Magnesium Stearate Dihydrate
Transcript of Magnesium Stearate Dihydrate
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