The effect of mixing time of magnesium stearate on crushing ...

Contents
<strong>The</strong> <strong>effect</strong> <strong>of</strong> <strong>mixing</strong> <strong>time</strong> <strong>of</strong>
<strong>magnesium</strong> <strong>stearate</strong> on
crushing strength <strong>of</strong> tablets
Helsinki Drug Research 10.6.2008
M.Sc. Satu Virtanen
Department <strong>of</strong> Pharmaceutical Technology
Faculty <strong>of</strong> Pharmacy
• Introduction
• Properties and behavior <strong>of</strong> <strong>magnesium</strong> <strong>stearate</strong>
• Methods
• Mixing, tableting
• SEM, EDX, Raman
• Results
• Scale up
• SEM/EDX
• Raman mapping
• Conclusions
• Discussion
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Introduction – Magnesium <strong>stearate</strong>
• Magnesium <strong>stearate</strong> (MS) is most commonly used lubricant in
the pharmaceutical industry
• It reduces frictional forces during tabletting
• MS is a boundary lubricant and it forms a thin hydrophobic
layer between particles
• Prolonged <strong>mixing</strong> causes over-lubrication
→ ”Magnesium <strong>stearate</strong> <strong>effect</strong>”
• MS can posses many negative properties
• Increase density <strong>of</strong> the mass
Introduction – Objective in MS <strong>mixing</strong>
• Usually the aim <strong>of</strong> the <strong>mixing</strong> process is homogeneity
• However, the objective in MS <strong>mixing</strong> differs from other
<strong>mixing</strong> scenarios e. g. homogeneity <strong>of</strong> MS in the powder
mixture is not <strong>of</strong> real interest
• <strong>The</strong> lubricant needs to be distributed into the mass
adequately well to allow for efficient and problem-free
tabletting
• Decrease the crushing strength <strong>of</strong> tablets
• Decrease the drug release from the tablet
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Mixtures <strong>of</strong> MCC and MS
• Microcrystalline cellulose (MCC) is widely use excipient in
pharmaceutical industry and its properties are well known
Materials - Methods
• Binary mixture <strong>of</strong>
• Microcrystalline Cellulose 99% (w/w)
• Magnesium Stearate 1% (w/w)
• MCC is sensitive for lubricant because it is a plastic
material
• Mixture <strong>of</strong> MS and MCC is example <strong>of</strong> ordered mixture as
MS covers the MCC particles
• Stable and segregation is hindered
• Three scales
• Laboratory (1 l), pilot (10 l), production
(80 l)
• Mixing <strong>time</strong>s
• 1, 2, 3, 5, 10, 30, 60 and 90 min
• Other variables were set as constant:
• the powder loading in the container
• the rate <strong>of</strong> rotation (48 rpm)
• the relative humidity
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Reference method
Methods - Analyzing the tablets
• <strong>The</strong> monitoring and measuring the lubricant <strong>mixing</strong> is a
very challenging task which is not solved yet
• <strong>The</strong>re are no valid method to measure primary response
in the lubricant <strong>mixing</strong> process
• Scanning electron microscopy (SEM)
• Energy Dispersive X-ray Analysis (EDX)
• Raman mapping
→ Secondary reference method
• <strong>The</strong> crushing strengths <strong>of</strong> tablets were selected as a
secondary reference for lubrication monitoring
• <strong>The</strong> crushing strength with an indirect diametral
compression tester
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0.9
0.9
1 l
1 l
0.8
0.8
CS/m
CS/m
Results
0.8
0.7
0.6
0.5
10 l
• A logarithmic
relationship
between <strong>mixing</strong>
<strong>time</strong> and crushing
strength <strong>of</strong> the
tablet
CS/m
0.7
0.6
0.8
0.7
0.6
0.7
0.6
0 20 40 60 80 100
Mixing <strong>time</strong> (min)
0.8
10 l
0.7
0.6
CS/m
0 20 40 60 80 100
Mixing <strong>time</strong> (min)
10 l
0.5
0.5
0.4
0 20 40 60 80 100
• All scales
0.8
0.4
0 20 40 60 80 100
Mixing <strong>time</strong> (min)
0.4
0.8
0 20 40 60 80 100
Mixing <strong>time</strong> (min)
80 l
80 l
0.7
0.7
CS/m
0.6
CS/m
0.6
0.5
0.5
9
0.4
0 20 40 60 80 100
Mixing <strong>time</strong> (min)
0.4
0 20 40 60 80 100
Mixing <strong>time</strong> (min)
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Effect <strong>of</strong> the scale size
SEM and EDX images
0.5 min 180 min
• With pilot and production
scale this decrease was
greater than with laboratory
scale
0.8
1l
10l
1 l
10l
SEM
0.7
80l
80l
• <strong>The</strong> results contrived in
laboratory scale did not give
the right <strong>mixing</strong> <strong>time</strong> for the
greater scale sizes
CS/w
0.6
0.5
EDX
0.4
0 10 20 30 40 50 60 70 80 90
Mixing <strong>time</strong> (min)
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• Raman spectra
Raman mapping
Raman mapping – preliminary results
1 min
5 min
• MCC
0.8
• MS
80 l
• Data processing
0.7
30 min
CS/m
0.6
0.5
13
0.4
0 20 40 60 80 100
Mixing <strong>time</strong> (min)
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Conclusions
• MCC is sensitive to the strength reduction <strong>effect</strong>s <strong>of</strong> MS
and magnitude <strong>of</strong> this is dependent on the <strong>mixing</strong> <strong>time</strong>
• <strong>The</strong> crushing strength <strong>of</strong> the tablets exhibited a clear
decrease as the <strong>mixing</strong> <strong>time</strong> was increased with all binary
mixture batches tested
• <strong>The</strong> negative <strong>effect</strong> <strong>of</strong> <strong>mixing</strong> <strong>time</strong> <strong>of</strong> MS was found to be
slightly stronger with the pilot-scale and production-scale
batches than that observed with small-scale batches
• Raman spectroscopy with optical microscopy can detect
differences in the compressed tablets
Discussion
• Monitoring and learning about MS <strong>mixing</strong> is complicated
• Tablets as secondary response
• Raman mapping
• Binary mixture → more complex mass
• MS concentration is small → intensity <strong>of</strong> the peaks is low
• <strong>The</strong> measurement and modeling parameters are crucial
• Slow measurement
• Resolution
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Acknowledgements
• NIRPATOR – project and Orion Pharma
• Henri Salokangas, Orion Pharma
• Anna Shevchenko, Orion Pharma
• Simo Siiriä, University <strong>of</strong> Helsinki
Thank You!
• Osmo Antikainen, University <strong>of</strong> Helsinki
• Jouko Yliruusi, University <strong>of</strong> Helsinki
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