WO2008035960A2 - Procédé de préparation d'un co-cristal - Google Patents

Procédé de préparation d'un co-cristal Download PDF

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Publication number
WO2008035960A2
WO2008035960A2 PCT/NL2007/000226 NL2007000226W WO2008035960A2 WO 2008035960 A2 WO2008035960 A2 WO 2008035960A2 NL 2007000226 W NL2007000226 W NL 2007000226W WO 2008035960 A2 WO2008035960 A2 WO 2008035960A2
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WO
WIPO (PCT)
Prior art keywords
moiety
aci
molecule
molecular model
solvent
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PCT/NL2007/000226
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English (en)
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WO2008035960A3 (fr
Inventor
Benjamin Mckay
Erik-Jan Ras
Jaroslaw Marek Mazurek
Peter Cains
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Avantium International B.V.
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Publication of WO2008035960A2 publication Critical patent/WO2008035960A2/fr
Publication of WO2008035960A3 publication Critical patent/WO2008035960A3/fr

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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/30—Prediction of properties of chemical compounds, compositions or mixtures
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C10/00—Computational theoretical chemistry, i.e. ICT specially adapted for theoretical aspects of quantum chemistry, molecular mechanics, molecular dynamics or the like

Definitions

  • the present invention relates to a method for the preparation of a co-crystal from an active chemical ingredient (ACI) molecule, in particular an active pharmaceutical ingredient (API) molecule and an co-moiety.
  • the invention also relates to a method for the selection of a co-moiety for co-crystallization with an active chemical ingredient (ACI) molecule, in particular an active pharmaceutical ingredient (API) molecule.
  • the invention further relates to a method for the selection for a solvent for use in the preparation of a co- crystal .
  • a pharmaceutical drug comprises an active ingredient, i.e. an active pharmaceutical ingredient.
  • the active pharmaceutical ingredient is the chemical compound that is used for treatment of a disease or pain relief or the like.
  • the pharmaceutical drug may comprise further compounds e.g.
  • the active pharmaceutical ingredient may need to be provided in the form of a co-crystal of the API with a co- crystallizing moiety. This is achieved by bringing the API in contact with a co-crystal forming molecule, which hereinafter may be referred to as a co-former, co-moiety molecule or a co-moiety.
  • co-crystals may exhibit different pharmacological behaviour, such as rate of dissolution, formulation behaviour, solubility etc which can influence the dose and dosage form. It is hence desirable to obtain co-crystals of active pharmaceutical ingredients.
  • WO2004078163 a large number of API's and possible co-crystal formers are described as an example, as well as methods for the preparation of some combinations of these co-crystals and the advantages of co-crystals. The document however, does not provide any insight on how to obtain co-crystals or how to select co-crystal formers.
  • the ACI is mixed with a known possible co-crystal forming moiety.
  • the combination is subjected to conditions (in solution or solid form, i.e. ball milling) that may lead to the formation of a co-crystal and it is determined whether or not a co- crystal has been formed between the ACI and the co-crystal forming moiety. This experiment is repeated for each co-crystal forming moiety.
  • the solvent needs to be suitable for dissolving both the active ingredient and the co-moiety. Finding a suitable solvent again requires a large number of experiments, again not governed by theory but based on trial and error.
  • ACI active chemical ingredient
  • API active pharmaceutical ingredient
  • the method according to the present invention comprises providing a molecular model for each co-moiety of a set of known co-moieties.
  • Each molecular model represents at least part of the physical and/or chemical properties of a respective co-moiety from the set of known co-moieties.
  • Any co-moiety not capable of hydrogen-bonding with the ACI molecule is excluded, thereby obtaining a set of possibly hydrogen-bonding co- moieties.
  • the number of possible co-moieties is reduced and a smaller amount of experiments may suffice to find a suitable co- moiety.
  • the determination whether a hydrogen bond is possible comprises determining which atoms in the molecular model of the ACI molecule are suitable as a hydrogen bond donor atom or a hydrogen bond acceptor atom; and determining which atoms in the molecular model of the co-moiety are suitable as a hydrogen bond donor atom or a hydrogen bond acceptor atom.
  • a hydrogen bond is only possible if the at least one of the ACI molecule and the co-moiety comprises a donor atom and the other comprises an acceptor atom.
