Patent Description:
The present disclosure relates to the field of medicinal chemistry, and in particular to a non-solvated crystal of N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide as well as preparation method thereof.

N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide is a protein kinase and histone deacetylase dual target inhibition, the chemical structure of it is shown in structural formula (I)
<CHM>.

Pharmacological activity of the compound of the formula (I) is described in Chinese patent application <CIT>, which has a protein kinase inhibitory activity and a histone deacetylase inhibitory activity, and can be used for the treatment of a disease associated with abnormal protein kinase activity or abnormal histone deacetylase activity, including inflammation, autoimmune diseases, cancer, nervous system diseases and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergies, asthma, and hormone-related diseases, and especially have excellent efficacy for treating blood cancer and solid tumors.

The present inventors prepared the compound of the formula (I) according to the method described in Example <NUM> of the Chinese patent application <CIT>, and the X-ray powder diffraction pattern of the obtained solid is shown in <FIG>. In fact, the solid of the compound of formula (I) prepared by this process inevitably contains N,N-dimethylformamide (DMF), which has been confirmed by its proton nuclear magnetic resonance spectrum (<NUM>H NMR). The resulting solid is a solvated crystal of N,N-dimethylformamide (DMF), which contains <NUM>% DMF.

Since organic solvents are potentially toxic to the drug user, it is generally not desirable to prepare crystals containing organic solvents. The International Conference of Harmonizition (ICH) specifies residual limits of various common organic solvents in pharmaceuticals. For example, the limits of N,N-dimethylformamide (DMF), chloroform, methanol, tetrahydrofuran, toluene, ethyl acetate, butyl acetate, dimethyl sulfoxide (DMSO), ethanol, and methyl isobutyl ketone are <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>% and <NUM>% respectively.

The compound of the formula (I) obtained by the method of Example <NUM> of the Chinese patent application <CIT> has a residual amount of DMF far exceeding the limit as prescribed by ICH. In addition, <CIT> and <CIT> both disclose the same compound of formula (I) in a solvated form of DMF. There are no methods in the art for preparing non-solvated crystals of the compounds of formula (I). Therefore, there is an urgent need to prepare non-solvated crystals of the compound of formula (I) for safe use in manufacture of a medicament.

It is an object of the present disclosure to overcome the disadvantages of the prior art, and to provide a non-solvated crystal of the compound of formula (I).

The present invention provides three non-solvated crystals of the compound of formula (I).

Provided is a non-solvated crystal A of the compound of formula (I). Its X-ray powder diffraction pattern has characteristic peaks at reflection angles 2θ of about <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; its infrared spectrum has characteristic absorption peaks at about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>-<NUM>; its differential scanning calorimetry curve has endothermic peaks at about <NUM>, <NUM>, and <NUM>; its proton nuclear magnetic resonance spectroscopy indicates that the crystal does not contain organic solvents, fully compliant with the limits for solvent residues as prescribed by ICH.

Provided is a non-solvated crystal B of the compound of formula (I). Its X-ray powder diffraction pattern has characteristic peaks at reflection angles 2θ of about <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; its infrared spectrum has characteristic absorption peaks at about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>-<NUM>; its differential scanning calorimetry curve has an endothermic peak at about <NUM>; its proton nuclear magnetic resonance spectroscopy indicates that the crystal does not contain organic solvents, fully compliant with the limits for solvent residues as prescribed by ICH.

Provided is a non-solvated crystal C of the compound of formula (I). Its X-ray powder diffraction pattern has characteristic peaks at reflection angles 2θ of about <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; its infrared spectrum has characteristic absorption peaks at about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>-<NUM>; its differential scanning calorimetry curve has endothermic peaks at about <NUM> and <NUM>; its proton nuclear magnetic resonance spectroscopy indicates that the crystal does not contain organic solvents, fully compliant with the limits for solvent residues as prescribed by ICH.

Thus, in a first aspect of the present disclosure, it is provided a non-solvated crystal of N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide.

In one embodiment, the non-solvated crystal comprises non-solvated crystals A, B and C of N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide.

