Developing Drugs? Take a Powder!

Transcription

1 Developing Drugs? Take a Powder!

2 Welcome Speakers Uwe Preckwinkel Marketing & Sales Manager, XRD Madison, WI Holger Cordes Senior Applications Scientist, XRD Madison, WI Today s Topics Use of powder X-ray Diffraction (XRD) in various stages of the drug development chain Differences between X-ray and other analytical methods to help you make informed decisions about the best approach for analysis and process control

3 Applications of XRD in the Pharmaceutical Industry Synthesis of new materials Solid-state characterisation Crystallinity Thermal behaviour Hygroscopical behaviour Grindability / compressability Polymorphism Bioavailability Scale-up Quality control assay Failure Analysis Patenting Counterfeiting

4 XRD Applications for Pharmaceutical Samples XRD & XRD 2 Single Crystal Several Grains Powder Finished Product Solutions Qualitative Phase ID Quantitative Rietveld analysis Quantitative analysis with standards X-ray movie, non-ambient Structure solution, indexing Microdiffraction, mapping Shape analysis High-throughput screening Grain size determination ( ) % Crystallinity ( ) ( )

5 Powder X-ray Diffraction Basics Diffraction of an ideal powder Diffraction of textured materials Diffraction of a small number of crystallites ("spotiness effect")

6 X-ray Diffraction Systems for Powders D8 ADVANCE: modular, expandable D4 ENDEAVOR: compact system, high throughput 6 Bruker Confidential

7 Detector Options for XRD Systems Point detectors Scintillation detector Sol-x detector Commonly used for routine analysis with Bragg-Brentano geometry Position-sensitive detectors (PSD) VÅNTEC-1 LynxEye High speed analysis, quality control Area detectors GADDS-HISTAR VÅNTEC 2000 For microdiffraction, polymorph screening, non-ideal powders with poor statistics

8 Audience Poll 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 spectroscopy Raman Spectroscopy Mass Spectroscopy Powder X-ray Diffraction Single Crystal X-ray Diffraction Particle size analysis Other

9 Small Sample Analysis: Gabapentin in Bragg-Brentano Geometry Lin (Counts) Lin (Counts) Several mg of sample dusted on silicon lowbackground holder VÅNTEC-1 detector Measurement range: Theta - Scale Total measurement time: 1:43 min! Theta - Scale

10 Small Sample Analysis: Low-angle Msmts with Position-sensitive Detectors 8000 Ibuprofen scan without air scatter screen Ibuprofen powder with air scatter screen Lin (Counts) Theta - Scale

11 Small Sample Analysis: VÅNTEC-1 Performance VÅNTEC-1 at low angles with air scatter screen Lin (Counts) Theta - Scale Ibuprofen 0.3 fixeddivergence slits, 2.5 soller slits on both sides step size, 0.1 sec/step, 4- min scan from 3 to 40 deg Scan on lowbackground holder without sample

12 Small Sample Analysis: Ibuprofen Sample in Capillary Lin (Counts) Lin (Counts) Theta - Scale 2-Theta - Scale (*) - Ibuprofen - C13H18O2 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

13 Small Sample Analysis: Microdiffraction with VÅNTEC-1 detector, Ibuprofen Lin (Counts) Theta - Scale All measurements with 0.1 sec/step and step size 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 mm collimator (scaled with factor 80)

14 Small Sample Analysis: Mapping

15 Small Sample Analysis: API Distribution in a Pill

16 Small Sample Analysis: Detection Limit ~3 ng * of silicon powder adhered to a 0.1 mm loop Lin (Cps) sec frame with background subtracted * Estimated by quantitative analysis of x-ray diffraction patterns of silicon powder [~ 5.8 cps/μg (111) reflection] 2-Theta - Scale? Frame: c:\bhuv\si\si2\micro_frame: c:\bhuv\si\si2\micro_2_ File: si_micro_less.raw - Type: 2Th alone - Start: End: Step: Step time: s - Temp.: 25 Operations: Import (*) - Silicon, syn - Si - Y: % - d x by: 1. - WL: Cubic - I/Ic PDF Powder pattern of Si to 70 o 2θ

