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WO2009152635A1 - Outils de tri basés sur gradient pour détection et identification de polymorphes - Google Patents

Outils de tri basés sur gradient pour détection et identification de polymorphes Download PDF

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WO2009152635A1
WO2009152635A1 PCT/CH2009/000210 CH2009000210W WO2009152635A1 WO 2009152635 A1 WO2009152635 A1 WO 2009152635A1 CH 2009000210 W CH2009000210 W CH 2009000210W WO 2009152635 A1 WO2009152635 A1 WO 2009152635A1
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template
gradient
compound
gradients
crystallization
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Nicolas Spencer
Eva Beurer
Sara Maria Morgenthaler
Stefan Zürcher
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Eidgenoessische Technische Hochschule Zurich ETHZ
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Eidgenoessische Technische Hochschule Zurich ETHZ
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
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    • C30B23/00—Single-crystal growth by condensing evaporated or sublimed materials
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
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    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
    • C30B7/02—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by evaporation of the solvent
    • C30B7/06—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by evaporation of the solvent using non-aqueous solvents
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
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    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00527—Sheets
    • B—PERFORMING OPERATIONS; TRANSPORTING
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Definitions

  • This invention is in the field of methods and devices for detecting and identifying polymorphs.
  • Polymorphism in material science refers to the ability of a solid material to exist in more than one crystal form or crystal structure. Polymorphism can be found in any crystalline material including polymers, minerals, small molecules, such as drugs, proteins, and metals. Polymorphism in crystalline materials is related to allotropy, which is the ability of elemental solids to take two or more different forms in which the atoms are bonded together in a different manner. Examples of polymorphism include glycine, which is able to form monoclinic and hexagonal crystals, and silica, which is known to form several polymorphs, including ⁇ -quartz, ⁇ -quartz, tridymite, cristobalite, coesite, and stishovite.
  • Polymorphism can exist as a result of differences in crystal packing, referred to as packing polymorphism. Polymorphism can also result from the existence of different conformers of the same molecule, referred to as conformational polymorphism. In pseudopolymorphism the different crystal types are the result of hydration or solvation.
  • the kinetics of the crystallization process can also be influenced by the surface properties ⁇ see e.g. Frostman, et ⁇ /. , Nucleation and Growth of Molecular-Crystals on Self-Assembled Monolayers, Langmuir, 10 (2):576- 58 (1994)).
  • a strong interaction with the surface leads to faster nucleation, meaning that more and smaller crystals are formed. This becomes important in crystallizing proteins.
  • the crystals need to be as large as possible.
  • Pham, et al. Well-ordered self-assembled monolayer surfaces can be used to enhance the growth of protein crystals.
  • Colloids and Surfaces B-Biointerfaces, 34, (3), 191-196 (2004) discloses surface modification of a crystallization vessel that inhibited protein interaction with the surface and allowed for the growth of large protein crystals.
  • the crystallization templates contain one or more surface- chemical and/or surface morphology gradients.
  • the crystallization template is typically exposed to a solution or vapor containing the composition to be tested. Then the compound of interest is allowed to crystallize on the surface. Next the template is analyzed to determine the various polymorphs of the compound. Analysis of the crystalline structure of the tested compound may be performed by any suitable detection and analysis technique. After identifying the different polymorphs one or more polymorphs may be selected for further testing, and/or production.
  • the surface of the template can influence the nucleation process; depending on the particular properties of the surface a particular polymorph may be formed.
  • the nucleation effects can be either morphological or chemical in nature.
  • a variety of surfaces, modified either chemically or morphologically in different ways, can be used to identify the presence and types of polymorphs in a compound or composition of interest.
  • Figure IA is an illustration of a crystallization template having a circular configuration.
  • Figure IB is an illustration of a crystallization template having a rectangular configuration.
  • the crystallization template may contain dividers, as illustrated in these Figures.
  • Figure 2 is a schematic of an experimental procedure for forming a hydrophilicity gradient followed by immersion in a solution of the molecule to be analyzed to from a further gradient over the immersion time.
  • Figure 3 is a bar graph showing % of the average crystal size (white bars) and % of the average number of crystals (dark shaded bars) as a function of immersion time (seconds) in a dodecanethiol solution for a substrate having surface-chemical wettability gradients on its surface.
  • the values for crystal size and number of crystals were normalized by setting the average for each immersion time as 100 %. Values greater than 100 % indicate that the crystals were larger than the average crystal size, and values smaller than 100 % indicate that the crystals were smaller than average crystal size for this particular immersion time.
