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WO2011115069A1 - Recherche exhaustive de cristaux - Google Patents

Recherche exhaustive de cristaux Download PDF

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Publication number
WO2011115069A1
WO2011115069A1 PCT/JP2011/055958 JP2011055958W WO2011115069A1 WO 2011115069 A1 WO2011115069 A1 WO 2011115069A1 JP 2011055958 W JP2011055958 W JP 2011055958W WO 2011115069 A1 WO2011115069 A1 WO 2011115069A1
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WIPO (PCT)
Prior art keywords
crystal
salt
amorphous
solvent
solvate
Prior art date
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Ceased
Application number
PCT/JP2011/055958
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English (en)
Japanese (ja)
Inventor
克弘 小林
宏之 山脇
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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Application filed by Daiichi Sankyo Co Ltd filed Critical Daiichi Sankyo Co Ltd
Publication of WO2011115069A1 publication Critical patent/WO2011115069A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides a method for easily and comprehensively preparing various salts of target compounds, their co-crystals, their solvates and their crystal forms, and the resulting salts, their co-crystals, their solvents
  • the present invention relates to a method for selecting a desired form from hydrates and their crystal forms.
  • salts and / or crystals with good solubility and stability are required as the drug substance form.
  • the drug substance forms that the drug can take include salts and solvates in addition to the free form, and furthermore, there are crystal polymorphs for each of these. Since the properties of a compound vary greatly depending on the state of the salt, solvation, and crystal polymorphism, selection of a preferred form of the compound is a very important matter particularly in the pharmaceutical field.
  • Non-Patent Documents 1 to 4 Examples of methods that can be used to obtain new salts of the target compounds and their co-crystals, their solvates, and / or their crystal forms include slurry methods, concentration methods, poor solvent addition methods, vapor diffusion methods, and cooling methods. And neutralization crystallization methods are known (for example, Non-Patent Documents 1 to 4).
  • the method of crystallizing a compound after dissolving it in a solution is not suitable for large-scale screening because it requires information on the solubility of the target compound in advance or requires a large amount of specimen. It is.
  • a method for screening a salt or crystal of a compound using a small amount of specimen high-throughput screening using a 96-well plate or the like using recrystallization, slurry purification, evaporation method, etc. has been developed (for example, non- According to Patent Document 2), recrystallization at a small scale, slurry purification, evaporation method and the like are difficult to adjust crystallization conditions, and anyone cannot easily perform crystallization screening with high reproducibility and high probability.
  • Non-patent Document 5 As for solvent vapor exposure, crystals are formed by exposing an amorphous lactose or erythromycin to solvent vapor (Non-patent Document 5), or by exposing co-crystals to various solvent vapors. (Non-Patent Document 6) is known.
  • a method for preparing various salts of a target compound, their co-crystals, their solvates and / or their crystal forms comprising: (1) A step of producing an amorphous free body or a salt thereof, or a low crystalline solid of a free body, a salt thereof, a co-crystal or a solvate thereof; (2) exposing the amorphous or the low crystalline solid to solvent vapor; (3) analyzing the crystal form of the compound obtained in the step (2); and (4) changing the conditions of the solvent vapor exposure and repeating the steps (1) to (3) one or more times.
  • the method for producing the amorphous or low crystalline solid is [1], wherein the free form, a salt thereof, a co-crystal thereof or a solvate thereof is pulverized, cooled by cooling, freeze-dried or spray-dried.
  • a drug substance form can be quickly and easily examined by anyone easily and comprehensively with a high crystallization probability.
  • recovered in Example 1 is shown (solvent exposure time: 1 day).
  • recovered in Example 1 is shown (solvent exposure time: 1 week).
  • the representative powder X-ray diffraction pattern of the sample collected in Example 2 is shown.
  • the representative powder X-ray diffraction pattern of the sample collected in Example 3 is shown.
  • the representative powder X-ray diffraction pattern of the sample collected in Example 3 is shown.
