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WO2006114705A1 - Systeme automatise d'analyse et de ciblage par birefringence - Google Patents

Systeme automatise d'analyse et de ciblage par birefringence Download PDF

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Publication number
WO2006114705A1
WO2006114705A1 PCT/IB2006/001067 IB2006001067W WO2006114705A1 WO 2006114705 A1 WO2006114705 A1 WO 2006114705A1 IB 2006001067 W IB2006001067 W IB 2006001067W WO 2006114705 A1 WO2006114705 A1 WO 2006114705A1
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Prior art keywords
samples
targets
sample
energy beam
regions
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Dainius Machikenas
Christopher Scott Seadeek
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/21—Polarisation-affecting properties
    • G01N21/23—Bi-refringence

Definitions

  • This invention relates to the characterization of samples using targetable energy beams, such as powder x-ray diffraction, infrared spectroscopy, Raman spectroscopy, and the like, and more particularly, to methods, devices, and systems for targeting and characterizing crystalline regions of solid-state samples using birefringence.
  • targetable energy beams such as powder x-ray diffraction, infrared spectroscopy, Raman spectroscopy, and the like
  • HTS high throughput screening
  • sample arrays which may be prepared using multi-vessel reactors having detachable bases.
  • the base serves as the bottom of individual reaction vessels and as a substrate for depositing compound samples during crystallization or precipitation.
  • the samples may appear as a regular or irregular array of discrete solid films disposed on the surface of the substrate.
  • Existing HTS systems often employ one or more 96-well microtiter plates, so the sample arrays frequently utilize a similar layout.
  • the regions of the substrate containing the compound samples are transparent or translucent so that light may be transmitted through the samples. Useful substrates are thus often made of glass plates and the like.
  • HTS systems employ various techniques for rapidly characterizing the solid samples, including powder x-ray diffraction (PXRD), infrared (IR) spectroscopy, Raman spectroscopy, and the like.
  • PXRD powder x-ray diffraction
  • IR infrared
  • Raman spectroscopy Raman spectroscopy
  • HTS systems employ various techniques for rapidly characterizing the solid samples, including powder x-ray diffraction (PXRD), infrared (IR) spectroscopy, Raman spectroscopy, and the like.
  • PXRD powder x-ray diffraction
  • IR infrared
  • Raman spectroscopy Raman spectroscopy
  • polarized light passes through the sample array, and a camera, which includes a polarizer that filters out light having the same polarization as the polarized light, records one or more images of the samples. Crystalline and amorphous regions of the samples appear as light (birefringent) and dark (non-birefringent) regions in the images, respectively. The images are subsequently used to target crystalline regions.
  • birefringence analysis still require the use of manual targeting, which like simple visual inspection, is time consuming and subject to operator error.
  • Certain standalone birefringence stations can be used to automatically target crystalline sample regions.
  • targeting birefringence analysis
  • beam positioning are carried out on separate instalments.
  • the present invention helps address one or more of the problems set forth above.
  • One aspect of the present invention provides a method of characterizing one or more samples using an apparatus having an energy beam and a polarizer.
  • the method comprises the steps of: illuminating the samples with polarized light; analyzing light from the samples using a polarizer to reveal one or more birefringent regions of the samples; selecting one or more targets from among the birefringent regions; directing the energy beam at the targets; and detecting the energy beam following interaction with the targets.
  • Another aspect of the present invention provides a device for characterizing one or more samples using an apparatus having an energy beam and a polarizer.
  • the device comprises a software routine tangibly embodied on a computer- readable medium and configured to select, with or without user intervention, one or more targets from among birefringent regions of the samples and to direct the energy beam at the targets, wherein the birefringent regions are located by illuminating the samples with polarized light and by analyzing light from the samples using the polarizer.
  • a further aspect of the present invention provides a system for characterizing one or more samples using an apparatus having an energy beam and a polarizer.
