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Measuring Primary and Secondary Nucleation in Crystallization
Joop H. ter HorstEPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC)Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS)Technology and Innovation CentreUniversity of Strathclyde99 George Street, Glasgow G1 1RD, U.K.
Email: [email protected]
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Ter Horst Group
Technology & Innovation Centre
Prof. Joop H. ter HorstEPSRC Future Manufacturing Research Hub (CMAC)Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS)Technology and Innovation CentreUniversity of Strathclyde99 George Street, Glasgow G1 1RD, U.K.
Phone: +44 141 548 2858Email: Joop.terHorst@strath.ac.ukwww.strath.ac.ukwww.cmac.ac.ukwww.coreitn.eu
Strathclyde Institute of Pharmacy and Biomedical Sciences
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Ter Horst Group
Industrial Crystallization• Continuous Crystallization
– Andrew Dunn, Sebastion Davidson
• Crystallization Kinetics in Complex Multicomponent Systems– Olayinka Olalere, Corin Mack, Suse Bebiano, Carlos Moreno, Dr.
Stephanie Urwin
• Protein Crystallization Technology– Dr. Maria Briuglia, Dr. Charline Gerard
• Chiral Resolution– Johannes Hoffmann, Raghu Venkatramanan, Giulio Valenti, Jose Luis
Capdevila Echeverria, Weiwei Li (Delft University of Technology)
Crystal StructureSize
ShapePurity
Crystallization is a highly efficient Separation Technology
With the added advantage that it results in a Particulate Product
Slide 6
Solution Primarynucleation crystal growth
Secondary nucleation
agglomeration
supersaturation
hydrodynamics
solid formcrystal size
crystal shapepurity
Product quality
Industrial Crystallization
Productivity
Slide 8
Crystallization Design WorkflowC.J. Brown, J.H. ter Horst, …, Enabling Precision Manufacturing of Active Pharmaceutical Ingredients: Workflow for Seeded Cooling Continuous Crystallisations. Molecular Systems Design Engineering (2018)
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Crystallization Design WorkflowC.J. Brown, J.H. ter Horst, …, Enabling Precision Manufacturing of Active Pharmaceutical Ingredients: Workflow for Seeded Cooling Continuous Crystallisations. Molecular Systems Design Engineering (2018)
The first hurdle towards Crystallization Process Design:
Know the solubility
Measuring Primary and Secondary Nucleation in Crystallization• Solubility• Primary Nucleation• Secondary Nucleation
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Crystallization from SolutionEvaporative Crystallization Cooling Crystallization Antisolvent Crystallization
Precipitation
J.H. ter Horst, C. Schmidt, J. Ulrich, Fundamentals of Industrial Crystallization, In: Nishinaga T, Rudolph P, editors, Handbook of Crystal Growth, Vol. II., Elsevier, 2015, pp. 1317–49, DOI: 10.1016/B978-0-444-63303-3.00032-8.
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Crystallization from Solution
C = 100 mg/ml solventC* = 20 mg/ml solvent
Yield C-C* = 80 mg crystals/ml solvent
80% is crystallized,20% remains in solution
Concentration CSolubility C*
[mg/ml]
Slide 15
Crystal Solubility Measurement
100% pureCrystalline phase
Crystal solubility C*:The solution concentration that is in equilibrium with the crystalline solid at a
specific temperature T and pressure P.
Solution withConcentration C*At temperature T,
Pressure T
EquilibriumSolubility behaviour determines crystallization method & Yield
How to measure solubility?
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Temperature Variation Method
• Increase solubility until suspension turns into a clear solution• Reproducing results fairly quick• Also metastable zone width
Temperature [°C]
Change solubility
Concentration[mg/mL]
Clear point temperature
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Clear & Cloud Point Measurements
T
Transmission
Clear point, 100% transmission
Ts=42.2 CTs=42.3 C
1440 min = 1 dayHeating rate = 0.3°C/min
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Clear Point & Solubility
ThermodynamicSaturation temperature
Concentration = Constant
If:• Crystal detection limit is low• Dissolution is fast• No fouling• No crowning• …
check the vialsDuring the
measurement!Often, a heating rate of
0.3°C/min gives sufficiently accurate data
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Solubility DiagramOf isonicotinamide (INA) in Ethanol
J.H. ter Horst, M.A. Deij, P.W. Cains, Discovering new co-crystals,
Crystal Growth Design 9(3) (2009) 1531-1537.
