1. Results
Process robustness - Project 3
• 18 solvents screened, 8 crystalline hits were
confirmed by XRPD
• 5 solvents were repeated, CPME, tBME and toluene gave
good quality crystals
5mg from CPME
5mg from toluene.
Crystal grown in
saturated solution
on standing
XRPD confirmed crystallinity
and indicated all samples
were identical morphic form
DSC indicated that toluene
sample may be solvated or
contain occluded solvent.
Process scalability - Project 2
• 20 solvents screened with 72hr evaporation cycle
• 3 crystalline hits from isohexane, tBME and THF
• THF and isohexane used in classical crystallisation
• Scaled from 5mg to 200mg, then multigram
Structure confirmation - Project 8
• Diastereomers separated by chiral SFC
• Enantiomeric pairs identified by NMR
• One of each pair crystallised in eXaltTM
• 10 solvents screened with 96hr evaporation cycle
• tBME gave crystalline material suitable for SCXR
• Absolute structure of all 4 diastereomers was deduced
1cm
Results
Crystalline Compounds
An investigation was carried out on a compound with propensity to form multiple
hydrates in final isolation process. If the hydrate could be replaced with a solvate
the process may prove to be more controllable. Five water miscible solvents
were screened. DSC data indicated that;
Carbamazepine was used as a tool compound to investigate polymorph
screening in the eXaltTM and initial XRPD indicated that 3 polymorphs were
formed in the 6 solvents screened. Another team in Japan have successfully
screened polymorphs on novel compounds.
Summary
The eXaltTM
technology has been shown to be a versatile tool and successfully
applied to novel compound classes in multiple drug discovery projects. It is a non-
destructive technique and structure confirmation data can be obtained on 5mg.
Hence it can be implemented in the optimisation phase of early research projects.
Acknowledgements
Colleagues in Discovery Chemistry, Analytical Sciences and Material
Characterisation in Novartis Horsham and Basle who generously provided
material and support. Education office funding for Huw Evans.
Hydrate converted to methanol solvate
Results
Amorphous Compounds
An investigation was carried out on compounds from a selection of
medicinal chemistry projects.
The eXaltTM
technology proved to be a useful tool for initial screening. Less
than 100mg material was screened in up to 22 different solvents selected
from a variety classes; hydrocarbons, esters, ethers, chlorinated, ketones,
alcohols, and to include a range of properties; boiling point, vapour pressure,
polarity hydrogen bonding. No cross contamination was noted.
Crystalline Non-Crystalline Not used Not confirmed
The successful hits were further characterised by X-ray powder diffraction
(XRPD), differential scanning calorimetry (DSC), thermo-gravimetric analysis
(TGA) and single crystal X-ray (SCXR). This analysis was carried out on the 5mg
sample produced.
Crystal Quality - Project 7
• 16 solvents screened with 96hr evaporation cycle
• 13 crystalline hits were confirmed by XRPD, DSC and TGA
• 7 were high quality and SCXR was obtained
• All confirmed as identical morphic form
Crystalline high quality confirmed by SXCR
Poor quality crystals – not suitable for SCXR
Amorphous
Uncontrolled ambient evaporation of a sample from acetone resulted in
crystalline material, confirmed by XRPD, DSC and TGA
Sample was subsequently
shown to be micro-crystals,
unsuitable for SCXR
Data courtesy of Philippe Piechon, Analytical Sciences, Novartis Basel
Project 1 2 3 4 5 6 7
95% IPA
Acetone
Acetonitrile
Anisole
Butan-1-ol
N-Butyl Acetate
CPME
DCM
Ethanol
Ethyl Acetate
Isohexane
Propan-2-ol
Methanol
Methyl Acetate
MEK
Me-THF
Propan-1-ol
N-Propyl Acetate
tBME
THF
Toluene
Water
Introduction
In the pharmaceutical industry, physical form can pose a significant
challenge for small molecule drug discovery projects transitioning between
the optimisation and characterisation phases. A crystalline batch is desirable
to confirm absolute structure and also to investigate solubility and the
formulation of a specific morphic form.
eXaltTM
is designed to control evaporation using restricting baffles. Multiple
solvents can be screened in parallel to identify crystallisation conditions for
amorphous material where availability of pure material is limited to 100mg.
Project Scope
To investigate application in medicinal chemistry for
• Production of seed crystals from amorphous material
• Supply of seed crystals for classical crystallisation
• Suitability of crystals for structure determination by single crystal X-ray
(SCXR)
To investigate value of application at interface of medicinal chemistry and
materials characterisation groups
• Identification of solvates and solvation exchange
• Polymorph and co-crystal screening
To assess user acceptance of eXaltTM
• Ease of use and applicability to open access
• Range of solvents and cross contamination
• Propensity to produce solvates
• Reproducibility and robustness
Equipment
Using a standard Genvac HT-4X evaporation
rates can be controlled using baffles,
enabling slow evaporation of solvents
irrespective of their volatility.
Programming a pressure cycle draws small
amounts of solvent through the condenser
Serial dilution of the atmosphere in the
samples enables control of the evaporation
rate.
The centrifugal force of the spinning rotor
cements the seal on the vials and creates
a chimney effect drawing the solvent
through the baffles
Baffles
Made up by placing the required washers inside
chambers. This restriction controls the rate of
evaporation of solvent. Examples of baffle selection for solvents is shown
in the table below:
Evaporation time at 35°C
Solvent VP 12 18 24 36 48 72 96 120
Dichloromethane 47000 11 16 18 19 20
Acetone 24000 10 12 14 16 17 18
Methyl acetate 23400 3 5 10 12 16 16 17
THF 19100 6 9 12 14 16
Methanol 12700 6 10 12 14
Ethyl acetate 9600 9 12 12
Acetonitrile 9300 0.5 1.5 3.0 3.0 4 8
Ethanol 5500 1.0 1.0 2.0 2.5 3.0
IPA 3100 0.5 0.5 1.0 1.5 2.0
Evaporative Crystallisation
using eXaltTM
Technology
Application to Drug Discovery Projects
Julia D I Hatto1
*, Huw Evans2
, Peter Hunt3
1
Genevac, SP Scientific, Ipswich; 2
University College, London; 3
GDC, Novartis Institutes for BioMedical Research, Horsham