Optimal Form Screening and Selection by Controlled ...
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Bringing to you the webinar on... Optimal Form Screening and Selection by Controlled Crystallization Carmen Guguta, PhD Technobis Crystallization Systems Edwin Aret, PhD Symeres
Transcript of Optimal Form Screening and Selection by Controlled ...
Bringing to you the webinar on...
Optimal Form Screening and Selection by Controlled Crystallization
Carmen Guguta, PhDTechnobis Crystallization Systems
Edwin Aret, PhDSymeres
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Discovery Screening Optimization
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Evaporation set upDiscover• Early-stage crystallization screening • Single crystal growth
Products
Screen• Solubility, MSZW• Phase diagrams• Solvent screening• Polymorphs, Salt and Co-crystals
screening
Optimize• Form control• Habit control• Particle size• Process optimization• Formulation
Vapour diffusion crystallization
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Your Speaker
Edwin Aret holds a PhD in solid state chemistry from Radboud UniversityNijmegen, the Netherlands. He has nearly 25 years of crystallizationexperience, supporting every facet of the pharmaceutical development cycle,from discovery to commercialization. Edwin’s in-depth expertise includes high-throughput screening crystallization, form selection, stability studies, solubilitydetermination and crystal habit optimization. Edwin is currently the principalscientist for solid state chemistry at MercachemSyncon, where he leads a teamof eight solid state chemists.
Dr Edwin Aret
Solid State Chemistry
optimal form screening en selection by controlled crystallization
Solid State Chemistry
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Solid
State
crystal habit
pre-
formulation
process R&D
support
solid form
screening
physchem
properties
crystallization
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• Salt Selection
• Polymorph Study
• Crystal Habit
• Solubility pH / simulated fluids
• Process Development
• IP-screens on Salts, Co-crystals and Polymorphs
• GMP Process: Crystallization, Isolation, Drying, Purity, Yield
• Crystallization
• PhysChem Properties
• Risk Assessment ‘Drugable’ API
• Solubility
• Stability
Pre-clinical Phase 1 / 2Discovery
Characterization OptimizationForm Selection
1 week 1 month 6 months
Solid State Chemistry
PHYSCHEM PROPERTIESbalance
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Class 1: High solubility, high permeabilityMarketed 35% - candidates 5-10%
Class 2: Low solubility, high permeabilityMarketed 30% - candidates 60-70%
Class 3: High solubility, low permeabilityMarketed 25% - candidates 5-10%
Class 4: Low solubility, low permeabilityMarketed 10% - candidates 10-20%
Biopharmaceutical classification system
physchem properties
physchem properties
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Stability
PermeabilitySolubility
Development Strategy
Risk Assessment
Target Product Profile
Balance Properties
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Brick dust
High doses
Toxic
Permeability
Aqueous solubility
– Polymorph, hydrate, particle size
– Salt, co-crystal
Permeability
– Pro-drug
– Complexation, carrier
Stability
– Crystallinity
– Hygroscopicity
Stability
Solubility
physchem properties
CRYSTALLIZATIONcontrol – control – control
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what is crystallization?
Self-assembly of molecules to form a highly organized crystal lattice
Separation technique – isolation of solids
Purification method for a compound
Improve properties – amorphous vs crystalline, polymorphism
IP protection of the molecule
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amorphous vs crystalline
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crystallization
NucleationSupersaturation (driving force):
σ ~ 𝛥𝜇
kT=
(c−ceq)
ceq
Control of concentration
Crystal growthBinding energy ϕ
Selection of solventFlux J
Control of mixing
IsolationFiltration and drying
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crystallization
NucleationSupersaturation (driving force):
σ ~ 𝛥𝜇
kT=
(c−ceq)
ceq
Control of concentration
Crystal growthBinding energy ϕ
Selection of solventFlux J
Control of mixing
IsolationFiltration and drying
Kinetically accessibleForm long enough stable to identify
Thermodynamically most stableSingle form all others will convert into
Pharmaceutically acceptableAnhydrate, hydrateSelection of counter ions or co-formers
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SOLID FORM SCREENINGnever enough
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discovery phase
When the first milligrams are isolatedmove from chromatography to crystallization
Thermocycle in 16 common process solventsavoid isolation by complete evaporationavoid freeze drying or spray drying
Solvent selection on class or active groupICH class is not leading
Aim for single crystal growthmolecule confirmationpatent
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crystallization methods
Research:Mild conditions
Close to equilibrium
Production:Severe conditionsNon-equilibrium
Months Days Hours Minutes Seconds
Cooling crystallization
Evaporative crystallization
Anti-solvent additionAnti-solvent vapour diffusion
Reactive crystallization
Precipitation
Melt crystallization Quenching
Crash cooling
Grinding
Thermal transformation
Slurrying
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crystallization methods
Discovery: whatever method works. Pre-clinical: only use scalable methods
Months Days Hours Minutes Seconds
Cooling crystallization
Anti-solvent addition
Reactive crystallization
Slurrying
Precipitation
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Co
nce
ntr
atio
n
Temperature
nucleation curve is variable,determined by crystallization conditions
solubility curve is fixed
Cooling
Temperature dependent solubility in process solvent
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crystallization methods
crystallization equipment
Technobis CrystalBreeder / Crystal16 / CrystallineParallel reactor systems Stirring, heating-cooling, turbidity, video, RamanScale-up steps ~ 5 times the volume
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pre-clinical phase
When a suitable process is knownsufficient material of good quality
Scalable methodscooling crystallization, anti-solvent addition
Solvent selection on maximized diversity, PCA basedpharmaceutical acceptability is leading
Find kinetically accessible polymorphs
Determine thermodynamically most stable form
Focus on a robust, reproducible crystallization with highest purity and yield
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polymorph
Same molecule(s)
Different crystal structure
Properties differActivitySpectroscopicThermodynamicSolubilityStabilityMorphology
PatentableNew polymorph is a novel substance
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solid form screening
Use high-throughput screening for broad overviewAvoid manual repetitive handling like dilution and sample transfer
Use single experiments for detailed crystallization behaviorMimic reactor conditions with continuous analytics
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solvent selection
20 classes of solvents based on structure
8 maximal different solvents based on most important properties using Principle Component Analysis
PC#: polarity, polarizability, H-bondsselect solvents far from the centerpointpredict behaviour in the entire solvent spacebe able to select other, similar solvents
Highest diversity for overview screening
Most different solvents for IP screening
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PC2
PC1
screening - analytics
HT-screen requires HT-analytics
Characterization all solids: XRPDkapton crystallization well-plateunique Bruker D8 Discover high-resolution high-throughput XRPDfour 96 well-plates auto-sampleranalyze full screen within 24 hoursimage of each well
Analyze all solutions: UPLCautomated dilutions from screensolubility at two temperaturespurity / solution stability
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Q: which polymorph to select?