  • Figure 4 is a bar graph showing % of the average crystal size (white shaded bars) and % of the average number of crystals (dark shaded bars) as a function of immersion time (seconds) in a dodecanethiol solution for a substrate having surface-chemical wettability gradients alternating with hydrophobic strips on its surface.
  • the values for crystal size and number of crystals were normalized by setting the average for each immersion time as 100 %. Values greater than 100 % indicate that the crystals were larger than the average crystal size, and values smaller than 100 % indicate that the crystals were smaller than average crystal size for this particular immersion time.
  • graded refers to a graded change in the magnitude of some physical or chemical property of the surface.
  • the graded change can be in the height, width, and/or distance of structures on the surface, such as grooves or other structures or textures, which can initiate crystallization.
  • the change can be a change in the density of functional groups on the surface, for example, which increase or decrease a chemical property of the surface, such as hydrophobicity, hydrophilicity, bioactivity, etc.
  • a simple example is a continuous change in hydrophobicity from one end of a substrate to the other. This is a chemical-composition gradient, and virtually any pair of surface-bound species can be combined into a gradient.
  • a further property that lends itself to gradient fabrication is morphology, and roughness gradients, for example, can readily be combined with surface-chemical gradients, either in parallel or orthogonally.
  • graded change refers to variations in the same increments in a given property for the template.
  • a crystallization template (10) may be used to induce the formation of polymorphs. Representations of a circular and rectangular template are shown in Figures Ia and Ib of the template.
  • the template may induce formation of a crystal form different from the crystal form found in solution.
  • the crystallization template contains a surface with one or more gradients of one or more properties of the surface.
  • the surface contains a chemical gradient, i.e. surface chemistry gradually changes.
  • the surface contains a morphological gradient, e.g., the surface roughness gradually changes.
  • the crystallization template may contain more than one gradient.
  • the crystallization template contains two gradients.
  • the two gradients are perpendicular to each other.
  • the gradients are parallel to each other.
  • the crystallization template contains one or more dividers (12 a, b, and c) separating the template into multiple regions (see Figure IB).
  • the surface of the crystallization template is patterned to selectively form crystals at certain locations on the surface.
  • patterned gradients can be prepared as described in Morgenthaler et ai, Biointerphases, Vol. 1, No. 4, 156-165 (2006).
  • the template may be formed of any suitable material. The choice of material for the surface of the template for chemical gradients is determined by the adsorbate-substrate interaction and method of analysis for polymorphs. The surface of the template does not form a covalent bond with the molecule to be tested.
  • the surface of the template allows for the formation of a variety of chemical gradients and is suitable for analysis of the substance to be tested using any suitable analysis method, such as Raman spectroscopy or x-ray diffraction.
  • the template material is an inorganic material including, but not limited to, glass, silicon or another semiconductor material, metals, metal oxides, metalloids, ceramics, and combinations thereof.
  • the surface may be the surface of a silicon wafer or other semiconductor.
  • the template is a metal, such as gold, silver, palladium, or copper.
  • the material is an organic material, such as a naturally occurring, semi-synthetic, or synthetic polymer.
  • the surface of the template may be treated to contain a metal coating, such as a layer of gold, silver, palladium, or copper.
  • a metal coating such as a layer of gold, silver, palladium, or copper.
  • the metal coating has a thickness ranging from about 50nm to about 300nm, preferably from about 80 run to about 100 nm.
  • the template is formed from glass or silicon, and the surface of the template has been modified to contain a metal coating, such as gold, silver, palladium, or copper, preferably a gold coating.
  • template is formed from a synthetic polymer, which is coated with a metal coating, preferably a gold coating.
  • a polyimide foil can be coated with a thin layer of gold (e.g. 80 nm).
  • the template can have any suitable dimensions. With respect to thickness, the thickness of the template should be sufficient to prevent deformation of the template during immersion. Typically templates are about 1 mm thick. Typical lengths range from 5 mm to 10 centimeters, or longer. In a preferred embodiment, the length of the surface is 1 cm or longer, and typically ranges from 1 cm to 5 cm. b. Gradients A wide range of different types of gradients may be created on the surface of the crystallization templates. Preferably the gradient is a chemical or morphological gradient. Morphological and chemical gradients can also be combined on a single surface. In one embodiment, morphological and chemical gradients are combined on a single surface forming 2-dimensional, orthogonal gradients, where one gradient is perpendicular to a second gradient. In another embodiment, the gradients are parallel to each other. 1. Surface Chemical Gradients
  • a gradual change in a physical property, such as the wettability, can be induced by a change in surface chemistry, for example a gradually changing surface composition.
