MATERIAL IDENTIFICATION AND CHARACTERIZATION

10 YEARS OF DEVELOPMENT PDF-4/Organics Database

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

MATERIAL IDENTIFICATION AND CHARACTERIZATION

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

10 Year Growth

2003 2004 2005 2006 2007 2008 2009 2010 2011 20120

50,000

100,000

150,000

200,000

250,000

300,000

350,000

400,000

450,000

500,000

PDF-4/Organics

00- Experimental 01- FIZ 02- CCDC

History of Continuous Improvements

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

PDF-4/Organics

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

% Crystallinity Amorphous Materials

Quantitative Phase Identification

Nanomaterials

Material Identification and Characterization

Formulation Analysis

(Excipients, Quality System)

Polymorph Identification

(Digital Calc. Patterns)Trace Phase Identification

with Data Mining(Searches)

Nano materialsAmorphous Materials

(Digital Experimental Patterns )

Database DevelopmentAnnual Product

Published

Customer Surveys

Customer Input (email, clinics,

workshops, symposia)

ICDD Organics Subcommittee

Software Developer Input

(Automation, Speed)

Development of Strategic Subfiles

2004 2005 2006 2007 2008 2009 2010 2011 20120

2,000

4,000

6,000

8,000

10,000

12,000

Strategic Subfiles

PharmaceuticalsExcipientsMerck

Pharmaceutical Materials – Release 2011Pharmaceuticals -6,370 Excipients – 1,916

ICDD53%

ICSD21%

CSD26%

NIST0%

Pharmaceuticals

ICDD38%

ICSD50%

CSD12%

NIST1%

Excipients

ICDD Grant Programs1,396 Pharmaceutical Phases

18 % of all known XRD patterns of pharmaceuticals, both single crystal

and powder, have come from the ICDD grant program

Prof. Shao Fan Lin

10 Year Growth

20032004200520062007200820092010201120120

50,000

100,000

150,000

200,000

250,000

300,000

350,000

400,000

450,000

500,000

PDF-4/Organics

02- CCDC01- FIZ00- Experimental

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

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

Pharma associated Subfiles

Polymers – 1,302 Bioactives -13,145

ICDD87%

ICSD0%

CSD13%

PolymersICDD2%

CSD98%

Bioactives

Bioactives are materials that exhibit someBioactive behavior

Bioactives by Publication Year13,864 Bioactives

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

File Size and 2θ Range- For full pattern methods

2007 2008 2009 2010 2011 20120

10,000,000

20,000,000

30,000,000

40,000,000

50,000,000

60,000,000

70,000,000

80,000,000

90,000,000

100,000,000

Interplanar Spacings

Axis Title

5.5 GB

22 GB

RietveldLeBailPauleyFullPAT

Quality System – Disordered Structures

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 %

Disordered StructuresCalculated vs Structural Density

Before Quality MarkSystem

After Quality Mark SystemDeletes removed

Missing H atoms

Quality System – Disordered Structures

Primary, Star Patterns

All Primary and AlternatesNo deletes

All Data

“S” Quality

Quality of CSD sourced Data

Star Quality266,129 Entries

165,230Not Star Quality

Sources of errors

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)

Sucrose – Which one is correct ?

Sucrose – Which one is correct ?

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

Closer Inspection

3 shown in previous slide

12 determinations of sucrose

Multiphase Analyses5- Phases 4 Star, 1 I quality

8 – Phase Matchwith data mining

Subfiles and Data Mining

Database98%

Excipients0.5% Pharmacueticals

2%

Subfiles

Dave Rendle, UKFanglingNeedham

What is in a pharmaceutical tablet ?

SubfilesTarget Subfiles

Target Materials

Have atomic coordinates

CrystallineHas Atomic Coordinates

Non-crystallineHas PD3 Patterns

Publications per year

29

Experimental digital patterns

Nanocrystalline or Amorphous ?Cellulose Polystyrene

Targeted DevelopmentInclude 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

Pepcid AC

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

Amorphous and nanocrystalline patterns

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.

Conclusions 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)

PDF-4/Organics