Magnesium Magnesium StearateStearate DihydrateDihydrate --A New High Performance A New High Performance

Pharmaceutical Lubricant forPharmaceutical Lubricant forLubricating Powder and Making TabletsLubricating Powder and Making Tablets

Presented by

Stephen H. Wu, Ph.DTechnical Fellow, Pharmaceutical R/D

Covidien/Mallinckrodt

Magnesium Magnesium stearatestearate isisused in >2500 pharmaceutical products.used in >2500 pharmaceutical products.

The Great Wall of MgSt…

• Look at the Wall – an old product• Shout at the Wall – mature business• Walk on the Wall – what is new?• Climb the Wall – where is the ladder?

Invite you to take a fresh look…

One water molecule can make a big difference - The Story ofMagnesium Stearate Dihydrate

Take a Closer lookTake a Closer look……

Voice of end usersUnmet needs

Technology ConsiderationImproving product quality

Regulatory TrendFDA initiatives (QbR, QbD, PAT)

Product InnovationValue-added products or new applications

OutlineOutline

Excipients technology trend Voice of customersDesirable product attributes The story of MgSt Mono- and Di-hydrate

ManufacturingCharacterizationUnique functional propertiesLubrication mechanismFuture challenges

You may identify with some problems, increase understanding of MgSt as a lubricant, and apply the learning to meet your needs.

ExcipientsExcipients Technology TrendsTechnology TrendsNeeds for Quality Functional Excicpients

Stabilizing fragile APIs (peptides, proteins and biotech materials)Enhancing drug solubilityNovel functionalities for drug deliveryMethods for characterizing excipient functionalitiesCompounded excipients for additional benefitsCost-effective excipients meeting Rx and Gx needs

Demand for Consistent ManufacturingUsing raw materials of vegetable originConsistent manufacturing process producing high quality products

Request for Application R/D and Technical SupportClose relationships with end-users and providing solutions to their application needs

When MgSt is used as a lubricant…It shows desirable functional properties

Anti-adherent activity Glidant activityLubricant activity

It has effects on -Powder flowabilityDie wall lubricationBlend uniformityTablet quality

MgSt is close to an ideal lubricantLow friction coefficientLarge covering potentialHigh melting temperature

Potential Problems of Using MgStDose Product Quality

Powder characteristics – compactability, flowabilityPowder blend uniformityTablet or capsule qualityProduct content uniformityAPI Compatibility and dissolution rate

Process SensitivityMgSt type, amount and mixing time

MgSt Product VariabilityVariability from manufacturers Lot-to-lot variations

Voice of CustomersVoice of Customers

“MgSt (monohydrate) is the cause of processinconsistency and poor product quality.”

“Dihydrate helps lubrication…”“Need to have a dihydrate product, or specifydihydrate content in MgSt product.”

Product and Process NeedsConsistent qualityWell-defined product compositionBetter understanding of lubrication mechanism

A Concept for LubricationA Concept for Lubrication

Wada and Matsubara, Powder Tech. 78 (1994) 109Ertel and Carstensen, J.Pharm. Sci. 77 (1988) 625

1. Proposed mechanism of lubrication

2. Our early study indicated high dihydrate content in MgSt was beneficial.

Hydrate water canenhance lubricity

Desirable Product CharacteristicsDesirable Product Characteristicsfor Lubricityfor Lubricity11

Bulk level (density, porosity, accessible surface area) => Absence of agglomeratesParticle level (size/size distribution, aggregation state) => Smaller particle size, => Larger specific surface area=> Plate-like crystal shapeMolecular level (fatty acid composition, hydration state)=> Consistent composition and crystalline structure=> More dihydrate and well defined composition

1. K. Phanidhara Rao et. Al. Pharmaceutical Development and Technology, Vol.10 (3), 2005 p. 423 - 437

Overall FitnessOverall Fitness--forfor--use Considerationuse ConsiderationSuitable feedstock materialsManufacturing know howAnalytical method for quantifying MgStdihydrate content in a typical MgSt product Meeting USP/NF monograph definitionMeasurable benefits on

Powder flowabilityBlend uniformity – (real time blend uniformity) Tableting easeTablet quality

Synthesis of Magnesium Synthesis of Magnesium StearateStearateC17 H35COOH* + NaOH →

C17H35COONa + H2O

2C17H35COONa + MgSO47H2O →Mg(C17H35COO)2●●nnH2O + Na2SO4 + 6H2O

Depending on reaction conditions, highly pure monohydrate and dihydrate can be made.*Stearic acid:palmitic acid = 2:1

MgSt monohydrate MgSt dihydrate

1000x 1000x

2500 x 2500 x

SEM

Thermal Properties (TGA) of MgSt Monohydrate & MgSt Dihydrate

Thermal Properties (DSC) of MgSt Monohydrate & MgSt Dihydrate

Powder X-Ray Diffraction Patterns 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

Ref

lect

ance

Mg Stearate MonohydrateMg Stearate Dihydrate

NIR Spectra of MgSt-M and MgSt-D

InterInter--conversion of conversion of MgStMgSt Hydrates*Hydrates*

MgSt dihydrate* MgSt Trihydrate

Amorphous MgSt

Anhydrous MgSt

RH > 70%

Dry at 100 – 105 oC100 % RHDry at 100 – 105 oC

Hydration100 – 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.

