linking solution chemistry to crystallization€¦ · 30.07.2020 · crystallization time at fixed...
TRANSCRIPT
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Linking Solution Chemistry to Crystallization
René Steendam, PhDArdena Amsterdam
The Netherlands
30-Jul-2020
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o A mid-sized CDMO that helps to navigate customers through drug development and drug approval process
o Integrated contractor offering full services that cover
chemistry and pharmaceutical development, product and
bioanalytical support and CMC dossier development.
o GMP and GLP certified
o Global reach
o Small, medium and large pharmaceutical companies
o Reliable, proactive and flexible with a focus on long-term
partnerships
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300Involved in the development of
500+ New Chemical
Entities
38m
io
Turnover of
active
customers
280 employees
>
6Facilities in4countries
€
Ardena in numbers
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Six purpose-built facilities in Europe
Belgium, Mariakerke
Drug Product, Clinical Supply and
Dossier Developmento 78 employees
o 2,500 m²
The Netherlands, Amsterdam
Solid State Researcho 15 employees
o 850 m²
The Netherlands, Oss
Drug Substance and
Nanomedicineo 82 employees
o 5,000 m²
The Netherlands, Assen
Bioanalyticso 50 employees
o 2,000 m²
Sweden, Södertälje
Drug Substance o 14 employees
o 1,100 m²
Latvia, Pinki
Drug Substanceo 13 employees
o 450 m²
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Seven teams to support your multidisciplinary project
Solid State Research
Drug Substance
NanomedicineDrug Product
ClinicalSupply
Bioanalysis Dossier Development
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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
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Overview Webinar
7
Linking solution chemistry to crystallization
Secondary nucleation
Primary nucleation
Solid phase transitions
Mechanical properties
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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
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Cooling Crystallization
9
Undersaturated solutionC<C* & S<1
SupersaturatedC>C* & S>1
S = supersaturation ratio = C / C*
Concentration API (C)
Temperature (T)
C*
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Crystal Nucleation
10
Primary nucleation
Secondary nucleation
Autocatalytic
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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
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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
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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
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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
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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
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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
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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%
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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
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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?
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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)
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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
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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
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Mechanical properties zwitterionic drugs
U. B. R. Khandavilli, M. Lusi and P. J. Frawley, IUCrJ 2019, 6, 630-634 23
Pregabalin (SPG) Gabapentin (GP)
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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?
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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
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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
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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
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Summary
28
Linking solution chemistry to crystallization
-H2O
+H2O
Anhydrate(stable, brittle)
Hydrate(unstable, bendable)
Crystal Engineering
Salt(stable, bendable)
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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