timothy g. fawcett, soorya n. kabbekodu,...timothy g. fawcett, soorya n. kabbekodu, fangling needham...
TRANSCRIPT
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
0
50,000
100,000
150,000
200,000
250,000
300,000
350,000
400,000
450,000
500,000
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
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)
0
2,000
4,000
6,000
8,000
10,000
12,000
2004 2005 2006 2007 2008 2009 2010 2011 2012
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
0
50,000
100,000
150,000
200,000
250,000
300,000
350,000
400,000
450,000
500,000
2003 2004 2005 2006 2007 2008 2009 2010 2011
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
0
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
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)