  • the representative powder X-ray diffraction pattern of the sample collected in Example 4 is shown.
  • the representative powder X-ray diffraction pattern of the sample collected in Example 4 is shown.
  • the representative powder X-ray diffraction pattern of the sample collected in Example 5 is shown.
  • the representative powder X-ray diffraction pattern of the sample collected in Example 5 is shown.
  • the representative powder X-ray diffraction pattern of the sample collected in Example 5 is shown.
  • the representative powder X-ray diffraction pattern of the sample collected in Example 5 is shown.
  • the present invention relates to a method for preparing various salts of the target compound, their co-crystals, their solvates and / or their crystalline forms, comprising the following steps: (1) A step of producing an amorphous free body or a salt thereof, or a low crystalline solid of a free body, a salt thereof, a co-crystal or a solvate thereof; (2) exposing the amorphous or the low crystalline solid to solvent vapor; (3) a step of analyzing the crystal form of the compound obtained in the step (2); and (4) a step of repeating the steps (1) to (3) one or more times while changing the conditions of the solvent vapor exposure.
  • the present invention also relates to a method of making various salts of the target compound, their co-crystals, their solvates and / or their crystalline forms, comprising the following steps: (1a) producing a low crystalline solid of a free form or a salt thereof, or a free form, a salt thereof, a co-crystal thereof or a solvate thereof in the first container; (2a) placing the first container in a second container and exposing the amorphous or low crystalline solid to solvent vapor; (3a) analyzing the crystal form of the compound obtained in step (2a); (4a) A step of repeating the steps (1a) to (3a) one or more times while changing the conditions of solvent vapor exposure.
  • the “target compound” means an organic compound to be investigated for a salt, a solvate, a co-crystal or a crystal form.
  • the “target compound” refers to a compound in a free form that is neither a salt form nor a solvate form, or a guest ( guest) A host compound that is looking for a compound.
  • crystal polymorph or “polymorph” means that the same compound in the chlorination state or the solvation state has two or more different crystal structures, or each such crystal.
  • crystal polymorph or “polymorph” used for a co-crystal means a co-crystal having the same host compound-guest compound combination and the same chlorination state and solvation state. It has two or more different crystal structures, or each such crystal. Since polymorphs have different crystal structures, they may show different peak characteristics in X-ray crystal analysis and infrared spectroscopy, draw different TG / DTA curves, and have different melting points and moisture absorption / desorption behavior. Are known.
  • crystal form means that the free form or the portion of the host compound is a crystal of two common compounds, even if the chlorinated state or the solvated state, or the combination of the host compound and the guest compound is different. That means.
  • crystal polymorph and “polymorph” are included in the range of “crystal form”.
  • a certain free form compound X shows two kinds of crystal polymorphs as a free form, two kinds of crystal polymorphs as a sodium salt anhydrate, and two kinds as a sodium salt pentahydrate.
  • crystal forms respectively or collectively.
  • co-crystal refers to a crystal formed from a plurality of compounds, generally two compounds. Looking at the “co-crystal” at the molecular level, the molecules of the two types of compounds have a crystal structure with a regular arrangement. This “co-crystal” is known to have a different crystal structure from the crystals formed by each of the two types of compounds that form the co-crystal, and thus may exhibit different physiochemical properties. ing.
  • amorphous is also referred to as amorphous, and refers to an amorphous solid having no regular three-dimensional crystal structure. Whether or not the target compound is amorphous is, for example, when the compound is subjected to powder X-ray diffraction analysis, a specific peak does not exist and a broad powder X-ray diffraction profile (halo) is generated. It is confirmed to be amorphous.
  • low crystalline solid means a metastable crystal having a low powder X-ray diffraction peak, which does not show a broader powder X-ray diffraction profile as amorphous, but has a low powder X-ray diffraction peak. To do.
  • amorphous and “low crystalline solid” may be collectively referred to as amorphous or the like.