  • the method according to the present invention may comprise determining a set of likely conformations of the ACI molecule, each conformation having an energy within a predetermined energy band and/or may comprise determining a number of likely conformations of each co-moiety in the set of co-moieties.
  • the atoms in a molecule may take a position with respect to each other, thereby allowing that a molecule comprised of a certain set of atoms may take a number of shapes. These different shapes are known in the art as conformations.
  • a conformation may be a likely conformation, if an energy level of the molecule is relatively low. More in particular, the conformation is likely, if a change of conformation would result in an increased energy level of the molecule, i.e.
  • the energy level is a locally low energy level.
  • a molecule may have a number of likely conformations. The actual conformation of the molecule may influence the ability to form a co-crystal. Therefore, each likely conformation of the ACI molecule and/or a co-moiety is determined and used for comparison.
  • the method comprises screening the set of known co-moieties for toxicity, in particular if the active chemical ingredient (ACI) is an active pharmaceutical ingredient (API) .
  • ACI active chemical ingredient
  • API active pharmaceutical ingredient
  • the co-moiety is preferably not toxic, but may be toxic dependent on the active pharmaceutical ingredient (API) and the actual resulting reaction of the body.
  • the co-moiety may exhibit a certain degree of toxicity, since the drug itself is in fact toxic.
  • the co-moiety may be toxic, but only at levels that are not reached when compared with the targeted dose of the API.
  • the toxicity screening may be performed prior to or after the above-described hydrogen bonding evaluation.
  • the molecular model of the ACI and the model of the co- moieties may comprise a set of parameters of the molecule representing a number of physical parameters and/or a number of chemical parameters.
  • the model may also be a two-dimensional model providing constitutional and topological information about the actual molecule.
  • the model is a three-dimensional model providing a geometrical representation of the actual molecule.
  • the method may further comprise steric comparison between the molecular model of the ACI molecule and the molecular model of the co-moiety for determining whether the ACI molecule and the co-moiety are sterically compatible. A co-moiety that is sterically incompatible is excluded. If the molecular model comprises geometrical information, in particular if the model comprises a three-dimensional representation, the method may further comprise electrical charge distribution comparison between the molecular model of the ACI molecule and the molecular model of the co-moiety for determining whether the ACI molecule and the co-moiety are electrically compatible.
  • the invention relates to a method for the preparation of a co-crystal by crystallising an ACI with a co-moiety that has been obtained or selected by the process of selecting a co- moiety as described herein elsewhere.
  • the method comprises selecting and/or providing an ACI.
  • the method comprises providing the one or more potentially suitable co-moieties.
  • the method comprises crystallising the co-crystal of the ACI and the co-moiety.
  • the method comprises providing the selected solvents.
  • the method comprises crystallising the co-crystal in the potentially suitable solvent.
  • Method for the preparation of a co-crystal from an active chemical ingredient (ACI) , in particular an active pharmaceutical ingredient, and a co-moiety comprising the steps of a) selecting and/or providing an ACI; b) providing a molecular model representing at least a part of the physical and chemical properties of the ACI molecule; c) providing a molecular model for each of a set of known co- moieties representing at least a part of the physical and chemical properties of each respective co-moiety; d) for each co-moiety in the set of step (c) , determining whether at least one non-covalent intermolecular bond between the ACI molecule and the co-moiety is possible by comparing the molecular model of the ACI molecule as provided in step (b) and the molecular model of the co- moiety as provided in step (c) ; where non-covalent intermolecular bonds comprise hydrogen bonds, dispersive interactions, pi-pi interactions and electrostatic interactions, e) excluding
  • One aspect of the present invention is the method for selecting a co- moiety for co-crystallization with an active chemical ingredient, ACI, molecule, API, molecule, the method comprising:
  • step (b) providing a molecular model for each of a set of known co-moieties representing at least a part of the physical and chemical properties of each respective co- moiety; (c) for each co-moiety in the set of step (b) , determining whether at least one non-covalent intermolecular bond between the ACI molecule and the co-moiety is possible by comparing the molecular model of the ACI molecule as provided in step (a) and the molecular model of the co- moiety as provided in step (b) ; where non-covalent intermolecular bonds comprise hydrogen bonds, dispersive interactions, pi-pi interactions and electrostatic interactions, and (d) excluding any co-moiety not capable of forming a non- covalent intermolecular bond with the ACI molecule, thereby obtaining a set of non-covalent binding co- moieties .
