Crystal Solubility: Importance, Measurement and More Prof. Joop H. ter Horst Industrial Crystallisation EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC) Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS) Technology and Innovation Centre University of Strathclyde 99 George Street, Glasgow G1 1RD, U.K. Phone: +44 141 548 2858 Email: [email protected] www.strath.ac.uk Slide 2 Product • Complex mul/component systems Crystal Chiral Nucleaon resoluon Phenomena Process • New level of • Flexible and sustainable understanding for produc/on facili/es predic/on and control Pharmaceucal & Protein Crystallisaon Crystal Solubility Binary Systems in Phenanthrene Intermolecular interactions between solute and benzene are essentially identical Benzene Anthracene Slide 4 Crystal Solubility Binary Systems x*=20.7 mol% Tm=100°C in Phenanthrene Intermolecular interactions in Anthracene crystal are much larger than in Phenanthrene crystal: Benzene Anthracene prefers the solid phase x*=0.81 mol% Tm=217°C Anthracene Slide 5 Crystal Solubility Binary Systems in Phenanthrene Solubility is determined by intermolecular interactions in both Benzene solution and solid Anthracene Slide 6 Crystal Solubility Binary Systems 100% pure Crystalline phase Solution with Concentration C* At temperature T, Pressure P Crystal solubility C*: The solution concentration that is in equilibrium with the crystalline solid at a specific temperature T and pressure P. Slide 7 Crystal Solubility • Crystallization • Solubility Measurements • Solubility Analysis • Solubility Measurements in Complex Multicomponent Systems • Solubility in Complex Multicomponent Systems • Crystallization Kinetics Slide 8 Crystallization from Solution Crystalline product 99.99% pure Single Synthesis stage of API Crystallization Filtration Solution containing impurities and dissolved synthesis product Slide 9 Crystallization from Solution supersaturation Product quality agglomeration solid form Primary crystal size distribution Solution crystal growth nucleation crystal shape purity Secondary nucleation hydrodynamics Productivity Slide 10 Crystallization from Solution Slide 11 Crystallization from Solution Binary Systems Solubility supersaturated Concentraon undersaturated Temperature Heat Slide 12 Crystallization from Solution Binary System at constant P,T Concentration C = 100 mg/ml solvent Solubility C* = 20 mg/ml solvent Yield C-C* = 80 mg crystals/ml solvent 80% is crystallized, 20% remains in solution The solubility curve is the first step towards a crystallization process design Slide 13 Crystal Solubility • Crystallization • Solubility Measurements • Solubility Analysis • Solubility Measurements in Complex Multicomponent Systems • Solubility in Complex Multicomponent Systems • Crystallization Kinetics Slide 14 Crystal Solubility Measurement 100% pure Crystalline phase Solution with Concentration C* At temperature T, Pressure T Crystal solubility C*: The solution concentration that is in equilibrium with the crystalline solid at a specific temperature T and pressure P. Slide 15 Equilibrium Method • Equilibrate suspension at constant temperature, pressure • Sample solution & analyze concentration • HPLC • Gravimetric • Etc. Concentraon [mg/mL] • Accurate • Time consuming Temperature [°C] Temperature Variation Method Clear point temperature Light X Light Suspension Clear solution (Low T) (high T) Clear point temperature: The temperature at which a suspension becomes a clear solution during heating with a certain rate Temperature Variation Method Clear point temperature • Increase solubility until suspension turns into a clear solution • Reproducing results fairly quick • Also metastable zone width TV method Concentraon [mg/mL] Change solubility Temperature [°C] Clear & Cloud Point Measurements Clear point, 100% transmission Transmission Transmission T Ts=42.2°C Ts=42.3°C Heating rate = 0.3°C/min 1440 min = 1 day Clear Point & Solubility Concentration = Constant Thermodynamic Saturation temperature If: • Crystal detection limit is low • Dissolution is fast • No fouling • No crowning • … Look at the vials! Often, a heating rate of 0.3°C/min gives sufficiently accurate data Crystal Solubility • Crystallization • Solubility Measurements • Solubility Analysis • Solubility Measurements in Complex Multicomponent Systems • Solubility in Complex Multicomponent Systems • Crystallization Kinetics Slide 21 Solubility Diagram Of isonicotinamide (INA) in Ethanol Solubility Solubility ideal system: Enthalpy of fusion of pure A ⎛ ΔH ⎛ 1 1 ⎞ ⎞ ⎛ A ⎞ x* = exp⎜ − ⎜ − ⎟ ⎟ = exp⎜ + B⎟ ⎝ R ⎝ T Tm ⎠ ⎠ ⎝ T ⎠ solubility Melting temperature of pure A Fitting the solubility data of a real system: A lnxB * =+ T Van ‘t Hoff-plot Of isonicotinamide (INA) in Ethanol