  • salt, co-crystal, solvate and / or crystal form thereof of “target compound” means free salt, free solvate, free form of target compound.
  • Amorphous and the like are appropriately selected in consideration of the thermal stability of a free form, a salt thereof, a co-crystal thereof, or a solvate thereof (hereinafter sometimes referred to as a free form). Can be done.
  • the lower limit of the amount of free body used for the production of amorphous or the like is not particularly limited, but may be at least 0.1 mg or more per one solvent exposure condition, and preferably 1 mg or more and 3 mg per one solvent exposure condition. As long as it is 5 mg or more, 6 mg or more, 7 mg or more, 8 mg or more, 9 mg or more, or 10 mg or more.
  • the upper limit of the amount of free body or the like is not particularly limited, and is determined depending on the amount of available free body or the like and the number of exposure conditions. Amorphous or the like may be produced for each solvent exposure condition, or a plurality of solvent exposure conditions may be produced together.
  • a method for preparing a plurality of solvent exposure conditions for a free body or the like for example, 1 to 10 g of a free body or the like is dissolved in 2 to 2000 mL of solvent, and the number of solvent exposure conditions to be examined The sample dissolved in the container may be divided and then processed so that amorphous or the like is formed.
  • the method for producing amorphous or the like is not limited to these.
  • a method of pulverizing a free body or the like a method of melting and cooling (sometimes referred to as a melting cooling method in this specification), and a method of freeze-drying.
  • a method of spraying and drying sometimes referred to as a spray-drying method in the present specification
  • a drying method is mentioned, More preferably, a freeze-drying method is mentioned.
  • a method for producing an amorphous compound is described in, for example, Ralph Hilfiker, Polymorphism, 2006, Willy-VCH Weinheim, p263-269.
  • what is necessary is just to use, when a free body etc. can be purchased as an amorphous etc.
  • an amorphous or the like can be prepared by a freeze-drying method.
  • amorphous materials such as free bodies by freeze-drying
  • the solution is frozen in liquid nitrogen or a low-temperature chamber, and then the solvent is gradually increased under reduced pressure. It can be freeze-dried by removing.
  • the solvent for dissolving the free form or the like is not particularly limited, and examples thereof include water, dioxane, dimethyl sulfoxide, methanol, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, trifluoroethanol, and the like.
  • the water content is appropriately selected according to the free form or the like or the solvent to be used, and is not particularly limited.
  • a water content in the range of 5% to 95% can be mentioned, preferably 5 %, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% water content.
  • the water content means the ratio of the volume of water to the total volume of the solvent.
  • the mixing ratio of each solvent can be suitably determined according to a free body etc. or the solvent to mix.
  • the amount of the solvent is not particularly limited.
  • the solvent is 2 mL to 200 mL, preferably 10 mL to 100 mL with respect to 1 g of the free form.
  • the temperature at which the free form or the like is dissolved in the solvent is appropriately selected according to the free form or the like or the solvent used, and is not particularly limited, but is, for example, 5 ° C. to 60 ° C., preferably 15 ° C. to 40 ° C.
  • the temperature for lyophilization is appropriately selected according to the free form or the like or the solvent used, and is not particularly limited. For example, it is preferably ⁇ 80 ° C. to 60 ° C., more preferably ⁇ 60 to 40 ° C.
  • the time until lyophilization is appropriately selected according to the free form, the solvent used, and the lyophilization temperature, and is not particularly limited. For example, it is preferably 12 hours to 1 week, more preferably 1 day to 3 days.
  • an amorphous or the like can be created by a melting cooling method.
  • the melting and cooling method can obtain amorphous or the like by melting a free body or the like and then rapidly cooling it with liquid nitrogen or the like.
  • the metal container used in the melting and cooling method is not particularly limited, but is selected depending on the amount and properties of the free body.
  • an aluminum container for thermal analysis a platinum container, an aluminum foil and the like can be mentioned, and an aluminum container for thermal analysis is preferable.
