Polymorph Transformation of Clopidogrel Hydrogen Sulfate (CHS) - - PowerPoint PPT Presentation

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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

0.001 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,

8 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 Induction Time Inverse 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???