Fitting equation: A lnxB * =+ T Convenient and accurate to extrapolate Van ‘t Hoff-plot Of isonicotinamide (INA) in Ethanol Fitting equation: A lnxB * =+ T Ideal solubility: ΔH ⎛ 1 1 ⎞ ln x* = − − R ⎜ T T ⎟ ⎝ m ⎠ Why is there a difference between ideal and real solubility? Chemical Potential Ideal system eq eq µL = µL * + kT ln xeq Real system eq eq µL = µL * + kT lnaeq The activity coefficient γ describes non-ideality a = γ x Crystal Solubility • Crystallization • Solubility Measurements • Solubility Analysis • Solubility Measurements in Complex Multicomponent Systems • Solubility in Complex Multicomponent Systems • Crystallization Kinetics Slide 27 Co-crystallization Of isonicotinamide (INA) and Carbamazepine (CBZ) in Ethanol Pure Component Solubility Of isonicotinamide (INA) and Carbamazepine (CBZ) in Ethanol T = 25°C INA x* = 33.3 mmol/mol (c* = 72 mg/ml) CBZ x* = 5.7 mmol/mol (c* = 24 mg/ml) Solubility of INA is 6 times higher than that of CBZ Solvent Addition Method Clear point concentration Suspended Solvent solid in mixture solvent mixture • Change the composition until clear point concentration at constant temperature Concentraon [mg/mL] • Faster than Equilibrium Method • Suitable for multicomponent systems • No limitation # components in sample and added solution Temperature [°C] Solvent Addition Method 2x4 Syringe Pumps: Each syringe can hold a different solvent composition. Two different flow rates can be tested in one go. Crystalline: 8 Reactors with independent temperature Slide 31 control and PVM Co-crystal Phase diagram Carbamazepine (CBZ) Isonicotinamide (INA) Ethanol 0.005 T = 20°C 0.004 0.003 xCBZ 0.002 0.001 0 0 0.01 0.02 0.03 0.04 xINA solubility CBZ Solubility INA Solubility Cocrystal Crystal Solubility • Crystallization • Solubility Measurements • Solubility Analysis • Solubility Measurements in Complex Multicomponent Systems • Solubility in Complex Multicomponent Systems • Crystallization Kinetics Slide 33 Crystal Form Form I Form II Polymorphism: The ability of a chemical compound to form 2 or more crystal structures Slide 34 Crystal Form Form II Form I Concentraon ! The clear point temperature depends on the polymorph that is present in the suspension Temperature Slide 35 Complex Phase Behavior T x [w%] (Normal) Salt, Co-crystal, solvate: Solid Solution: The crystal phase might The crystal phase might contain contain more components more components in varying ratios in specific ratios Slide 36 M. Matsuoka,1978 Chirality Introduction enantiomers (S) (R) Slide 37 Chiral compounds Binary phase diagram Conglomerate Racemic compound Solid solution The phaseL diagram reflectsL the kind of solid Lstate T S+L R+L RS+L S+L R+L RS R+S S+RS R+RS S R S R S R yR yR yR Slide 38 Chiral Compound Solubility Asparagine in Water Ternary phase diagram screening Sample composition Clear point temperatures 30 80 a x=25 x=25 b x=15 x=15 25 70 20 Conglomerate T 15 s 60 x s [°C] [mmol/mol] 10 50 5 0 40 0 5 10 15 20 25 30 0 0.25 0.5 0.75 1 x R [mmol/mol] y R [-] yR = xR/(xR+xS) Slide 39 Chiral Compound Solubility: Ibuprofen in Hexane Ternary phase diagram screening 200 60 x =175 c d 50Racemic compound 150 40 x s [mmol/mol] T 100 s 30 [°C] 20 50 10 0 0 0 50 100 150 200 0 0.25 0.5 0.75 1 y [-] x R [mmol/mol] R yR = xR/(xR+xS) Slide 40 Chiral Compound solubility: Atenolol in Ethanol Ternary phase diagram screening 30 60 e x=25x=25 x=25x =25 f x=10x=10 x=10x =10 50 20 40 x T s s 30 Solid solution [mmol/mol] [°C] 10 20 10 0 0 0 10 20 30 0 0.25 0.5 0.75 1 x R [mmol/mol] y R [-] S. Sukanya, J.H. ter Horst, Racemic Compound, Conglomerate, or Solid Solution: Phase Diagram Screening of Chiral Compounds, Slide 41 Crystal Growth Design 10(4) (2010) 1808-1812. Crystal Solubility • Crystallization • Solubility Measurements • Solubility Analysis • Solubility Measurements in Complex Multicomponent Systems • Solubility in Complex Multicomponent Systems • Crystallization Kinetics Slide 42 Metastable Zone Width 60 100 55 90 50 80 45 70 Clear point 40 C) o 60 35 50 Temperature 30 MSZW Cloud point Transmission 40 [°C] Temperature ( of light 25 Transmissivity (%) 30 [%] 20 20 15 10 10 5 0 6:00 7:12 8:24 9:36 10:48 12:00 Time (hour) Measuring Induction Times The time until detection of crystals at a constant supersaturation • Accurate temperature control 60 100 50 75 Temperature 40 50 Transmission [oC] [%] 30 t 25 1 ml 20 0 7 8 9 10 11 12 Time [hr] Measuring Induction Times • Create constant supersaturation • Measure induction time • Do this a large number of times, say M times + P (t)=M (ti)/M Constant S S. Jiang, J.H. ter Horst, Crystal Growth Design 11 (2011) 256-261 Induction Time Distributions S = 3 J = 668 m-3s-1 J.H. ter Horst, C. Brandel, Measuring Induction Times and Crystal Nucleation Rates, Faraday