  • the surface-chemical gradients may form hydrophobicity gradients, where the hydrophobicity/hydrophilicity of the surface increases or decreases along the length (or radius) of the substrate surface, or gradients that contain bioactive molecules, where the concentration of bioactive molecule increases or decreases along the length (or radius) of the substrate surface.
  • the gradients are typically self- assembled monolayers (SAMs).
  • the surface-chemical gradients typically display a high packing density, as demonstrated by the low hysteresis in dynamic contact angle and x-ray photoelectron spectroscopy (XPS) and reflection-absorption infrared spectroscopy (RAIRS) measurements.
  • the surface-chemical gradient may be a packing density gradient.
  • a packing density gradient leads to a gradual change in the order and disorder of the molecule(s) on the surface of the template as demonstrated the dynamic contact angle, RAIRS, and x-ray photoelectron spectroscopy (XPS) measurements.
  • poly (L-lysine)-g-poly(ethylene glycol) may be attached to the surface via interactions between the surface and the polylysine end to form a gradient.
  • PLL-g-PEG poly(ethylene glycol)
  • the polyethyleneglycol is end- functionalized with a functional group.
  • the end-functionalized molecules may be coupled to biomolecules to form a biochemical gradient.
  • the surface is modified by immobilizing chiral compounds on the surface. This allows for enantioselective crystallization of the compound to be tested.
  • Any method that forms a surface chemistry gradient having the desired properties may be used.
  • a number of methods for forming surface chemistry gradients are known (see e.g. Ruardy, T.G., et al., Surf. Sci. Rep. 1997, 29, 1-30; Liedberg, B. and Tengvall, P. Langmuir, 1995, 11, 3821- 3827; Efimenko K., et al., Macromolecules 2003, 36, 2448-2453; Morgenthaler et al, Soft Matter, Vol. 4, 419-434 (2008); and Genzer et al., Langmuir, Vo. 24, No. 6, 2294-2317 (2008)).
  • thiol-based chemical gradients including (1) the cross- diffusion of two thiol solutions through a polysaccharide matrix (Liedberg, B. and Tengvall, P. Langmuir, 1995, 11, 3821-3827), (2) applying an electrochemical potential to a substrate during adsorption (Terrill R.H., et al., J.Am.Chem.Soc 2000, 122, 988-989), (3) the use of microfluidic devices (Jeon N.L., et al., Langmuir 2000, 16, 8311-8316; Dertinger S.K.W., et al., Anal.Chem.
  • Vapor deposition methods may be used to form gradients (see e.g. U.S. Patent No. 6,770,323 to Genzer).
  • European Patent No. 1 610 909 discloses forming a surface chemical gradient using an adsorbate-containing liquid boundary that is in relative motion to the substrate. This may be accomplished through controlled immersion of a substrate into one or more solutions containing an adsorbate using a linear-motion drive to form one or more linear gradients. Alternatively a syringe and a syringe pump may be used to form a radial gradient.
  • the speed at which the substrate is exposed to the advancing front of a solution containing an adsorbate is selected based on the absorption kinetics of the adsorbate to ensure that the adsorbate is exposed to the advancing front of the solution for a sufficient time period to adsorb the adsorbate onto the surface of the substrate and form a chemical gradient.
  • Any solution containing a compound that adsorbs onto the surface of the substrate can be used.
  • Any solvent or solvent system (such as a co- solvent) can be used provided is dissolves the organic or inorganic material to be screened.
  • the solvent can be an aqueous solvent or an organic solvent.
  • the adsorbate solution contains a thiol.
  • thiols include thiols with larger cross sectional areas, such as functionalized mercaptobiphenyl.
  • the alkanes are end- functionalized with reactive groups.
  • reactive groups include biotin, vinylsulfone, maleimide, or N-hydroxy succinimide. These reactive groups may be coupled to biomolecules to prepare a biochemical gradient.
  • the biomolecules may be any bioactive molecule, including for example peptides, proteins, oligosaccharides, polysaccharides, DNA, RNA, or lipids.
  • linear and radial gradients may be produced on, for example, oxidized silicon wafers, by means of two different adsorbing polyelectrolytes, such as poly (L-lysine)-g-poly(ethylene glycol), with or without end functionalization.
