Tim Fawcett Cyrus Crowder Fangling NeedhamExecutive Director Principal Scientist Senior ScientistICDD ICDD ICDD

This document was presented at PPXRD -Pharmaceutical Powder X-ray Diffraction Symposium

Sponsored by The International Centre for Diffraction Data

This presentation is provided by the International Centre for Diffraction Data in cooperation with the authors and presenters of the PPXRD symposia for the express purpose of educating the scientific community.

All copyrights for the presentation are retained by the original authors.

The ICDD has received permission from the authors to post this material on our website and make the material available for viewing. Usage is restricted for the purposes of education and scientific research.

ICDD Website - www.icdd.comPPXRD Website – www.icdd.com/ppxrd

Introduction to PDF databases

Material IdentificationFormulation AnalysisPolymorph AnalysisCrystallite SizeQuantitative Analysis

NanomaterialsStructure AnalysisCluster AnalysesCrystallinityIntegral Index

1941 – Joint Committee for Powder Diffraction Standards 2006 –General member and customer survey2007 – PDF‐4/Organics customer surveyAnnual input by member technical committees of the ICDD

Phase Identification (95%)

20‐30%Quantitative Analysis – Several MethodsCrystallinityCrystallite SizePolymorph ScreeningPowder Structure Analysis

PDF-2 Inorganic Material Identification

PDF-4+ Identification and Quantitation

PDF4/Organics Pharmaceutical Identification and Quantitation

PDF4/Minerals Mineral Identification and Quantitation

Powder Diffraction 

File

LPFICSD

NIST

CSDICDD Grants 

and Contributes

PDF-2

PDF-4+

PDF-4/Organics

Release 2009

PDF ‐ 674,139 Unique Entries

For Release 2009, Published 48,658 New Entries 

ICDD

ICSD

LPFCCDC

NIST

1998ICSD

2002CSD

2001NISTM&A

2005LPF

2006JAVAInterface2002

FullRDB 2005

Sybase

2003‐Calc.DigitalPatterns

2008SybaseUpgrade

2006EDEBSD

2007CrystalliteSize

2002‐05SubfileReorg

2007AutoSubfiles

2006AutoDup. Review

Software Dev IntegrationFully automated RIR, RietveldAnd LeBail Fitting

2005Calc. Pat.QualityAnalysis

1998‐2001RDBDevelopment

2006AtomWgt %

2008QualityExp. Pat.

2007AutoCrossRef

Science

Publication

SoftwareDevelopers

2009

2007StatisticsPgm

2008ExpPatterns

Strategic Alliances

2007 Integral Index

Densities>3000 Zeolites

Launched in fall 2007Database Tutorials (35)

Launched in April, 2009Knowledge Center  ‐ linksDXC, ICDD, AIP, PPXRD 

Searches on ~ 2400 articles and abstracts, including PPXRD

ToolsPDF‐4/Organics

1938

Hanawalt, Rinn and Frevel

Hanawalt

Card 1, 1941

1941

PDF978 Entries

Experimental patternPositions and Intensities

Total Pattern Analysis

Reduced data d, I pairs

Rietveld 1967Pawley    1981Toraya 1986LeBail 1988

Hanawalt , Frevel & Rinn1938

7. (1) 198,402 out of 370,844(1.11 Million d‐spacings)

7.2 (0.1) A 27,559

7.22 (0.01) A 2,839

7.222 (0.001) A 291

7.2222 (0.0001) A 33

7.22222 (0.00001) A 1

Phase Identification works because of theprecision and accuracy in measuring d‐spacings‐ Both in the experiment and for reference patterns

No calibration 1‐10 parts per thousandWith standard calibration 1‐100 parts per million

Quality with Time205,774 S Entries

Required of the userGood specimen preparation (particle statistics, preferred orientation)Appropriate particle size for good counting statisticsStandardize and calibrate the instrument (Certified Standards)Internal standard for the most important work Use instrument settings appropriate for what your trying to measure

Done by the ICDD – Effective databaseData are standardizedReference quality is measured and evaluatedA range of tools are available for supplemental analytical observations

(searches, indexes, physical properties, structural classifications)