Are there measurable differences between MgSt mono- and di-hydrate in functionality?

To determine the effects of using MgSt mono- and di-hydrate in direct-compressible blends –MCC/DCP and MCC/LAC on these properties:

powder flowabilitytableting easeblend uniformitytablet quality

To pin point beneficial effects of using MgStdihydrate in the tableting processTo better understand the lubrication mechanism

Lubricity Comparison MgSt Monohydrate vs. MgSt Dihydrate

42.51dihy25(13) 75

42.51mono25(7) 75

1050.3dihy25(12) 75

1050.3mono25(1) 75

Lube time(min)

APAP%

MgSt%

MgStType

Dical (Anhy)%

Avicel (101) %

95.4

0

MgStDihydrate

%

0

92.0

MgStMonohydrate

%

5.60< 0.4 16.6

0

DihydrateWater

%

2.8

Monohydrate Water

%

0.6

Free Water

%

14.8

Particle Size

(microns)

Materials

Experimental Design (No. 1, 12, 7, 13)

Particle Size DistributionParticle Size Distribution

MgSt-M

MgSt-D

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

For Experiments No. 1 and 12.

1. Rotating probe moving through 25 grams of powder samples in a cylinder bed.MgSt in the powder = 0.3 %.

Total Energy of LubricationTotal Energy of Lubrication

0

2

4

6

8

10

12

kg-force

anhyd@

0.3%

mono@

0.3%

dihydr@

0.3%

monoh@ 1%

dihydr@ 1%

MgSt Type

AvgEjectionforce

Tablet Knock-off

0

0.01

0.02

0.03

0.04

0.05

0.06

0.30% 1.00%

kpMgSt mono

MgSt dihy

0100200300400500600700800900

1000

kg-force

anhyd@

0.3%

mono@

0.3%

dihy@

0.3%

mono@ 1%

dihy@ 1%

MgSt Type

Avg Compforce

Avg pre-compforce

Comparison of • A. Compression force • B. Ejection force • C. Take-off force

MgSt anhydrous was also used as a reference point in expts.

A

B

C

MgSt type % MgSt

-1 1 -1 1

11.00

11.25

11.50

11.75

12.00

Tota

l com

p fo

rces

% M gS tM gS t ty pe

1-1 1- 1

1 0 .5

1 0 .0

9 .5

9 .0

8 .5

Ejec

tn fo

rce

Effect on Compression and Ejection ForcesEffect 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

Dihydratehas better lubricity

Mea

n of

UC

F/LC

F

MonohydrateDihydrate

1.12

1.10

1.08

1.06

1.04PH102PH101 21

4321

1.12

1.10

1.08

1.06

1.04321

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)

MgMg

MgMg

O

C

O

O

O

C

O

O

O O

CC

CC

O

OO

O

HH

HH

HH

HH

Proposed Structure of MgSt Dihydrate

MgSt Coating

Effect of Effect of MgStMgSt GlidantGlidant Properties on Properties on Powder Powder FlowabilityFlowability

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 UniformityUsing Real Time Effusivity Measurement

Effusivity= (ρкcp) 1/2

(unit: Ws1/2/m2K)

ρ = density, к = thermal conductivity, Cp = heat capacity

250

270

290

310

330

350

370

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85Blend Time (minutes)

Ther

mal

Eff

usiv

ity(W

s1/2 /m

2 K)

Comparison of Blend Uniformity using ESPTM

Blend 1

Blend 12

Addition of MgSt (M)

Addition of MgSt (D)

1 mst = 20 secs

Blend 7

Blend 13

Addition of MgSt (M)

Addition of MgSt (D)

1 mst = 20 secs

Batch# % MgSt/Type Prelube Postlube crest Delta on Eff Lube time Batch 1 0.3 % mono 182 192 10 10 minsBatch 12 0.3 % dihydrate 189 192 3 10 minsBatch 7 1.0 % mono 188 195 7 4 minsBatch 13 1.0 % dihydrate 186 189 3 4 mins

Average Effusivity for batches lubed with MgSt mono & dihy

Blend Characteristics (Uniformity)by Measuring Effusivity

Effusivity= (ρкcp)1/2 (unit: Ws1/2/m2K)

ρ = density, к = thermal conductivity, Cp = heat capacity

Batch# % MgSt/Type Mean RSD Mean RSDBatch 1 0.3 % mono 94.1 1.5 97.7 1.5Batch 12 0.3 % dihydrate 99.3 2.0 97 1.4Batch 7 1.0 % mono 100.2 1.5 97.5 1.7Batch 13 1.0 % dihydrate 96.9 2.0 94.6 1.5

Blend Chemical Result for batches lubed with MgSt mono & dihyPrelube (%) Postlube (%)

