Polymorph Transformation of Clopidogrel Hydrogen Sulfate (CHS)
Transcript of Polymorph Transformation of Clopidogrel Hydrogen Sulfate (CHS)
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Polymorph Transformation of Clopidogrel Hydrogen Sulfate (CHS)
Nicole W. M. Lai, Chemical and Biomolecular Engineering, UC Berkeley; Michael Lovette, Zubin Kuvadia and Prof. Michael Doherty, Chemical Engineering, UC Santa Barbara
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Background
• Polymorphs – same compound, different crystal structures, ex: diamond and graphite
• Pharmaceutical compounds, ex.
Ritonavir (5 polymorph forms)
• FDA requires precise polymorph registered
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Clopidogrel Hydrogen Sulfate (CHS) C16H16ClNO2S . H2SO4
• Active ingredient in Plavix • 2 polymorphs found • Understand nature of shift, and
regeneration of a form
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Project Goal x
T
Solubility and Metastable Zone
Metastable Zone Width
Metastable Zone Curve
Solubility Curve
1. Solubility
2. Metastable Zone Width
3. Polymorph Transformation
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x
T
Form I
Form II
Solubility of Polymorphs
• Form I is the metastable form
• Form II is the thermodynamically stable form
* Saturation temperature detected here
Temperature Course During Solubility Measurements (Polythermal Method)
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T
t
Saturation Temperature
Metastable Zone Temperature
Solubility Values for CHS in Methanol-IPA (0.14)
*Exponential Fit
0
0.001
0.002
0.003
0.004
0.005
0.006
0.007
0.008
0.009
0.01
300 305 310 315 320 325 330
x
T
At equilibrium:
,
Assume ideal solution:
Therefore,
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ln(x) = -5973.3(1/T) + 13.592 R² = 0.9277
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-5.8
-5.6
-5.4
-5.2
-5
-4.8
-4.6
-4.4 0.00306 0.00308 0.0031 0.00312 0.00314 0.00316 0.00318 0.0032 0.00322 0.00324 0.00326
Ln(x
)
1/T (1/K)
Solubility Values for CHS (Analysis)
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Metastable Zone Width (Method) T
Time t
Temperature Profile
Cloudiness Induction time
Undercooling
Temperature of Saturation
Indu
ctio
n Ti
me
Inve
rse
Undercooling
Maximum Allowable Undercooling
Metastable Zone Width
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x
T
Metastable Zone Width ???
Solubility Curve
Metastable Zone Width (Result)
•Nucleation was not observed even with an undercooling of ~45K
• The metastable zone of CHS is observed to be too large to interrupt any crystallization experiments
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Polymorph Transformations (Peltier Cell Experiments)
1. Prepare seed crystals and solutions
2. Observe supersaturated solution
3. Control temperature
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Peltier Cell Experiments (Failed Attempts)
• Crystallization with Methanol-IPA solutions
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Peltier Cell Experiments (Results)
Powdered form CHS
Form II CHS seed crystals
Grown in IPA
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Conclusions/ Summary
• Solubility of form II CHS was measured with crystal growth in solvent methanol/IPA • Metastable zone width for CHS was too large to considered for polymorph transformation experiments
• Growth and dissolution of CHS is observed underneath the microscope
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Acknowledgements
Professor Michael Doherty Mike Lovette Zubin Kuvadia David Fowler UC LEADS (Arica and Matt) CAL NERDS (Diana and Chris)
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Questions???
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Questions???