Done by the vendorRigorous validated methods of Search/MatchBatch processing for high speed, cluster tools for looking at large data setsAvailability of high resolution optics and  highly efficient detectorsTools for assisting in calibration and instrument standardization

MgO and TiO2

Synchrotron Data10 PhasesMultiple Databases

Quantitation of 8Components

Celebrex – Digital Pattern Comparison

Alpha LactoseMonohydrate02‐063‐2272

Celecoxib02‐075‐7351

Stearate

New in 2009, data to 60 degrees

Celecoxib

Alpha Lactose Monohydrate

22,389,668 d‐spacingsto 

66,275,578 d‐spacings

SIeve –Goodness of MeritComparison

Celebrex – Match and Identification Process

13 Case Studies•10 Diffractometer•3 Synchrotron

10 Case Studieswith thePDF‐4/Organics

SubfilesExcipientsInorganic  ‐ Salts !MerckPharmacueticalBioactivityPolymersPigmentsForensicExplosives

5,703Inorganics

18,691 EntriesIn these 5 subfiles

Pharmaceuticals Vitamins  Supplements FertilizersAlka‐Selzer Plus Centrum Performance Saw Palmetto MirAcidTums® EX (Extra Strength) Centrum St. John’s Wort Miracle GrowPepcid® AC Centrum Silver Oyster Calcium Bone MealPromethazine Hydrochloride Centrum Carb Smart EchanaceaGoldenseal  Rose BloomBenadryl® Vitapower Red* Melatonin Slow ReleaseKroger Decongestant ®  VitapowerYellow* LipoicAcid StarterFertilizerAlavert™  Vitapower Grey* StickRobitussin® Cough Drops  Senior Vitae Weight Loss Garden ToneClaritin® Childrens Chewable StackerCelebrex™ Capsules Vitamin E with Fe TrimSpaDonnatal MegaMan CortiSlimEffexor® MegaWoman FireStarter

WomenUltra AnabolXOne‐a‐Day Acclimate

SunTheanine

Five groups of materialsFour year study

Materials fromKroger Supermarket, Happy Harry’s, Ace Hardware, CVS PharmacyGenaurdi’s Supermarket, Argonne and Oak Ridge, GNC

Calcite

Calcium HydroxyPhosphate

Glucosamine Hydrochloride

Caffeine

TRIMSPA, reduced data d,I pairs

TrimSpa

Intensityon log scale

The Food and Drug Administration (FDA) has notified Trimspa

that it has not demonstrated that claims for their product are scientifically supportable.

USE SUBFILES !!!!!

1. Eliminates false positives particularlywith complex patterns

2. Greatly assists in the statistics of trace/minor phase analysis

Tutorialshttp://www.icdd.com/resoures/tutorials

3 Case Studies – Inorganic Materials

Peaks at 13.56 and 11.90 A, 

Use the excipients subfile

2 Unknown peak locations match 2/3 of top 3 peaks of stearic acid with the3rd peak overlapping with Celecoxib

Major phases –Celecoxib and Alpha Lactose Monohydrate

Cellulose II

Cellulose I beta

Tablet of Pepcid AC

Same molecule, two different crystalline forms

Use ICDD software – Its designed for data miningVendor software – designed for high throughput 

identification

Data mining is an effective tool for identifying polymorphs

Molecular Symmetry

Molecular Volume

Molecular Packing

Examine Crystal System, Space Group,Space Group Number, Pearson Symbols

Examine Author Cell, Crystal Cell andReduced Cells, Cell Axis Ratio’s, Cell Volumes

Examine Powder patterns for differencesin interplanar spacing, examine strong lines (d1, d2, d3) and long lines (l1, l2, l3)

Search Fields in PDF‐4/Organics

908 Glycine and glycine derivatives

Symmetry vsVolume with inserts of the diffraction patterns forthe points in question

Plots two parameters (edge vs volume) 

References for Form I alpha,Form I beta and Form II

Pepcid AC

Simulation of microcrystallinestates of cellulose

Via PDF-4+

Scardi, LeoniFaber

PDF 00‐056‐1717 Cell IIPDF 00‐056‐1718 Cell I betaPDF 00‐056‐1719 Cell I alpha

Tools

Comprehensive Database with common polymorphs(Key polymorph data  on cellulose added 2006)