Blend Uniformity by Chemical Analysis

A Novel Function DiscoveredA Novel Function DiscoveredComparing onComparing on--time blend uniformity for time blend uniformity for MCC/LAC/APAP MCC/LAC/APAP BlendBlend

Addition of 1 % MgSt-MonoInduced more densification

Addition of 1 % MgSt-DiInduced less densification

Effusivity= (ρкcp)1/2 (unit: Ws1/2/m2K) ρ = density, к = thermal conductivity, Cp = heat capacity

Effect on Blend UniformityEffect on Blend UniformityMCCMCC--LAC (75/25)/APAP (1.25 %) using 1 % LAC (75/25)/APAP (1.25 %) using 1 % MgStMgStCompare blend uniformity vs. blending timeCompare blend uniformity vs. blending time

16128420

MgSt Type Mean and [RSD], % (no more than 5 %)

98.8[2.7]

92.6[3.2]

Blending Time, min

95.7[1.5]

96.8[3.3]

97.1[2.1]

98.1[3.7]

95.5[2.0]

94.9[1.7]

Dihydrate

97.1[0.9]

95.6[2.7]

92.0[8.1]

98.7[36.0]

Mono-hydrate

1012.130.3dihy75-25MCC-DCP

101.0dihy50-50MCC-LAC

161.0mono50-50MCC-LAC

6.79.361.0dihy75-25MCC-LAC

8.610.3101.0mono75-25MCC-LAC

911.231.0dihy75-25MCC-DCP

1113.171.0Mono75-25MCC-DCP

1112.0100.3mono75-25MCC-DCP

Ejection force

(N)

Total comp force (kN)

Delta EffusivitybMgSt, %MgSt type

DiluentRatioDiluent Type

a – Tablets were made to same weight and hardness b – Delta effusivity is defined as the change in average effusivity between post-lubrication and pre-lubrication. Effusivity Unit = Ws1/2/m2K. All batches in were lubricated for 4 minutes.

Effect of MgSt Type and Concentration on Diluent Effusivity and Compression and Ejection Forcesa

Mathis Protocol Profiles

40.0

50.0

60.0

70.0

80.0

90.0

100.0

0 5 10 15 20 25 30

Time, min

% R

elea

sed

Batch 1Batch 7Batch 12Batch 13

Tablet Release Profiles for Experimental Batches 1,12, 7, 13

0

20

40

60

80

100

120

5 10 15 30

Time (min)

Dru

gdi

ssol

ved

(%)

0

20

40

60

80

100

0 10 20 30Time (min)

Dissolution Profiles for MCC-DCP-APAP Batches with

1.0% MgSt, 4 min Lube

Dissolution Profiles for MCC-LAC-APAP Batches with

1.0% MgSt, 4 min Lube

MgSt–M vs. MgSt-DMCC/DCP 75/25

APAP 2.5 %

MgSt–M vs. MgSt-DMCC/LAC 75/25

APAP 1.25 %

• Both MgSt monohydrate and dihydrate showed comparable post-lubrication blend uniformity results.

• For MCC-DCP and MCC-Lac diluent systems, effusivitymeasurement predicted blend uniformity of APAP down to 1.25 % in multiple formulations when MgSt mono- and dihydrate were used at 0.3 and 1.0 % levels.

• The blend uniformity results were confirmed with chemical analysis.

• Comparable dissolution profiles for tablets using MgStmono- and dihydrate.

Both MgSt Mono- and Dihydrate have similar functionalities

Summary of Measurable Summary of Measurable MgStMgSt DihydrateDihydratePropertiesProperties

More effective in lowering cohesive energy of the powder blends. Induces less degree of densification in a uniform blend as effusivity data suggested.Less sensitive to blending timeExhibits a lower ratio of upper compression force to lower compression force. (R-value is closer to 1.0) Requires less total compression, ejection and take-off forces during tableting to make tablets of constant weight and hardness.

Benefits of MgSt Dihydrate

1. More robust powder blending processDihydrate induces less degree of densification (disturbance) in a uniform blendShorten time to reach blend uniformity Reduce blending time sensitivity.

2. Better lubricityRequire less compression, ejection and take-off forces during tableting to make tablets of constant weight and hardness.

3. Good tablet qualityEquivalent to or better than tablets using MgStmonohydrateComparable dissolution profiles

Key MessagesKey Messages

Pure Mg Stearate dihydrate can be made consistently.

MgSt dihydrate is a stable crystalline state.MgSt dihydrate has better lubricity and other value-added functionalities. MgSt dihydrate has many potential benefits, yet to be determined.

Results of MgSt Dihydrate offer new possibilities and new way of thinking a lubricant…

Improved powder flowImproved powder flowConsistent blending and blend uniformityConsistent blending and blend uniformity

Lower ejection force in Lower ejection force in tabletingtabletingLess sticking at the pressLess sticking at the pressFewer capping problemsFewer capping problems

Reduced tooling wearReduced tooling wearFaster production rates Faster production rates

Challenges just begin! Need New Application Data

Examples in end-user’s scale up Evaluation