  • the temperature for melting the free body or the like is selected in consideration of the stability of the free body or the like, and is, for example, from about the melting point to about 30 ° C. higher than the melting point, and preferably from the melting point to about 5 ° C. higher than the melting point.
  • a cooling method liquid nitrogen, dry ice, or a freezer can be used, but liquid nitrogen is preferable.
  • the amorphous body In order to handle amorphous at room temperature, it is necessary to return the cooled amorphous body or the like to room temperature. However, in order to suppress crystallization, the amorphous body is stored in a container with controlled humidity. For example, it is left in a container containing a desiccant such as silica gel or phosphorus pentoxide or in a thermo-hygrostat controlled at low humidity. Silica gel is preferable as the desiccant, and a constant temperature and humidity machine is also preferable.
  • the standing time is not particularly limited, but is about 10 minutes to about 1 day, preferably about 30 minutes to about 2 hours.
  • the step of producing the amorphous body such as the free body is preferably performed in a first container (where the first container is sized to be accommodated in the second container) as described later.
  • the free form may be chlorinated or co-crystallized.
  • the salt when preparing a crystalline form of a free-form salt, if the material to be used is a salt, the salt may be subjected to the above-described amorphization or low-crystallization step. Alternatively, after adding a base to salify the free form, the above-described amorphization or low crystallization may be performed. In addition, for example, when a crystal form of a co-crystal is produced, if the material used is a co-crystal, the co-crystal may be subjected to the above-described low crystallization step. If the material used is a host compound, After adding a co-crystal partner, the above-described low crystallization may be performed.
  • the timing of addition is before and after dissolving the target compound in the solvent. Any of these may be used, but it is preferable to add the target compound after dissolving it in a solvent.
  • the amount of acid or base to be added is not particularly limited, but is determined with reference to the number of dissociable groups and the pKa value of the target compound. For example, the amount is 0.75 to 2.0 equivalents, preferably 0.9 to 1.1 equivalents, with respect to the target compound having one dissociating group.
  • Step 2 relates to a step of exposing amorphous or the like to solvent vapor.
  • the solvent vapor exposure of the target compound such as amorphous is not limited to this method, but examples include the following method. First, a first container and a second container that is smaller than the first container and can be stored in the first container are prepared, an exposure solvent is put in the first container, and the amorphous or the like is put in the second container. Or place and leave each until exposure temperature conditions are reached. When each container is at an exposure temperature condition, the second container is placed in the first container without sealing.
  • the said exposure solvent is a liquid, the said solvent liquid is not made to contact amorphous etc.
  • the first container In a state where the second container is in the first container, the first container is sealed with a lid, a parafilm, or the like of the first container, so that the amorphous material in the second container or on the second container Etc. are exposed to the vapor of solvent that was in the first container. After the amorphous or the like is exposed to the solvent at the target temperature and time, the first container is opened and the crystals in the second container or on the second container exposed to the solvent can be collected.
  • the type of the first container is not particularly limited as long as it can accommodate the second container, and can be appropriately selected according to the nature and amount of the target compound.
  • the material of the first container is not particularly limited, and examples thereof include glass and metal containers, and can be appropriately selected according to the nature and amount of the target compound. Examples of the first container include a beaker, a vial bottle, a glass bottle, and a metal drum.
  • the method for sealing the first container is not particularly limited, and a container with a lid may be used, or sealing may be performed by plugging with a parafilm or the like.
  • the type of the second container is not particularly limited as long as amorphous or the like can be disposed and can be stored in the first container, and can be appropriately selected according to the property and amount of the target compound.
  • the material of the first container is not particularly limited, and examples thereof include glass and metal containers, and can be appropriately selected according to the nature and amount of the target compound.
  • Examples of the second container include a flask, a beaker, a test tube, a vial bottle, a glass bottle, a petri dish, or a plate.
  • the first container and the second container may be integrated or separable.