  • the system comprises a computer having a graphical user interface enabling a user to interact with a software routine running on the computer, the software routine configured to select, with or without user intervention, one or more targets from among birefringent regions of the samples and to direct the energy beam at the targets, wherein the birefringent regions are located by illuminating the samples with polarized light and by analyzing light from the samples through the polarizer.
  • An additional aspect of the present invention provides a system for targeting and characterizing crystalline regions of one or more samples.
  • the apparatus comprises: an energy beam and a first detector, the energy beam and the first detector adapted to characterize the crystalline regions of the samples; a source of polarized light for illuminating the samples, a second detector which is adapted to sense the polarized light, and a polarizer which is positioned between the samples and the detector so that illuminating the samples with polarized light reveals one or more birefringent regions of the samples; and a computer which enables a user to interact with a software routine running on the computer, the software routine configured to select, with or without user intervention, one or more targets from among the birefringent regions of the samples and to direct the energy beam at the targets.
  • the present invention provides numerous advantages over existing targeting systems.
  • the fully automated system avoids positioning errors inherent in manual targeting systems.
  • the inventive system automatically finds optimal positions (coordinates) for data collection, reduces experiment time, and avoids the cost and complexity associated with the use of separate birefringence stations. Since the system performs most of the steps without user input (other than initial experimental setup), the system reduces potential for human error and can be run during off-hours. Finally, the system provides numerical representations of strength of birefringence, which is useful for reporting purposes and subsequent analysis.
  • FIG. 1 depicts a system 10 for targeting and characterizing one or more solid samples having crystalline (birefringent) regions.
  • FIG. 2 shows a method 100 for targeting and characterizing crystalline regions of the sample array 18 using the system 10 shown in FIG. 1.
  • FIG. 3 to FIG. 5 show three screens 200, 300, 400 from a user interface for selecting screening options 102 of FIG. 2.
  • FIG. 6 illustrates a typical sample array 18'.
  • FIG. 7 and FIG. 8 show examples of an original sample image and corresponding mapped sample image that were prepared using a color-overlay procedure.
  • FIG. 9 shows a composite picture of a sample array.
  • FIG. 10 shows a screen shot 600 of a manual targeting portion of the software.
  • FIG. 11 to FIG 14 show a method for automated targeting.
  • FIG. 15 shows a method for applying boundary conditions for each sample- image.
  • FIG. 16 shows a target picture 800.
  • FIG. 17 shows a flow chart, which describes various software routines used to implement the method 100 shown in FIG. 2.
  • FIG. 18 shows a composite picture of the birefringent samples from the Example.
  • FIG. 19 shows a corresponding composite picture of the sample target pictures from the Example.
  • FIG. 20 shows PXRD patterns for various samples from the Example.
  • Solvate refers to a molecular complex comprising a biologically active compound and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g., ethanol).
  • solvent molecules e.g., ethanol
  • Hydrate refers to a solvate comprising a biologically active compound and a stoichiometric or non-stoichiometric amount of water.
  • “Pharmaceutically acceptable complexes, salts, solvates, or hydrates” refers to complexes, acid or base addition salts, solvates or hydrates of claimed and disclosed compounds, which are within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Treating refers to reversing, alleviating, inhibiting the progress of, or preventing a disorder or condition to which such term applies, or to preventing one or more symptoms of such disorder or condition.
  • Treatment refers to the act of "treating,” as defined immediately above.
  • FIG. 1 provides a schematic drawing of a system 10 for targeting and characterizing one or more solid samples having crystalline (birefringent) regions.
  • the system 10 is useful for characterizing sample arrays generated using HTS methodologies, including arrays of biologically active compounds, including drug candidates.
  • the system 10 includes an apparatus for characterizing the solid samples, such as a PXRD diffractometer, an ER spectrometer, a Raman spectrometer, and the like, each having a targetable energy source 12 and a detector 14.
  • the system 10 includes a motorized stage 16, which communicates with a computer (not shown) and is adapted to position a sample array 18 relative to an energy beam 20 emanating from the targetable energy source 12.