17 High-throughput Screening (HTS) Multiple Samples Library Analysis Screening Properties Screening Results

18 High-throughput Screening (HTS) D8 DISCOVER powder diffractometer with 2D detector and XYZ sample handling Reflection mode (CS) Transmission mode (CST)

19 D8 DISCOVER GADDS HTS: = 3 + = CST CS HTS

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

21 PILOT Software for HTS

22 IμS Microfocus Source: Small Spot Analysis

23 IμS & VÅNTEC-2000 vs. Classic Setup: Corrundum Comparison IμS & VÅNTEC kv, ma, 0.3 mm snout Total counts: 1235K Single 40 mm Goebel mirror, 45 kv, 40 ma, 0.3 mm snout Total counts: 78K

24 Comparison After Data Integration Black: Sealed Tube Red: IμS & VÅNTEC Lin (Cps) Observation - (104) reflection Black: Max Int: 1.25 cps FWHM : Red: Max Int: 21.1 cps FWHM: Theta - Scale corundum File: corundum _05.raw - Type: 2Th alone - Start: End: Step: Step time: 100. s - Temp.: 25 C (Room) - Time S 1) corundum Obs. Max: Max Int.: 1.25 Cps - FWHM: Operations: Import Corundum _newsource - File: Corundum _newT_01.raw - Type: 2Th alone - Start: End: Step: Step time: 100. s - Temp.: 1) Corundum _newsource - Obs. Max: Max Int.: 21.1 Cps - FWHM: Operations: Import

25 Comparison of Intensities Optics IμS UBC UBC UBC UBC Collimator 0.3mm 0.8mm 0.5mm 0.3mm 0.3mm front pinhole removed Frame Intensity (cps) Peak Intensity (cps) Corundum (104) FWHM 12.3K 10.2K 3K 0.78K 8.9K

26 IμS & VÅNTEC-2000 vs. Classic Setup: Millisecond Snapshot IμS & VÅNTEC kv, ma, 0.3 mm snout Total counts: 1942 Single 40 mm Goebel mirror, 45 kv, 40 ma, 0.3 mm snout Total counts: 607

27 Quartz Powder Symmetrical reflection 600 seconds Sample to detector: 15 cm

28 The Five Fingers of Quartz 300 Lin (Counts) D8 DISCOVER GADDS with IμS and VÅNTEC-2000

29 Transmission Beam Path

30 Ibuprofen, Measured in Transmission with Sealed Tube Sample to detector: 29 cm 0.3 mm collimator VÅNTEC-2000 detector Measurement time: 120 sec

31 Ibuprofen, Measured in Transmission with IμS and VÅNTEC-2000

32 Gabapentin, Measured in Transmission with Sealed Tube Sample to detector: 29 cm 0.3 mm collimator VÅNTEC-2000 detector 120 sec collection time

33 Gabapentin, Measured in Transmission with IμS and VÅNTEC sec collection time

34 High-resolution Screening System with Vαrio1 and VÅNTEC-1 detector D8 ADVANCE HTS High throughput and high resolution for transmission samples

35 Application: VÅNTEC-1 Detector with Vαrio1 in Transmission Lin (Counts) Sample: 3 mg Citric Acid Hydrate between Prolene foils Lin (Counts) Theta - Scale File: 3mg Citric acid H2O transmission vario 6mm exit slit vantec slits _0.2sec.raw (*) - Citric acid - C6H8O (*) - Citric acid hydrate - C6H8O7 H2O Theta - Scale File: 3mg Citric acid H2O transmission vario 6mm exit slit vantec slits _0.2sec.raw (*) - Citric acid - C6H8O (*) - Citric acid hydrate - C6H8O7 H2O

36 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 manufacturing Influencing 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

37 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 database Not only can you say it is the same.you can also identify materials that do not belong

38 Polymorph Screening Searching Against a Defined Database Lin (Counts) 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 Theta - Scale sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw- Type: 2Th/Th locked - Start: End: Step: Step time: s - Temp.: 25 C ( Operations: Range Op. Merge Import [003]

39 Polymorph Screening Searching Against a Defined Database Lin (Counts) Theta - Scale sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw- Type: 2Th/Th locked - Start: End: Step: Step time: s - Temp.: 25 C ( Operations: Range Op. Merge Import [003] (*) - Acetaminophen paracetamol - C8H9NO2 - Y: %- d x by: 1. - WL: 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.

