ResultsProcess 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

ResultsCrystalline CompoundsAn 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.

SummaryThe 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.

AcknowledgementsColleagues 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

ResultsAmorphous CompoundsAn 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

IntroductionIn 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 ScopeTo 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

EquipmentUsing 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

BafflesMade 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 ProjectsJulia D I Hatto1*, Huw Evans2, Peter Hunt3 1Genevac, SP Scientific, Ipswich; 2University College, London; 3GDC, Novartis Institutes for BioMedical Research, Horsham