Systematic Study into Salt Formation of Functionalised Organic Substrates

1
Systematic Study into Salt Formation of
Functionalised Organic Substrates

• Suzanna Ward

Supervisor Professor Mike Hursthouse
University of Southampton
2
Overall Aim

• The investigation into salts has two main
  constituents
• Firstly the fundamental study into salt formation
• Coupled with more specific work on
  crystallisation
• The aim is to accumulate as much data as possible
  to provide an insight into the formation of salts
  and form part of rigorous study into the
  formation of crystal structures

3
Pharmaceutical Salts

• Why are salts important?
• The physiochemical and resultant biological
  characteristics of a drug can be modified without
  altering the chemical structure by conversion to
  a new salt form
• Each salt imparts unique properties to the parent
  compound
• Selection of appropriate salt can significantly
  reduce time to market

4
The Idea

• Take a variety of pharmaceutical type substrates
  and explore salt formation using classical
  approaches
• Investigate all the possible variables
• Identify to what extent the choice of salt is
  governed by the acidity/basicity of the ionisable
  group
• Does the rule of three in terms of pKa values
  hold true?
• Generate a salt map

5
Software

• HyperChem
• Spartan
• Maestro Jaguar
• DRAGON

Electropositive
Electronegative
6
Investigating the CSD1

• Succinic acid
• - pKa 4.2
• - 2 polymorphic forms
• - 5 organic salts
• - 8 co-crystals

2 polymorphs
5 organic salts
8 co-crystals
A chart to show the pKa of the bases involved
1. F. H. Allen, Acta Crystallogr., B58, 380-388,
2002
7
The Process

• Explore chemical space
• Analyse pKa values
• Set up an array of acids, bases and solvents
  using a LHS
• Vary the conditions
• Analyse the products and interpret data
• X-ray diffraction
• Predict which acids/bases will readily form salts

8
A Family of Salts and Co-Crystals
9
Experimental Results

• Example - 1-phenylcyclopentanecarboxylic acid
• 1 structure in CSD - 0 organic salts/co-crystals

Base pKa Product Product
2-amino-4-methylpyridine 7.38 Salt
2-amino-5-nitropyridine 2.82 Parent
2-aminopyridine 6.67 Salt
2,2-bipyridine 4.40 Parent
2,4-diamino-6-hydroxypyrimidine 3.96 Parent
3,5-dichloropyridine 0.66 Parent
2-aminopyrimidine 3.86 Co-crystal
4-aminopyridine 9.25 Salt hydrate
4-dimethylaminopyridine 9.52 Salt hydrate
Results from nine bases with 1-phenylcyclopropanec
arboxylic acid
10
2-Amino-4-methylpyridine
Acid centroid Base centroid Acid in chain 1 Base
in chain 1 Acid in chain 2 Base in chain 2

• 11 Salt
• The pKa difference 2.99
• 2 infinite one-dimensional hydrogen bonded
  chains
• 0 1 0
• Acid forms 3 hydrogen bonds

11
Other Techniques Used

• Optical microscopy
• Powder X-ray diffraction
• Thermal Analysis
• - DSC and TGA
• ReactArray

12
Acknowledgements

• Prof. Mike Hursthouse
• Crystallography group at Southampton
• Prof. Sue Lewis and Dr. Woods from the statistics
  department
• AstraZeneca Sweden for Sponsorship
• E-Science for their funding