Comparison of MgSt Lubricity Using Texture Analyzer1
1. Rotating probe moving through 25 grams of powder samples (MCC/Dical) in
a cylinder bed. MgSt in the powder = 0.3 %.
Comparison of BFE of A Model Blend Lubricated with
Mixtures of Mono- and Di-hydrate MgSt
1. BFE: Basic flow energy measured by Freeman FT4 powder rheometer
2. Model blend: MCC/Lactose/APAP (47/47/5)
3. Lubricant 1 %, Mono/Di mixtures: 100/0, 75/25, 50/50, 25/75, 0/100
DD
01 D
100)
DM
01 (
M100)
DA
01 (
A100)
D12 (
D25:M
75)
D11 (
D75:M
25)
D10 (
D50:M
50)
D6 (
D25:A
75)
D5 (
D75:A
25)
D4 (
D50:A
50)
D3 (
A75:M
25)
D2 (
A25:M
75)
D1 (
A50:M
50)
675
650
625
600
575
550
525
500
BFE
(m
J)
95% CI for the Mean
Basic Flow Energy of Varying Ratios of Magnesium Stearate Polymorphs
Lowest BFE for Blends Lubricated with
MgSt Dihydrate or Its Anhydrous Form
Flow Properties of CompapTM L with 0.3%
Lubricant Using Freeman FT4 Rheometer
Lubricant
(0.3 %)
Bulk
density
BD (g/ml)
Basic Flow
Energy
BFE (mJ)
Stability
index
SI
Flow rate
Index
FRI
Specific
Energy
SE (mJ/g)
No lubricant 0.481 630 0.988 0.891 3.62
MgSt-M 0.516 651 0.949 0.834 3.26
MgSt-D 0.501 627 1.05 0.872 3.31
MgSt-FG 0.518 686 0.996 0.857 3.38
SOW 0.510 685 0.918 0.856 3.53
SSF 0.506 731 1.22 1.05 3.80
SLS 0.499 659 0.925 0.945 3.73
Powder Composition: CompapTM L(93.0 %), MCC (6.7 %), Lubricant (0.3 %).
CompapTM L: Direct compressible APAP (Covidien/Mallinckrodt)
MgSt Coating
Effect of MgSt on Powder Flow
At the particle level…•Reduction of inter-particulate friction
•Separation of coarse particles
•Reduction of liquid or solid bridging
•Elimination of static charge
•Changing particle thermal conductivity
•Reduction of trapped air
MgSt Coating
Effect of MgSt on Blend Uniformity
Using Real Time Effusivity Measurement
Effusivity= (ρкcp) 1/2
(unit: Ws1/2/m2K)
ρ = density,
к = thermal conductivity,
Cp = heat capacity250
270
290
310
330
350
370
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85
Blend Time (minutes)
Th
erm
al
Eff
usiv
ity
(Ws
1/2/m
2K
)
A Novel Function DiscoveredComparing on-time blend uniformity for MCC/LAC/APAP Blend
Addition of 1 % MgSt-Mono
Induced more densification
Addition of 1 % MgSt-Di
Induced less densification
Effusivity= (ρкcp)1/2 (unit: Ws1/2/m2K)
ρ = density, к = thermal conductivity, Cp = heat capacity
Effect on Blend Uniformity
MCC-LAC (75/25)/APAP (1.25 %) using 1 % MgSt
Compare blend uniformity vs. blending time
Blending Time, min
0 2 4 8 12 16
MgSt Type Mean and [RSD], % (no more than 5 %)
Mono-
hydrate
92.6
[3.2]
98.7
[36.0]
92.0
[8.1]
95.6
[2.7]
96.8
[3.3]
97.1
[0.9]
Dihydrate 98.8
[2.7]
94.9
[1.7]
95.5
[2.0]
98.1
[3.7]
95.7
[1.5]
97.1
[2.1]
MgSt type % MgSt
-1 1 -1 1
11.00
11.25
11.50
11.75
12.00
To
tal c
om
p fo
rce
s
% MgStMgSt type
1-1 1-1
10.5
10.0
9.5
9.0
8.5
Eje
ctn
forc
e
Effect on Compression and Ejection ForcesMCC/DCP (75/25)/APAP (1.25 – 5 %)
MgSt -M
MgSt -M
MgSt -D
MgSt -D
0.3 % 1.0 %
0.3 % 1.0 %
Total
Compres
sion
Force
Ejection
force
Dihydrate
has
better
lubricity
Me
an
of
UC
F/
LC
F
MonohydrateDihydrate
1.12
1.10
1.08
1.06
1.04
PH102PH101 21
4321
1.12
1.10
1.08
1.06
1.04
321
MgSt Avicel Type AvicelLevel
CompLevel BT Level
Main Effects Plot (data means) for UCF/LCF
Comparison of Upper and Lower Compression
Force Ratio for MgSt-M and MgSt-D
R= LCF/UCF
(R > 0.88 to
avoid sticking)
(R= 0.95)
(R= 0.92)
% Lubricant
Eje
cti
on
Fo
rce
(N
)
3.02.52.01.51.00.5
130
120
110
100
90
MgSt-D PH
MgSt-M PH
MgSt-D HFE
MgSt-M HFE
Variable
Upper Compression Force = 8 KN
% Lubricant Loading
R V
alu
e
3.02.52.01.51.00.5
1.06
1.05
1.04
1.03
1.02
MgSt-D PH
MgSt-M PH
MgSt-D HFE
MgSt-M HFE
Variable
Compression Force = 8 KN
%Lubricant
Co
mp
acta
bili
ty (
N/
KN
)
2.001.751.501.251.000.750.50
30.0
27.5
25.0
22.5
20.0
17.5
15.0
MgSt-D PH
MgSt-M PH
MgSt-D HFE
MgSt-M HFE
Variable
Upper Compression Force = 8 KN
Comparison of Lubrication Efficiency for Avicel 102,
and Avicel HFE 102 (90% Avicel/10% Mannitol)
Lubricity Dihydrate more efficient.
