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East Caroli olina na Uni niversit ersity Monitoring and Optimization of Industrial Batch Crystallization Processes using NIR and ATR UV-vis Spectroscopy Chun H. Hsieh Literature Seminar November 16 th , 2010 East Caroli olina na Uni

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Monitoring and Optimization of Industrial Batch Crystallization Processes using NIR and ATR UV-vis Spectroscopy

Chun H. Hsieh Literature Seminar November 16th, 2010

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Outline

 Motivations  Use of Process Analytical Technology for the Optimization

  • f Batch Crystallization Processes in Industry

 Monitoring and Analyzing of Crystallization Processes using NIR Spectroscopy  Application of ATR UV-vis Spectroscopy for Monitoring the Crystallization

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Motivations

 The Gemperline’s group is interested in slurry reactions and the modeling of reactive dissolutions and reactive crystallization (e.g. API)  Analytical techniques

Kinetic modeling and chemometrics

 Instrumental techniques

NIR Reflectance Spectroscopy ATR UV-vis Spectroscopy Raman Spectroscopy Liquid Chromatography (HPLC)

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A Review of the Use of Process Analytical Technology for the Understanding and Optimization of Production Batch Crystallization Processes

Paul Barrett *, Ben Smith*, Joerg Worlitschek*, Veronica Bracken*, Brian O’Sullivan**, and Des O’Grady**

* Mettler-Toledo Autochem, USA, ** University College Dublin, Ireland 4

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Process Analytical Technologies (PATs)

 Poor understanding of crystallization at production scale  Significant impact on both product quality and downstream process unit operations

filtration, drying, milling and product formulation

 Challenges within production crystallizers

inconsistencies of batch-to-batch; size and amount of crystals produced and purity profile

 Review typical problems encountered in production

e.g. poor mixing

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Particles in Pharmaceutical manufacturing

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Solubility curve and metastable zone (MSZ)

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Population balance equation

] ln exp[ ] ) (ln exp[

2

 

II II NII I I NI

B S A J B A J    

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Blandin, A.; Mangin, D.; Nallet, V.; Klein, J.; Bossoutrot, J. Chemical Engineering Journal, 2001, 81, 91-100

Nucleation (B)

   

* 1 L L J J L G t V V

NII NI

          

j r v s c s s

C C d k M dt dL G *) ( 3      

Crystal Growth (G) Population Balance Equation

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Comparison of gradient of temperature

time ΔC, T Linear gradient of Temperature Optimised gradient of Temperature time ΔC, T

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G, B G, B

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Temperature cycle optimization

Gradient of Temperature Particle size distribution

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Gibbs-Thomson effect: Smaller particles dissolve faster than larger particles

1 2 3 4 5

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Applications of NIR Spectroscopy to Monitoring and Analyzing the Solid State during Industrial Crystallization Processes

  • G. Fevotte*, J. Calas**, F. Puel*, C. Hoff**

* Université Claude Bernard Lyon 1, France, ** SANOFI Chimie, France

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Choices of NIR probes

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Transflectance Diffuse Reflectance

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Introduction

 Investigation of the polymorphic transitions of SaC during the crystallization and filtration  Investigation of the kinetic behavior of the phase transition against different operating conditions using NIR spectroscopy  Study the effect of residual water in the solvent on the transition during filtration

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Two polymorphic forms of SaC

Form I: Parallelepipeds Form II: Needles

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Temperature dependency of the transition kinetics

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Effect of the size of SaC-II seed crystals on the transition kinetics

Transition kinetics at 20 ◦C, with 2% seed, as a function of the specific area of the seed form II crystals. 16

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Effect of the water on the transition kinetics

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Application of ATR-UV Spectroscopy for Monitoring the Crystallization of UV Absorbing and Nonabsorbing Molecules

Pascal Billot*, Magdalena Couty*, and Patrik Hosek* * Sanofi Aventis, France

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Principle of Attenuated Total Reflectance (ATR)          ) ( ) ( arcsin ) (

1 2

    n n

c

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Total Internal Reflection External Reflection

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Principle of Attenuated Total Reflectance (ATR)

2 2 2 2 1 1

) ( sin ) ( 2 ) ( ) ( ) log( sin n n d zd l Cl A I I A n n

p p crit

            

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Critical Refractive Index Absorbance (attenuated) Beer Lambert’s Law Depth of penetration

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Introduction

 Monitor crystallization process by using ATR UV-vis spectroscopy  Advantages offered by the ATR UV-vis spectroscopy to measure supersaturation levels  Feasible for monitoring crystallizations for non-UV-absorbing molecules

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Instrumentation

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Variation of refractive index with wavelength

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literature values calculated depth of penetration (dp) values

Wavelength (cm) Wavelength (cm) Refractive Index at 20 C Depth of penetration at 20 C (um) Sapphire Toluene Chloroform Water Toluene Chloroform Water

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Variation of refractive index with temperature

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literature values calculated depth of penetration (dp) values

Temperature [C] Temperature [C] Refractive Index at 589 nm Depth of penetration at 589 nm (um) Water Toluene Sapphire Ethanol Toluene Ethanol Water

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UV cut-off wavelengths

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The depth of penetration for non- absorbing molecules

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Choice of the test compound 6-MNA

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6-methoxy-2-naphthaleneacetic acid

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Instrumental stability

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Determination of solubility curve and metastable zone width

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Application to non-UV-absorbing substances

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For non-absorbing species

  • 1. Absorption (A)
  • 2. Optical path length (l)
  • 3. Depth of penetration (dp)
  • 4. Refractive index (n2)
  • 5. Concentration of non-

absorbing species

2 2 2 2 1

) ( sin ) ( 2 n n d p     

Cl A ) ( ) (    

p

zd l 

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Application to non-UV-absorbing substances

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Application to non-UV-absorbing substances

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Conclusion

Demonstrated the NIR & ATR UV-vis spectroscopy can be used to monitor the crystallization processes

  • 1. NIR spectroscopy provided highly valuable information on

the kinetic of polymorphic transitions of API and particles size distribution in the solid phase concentration

  • 2. ATR UV-vis spectroscopy provided the access to solubility

curve, metastable zone width and the measurements in the liquid phase concentration

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References

 Abu Bakar, M.; Nagy, Z.; Rielly, C. Organic Process Research & Development, 2009, 13, 1343- 1356  Aoun, M.; Plasari, E.; David, R.; Villermaux, J. Chemical Engineering Science, 1999, 1161-1180  Barrett, P.; Smith, B.; Worlitschek, J.; Bracken, V.; O’Sullivan, B.; O’Grady, D. Organic Process Research & Development, 2005, 9, 348-355  Billot, P.; Couty, M.; Hosek, P. Organic Process Research & Development, 2010, 14, 511-523  Blandin, A.; Mangin, D.; Nallet, V.; Klein, J.; Bossoutrot, J. Chemical Engineering Journal, 2001, 81, 91-100  Fevotte, G.; Calas, J.; Puel, F.; Hoff, C. International Journal of Pharmaceutics, 2004, 273, 159- 169  Groen, H.; Roberts, K. Journal of Physical Chemistry, 2001, 105, 10723-10730  Groen, H.; Roberts, K. Crystal Growth & Design, 2004, 4, 929-936  Nallet, V.; Mangin, D.; Klein, J. Computers Chemical Engineering, 1998, 22, 649-652  Roelands, C.; Horst, J.; Kramer, H.; Jansens, P. Crystal Growth & Design, 2006, 6, 1380-1392  Scholl, J.; Lindenberg, C.; Vicum, L.; Mazzotti, M. Crystal Growth & Design, 2007, 7, 1653- 1661

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