Measuring Solubility Crystallization Behaviour...Maria Briuglia, Jan Sefcik, Joop H. ter Horst, Measuring secondary nucleation through single crystal seeding, Crystal Growth Design

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