40 Polymorph Screening Searching Against a Defined Database Lin (Counts) 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 Theta - Scale sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw - Type: 2Th/Th locked - Start: End: Step: Step time: s - Temp.: 25 C( Operations: Range Op. Merge Import [003] (*) - Sucrose - C12H22O11 - Y: %- d x by: 1. - WL: I/Ic PDF0.7 - S-Q %-

41 Polymorph Screening Searching Against a Defined Database Acetaminophen Sucrose Lin (Counts) Theta - Scale sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw - Type: 2Th/Th locked - Start: End: Step: Step time: s - Temp.: 25 C ( Operations: Range Op. Merge Import [003] (*) - Acetaminophen paracetamol - C8H9NO2 - Y: % - d x by: 1. - WL: (*) - Sucrose - C12H22O11 - Y: % - d x by: 1. - WL: I/Ic PDF 0.7 -

42 Polymorph Screening Searching Against a Defined Database Searching against a defined database is a very powerful tool for polymorph 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.

43 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 all pattern 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 their similarity 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!

44 PolySNAP Full Pattern Analysis

45 PolySNAP Auto-detection of Identical Samples

46 PolySNAP Auto-detection of Identical Samples

47 PolySNAP Auto-detection of Different Samples Automatic phase ID of knowns Identical colors = identical samples

48 PolySNAP Auto-detection of Different Samples Automatic phase ID of knowns Identical colors = identical samples

49 PolySNAP Auto-detection of Unknown or Unexpected Phases or Samples Automatic phase ID of knowns Identical colors = identical samples Different colors = different samples

50 PolySNAP Auto-detection of Unknown or Unexpected Phases or Samples Automatic phase ID of knowns Identical colors = identical samples Different colors = different samples

51 PolySNAP Auto-detection of Mixtures Automatic phase ID of knowns Identical colors: identical samples Different colors: different samples Automatic detection of unknown or unexpected phases or patterns

52 PolySNAP Auto-detection of Mixtures Form B+C Automatic phase ID of knowns Identical colors = identical samples Different colors = different samples Form B Form C Automatic detection of unknown or unexpected phases or patterns

53 PolySNAP Auto-detection of Amorphous Phases Automatic phase ID of knowns Identical colors = identical samples Different colors = different samples Automatic detection and quantification of mixtures Form B+C Automatic detection of unknown or unexpected phases or patterns Form B Form C

54 PolySNAP Auto-detection of Amorphous Phases Automatic phase ID of knowns Identical colors = identical samples Different colors = different samples Automatic detection and quantification of mixtures Form B+C Automatic detection of unknown or unexpected phases or patterns Form B Form C

55 PolySNAP Full Pattern Analysis Automatic detection of amorphous phases Automatic phase ID of knowns Identical colors = identical samples Different colors = different samples Automatic detection and quantification of mixtures Form B+C Automatic detection of unknown or unexpected phases or patterns Form B Form C

56 PolySnap Visualization Options 6-dimensional Plots Selected sample pattern Sample crystallization conditions Display of crystallization parameters as - symbol size - symbol shape - symbol color Video image of sample well

57 PolySnap True Full Pattern Matching Pharma Approved

58 D8 SCREENLAB Combined XRD and Raman Spectroscopy

59 D8 SCREENLAB Combined XRD and Raman Spectroscopy

60 D8 SCREENLAB Combined XRD and Raman Spectroscopy

61 D8 SCREENLAB Combined XRD and Raman Spectroscopy No sample reloading between XRD and Raman measurements PILOT software that controls XRD and Raman measurements PolySNAP software for combined full pattern matching of XRD and Raman patterns Analysis of amorphous phases using Raman spectroscopy