  • the present invention provides a method for selecting a potentially suitable solvent for dissolving an active chemical ingredient, ACI, molecule, in particular an active pharmaceutical ingredient, API, molecule.
  • the invention provides a method for selecting a solvent for dissolving an active chemical ingredient, ACI, molecule, in particular an active pharmaceutical ingredient, API, molecule, the method comprising:
  • the present invention provides a computer program comprising computer readable instructions for operating a computer system, the instructions comprising instructions for performing at least one of the methods according to the present invention.
  • FIG. 1 shows a diagram illustrating an embodiment of the method according to the present invention.
  • step SIl a library of known co-moieties is provided.
  • the library may be a virtual library comprising descriptions of the co- moieties.
  • Co-moieties can be described by a set of parameters that represent a number of physical parameters and/or a number of chemical parameters. Such a set is also called a set of 'molecular descriptors' .
  • each co-former or solvent can be characterised using a set of molecular descriptors.
  • Molecular descriptors in themselves are known, and are used to describe single molecular species properties.
  • Typical molecular descriptors can be based on bulk physical properties such as boiling points, critical temperature, vapour pressure, flash point, auto-ignition temperature, density, refractive index, melting point, octanol-water partition coefficient, aqueous solubility of liquids and solids, molecular mass, water-air partition coefficients, GC retention times and response factor, critical micelle concentration, and molecular descriptors such as partial charge and charge densities, dipole moment, molecular surface area, molecular volume, electrostatic potential, bond lengths, bond angle, heat of formation, hydrogen bonding ability, etc. See also Katritzky et al . Chem. Inf. Comput.
  • Molecular descriptors can also include hash-key or structure fingerprints, constitutional descriptors such as functional group counts, fragment contribution, atomic contributions, topological descriptors such as connectivity indices, Wiener numbers and Balaban indices or geometric descriptors such as solvent excluded volume and WHIM descriptors. It will be clear that molecular descriptors can easily be generated by the skilled person based on the above non-limiting examples thereof. Additionally, the library may also comprise an actual library of known co-moieties as may be used in accordance with the prior art for performing experiments in order to find a suitable co-moiety by trial and error.
  • step S12 for each co-moiety in the library of step SIl, one or more likely conformations of the co-moieties is determined. These likely conformations can be determined by developing and analysing a molecular model for each of the co-moieties in the library.
  • the molecular model preferably comprises a three-dimensional representation of the molecular structure. Alternatively, these likely conformations may be determined, may be known or may be determined from a database or library.
  • a molecular model is determined.
  • the molecular model may comprise a three-dimensional representation of the molecular structure.
  • the molecular model may further comprise a representation of the electronic properties of the molecule .
  • step S14 the co-moieties are screened with respect to toxicity.
  • a toxicity screening is preferred if the active ingredient is a pharmaceutical drug that is to be administered to a patient. If the active ingredient is not a pharmaceutical drug, a toxicity screening may be omitted. However, a screening for any other aspect may be performed instead. For example, a co-moiety may chemically react with another compound such as the active ingredient. If such a reaction is not desired, a screening may be performed.
  • the screening of step S14 may also include a screening of the characteristic numbers of the co-moieties.
  • a number of co-moieties, or conformations of co-moieties, may be excluded based on these characteristic numbers. These numbers may be comprised in the molecular descriptors as described herein elsewhere.
  • a toxic co-moiety may be excluded prior to determining a number of conformations, e.g. because it is known that all conformations are toxic.
  • conformations of a co-moiety are determined using a model, e.g. a three-dimensional model.
  • a step may be performed comprising providing a molecular model suitable for determining conformations of the co-moiety.
  • the step S12 is then performed using the model provided.
  • a model may as well be used for determining which conformations are likely conformations.
  • a conformation is likely, if its energy is at a local minimum, meaning that a transition to another conformation would require energy.
  • the more energy that would be required for a transition the more stable the conformation is, and hence the more likely such a conformation is .