  • the first container and the second container for example, a commercially available square 96-well deep plate, an aluminum container for thermal analysis having the same size as the diameter of the well, and an aluminum container slightly smaller than the diameter of the well are combined. Can also be exposed to steam.
  • the aluminum container is placed in the middle of the well. stay.
  • Examples of the solvent exposed to vapor include anisole, acetone, 2-butanone, toluene, benzene, phenol, naphthalene, acetonitrile, dimethoxyethane, dimethoxymethane, chloroform, acetic acid, ethyl acetate, dioxane, dimethyl sulfoxide, tetrahydrofuran, 1-propanol.
  • 2-propanol, ethanol, methanol or water, or a mixed solvent thereof preferably acetone, toluene, benzene, phenol, naphthalene, acetonitrile, 2-dimethoxyethane, chloroform, acetic acid, ethyl acetate, 1,4- Examples thereof include dioxane, dimethyl sulfoxide, tetrahydrofuran, 1-propanol, 2-propanol, ethanol, methanol or water, or a mixed solvent thereof.
  • the solvent exposed to vapor includes benzene, phenol, naphthalene, acetic acid, 1,4-dioxane, dimethyl sulfoxide, or a mixed solvent thereof.
  • the solvent to be exposed to vapor is not limited to a solvent that is liquid at the exposure temperature, and may be a solid as long as it has a vapor pressure.
  • these polymorphs can be obtained by exposing a target compound, a salt thereof, an amorphous form of a co-crystal or the like to a vapor of these solvents.
  • the vapor exposure solvent in step 3 may be a mixed solvent of a solvent for screening polymorphs and a solvating solvent, and may be arbitrarily selected according to the purpose.
  • the temperature at the time of solvent vapor exposure can be appropriately selected depending on the solvent to be exposed, and is not particularly limited, but is, for example, ⁇ 20 ° C. to 80 ° C., preferably 5 ° C. to 60 ° C.
  • the preferred temperature and time of the solvent vapor exposure are 5 ° C. to 60 ° C. for 1 day to 4 days, preferably 5 ° C. to 40 ° C. for 2 days to 3 days.
  • the amount of the solvent put into the first container is not particularly limited, but is usually an amount from the amount covering the entire bottom of the first container to about 1 cm below the edge of the second container, preferably the first container The amount from about 1 cm from the bottom of the container to about 1 cm below the edge of the container. If the exposed solvent remains in the first container after the solvent is exposed to amorphous or the like, the solvent can be used for exposure of another amorphous or the like.
  • the analysis includes various devices useful for crystal analysis, such as a powder X-ray diffractometer well known to those skilled in the art of crystal chemistry, such as an infrared spectrometer, a thermal analyzer (TG / TDA), and water vapor adsorption.
  • a powder X-ray diffractometer well known to those skilled in the art of crystal chemistry
  • TG / TDA thermal analyzer
  • water vapor adsorption water vapor adsorption.
  • An analysis using a measuring device can be mentioned. These analyzes are described, for example, in Ralph Hilfiker, Polymorphism, 2006, Willy-VCH Weinheim, p43-207, edited by Stephen Byrn, et al., Solid-state Chemistry of Drug, 1999, SS45. Yes.
  • Step 4 relates to a step of repeating the steps (1) to (3) one or more times using conditions different from the previously used conditions of chlorination, cocrystallization or solvent vapor exposure for the target compound.
  • steps (1) to (3) using a plurality of exposed solvents, another type of crystal form of the target compound can be found, or different crystallization conditions can be used for the same crystal form. Can be found.
  • steps (1) to (3) can be repeated multiple times.
  • the number of times the steps (1) to (3) are repeated is preferably 10 times or more, 20 times or more, 30 times or more, 40 times or more, 50 times or more, or 100 times or more, preferably 30 times or more, 40 times More than once, 50 times or more or 100 times or more are more preferable. It is preferable that the steps (1) to (3) are repeated more frequently because the salt, crystal form, etc. of the target compound can be examined more comprehensively, and the choices for selecting the desired drug substance form are expanded.