In one embodiment, the non-solvated crystal A is characterized in that its X-ray powder diffraction pattern has characteristic peaks at reflection angles (2Θ) of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; preferably, its X-ray powder diffraction pattern has characteristic peaks at reflection angles (2Θ) of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; more preferably, its X-ray powder diffraction pattern has characteristic peaks at reflection angles (2Θ) of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; most preferably, its X-ray powder diffraction pattern is shown in <FIG>.

In one embodiment, the infrared spectrum of the non-solvated crystal A has characteristic absorption peaks at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>-<NUM>, and is preferably shown in <FIG>; its differential scanning calorimetry curve has endothermic peaks at <NUM>, <NUM>, and <NUM>, and is preferably shown in <FIG>.

In one embodiment, the non-solvated crystal B is characterized in that its X-ray powder diffraction pattern has characteristic peaks at reflection angles (2Θ) of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; preferably, its X-ray powder diffraction pattern has characteristic peaks at reflection angles (2Θ) of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; more preferably, its X-ray powder diffraction pattern is shown in <FIG>.

In one embodiment, the infrared spectrum of the non-solvated crystal B has characteristic absorption peaks at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>-<NUM>, and is preferably shown in <FIG>; its differential scanning calorimetry curve has an endothermic peak at <NUM>, and is preferably shown in <FIG>.

In one embodiment, the non-solvated crystal C is characterized in that its X-ray powder diffraction pattern has characteristic peaks at reflection angles (2Θ) of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM> and <NUM>°; preferably, its X-ray powder diffraction pattern has characteristic peaks at reflection angles (2Θ) of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; more preferably, its X-ray powder diffraction pattern has characteristic peaks at reflection angles (2Θ) of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; most preferably, its X-ray powder diffraction pattern is shown in <FIG>.

In one embodiment, the infrared spectrum of the non-solvated crystal C has characteristic absorption peaks at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>-<NUM>, and is preferably shown in <FIG>; its differential scanning calorimetry curve has endothermic peaks at <NUM> and <NUM>, and is preferably shown in <FIG>.

The invention further provides a method for preparing the three non-solvated crystals of the compound of formula (I).

The method for preparing the non-solvated crystal A of the compound of formula (I) comprises the steps of: adding N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide to methanol, heating at <NUM> until dissolved and cooling at <NUM> to precipitate. In a preferred embodiment, the method for preparing the non-solvated crystal A comprises the steps of: adding N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide to methanol, heating at <NUM> until dissolved and cooling at <NUM> to precipitate, filtering to collect solid, and drying it under vacuum at <NUM> for <NUM> hours to obtain the product.

The method for preparing the non-solvated crystal B of the compound of formula (I) comprises the steps of: adding N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide to acetonitrile, heating at <NUM> until dissolved and cooling at <NUM> to precipitate. In a preferred embodiment, the method for preparing the non-solvated crystal B comprises the steps of: adding N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide to acetonitrile, heating at <NUM> until dissolved and cooling at <NUM> to precipitate, filtering to collect solid, and drying it under vacuum at <NUM> for <NUM> hours to obtain the product.

The method for preparing the non-solvated crystal C of the compound of formula (I) comprises the steps of: adding N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide to dimethyl sulfoxide, stirring at room temperature until dissolved, and adding dropwise the resulting solution to water under stirring, and filtering to collect solid. In a preferred embodiment, the method for preparing the non-solvated crystal C comprises the steps of: adding N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide to dimethyl sulfoxide, stirring at room temperature until dissolved, and adding dropwise the resulting solution to water under stirring, and filtering to collect solid, washing it with water, and drying it under vacuum at <NUM> for <NUM> hours to obtain the product.

In another aspect of the present disclosure, it is provided a pharmaceutical composition comprising the non-solvated crystal of N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide. In one embodiment, the present disclosure provides a pharmaceutical composition for the treatment of a disease associated with abnormal protein kinase activity or abnormal histone deacetylase activity, comprising the non-solvated crystal of N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide, and optionally pharmaceutically acceptable excipients and/or carriers.

