Developing Drugs? Take a Powder! - Bruker · Welcome Today’s Topics Use of powder X-ray...

$: Developing Drugs? Take a Powder! - Bruker · Welcome Today’s Topics Use of powder X-ray Diffraction (XRD) in various stages of the drug development chain Differences between X-ray$
Developing Drugs?Take a Powder!

Welcome

Today’s TopicsUse of powder X-ray Diffraction (XRD) in various stages of the drug development chainDifferences between X-ray and other analytical methods to help you make informed decisions about the best approach for analysis andprocess control

Speakers

Uwe PreckwinkelMarketing & Sales Manager, XRDMadison, WI

Holger CordesSenior Applications Scientist, XRDMadison, WI

Applications of XRD in the Pharmaceutical Industry

Synthesis of new materialsSolid-state characterisation

• Crystallinity• Thermal behaviour• Hygroscopical behaviour• Grindability / compressability• Polymorphism• Bioavailability

Scale-upQuality control assayFailure AnalysisPatentingCounterfeiting

XRD Applications for Pharmaceutical Samples

XRD & XRD2 Single Crystal

Several Grains Powder Finished

Product Solutions

Qualitative Phase ID

Grain size determination ( )

( )

Quantitative Rietveld analysisQuantitative analysis with standards

Shape analysisHigh-throughput screening

X-ray movie, non-AmbientStructure solution, indexing

Microdiffraction, mapping

% Crystallinity ( )

Powder X-ray Diffraction Basics

Diffraction of an ideal powder

Diffraction of a small numberof crystallites ("spotiness effect")

Diffraction of textured materials

31.01.2008Bruker Confidential6

X-ray Diffraction Systems for Powders

D8 ADVANCE: modular, expandable

D4 ENDEAVOR: compact system, high throughput

Detector Options for XRD Systems

Point detectors • Scintillation

detector• Sol-x detector

Position-sensitive detectors (PSD)• VÅNTEC-1• LynxEye

Area detectors• GADDS-HISTAR• VÅNTEC 2000

Commonly used for routine analysis with Bragg-Brentano geometry

For microdiffraction, polymorph screening, non-ideal powders with poor statistics

High speed analysis, quality control

Please use your mouse to answer the question on the right of your screen:

What process analytical techniques are you currently using for the analysis of your materials? (Check all that apply):

Chromatography (HPLC)Thermal Analysis (DSC)Infrared spectroscopyRaman SpectroscopyMass SpectroscopyPowder X-ray Diffraction Single Crystal X-ray DiffractionParticle size analysisOther

Audience Poll

Small Sample Analysis: Gabapentinin Bragg-Brentano Geometry

Several mg of sample dusted on silicon low-background holder

• VÅNTEC-1 detector

• Measurement range: 3-50°

• Total measurement time: 1:43 min!

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Small Sample Analysis: Low-angle Msmtswith Position-sensitive Detectors

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Ibuprofen powder with air scatter screen

Ibuprofen scan without air scatter screen

Small Sample Analysis: VÅNTEC-1 Performance

VÅNTEC-1 at low angles with air scatter screen

• Ibuprofen

• 0.3° fixed-divergence slits, 2.5° soller slits on both sides

• 0.015° step size, 0.1 sec/step, 4-min scan from 3 to 40 deg

• Scan on low-background holder without sample

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Small Sample Analysis: Ibuprofen Sample in Capillary

60 mm Goebel mirror

Capillary stage

Radial Soller slit

Step size 0.02°

Time per step 0.1 sec

0.7 mm glass capillary

Measurement time: less than 4 minutes

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32-1723 (*) - Ibuprofen - C13H18O2

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Small Sample Analysis: Microdiffraction with VÅNTEC-1 detector, Ibuprofen

All measurements with 0.1 sec/step and step size 0.023°Measurement time: 2.5 min 40 mm Goebel mirror, 1 mm exit slit, no collimator (unscaled)40 mm Goebel mirror + 1 mm collimator (scaled with factor 15)40 mm Goebel mirror + 0.5 mm collimator (scaled with factor 80)

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Small Sample Analysis: Mapping

Small Sample Analysis: API Distribution in a Pill

Small Sample Analysis: Detection Limit

~3 ng* of silicon powder adhered to a 0.1 mm loop

Powder pattern of Si to 70o 2θ

* Estimated by quantitative analysis of x-ray diffraction patterns of silicon powder [~ 5.8 cps/μg (111) reflection]

