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Linking Solution Chemistry to Crystallization
René Steendam, PhDArdena Amsterdam
The Netherlands
30-Jul-2020
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Ardena in numbers
Six purpose-built facilities in Europe
Belgium, Mariakerke
Drug Product, Clinical Supply and
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The Netherlands, Amsterdam
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Seven teams to support your multidisciplinary project
Solid State Research
Drug Substance
NanomedicineDrug Product
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Bioanalysis Dossier Development
Polymorph
selectionSalt selection
Cocrystal screening
Amorphous solid
dispersions
Crystallisation process
development
Analytical chemistry
Single crystal structure
determination
Intellectual property support
Solid state research at Ardena
www.ardena.com
Overview Webinar
7
Linking solution chemistry to crystallization
Secondary nucleation
Primary nucleation
Solid phase transitions
Mechanical properties
Benefits of Crystallization from Solution
8
Active pharmaceutical ingredients (API’s) in solid form✓Patient acceptance✓Processing✓Physical and chemical stability
Crystallization from solution✓Widely applicable✓Generally simple✓Cost-efficient✓Purification
Crystallization methods✓Cooling (most applied)✓Anti-solvent✓Evaporative✓Reactive crystallization
Cooling Crystallization
9
Undersaturated solutionC<C* & S<1
SupersaturatedC>C* & S>1
S = supersaturation ratio = C / C*
Concentration API (C)
Temperature (T)
C*
Crystal Nucleation
10
Primary nucleation
Secondary nucleation
Autocatalytic
Crystal Nucleation
11
➢ Seeded crystallization / crystals needed
➢ Dominant mechanism in industry
➢ Low energy barrier / low supersaturation
➢ Stirred suspensions
➢ Control polymorphism / chirality
➢ High energy barrier, high supersaturation
➢ Generally heterogeneous nucleation
➢ Physical/chemical properties solvent
➢ Influences solid form (chirality, polymorph)
➢ Primary nucleation triggers secondary nucleation
Control primary nucleation → Control secondary nucleation → Control final API
Nucleation Study on NaClO3
12R. R. E. Steendam, L. Keshavarz, M. A. R. Blijlevens, B. de Souza, D. M. Croker and P. J. Frawley, Cryst. Growth & Des. 2018, 18, 9, 5547-5555
1x Primary
nucleation
Secondarynucleation
>1x Primary
nucleation
S > 1 S >>> 1
Controlling primary nucleation is essential
Primary Nucleation Theory
13
Two-step nucleationLiquid-like intermediate becomes crystalline over time
R. J. Davey,S. L. M. Schroeder and J. H. ter Horst, Angew. Chem. Int. Ed. 2013, 52, 2-16
Classical Nucleation Theory (CNT)Cluster has same structure as final crystal
Primary Nucleation Theory
14
J = nucleation rateS = supersaturation ratioA = kinetic parameter (molecular kinetics of nucleation)B = thermodynamic parameter (reflects structure nucleus)
Primary nucleation
A B
n*
• Gain in bulk free energy vs. interfacial energy• Molecular packing motif• Interaction between nucleus and solution
• Attachment frequency• Solvated state → solvation shell → conformation change → absorbed
R. J. Davey,S. L. M. Schroeder and J. H. ter Horst, Angew. Chem. Int. Ed. 2013, 52, 2-16
Case study: Pregabalin (SPG)
15
➢ No data on crystallization of Pregabalin
o Elucidate crystallization of Pregabalin using CNT: effect of solvent
➢ Trade name: Lyrica (Pfizer)
➢ Top 20 prescription medications
➢ Epilepsy, generalized anxiety disorder, pain treatment
➢ Generic in 2019
➢ Chemical structure
o Extremely brittle
➢ Physical properties
o Zwitter-ionico (S)-configurationo Similar to L-leucineo Anhydrate
Induction times: Data input for CNT
16
Laser
Time = 0, S>1 Induction timeTransmittance = <100%
Primary nucleation Secondary nucleation
Detector
Transmittance = 100%
Crystallization time at fixed S and fixed T: Induction time
Nucleation is stochastic: many induction times needed for CNT
Induction times: Feedback loop
17
• Induction time measurements (Crystal 16)
R. R. E. Steendam, U. B. R. Khandavilli, L. Keshavarz and P. J. Frawley, Cryst. Growth & Des. 2019, 19, 8, 4483-4488
With feedback loop
✓ Feedback loop1) Dissolve at high T2) Slowly cool to S>13) Wait for crystallization (induction time)4) Start again at step 1 when transmissivity <90%
Induction times Pregabalin
18
• >1800 crystallization experiments with Crystal 16 feedback loop• 5 solvent systems• 50-160 induction times per S
R. R. E. Steendam, U. B. R. Khandavilli, L. Keshavarz and P. J. Frawley, Cryst. Growth & Des. 2019, 19, 8, 4483-4488
S = 1.21-1.27
Water
S = 2.83-3.43
MeOH
J = nucleation ratetg = growth time nucleus
Pregabalin data
19R. R. E. Steendam, U. B. R. Khandavilli, L. Keshavarz and P. J. Frawley, Cryst. Growth & Des. 2019, 19, 8, 4483-4488
Solvent Mole fraction water (x)
S tg (s) γef (mJ/m2) XRPD
water 1.000 1.2-1.3 100-430 1.01 (±0.34) Anhydrate
water/methanol
0.727 1.4-1.5 270-1660 1.54 (±0.17) Anhydrate
water/methanol
0.544 1.5-2.0 200-2900 1.41 (±0.20) Anhydrate
water/2-propanol
0.454 2.2-2.6 1300-4400 1.95 (±1.17) Anhydrate
methanol 0.000 2.8-3.4 1030-7400 2.63 (±0.48) Anhydrate
➢ Solvent influences nucleation kinetics. However, solid form is the same by XRPD• 2-step nucleation?• Metastable precursor?