  • the end-functionalized molecules may be coupled to biomolecules to form a biochemical gradient.
  • the concentration of the adsorbing solution typically ranges from about 0.1 ⁇ M to about 0.1 M, preferably from about 1 ⁇ M to about 1 mM.
  • the concentration is selected, along with the speed, to produce a surface where the concentration of the adsorbate increases from one end to the other. Thus one end contains little or none of the first adsorbate, while the other end is fully saturated, or nearly saturated with the first adsorbate. If a second adsorbate is added, it has an opposite concentration gradient to the concentration gradient of the first adsorbate.
  • a surface-chemical gradient film composed of a single component is a result of the varied coverage and packing of the adsorbate along the immersion axis of the substrate. Since partial monolayers are generally less ordered than full monolayers, this initial surface also displays a gradient in order.
  • the substrate is immersed in a second adsorbate solution in a second step. Generally, in the second step, a more concentrated adsorbate solution is used.
  • the gradient may be formed using two perpendicular immersions into two separate adsorbates. This process forms a 2- dimensional, orthoganol chemical gradient.
  • the self-assembling monolayers can be functionalized in order to generate surfaces that present a range of functionalities, such as nonpolar, polar, electroactive, biologically active, etc.
  • functionalities such as nonpolar, polar, electroactive, biologically active, etc.
  • Methods for engineering surfaces are described in Whitesides et ah, Chem. Rev., 105, 1103-1169 (2005) and fall into three categories: (1) synthesis of functionalized thiols for forming single component or mixed SAMs by (co- )adsorption; (2) insertion of synthesized thiols into defect sites of preformed SAMs; and (3) modification of the surface composition of a preformed SAM.
  • Covalent reaction and non-covalent interactions can be used to generate new surfaces.
  • Bioactive molecules can be coupled to the SAM by direct reaction with exposed functional groups on SAMs. Exposed functional groups immersed in a solution of bioactive molecules can react directly with the molecules in solution under appropriate reaction conditions.
  • bioactive molecules such as peptides and carbohydrates can react with SAMs having maleimide functionalities on the surface. Examples of other reactive surface groups are provided in Table 1.
  • ligands can be attached to the surface of SAMs by forming a reactive intermediate, which is then coupled to the ligand or bioactive molecules to be immobilized on the surface.
  • a reactive intermediate can react with a variety of ligands; and (2) it allows the spatial discrimination of active and inactive regions of the SAM, i.e., the reactivity of the regions on the surface can be turned "on” or "off. Such spatial discrimination can be used to create a gradient of bioactive molecules on the surface.
  • methods for spatial patterning such as microcontact printing and scanning probe lithography can be used in combination with reactive intermediates to attach biomolecules in specific locations to form the desired gradient.
  • Functional groups on the surface of the SAM may be converted to reactive intermediates by chemical reaction and/or by the application of external stimuli, such as electrochemical potentials, photoradiation, ultrasound, and combinations thereof.
  • reactive functional groups may be introduced onto the surface of the SAM by cleaving covalent bonds of surface functional groups to generate a reactive functional group.
  • bioactive molecules can be immobilized on the surface of the SAM via a linker. Suitable linkers include small organic molecules, oligomers, and polymers. For example, a polymer can be grafted to the surface of the SAM and the bioactive molecule(s) can be coupled to the grafted polymer. A list of exemplary polymers that can be grafted to SAMs is provided in Table 3 along with a corresponding mechanism for attachment.
  • Table 3 Examples of Polymers Grafted to SAMs via Surface Initiation polymer r ⁇ f polystyrene ph ⁇ toicitlated radical po ⁇ ymerfzatt ⁇ n 379 thermal radical pdymeriiation 380 ifvfmg anionic poljnierizaticn 381 polyacrylonitrfl ⁇ pltotoiniiiatect radical poiynioriZatico 382 polyacryl ⁇ mide ATRP 383 polydiorb ⁇ rnens) ring-opening metathesis 384 poiy(methYl m ⁇ thacrylaie) ATRI* 385 poljtBiycidyl m ⁇ thacrylat ⁇ ) ATRP 385 ⁇ oly( butyl mathacrylale) ATRP 385 po!y(2-hydroryetliyl methacrylate) ATRP 385 polylactlds ring-opening polymerization 386 poly(p-di ⁇ ianone) ring-open
  • the surface of the SAM may be modified non-covalently by using the intrinsic properties of the surface (e.g., hydrophobicity, electrostatics, etc.) or selective interactions with preformed chemical functional groups on the surface to promote absorption of materials on the surface.
