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?


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







Conclusions








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

s

s sss

s

s

s

s

s

ss

s

ss

s s

s

ss

s

s

s

s

s

s

s

ss

s

s



Conclusions








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

s

s sss

s

s

s

s

s

ss

s

ss

s s

s

ss

s

s

s

s

s

s

s

ss

s

s

AAAAAAAAAAAA A A A A A A A A A A

A A A A A A A A A A AAAAAAAAAAAA




Conclusions








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

s

s sss

s

s

s

s

s

ss

s

ss

s s

s

ss

s

s

s

s

s

s

s

ss

s

s




A sA sA sA sA sA sA s







Conclusions








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

s

s sss

s

s

s

s

s

ss

s

ss

s s

s

ss

s

s

s

s

s

s

s

ss

s

s












AsAsAsAsAsAsAs

AsAsAsAsAsAsAs



Conclusions


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



Conclusions


Example



Conclusions


Analytical methods

IR & RamanCalorimetry (TGA & DSC)Solid-state NMRSingle crystal X-ray diffractionPowder diffraction



Conclusions


Information in XRPD pattern

Overall pattern

10 20 30 40 502θ /

o

0

2000

4000

6000

8000C

ount

s



Conclusions



Peak positions→ unit cell parameters

10 20 30 40 502θ /

o

0

2000

4000

6000

8000C

ount

s



Conclusions



Peak intensities→ atomic positions

10 20 30 40 502θ /

o

0

2000

4000

6000

8000C

ount

s



Conclusions


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



Conclusions

DiclofenacSulindacSparfloxacin

Diclofenac: structure

NSAID: uses include arthritis and acute injurySingle solubility for neutral form: 1.0 ± 0.1 µg. ml−1



Conclusions


Diclofenac: solubility



Conclusions


Diclofenac: chasing equilibrium



Conclusions


Diclofenac: neutral form XRPD

20 402θ /

o

0

500

1000

1500

2000

2500C

ount

s



Conclusions


Diclofenac: neutral form XRPD, plus database hit

20 402θ /

o

0

500

1000

1500

2000

2500C

ount

s



Conclusions


Sulindac: structure

S

O

F

O

HO

NSAID (prodrug) used to treat acute or chronic inflammationAfter 20 minutes, solubility changes: 70 µg.ml−1 → 10 µg.ml−1



Conclusions


Sulindac: commercial form XRPD

10 20 30 40 502θ /

o

0

1000

2000

3000C

ount

s



Conclusions


Sulindac: commercial form XRPD + database hit

10 20 30 40 502θ /

o

0

1000

2000

3000C

ount

s



Conclusions


Sulindac: precipitate XRPD

10 20 30 40 502θ /

o

0

1000

2000

3000C

ount

s



Conclusions


Sulindac precipitate: Rietveld

| | | | || | ||| || ||| ||| ||| | | ||||| | |||| ||||||||| |||||||||||| || |||||| || | || |||||||||||||||| |||||||||||| ||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

10 20 30 40 50 60 702θ / ο

-2000

0

2000

4000

6000

8000

10000C

ount

s

ObservedCalculatedAllowed Reflections|

Difference



Conclusions


Sulindac: structures



Conclusions


Sparfloxacin: structure

Antibiotic, single stable value for intrinsic solubility: 167 ± 14µg.ml−1



Conclusions


Sparfloxacin: commercial

10 20 30 40 502θ /

o

0

2000

4000

6000

Cou

nts



Conclusions


Sparfloxacin: commercial + calculated anhydrous

10 20 30 40 502θ /

o

0

2000

4000

6000

Cou

nts



Conclusions


Sparfloxacin: precipitate

0 10 20 30 40 50 602θ /

o

0

2000

4000

6000

8000

Cou

nts



Conclusions


Sparfloxacin: precipitate, calculated anhydrous

0 10 20 30 40 50 602θ /

o

0

2000

4000

6000

8000

Cou

nts



Conclusions


Sparfloxacin: precipitate, calculated trihydrate

0 10 20 30 40 50 602θ /

o

0

2000

4000

6000

8000

Cou

nts



Conclusions


Sparfloxacin: precipitate, calculated trihydrate

0 10 20 30 40 50 602θ /

o

0

2000

4000

6000

8000

Cou

nts

*

*

*

*

*



Conclusions


Sparfloxacin: hydrate crystal structure

Form II

Single crystal microdiffraction, Station 9.8, Daresbury SRS



Conclusions


Sparfloxacin: hydrate crystal structure

Form I

Form II

Single crystal microdiffraction, Station 9.8, Daresbury SRS



Conclusions


Sparfloxacin: precipitate, two trihydrates

| | | | | | | || || || | | | | | ||| | || |||| | || | ||| || ||||| | | || |||||||| | ||||| || ||| ||| |||| | |||||| ||||| ||||||||| ||||||| |||| |||||||||| |||||||||||||| |||| ||||| ||||||||| ||||||| ||||||||||||||||||| |||||| ||||||||||||||||||| |||||||||||||||| ||||| | || || || | || || ||| |||||| ||||| | ||| |||||||||| | |||| ||| |||||| || |||||| |||||| ||| ||||| ||||||||| ||||||||||||||||||||||| |||||||||| ||||||||||||||||||||||||||||||||| || |||||||||| |||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

10 20 30 40 50 602θ / ο

-2000

0

2000

4000

6000

8000

Cou

nts

ObservedCalculatedPhase 1|

Phase 2|

Difference



Conclusions


Sparfloxacin: hydrate polymorphism



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!



Conclusions

SummaryThanks

Solubility: Diclofenac






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

s

s sss

s

s

s

s

s

ss

s

ss

s s

s

ss

s

s

s

s

s

s

s

ss

s

s












AsAsAsAsAsAsAs

AsAsAsAsAsAsAs



Conclusions

SummaryThanks

Solubility: Sulindac






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

s

s sss

s

s

s

s

s

ss

s

ss

s s

s

ss

s

s

s

s

s

s

s

ss

s

s












AsAsAsAsAsAsAs

AsAsAsAsAsAsAs



Conclusions

SummaryThanks

So, what are we measuring the solubility of?

We don’t know until we look!



Conclusions

SummaryThanks

People involved with the work presented

CambridgeToni LlinasJonathan GoodmanRobert Glen

Sirius AnalyticalKarl Box

Daresbury Labs SRSTimothy Prior


What are we actually measuring the solubility of?physchem.org.uk/Symp05/3_jonathan_burley.pdf ·...

Documents

Transcript of What are we actually measuring the solubility of?physchem.org.uk/Symp05/3_jonathan_burley.pdf ·...