EP1751527A2 - Analyse et criblage de formes solides au moyen de la fonction de distribution de paires atomiques - Google Patents

Analyse et criblage de formes solides au moyen de la fonction de distribution de paires atomiques

Info

Publication number
EP1751527A2
EP1751527A2 EP05723818A EP05723818A EP1751527A2 EP 1751527 A2 EP1751527 A2 EP 1751527A2 EP 05723818 A EP05723818 A EP 05723818A EP 05723818 A EP05723818 A EP 05723818A EP 1751527 A2 EP1751527 A2 EP 1751527A2
Authority
EP
European Patent Office
Prior art keywords
substance
pdf
sample
traces
trace
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP05723818A
Other languages
German (de)
English (en)
Inventor
Simon Bates
Igor Ivanisevic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Catalent CTS Kansas City LLC
Original Assignee
SSCI Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SSCI Inc filed Critical SSCI Inc
Publication of EP1751527A2 publication Critical patent/EP1751527A2/fr
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
    • G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
    • G01N23/207—Diffractometry using detectors, e.g. using a probe in a central position and one or more displaceable detectors in circumferential positions

Definitions

  • This invention relates to the analysis and screening of solid forms using the atomic pair distribution function ("PDF").
  • PDF atomic pair distribution function
  • One embodiment of the invention is a method that comprises providing a PDF trace of a first sample of a substance, providing a PDF trace of a second sample of the substance, and comparing the PDF traces to determine whether the substance of the first sample and the substance of the second sample have the same or different solid forms.
  • the PDF trace is derived from the X-ray powder diffraction ("XRPD”) pattern of the solid substance.
  • This and other embodiments of the invention may be used, for example, to distinguish one solid form of a compound from another, to screen for new solid forms of a compound, or to determine whether a disordered crystalline compound has the same solid form as another crystalline sample of the compound.
  • the embodiments of the invention may be applied, for example, to a substance that is a chemical compound, for instance a pharmaceutical compound.
  • the embodiments of the invention may also be applied, for example, to a substance that is a mixture of chemical compounds, for instance a co-crystal.
  • FIG. 3 illustrates PDF traces of the highly crystalline solid substance (top) and the disordered crystalline solid substance (bottom) having the same solid form.
  • FIG. 4 illustrates XRPD patterns of a substance before cryogrinding (top), after 12 minutes of cryogrinding (middle) and after 30 minutes of cryogrinding (bottom).
  • FIG. 5 illustrates PDF traces of a substance before cryogrinding (top), after 12 minutes of cryogrinding (middle) and after 30 minutes of cryogrinding (bottom).
  • the substances used in the invention include chemical compounds, for example, pharmaceutical compounds. They include salts of chemical compounds, for instance pharmaceutical compounds as pharmaceutically acceptable salts. They also include mixtures of two or more chemical compounds, for instance cocrystals.
  • the substances of the invention include amorphous solid forms as well as crystalline solid forms. They may be, for example, cocrystals, hydrates, solvates, polymorphs, dehydrated hydrates, desolvated solvates, molecular complexes, and clathrates.
  • the term "crystalline" as used herein includes polycrystalline, microcrystalline, nanocrystalline, mesocrystalline, liquid crystalline, mesophases, and partially or wholly crystalline substances, as well as disordered crystalline substances.
  • the solid forms of the invention may be generated in any suitable manner. For example, a plurality of samples of a substance can be generated in capillary tubes or in wells of a well-plate. The samples may be crystallized in different environments, for instance using different solvents, different temperatures, different humidities, or different pressures. One skilled in the art will appreciate the variety of approaches that may be taken to generate different solid forms of a substance.
  • the PDF trace is derived from the XRPD pattern of a solid form.
  • computing platform 110 may be implemented on a distributed network, such as a network of computers connected, e.g., by a LAN, WAN, etc., or the Internet.
  • the PDF trace of a substance may be provided to computing platform 110 from input module 120.
  • the XRPD pattern of a substance may be provided to computing platform 110 from input module 120, and computing platform 110 calculates the PDF trace from the XRPD pattern.
  • the PDF traces or XRPD patterns may be received from, for example, storage device 124 or a computer readable medium or media linked to input interface 126.
  • Computing platform 110 may then store any information received from input module 120 in storage module 140.
  • Computer readable media may be implemented using physical media (e.g., a punch card), magnetic media (e.g., a magnetic disk or tape), optical media (e.g., an optical disk), a carrier wave (e.g., from a computer network, such as the Internet), etc.
  • Computing platform 110 may calculate the PDF trace from an XRPD pattern as detailed in Peterson et al., "Improved measures of quality for the atomic pair distribution function," J. Appl. Cryst, vol. 36, pp. 53-64 (2003), the contents of which are incorporated by reference herein.
  • the PDF is the instantaneous atomic density-density correlation function, which describes the atomic arrangements in materials.
  • the sin transform can be evaluated over an artificial range of "r" values not determined by the measurement range.
  • the PDF can be reconstructed using an "r" step size of 0.2 Angstroms, which is equivalent to measuring out to 180 degrees 2Theta using an x-ray wavelength of 1.0 Angstroms.
  • the resulting PDF is reconstructed over the range of inter atomic distances of interest and displayed in real space Angstroms.
  • the PDF trace provides a unique finger-print of the inter-atomic distances that define a particular solid form. As such, it provides a valuable tool to match solid forms and, more particularly, to identify relationships between disordered crystalline and other crystalline substances.
  • PDF peak positions correspond to atom - atom distances and the relative peak intensities correspond to the number of atoms having that specific separation. Both the peak positions and relative peak intensities should match between PDF traces of the same solid form, within experimental limitations. However, when matching crystalline and disordered crystalline substances, relative peak intensities of intermolecular peaks should be adjusted because of loss of order.
  • An automatic matching algorithm for PDF traces from laboratory X- ray powder diffraction data may be provided to score the degree of sameness by matching peak position and relative peak intensities over a range of inter-atomic distances from 5.0 Angstroms out to 50 Angstroms, for example. For disordered materials, the larger inter-atomic distance cut-off can be automatically reduced as the degree of disorder increases.
  • Results of operations performed by computing platform 110 may be stored, for example, in storage module 140.
  • PDF traces may be stored in a PDF trace database 154