27-1402 (*) - Silicon, syn - Si - Y: 50.00 % - d x by: 1. - WL: 1.54056 - Cubic - I/Ic PDF 4.7 - Operations: Import? Frame: c:\bhuv\Si\Si2\micro_Frame: c:\bhuv\Si\Si2\micro_2_01.001 - File: si_micro_less.raw - Type: 2Th alone - Start: 7.000 ° - End: 70.000 ° - Step: 0.050 ° - Step time: 10035.8 s - Temp.: 25

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6000 sec frame with background subtracted

High-throughput Screening (HTS)

Multiple Samples Library Analysis

Screening Properties

Screening Results

High-throughput Screening (HTS)

D8 DISCOVER powder diffractometer with 2D detector and XYZ sample handling

Reflection mode (CS)

Transmissionmode (CST)

D8 DISCOVER GADDS HTS: 1 + 1 = 3

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CST

HTS

Crystallization

Glass reactor bottoms 1 mm above block Crystals in direct access to XRPD

PILOT Software for HTS

IμS Microfocus Source: Small Spot Analysis

IμS & VÅNTEC-2000 vs. Classic Setup:Corrundum Comparison

Single 40 mm Goebel mirror,

45 kV, 40 mA,

0.3 mm snout

Total counts: 78K

IμS & VÅNTEC-2000

45 kV, 0.650 mA,

0.3 mm snout

Total counts: 1235K

Operations: Import1)Corundum06192007_newsource - File: Corundum06192007_newT_01.raw - Type: 2Th alone - Start: 22.000 ° - End: 55.200 ° - Step: 0.020 ° - Step time: 100. s - Temp.: Operations: Import1)corundum6282007 - File: corundum6282007_05.raw - Type: 2Th alone - Start: 22.000 ° - End: 55.200 ° - Step: 0.020 ° - Step time: 100. s - Temp.: 25 °C (Room) - Time S

Corundum06192007_newsource - Obs. Max: 35.150 ° - Max Int.: 21.1 Cps - FWHM: 0.187 °

corundum6282007 - Obs. Max: 35.144 ° - Max Int.: 1.25 Cps - FWHM: 0.189 °

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Black: Sealed Tube

Red: IμS & VÅNTEC-2000

Observation - (104) reflection

Comparison After Data Integration

Black: Max Int: 1.25 cps

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Red: Max Int: 21.1 cps

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0.187 0.212 0.202 0.265

Comparison of Intensities

Single 40 mm Goebel mirror, 45 kV, 40 mA,0.3 mm snoutTotal counts: 607

IμS & VÅNTEC-200045 kV, 0.650 mA,0.3 mm snout Total counts: 1942

IμS & VÅNTEC-2000 vs. Classic Setup: Millisecond Snapshot

Quartz Powder

Symmetrical reflection

600 seconds

Sample to detector: 15 cm

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The Five Fingers of Quartz

D8 DISCOVER GADDS with IμS and VÅNTEC-2000

Transmission Beam Path

Ibuprofen, Measured in Transmission with Sealed Tube

Sample to detector: 29 cm0.3 mm collimatorVÅNTEC-2000 detectorMeasurement time: 120 sec

Ibuprofen, Measured in Transmission with IμS and VÅNTEC-2000

Gabapentin, Measured in Transmission with Sealed Tube

Sample to detector: 29 cm0.3 mm collimatorVÅNTEC-2000 detector120 sec collection time

Gabapentin, Measured in Transmission with IμS and VÅNTEC-2000

15 sec collection time

High-resolution Screening System with Vαrio1 and VÅNTEC-1 detector D8 ADVANCE HTS

High throughput and high resolution for transmission samples

Application: VÅNTEC-1 Detector with Vαrio1in Transmission

00-015-0985 (*) - Citric acid hydrate - C6H8O7·H2O00-016-1157 (*) - Citric acid - C6H8O7File: 3mg Citric acid H2O transmission vario 6mm exit slit vantec slits 8-12 0.085_0.2sec.raw

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00-015-0985 (*) - Citric acid hydrate - C6H8O7·H2O00-016-1157 (*) - Citric acid - C6H8O7File: 3mg Citric acid H2O transmission vario 6mm exit slit vantec slits 8-12 0.085_0.2sec.raw

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Sample: 3 mg Citric Acid Hydrate between Prolene foils

Polymorph Screening

Very powerful tool for QC: the ability to make sure that the drug substance you want to be in the final product is actually the one that is being produced in manufacturingInfluencing factors• Changes in temperature• Changes pressure• Changes in raw materials• Stirring rate• etc.

