The Grid in a Combinatorial Laboratory Jeremy Frey Department of Chemistry University of Southampton

The Grid in a Combinatorial LaboratoryJeremy FreyDepartment of ChemistryUniversity of Southampton

Bristol ChemistryECSStatsChemistryCombi CentreSouthamptonIBMCCDCPfizerIT InnovationCombeChemGSKAZNCS

DesignAutomationAnalysisStructuresModelsPropertiesExperiment

Comb-e-Chem VisionA Pervasive Grid-Based e-Science EnvironmentStructures DBProperties DBSimulation andcalculationStructure + PropertiesKnowledge + Prediction

Pharmaceutical SaltsS.C. WardSalts allow the properties of the solid forms to be modified without altering the biochemical properties of a drug. Selecting the best salt form for an ionisable drug is now of paramount importance in the pharmaceutical development of new chemical entities. No accepted procedure for selecting such a form during the drug development process.

One such parent acid is succinic acid, it is a pharmaceutically acceptable acid and can exist in two polymorphic forms. In each case the succinic acid molecules are linked into zigzag chains by strong O-H.O hydrogen bonds.

Salt ScreenMore often than not, salts selected on a practical basis, such as previous experience with the salt type, ease of synthesis, percentage yield, etc.A detailed systematic study of organic salt formation is required to enhance our understanding of all the factors that affect salt formation. The process of identifying chemical space begins with the choice of descriptors.

Salt Formation SpaceS.C. Ward, D. Woods, S.M. Lewis, M.B. Hursthouse

A variety of traditional descriptors have been investigated along with BCUT descriptors. Use Design of Experiments (DoE) statistical techniques to ensure coverage of the space with a reasonable size sample.Still lots of experimentsNeed high throughput automated crystalography

National Crystallography Service: NCSSYNTHON ProjectVoronoi ProjectSingle Crystal Structure DeterminationPowder DiffractionSingle Molecule Shape Determination Property Prediction ServicesStructure DeterminationServices

userNCStechnicianAudioVNC monitorcontrolVNC ideal for connecting existing programstechnicianLABOfficeVNC ControlAudio

VNC Web Service

NCS Lab Service

NCS Scenario (1)

Sample Processing(X-ray Experiment (1))

User Authorisation(X-ray Experiment)

Portal Access

Public / Private Key EncryptionA subscriber generates a key paircomprising a complimentary private and public keyThe private key is kept strictly privateThe public key is distributed to anyone its owner wishes to communicate with

When the public key is used to encrypt data, only the private key may decrypt this data

CertificatesA certificate comprises:a public keyan identity assertionfor Combechem, this is in the form of an X.500 Distinguished Name (DN)a signature of a trusted authority asserting: the validity of the public key the validity of the identity assertionthat the public key is the one generated by the person represented in the identity assertionfor Combechem, this trusted authority is the Combechem Certificate Authority (CA)

Use of CertificatesThe Certificate performs two main functions:secure communication through encryption using its public keypositive identification of the Subscriber through the identity assertionthe DN in the certificate is used as an identifier for the Subscriber in the sample tracking databaseThe Certificates integrity is vouched for through the the CAs signatureThe Certificate is distributed to all parties with whom its owner wishes to communicate

Remote interactionRemote control of equipmentInteraction with people & equipmentSecurity IssuesAuthentication and Authorisation within and across organisationsSafety Critical SystemsExternal & Internal control of systems can lead to safety conflictsMission critical software (avoid at this stage)

Laser x-ray single molecule scatteringHigh Power LaserX-Ray TargetInterlock SystemsSafety

AnalysisStructural Similarity & DifferenceGraham Tizard & Thomas Gelbrich

Develop process on fewApply to the whole librarySynthesis, analysis, measurementsDesign of experiments

Full combinatorial spacepolymorphsSalts

Influence of electrostatic potentials on the formation of a non-centro-symmetric member of a set of polymorphic crystal structures Polymorphic FamiliesG. Tizard

Unit cell parameters and isostructurality

Spgr.

a ()

b ()

c ()

I3B

(PMe3

Pnma

13.033

11.636

7.282

Cl3B

(NMe2F

Pn21a

10.744

10.108

6.449

Cl3B

(NMe2Cl

Pnma

11.626

9.984

6.515

I3B

(AsMe3

Pnma

13.113

11.733

7.387

Me3Al

(NMe3

Pnma

12.204

10.732

7.224

Me2IAl

(NMe3

Pnma

12.590

10.750

7.580

Me3Ga

(PMe3

Pnma

12.704

11.174

7.806

(BH4)3Al

(NMe3

Pnma

12.880

11.400

7.150

I3B(PMe3

Cl3B(NMe2F

Cl3B(NMe2Cl

I3B(AsMe3

Me3Al(NMe3

Me2IAl(NMe3

Me3Ga(PMe3

(BH4)3Al(AsMe3

Unit cell parameters and isostructuralityCheck the atomic coordinates!