  • Suitable classes of molecules that can absorb onto the exposed surface of a SAM include, but are not limited to, surfactants, polymers, polyelectrolytes, proteins, organic dyes, and colloidal particles.
  • hydrophobic SAMs readily absorb amphiphilic molecules (e.g., surfactants), some polymers, and most proteins.
  • the morphology on the surface of the crystallization template can be controlled, such that it changes over a given distance, creating a morphological gradient.
  • the morphological gradient can be any physical change or alteration to the surface, such as smooth to rough. Typically changes in the surface morphology are on the nanometer scale. The imperfections or rough areas of the surface may serve as nucleation sites and thereby influence crystallization and the formation of polymorphs. Usually nucleation starts heterogeneously from a surface or an interface, such as the surface of the crystallization template.
  • Morphology gradients can be fabricated using a variety of techniques known in the art. For example, morphology gradients can be fabricated using a two-step roughening and smoothening process.
  • the template is bead blasted to form a homogeneous roughness on the surface of the template.
  • a polishing solution such as a hot acidic solution (e.g. a combination of phosphoric, nitric and sulphuric acid), and continuously withdrawn by means of a linear motion drive.
  • the polishing solution depending on the residence time of a specific surface location, preferentially removes features with a small radius of curvature and thus leads to the smoothing out of the surface topography and resulting in a roughness gradient. This method is particularly preferred for forming a morphology gradient on a metal surface.
  • lithography such as photolithography; chemical vapor deposition (e.g., followed by solvent vapor exposure); crystallization of breath figures (i.e. spherical cavities); pulsed laser ablation; etc.
  • chemical vapor deposition e.g., followed by solvent vapor exposure
  • crystallization of breath figures i.e. spherical cavities
  • pulsed laser ablation etc.
  • the templates and methods described herein can be used to identify a variety of polymorphs for a given compound.
  • the templates and methods described herein can also be used to determine the most thermodynamically favorable polymorph or one or more metastable polymorphs.
  • a metastable pharmaceutical solid form can change crystalline structure or solvate/desolvate in response to changes in environmental conditions, processing, or over time.
  • Polymorphs of a compound may be induced to crystallize on a surface by exposing the surface of a crystallization template to a solution containing the compound to be tested. The entire surface may be exposed to the solution, hi another embodiment, only portions of the surface are selected and exposed to the solution, where each portion of the surface is separated from the other portions by one or more dividers.
  • the method by which the template is exposed to the compound to be tested also creates a gradient.
  • the entire surface of the template may be exposed to the solution or vapor containing the compound to be tested and then slowly withdraw from the solution or vapor containing the compound to be tested. This creates an immersion time or exposure time gradient with respect to the compound to be tested. Suitable means of exposure include immersing the gradient in a solution of the compound to be crystallized, or painting, spraying, or otherwise applying a solution of the compound to be crystallized to the gradient.
  • the surface of the crystallization template is exposed to a vapor containing the compound to be tested. The compound to be tested sublimates and is thereby deposited on the surface of the template.
  • the solution or vapor containing the compound to be analyzed is oversaturated with the compound. Oversaturation can be achieved by lowering the temperature of the solution to be analyzed, reducing the amount of the solvent in the solution to be analyzed, and/or lowering the temperature of the gradient.
  • parameters such as temperature, pressure and/or humidity of the environment, may be controlled to ensure that one or more polymorphs are formed and detected.
  • the compound Crystallizes and forms one or more polymorphs depending on the properties of the portion of the surface to which the compound is exposed.
  • surface gradient separation as described above, can be combined with solvent-mediated polymorphic transformation and temperature programs in order to increase the probability that all polymorphs have been identified for a particular compound. It is known that unstable polymorphic forms have a greater solubility than the metastable forms in a particular solvent and that monotropic forms have a lower melting point than enantiotropic forms. These observations have been related to the phenomenon of supersaturation and supercooling in Ostwald's Rule of Steps or Law of Successive Reactions.
  • Solvent-mediated polymorphic transformation can be used to obtain the most stable polymorph of a material.
  • the most stable polymorph can be obtained by (1) dissolving the metastable phase to form a solution which is supersaturated with respect to the more stable phase; (2) nucleation of the more stable phase; and (3) growth of the more stable phase.
