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