  • step S21 the active ingredient, usually an active pharmaceutical ingredient (API) , but in general an active chemical ingredient (ACI), is provided.
  • the active ingredient of step S21 may have a number of conformations, of which a number are likely conformations and another number are not likely conformations. Considering that a relatively large number of likely conformations may be present and further considering that the likely conformations have overlapping characteristics and/or structures, in step S23, a principle component analysis (PCA) and/or clustering may be performed in order to reduce the number of conformations that need to be examined.
  • PCA principle component analysis
  • PCA and/or clustering sufficient insight into the separate structural differences may be obtained, such that the behaviour of any other conformation may be theoretically predicted based on the results of the conformations selected in step S23.
  • the PCA/ clustering may as well, or instead, be performed on any characteristic number or features of the conformations as compared to structural differences.
  • step S24 for each active ingredient as selected in step S23, a molecular model is provided that will yield a variety of conformations.
  • the model may comprise characteristic numbers, parameters, three-dimensional representations, and any other relevant information.
  • molecular models of solvents, co-moieties and the active ingredient are provided and a variety of conformations of each are provided.
  • steps S41 - S43 a conformation of the molecular model of the active ingredient and a conformation of the molecular model of one of the co-moieties are compared.
  • step S41 it is determined whether one or more hydrogen bonds may be formed between the active ingredient conformation and the co-moiety conformation.
  • a number of hydrogen bonds may be formed, thereby providing a hydrogen bond complex.
  • a steric comparison S42 and/or an electric charge distribution comparison S43 may be performed in order to determine whether the acceptor atoms and the donor atoms may get near each other, preferably in one of the likely conformations such that the energy of the combination of conformations is relatively low.
  • the electric charge at a certain part of one of the molecules may repel a part of the other molecule such that the donor atom and the acceptor atom cannot engage in an electronic interaction and hence a hydrogen bond, or a partial hydrogen bond cannot be formed.
  • the steric and electric charge distribution comparisons may require a relatively large number of computations as they require a spatial comparison, preferably a three-dimensional comparison.
  • the number of computations may be large.
  • the number of ACI, preferably API, conformations and the number of co-moieties, more specifically the number of conformations of the co-moieties is relatively large, the number of computations may become prohibitive for performing the method cost-effectively. Therefore, it may be expedient to make a first selection based on characteristic numbers and the number of donor atoms and/or acceptor atoms such that a smaller number of conformations need to be compared spatially.
  • step S44 a principle component analysis (PCA) and/or cluster analysis may be performed in step S44, thereby selecting a broad range (i.e. a broad parameter space) of possibly suitable co- moieties .
  • step S45 the remaining co-moiety conformations that appear the most promising co-moieties are used in experiments and their number is further reduced by trial and error.
  • step S51 a hydrogen bonding comparison is performed.
  • the step S51 is mutatis mutandis similar to the step S41 for selecting a co-moiety.
  • a steric comparison may not be of interest.
  • an electric charge distribution may not be of interest.
  • a PCA and/or a cluster analysis may be performed in step S52, substantially similar to step S44. After the theoretical selection, the remaining possibly suitable solvents are used in experiments in step S45.
  • the method according to the present invention may be improved using the experimental results obtained in step S45.
  • the present invention includes a method for improving the above-described method for selecting a co-moiety and/or selecting a solvent.
  • the co-crystallization may be performed in the solvent after dissolving both the active ingredient and the co- moiety. Therefore, in an embodiment, the co-moiety and the solvent are compared in accordance with e.g. the steps S51 - S53. One of the purposes of this comparison is to determine whether the solvent will compete with the co-former to create a solvate of the API instead of a co-crystal of the API and the co-former.
  • a suitable co-moiety such that the co-moiety and the active ingredient may form a co-crystal and such that the co- moiety and the active ingredient may be dissolved in the solvent, and it is not likely that a solvate will be formed, a further examination may be performed in order to determine whether the co-crystal will crystallize in the solvent and precipitate such that a solid co- crystal remains.