Most occurring is not necessarily the most stable
Design of the study determines outcome – solvents, starting material, conditions
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↓WellsXRPD pattern
100% solvent
80% solvent 60% solvent 40% solvent 20% solvent 5% solvent
A1-A6 Form 2 No solids No solids No solids No solids No solids
B1-B6 Form 4 Form 1 Form 1 No solids Form 1 No solids
C1-C6 Form 3 No solids Form 1 Form 1 No solids No solids
D1-D6 Form 2 Form 1 Form 1 Form 1 Form 1 No solids
E1-E6 Form 1 Form 1 Form 1 Form 2 Form 2 Form 2
F1-F6 Form 1 Form 1 Form 2 Form 2 Form 2 Form 1
G1-G6 Glass like Glass like Glass like Glass like Form 2 Mix 1 + 2
H1-H6 No solids Form 2 Form 2 Form 2 Mix 1 + 2 Form 1
A7-A12 No solids No solids No solids No solids No solids Form 2
B7-B12 No solids No solids No solids No solids No solids No solids
C7-C12 No solids No solids No solids Form 2 No solids No solids
D7-D12 No solids No solids No solids No solids No solids Form 2
E7-E12 Form 2 Form 1 Amorphous Amorphous Amorphous Amorphous
F7-F12 No solids Form 1 Amorphous Amorphous Amorphous Amorphous
G7-G12 Form 2 Form 2 Form 2 Form 2 Form 1 Glass like
H7-H12 No solids No solids No solids No solids No solids No solids
crystallization – polymorph study
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96-well Master Plate
Hot filtration
Anti-solventSlurry plate LC plate
Analytics
EvaporationCooling
16 solvents
4 co-solvents
2 anti-solvents
crystallization – polymorph study
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96-well Master Plate
Hot filtration
Anti-solventSlurry plate LC plate
Analytics
EvaporationCooling
16 solvents
4 co-solvents
2 anti-solvents
Different concentrations
Different temperatures
next steps
Characterize materials from well-plateTGA (solvate?)DSC (thermal events?)
Reproduce experiment at 200 mg scaleFull characterizationMutual stability → solubility curvesInterconversion conditions
Reproduce selected form at gram scaleProducibilityCrystal habit
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0
200
400
600
800
1000
1200
0 10 20 30 40 50 60 70 80
Co
nce
ntr
atio
n (
mg/
mL)
Temperature (C)
Transition temperature (Tt)
Form 1
Form 2
form ranking
Stability40C/75%RH
Competitive slurrydifferent solvents and temperatures
Melting pointtemperature and energy
Ranking criteriaProducible, scalable method and suitable solvent.XRPD crystallinity, unique form with low amorphous content.DSC melting, single sharp event. TGA mass loss, anhydrous form. DVS hygroscopicity, reversible and reproducible, without form change. Microscopy, homogeneous well-defined crystal habit.
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Form 3
Form 4
Heat > 75C / time
heat > 80C
Form 1SM
Form 2
hydrate
Slurry > 75C
Slurry < 50C
Wet slurryDrying / heat >100C
1,3-dioxolane
amorphous
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acetonitrile
form conversion conditions
Q: selection of The best form?
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Crystallization (form 1):[best form Solid State]
Q: selection of The best form?
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Crystallization (form 1):[best form Solid State]
Optimized process (form A):[best form R&D chemist]
Q: selection of The best form?
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Crystallization (form 1):[best form Solid State]
Optimized process (form A):[best form R&D chemist]
Formulated product (solvate):[result formulation]
Q: why MSZW data?
Good solubility curve, poor nucleation controlOther solvent? Cooling rate?Anti-solvent?Seeding range?Low temperature?
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form screening and selection
Drug substance development is continuous troubleshooting and risk
management. A broad overview of the crystallization behavior
gives understanding and avoids undesired changes.
Have all data, decisions and conclusions accessible and searchable
for the project team, not only the report with successful results.
Use of automation leads to smart experiments for the overview to select
optimal conditions. Screen more different factors, apply high diversity
in methods, solvent mixtures, concentrations and starting materials.
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Discover• Early-stage crystallization screening • Single crystal growth
Screen• Solubility, MSZW• Phase diagrams• Solvent screening• Polymorphs, Salt and Co-crystals
screening
Optimize• Form control• Habit control• Particle size• Process optimization• Formulation
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