62 Methodology PXRD + Raman n XRPD Patterns Full profile matching All patterns against all patterns nxn Correlation matrix nxn Distance matrix XRD results Combined results Combine nxn Distance matrix n Raman Patterns Full profile matching All patterns against all patterns nxn Correlation matrix nxn Distance matrix Raman results

63 Combined Datasets Example 1 48 patterns of 3 forms of Sulfathiazol (forms 2, 3 and 4) PXRD and Raman data collected PXRD Data only: splits Form 3 into two separate clusters Form 4 Form 3 Form 2 Form 3

64 Combined Datasets Example 1 48 patterns of 3 forms of Sulfathiazol (forms 2, 3 and 4) PXRD and Raman data collected Raman data only: doesn t distinguish between Form 3 and Form 4 Forms 3 & 4 Form 2

65 Combined Datasets Example 1 48 patterns of 3 forms of Sulfathiazol (forms 2, 3 and 4) PXRD and Raman data collected Combined PXRD + Raman using Automatic Weights: does much better than the individual methods alone Form 4 Form 3 Form 2

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

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

68 Combined Results Example 2 46 patterns of 2 anhydrous forms of Carbamazepeine (Forms 1 & 3) PXRD and Raman data collected PXRD & Raman data combined: F7 highlighted as an outlier due to this inconsistency Other outliers (yellow) are mixtures of the 2 forms

69 Combined Results Matching method does very well in distinguishing forms automatically using either Raman or PXRD data Combined results using Automatic Weights seem to be better than either PXRD or Raman alone Identification of pure phases / mixtures improved Use 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

70 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.

71 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

72 Audience Poll 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 quantification Reference-intensity ratio Full pattern scaling based on reference scans of pure phases Standardless Rietveld Analysis (because of peak overlap or because standards are not available)

73 Quantitative Analysis Scaling Method Lin (Counts) Acetaminophen Sucrose Theta - Scale sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw- Type: 2Th/Th locked - Start: End: Step: Step time: s - Temp.: 25 C (Room) - Operations: Range Op. Merge Import [003] (*) - Acetaminophen paracetamol - C8H9NO2 - Y: %- d x by: 1. - WL: Monoclinic - I/Ic User S-Q97.2 % (*) - Sucrose - C12H22O11 - Y: 8.40 %- d x by: 1. - WL: Monoclinic - I/Ic PDF S-Q2.8 %- 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.

74 Quantitative Analysis Scaling Method Lin (Counts) Acetaminophen Sucrose Theta - Scale sugar [003] - File: Front loaded sugar 0.5 div 0.2 det slit sol-x [003].raw- Type: 2Th/Th locked - Start: End: Step: Step time: s - Temp.: 25 C(Room) - Operations: Range Op. Merge Import [003] (*) - Acetaminophen paracetamol - C8H9NO2 - Y: %- d x by: 1. - WL: Monoclinic - I/Ic User S-Q68.5 % (*) - Sucrose - C12H22O11 - Y: %- d x by: 1. - WL: Monoclinic - I/Ic PDF0.7 - S-Q31.5 %- 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. Material % Acetaminophen 2.8% Sucrose 97.2%

75 Quantitative Analysis: Lower Detection Limits with Faster Detectors Sqrt (Counts) 2e5 1e5 1e % peak of impurity peak (0.08wt.%) (*) - Ibuprofen - C13H18O2 2-Theta - Scale Example: Ibuprofen with known amount of impurity Measurement circle: 500 mm VÅNTEC-1 detector 40 kv, 40 ma Step size: 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

76 Standard-based Quantitative Analysis: Powder Samples, Comparison Lin (Counts) Polymorph A Polymorph B For quantification based on single peak areas, the peak at approx can be used to best distinguish Form B from Form A, because there is no overlap Theta - Scale poly a ground 3 0.5div 500mm LynEye2.5 dg - Step: Operations: Import PolyB ground lynxeye 0.5dg div 2.5 dg soller - Step: Operations: Import

77 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.