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  • Chemical & Material Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Computing Systems (AREA)
  • Theoretical Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un co-cristal à partir d'un ingrédient pharmaceutique actif (IPA) et d'une co-fraction, et qui consiste à fournir un modèle moléculaire représentant au moins une partie des propriétés physiques et chimiques de l'IPA; à fournir un modèle moléculaire pour chaque ensemble de co-fractions connues représentant au moins une partie des propriétés physiques et chimiques de chaque co-fraction respective; pour chaque co-fraction de l'ensemble de l'étape (b), à déterminer si au moins une liaison hydrogène située entre la molécule ACI et la co-fraction est possible en comparant le modèle moléculaire de la co-fraction de l'étape (a) au modèle moléculaire de la co-fraction de l'étape (b); et à exclure toute co-fraction non apte à une liaison hydrogène avec la molécule ACI, ce qui permet d'obtenir un ensemble de co-fractions de liaison hydrogène, de sélectionner un solvant approprié et de réaliser un ensemble d'expériences fournissant des co-cristaux de l'IPA.
PCT/NL2007/000226 2006-09-21 2007-09-13 Procédé de préparation d'un co-cristal WO2008035960A2 (fr)

Applications Claiming Priority (2)

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US84609806P 2006-09-21 2006-09-21
US60/846,098 2006-09-21

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WO2008035960A2 true WO2008035960A2 (fr) 2008-03-27
WO2008035960A3 WO2008035960A3 (fr) 2008-10-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110222440A (zh) * 2019-06-12 2019-09-10 广东药科大学 药物晶体产出的溶剂优选预测方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030224006A1 (en) * 2002-03-01 2003-12-04 Zaworotko Michael J. Multiple-component solid phases containing at least one active pharmaceutical ingredient

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030224006A1 (en) * 2002-03-01 2003-12-04 Zaworotko Michael J. Multiple-component solid phases containing at least one active pharmaceutical ingredient

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ALLEN FRANK H ET AL: "Applications of the Cambridge Structural Database in organic chemistry and crystal chemistry." ACTA CRYSTALLOGRAPHICA. SECTION B, STRUCTURAL SCIENCE JUN 2002, vol. 58, no. Pt 3 Pt 1, June 2002 (2002-06), pages 407-422, XP002492054 ISSN: 0108-7681 *
KARAMERTZANIS PANAGIOTIS G ET AL: "Ab initio crystal structure prediction-I. Rigid molecules" JOURNAL OF COMPUTATIONAL CHEMISTRY, JOHN WILEY AND SONS, CHICHESTER, GB, vol. 26, no. 3, 1 February 2005 (2005-02-01), pages 304-324, XP002428235 ISSN: 0192-8651 *
MORISSETTE SHERRY L ET AL: "HIGH-THROUGHPUT CRYSTALLIZATION: POLYMORPHS, SALTS, CO-CRYSTALS AND SOLCATES OF PHARMACEUTICAL SOLIDS" ADVANCED DRUG DELIVERY REVIEWS, AMSTERDAM, NL, vol. 56, no. 3, 1 January 2004 (2004-01-01), pages 275-300, XP009072233 ISSN: 0169-409X *
SHAN N ET AL: "Co-crystal structures of 4,7-phenanthroline and carboxylic acids: synthon competition and prediction" TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, vol. 43, no. 48, 25 November 2002 (2002-11-25), pages 8721-8725, XP004390470 ISSN: 0040-4039 *
VISHWESHWAR P ET AL: "Pharmaceutical co-crystals" JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 95, no. 3, March 2006 (2006-03), pages 499-516, XP002443334 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110222440A (zh) * 2019-06-12 2019-09-10 广东药科大学 药物晶体产出的溶剂优选预测方法
CN110222440B (zh) * 2019-06-12 2023-08-11 广东药科大学 药物晶体产出的溶剂优选预测方法

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