Systematic Study into Salt Formation of Functionalised Organic Substrates

Systematic Study into Salt

Formation of Functionalised Organic

Substrates

Suzanna Ward

Supervisor

Professor Mike Hursthouse

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

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

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?

Software

Electropositive

Electronegative

• HyperChem

• Spartan

• Maestro – Jaguar

Investigating the CSD

Succinic acid - p

K

- 2 polymorphic forms - 5 organic salts

- 8 co-crystals

2 polymorphs

5 organic salts

8 co-crystals

0 2

0 2 4 6 8 10 12

A chart to show the p

K

of the bases involved

The Process

 Explore chemical space

 Analyse p

K

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

A Family of Salts and Co-Crystals

2-aminopyridine 3-aminopyridine 2-aminopyrimidine

benzoic acid LUPZOL oil co-crystal 2:1 salt 1:1 chain trimer 4-aminobenzoic salt 1:1 oil co-crystal 1:1

acid sheet chain

4-aminosalicyclic salt 1:1 oil co-crystal 1:1

acid sheet sheet

4-acetamidobenzoic 4-aab 4-aab 4-aab

acid acid parent acid parent acid parent

2-bromobenzoic acid salt 1:1 2-bb acid co-crystal 1:2 tetramer parent tetramer & chain 3-bromobenzoic acid salt 1:1 salt 2:1 co-crystal 2:1

chain sheet trimer 2-fluorobenzoic acid salt 1:1 salt 1:1 co-crystal 1:1

chain sheet tetramer 4-fluorobenzoic acid salt 1:1 oil co-crystal 2:1

chain trimer

pentafluorobenzoic salt 1:1 oil salt 1:1

acid chain chain

4-chlorobenzoic acid salt 1:1 4-cb acid co-crystal 2:1 chain parent trimer

Experimental Results

 Example - 1-phenylcyclopentanecarboxylic acid

– 1 structure in CSD - 0 organic salts/co-crystals

Base pKa 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

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

Other Techniques Used

 Optical microscopy

 Powder X-ray diffraction

 Thermal Analysis

- DSC and TGA

Acknowledgements



Prof. Mike Hursthouse



Crystallography group at Southampton



Prof. Sue Lewis and Dr. Woods from the statistics

department



AstraZeneca Sweden for Sponsorship