Technique can also be used to verify that the correct excipients are in the final product, as well as the drug substance

Polymorph Screening – Searching Against a Defined Database

The manual method allows for direct comparison but it is subjective• The user must use their objectivity to make the comparison

The other drawback of the manual method is the fact that you do not have an unequivocal comparison of what the materials present are. In other words you say it is the same or not, but if it is not the same then you are left guessing as to the difference.This is the advantage of the screening method when comparing against a databaseNot only can you say it is the same….you can also identify materials that do not belong


Here is an XRD pattern from a drug sample.We have set up a database of all of the drug substances and excipients that could be present for this type of sample.This particular sample should be only the pure drug polymorph. There should be nothing else in the material.So we search the database to determine if this is the case.

Operations: Range Op. Merge | Import [003]sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 89.980 ° - Step: 0.017 ° - Step time: 6005. s - Temp.: 25 °C (

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After searching the database, the software has found that indeed the polymorph drug substance is present and is Acetaminophen.However there are other peaks in the pattern that the database pattern of Acetaminophen does not account for.Conclusion: There are other materials in the pattern. At a cursory glance, this material can be rejected, but for the purpose of troubleshooting we need to know what the contamination is.

00-039-1503 (*) - Acetaminophen paracetamol - C8H9NO2 - Y: 33.33 % - d x by: 1. - WL: 1.5406 - 0 - Operations: Range Op. Merge | Import [003]sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 89.980 ° - Step: 0.017 ° - Step time: 6005. s - Temp.: 25 °C (

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We then search the database for the remaining peaks.The software now reports that the remaining peaks are from the material Sucrose.We now know the material is contaminated and what it is contaminated with.

00-024-1977 (*) - Sucrose - C12H22O11 - Y: 79.17 % - d x by: 1. - WL: 1.5406 - 0 - I/Ic PDF 0.7 - S-Q 100.0 % - Operations: Range Op. Merge | Import [003]sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 89.980 ° - Step: 0.017 ° - Step time: 6005. s - Temp.: 25 °C (

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00-024-1977 (*) - Sucrose - C12H22O11 - Y: 79.17 % - d x by: 1. - WL: 1.5406 - 0 - I/Ic PDF 0.7 - 00-039-1503 (*) - Acetaminophen paracetamol - C8H9NO2 - Y: 33.33 % - d x by: 1. - WL: 1.5406 - 0 - Operations: Range Op. Merge | Import [003]sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 89.980 ° - Step: 0.017 ° - Step time: 6005. s - Temp.: 25 °C (

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AcetaminophenSucrose


Searching against a defined database is a very powerful tool forpolymorph screening.Not only can you tell if a sample meets specifications, you can also determine the materials, or lack of materials, that caused the sample to fail.However, the ideal polymorph screen would be to provide the information to a manual search and a database search all in one with no user interaction.This is called pattern recognition and is available in PolySNAP software.

PolySNAP – Pattern Matching

Full profile analysis:

PolySNAP pattern matching is based on a statistical comparison of each measured data point in each pattern.This true, full pattern analysis approach takes advantage of allpattern information, including presence or absence of peaks, peak shoulders, and background regions.PolySNAP provides an easy-to-use interface to several powerful and novel statistical methods to rank patterns in order of theirsimilarity to any selected sample, allowing known as well as unknowns to be identified quickly.

Every data point in every pattern is used to compare samples!