78 Standard-based Quantitative Analysis: Calibration Curve Consistent sample preparation with identical sample volumes is necessary to get sufficient accuracy

79 Failure Analysis: Quality Control on Tablets Measurement on small tablet with 50 mg API without sample preparation Pure Polymorph A Pure Polymorph B Tablet with 50 mg API: Polymorph B present Tablet with 50 mg API: no Polymorph B Higher background of tablet scans caused by excipients. LynxEye detector: 0.5 divergence slit 4 soller slits /step 1 sec/step Measurement time: 10 minutes from 18 to 25

80 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.

81 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 databases There is considerable peak overlap between the two phases and preferred orientation for Ibuprofen

82 Quantitative Analysis of Test-Mixture: Rietveld Analysis using TOPAS Individual calculated curves are highlighted The full pattern can be used for quantitative analysis despite considerable peak overlap 14,000 12,000 beta d-mannitol % Ibuprofen % 10,000 8,000 Counts 6,000 4,000 2, ,000-4, Th Degrees

83 Percent Crystallinity Lin (Cps) Theta - Scale POLYMERDATA Converted fromuxdformat byconverted fromuxdformat by XCHVersion 1 FFT Smoothed - File: Poly.raw- Type: 2Th alone - Start: End: Operations: Bezier Background 4.571,1.000 Import QUARTZ - File: Quartz.raw- Type: 2Th/Th locked - Start: End: Step: Step time: 10. s - Temp.: 25 C(Room) - Time Started: 0 s - 2-Theta: Theta: Operations: YScale Mul Import Another critical piece of information that is important to the pharmaceutical community is how crystalline is a sample XRD is an excellent tool for determining this parameter Crystalline peaks are very sharp and defined Amorphous or noncrystalline peaks are very broad By simply dividing the areas under each of the peaks the percent crystallinity can be easily obtained

84 Percent Crystallinity Lin (Counts) When both amorphous and crystalline phases are present in the same material you will get a pattern that is a combination of both A large amorphous region with a crystalline region overlaid on top Again by obtaining the area under the curves and simply dividing the percent crystallinity can be obtained Theta - Scale POLYMERDATA Converted fromuxdformat byconverted fromuxdformat by XCHVersion 1 FFT Smoothed - File: Poly.raw- Type: 2Th alone - Start: End: Operations: Import POLYMERDATA Converted fromuxdformat byconverted fromuxdformat by XCHVersion 1 FFT Smoothed - File: Poly.raw- Type: 2Th alone - Start: End: Operations: Bezier Background 5.623,1.000 Import

85 Percent Crystallinity Lin (Counts) Theta - Scale POLYMERDATA Converted fromuxdformat byconverted fromuxdformat by XCHVersion 1 FFT Smoothed - File: Poly.raw - Type: 2Th alone - Start: End: Operations: Import POLYMERDATA Converted fromuxdformat byconverted fromuxdformat by XCHVersion 1 FFT Smoothed - File: Poly.raw - Type: 2Th alone - Start: End: Operations: Background 5.623,0.000 Import 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 curves The software then tells us that this sample is 25% crystalline and 75% amorphous The only issue with this technique is again the user intervention that needs to occur

86 Percent Crystallinity 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 crystallinity This 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

87 Structure Determination from Powder Data Peak Finding (FPA) Indexing, Space Group Determination Intensity Extraction LeBail, Pawley Structure Determination Structure Refinement "Profiling" LeBail, Pawley Structure Determination AND Refinement from y i (obs) TOPAS Approach Coelho (2000)

88 D8 ADVANCE Vαrio1 Monochromator for Transmission and Reflection Johansson-type monochromator for pure Kα 1 radiation Six pre-defined geometries for reflection and capillary transmission measurements Geometry change by moving the Vαrio1 along the track

89 Indexing of Ibuprofen with TOPAS Get the first 20 d-spacings by profile fitting for input file seed index_zero_error Bravais_Cubic_sgs Bravais_Trigonal_Hexagonal_sgs Bravais_Tetragonal_sgs Bravais_Orthorhombic_sgs Unique_Monoclinic_sgs Bravais_Triclinic_sgs load index_d { good }