  • Results of the comparison of PDF traces may also be stored in storage module 140.
  • Storage module 140 may be implemented as any appropriate type of computer readable medium or media.
  • An embodiment of the invention comprises generating a plurality of solid samples of a substance, such as a chemical compound, preparing XRPD patterns of the solid samples, calculating the corresponding PDF traces of the solid samples, and grouping the plurality of PDF traces by similarly into two or more groups.
  • the PDF traces may be grouped, for example, using hierarchical cluster analysis.
  • the grouping of PDF traces by similarity into different groups can identify those samples likely having the same solid form (within each group) and those likely having different solid forms (between groups).
  • the pattern matching technique disclosed in US 2004/0103130 A1 may be used to group together PDF traces that most likely represent the same solid form.
  • a subsequent step could involve practicing an aspect of the embodiment of Example 4 of comparing the PDF trace of one or more of the resulting solid forms to the PDF trace of a known solid form of the substance to determine whether any of the solid forms of the substance made in a production run are new.
  • This method as well as that of Example 1 , may be implemented, for example, to manually or in an automated fashion match or distinguish solid forms of samples made in a production run.
  • a subsequent step could involve practicing an aspect of the embodiment of Example 4 of comparing the PDF trace of one or more of the resulting solid forms to the PDF trace of a known solid form of the substance to determine whether any of the solid forms of the substance made in a production run are new.
  • Example 3 Another embodiment of the invention comprises generating a plurality of solid samples of a substance, such as a chemical compound, preparing XRPD patterns of the solid samples, grouping the plurality of XRPD patterns of the substance by similarly into two or more groups, creating a composite XRPD pattern for each group, calculating the corresponding PDF trace of each of the composite XRPD patterns, and comparing the PDF traces to determine whether the groups of samples represent the same or different solid form of the substance.
  • the XRPD patterns may be grouped by similarity using the pattern matching technique disclosed US 2004/0103130 A1.
  • a subsequent step could involve practicing an aspect of the embodiment of Example 4 of comparing the PDF trace of one or more of the resulting solid forms to the PDF trace of a known solid form of the substance to determine whether any of the solid forms of the substance made in a production run are new.
  • Example 4 Another embodiment of the invention comprises generating one or more solid test samples of a substance, such as a chemical compound, preparing XRPD patterns of the one or more solid test samples, calculating the corresponding PDF traces of the one or more solid test samples, and comparing one or more of the PDF traces of the test samples to the PDF trace of a known solid form of the substance to determine whether the test samples are of the same or different solid form as the known solid form.
  • This embodiment may be used, for example, to determine if a solid form produced from a production run is a disordered relative of a known solid form, or if it is a new solid form. This embodiment may also be used to screen various solid forms on the basis of their PDF trace.
  • the present invention comprises a method of screening for new solid forms of a substance, which comprises providing the PDF trace of each of a plurality of samples of the substance, comparing the PDF traces of the samples to the PDF traces of one or more known solid forms of the substance, and identifying those samples that have a PDF trace different from that of the known solid forms.
  • Example 5 It is often desirable to know which crystalline solid form is the parent of a given disordered crystalline material.
  • Another embodiment of the invention therefore comprises calculating the PDF trace of a disordered crystalline solid form of a substance and comparing it to the PDF trace of the another crystalline sample of the substance, for example one having a known crystalline solid form, to determine whether the two substances have the same solid form, being related through disorder, or whether the two have different solid forms.
  • the range of the PDF transform in real space should be truncated to below the average crystal size in the disordered material in order to maximize the match score. Inspection of the PDF transform from the disordered material may identify the maximum real space range to be matched.
  • the pattern comparison system may set the maximum range to the real space distance where the PDF transform for the disordered material falls to a flat zero line. Typically for most small and medium organic molecules this distance is between 15 Angstroms and 30 Angstroms for very disordered material.
  • FIG. 2 illustrates a typical disordered XRPD pattern (top) and how it compares to the XRPD pattern of a highly crystalline compound (bottom). It is difficult to determine the exact relationship between the two purely through visual inspection of the XRPD patterns, as the peaks in the disordered pattern are quite broad.
  • FIG. 2 illustrates a typical disordered XRPD pattern (top) and how it compares to the XRPD pattern of a highly crystalline compound (bottom). It is difficult to determine the exact relationship between the two purely through visual inspection of the XRPD patterns, as the peaks in the disordered pattern are quite broad.
  • FIG. 2 illustrates a typical disordered XRPD pattern (top) and how it compares to the XRP
  • Example 6 [047] Another embodiment of the invention comprises identifying residual crystalline "memory" within an amorphous matrix of a substance.
  • FIG. 4 illustrates XRPD patterns of a compound before cryogrinding (top, 0 minutes), after 12 minutes of cryogrinding (middle) and after 30 minutes of cryogrinding (bottom).
  • FIG. 5 illustrates the corresponding PDF traces of the materials before cryogrinding (top) after 12 minutes of cryogrinding (middle) and after 30 minutes of cryogrinding (bottom). A comparison of the PDF traces clearly shows that the two cryoground substances retain residual crystallinity of the original crystalline substance.
  • Example 7 Another embodiment of the invention comprises determining the crystalline correlation length of a disordered crystalline substance.
  • a PDF trace derived from an XRPD pattern of a disordered crystalline substance will show a fall off in signal at larger atom-atom distances. By tracing the signal fall off to the base line, an estimation of the crystalline correlation length can be achieved. This correlation length can be contrasted to the length scale extracted from the observed peak broadening in the XRPD pattern using the Scherrer equation.
  • a regression analysis of PDF peak signal values can be used to determine the crystal correlation lengths (crystal size or crystal perfection) by 1 ) determining peak signal in PDF peaks as a function of atom-atom distance, 2) performing linear regression least squares best estimate of line through the peak signal values, and 3) determining atom-atom distance where the best estimate line crosses the base line of the PDF plot.

