Pharmaceutical Salt Selection

1
Pharmaceutical Salt Selection

• Suzanna Ward

BRAINFEST II
2
Overall Aim

• The investigation into salts involves
• Fundamental study into salt formation
• Specific work on crystallisation
• Examining chemical space
• Aim - 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

• Salt An ionic compound whose cation comes from
  a base and whose anion comes from an acid
• Why are salts important?
• The 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

4
The Idea

• Take a variety of pharmaceutical type substrates
  and explore salt formation
• Investigate all the possible variables
• - Including the exploration of chemical space
• Identify to what extent the choice of salt is
  governed by the acidity/basicity of the ionisable
  group
• Generate a salt map

5
The E-Science Part

• A collaboration with the Statistics Department
  has been established
• The first aim was to establish the process
  variables involved
• The collaboration highlighted the necessity of
  descriptors to describe salt formation space

6
Process Variables
The experiment involves changing a number of
different conditions to find out which variables
have an effect on salt formation and to what
extent they effect it. The different variables
include

• Acid/Base/Solvent
• Rate of evaporation (change solvent evaporation
  speed)
• Temperature
• Stoichiometric coefficients
• Different stirring rate

• Degree of under-saturation
• Volume
• Order of addition
• Stirring rate/degree of agitation
• Seeding agent

• Aim to keep all the available data and record
  all possible variables even if as yet we have no
  control on them, i.e. air pressure no loss of
  data
• A multi-dimensional array of variables ? Salt Map

7
Exploring Chemical Space

• Aim find a set of chemical descriptors to
  describe the 3 component system (acid, base and
  solvent)
• Descriptors should include information on
• Molecular weight - Molecular volume
• Shape anisotropy - Possible H-bond sites
• Functionality - Basicity/Acidity
• Use Perl to automate the process and embed
  software
• Use correlation analysis to avoid correlation
• Find six descriptors to describe the molecules

8
The Process

• Explore chemical space
• Analyse pK values
• Set up an array of acids, bases and solvents
  using a LHS
• Vary the conditions
• Analyse the products and interpret data
• predict which acids/bases will readily form salts
  with any given parent molecule, and identify how
  the properties of the salts differ

9
The Experiment

• 1. Prepare stock solutions of acid/base using a
  variety of solvents
• 2. Using the LHS to add the required amount of
  solution into each well
• X-direction same base/solvent vary acid
• Y-direction same acid vary base/solvent
• 3. Change variables
• 4. Scale up?

10
Analysing the products

• If suitable single crystals formed use single
  crystal x-ray diffraction to identify product(s)
• If powder formed use powder diffractometer
• C2-capable of analysing well plates
• Identify any new products that are present
• Scale up to try to produce single crystals
• Pattern Recognition

11
The Way Forward

• Find key molecular descriptors and explore
  chemical/salt space
• Identify key experiments to be performed
• Automated way of analysing products
• Use pattern recognition programs to identify
  frameworks
• Predict stable salts and their properties
  generate a salt map

12
Summary

• Fundamental background learning program in
  pharmaceutical salts and molecular descriptors
• N-dimensional array experiment
• Analyse all results
• Produce salt maps providing information on salt
  formation