Timothy G. Fawcett, Soorya N. Kabbekodu,...Timothy G. Fawcett, Soorya N. Kabbekodu, Fangling Needham...

Timothy G. Fawcett, Soorya N. Kabbekodu,Fangling Needham and Cyrus E. CrowderInternational Centre for Diffraction Data,

Newtown Square, PA, USA

Experimental X-Ray Diffraction Data provided by ICDD members and ICDD grantees

All entries have powder patterns Most have spot, ring, EBSD patterns

Database contains organic, organometallic, polymer and inorganic materials

(Drugs, excipients, packaging materials, common salts, common corrosion phases)

Database has a relational database design Entries contain physical properties Entries contain instrumental and experimental conditions Entries contain bibliographic information Entries contain crystallographic information All entries have been standardized All entries have been evaluated for quality Searches based on chemistry, crystallography and analytical data

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PDF-4/Organics

00- Experimental 01- FIZ 02- CCDC

2003 – Targeted pharmaceuticals for grants (2003- now) Product designed as a relational database Cross referenced ICDD (PDF No.), CSD databases (Refcode)

2004 – Added excipient file, Cross referenced ICSD (Entry numbers)

2005 – Implemented calculated pattern quality system 2006 – Implemented JAVA point and click interfaces 2007 – Implemented automated cross referencing system

Introduced integral index Crystallite size simulation program

2008 – Introduced experimental digital patterns 2009 – Expanded d-spacing ranges

Subfile enhancements for forensics and polymers

2010 – More organic subfile additions – amino acids, steroids, carbohydrates First amorphous references for % crystallinity determinations

2012 – Significant additions of atomic coordinates 2nd Generation integral index

2003 – Targeted pharmaceuticals for grants (2003- now) Product designed as a relational database Cross referenced ICDD (PDF No.), CSD databases (Refcode)

2004 – Added excipient file, Cross referenced ICSD (Entry numbers)

2005 – Implemented calculated pattern quality system

2006 – Implemented JAVA point and click interfaces

2007 – Implemented automated cross referencing system Introduced integral index Crystallite size simulation program

2008 – Introduced experimental digital patterns

2009 – Expanded d-spacing ranges Subfile enhancements for forensics and polymers

2010 – More organic subfile additions – amino acids, steroids, carbohydrates First amorphous references

2012 – Significant additions of atomic coordinates 2nd Generation integral index

Data MiningPolymorph ID

Enhanced Phase Identification

% CrystallinityAmorphous Materials

Quantitative PhaseIdentification

Nanomaterials

Formulation Analysis

(Excipients, Quality System)

Polymorph Identification

(Digital Calc. Patterns)

Trace Phase Identificationwith Data Mining

(Searches)

Nano materialsAmorphous Materials

(Digital Experimental Patterns )

Annual Product

Published

Customer Surveys

Customer Input

(email, clinics,

workshops, symposia)

ICDD Organics

Subcommittee

Software Developer Input

(Automation, Speed)

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Strategic Subfiles

Pharmaceuticals

Excipients

Merck

Pharmaceuticals -6,370 Excipients – 1,916

ICDD

53%ICSD21%

CSD26%

NIST0%

Pharmaceuticals

ICDD38%

ICSD49%

CSD12%

NIST1%

Excipients

18 % of all known XRD patterns of pharmaceuticals, both single crystaland powder, have come from the ICDD grant program

Prof. Shao Fan Lin

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PDF-4/Organics

02- CCDC

01- FIZ

00- Experimental FIZ (01) contributes49 % of all excipients,21 % pharmaceuticals

ICDD (00) experimentalcontributes 53 % ofall pharmaceuticals, 38 % of excipients

Polymers – 1,302 Bioactives -13,145

ICDD87%

ICSD0%

CSD13%

Polymers ICDD2%

ICSD0%

CSD98%

NIST0%

Bioactives

Bioactives are materials that exhibit someBioactive behavior

Would include exploratory drugs, drug salts, herbicides, pesticides, gramicides

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2007 2008 2009 2010 2011 2012

Axi

s Ti

tle

Interplanar Spacings

5.5 GB

22 GB

RietveldLeBailPauleyFullPAT

Missing electron density

Is the powder pattern accurate

How much electron density is missing ?

50,757 not published !

68,608 published, most with low quality marks

0 % 1-3 % 4-15 %

> 15 %

Before Quality MarkSystem

After Quality Mark SystemDeletes removed

Primary, Star Patterns

All Primary and AlternatesNo deletes

All Data

“S” Quality

Star Quality266,129 Entries

165,230Not Star Quality

Missing electron density- disorders- missing hydrogens- missing molecules (water, other solvates)

Non positive thermal displacement parameters

Unrealistic bond angles and distances

Chemical analysis does not match crystallographic determination(Author formula vs calculated formula)

Star, based on single crystal dataall atoms foundReflection geometry

Blank, missing 6.3 % densityfrom hydrogens

O quality from 1956 film data,Intensities visually calibratedTransmission geometry

3 shown in previous slide

12 determinations of sucrose

5- Phases 4 Star, 1 I quality

8 – Phase Matchwith data mining

Database98%

Excipients0.5% Pharmacueticals

2%

Subfiles

Dave Rendle, UK

FanglingNeedham

What is in a pharmaceutical tablet ?

Target Subfiles

Have atomic coordinates

CrystallineHas Atomic Coordinates

Non-crystallineHas PD3 Patterns

Publications per year

Nanocrystallineor Amorphous ?

Cellulose Polystyrene

29

Include all target subfiles

Add atomic coordinate data sets through bibliographic extraction

Fix disorders – site occupancies included

Add anisotropic thermal displacement parameters

Extract supporting analytical data

80-85 %

15-20 %Pepcid AC - 2012

Kaduk & Langan

McBride, Shankland, DavidShankland, Steele

Nano

Amorphous

Highly crystalline

Calculated patternExperimental amorphous patternExperimental nano pattern

US PatentPowder Pattern – bestReference for identification

Best Fit among single crystalpolymorphs – best reference

for quantitation

Patent exhibits orientation along (h 0 0)Data on Pepcid AC matches patent data over single crystal !

Famotidine – Similarity Index

Often requires support analytical data to help with the diffraction pattern interpretations.In this case the PDF confirms that in some cases the materials are nanocrystalline andin other cases the materials are amorphous. In these cases the support data are includedwith the PDF reference.

PDF-4/Organics is designed for material identification and characterization

Database, data mining and identification software are all being continuously improved – expanding analysis capabilities for identification and characterization

Feedback from users and members redesigns the database

(2012 Global User Survey)