What are we actually measuring the solubility of?physchem.org.uk/Symp05/3_jonathan_burley.pdf ·...
Transcript of What are we actually measuring the solubility of?physchem.org.uk/Symp05/3_jonathan_burley.pdf ·...
IntroductionReal-world examples
Conclusions
What are we actually measuring thesolubility of?
Dr Jonathan [email protected]://research.jonathanburley.com
School of PharmacyNottingham University
Thursday 19th June 2008
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Solubility: Compound A in solvent s
A A A A A A A A A A A
A A A A A A A A A A A
A A A A A A A A A A A
A A A A A A A A A A A
A A A A A A A A A A A
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Solubility: Compound A in solvent s
A A A A A A A A A A A
A A A A A A A A A A A
A A A A A A A A A A A
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Solubility: Compound A in solvent s
A A A A A A A A A A A
A A A A A A A A A A A
A A A A A A A A A A A
A A A A A A A A A A A
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AAAAAAAAAAAA A A A A A A A A A A
A A A A A A A A A A AAAAAAAAAAAA
A A A A A A A A A A A
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Solubility: Compound A in solvent s
A A A A A A A A A A A
A A A A A A A A A A A
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AAAAAAAAAAAA A A A A A A A A A A
A A A A A A A A A A AAAAAAAAAAAA
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A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Solubility: Compound A in solvent s
A A A A A A A A A A A
A A A A A A A A A A A
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A A A A A A A A A A A
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
AsAsAsAsAsAsAs
AsAsAsAsAsAsAs
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Polymorphism: definition
Materials made from same molecules, which have differentcrystal structures
Equivalent of
Materials made from same building blocks but with differentarrangements of building blocks
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Example
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Example
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Analytical methods
IR & RamanCalorimetry (TGA & DSC)Solid-state NMRSingle crystal X-ray diffractionPowder diffraction
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Information in XRPD pattern
Overall pattern
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Information in XRPD pattern
Peak positions→ unit cell parameters
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Information in XRPD pattern
Peak intensities→ atomic positions
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
XRPD analysis approaches
Simple comparison:Visually compare pattern with database
PDF4, CSD, in-house
More rigorous approaches:Automated comparison
Principal component analysis, dendrogramsFull-pattern approaches
Rietveld, LeBail, Pawley etc
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Diclofenac: structure
NSAID: uses include arthritis and acute injurySingle solubility for neutral form: 1.0 ± 0.1 µg. ml−1
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Diclofenac: solubility
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Diclofenac: chasing equilibrium
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Diclofenac: chasing equilibrium
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Diclofenac: neutral form XRPD
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
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DiclofenacSulindacSparfloxacin
Diclofenac: neutral form XRPD, plus database hit
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sulindac: structure
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NSAID (prodrug) used to treat acute or chronic inflammationAfter 20 minutes, solubility changes: 70 µg.ml−1 → 10 µg.ml−1
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sulindac: commercial form XRPD
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sulindac: commercial form XRPD + database hit
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sulindac: precipitate XRPD
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sulindac precipitate: Rietveld
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sulindac: structures
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sulindac: structures
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: structure
Antibiotic, single stable value for intrinsic solubility: 167 ± 14µg.ml−1
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: commercial
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: commercial + calculated anhydrous
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: precipitate
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: precipitate, calculated anhydrous
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: precipitate, calculated trihydrate
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: precipitate, calculated trihydrate
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: hydrate crystal structure
Form II
Single crystal microdiffraction, Station 9.8, Daresbury SRS
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: hydrate crystal structure
Form I
Form II
Single crystal microdiffraction, Station 9.8, Daresbury SRS
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: precipitate, two trihydrates
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparfloxacin
Sparfloxacin: hydrate polymorphism
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
Various behaviours
We have observed:Single solubility value due to single precipitateTwo solubility values due to polymorphism of precipitateSingle solubility value due to polymorphic hydrate!
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
Solubility: Diclofenac
A A A A A A A A A A A
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
Solubility: Sulindac
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
Solubility: Sulindac
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AsAsAsAsAsAsAs
AsAsAsAsAsAsAs
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
So, what are we measuring the solubility of?
We don’t know until we look!
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
People involved with the work presented
CambridgeToni LlinasJonathan GoodmanRobert Glen
Sirius AnalyticalKarl Box
Daresbury Labs SRSTimothy Prior
Dr Jonathan Burley What are we measuring?