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  • Chemical & Material Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Analysing Materials By The Use Of Radiation (AREA)

Abstract

La présente invention se rapporte à un procédé consistant à produire une trace PDF (fonction de distribution de paires) d'un premier échantillon de substance, à produire une trace PDF d'un second échantillon de la substance et à comparer les traces PDF de manière à déterminer si la substance du premier échantillon et la substance du second échantillon possèdent des formes solides identiques ou différentes. Ce mode de réalisation de l'invention peut être mis en oeuvre, par exemple, pour distinguer une forme solide d'un composé d'une autre forme, afin d'effectuer un criblage permettant de déterminer de nouvelles formes solides d'un composé, ou pour déterminer si un composé cristallin désordonné présente la même forme solide qu'un autre échantillon cristallin du composé.
EP05723818A 2004-02-24 2005-02-24 Analyse et criblage de formes solides au moyen de la fonction de distribution de paires atomiques Ceased EP1751527A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54697604P 2004-02-24 2004-02-24
PCT/US2005/006114 WO2005082050A2 (fr) 2004-02-24 2005-02-24 Analyse et criblage de formes solides au moyen de la fonction de distribution de paires atomiques

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EP1751527A2 true EP1751527A2 (fr) 2007-02-14

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Publication number Priority date Publication date Assignee Title
WO2007038398A1 (fr) * 2005-09-26 2007-04-05 Ssci, Inc. Procedes de caracterisation de compositions
WO2009091856A2 (fr) 2008-01-18 2009-07-23 Merck & Co., Inc. Inhibiteurs de bêta-lactamase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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WO2005082050A3 (fr) 2007-08-30
WO2005082012A2 (fr) 2005-09-09

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