R-Value Dihydrate is closer to 1.0
Compactability
HFE higher than Avicel. Dihydrate did not lower the compactability
Effect of Lubricant Levels and Tabletting Speed on
CompapTM L Compactability* (N/KN)
Lubricant
%
Tableting
rpm
Compactability, N/KN
MgSt-D MgSt-M
0.3 50 5.67 5.76
0.6 50 5.30 4.85
0.3 80 5.92 5.37
0.6 80 4.77 4.67
•MgSt-D caused less powder densification, and enables better
powder compactability.
•In making 200 mg concaved tablets at 80 rpm, MgSt - D had no
capping, sticking and lamination problems, but tablets could not
be made under the same conditions using MgSt – M.
Compression force vs. Ejection force
200.00
300.00
400.00
500.00
600.00
700.00
800.00
900.00
1000.00
0.00 10.00 20.00 30.00 40.00
Compression force (kN)
Ejectio
n fo
rce (N
)
Compap 90-2257-0.5%-5mins
Compap 90-2V-0.5%-5mins
Compap 90-5712-0.5%-5mins
Compap 90-3V-0.5%-5mins
Compap 90-1729-0.5%-5mins
Compap 90-SOWM-0.5%-5mins
Compap 90-SOWD-0.5%-5mins
Compression force vs. Ejection force
150.00
250.00
350.00
450.00
550.00
650.00
750.00
0.00 10.00 20.00 30.00 40.00
Compression force (kN)
Eje
ctio
n f
orc
e (
N)
Compap 90-2257-2.0%-10mins
Compap 90-2V-2.0%-10mins
Compap 90-5712-2.0%-10mins
Compap 90-3V-2.0%-10mins
Compap 90-1729-2.0%-10mins
Compap 90-SOWM-2.0%-10mins
Compap 90-SOWD-2.0%-10mins
Mono-
Di-
Mono-
Di-
Effect of Lubricant Level and Blending Time on
Ejection Force
Tablet formulation: Direct compressible Compap 0900 (99.5,
98.0 %) and Lubricant (0.5, 2 %). Blending time: 5, 10 min
Mg - Distribution at Tablet Surface (Tablet Composition: Direct compressible APAP 94 %, MCC 5.6 %, Lubricant, 0.6 %)
Monohydrate Dihydrate Stear-O-Wet
MgSt dihydrate evenly
distributed and more
concentrated on tablet
surface.
Decreasing MgSt conc into
tablet interior layers
(~ 50 micron/layer).
Monohydrate MgSt
0.06
0.07
0.08
0.09
0.1
0.11
0.12
0.13
0.14
0.15
0.16
0 2 4 6 8 10 12
Laser shot layers
Mg
In
ten
sit
y V
alu
e
Mg-Normalized
C2-Normailized
Mg/C2-Normailized
Dihydrate MgSt
0.06
0.07
0.08
0.09
0.1
0.11
0.12
0.13
0.14
0.15
0.16
0 2 4 6 8 10 12
Laser shot layers
No
rmai
lize
d I
nte
nsit
y V
alu
e
Mg-Normalized
C2-Normailized
Mg/C2-Normailized
Stear-O-Wet
0.06
0.07
0.08
0.09
0.1
0.11
0.12
0.13
0.14
0.15
0.16
0 2 4 6 8 10 12
Laser Shot Layers
No
rmail
ized
In
ten
sit
y V
alu
e
Mg-Normalized
C2-Normailized
Mg/C2-Normailized
Mg- and C2- Distribution, and Mg/C2 Ratio at Tablet Surface
MgSt-D and tends to enrich at
tablet surface more than
MgSt-M and SOW.
Summary
MgSt Polymorphs Can Make Difference
1. Dihydrate gave more robust powder blending process
Dihydrate induces less degree of densification (disturbance) in a uniform blend
Shorten time to reach blend uniformity
Reduce blending time sensitivity.
2. Better lubricity
Require less compression, ejection and take-off forces during tableting to make tablets of constant weight and hardness.
3. Good tablet quality
Equivalent to or better than tablets using MgSt
monohydrate
Comparable dissolution profiles
• In mixing with other powder ingredients, agglomerated Stear-
O-Wet® particles fracture into smaller particles and disperse in
the powder blend, results in an adjacent uniform distribution of
MgSt/SLS in the powder blend.