  • the profile of the salt of the target compound, their co-crystals, their solvates or their crystal forms (Sometimes referred to herein as a compound profile)
  • the preferred salt of the target compound, their co-crystals, their solvates and / or their crystal forms You can choose.
  • another aspect of the present invention provides a step of creating a profile of the target compound using the result of step (3) and the results obtained by repeating steps (1) to (3) one or more times, and Selecting a preferred salt of the target compound, their co-crystal, their solvate and / or their crystal form using a profile, preferred salt of the target compound, their co-crystal, their solvation
  • the invention relates to a method for selecting products and / or their crystal forms.
  • the method of the present invention can easily perform a large number of crystallization conditions for a desired compound with a small amount of sample without using complicated operations. This facilitates the creation of profiles relating to the salt, co-crystal, solvate and crystal form of the target compound.
  • An exhaustive search of the present invention enables the creation of a more detailed compound profile of the target compound. By using the detailed compound profile obtained by the method of the present invention, it is possible to select a preferable crystal form without further analyzing each crystal form by elemental analysis or the like.
  • the salt, co-crystal, solvate and crystal form of the target compound can all be screened at the same time, or desired items can be screened according to the purpose.
  • one compound can be screened for salt forms and crystal forms of those salt forms (see, eg, Example 3 or Example 4), and another compound can be co-crystal form. And their co-crystal forms can also be screened (see, eg, Example 5).
  • Table 1 shows the results of indomethacin crystal search created from the powder X-ray diffraction results.
  • the alphabetical notation from a to d in Table 1 indicates the pattern of the powder X-ray diffraction profile, and the same alphabetical notation indicates that the powder X-ray diffraction profiles are similar to each other. * Indicates that the solid was amorphous. The parentheses indicate that although the crystal form was identified, the powder X-ray diffraction peak was weak and the crystallinity was low.
  • Cholic acid crystal search Cholic acid crystal polymorphism screening was performed under 96 solvents and 3 temperature conditions.
  • Cholic acid (1.20 g, 0.561 mmol) was dissolved in 30 mL of a 1,4-dioxane / dimethylsulfoxide (volume ratio: 5/1) mixed solution, and 100 ⁇ L was dispensed into 288 HPLC vials. These vials were placed in a lyophilizer, and the dispensed solution was lyophilized while changing the shelf temperature from ⁇ 45 ° C. to 40 ° C.
  • Table 2 shows the results of crystal search for cholic acid prepared from the results of powder X-ray diffraction.
  • the alphabetical notation from A to L in Table 2 indicates the pattern of the powder X-ray diffraction profile, and the same alphabetical notation indicates that the powder X-ray diffraction profiles are similar to each other.
  • Low indicates that the solid was low crystalline
  • * indicates that the solid was amorphous
  • Can indicates that the specimen was candy-like.
  • the salt was obtained as a solid as monohydrochloride, hydrobromide, mononitrate, fumarate, and oxalate.
  • Table 3 shows the results of searching for the salt and crystal form of nicardipine prepared from the results of powder X-ray diffraction.
  • the salt type and its crystal form are distinguished using the salt type abbreviations (HCl, HBr, HNO, Fum or Oxa) and alphabetical notation from A to D.
  • the same alphabetical letters at the end indicate that the powder X-ray diffraction profiles are homologous to each other.
  • monohydrobromide exposed to solvent vapor in dichloromethane or ethyl acetate are both labeled as HBr_A, indicating that both powder X-ray diffraction profiles were homologous.
  • HCl_B and HBr_B have the same alphabet at the end, but the types of salt differ between monohydrochloride and monohydrobromide, so the powder X-ray diffraction profiles do not correspond to each other.