PolySNAP – Full Pattern Analysis

PolySNAP – Auto-detection of Identical Samples

PolySNAP – Auto-detection of Different Samples

Automatic phase ID of knownsIdentical colors = identical samples

PolySNAP – Auto-detection of Unknown or Unexpected Phases or Samples

Automatic phase ID of knownsIdentical colors = identical samplesDifferent colors = different samples

PolySNAP – Auto-detection of Mixtures

Automatic detection of unknownor unexpected phases or patterns

Automatic phase ID of knownsIdentical colors: identical samplesDifferent colors: different samples

PolySNAP – Auto-detection of Mixtures

Automatic detection of unknownor unexpected phases or patterns


Form B Form C

Form B+C

PolySNAP – Auto-detection of Amorphous Phases

Automatic detection andquantification of mixtures

Form B Form C

Form B+C Automatic detection of unknownor unexpected phases or patterns


PolySNAP – Full Pattern Analysis

Automatic detection ofamorphous phases

Automatic detection andquantification of mixtures

Form B Form C

Form B+C Automatic detection of unknownor unexpected phases or patterns


PolySnap Visualization Options –6-dimensional Plots

Display of crystallization parameters as - symbol size- symbol shape - symbol color

Video image of sample well

Selected sample pattern

Sample crystallization conditions

PolySnap

True Full Pattern Matching – Pharma Approved

D8 SCREENLAB – Combined XRD and Raman Spectroscopy

No sample reloading between XRD and Raman measurementsPILOT software that controls XRD and Raman measurementsPolySNAP software for combined full pattern matching of XRD and Raman patternsAnalysis of amorphous phases using Raman spectroscopy

D8 SCREENLAB – Combined XRD and Raman Spectroscopy

Methodology – PXRD + Raman

Full profile matching

All patterns against all patterns

nXRPD

Patterns

nxnCorrelation

matrix

Full profile matching

All patterns against all patterns

nRaman Patterns

nxnCorrelation

matrix

nxnDistance matrix

Combine

XRD results

Ramanresults

Combined results

nxnDistance matrix

nxnDistance matrix

Combined Datasets – Example 1

48 patterns of 3 forms of Sulfathiazol (forms 2, 3 and 4)PXRD and Raman data collectedPXRD Data only: splits Form 3 into two separate clusters

Form 4 Form 3 Form 2 Form 3


48 patterns of 3 forms of Sulfathiazol (forms 2, 3 and 4)PXRD and Raman data collectedRaman data only: doesn’t distinguish between Form 3 and Form 4

Forms 3 & 4 Form 2


48 patterns of 3 forms of Sulfathiazol (forms 2, 3 and 4)PXRD and Raman data collectedCombined PXRD + Raman using Automatic Weights: does much better than the individual methods alone

Form 4 Form 2Form 3

Combined Results – Example 2

46 patterns of 2 anhydrous forms of Carbamazepeine (Forms 1 & 3)PXRD and Raman data collectedPXRD data only: E3 and F7 in different clusters


46 patterns of 2 anhydrous forms of Carbamazepeine (Forms 1 & 3)PXRD and Raman data collectedRaman data only: E3 and F7 in same cluster!


46 patterns of 2 anhydrous forms of Carbamazepeine (Forms 1 & 3)PXRD and Raman data collectedPXRD & Raman data combined: F7 highlighted as an outlier due to this inconsistency

Other outliers (yellow) are mixtures of the 2 forms

Combined Results

Matching method does very well in distinguishing forms automatically using either Raman or PXRD dataCombined results using Automatic Weights seem to be better than either PXRD or Raman aloneIdentification of pure phases / mixtures improvedUse of combined data highlights any inconsistencies in separate analyses• Such inconsistencies would not be obvious with only one data source• User can then examine outliers manually in detail

Seeing similar clustering from multiple original data sources increases confidence in the results

Quality Control

Given a set of reference patterns, new patterns can be considered to be similar enough to the references to ‘pass,’ or different enough to ‘fail.’Graphical representation:

new samples within the green Pass surface are OK, samples falling outside the surface fail.

Quantitative Analysis

We have now seen many different ways to screen samples to make sure we have made what we want to make.

The next question that needs to be asked is… Am I making these materials in the correct amounts?This can be answered with quite a few different methods

• Reference intensity ratio• Full pattern scaling• Standard-based quantification• Quantitative Rietveld Analysis

Please use your mouse to answer the question on the right of your screen:

Which method do you prefer for quantitative phase analysis?