90 Indexing of Ibuprofen Output after approx. 150 sec calculation time Space Group Un-indexed peaks GOF Zero error Lattice parameters Figure of merit versus cell volume

91 Indexing of Ibuprofen Run whole powder pattern fitting for best matching unit cells

92 Ibuprofen: Comparison with ICDD Database Lin (Counts) Note the missing lines in ICDD file With those lines not being resolved or detected, indexing from powder data becomes more difficult Pure Kα 1 radiation really does help for indexing Theta - Scale (*) - Ibuprofen - C13H18O2

93 Structure Determination TOPAS software for powder crystallography Indexing Structure solution Structure refinement Caffeine Anhydrous V = Å3 C8H10N4O2 5 molecules (rigid bodies) in the asymmetric unit 70 non-hydrogen atoms in asymmetric unit

94 Non-ambient Measurements: Stages for Use with Area Detector Anton Paar DHS 900 MRI BTS

95 Environmental Stages: Humidity Stage D8 ADVANCE powder diffractometer with integrated Hot-Humidity System

96 Lactose Monohydrate: Dehydration and Hydration in MRI Humidity Stage Lin (Counts) Room temperature sample as received Dehydrated at 160 C and cooled to 45 C Rehydrated at 40 C and 76% relative humidity LynxEye detector: 0.5 divergence slit /step 0.1 sec/step Theta - Scale File: lactose monohydrate at RT_0.5dg div Lynxeye1.5dg.raw Y mm - File: lactose monohydrate at 45C_after heating 0.5dg div Lynxeye1.5dg.raw Y mm - File: lactose monohydrate after rehydration at 40C 76pc hum.raw (I) - Lactose hydrate - C12H22O11 H2O

97 Temperature Study with VÅNTEC-1 Detector in Snapshot Mode Sample: beta d-mannitol 140 fixed scans with a 10 2theta angular coverage The sample was heated to 170 C and slow-cooled Measurement time for each snapshot: 2 sec The measurement was performed in air using a Pt strip heater Heating rate and cooling rate: 0.2 /sec Cursor at 169 C

98 Temperature Study with VÅNTEC-1 Detector in Snapshot Mode, Level Plot Sample: beta d-mannitol Alpha D-Mannitol + Beta D-Mannitol heating cooling Beta D-Mannitol

99 21CFR Part 11 is Good for You... Benefits of being compliant are numerous for areas where the FDA is 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

100 Meeting Quality System Regulations at 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 procedures For software, additional written standards exist, such as coding standards, configuration management, programmer qualifications, software version control, maintenance, formal testing of software/hardware, incident reporting and tracking, and disaster recovery (Bruker AXS SW404)

101 Meeting Quality System Regulations at Bruker AXS External system testing (holistic testing at the customer site) Bruker AXS IQ/OQ/PQ Procedure for regulated industries Bruker AXS Instrument Verification Procedure for all other customers* IQ OQ Internal system testing (component-based testing in the test field) Test procedure for internal IQ/OQ/PQ before shipping including a Final holistic test using the Bruker AXS Instrument Verification Procedure * System acceptance test required by Bruker AXS (subset of the Bruker AXS IQ/OQ/PQ Procedure) PQ

102 Meeting Quality System Regulations at Bruker AXS 21 CFR Part 11 To integrate into an FDA 21 CFR Part 11 (or OECD) compliant laboratory, DIFFRAC plus 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 records White Paper DIFFRAC plus BASIC: Meeting the Requirements of the FDA s 21CFR Part11 Regulation

103 Challenge us with your analytical tasks and expect comprehensive answers directly meeting your needs

104 Thank you for attending! Please provide feedback by completing our brief survey. Also, please type any questions you may have in the Q&A panel and click Send.

105 Upcoming events: PPXRD-07, The Pharmaceutical Powder X-ray Diffraction Symposium, February 2008, Orlando Pittcon, 3-7 March 2008, New Orleans