Pregabalin clusters
20R. R. E. Steendam, U. B. R. Khandavilli, L. Keshavarz and P. J. Frawley, Cryst. Growth & Des. 2019, 19, 8, 4483-4488
Open symbols: molecular kinetics:
Closed symbols: number of
molecules in critical nucleus:
➢ In solution, cluster size of Pregabalin depends on water fraction solvent
➢ Isolated solids are always anhydrate… ➢ Metastable hydrate?
Dynamic Light Scattering (DLS)
In-line Raman Spectroscopy
21R. R. E. Steendam, U. B. R. Khandavilli, L. Keshavarz and P. J. Frawley, Cryst. Growth & Des. 2019, 19, 8, 4483-4488
Nucleation hydrate
Hydrate → Anhydrate
➢ Pregabalin is structurally similar to L-Leucine
➢ Transition time hydrate to anhydrate❑ Water: 100 min❑ Water/MeOH (1/1): 25 min
Anhydrate
Crystal structure confirmation Pregabalin hydrate
U. B. R. Khandavilli, M. Lusi and P. J. Frawley, IUCrJ 2019, 6, 630-634
AnhydrateBrittle
Hydrate Form I>150 K
Hydrate Form II<150 K
T
22
Slip planes → bendable crystals
Mechanical properties zwitterionic drugs
U. B. R. Khandavilli, M. Lusi and P. J. Frawley, IUCrJ 2019, 6, 630-634 23
Pregabalin (SPG) Gabapentin (GP)
Mechanism dehydration Pregabalin
R. R. E. Steendam, U. B. R. Khandavilli, L. Keshavarz and P. J. Frawley, Cryst. Growth & Des. 2019, 19, 8, 4483-4488 24
➢ In solution, hydrate is formed easier (kinetics). In solid phase, transition into anhydrate is irreversible
➢ How to obtain a stabilized form which is less brittle than anhydrate?
Crystal engineering: Multi-component systems
U. B. R. Khandavilli, M. Yousuf, B. E. Schaller, R. R. E. Steendam, L. Keshavarz, P. McArdle and P. J. Frawley, CrystEngComm 2020, 22, 412-415 25
Multi-component systems of Pregabalin
U. B. R. Khandavilli, M. Yousuf, B. E. Schaller, R. R. E. Steendam, L. Keshavarz, P. McArdle and P. J. Frawley, CrystEngComm 2020, 22, 412-415 26
Anhydrate (interdigitated structure) Oxalic acid Salicylic acid
Multi-component systems of Pregabalin
U. B. R. Khandavilli, M. Yousuf, B. E. Schaller, R. R. E. Steendam, L. Keshavarz, P. McArdle and P. J. Frawley, CrystEngComm 2020, 22, 412-415 27
TabletabilitySolubility in water
Summary
28
Linking solution chemistry to crystallization
-H2O
+H2O
Anhydrate(stable, brittle)
Hydrate(unstable, bendable)
Crystal Engineering
Salt(stable, bendable)
Acknowledgements
29
Udaya KhandavilliLeila KeshavarzLian BlijlevensBrian de SouzaDenise CrokerPatrick Frawley
Carmen GugutaDanny Stam
For further information or questions on this webinar, feel free to send me an email:[email protected]
Ana Fernández CasarezMatteo SeregniMichiel van SpeybroeckJoren de Koning