The pharmaceutical compositions of the present disclosure may contain any suitable pharmaceutically acceptable excipients and/or carriers. The pharmaceutical compositions of the present disclosure can be prepared by conventional techniques, such as those described in <NPL>, which is incorporated herein by reference. The composition may be presented in conventional forms such as tablets, capsules, powders, granules, suspensions, syrups, solutions, injections, ointments, and the like. The preparations usually contain <NUM>% to <NUM>% by weight of the compound of the formula (I) and <NUM>% to <NUM>% by weight of the pharmaceutical adjuvants, preferably <NUM>% to <NUM>% by weight, <NUM>% to <NUM>% by weight, <NUM>% to <NUM>% by weight, <NUM>% to <NUM>% by weight, <NUM>% to <NUM>% by weight, <NUM>% to <NUM>% by weight, <NUM>% to <NUM>% by weight or <NUM>% to <NUM>% by weight of the compound of formula (I).

A typical composition comprises a compound of the present disclosure and an excipient or carrier. For example, the active compound is usually mixed with a carrier, or diluted by a carrier, or sealed in a carrier which may be in the form of an ampule, capsule, sachet, paper or other container. If the active compound is mixed with a carrier, or if a carrier serves as a diluent, the carrier can be a solid, semi-solid or liquid material that serves as a carrier, excipient or medium for the active compound. The active compound can be adsorbed onto a particulate solid carrier (e.g., contained in a sachet). Some examples of the suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, white earth, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and glycerol diester, pentaerythritol fatty acid ester, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or their mixture with a wax.

The non-solvated crystals A, B and C of the compound of formula (I) were placed under high temperature (<NUM>), high humidity (<NUM>% ± <NUM>%) and intense light irradiation (<NUM> Lx ± <NUM> Lx) for <NUM> days, the three crystals remain unchanged in their original crystal forms, and the content of each crystal does not change significantly, indicating that the three crystals are all suitable for pharmaceutical manufacturing and long-term storage.

The contents of the present disclosure are further described below with reference to examples. The percentages stated in the present disclosure are all percentages by weight unless otherwise specified. The range of values described in the specification, such as units of measure, reaction conditions, physical state of the compound, or percentage, are intended to provide an unambiguous written reference. Those skilled in the art, when practicing the patent, will still be able to obtain the desired results using temperatures, concentrations, amounts, number of carbon atoms, etc. outside of this range or different from a single value.

Test conditions of X-ray powder diffraction: instrument: D/MAX-<NUM> (Rigaku, Japan); radiation source: Cu-Kα (<NUM> kV, <NUM> mA).

Test conditions of infrared spectroscopy: instrument: RFX-65A (Analect, USA); KBr tableting method.

Test conditions of differential scanning calorimetry: instrument: Pyris-<NUM>-DSC (PerkinElmer, USA); heating rate: <NUM>/min; nitrogen flow rate: <NUM>/min.

Test conditions of proton nuclear magnetic resonance: instrument: AV-<NUM> (BRUKER, Germany); solvent: DMSO-d<NUM>.

Test conditions of stability: high temperature (<NUM>), high humidity (<NUM>%) and strong light irradiation (4500Lx) tests are performed according to the <NPL>.

Test conditions of HPLC: instrument: Dionex UltiMate3000; column: Shim-pack VP-ODS <NUM> <NUM> × <NUM>; detector: VWD-<NUM>, detection wavelength: <NUM>; mobile phase: methanol-water-glacial acetic acid (<NUM>:<NUM>:<NUM>); flow rate: <NUM>/min, column temperature: <NUM>.

<NUM> of N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide was placed in a <NUM> three-necked flask, and <NUM> of methanol was added. The mixture was heated with stirring in an oil bath at <NUM> until dissolved. The resulting solution was placed in a <NUM> ice water bath to cool and crystallize for <NUM> hours, filtered to collect the solid, and dried under vacuum at <NUM> for <NUM> hours to obtain non-solvated crystal A. As shown in <FIG>, its X-ray powder diffraction pattern has characteristic peaks at reflection angles 2θ of about <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; as shown in <FIG>, its infrared spectrum has characteristic absorption peaks at about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>-<NUM>; as shown in <FIG>, its differential scanning calorimetry curve has endothermic peaks at about <NUM>, <NUM>, and <NUM>; its proton nuclear magnetic resonance spectroscopy indicates that the crystal does not contain organic solvents.