Conventional standard-based quantificationReference-intensity ratioFull pattern scaling based on reference scans of pure phasesStandardless Rietveld Analysis (because of peak overlap or because standards are not available)

Audience Poll

00-024-1977 (*) - Sucrose - C12H22O11 - Y: 8.40 % - d x by: 1. - WL: 1.5406 - Monoclinic - I/Ic PDF 0.7 - S-Q 2.8 % - 00-039-1503 (*) - Acetaminophen paracetamol - C8H9NO2 - Y: 41.66 % - d x by: 1. - WL: 1.5406 - Monoclinic - I/Ic User 0.1 - S-Q 97.2 % - Operations: Range Op. Merge | Import [003]sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 89.980 ° - Step: 0.017 ° - Step time: 6005. s - Temp.: 25 °C (Room) -

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Quantitative Analysis – Scaling Method

This method takes the information from the database and, using the scaling factors that can be applied to the patterns, quantitative information can be obtained.The user simply has to scale the intensity of the database pattern to the intensity of the unknown.This pattern is a zoom region of the Sucrose, Acetaminophen sample.The scale factors here are obviously wrong.


Quantitative Analysis – Scaling Method

However the user can simply scale these patterns with the mouse and obtain the correct match to the unknown samples.Once the data are properly scaled, the software will automatically report the correct concentrations.

00-024-1977 (*) - Sucrose - C12H22O11 - Y: 67.19 % - d x by: 1. - WL: 1.5406 - Monoclinic - I/Ic PDF 0.7 - S-Q 31.5 % - 00-039-1503 (*) - Acetaminophen paracetamol - C8H9NO2 - Y: 20.83 % - d x by: 1. - WL: 1.5406 - Monoclinic - I/Ic User 0.1 - S-Q 68.5 % - Operations: Range Op. Merge | Import [003]sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 89.980 ° - Step: 0.017 ° - Step time: 6005. s - Temp.: 25 °C (Room) -

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Material %

Acetaminophen 2.8%

Sucrose 97.2%

Quantitative Analysis: Lower Detection Limits with Faster Detectors

Example: Ibuprofen with known amount of impurity

• Measurement circle: 500 mm

• VÅNTEC-1 detector• 40 kV, 40 mA• Step size: 0.015°• Step time: 1° sec/step

0.08 wt% of known impurity was added

Actual detection limits depend on:

• Crystallinity• Peak overlap• Crystal symmetry• Preferred orientation• Crystallite statistics

00-032-1723 (*) - Ibuprofen - C13H18O2

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Standard-based Quantitative Analysis: Powder Samples, Comparison

For quantification based on single peak areas, the peak at approx. 22.1° can be used to best distinguish Form B from Form A, because there is no overlap

Operations: ImportPolyB ground lynxeye 0.5dg div 2.5 dg soller - Step: 0.020 °Operations: Import90089 poly a ground 3 0.5div 500mm LynEye2.5 dg - Step: 0.019 °

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Polymorph APolymorph B

Standard-based Quantitative Analysis: Quantification of Polymorph B with DQuant

The peak area (highlighted green) was used to quantify Polymorph B.The yellow areas are background areas. This also works for the degree of crystallinity quantification of partially amorphous samples.

Standard-based Quantitative Analysis: Calibration Curve

Consistent sample preparation with identical sample volumes is necessary to get sufficient accuracy

Failure Analysis: Quality Control on Tablets

Higher background of tablet scans caused by excipients.LynxEye detector:

• 0.5° divergence slit

• 4° soller slits• 0.019°/step• 1 sec/step• Measurement

time: 10 minutes from 18 to 25°

Measurement on small tablet with 50 mg API without sample preparation

Pure Polymorph APure Polymorph BTablet with 50 mg API: Polymorph B presentTablet with 50 mg API: no Polymorph B

Quantitative Analysis: Basic Principle of the Rietveld Method

The Rietveld method is a full-profile approach to quantitative phase analysis using powder diffraction data.The Rietveld method generates a calculated diffraction pattern that is compared with the observed data.Least-squares procedures are used to minimize the difference between the complete observed and calculated diffraction patterns. The following parameters is simultaneously refined:

• the structural parameters of each phase (lattice parameters, atomic coordinates, site occupancies). These are normally obtained from a data base or the literature

• the various experimental parameters affecting the pattern (displacement correction, peak shape, background, etc.)

The Rietveld method is standard-less.The Rietveld refinement method can be used to characterize several phases simultaneously. The relative masses of all phases contributing to the diffraction pattern can be derived from the refinement.

