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Pharmaceutical Salt Selection Suzanna Ward BRAINFEST II.

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Presentation on theme: "Pharmaceutical Salt Selection Suzanna Ward BRAINFEST II."— Presentation transcript:

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

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