  • the motorized stage 16 moves the sample array 18 so that the energy beam 20 strikes each of the targeted regions of the samples. After striking a targeted region, the detector 14 senses changes in the energy beam 18, which serve to characterize the sample containing the targeted region.
  • the system 10 includes elements for targeting crystalline regions of the samples using birefringence.
  • the targeting elements include a source of polarized light 22, a light detector 24, such as a digital camera, and an analyzer 26.
  • the source of polarized light 22 includes a light panel 28 together with a first polarizer 30 (e.g., an optical polarizing filter such as polarizing film), though other embodiments may employ a source of inherently polarized light, such as a laser or a laser diode.
  • the analyzer 26 comprises a second polarizer that filters out light having the same polarization as the polarized light.
  • polarized light passes through the sample array 18 and the analyzer 26 and is subsequently captured by the light detector 24.
  • crystalline and amorphous regions of the samples appear as light (birefringent) and dark (non-birefringent) regions within each of the samples, respectively.
  • the sample array 18, or at least the portions of the sample array substrate that contain the samples is transparent.
  • the polarization directions of the first polarizer 30 and the analyzer 26 are usually orthogonal (i.e., they are cross-polarized) unless the sample array substrate is birefringent.
  • the polarization of the analyzer 26 can be adjusted to account for any changes in polarization due to a birefringent substrate.
  • FIG. 2 shows a method 100 for targeting and characterizing crystalline regions of the sample array 18 using the system 10 shown in FIG. 1.
  • the method 100 is described in terms of a specific characterization apparatus, namely a BRUKER® D8 x-ray diffraction system running GADDS® software, and in terms of sample arrays 18 having sample locations corresponding to the well positions in a standard 96- or (staggered) 48-well microtiter plate.
  • the method 100 employs custom software routines written in the Visual Basic programming language, running under the WINDOWS® operating system.
  • the method 100 can be applied to other instruments that employ targetable energy beams 20, including IR and Raman spectrometers, and to regular or irregular sample arrays 18 having more or less than 96 samples. It should also be clear that the method 100 may employ virtually any programming language, running under virtually any operating system, and that at least some steps of the method 100 may be carried out manually (i.e., without software).
  • the method 100 includes selecting screening options 102 via a user interface comprised of three screens 200, 300, 400 shown in FIG. 3 to FIG. 5.
  • the first screen is a run setup screen 100, which allows a user to define the parameters of the run. As shown in FIG.
  • the user can input user id, output directory, report path, sample array (plate) information (wells to scan, 48- or 96-well plate, x,y,z-position of the first sample, Al, on the motorized stage), scan options (exposure time, oscillation, background subtraction, expanded 2-theta scan, zoomed in picture), analysis options (composite stitching, birefringence analysis, manual or automatic targeting), and plate conditions (crystallization conditions, sample prep, comments, initial temperature, cooling rate, final temperature, and stirring rate).
  • sample array (plate) information wells to scan, 48- or 96-well plate, x,y,z-position of the first sample, Al, on the motorized stage
  • scan options exposure time, oscillation, background subtraction, expanded 2-theta scan, zoomed in picture
  • analysis options composite stitching, birefringence analysis, manual or automatic targeting
  • plate conditions crystallization conditions
  • advanced users may also decide to enter an image setup screen 300.
  • the software generates a 640x480 pixel image or picture of each sample, but has the ability to crop these pictures to reduce analysis time.
  • the software allows cropping to occur anywhere within the picture so that, if desired, the user may request that only the lower right 100x100 pixel area be analyzed.
  • the software defaults to a 480x480 pixel area in the middle of each picture. Typically, this is a sufficient area to capture the entire sample using the lowest zoom level of the camera.
  • the image setup screen 300 includes a visual layout, which shows the cropped area and the relative size of the sample within the picture.