  • Sulfasalazine 400 mg, 1 mmol is dissolved in 10 mL of 1,4-dioxane / dimethyl sulfoxide (volume ratio: 50/50), and this solution is added to 1200 ⁇ l (equivalent to 48 mg, equivalent to 0.123 ⁇ mol) in 8 glass sample tubes. Each was dispensed. None was added to one of these tubes, and it was directly subjected to the next freeze-drying step.
  • Table 4 shows the results of searching for alkali metals and alkaline earth metal salts of sulfasalazine and their crystal forms prepared from the results of powder X-ray diffraction.
  • the salt type and its crystal form are distinguished by using the salt type abbreviations (Fr, Li, Na, K, HMg, HCa, HZn, or TAl) and the alphabetical notation from A to F.
  • the salt type is the same, the same alphabetical letters at the end indicate that the powder X-ray diffraction profiles are homologous to each other.
  • monolithium salts exposed to solvent vapor in acetonitrile or acetone are both labeled LiA, indicating that both powder X-ray diffraction profiles were homologous.
  • the salt types are different, their powder X-ray diffraction profiles are not relevant even if the alphabetical suffix is the same.
  • LiA and HCaA have the same alphabet at the end, the powder X-ray diffraction profiles do not correspond to each other because the type of salt differs between 1 lithium salt and 1/2 calcium salt.
  • the peak positions of the powder X-ray diffraction are slightly different from each other, those that are homologous as an overall profile are distinguished by numbers described after the alphabet.
  • the monosodium salt two types of powder X-ray diffraction profiles that are totally homologous were obtained (NaA1 and NaA2) although the peak positions of the powder X-ray diffraction were slightly different from each other.
  • Piroxicam 1000 mg, 3.018 mmol was dissolved in a dioxane solution (60 mL), and this was dispensed in 1680 ⁇ l portions into 32 glass sample tubes. Further, 1 equivalent each of water of a co-crystal partner or a mixed solution of 1,4-dioxane / dimethyl sulfoxide (volume ratio 50:50) was added. When a precipitate was deposited, water or dimethyl sulfoxide was added to obtain a uniform solution. These 32 sample tubes were stirred with a vortex mixer for about 10 minutes, and each sample tube was then dispensed in 7 HPLC vials to an equal volume. A total of 224 HPLC vials prepared in this manner were placed in a freeze dryer, and freeze-dried while changing the shelf temperature from ⁇ 45 ° C. to 25 ° C.
  • Table 5 shows the co-crystals of piroxicam prepared from the results of powder X-ray diffraction and the results of searching for these crystal forms.
  • the co-crystal partners and their crystal forms are distinguished by using the abbreviations of the co-crystal partners (Fr to Pgt) and alphabetical notations from A to F. If the co-crystal partners are the same, those with the same alphabetical letter at the end indicate that they have powder X-ray diffraction profiles that are homologous to each other.
  • the co-crystals of piroxicam and oxalic acid exposed to solvent vapor in tetrahydrofuran or methanol are both labeled OxaA, indicating that both powder X-ray diffraction profiles were homologous.
  • the co-crystal partners are different, their powder X-ray diffraction profiles are not relevant even if the alphabetical suffix is the same. For example, FumA and MleA have the same alphabet at the end, but the powder X-ray diffraction profiles do not correspond to each other because the co-crystal partners are different between fumaric acid and maleic acid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation des divers sels d'un composé cible, du co-cristal des sels, du solvate des sels et du co-cristal, et/ou de la forme cristalline des sels, du co-cristal et du solvate. Ce procédé met en jeu: une étape (1) de préparation d'un solide amorphe d'une forme libre ou du sel de celui-ci, ou d'un solide de faible cristallinité de la forme libre, du sel de celui-ci, du co-cristal de la forme libre et du sel, ou du solvate de la forme libre, du sel et du co-cristal ; une étape (2) d'exposition dudit solide amorphe ou dudit solide à faible cristallinité à une vapeur de solvant ; une étape (3) d'analyse de la forme cristalline du composé obtenu à l'étape (2) ; et une étape (4) de répétition des étapes (1) à (3) pas moins d'une fois par variation des conditions d'exposition à la vapeur de solvant.
