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

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 1

Background • Polymorphs – same compound, different crystal structures, ex: diamond and graphite • Pharmaceutical compounds, ex. Ritonavir (5 polymorph forms) • FDA requires precise polymorph registered 2

Clopidogrel Hydrogen Sulfate (CHS) C 16 H 16 ClNO 2 S . H 2 SO 4 • Active ingredient in Plavix • 2 polymorphs found • Understand nature of shift, and regeneration of a form 3

Project Goal 1. Solubility Solubility and Metastable Zone 2. Metastable Zone Width Metastable 3. Polymorph Zone Curve Transformation Metastable x Solubility Zone Width Curve T 4

Solubility of Polymorphs • Form I is the metastable form • Form II is the thermodynamically x Form I stable form Form II T 5

Temperature Course During Solubility Measurements (Polythermal Method) Saturation Temperature T Metastable Zone Temperature * Saturation temperature detected here t 6

, Solubility Values for CHS in Methanol-IPA (0.14) At equilibrium: 0.01 0.009 0.008 0.007 * Exponential Fit Assume ideal solution: 0.006 0.005 x 0.004 Therefore, 0.003 0.002 0.001 0 300 305 310 315 320 325 330 T

Solubility Values for CHS (Analysis) -4.4 0.00306 0.00308 0.0031 0.00312 0.00314 0.00316 0.00318 0.0032 0.00322 0.00324 0.00326 -4.6 -4.8 -5 Ln(x) ln(x) = -5973.3(1/T) + 13.592 -5.2 R² = 0.9277 -5.4 -5.6 -5.8 -6 1/T (1/K) 8

Metastable Zone Width (Method) Temperature Profile Maximum Allowable Undercooling Induction Time Inverse Temperature of Saturation Undercooling T Metastable Cloudiness Zone Induction Width time Time t Undercooling 9

Metastable Zone Width (Result) • Nucleation was not observed even with an undercooling of ~45K • The metastable zone of CHS Metastable is observed to be too large to Zone Width ??? interrupt any crystallization x Solubility experiments Curve T 10

Polymorph Transformations (Peltier Cell Experiments) 3. Control temperature 1. Prepare seed 2. Observe crystals and supersaturated solutions solution 11

Peltier Cell Experiments (Failed Attempts) • Crystallization with Methanol-IPA solutions 12

Peltier Cell Experiments (Results) Powdered Form II CHS form CHS seed crystals Grown in IPA 13

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 14

Acknowledgements Professor Michael Doherty Mike Lovette Zubin Kuvadia David Fowler UC LEADS (Arica and Matt) CAL NERDS (Diana and Chris) 15

Questions??? 16

Questions??? 17