Quantitative Analysis of Test-Mixture: Rietveld Analysis using TOPAS

13.2 wt% beta-d-Mannitol was added to Ibuprofen as a test mixture Both crystal structures are known and available in databasesThere is considerable peak overlap between the two phases and preferred orientation for Ibuprofen

Quantitative Analysis of Test-Mixture: Rietveld Analysis using TOPAS

Individual calculated curves are highlightedThe full pattern can be used for quantitative analysis despite considerable peak overlap

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Percent Crystallinity

Another critical piece of information that is important to the pharmaceutical community is how crystalline is a sampleXRD is an excellent tool for determining this parameterCrystalline peaks are very sharp and definedAmorphous or non-crystalline peaks are very broadBy simply dividing the areas under each of the peaks the percent crystallinity can be easily obtainedOperations: Y Scale Mul 0.083 | Import

QUARTZ - File: Quartz.raw - Type: 2Th/Th locked - Start: 18.000 ° - End: 90.000 ° - Step: 0.020 ° - Step time: 10. s - Temp.: 25 °C (Room) - Time Started: 0 s - 2-Theta: 18.000 ° - Theta: Operations: Bezier Background 4.571,1.000 | ImportPOLYMER DATA Converted from UXD format byConverted from UXD format by XCH Version 1 FFT Smoothed - File: Poly.raw - Type: 2Th alone - Start: 8.600 ° - End: 58.360

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When both amorphous and crystalline phases are present in the same material you will get a pattern that is a combination of bothA large amorphous region with a crystalline region overlaid on topAgain by obtaining the area under the curves and simply dividing the percent crystallinity can be obtained

Operations: Bezier Background 5.623,1.000 | ImportPOLYMER DATA Converted from UXD format byConverted from UXD format by XCH Version 1 FFT Smoothed - File: Poly.raw - Type: 2Th alone - Start: 8.600 ° - End: 58.360Operations: ImportPOLYMER DATA Converted from UXD format byConverted from UXD format by XCH Version 1 FFT Smoothed - File: Poly.raw - Type: 2Th alone - Start: 8.600 ° - End: 58.360

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The easiest way to accomplish this is to have the user subtract the amorphous portion of the pattern and have the software calculate the area under the curvesThe software then tells us that this sample is 25% crystalline and 75% amorphousThe only issue with this technique is again the user intervention that needs to occur

Operations: Background 5.623,0.000 | ImportPOLYMER DATA Converted from UXD format byConverted from UXD format by XCH Version 1 FFT Smoothed - File: Poly.raw - Type: 2Th alone - Start: 8.600 ° - End: 58.360Operations: ImportPOLYMER DATA Converted from UXD format byConverted from UXD format by XCH Version 1 FFT Smoothed - File: Poly.raw - Type: 2Th alone - Start: 8.600 ° - End: 58.360

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The best way to accomplish this is by mathematically fitting the unknown pattern and then allowing the software to automatically calculate the areas and thus the crystallinityThis can also be completely automated to the point that all the user has to do is put the ample in the instrument and walk away

Structure Determination fromPowder Data

Intensity Extraction• LeBail, Pawley

Structure DeterminationStructure Refinement

"Profiling"• LeBail, Pawley

Structure Determination AND Refinementfrom yi(obs)

Peak Finding (FPA)Indexing, Space Group Determination

TOPAS ApproachCoelho (2000)

D8 ADVANCE Vαrio1 Monochromator for Transmission and Reflection

Johansson-type monochromator for pure Kα1 radiation

Six pre-defined geometries for reflection and capillary transmission measurements

Geometry change by moving the Vαrio1 along the track

Indexing of Ibuprofen with TOPAS

seed index_zero_errorBravais_Cubic_sgs Bravais_Trigonal_Hexagonal_sgs Bravais_Tetragonal_sgs Bravais_Orthorhombic_sgs Unique_Monoclinic_sgsBravais_Triclinic_sgs load index_d {14.51938 good7.2446436.9220056.3327196.0032815.3335145.297815.2665625.0090334.822784.726984.6511164.5425444.3922064.1112154.0536233.9746923.8974493.8060733.6920023.6663443.620241}

