3 jonathan burley
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IntroductionReal-world examples
Conclusions
What are we actually measuring thesolubility of?
Dr Jonathan [email protected]
http://research.jonathanburley.com
School of Pharmacy
Nottingham University
Thursday 19 th June 2008
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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 AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A A
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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 AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A A
A
A
A
A
A A
A
A AA
A
A
A A
A A A
A
A
A A
A A
A
A A
A A
s
s s
s s
s ss
s
ss s
s s
s s s
s
s s
s s s s
s
s s
s
s s
s
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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 AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A A
A
A
A
A
A A
A
A AA
A
A
A A
A A A
A
A
A A
A A
A
A A
A A
s
s s
s s
s ss
s
ss s
s s
s s s
s
s s
s s s s
s
s s
s
s s
s
A A A A A A A A A A AA 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?
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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 AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A A
A
A
A
A
A A
A
A AA
A
A
A A
A A A
A
A
A A
A A
A
A A
A A
s
s s
s s
s ss
s
ss s
s s
s s s
s
s s
s s s s
s
s s
s
s s
s
A A A A A A A A A A AA 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 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 s
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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 AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A A
A
A
A
A
A A
A
A AA
A
A
A A
A A A
A
A
A A
A A
A
A A
A A
s
s s
s s
s ss
s
ss s
s s
s s s
s
s s
s s s s
s
s s
s
s s
s
A A A A A A A A A A AA 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 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 s
A sA sA sA sA sA s A s
A sA sA sA sA sA s A s
A sA sA sA sA sA s A s
A s A s A s A s A s A s A s
A s A s A s A s A s A s A s
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IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Polymorphism: denition
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?
I d i Wh d b l bili ?
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IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Example
Dr Jonathan Burley What are we measuring?
Introd ction What do e mean b sol bilit ?
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IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Example
Dr Jonathan Burley What are we measuring?
Introduction What do we mean by solubility?
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IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Analytical methods
IR & Raman
Calorimetry (TGA & DSC)Solid-state NMRSingle crystal X-ray diffractionPowder diffraction
Dr Jonathan Burley What are we measuring?
Introduction What do we mean by solubility?
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IntroductionReal-world examples
Conclusions
What do we mean by solubility?PolymorphismUnderstanding solid forms?
Information in XRPD pattern
Overall pattern
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C o u n t s
Dr Jonathan Burley What are we measuring?
Introduction What do we mean by solubility?
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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?
Introduction What do we mean by solubility?
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Real-world examplesConclusions
y yPolymorphismUnderstanding solid forms?
Information in XRPD pattern
Peak intensities atomic positions
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C o u n t s
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Introduction Diclofenac
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Real-world examplesConclusions
SulindacSparoxacin
Diclofenac: structure
NSAID: uses include arthritis and acute injurySingle solubility for neutral form: 1.0 0.1 g. ml 1
Dr Jonathan Burley What are we measuring?
Introduction Diclofenac
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Real-world examplesConclusions
SulindacSparoxacin
Diclofenac: solubility
Dr Jonathan Burley What are we measuring?
Introduction Diclofenac
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Real-world examplesConclusions
SulindacSparoxacin
Diclofenac: chasing equilibrium
Dr Jonathan Burley What are we measuring?
Introduction Diclofenac
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Real-world examplesConclusions
SulindacSparoxacin
Diclofenac: chasing equilibrium
Dr Jonathan Burley What are we measuring?
IntroductionR l ld l
DiclofenacS li d
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Real-world examplesConclusions
SulindacSparoxacin
Diclofenac: neutral form XRPD
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C o u n t s
Dr Jonathan Burley What are we measuring?
IntroductionR l ld l
DiclofenacS li d
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Real-world examplesConclusions
SulindacSparoxacin
Diclofenac: neutral form XRPD, plus database hit
20 40
2 / o
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C o u n t s
Dr Jonathan Burley What are we measuring?