Slide 20
Supersaturation RatioOf isonicotinamide (INA) in Ethanol
12.5°C
Solubility x*
Concentration x
S = xx*
Measuring Primary and Secondary Nucleation in Crystallization• Solubility• Primary Nucleation• Secondary Nucleation
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Primary Nucleation Characteristics
Develop a method for measuring Primary Nucleation Rate
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Primary Nucleation Characteristics
Clear point - Upon heating there is a temperature that a suspension turns into a clear solutionCloud point - Upon cooling a solution there is a temperature that crystals will be detectedMetastable Zone Width - The difference between the saturation temperature (Clear point) and cloud point
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Metastable zone width
0
25
50
75
100
0
10
20
30
40
50
60
6:00 7:00 8:00 9:00 10:00 11:00 12:00
Time [hrs]
Temperature[ C]
Transmissionof light
[%]MSZW
Clear PointTemperature
Cloud PointTemperature
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Measuring Induction TimesThe time until detection of crystals at constant supersaturation
• Accurate temperature control = accurate supersaturation control• A certain minimum volume fraction of crystals in the stirred suspension is
needed for detection
0
25
50
75
100
20
30
40
50
60
7 8 9 10 11 12
Transmission [%]
Temperature [oC]
Time [hr]
t
1 mlStirred solutions
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Measuring Induction TimesS. Jiang, J.H. ter Horst, Crystal Growth Design 11 (2011) 256-261
Constant S • 1ml stirred solutions
• Create constant supersaturation
• Measure induction time
• Do this a large number of times
Crystal nucleation rate is very low
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Single Nucleus Mechanism
Observed in 3 ml stirred solutions for:• Isonicotinamide in Ethanol, butanol, nitrobenzene, nitromethane• Paracetamol, succinic acid in water• Hydroxyacetophenone in acetyl acetate
S.S. Kadam, J.H. ter Horst et al., Cryst. Growth Des. 11(4) (2011) 1271–1277
Parent crystal Crystal suspension
Clear solution
Secondarynucleation
PrimaryHeterogeneous
nucleationGrowth
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Measuring Induction TimesS. Jiang, J.H. ter Horst, Crystal Growth Design 11 (2011) 256-261
P(t)=M +(ti)/MConstant S
P(t)= 1 - exp(-JV(t - tg))
J = 630±20 m-3s-1
tg = 1170±20 s
Model:
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Induction Time Distributions
m-ABA in 50 wt % water/ethanol L-His in water Isonicotinamide in ethanol
S. Jiang, J.H. ter Horst, Crystal Growth Design 11 (2011) 256-261S. Kulkarni, J.H. ter Horst, Crystal Growth Design 13 (2013) 2435-2440
S=1.83
S
S=2.15
S=1.55
S
S=1.74
S=1.264
S
S=1.48
Supersaturation S = Concentration / Solubility
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Induction Time Distributions
Nucleation of Metal Organic Framework
0
0.25
0.5
0.75
1
0 40000 80000 120000
P(t)
t [s]
With Silica ParticlesWithout Silica
Nucleation of Proteins
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Nucleation Rates
In IPA In DMF
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Crystal Nucleation Rates Analysis
System A [m-3s-1] BDPL form RII in IPA 576 0.68DPL form RI in DMF 499 4.57
• Nucleation work B/ln2S in DMF much higher
• Pre-exponential factors A very low => heterogeneous nucleation
2explnBJ ASS
æ ö= -ç ÷è ø
LowSHighS
J.H. ter Horst, C. Brandel, Measuring Induction Times and Crystal Nucleation Rates, Faraday Discuss. 179 (2015) 199
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!
□ - Untreated sample○ - Solution in silanized vials∆ - Filtered solution
Filtration removes (part of) the heterogeneous particles
Nucleation occurs in bulk of solutiononto heterogeneous (dust) particle
Heterogeneous Crystal Nucleation
Crystal Nucleation Rate Mechanism
P(t)
t [s]
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Heterogeneous Nucleationof CO2 bubbles on a Mentos in Diet Coke
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Crystal Nucleation
nucleation
primary secondary
homogeneous heterogeneous
Measuring Primary and Secondary Nucleation in Crystallization• Solubility• Primary Nucleation• Secondary Nucleation
Slide 37
Secondary Nucleation is the formation of particles due to the presence of other particles
Attrition Fluid Shear
Develop a systematic method for secondary nucleation assessment
Secondary Nucleation
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Metastable Zone WidthOf isonicotinamide (INA) in Ethanol
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Induction time measurementsOf isonicotinamide (INA) in Ethanol
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Induction time measurementsOf isonicotinamide (INA) in Ethanol
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Single Crystal Seed Experiment
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Calibrating Suspension Density
0
50
100
150
200
0 50 100 150
N[#]
Nρx 103 [#/ml]
Number N of particles determined by Crystalline software versus suspension density N!
50 μm monodisperse polymer particles
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Seeded experiment Unseeded experiment
Single Crystal Seed Experiment
N!x1000[#/ml]
Suspension density in time after seeding single crystal
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Seeded experiment Unseeded experiment
Single Crystal Seed Experiment
N!x1000[#/ml]
Suspension density in time after seeding single crystal
Secondary Nucleation Rate B=
Slope of suspension density in time
B = 12.8 . 103 #/ml.min
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Seeds size: 1.7 – 2.4 mm
Secondary nucleation rate
Bx1000
[#/ml.min]
Secondary Nucleation threshold
Slide 46
Crystallization Design Workflow
C.J. Brown, …, J.H. ter Horst, …, Enabling Precision Manufacturing of Active Pharmaceutical Ingredients: Workflow for Seeded Cooling Continuous Crystallisations. Molecular Systems Design Engineering (2018) https://doi.org/10.1039/C7ME00096K.