Calculated Digital Patterns(Added in 2003)

Crystallite Size Simulation(Added in 2007)

Tutorials

48 Searches66 Field DisplayGraphics Interface

Use multiple measurements of symmetry, molecular size, molecular volume, packing and molecular orientation to discover and identify polymorphism

Point and ClickJAVA interface

Use of the database for multi‐component mixtures

Identification link to correct phase (especiallyfor polymorphs)

Round Robin example: Acetaminophen, Mannitol, Silicon

β – D‐Mannitol02‐069‐8458Orthorhombica= 8.6940(70)b= 16.9020(80)c= 5.5490(60)P212121 (19)Z= 4.00V= 815.40

AcetaminophenPolymorph Form I02‐076‐2269Monoclinica= 12.7630(60)b=9.2500(40)c=7.0820(20)β =115.52(3) P21/a (14) Z= 4.00V=754.51

SiliconCubica = 5.431Fd‐3m(227)Z=8V=160.19

12 Choices 15 Choices

Quality Marks, Status,  I/Ic, R‐factors(lack of electron density, (i.e. H’s lowers quality mark !)

02‐069‐8458  β – D‐Mannitol

Step 1: Phase Identification3) Cross Reference to CSDReference Code DMANT07Rietveld

2) I/Ic = 0.51By RIR

Digital PatternCalculation and ExportPattern Fitting(Cluster Analyses)

3D Structure

Simulated Electron Pattern

Electron Backscattering Pattern

Calculated Diffraction Pattern

PD3 full digital experimental data overlaid on historic stick pattern

Bond Distances/Angles

ICDD Databases

Material IdentificationFormulation AnalysisPolymorph AnalysisQuantitative AnalysisStructure Refinement

Case HistoriesTools for AnalysisLinks to TutorialsLinks to More CaseHistories

Database, Tools, Methods

PPXRD2-PPXRD8

Phase Identification

Formulation Analysis‐Health 

Supplements‐ Pharmacueticals

Crystallinity‐Celullose

Cluster Analysis4 Case Studies

RietveldAnalysis

Polymorph Analyses‐ 6 Drug Examples‐Cellulose, Tegafur‐ Bone, Teeth

Nanomaterials

Low Temp Form

2 Room Temp FormsSubtle polymorphism ‐Molecular visualization (CSD)shows 2 similar configurations that vary inmethyl group rotation and close contacts

Note: The low temperatureform has a molecular configurationchange from room temperatureforms

Application PDF-4/OrganicsIdentification and QuantitationBy Reference Intensity Ratiousing PDF-4/Organics

9 Phase solution used data from 3 different databasesICDD-powder, ICSD – single crystal, CCDC- single crystalNote: Scale of 240,000 counts for this data set, 119 peaks

Minerals, Vitamins andAmino acids

MegaMen Vitamin

143

412318

ListedComp*

•Five compounds are46.5 wt % of tabletNormalized to 100%

Quantitation by Reference Intensity Ratio –CentrumPerformance

Quantitation by Reference Intensity RatioCentrum Silver ‐MultiVitamin

Advanced Techniques% Crystallinity Crystallite SizePolymorph Analysis

Using Pattern Fitting Techniques

Digital Library ofCrystalline Polymorphs withvaried crystallite sizeand amorphous cellulose

Use digital Library to analyzepolymorphs and crystallinity

Key Reference PatternAmorphous CelluloseNot currently in the PDF

All calcium phosphate polytypesAZTCarbamazepineCelluloses

SRM 640SRM 660SRM 676 and SRM 1776

Used all reference materials, used combined experimental and reference data,used all experimental data – mix and match

Human dental enamel, 1999‐OH rich, Ca 9.87, J.C. Elliot

Mineral, R. Young, 1964

An OCP derivative with 16 watersWatanabe et al 1998

OCP, Brown et. al, 1962

Another OCP  ??, 1957

Apatites

Naturally occuringtooth enamels

Synthetics, some D,Na, CO3 doped (B types)

Ca9 – calcium deficient

Low resolution dataDeleted by editors

OCP – Ca8

Ca8‐Ca9

SyntheticsandMineral