IntroductionReal world examples
DiclofenacSulindac
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Real-world examplesConclusions
SulindacSparoxacin
Sulindac: structure
S
O
F
O
HO
NSAID (prodrug) used to treat acute or chronic inammationAfter 20 minutes, solubility changes: 70 g.ml 1 10 g.ml 1
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
DiclofenacSulindac
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Real-world examplesConclusions
SulindacSparoxacin
Sulindac: commercial form XRPD
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C o u n t s
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
DiclofenacSulindac
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Real world examplesConclusions
SulindacSparoxacin
Sulindac: commercial form XRPD + database hit
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C o u n t s
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
DiclofenacSulindac
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Real world examplesConclusions
SulindacSparoxacin
Sulindac: precipitate XRPD
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C o u n t s
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
DiclofenacSulindac
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pConclusions Sparoxacin
Sulindac precipitate: Rietveld
| | | | || | ||| | | ||| ||| ||| | |||||| | ||||| |||| |||| |||||||||||| || |||||| || | || ||||| ||||| |||||| ||| ||||||||| |||||||| ||||| |||| |||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||| || ||||||||||||| ||||||||||||||||||||||||||||||||||| |||||||||||||||| |||||||||||||||||||||||| |||||||||||||| |||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||| || ||||||||| ||||||||||||||||| ||||||||||| ||||||||| |||||| ||||| |||||||| ||||||||| ||||||| ||||||||||||||||||||||||| ||||||||||||||| ||||||
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C o u n t s
ObservedCalculatedAllowed Reflections|Difference
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
DiclofenacSulindac
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Conclusions Sparoxacin
Sulindac: structures
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
DiclofenacSulindac
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Conclusions Sparoxacin
Sulindac: structures
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
DiclofenacSulindac
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Conclusions Sparoxacin
Sparoxacin: structure
Antibiotic, single stable value for intrinsic solubility: 167 14g.ml 1
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
DiclofenacSulindac
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Conclusions Sparoxacin
Sparoxacin: commercial
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C o u n t s
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
C l i
DiclofenacSulindacS i
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Conclusions Sparoxacin
Sparoxacin: commercial + calculated anhydrous
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C o u n t s
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
C l i
DiclofenacSulindacS i
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Conclusions Sparoxacin
Sparoxacin: precipitate
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Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparoxacin
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Conclusions Sparoxacin
Sparoxacin: precipitate, calculated anhydrous
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IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparoxacin
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Conclusions Sparoxacin
Sparoxacin: precipitate, calculated trihydrate
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C o u n t s
*
*
*
*
*
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparoxacin
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Conclusions Sparoxacin
Sparoxacin: hydrate crystal structure
Form II
Single crystal microdiffraction, Station 9.8, Daresbury SRS
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparoxacin
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p
Sparoxacin: 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
DiclofenacSulindacSparoxacin
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p
Sparoxacin: precipitate, two trihydrates
| | | | | | | || || || | | | | | ||| | || ||| | | || | ||| || ||||| | | || |||||||| | ||||| ||| || ||| |||| | |||||| ||||| ||||||||| |||||| | || || |||||||||| || ||||||||||||||||| ||| | ||| |||||| | |||||| ||||||||||||||||||| |||||| |||||||||| ||||||||| |||||||||| |||||| ||| |
| | || || ||| || || ||| |||||| ||||| | ||| |||||||||| ||||| ||| ||| ||| || |||||| |||||| || | ||||| ||| |||||| |||| ||||||||||||||||||| || |||||||| ||| ||||||| ||||||| |||||||||||| |||| || ||||||||| | |||||||||| |||||||||||||||||||| ||| ||||||||| |||||||||||||||||||||||||| ||||||| |||||| ||||| ||||||||||||| |||||||| ||||||||||||| |||||||||||||||||||||||||||| ||||| |||||||||||||||| ||||||||||||||| ||||||||| |||||||||
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ObservedCalculatedPhase 1|Phase 2|Difference
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
DiclofenacSulindacSparoxacin
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Sparoxacin: hydrate polymorphism
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
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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
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Solubility: Diclofenac
A A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A A
A
A
A
A
A A
A
A AA
A
A
A A
A A A
A
A
A A
A A
A
A A
A A
s
s s
s s
s ss
s
ss s
s s
s s s
s
s s
s s s s
s
s s
s
s s
s
A A A A A A A A A A AA 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 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 s
A sA sA sA sA sA s A s
A sA sA sA sA sA s A s
A sA sA sA sA sA s A s
A s A s A s A s A s A s A s
A s A s A s A s A s A s A s
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
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Solubility: Sulindac
A A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A A
A
A
A
A
A A
A
A AA
A
A
A A
A A A
A
A
A A
A A
A
A A
A A
s
s s
s s
s ss
s
ss s
s s
s s s
s
s s
s s s s
s
s s
s
s s
s
A A A A A A A A A A AA 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 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 s
A sA sA sA sA sA s A s
A sA sA sA sA sA s A s
A sA sA sA sA sA s A s
A s A s A s A s A s A s A s
A s A s A s A s A s A s A s
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
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Solubility: Sulindac
A A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A AA A A A A A A A A A A
A
A
A
A
A A
A
A AA
A
A
A A
A A A
A
A
A A
A A
A
A A
A A
s
s s
s s
s ss
s
ss s
s s
s s s
s
s s
s s s s
s
s s
s
s s
s
A A A A A A A A A A AA 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 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 s
A sA sA sA sA sA s A s
A sA sA sA sA sA s A s
A sA sA sA sA sA s A s
A s A s A s A s A s A s A s
A s A s A s A s A s A s A s
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examples
Conclusions
SummaryThanks
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So, what are we measuring the solubility of?
We dont know until we look!
Dr Jonathan Burley What are we measuring?
IntroductionReal-world examplesConclusions
SummaryThanks
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People involved with the work presented
CambridgeToni LlinasJonathan GoodmanRobert Glen
Sirius AnalyticalKarl Box
Daresbury Labs SRSTimothy Prior
Dr Jonathan Burley What are we measuring?
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