East Car East Carolina Uni University ersity Kinetic Modeling of Batch Slurry Reactions Paul J. Gemperline 1 , Mary Ellen McNalley 2 , Ron Hoffman 2 , Chun Hsieh 1 , David Joiner 1 , Julien Billeter 1 (1) East Carolina University, (2) DuPont Crop Protection June 27, 2012 XIII Chemometrics in Analytical Chemistry Budapest, Hungary 1
East Car East Carolina Uni University ersity Overall project goal – develop monitoring technique for batch processes involving slurries • Extend kinetic modeling approach to a prototypical slurry reaction at DuPont: sulfonylurea coupling reaction for monitoring purposes • Make optical measurements in light-scattering medium • Modify kinetic models to include: • Dissolution of starting material A & flow-in of reagent B • Nucleation and crystallization of product, P • Develop empirical models for dissolution, nucleation and crystallization • Kinetic models with reagent flow-in impose strict mass balance 2
East Car East Carolina Uni University ersity Isothermal model with flow-in reagents r k C C dC C = 1 1 SA AA r F W W = − − 3 AA dt V r k C = 2 2 I dC C r k C C = r F ASAA ASAA 3 3 W AA = − 4 AA dt V r k C C = 4 4 ASA AA dC C r 2 r r F HA HA = + + − 2 3 4 AA dt V dC C C − r r r F AA AAin AA dV = − − − + 1 3 4 AA F dt V = AA dt dC C r r F I I = − − 1 2 AA dt V conc x Est. pure spectra Est. dC C r F SA SA Batch 1 = = − − 1 AA dt V spectra 3
East Car East Carolina Uni University ersity Slurries • Crystal products – Often desire specific properties • A dynamic system of crystalline material suspended in a liquid • Size distribution, lattice form, etc. medium – Relative rates determine • Common Examples properties – Production of pharmaceuticals – Factors governing process – Production of fine chemicals rates – Biological absorption of pharmaceuticals • Temperature • Rate of stirring • Dynamic processes • Crystal surface area – Dissolution of starting materials • Attrition – Nucleation and crystal growth of products • Agglomeratio n 4
East Car East Carolina Uni University ersity Challenges – Optical Methods in Slurries • Linear response is needed for kinetic modeling and self-modeling curve resolution • Reflectance measurements include both light scattering and light absorption signals – Mathematical resolution of the two is needed to estimate solid fraction and dissolved fraction – Effective path length is dependent on • Number density of light scattering particles • Particle size distribution • Wavelength • ATR measurements for light absorption (dissolved fraction) 5
East Car East Carolina Uni University ersity Project 1: modeling of dissolution of salicylic acid n r k ( c c ) = − sat Develop a kinetic model for the dissolution of salicylic acid in a solvent mixture (52% ethanol, 48% water), based on a power law equation simpler system, easily controlled help gain understanding about kinetic of dissolution Salicylic acid and crystallization in general M.W. 138.12 g mol -1 Precisely controlled conditions will facilitate model pKa 2.97 Monoclinic validation Optimize the rate constant ( k ) and the exponent ( n ) of the power law equation 6
East Car East Carolina Uni University ersity Laboratory scale batch reactors Batch Titration Reactor 7
East Car East Carolina Uni University ersity Laboratory scale batch reactors Batch Titration Reactor 8
East Car East Carolina Uni University ersity Dissolution of salicylic acid Saturated Supersaturated Undersaturated Addition 1 Addition 2 Addition 3 Addition 4 Dilution 2 Dilution 6 Seeding Dilution 4 Dilution 1 Dilution 3 Dilution 5 9
East Car East Carolina Uni University ersity Simplifying Assumptions • Crystallization Rate • Dissolution Rate high theory model MW k 2 MW k Φ g s s c r ( c c ) s d r ( c c ) = η − = − c r sat d sat 3 d d Φ s v s low theory model n g r m k ( c c ) r k ( − c c ) = ⋅ − = c c sat d d sat Assumptions: Well-mixed slurries, the length of crystals, solid density, effectiveness factor, molecular weight of the solid, surface factor and volumetric shape factor do not change significantly in these experiments. 10 Blandin, A. et. al., Chemical Engineering Journal , 2001 , 81, 91-100 Bhattacharya A. Chemical Engineering and Processing, 2007 , 46, 573-583
