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 A H B A-A- B+B+ H+

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 pK a values hold true? Generate a salt map

5. Software Electropositive Electronegative HyperChem Spartan Maestro – Jaguar DRAGON

6. Investigating the CSD [1] Succinic acid - pK a = 4.2 - 2 polymorphic forms - 5 organic salts - 8 co-crystals 2 polymorphs5 organic salts 8 co-crystals A chart to show the pK a of the bases involved 1. F. H. Allen, Acta Crystallogr., B58, 380-388, 2002

7. The Process Explore chemical space Analyse pK a 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 BasepKapKa Product 2-amino-4-methylpyridine7.38Salt 2-amino-5-nitropyridine2.82Parent 2-aminopyridine6.67Salt 2,2-bipyridine4.40Parent 2,4-diamino-6-hydroxypyrimidine3.96Parent 3,5-dichloropyridine0.66Parent 2-aminopyrimidine3.86Co-crystal 4-aminopyridine9.25Salt hydrate 4-dimethylaminopyridine9.52Salt hydrate Results from nine bases with 1-phenylcyclopropanecarboxylic acid

10. 2-Amino-4-methylpyridine 1:1 Salt The pK a difference = 2.99 2 infinite one-dimensional hydrogen bonded chains -[ 0 1 0] -Acid forms 3 hydrogen bonds Acid centroid Base centroid Acid in chain 1 Base in chain 1 Acid in chain 2 Base in chain 2

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