  • the user interface includes a third screen 400, which allows users to rescan a previous plate. This option permits users to expose samples to different conditions and to allow for the rescan of samples without repeating the targeting step described below.
  • the user is prompted for the location of the previous data and a new output path. The information is loaded into the software, which skips directly to the collection of PXRD patterns discussed below.
  • the method 100 provides for acquiring 104 digital images or pictures of the samples.
  • the software generates a "slam script," which moves the motorized stage to successively align the center of each sample 502 (based on the coordinates of the "Al" sample and the geometry of the sample array) with the focal line of the digital camera.
  • the GADDS software executes the slam script, which acquires a picture of the center of each sample. A predefined background "blank" picture is also acquired. As shown in FIG. 6, which illustrates a typical sample array 18', the position of the blank picture is determined from an offset of the location of the Al sample 504.
  • the offsets are such that the picture should end up near the left edge of the sample array 18' between row A and B.
  • the software uses quasi-optimized paths 506, 508 to reduce the time required for acquiring pictures of a staggered 48-sample and 96-sample array 18', respectively. This step typically takes about ten to fifteen minutes to acquire the images of 96 samples.
  • the software creates and analyzes 24-bit images. Each pixel is a combination of three 8-bit samples, which describe the intensity of three primary colors (red, blue, and green). Eight-bit sampling allows for 2 8 or 256 different levels of intensity of each color, which in turn provides 256 3 or 16.7 million different color values. These color values are assigned to each pixel with a scale ranging from 0 (absolute dark) to 16.7 million (absolute white).
  • the method 100 provides for analyzing 108 the images for birefringence.
  • any pixels having brightness above a threshold are considered to be birefringent, while any pixels having brightness below the threshold are considered to be non- birefringent.
  • the threshold is determined based on a calculation of the average intensity of the background "blank" picture.
  • the software creates a color overlay to make it more apparent as to which pixels the software considers to be birefringent.
  • FIG. 7 and FIG. 8 show examples of an original sample image and corresponding mapped sample image that were prepared using the color-overlay procedure. A scale from dark blue to bright red indicates the intensity of the pixels as they increase from just above the threshold to absolute bright white.
  • FIG. 9 shows a composite picture of the sample array.
  • One attribute of the software is the ability to stitch files together to form a composite map of the sample array, as shown in FIG. 9. Any samples without pictures are replaced with a blank white picture (not shown in FIG. 9).
  • Composite pictures can be generated for the original pictures (without color overlay), the birefringent pictures (with color overlay), and the final target pictures (described below), and can be selected during the run setup mentioned earlier.
  • the method 100 also includes targeting 110 crystalline regions within each of the samples. The method 100 provides both manual and automatic target selection. Manual targeting allows a user to select the spots or regions for characterization after the completion of the birefringence analysis 108.
  • the software permits the user to select up to ten targets per sample, although rarely more than two targets are selected for each sample.
  • FIG. 10 which shows a screen shot 600 of the manual targeting portion of the software, the user may examine digital images of the samples before and after birefringence analysis. Using a mouse, the user positions an outline 602 of the target area 604 over the sample 606 to select the target position of the x-ray beam.
  • Automated targeting uses a method shown in FIG. 11 to FIG 14 to determine the targets for each sample.
  • the software starts at the top left and moves ten pixels to the right until the end of the row has been reached and then moves down ten pixels to start the next row.
  • the software evaluates a potential target area (group of pixels) centered at that location. Every pixel within the potential target area is evaluated for its pixel number and intensity number, which are described below. The potential target area with the greatest total intensity value (i.e., individual pixel intensities summed over all of the pixels in the target area) is selected as the target.
  • the method permits dual targeting: the method selects two targets if one target comprises a comparatively small number of very bright (birefringent) pixels, while another target comprises a comparatively large number of less bright pixels.