  • Analysis of the crystalline structure of the tested compound may be performed by any suitable technique. Suitable techniques include, but are not limited to, X-ray powder diffraction (XRPD), Raman spectroscopy, differential scanning calorimetry (DSC), infrared (IR) spectroscopy, solid stated nuclear magnetic resonance (NMR), and/or optical microscopy ⁇ see e.g. Kamat et al, Pharm. Res., 5(7): 426-429 (1988); Pan, et al, AAPS Pharm Sci Tech, 7(l):Article 11, pages E1-E7, El, right col., (2006)).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • IR infrared
  • NMR solid stated nuclear magnetic resonance
  • one or more polymorphs can be selected for further testing, production and/or scale up, based on a variety of characteristics, such as melting point, chemical reactivity, apparent solubility, dissolution rate, optical and electrical properties, vapor pressure, density, and combinations thereof. These properties can directly impact the processability of drug substances and the quality/performance of drug products, such as stability, dissolution, and bioavailability.
  • the compound to be tested is a bioactive molecule, such as a molecule having therapeutic, prophylactic or diagnostic properties.
  • the method and device described herein may be used to test polymorphs in a variety of compounds, which may be inorganic or organic compounds. Additionally, the method and device may be used to test polymorphs in a composition containing more than one compound. However, the method and device described herein are particularly preferred for use in detecting polymorphs in pharmaceutical compositions and/or pharmaceutical compounds. The detection of polymorphs in a given composition can aid in selecting storage containers and conditions for the composition of interest.
  • Exemplary classes of therapeutic agents that can be tested using the method and device described herein include, but are not limited to, analeptic agents; analgesic agents; anesthetic agents; antiasthmatic agents; antiarthritic agents; anticancer agents; anticholinergic agents; anticonvulsant agents; antidepressant agents; antidiabetic agents; antidiarrheal agents; antiemetic agents; antihelminthic agents; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; anti-inflammatory agents; antimigraine agents; antineoplastic agents; antiparkinsonism drugs; antipruritic agents; antipsychotic agents; antipyretic agents; antispasmodic agents; antitubercular agents; antiulcer agents; antiviral agents; anxiolytic agents; appetite suppressants (anorexic agents); attention deficit disorder and attention deficit hyperactivity disorder drugs; cardiovascular agents including calcium channel blockers, antianginal agents, central nervous system (“CNS”) agents, beta-block
  • Exemplary therapeutic agents that can be tested using the method and device described herein include, but are not limited to, ceclofenac, acetaminophen, adomexetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amolodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, cho
  • polymorphs of theophylline can be identified using a hydrophobic/hydrophilic gradient.
  • Hydrophobic/hydrophilic gradients can be prepared by controlled immersion of a gold-coated glass slide with a chromium adhesive layer into a dilute solution (e.g. 0.005 mM) of a thiol- terminated molecule, such as dodecanethiol.
  • the chemical gradient can be completed by immersing the whole substrate into an 11-mercaptoundecanol solution (e.g. 0.01 mM) over night.
  • polymorphs in a drug such as theophylline (also known as dimethylxanthine)
  • a drug such as theophylline (also known as dimethylxanthine)
  • Pseudopolymorph-selective crystallization can occur during evaporation of the solvent.
  • Similar hydrophobic/hydrophilic gradients can be used to identify polymorphs of anthranilic acid.
  • Polymorphs of other compounds can be identified using hydroxyl/acid gradients.
  • Such gradients can be prepared by controlled immersion of a gold-coated glass slide with a chromium adhesive layer into a dilute solution (e.g.
  • a thiol- terminated molecule such as 11- mercaptoundecanol.
  • the chemical gradient can be completed by immersing the whole substrate into an 11-mercaptoundecanoic acid solution (e.g. 0.01 mM) overnight.
  • the presence of polymorphs in a drug, such as carbamazepine can be tested by immersing the gradient into a solution of carbamazepine (nearly saturated). Phase-selective crystallization occurs during evaporation of the solvent.
  • the gradients described herein can also be used to induce enantionselective crystallization.
  • a full monolayer of 11-mercaptoundecanoic acid can be formed on a gold-coated glass slide with a chromium adhesive layer.
  • the monolayer can be immersed into a 0.2 M N-hydroxysuccinimide solution in the presence of 0.8 M water-soluble carbodiimide ( 1 -ethyl-3 -(3 - dimethylaminopropyl)-carbodiimide hydrochloride).
