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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

-6

-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???