• Stear-O-Wet® exhibits better lubricity than a mixture of
MgSt/SLS. The lubricating effect is retained as fresh MgSt
surfaces are generated during the blending.
Surface-Treated Magnesium Stearate
Stear-O-Wet®
Individual 95% CIs For Mean Based on Pooled StDev
Level N Mean StDev ---------+---------+---------+---------+
Stear-O-Wet® 24 40.21 8.36 (-----*-----)
Mixture 24 56.25 8.06 (-----*----)
---------+---------+---------+---------+
Pooled StDev = 8.21 42.0 48.0 54.0 60.0
0.5 %
mix
0.5 %
SOW
1 %
mix
1 %
SOW
15 Sec
30 Sec
45 Sec
Stear-O-Wet® provides better wetting
than a mixture of MgSt and SLS
Comparison of Stear-O-WetTM with
MgSt/SLS Mixture
Stear-O-Wet®Mixture of MgSt/SLS
(94/6)
Powder densification Lower Higher
Powder cohesiveness Lower Higher
Lubricity Higher Lower
Powder compressibility at
low pressure
Higher Lower
Compactability Higher Lower
Tablet Wettability Higher Lower
Dissolution Not distinguishable Not distinguishable
Comparison of Powder Flow and Compression Characteristics
of MCC/Lactose (1:1)/APAP (5 %) at lubricant level of 0.5, 1.0
and 2.0 % and blending times of 2, 5, and 10 min.
0
50
100
150
200
250
300
350
SOW-2.0 SOWD-
2.0
1729-2.0 2257-2.0 2V-2.0 5712-2.0 3V-2.0
Avera
ge d
isin
teg
rati
on
tim
e (
n=
6)
Series1
P-2 P-3
Comparison of Disintegration Times for
Tablets Containing 2% Lubricants
1. Tablets composition: Compap 0900 98 %, and 2 % Lubricant
2. SOW – Stear-O-WetTM (MgSt treated with SLS)
1729 – MgSt dihydrate
2257 and 5712 - Covidien MgSt monohydrate with different particle size
P-2 and P-3 - MgSt with different particle sizes from source P
Minute
Protocol 24 Profiles
0
20
40
60
80
100
0 10 20 30 40 50 60 70
minutes
Pct
Dis
solv
ed
200rpm 2% SOW100rpm 2% SOW200rpm 2% SOW-D200rpm 0.5% SOW200rpm 0.5% SOW-D200rpm 0.5% 2257200rpm 0.5% 1729200rpm 2% 1729
Comparison of Dissolution Profiles
Tablet formulation: Compap 0900 plus 0.5, or 2 % lubricant, 10 min
blending time, and compressed at 7 kN.
Dissolution - Lubrication Study
7.5mg - lot: 7819p015 (-007A)
50.0
60.0
70.0
80.0
90.0
100.0
110.0
0.00 10.00 20.00 30.00 40.00 50.00 60.00
Time Pull (min)
% la
be
l
Vessel 1
Vessel 2
Vessel 3
Vessel 4
Vessel 5
Vessel 6
Dissolution - Lubrication Study
7.5mg - lot: 7819p015 (-007B)
50.0
60.0
70.0
80.0
90.0
100.0
110.0
0.00 10.00 20.00 30.00 40.00 50.00 60.00
Time Pull (min)
% la
be
l
Vessel 1
Vessel 2
Vessel 3
Vessel 4
Vessel 5
Vessel 6
Dissolution - Lubrication Study
7.5mg - lot: 7819p015 (-007C)
70.0
75.0
80.0
85.0
90.0
95.0
100.0
105.0
110.0
0.00 10.00 20.00 30.00 40.00 50.00 60.00
Time Pull (min)
% la
be
l
Vessel 1
Vessel 2
Vessel 3
Vessel 4
Vessel 5
Vessel 6
MgSt Mono Di SOW
% API Dissolved in 30 min
% 87.1 95.4 96.2
RSD 2.69 1.09 1.97
Mono
Di
SOW
Dissolution Profile for a Capsule Formulation
Capsule formulation: 96 % lactose, 3 % API, 1 % lubricant; blending time 30 min.
Key Message
Not all MgSt are created equal
Lubricant material properties - crystalline state, particle size/size
distribution, specific surface area - are critical quality parameters
influencing powder flow and compaction, and QbD considerations.
Using consistent and high quality lubricant in making tablets is
critically important to tablet quality.
The crystalline states of Mg-stearate affect its lubricity.
Mg stearate dihydrate is a stable crystalline state. MgSt dihydrate
has better lubricity, disperses quickly into the powder bed, and
exhibits other functional benefits.
Stear-O-WetTM is a wettable surface-treated lubricant containing
MgSt monohydrate and sodium lauryl sulfate (94/6 by wt.). It is
particularly suitable for overcoming disintegration and dissolution
issues caused by tablet lubricants.
Key Factors in Selecting
Pharmaceutical Lubricant
Thank You
Thoughts and comments
Questions