  • Gradient formation can be achieved by controlled immersion of the substrate into a saturated R- leucine solution containing 10 mM Tris-HCl and 0.2 M NaCl (pH 7.8) for the covalent immobilization of R-leucine on the mercaptoundecanoic acid.
  • the formation of the gradient can be completed by immersing the whole substrate into a saturated L-leucin solution overnight.
  • the gradient can then be immersed into a solution of a racemic product (nearly saturated); and enantioselective crystallization can occur during evaporation of the solvent.
  • IV. Kits The gradients can be packaged in a kit.
  • the finished template (with one or more gradients already formed on the surface) is packaged and incorporated into a kit.
  • the kit contains the substrate on which the gradient will be formed, along with one or more containers containing reagents for forming the gradient.
  • the kit optionally contains directions for preparing and/or using the template.
  • Type A Surface-chemical wettability gradients created by a dodecanethiol/ mercaptoundecanethiol surface-concentration ratio gradient prepared with immersion technique (S. Morgenthaler, et al, Langmuir, Vol. 19, No. 25, 10459-10462 (2003)).
  • Type B 1 mm thick stripes of surface-chemical gradients of the same type as described above alternating with 1 mm thick hydrophobic stripes (hexadecanethiol) along the gradient.
  • Screening Tool Type B was been prepared in order to create a chemical contrast.
  • a surface-chemical gradient was prepared by immersing the wafer into a 0.005 mM dodecanethiol ethanol solution by means of a linear motion drive with a speed of 0.0375 mm/s (see e.g. Step 1 illustrated in Figure 2). After complete immersion, the wafer was withdrawn from the solution, rinsed with ethanol and blow-dried with nitrogen. Then, the wafer was immersed into 0.01 mM 11-mercaptoundecanethiol solution over night (about 15hours), rinsed with ethanol and blow-dried with nitrogen.
  • the stamp was placed on the surface of the wafer and, initially, a soft force was manually applied to the stamp with a fingertip for a very short period of time, e.g., a fraction of second to a second. After 60 seconds, the stamp was removed, the wafer was rinsed with ethanol and blow-dried with nitrogen.
  • a surface-chemical gradient was prepared by immersing the wafer into a 0.005 mM dodecanethiol ethanol solution by means of a linear motion drive with a speed of 0.0375 mm/s. After complete immersion, the wafer was withdrawn from the solution, rinsed with ethanol and blow-dried with nitrogen. Then, the wafer was immersed into 0.01 mM 11- mercaptoundecanethiol solution over night (about 15 hours), rinsed with ethanol and blow-dried with nitrogen.
  • FIG. 2 is a schematic of a portion of the above-described experimental procedure.
  • a computer is electrically connected to the linear motion drive.
  • Step 1 represents the immersion of the substrate in diluted dodecanethiol solution.
  • the subsequent backfilling process by total immersion of the substrate into mercaptoundecanol solution is not illustrated in Figure 2.
  • Step 2 of Figure 2 The sample is slowly withdrawn from an oversaturated solution of the compound to be crystallized, which creates a gradient of the compound to be tested, and analyzed for polymorphs.
  • substrates of Type A and B were immersed in an oversaturated Carbamazepine solution.
  • the crystals formed on the surface were recorded with optical microscopy and their average size and their distribution density on the surface was analyzed.
  • Raman spectroscopy can be used, using standard procedures, to determine the polymorphic forms of the crystal on the surface.
  • the crystals on the substrate surface were imaged with a 4 x enlarging microscope. The whole substrate surface was mapped (10 x 10 images). The images were analyzed with the software ImageJ to determine an average crystal size, and the number of crystals for each image. From these images, an overall average crystal size and an average number of crystals for a given immersion time were calculated. The values were normalized by setting the average for each immersion time as 100 %. Therefore, values greater than 100 % indicate that the crystals were larger than the average crystal size, and values smaller than 100 % indicate that the crystals were smaller than average crystal size for this particular immersion time. These normalized values were summarized for all immersion times.
  • CS D average crystal size for immersion time (D) into dodecanethiol
  • N D number of analysis points for immersion time (D) into dodecanethiol solution
  • Nc number of analysis points for immersion time (C) into
  • the number of crystals for immersion time (D) in dodecanethiol and immersion time (C) in carbamazepine solution can be calculated using
  • NC n ⁇ N i y D
  • NC DC number of crystals for immersion time (D) into dodecanethiol and for immersion time (C) into carbamazepine solution
  • NC D number of crystals for immersion time (D) into dodecanethiol
  • N D number of analysis points for immersion time (D) into dodecanethiol solution
  • Nc number of analysis points for immersion time (C) into Carbamazepine solution Discussion
  • Type A substrates dodecanethiol vs. 11- mercaptoundecanethiol gradient
  • Figure 3 The results for Type A substrates, the number of crystals and crystal size increased with increasing hydrophilicity.