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Secondary Nucleation Understanding
Metastable Zone Width
Choose Supersaturation S
Measure Induction Times at Selected S
Single Crystal Seeds Preparation
Measure Secondary Nucleation Rates at Selected S
Secondary Nucleation Threshold
Measuring Primary and Secondary Nucleation in Crystallization• Solubility• Primary Nucleation• Secondary Nucleation
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Acknowledgements
Solubility• Marloes Reus
Primary Nucleation• Shanfeng Jiang, Samir
Kulkarni, Maria Briuglia, Clement Brandel
Secondary Nucleation• Maria Briuglia, Jan Sefcik
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LiteratureSolubility• J.H. ter Horst, M.A. Deij, P.W. Cains, Discovering new co-crystals, Crystal Growth Design 9(3) (2009) 1531-1537. • S. Srisanga, J.H. ter Horst, Racemic Compound, Conglomerate, or Solid Solution: Phase Diagram Screening of Chiral Compounds, Crystal Growth
Design 10(4) (2010) 1808-1812.• J. Vellema, N.G.M. Hunfeld, H.E.A. Van den Akker, J.H. ter Horst, Avoiding Crystallization of Lorazepam during Infusion, Eur. J. Pharm. Sci. 44 (2011)
621–626.• António O.L. Évora, Ricardo A.E. Castro, Teresa M.R. Maria, M. Ramos Silva, J.H. ter Horst, João Canotilho, M. Ermelinda S. Eusébio, Thermodynamic
based approach on the investigation of a diflunisal pharmaceutical co-crystal with improved intrinsic dissolution rate, International Journal of Pharmaceutics 466 (2014) 68–75.
• M.A. Reus, A.E.D.M. van der Heijden, J.H. ter Horst, Solubility Determination from Clear Points upon Solvent Addition, Org. Process Res. Dev. 19 (8) (2015) 1004–1011, DOI: 10.1021/acs.oprd.5b00156
• A.O.L. Evora, R. Castro, T. Maria, M.R. Silva, J.H. ter Horst, J. Canotilho, M.E.S. Eusébio, Co-crystals of diflunisal and isomeric pyridinecarboxamides–a thermodynamics and crystal engineering contribution, CrystEngComm, 18 (2016) 4749–4759, DOI: 10.1039/c6ce00380j (May 3, 2016).
Primary Nucleation• S. Jiang, J.H. ter Horst, Crystal Nucleation Rates from Probability Distributions of Induction Times, Crystal Growth Design 11 (2011) 256-261.• S.S. Kadam, S.A. Kulkarni, R. Coloma Ribera, A.I. Stankiewicz, J.H. ter Horst, Herman J.M. Kramer, A new view on the metastable zone width during
cooling crystallization, Chem. Eng. Sci. 72 (2012) 10–19.• S.A. Kulkarni, S.S. Kadam, H. Meekes, A.I. Stankiewicz, J.H. ter Horst, Crystal Nucleation Kinetics from Induction Times and Metastable Zone Widths,
Crystal Growth Design 13(6) (2013) 2435-2440.• R.J. Davey, S.L.M. Schroeder, J.H. ter Horst, Nucleation of Organic Crystals – A Molecular Perspective, Angewandte Chemie International Edition 52
(2013) 2166-2179, DOI: 10.1002/anie.201204824.• R. A. Sullivan, R. J. Davey, G. Sadiq, G. Dent, K. R. Back, J. H. ter Horst, D. Toroz, R. B. Hammond, Revealing the Roles of Desolvation and Molecular
Self-Assembly in Crystal Nucleation from Solution: Benzoic and p-Aminobenzoic Acid, Cryst. Growth Des. 14 (2014) 2689−2696.• Antonella Caridi, Samir A. Kulkarni, Gianluca Di Profio, Efrem Curcio, Joop H. ter Horst, Template-Induced Nucleation of Isonicotinamide
Polymorphs, Cryst. Growth Des. 14 (2014) 1135−1141.• J.H. ter Horst, C. Brandel, Measuring Induction Times and Crystal Nucleation Rates, Faraday Discuss. 179 (2015) 199• C. Brandel, Y. Cartigny, S. Petit, J.H. ter Horst, G. Coquerel, Pre-Nucleation Self-Assembly and Chiral Discrimination Mechanisms during Solution
Crystallization of Racemic Diprophylline, Chemistry-A European Journal 22 (2016) 16103-16112, DOI: 10.1002/chem.201602707 (September 26, 2016).
• H. Yang, J.H. ter Horst, Crystal Nucleation of Small Organic Molecules, pp 317-337, In: New Perspectives on Mineral Nucleation and Growth, Editors: A.E.S. Van Driessche, M. Kellermeier, L.G. Benning, Denis Gebauer (2017), Springer International Publishing, DOI: 10.1007/978-3-319-45669-0_16.
Secondary Nucleation• C.J. Brown, …, J.H. ter Horst, …, Enabling Precision Manufacturing of Active Pharmaceutical Ingredients: Workflow for Seeded Cooling Continuous
Crystallisations. Molecular Systems Design Engineering (2018) https://doi.org/10.1039/C7ME00096K.• M. Briuglia, J. Sefcik, J.H. ter Horst, submitted
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