Spgr.

a ()

b ()

c ()

I3B

(PMe3

Pnma

13.033

11.636

7.282

Cl3B

(NMe2F

Pn21a

10.744

10.108

6.449

Cl3B

(NMe2Cl

Pnma

11.626

9.984

6.515

I3B

(AsMe3

Pnma

13.113

11.733

7.387

Me3Al

(NMe3

Pnma

12.204

10.732

7.224

Me2IAl

(NMe3

Pnma

12.590

10.750

7.580

Me3Ga

(PMe3

Pnma

12.704

11.174

7.806

(BH4)3Al

(NMe3

Pnma

12.880

11.400

7.150

SynthonComparisonMolecules Crystal Structures AA Space groupUnit cellAtom lisBB Space groupUnit cellAtom listConventional crystal structure parameters do not support the analysisof packing similarities!

ComparisonMolecules Crystal Structures AA Space groupUnit cellAtom listAlternative parametersBB Space groupUnit cellAtom list Alternative parameters

AnalysisSynthon

SulfathiazoleT. Gelbrich: The SYNTHON Project 1/3

Polymorph

III

IV

V

Space Group

P21/c

P21/c

P21/n

Unit Cell a[]

17.570

8.193

10.774

b[]

8.574

8.538

8.467

c[]

15.583

15.437

11.367

beta[(]

112.93

94.01

91.65

Z

2

1

1

Prototype

I

Br

Cl

Me

H

F

Cl

Br

I

CF3

Me

H

NH2

NHCHOMe

NHCHO

Prototype

I

Br

Cl

Me

H

F

Cl

Br

I

CF3

Me

H

NH2

NHCHOMe

NHCHO

Prototype

I

Br

Cl

Me

H

F

Cl

Br

I

CF3

Me

H

NH2

NHCHOMe

NHCHO

0D:DimersI = (pseudo*)- inversionR = (pseudo*)- rotationIIIIII*IIII*IIIIII*IIIIIIIIIIIIIII R*IIII R*R*,R*II R*IIIIIIIII / / R*II II / III /II / I / R*I /D / IR* / IIIII

I

Br

Cl

Me

H

F

Cl

Br

I

CF3

Me

H

NH2

NHCHOMe

NHCHO

Type A Type B A A AA A A A AA AB ABAB AB A A A1D:Chains ABABABABAB A A A

I

Br

Cl

Me

H

F

Cl

Br

I

CF3

Me

H

NH2

NHCHOMe

NHCHO

The Synthons of Sulfathiazole III, IV, V

Back to the LaboratoryIf information is destined for the Grid then this should be implicit from the beginning.

Pervasive Computing and the Laboratory GridAutomatic capture of metadataSample trackingConditions monitoredData recordedRelational Databases common in industrial research not so in universityRoom/People/ExperimentTypes of information

DatabasesDatabase will become the key method of handling all dataMetadata must be generated at inception and added as data traverses the workflowVersion control, audit and backup handled at the database level.Change in the outlook of most bench chemists

MetadatamaterialBatch no.IdentifierSupplier dbprocessmeasureLab databaseSafety dbIn the Grid world the databases are distributed not local copiesNeed a language to convey all details in a standard manner XML cf CatML description of catalysts - IUPAC role

Second Harmonic GenerationUsed to study liquid surfaces and liquid-liquid interfacesModel membranes for industrial and biochemical processes.Used to develop the tight coupling of design experiment analysis.Results of one experiment modify the procedure used in the next.

Second Harmonic Generation a liquid liquid interfaces under electrochemical control

Polarisation dependence of SHG signal

Chart2

1.13639635061.3415012084

0.06461227590.0498723763

0.34609574570.4226369724

1.84913751631.7729263209

3.87044763863.2214381527

5.46423264224.4741087478

5.88474281086.0150738739

4.93521676325.3737383604

3.05994828982.7420423518

1.13639635061.6095912535

0.06461227590.1541410225

0.34609574570.1783290684

Sheet1

REIMREIM

a10.25Chi 1(zzz)8.16488070819712+24.1562658990699i8.164880708224.1562658991A0.58343516242.768235063

a2-0.22Chi 2(zxx)-1.23606318