Introduction

Real-world examples
Conclusions

What are we actually measuring the

solubility of?

Dr Jonathan Burley
jonathan.burley@nottingham.ac.uk
http://research.jonathanburley.com
School of Pharmacy
Nottingham University

Thursday 19th June 2008

Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Solubility: Compound A in solvent s

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Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Solubility: Compound A in solvent s

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Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Solubility: Compound A in solvent s

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Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Solubility: Compound A in solvent s

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ss s s A
A
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Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Solubility: Compound A in solvent s

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ss s s A
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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?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Polymorphism: definition

Materials made from same molecules, which have different

crystal structures

Equivalent of

Materials made from same building blocks but with different

arrangements of building blocks

Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Example

Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Example

Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Analytical methods

IR & Raman
Calorimetry (TGA & DSC)
Solid-state NMR
Single crystal X-ray diffraction
Powder diffraction

Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Information in XRPD pattern

Overall pattern
8000

6000
Counts

4000

2000

0
10 20 30 40 50
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Information in XRPD pattern

Peak positions → unit cell parameters

8000

6000
Counts

4000

2000

0
10 20 30 40 50
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

Information in XRPD pattern

Peak intensities → atomic positions

8000

6000
Counts

4000

2000

0
10 20 30 40 50
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction What do we mean by solubility?
Real-world examples Polymorphism
Conclusions Understanding solid forms?

XRPD analysis approaches

Simple comparison:
Visually compare pattern with database
PDF4, CSD, in-house
More rigorous approaches:
Automated comparison
Principal component analysis, dendrograms
Full-pattern approaches
Rietveld, LeBail, Pawley etc

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Diclofenac: structure

NSAID: uses include arthritis and acute injury

Single solubility for neutral form: 1.0 ± 0.1 µg. ml−1

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Diclofenac: solubility

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Diclofenac: chasing equilibrium

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Diclofenac: chasing equilibrium

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Diclofenac: neutral form XRPD

2500

2000

1500
Counts

1000

500

0
20 40
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Diclofenac: neutral form XRPD, plus database hit

2500

2000

1500
Counts

1000

500

0
20 40
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sulindac: structure

HO
S

NSAID (prodrug) used to treat acute or chronic inflammation

After 20 minutes, solubility changes: 70 µg.ml−1 → 10 µg.ml−1

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sulindac: commercial form XRPD

3000

2000
Counts

1000

0
10 20 30 40 50
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sulindac: commercial form XRPD + database hit

3000

2000
Counts

1000

0
10 20 30 40 50
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sulindac: precipitate XRPD

3000

2000
Counts

1000

0
10 20 30 40 50
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sulindac precipitate: Rietveld

10000
Observed
Calculated
| Allowed Reflections
8000 Difference

6000
Counts

4000

2000

0 | | | | || | ||| | ||| || || | ||||| | ||| ||||||| ||||| |||| || ||||||| | | || | ||| ||||||||||| || ||||| |||||||||||| | |||||||||| ||||||||||||||| ||||||| || | |||||||||| |||| |||| |||||||||||| ||| |||||||||| |||||||||||||||||||| ||||||||||| |||||||||||||||||||||||||||||||||||

-2000
10 20 30 40 50 60 70
ο
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sulindac: structures

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sulindac: structures

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: structure

Antibiotic, single stable value for intrinsic solubility: 167 ± 14

µg.ml−1

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: commercial

6000
Counts

4000

2000

0
10 20 30 40 50
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: commercial + calculated anhydrous

6000
Counts

4000

2000

0
10 20 30 40 50
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: precipitate

8000

6000
Counts

4000

2000

0
0 10 20 30 40 50 60
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: precipitate, calculated anhydrous

8000

6000
Counts

4000

2000

0
0 10 20 30 40 50 60
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: precipitate, calculated trihydrate

8000

6000
Counts

4000

2000

0
0 10 20 30 40 50 60
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: precipitate, calculated trihydrate

8000

6000
Counts

*
4000
*
*
2000
*
*

0
0 10 20 30 40 50 60
o
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: hydrate crystal structure

Form II

Single crystal microdiffraction, Station 9.8, Daresbury SRS

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: hydrate crystal structure

Form I

Form II

Single crystal microdiffraction, Station 9.8, Daresbury SRS

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: precipitate, two trihydrates

Observed
8000 Calculated
| Phase 1
| Phase 2
Difference
6000
Counts

4000

2000

0 | || | | | | | | | | | || | ||| | | || | || | || || ||||| | | | |||||| | ||| | ||| || ||| | ||| |||| |||||||| ||| ||| | | ||||||||| |||||| ||| ||||| ||| |||| |||||| |||| ||||||| | || | || | |||| |||| |||||| ||
| | || || || || || | ||||| | ||| | ||| |||||| || ||||| ||| |||| || ||| ||||| | |||| ||||| || | || ||| | ||||||| ||||| | ||||||||||| ||||| || ||||||| |||||| |||||||| | ||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||| ||||||||||| |||

-2000
10 20 30 40 50 60
ο
2θ /

Dr Jonathan Burley What are we measuring?

 Introduction Diclofenac
Real-world examples Sulindac
Conclusions Sparfloxacin

Sparfloxacin: hydrate polymorphism

Dr Jonathan Burley What are we measuring?

 Introduction
Summary
Real-world examples
Thanks
Conclusions

Various behaviours

We have observed:
Single solubility value due to single precipitate
Two solubility values due to polymorphism of precipitate
Single solubility value due to polymorphic hydrate!

Dr Jonathan Burley What are we measuring?

 Introduction
Summary
Real-world examples
Thanks
Conclusions

Solubility: Diclofenac

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Dr Jonathan Burley What are we measuring?

 Introduction
Summary
Real-world examples
Thanks
Conclusions

Solubility: Sulindac

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Dr Jonathan Burley What are we measuring?

 Introduction
Summary
Real-world examples
Thanks
Conclusions

Solubility: Sulindac

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ss s s A
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A sA sA sA sA sA sA s
A sA sA sA sA sA sA s
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A sA sA sA sA sA sA s
A sA sA sA sA sA sA s

Dr Jonathan Burley What are we measuring?

 Introduction
Summary
Real-world examples
Thanks
Conclusions

So, what are we measuring the solubility of?

We don’t know until we look!

Dr Jonathan Burley What are we measuring?

 Introduction
Summary
Real-world examples
Thanks
Conclusions

People involved with the work presented

Cambridge
Toni Llinàs
Jonathan Goodman
Robert Glen
Sirius Analytical
Karl Box
Daresbury Labs SRS
Timothy Prior

Dr Jonathan Burley What are we measuring?