  • Type B substrates dodecanethiol vs 11- mercaptoundecanethiol gradient, including ⁇ CP stripes
  • Figure 4 The results for Type B substrates the number of crystals decreased with increasing hydrophilicity while crystal size increased with increasing hydrophilicity
  • the differences in crystal distribution and crystal size along the gradient indicate that different kinetic processes take place on the substrate for surfaces with different surface chemistries.
  • the small changes in the crystallization kinetics may lead to different polymorphic systems.
  • tests for a given sample on a substrate containing one or more surface gradients allow for varying surface properties to be tested for the crystallization process in one experiment. If a difference is observable on the gradient it must arise from the different surface chemistry since the crystallization solution is the same for the whole gradient.

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Abstract

L'invention concerne des procédés, des kits et des modèles de cristallisation destinés à induire et déterminer des polymorphes dans un composé. Dans un mode de réalisation, les modèles de cristallisation contiennent un ou plusieurs gradients chimiques de surface et/ou gradients de morphologie de surface. Le modèle de cristallisation est typiquement exposé à une solution ou vapeur contenant la composition à tester. On laisse ensuite le composé étudié cristalliser à la surface. Les effets de nucléation peuvent être de nature morphologique ou chimique. Différentes surfaces modifiées chimiquement ou morphologiquement de différentes manières peuvent être utilisées pour identifier la présence et les types de polymorphes dans un composé ou une composition étudiés. L'analyse de la structure cristalline du composé testé peut être exécutée par toute technique appropriée de détection et d'analyse. Après l'identification des différents polymorphes, un ou plusieurs polymorphes peuvent être sélectionnés pour être encore testés et/ou produits.
PCT/CH2009/000210 2008-06-20 2009-06-19 Outils de tri basés sur gradient pour détection et identification de polymorphes Ceased WO2009152635A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042731A2 (fr) * 2000-11-20 2002-05-30 Parallel Synthesis Technologies, Inc. Procedes et dispositifs pour une cristallisation a haut debit
EP1336671A1 (fr) * 2002-02-15 2003-08-20 Paul Scherrer Institut Procédé de fabrication d'un substrat structuré pour activer la cristallisation d'une biomolécule et procédé pour activer la cristallisation des biomolécules
WO2005002743A1 (fr) * 2003-03-31 2005-01-13 Eidgenossische Technische Hochschule Zurich Gradients chimiques de surface regules
US20060099572A1 (en) * 2003-07-09 2006-05-11 Kwong Peter D Crystallization reagent matrices and related methods and kits
US20060096523A1 (en) * 2004-11-10 2006-05-11 Myerson Allan S Method for producing crystals and screening crystallization conditions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042731A2 (fr) * 2000-11-20 2002-05-30 Parallel Synthesis Technologies, Inc. Procedes et dispositifs pour une cristallisation a haut debit
EP1336671A1 (fr) * 2002-02-15 2003-08-20 Paul Scherrer Institut Procédé de fabrication d'un substrat structuré pour activer la cristallisation d'une biomolécule et procédé pour activer la cristallisation des biomolécules
WO2005002743A1 (fr) * 2003-03-31 2005-01-13 Eidgenossische Technische Hochschule Zurich Gradients chimiques de surface regules
US20060099572A1 (en) * 2003-07-09 2006-05-11 Kwong Peter D Crystallization reagent matrices and related methods and kits
US20060096523A1 (en) * 2004-11-10 2006-05-11 Myerson Allan S Method for producing crystals and screening crystallization conditions

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* Cited by examiner, † Cited by third party
Title
MORGENTHALER S ET AL: "Surface-chemical and -morphological gradients", SOFT MATTER 2008 ROYAL SOCIETY OF CHEMISTRY; THOMAS GRAHAM HOUSE; SCIENCE PARK GB, vol. 4, no. 3, 30 January 2008 (2008-01-30), pages 419 - 434, XP002547804, Retrieved from the Internet <URL:http://www.rsc.org/ej/SM/2008/b715466f.pdf> [retrieved on 20090928] *

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