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 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 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: 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