Measuring Solubility &
Crystallization Behaviour
Joop H. ter Horst 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. Email: [email protected]
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Ter Horst Group
Technology & Innovation Centre
Prof. Joop H. ter Horst EPSRC Future Manufacturing Research Hub (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 www.cmac.ac.uk www.coreitn.eu
Strathclyde Institute of Pharmacy and Biomedical Sciences
Crystal Structure Size
Shape Purity
Crystallization is a highly efficient Separation Technology
With the added advantage that it results in a Particulate Product
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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Solution Primary
nucleation crystal growth
Secondary nucleation
agglomeration
supersaturation
hydrodynamics
solid form crystal size
crystal shape purity
Product quality
Industrial Crystallization
Productivity
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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)
Measuring Solubility & Crystallization Behaviour
• Solubility
• Solubility in Complex Multicomponent Systems
• Primary Nucleation
• Secondary Nucleation
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Crystallization from Solution
Evaporative Crystallization Cooling Crystallization Antisolvent Crystallization
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.
Solubility behaviour determines crystallization method & Yield
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Crystal Solubility Measurement
100% pure Crystalline phase
Crystal solubility C*: The solution concentration that is in equilibrium with the crystalline solid at
a specific temperature T and pressure P.
Solution with Concentration C* At temperature T,
Pressure T
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
Tra
nsm
ission
Clear point, 100% transmission
Ts=42.2°C
Ts=42.3°C
1440 min = 1 day Heating rate = 0.3°C/min
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Temperature Variation Method
• Crystal detection limit is sensitive
• Dissolution is fast
• No fouling
• No crowning
• No solvent evaporation from vial
• …
Temperature [°C]
Change solubility
Concentration [mg/mL]
Clear point temperature
Thermodynamic Saturation Temperature if:
Check the vials During the measurement!
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Solubility Diagram Of isonicotinamide (INA) in Ethanol
Prepared Sample
composition
Measured Clear Point
Temperature
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Crystallization Of isonicotinamide (INA) in Ethanol
Measured Clear Point
Temperature
yield
Measuring Solubility & Crystallization Behaviour
• Solubility
• Solubility in Complex Multicomponent Systems
• 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 solution
Cloud point - Upon cooling a solution there is a temperature that
crystals will be detected
Metastable 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]
Transmission of light
[%] MSZW
Clear Point Temperature
Cloud Point Temperature
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Supersaturation Ratio Of isonicotinamide (INA) in Ethanol
12.5°C
Solubility x*
Concentration x
S =x
x*
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Measuring Induction Times The 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 ml Stirred solutions
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Measuring Induction Times S. 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
Secondary nucleation
Primary Heterogeneous
nucleation Growth
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Measuring Induction Times S. Jiang, J.H. ter Horst, Crystal Growth Design 11 (2011) 256-261
P(t)=M +(ti)/M
Constant S
P(t)= 1 - exp(-JV(t - tg))
J = 630±20 m-3s-1
tg = 1170±20 s
Model:
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Nucleation Rates
In IPA In DMF
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Crystal Nucleation Rates Analysis
System A [m-3s-1] B
DPL form RII in IPA 576 0.68
DPL form RI in DMF 499 4.57
• Nucleation work B/ln2S in DMF much higher
• Pre-exponential factors A very low => heterogeneous nucleation
2exp
ln
BJ AS
S
Low S High S
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 solution onto heterogeneous (dust) particle
Heterogeneous Crystal Nucleation
Crystal Nucleation Rate Mechanism
P(t)
t [s]
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Heterogeneous Nucleation of CO2 bubbles on a Mentos in Diet Coke
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Crystal Nucleation
nucleation
primary secondary
homogeneous heterogeneous
Measuring Solubility & Crystallization Behaviour
• Solubility
• Solubility in Complex Multicomponent Systems
• Primary Nucleation
• Secondary Nucleation
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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 Width Of isonicotinamide (INA) in Ethanol
Clear point temperature: Increase solubility until suspension turns into a clear solution Cloud point temperature: Decrease solubility until clear solution turns into a suspension
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Induction time measurements Of isonicotinamide (INA) in Ethanol
Induction time: the time it takes for crystals to be detected at constant supersaturation
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Induction time measurements Of 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
[#]
Nρ
x 103 [#/ml]
Number N of particles determined by Crystalline software versus suspension density N𝝆
50 μm monodisperse polymer particles
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Seeded experiment Unseeded experiment
Single Crystal Seed Experiment
N𝝆 x1000 [#/ml]
Suspension density in time after seeding single crystal
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Seeded experiment Unseeded experiment
Single Crystal Seed Experiment
N𝝆 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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Seed sizes: 1.7 – 2.4 mm
Secondary nucleation rate
B x1000
[#/ml.min]
Secondary Nucleation threshold
Prevent secondary nucleation
during seeded crystallization processes
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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
Maria Briuglia, Jan Sefcik, Joop H. ter Horst, Measuring secondary nucleation through single crystal seeding,
Crystal Growth Design 19 (2019) 421-429, DOI: 10.1021/acs.cgd.8b01515
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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.
Measuring Solubility & Crystallization Behaviour
• Solubility
• Solubility in Complex Multicomponent Systems
• Primary Nucleation
• Secondary Nucleation
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Acknowledgements
Solubility • Marloes Reus, Weiwei Li
Primary Nucleation • Shanfeng Jiang, Samir
Kulkarni, Maria Briuglia, Clement Brandel
Secondary Nucleation • Maria Briuglia, Jan Sefcik
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BACG 50 – July 9-11, 2019
www.bacg.co.uk
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Literature Solubility • 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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