East Car East Carolina Uni University ersity Hessian 1.0000 -0.9383 -1.0000 0.6118 0.1929 0.1540 -0.9383 1.0000 0.9384 -0.5082 -0.2022 -0.1508 Model batch (08-29-10) -1.0000 0.9384 1.0000 -0.6116 -0.1928 -0.1540 0.6118 -0.5082 -0.6116 1.0000 0.7244 0.0860 0.1929 -0.2022 -0.1928 0.7244 1.0000 -0.0514 0.1540 -0.1508 -0.1540 0.0860 -0.0514 1.0000 UV-vis range used:: 270 – 360 nm , NIR range used: 1100 nm Fitted ATR & NIR 1 2 1 2 3 4 3 4 PLS est. of undissolved mass Optimized Parameters: Initial Conditions: Dissolution rate constant (kd) = 22.16 L n-1 /(mol n-1 min) Dissolution rate constant (kd) = 30.00 L n-1 /(mol n-1 min) Crystallization rate constant (kc) = 9.115 L n-1 /(mol n-1 min) Crystallization rate constant (kc) = 15.00 L n-1 /(mol n-1 min) Order parameter (n) = 2.034 Order parameter (n) = 1.800 Order parameter (g) = 1.194 Order parameter (g) = 1.700 Saturation limit (csat) = 1.010 (mol/L) Total SA mass added (mt) = 3.1882 g Correction factor (cf) = 14.27 Concentration (c0) = 1.0176 (mol/L) Saturation limit (csat) = 0.9075 Sum of Square (SSQ) = 0.5221 Initial volume (v0) = 22.7 mL Correction factor (cf) = 15 11
East Car East Carolina Uni University ersity Experiment 2 • Reaction of Salicylic Acid to form Acetylsalicylic Acid (Aspirin) – Simple, well understood reaction to test modeling ability • Process includes: – Dissolution – 4 Primary Reactions – Crystallization 12
East Car East Carolina Uni University ersity Reaction Mechanisms Catalyzed Reaction k SA AA ASA HA 1 + ⎯ ⎯→ + k ASA AA 2 ASAA HA + ⎯ ⎯→ + Water Addition k ASAA H O 3 ASA HA + ⎯ ⎯→ + 2 k AA H O 4 2 HA + ⎯ ⎯→ 2 13
East Car East Carolina Uni University ersity Time (min) 14
East Car East Carolina Uni University ersity 15
East Car East Carolina Uni University ersity Addition of Solid SA 16
East Car East Carolina Uni University ersity Addition of Water 17
East Car East Carolina Uni University ersity Onset of Crystallization 18
East Car East Carolina Uni University ersity Begin Cooling Ramp 19
East Car East Carolina Uni University ersity 20
East Car East Carolina Uni University ersity Saturation and Supersaturation • Considered relative to equilibrium solubility • Super-saturation – “ Driving force ” of nucleation and crystal growth – Metastable – Generated by • Cooling • Anti-solvent addition • Solvent evaporation 21
East Carolina Uni East Car University ersity Differential Equations d [SA] solid d [ASAA] = r 2 − dV [ASAA] = − r d dt dt dt V d [SA] 1 − dV [SA] d [ASA] 1 − r 2 + r 3 − r c − dV [ASA] = r d − r = r dt dt V dt dt V d [AA] 1 − r 2 − r 4 − dV [AA] d [H 2 O] − dV = − r 3 − r 4 + f [H 2 O] in [H 2 O] = − r dt dt V dt V dt V d [HA] 1 + r 2 + r 3 + r 4 − dV [HA] d [ASA] solid = r = r c dt dt V dt 22
East Carolina Uni East Car University ersity Differential Equations d [SA] solid d [ASAA] = r 2 − dV [ASAA] = − r d dt dt dt V d [SA] 1 − dV [SA] d [ASA] 1 − r 2 + r 3 − r c − dV [ASA] = r d − r = r dt dt V dt dt V d [AA] 1 − r 2 − r 4 − dV [AA] d [H 2 O] − dV = − r 3 − r 4 + f [H 2 O] in [H 2 O] = − r dt dt V dt V dt V d [HA] 1 + r 2 + r 3 + r 4 − dV [HA] d [ASA] solid = r = r c dt dt V dt 23
East Car East Carolina Uni University ersity Concentration Profile of Active Species 24
East Car East Carolina Uni University ersity Concentration Profiles of All Species 25
East Car East Carolina Uni University ersity Validation of ASA Concentration Profiles by HPLC – Preliminary results 26
East Car East Carolina Uni University ersity Project 3: modeling of sulfonylurea coupling reaction Develop a combined kinetic model for the reaction, dissolution and crystallization for the slurry-based sulfonylurea coupling reaction. Use NIR diffuse reflectance spectroscopy 3 and kinetic model for monitoring purpose, and to perform endpoint and fault detections. Use High Performance Liquid Chromatography (HPLC) samples taken from the reaction mixture to validate kinetic models Barrett P., Smith B. et al. (2005). Organic Process Research & Development 9: 348-355. 27
East Car East Carolina Uni University ersity Sulfonyl Urea Coupling Reaction + ⎯ ⎯→ CMBSI A4098 T6376 benzoic acid 2- 2-amino-4-methoxy- metsulfuron methyl [(Isocyanato)sulfonyl]- 6-methyl-1,3,5- methyl ester triazine 28
East Car East Carolina Uni University ersity Apparatus setup at DuPont Sampling valve Overhead stirrer Oil bath NIR reflectance probe Thermocouple Peristaltic Pump Balance Recirculation tube 29
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