  • the method attempts to select the most representative targets for each sample, based on several heuristic criteria. For example, the method assumes that several overlapping target areas are likely to exhibit similar birefringence. The method also assumes that targets having the brightest pixels in the middle of the target area will result in more representative PXRD patterns than targets having the brightest pixels along the edge of the target area. Furthermore, the method assumes that targets located near the center of the sample will result in more representative PXRD by avoiding cross-contamination of any neighboring samples.
  • the method 100 uses information about the size and shape (round, square, octagon, ellipse, etc) of the analysis beam 20 (see FIG. 1).
  • the software can accommodate any shape as long as it can be described mathematically.
  • the collimator produces a beam with a width of 0.5 mm.
  • the beam strikes the sample at a known angle, ⁇ , which is measured from the surface of the sample array, and travels a known (horizontal) distance (d).
  • ⁇ the angle
  • d horizontal distance
  • X - Xc 2 (Y - Yc) 2 a 2 b 2
  • Xc and Yc are the x- and y-coordinates of the center of the ellipse
  • 2a and 2b describe the major and minor axis, respectively.
  • the major axis corresponds to the direction of the collimator-detector, and for the known values of ⁇ and d is 5 mm; the minor axis corresponds to the beam width (0.5 mm width).
  • a calibration can be used to interconvert the physical dimensions of the sample array and pixel distances in the 640x480 pixel images.
  • An ellipse that is 5 mm long and 0.5 mm wide corresponds to an ellipse that is of 240 pixels long and 24 pixels wide on a zoom level of 1 of the BRUKER® D-8 x-ray diffractometer.
  • each pixel in the boundary rectangle 702 is first evaluated to determine if it exists (i.e., lies within the sample image 700) and then to determine whether it is lies within the elliptical targeting area 704. Pixels falling outside of the sample area 706 are discarded, as are pixels 708 located within the rectangular boundary 702, but outside of the elliptical targeting area 704.
  • Each pixel in the sample images is assigned two numbers — a pixel value and a pixel intensity. The pixel value is a binary number, either 0 or 1.
  • a pixel is assigned a 0 if its intensity is below a given threshold and is assigned a value of 1 if it is above the threshold.
  • the pixel value can be thought of as a yes/no indication of whether the pixel is above the threshold, but it provides no information about how bright the pixel actually is.
  • the pixel values are then linearly scaled by their distance from the center of the target area (ellipse) so that pixels farthest away have a value of 1 and those directly at the center of the target area have a value of 3.
  • the pixel intensity is a scaled number, which indicates the brightness of a pixel.
  • the brightest (white) pixels are assigned a value of 10 while those just above the threshold are assigned a value of 1.
  • the pixel intensities are scaled by their linear distance from the center of the target ellipse, so that the brightest pixel at the center of the target area would have an intensity of 30.
  • the total pixel value and total birefringent value are the sum of all the pixel numbers and birefringent numbers of all the pixels in the target area. These numbers are then scaled by their distance from the center of the picture so that targets at edge of the sample image are scaled by a factor of 1, while those in the center of the sample image are scaled by a factor of 1.2.
  • the method 100 also includes creating 112 a target picture.
  • the scaled picture generated during the birefringence analysis is overlaid with the targets to create the target picture 800, which is shown in FIG. 16.
  • Targets that the software automatically generates appear as gray outlines 802 in the target picture 800, while targets that the user selects appear as white outlines (not shown).
  • the software overlays the birefringence number on the lower right portion of the target picture 800. This number represents the total pixel intensity of the picture relative to the most birefringent sample on the plate. If desired, the software can stitch together target pictures 800 to create a composite picture of the sample array similar to that shown in FIG. 9.
  • the method 100 also includes the step of determining 114 stage coordinates for the targets.
  • the pixel distances from the center of the sample images to the center of the target areas in both the x- and y-directions are first determined.
  • the pixel distances are then converted into stage distances using the calibration between motorized stage-distance and the pixel distance for a given zoom setting.
  • the stage coordinates for targets are subsequently used to generate a slam script, which the GADDS® software uses to collect PXRD data.