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JP2019504054A (ja) * 2015-12-31 2019-02-14 シャンハイ ファーマシューティカルズ ホールディング カンパニー，リミティド キノリン系化合物の塩、その結晶形、調製方法、組成物及び用途
WO2020100712A1 (fr) * 2018-11-12 2020-05-22 昭和電工株式会社 Procédé de production d'un dérivé d'acide orotique
CN113072483A (zh) * 2021-03-30 2021-07-06 济南良福精合医药科技有限公司 盐酸尼卡地平的精制方法
JP2023522331A (ja) * 2020-04-17 2023-05-30 武田薬品工業株式会社 血漿カリクレインの阻害剤の形態及び組成物
JP2024156899A (ja) * 2019-04-09 2024-11-06 ロッタファーム・バイオテック・エッセ・エッレ・エッレ 腫瘍を処置するためのｅｐ４アンタゴニストと免疫チェックポイント阻害剤の配合医薬
JP2025502542A (ja) * 2022-01-28 2025-01-24 チェンドゥ ヘンハオ イノベイティブ サイエンス アンド テクノロジー カンパニー リミテッド フェノチアジン系化合物の結晶形、塩、製造方法及び用途
JP2025017374A (ja) * 2019-01-25 2025-02-05 ベイジーン リミテッド Ｂ－ｒａｆキナーゼ二量体阻害剤の安定な固体分散体、その調製方法及び使用
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Publication number Priority date Publication date Assignee Title
JP2019504054A (ja) * 2015-12-31 2019-02-14 シャンハイ ファーマシューティカルズ ホールディング カンパニー，リミティド キノリン系化合物の塩、その結晶形、調製方法、組成物及び用途
US10344035B2 (en) 2015-12-31 2019-07-09 Shanghai Phaarmaceuticals Holding Co., Ltd. Salt of quinolone compound, polymorphs thereof, preparation method therefor, composition, and applications
US12391726B2 (en) 2017-09-13 2025-08-19 Emmyon, Inc. Ursolic acid morpholine salt
US12264178B2 (en) 2017-09-13 2025-04-01 Emmyon, Inc. Ursolic acid morpholine and diethanolamine salts
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JPWO2020100712A1 (ja) * 2018-11-12 2021-09-30 昭和電工株式会社 オロト酸誘導体の製造方法
JP7363805B2 (ja) 2018-11-12 2023-10-18 株式会社レゾナック オロト酸誘導体の製造方法
CN112969462B (zh) * 2018-11-12 2024-03-19 株式会社力森诺科 乳清酸衍生物的制造方法
CN112969462A (zh) * 2018-11-12 2021-06-15 昭和电工株式会社 乳清酸衍生物的制造方法
WO2020100712A1 (fr) * 2018-11-12 2020-05-22 昭和電工株式会社 Procédé de production d'un dérivé d'acide orotique
JP2025017374A (ja) * 2019-01-25 2025-02-05 ベイジーン リミテッド Ｂ－ｒａｆキナーゼ二量体阻害剤の安定な固体分散体、その調製方法及び使用
JP2024156899A (ja) * 2019-04-09 2024-11-06 ロッタファーム・バイオテック・エッセ・エッレ・エッレ 腫瘍を処置するためのｅｐ４アンタゴニストと免疫チェックポイント阻害剤の配合医薬
JP2023522331A (ja) * 2020-04-17 2023-05-30 武田薬品工業株式会社 血漿カリクレインの阻害剤の形態及び組成物
CN113072483A (zh) * 2021-03-30 2021-07-06 济南良福精合医药科技有限公司 盐酸尼卡地平的精制方法
JP2025502542A (ja) * 2022-01-28 2025-01-24 チェンドゥ ヘンハオ イノベイティブ サイエンス アンド テクノロジー カンパニー リミテッド フェノチアジン系化合物の結晶形、塩、製造方法及び用途

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