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Systematic Study into Salt Formation of Functionalised Organic Substrates

Systematic Study into Salt Formation of Functionalised Organic Substrates. Suzanna Ward. Supervisor Professor Mike Hursthouse. University of Southampton. Overall Aim. The investigation into salts has two main constituents Firstly the fundamental study into salt formation

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Systematic Study into Salt Formation of Functionalised Organic Substrates

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  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. A A- B+ B H + H 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 CSD[1] Succinic acid - pKa = 4.2 - 2 polymorphic forms - 5 organic salts - 8 co-crystals 8 co-crystals 2 polymorphs 5 organic salts 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 Results from nine bases with 1-phenylcyclopropanecarboxylic 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 • 1:1 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

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