  • the method also includes the step of updating 116 a database, which is an EXCEL® file located on a network shared drive.
  • a database which is an EXCEL® file located on a network shared drive.
  • the software updates that database, which includes information about each of the samples (compound, counterions, solvents, etc.) to include run set-up information (date, operator, sample array conditions, etc.), and birefringence and targeting information (birefringence number, picture location, number of targets, target coordinates, etc.).
  • the method also includes collecting 118 and analyzing 120 PXRD patterns.
  • the GADDS® software executes the slam script, which drives the motorized stage to the location of each target area.
  • the files generated are renamed and transferred to a project output directory.
  • FIG. 17 shows a flow chart, which describes various software routines used to implement the method 100 shown in FIG. 2.
  • a GADDS® slam script called BATS.slm.
  • the main function of this file is to keep track of the process and to call the right routines, files, or programs at the correct time.
  • the system is composed of four Visual Basic executable files, two instruction files (.ini files), three GADDS® slam scripts (.slm files) and external programs, such as GADDS® and MraView® (image manipulation software).
  • Suitable processors include, for example, both general and special purpose microprocessors.
  • a processor receives instructions and data from a read-only memory and/or a random access memory.
  • Storage devices suitable for tangibly embodying computer program instructions and data include all forms of non- volatile memory, including, for example, semiconductor memory devices, such as EPROM (erasable programmable read-only memory), EEPROM (electrically erasable programmable read-only memory), and flash memory devices; magnetic disks such as internal hard discs and removable disks; magneto-optical disks; and optical disks, including CDs (compact disks) and DVDs (digital video disks) such as CD-ROM and DVD-ROM (read-only memory) disks, CD-R and DVD-R (recordable) disks, and CD-RW (rewritable) and DVD-RW disks.
  • ASICs application-specific integrated circuits
  • a computer system having devices for displaying information to the user and for allowing the user to input information to the computer system.
  • Useful display devices include a monitor, LCD screen, plasma screen and the like; suitable input devices include a keyboard, which can be used with a pointing device such as a pressure-sensitive stylus, a touch pad, a mouse or a trackball.
  • the computer system may provide a graphical user interface through which the computer routines interact with the user.
  • the pharmaceutically active compounds are typically capable of forming pharmaceutically acceptable salts.
  • These salts include, without limitation, acid addition salts (including di-acids) and base salts.
  • Pharmaceutically acceptable acid addition salts include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like.
  • Pharmaceutically acceptable base salts include nontoxic salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines.
  • suitable metal cations include, without limitation, sodium cations (Na + ), potassium cations (K + ), magnesium cations (Mg 2+ ), calcium cations (Ca 2+ ), and the like.
  • suitable amines include, without limitation, N, ⁇ P-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, iV-methylglucamine, and procaine.
  • S. M. Berge et al. "Pharmaceutical Salts," 66 J. ofPharm. ScL, 1-19 (1977); see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).
  • Certain physical properties e.g., solubility, crystal structure, hygroscopicity, etc.
  • a compound's free base, free acid, or zwitterion may differ from its acid or base addition salt.
  • the pharmaceutically active compounds may exist in both unsolvated and solvated forms and as other types of complexes besides salts.
  • Useful complexes include clathrates or compound-host inclusion complexes where the compound and host are present in stoichiometric or non-stoichiometric amounts.
  • Useful complexes may also contain two or more organic, inorganic, or organic and inorganic components in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized, or non-ionized.
  • Pharmaceutically acceptable solvates also include hydrates and solvates in which the crystallization solvent may be isotopically substituted, e.g. D 2 O, ⁇ Vacetone, O 6 - DMSO, etc.