Get the first 20 d-spacings by profile fitting for input file

Indexing of Ibuprofen

Output after approx. 150 sec calculation time

Figure of merit versus cell volume

Space Group Un-indexed peaks GOF Zero error Lattice parameters

Indexing of Ibuprofen

Run whole powder pattern fitting for best matching unit cells

Ibuprofen: Comparison with ICDD Database

Note the missing lines in ICDD fileWith those lines not being resolved or detected, indexing from powder data becomes more difficult

Pure Kα1 radiation really does help for indexing

00-032-1723 (*) - Ibuprofen - C13H18O2

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2-Theta - Scale11 12 13 14 15 16 17 18 19 20 21 22

Structure Determination

TOPAS software for powder crystallographyIndexingStructure solutionStructure refinement

Caffeine AnhydrousV = 4453.7 Å3C8H10N4O25 molecules (rigid

bodies) in the asymmetric unit

70 non-hydrogen atoms in asymmetric unit

Non-ambient Measurements:Stages for Use with Area Detector

Anton Paar DHS 900 MRI BTS

Environmental Stages: Humidity Stage

D8 ADVANCE powder diffractometer with integratedHot-Humidity System

Lactose Monohydrate: Dehydration and Hydration in MRI Humidity Stage

LynxEye detector:• 0.5° divergence

slit• 0.019°/step • 0.1 sec/step

00-027-1947 (I) - Lactose hydrate - C12H22O11·H2OY + 40.0 mm - File: lactose monohydrate after rehydration at 40C 76pc hum.rawY + 20.0 mm - File: lactose monohydrate at 45C_after heating 0.5dg div Lynxeye1.5dg.rawFile: lactose monohydrate at RT_0.5dg div Lynxeye1.5dg.raw

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Room temperature sample as receivedDehydrated at 160°C and cooled to 45°CRehydrated at 40°C and 76% relative humidity

Temperature Study with VÅNTEC-1 Detector in Snapshot Mode

140 fixed scans with a 10° 2theta angular coverageThe sample was heated to 170°C and slow-cooledMeasurement time for each snapshot: 2 secThe measurement was performed in air using a Pt strip heaterHeating rate and cooling rate: 0.2°/secCursor at 169°C

Sample: beta d-Mannitol

Temperature Study with VÅNTEC-1 Detector in Snapshot Mode, Level Plot

Alpha D-Mannitol+ Beta D-Mannitol

Beta D-Mannitol

heat

ing

cool

ing

Sample: beta d-Mannitol

21CFR Part 11 is Good for You...

Benefits of being compliant are numerous for areas where the FDAis currently not asking for records, or maybe never will:• It is easier and cheaper to buy new equipment with Part 11 in

mind now, than to deal with unnecessary risk assessments and future Part 11 remediation

• Exact records support any patent filing or later patent disputes• Electronic records have less space requirements and can be

more easily retrieved• Dividing line between the discovery and development stages

are not clear cut, and drug candidates often cycle between the two stages

Meeting Quality System Regulationsat Bruker AXS

Bruker AXS quality system:Hardware and software are being developed by applying a formal design process and product development life cycle according to Bruker AXS's ISO9001 certified product development proceduresFor software, additional written standards exist, such as codingstandards, configuration management, programmer qualifications, software version control, maintenance, formal testing of software/hardware, incident reporting and tracking, and disasterrecovery (Bruker AXS SW404)


External system testing(holistic testing at the customer site)

Bruker AXS IQ/OQ/PQ Procedure for regulated industriesBruker AXS Instrument Verification Procedure for all other customers*

* System acceptance test required by Bruker AXS (subset of the Bruker AXS IQ/OQ/PQ Procedure)

Internal system testing(component-based testing in the test field)

Test procedure for internal IQ/OQ/PQ before shippingincluding aFinal holistic test using the Bruker AXS Instrument Verification Procedure

IQ

OQ

PQ


21 CFR Part 11To integrate into an FDA 21 CFR Part 11 (or OECD) compliant laboratory, DIFFRACplus BASIC offers several tools to provide and guarantee authenticity, integrity and confidentiality of electronic records and electronic signatures, including:• Secure system log-ins• Automatic audit trail generation• Electronic signatures with reports and data• Network security with Windows NT4 / 2000• Tamper-proof data files with the ability to discern invalid or

altered recordsWhite Paper

DIFFRACplus BASIC: Meeting the Requirements of the FDA’s “21CFR Part11” Regulation

Challenge us with your analytical tasks and expect comprehensive answers

directly meeting your needs

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