  • a stock solution of 2,6-di-isopropylaniline was prepared by mixing 1.074 g of DIPA with 10 mL methanol. Aqueous stock solutions (0.05 M) of the acids listed in the Table 2 were also prepared. A liquid handling system similar to the system described in US20030124028A1 was used to deliver 6.8 mg of DIPA into a 96-well crystallizer, and 1 equivalent of each acid was added, as shown in the Table 2. Solvents were allowed to evaporate by gently blowing air over each sample using a 96-port evaporator. The solvents (0.23 mL) shown in Table 2 were delivered by the system so as to make target 30 mg/mL solutions (calculated with respect to DIPA).
  • the whole crystallizer was then equilibrated at 35 0 C for 2 hours followed by slow evaporation of solvents at room temperature.
  • the sample substrate borosilicate glass or similar
  • BATS birefringence analysis and targeting system
  • the sample substrate was placed in an opening of matching dimensions in a light box, equipped with plastic sheet linear polarizer filter, while the instrument camera was equipped with another polarizer, acting as an analyzer filter.
  • the library information from the liquid handler was then retrieved and experimental parameters entered by an operator, such as output directory for storing experimental results, powder X-ray diffraction experiment time, etc. No further operator input was needed for subsequent steps.
  • the BATS software controlled the instrument to take digital polarized light pictures of each position, analyze the pictures to determine whether enough birefringent sample was present and if so, to find optimal positions (coordinates) for X-ray analysis. Pictures were updated with birefringence numerical values (birefringence numbers) and targeted location drawn on the pictures (for reporting purposes).
  • the individual pictures were stitched together into a 96-sample array format picture for convenient visualization and a sample database was updated with birefringence numbers and target information.
  • the BATS software then generated a final script (macro) to control the instrument for data collection at targeted locations.
  • the software identified powder diffraction patterns of the same acids (when available) and overlaid them inside the powder X-ray diffraction analysis software (called EVA) along with, when available, reference powder diffraction pattern of the acid and starting material (here, the starting material is in a liquid state).
  • EVA powder X-ray diffraction analysis software
  • FIG. 18 shows a composite picture of the birefringent samples
  • FIG. 19 shows a corresponding composite picture of the sample target pictures
  • FIG. 20 shows PXRD patterns for selected samples.
  • Nicotinic Toluene B 1 l_Nicotin_Toluene 6.8 0.23

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Abstract

L'invention concerne des procédés, des dispositifs et des systèmes de ciblage et de caractérisation de zones cristallines d'échantillons solides utilisant la biréfringence. Les données acquises d'une image de biréfringence servent à cibler des zones cristallines à l'aide de techniques complémentaires, telles que la cristallographie par rayons X, la spectroscopie infrarouge, la spectroscopie Raman, et analogue.
PCT/IB2006/001067 2005-04-27 2006-04-18 Systeme automatise d'analyse et de ciblage par birefringence Ceased WO2006114705A1 (fr)

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US60/675,562 2005-04-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10247661B2 (en) 2016-07-20 2019-04-02 Cook Medical Technologies Llc Optical technique for coating characterization

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051919A2 (fr) * 2000-01-07 2001-07-19 Transform Pharmaceuticals, Inc. Formation, identification et analyse a productivites elevees de formes solides diverses
US20030118078A1 (en) * 2001-08-10 2003-06-26 Carlson Eric D. Apparatuses and methods for creating and testing pre-formulations and systems for same
US20040021803A1 (en) * 2002-06-19 2004-02-05 Ewald Moersen Method of determining local structures in optical crystals

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051919A2 (fr) * 2000-01-07 2001-07-19 Transform Pharmaceuticals, Inc. Formation, identification et analyse a productivites elevees de formes solides diverses
US20030118078A1 (en) * 2001-08-10 2003-06-26 Carlson Eric D. Apparatuses and methods for creating and testing pre-formulations and systems for same
US20040021803A1 (en) * 2002-06-19 2004-02-05 Ewald Moersen Method of determining local structures in optical crystals

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10247661B2 (en) 2016-07-20 2019-04-02 Cook Medical Technologies Llc Optical technique for coating characterization

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