<NUM> of N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide was placed in a <NUM> three-necked flask, and <NUM> of acetonitrile was added. The mixture was heated with stirring in an oil bath at <NUM> until dissolved. The resulting solution was placed in a <NUM> ice water bath to cool and crystallize for <NUM> hours, filtered to collect solid, and dried under vacuum at <NUM> for <NUM> hours to obtain non-solvated crystal B. As shown in <FIG>, its X-ray powder diffraction pattern has characteristic peaks at reflection angles 2θ of about <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; as shown in <FIG>, its infrared spectrum has characteristic absorption peaks at about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>-<NUM>; as shown in <FIG>, its differential scanning calorimetry curve has an endothermic peak at about <NUM>; its proton nuclear magnetic resonance spectroscopy indicates that the crystal does not contain organic solvents.

<NUM> of N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide was placed in a <NUM> three-necked flask, and <NUM> of dimethyl sulfoxide was added. The mixture was stirred at room temperature until dissolved. The resulting solution was added dropwise to <NUM> water under stirring and allowed to stand for <NUM> hours, filtered, washed with water, and the solid was collected and dried under vacuum at <NUM> for <NUM> hours to obtain a non-solvated crystal C. As shown in <FIG>, its X-ray powder diffraction pattern has characteristic peaks at reflection angles 2θ of about <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; as shown in <FIG>, its infrared spectrum has characteristic absorption peaks at about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>-<NUM>; as shown in <FIG>, its differential scanning calorimetry curve has endothermic peaks at about <NUM> and <NUM>; its proton nuclear magnetic resonance spectroscopy indicates that the crystal does not contain organic solvents.

High temperature (<NUM>), high humidity (<NUM>%) and strong light irradiation (4500Lx) tests of the non-solvated crystal A of example <NUM>, non-solvated crystal B of example <NUM>, and non-solvated crystal C of example <NUM> were performed according to the <NPL>. Samples on day <NUM> and day <NUM> respectively were taken to determine the X-ray powder diffraction pattern and content (HPLC method). The test results showed that all three crystals remain unchanged in their original crystal forms, and the content of each crystal does not change significantly, indicating that the three crystals are all suitable for pharmaceutical manufacturing and long-term storage.

Preparation process: Non-solvated crystal A of example <NUM> was pulverized and passed through a <NUM> mesh sieve, and microcrystalline cellulose, sodium carboxymethyl starch and talc powder were passed through an <NUM> mesh sieve. Prescribed amount of microcrystalline cellulose, sodium carboxymethyl starch and non-solvated crystal A were weighed and mixed uniformity. <NUM>% povidone K30 solution in ethanol was added in an appropriate amount, and the mixture was granulated and dried. Prescribed amount of talcum powder was added, and the mixture was mixed uniformity and tableted to obtain the product.

Preparation process: Non-solvated crystal A of example <NUM> was pulverized and passed through a <NUM> mesh sieve, and microcrystalline cellulose, lactose, sodium carboxymethyl starch and magnesium stearate were passed through an <NUM> mesh sieve. Prescribed amount of microcrystalline cellulose, lactose, sodium carboxymethyl starch, non-solvated crystal A and magnesium stearate were weighed and mixed uniformity. The mixture was filled into capsules to obtain the product.

Preparation process: Non-solvated crystal B of example <NUM> was pulverized and passed through a <NUM> mesh sieve, and microcrystalline cellulose, sodium carboxymethyl starch and talc powder were passed through an <NUM> mesh sieve. Prescribed amount of microcrystalline cellulose, sodium carboxymethyl starch and non-solvated crystal B were weighed and mixed uniformity. <NUM>% povidone K30 solution in ethanol was added in an appropriate amount, and the mixture was granulated and dried. Prescribed amount of talcum powder was added, and the mixture was mixed uniformity and tableted to obtain the product.

Preparation process: Non-solvated crystal B of example <NUM> was pulverized and passed through a <NUM> mesh sieve, and microcrystalline cellulose, lactose, sodium carboxymethyl starch and magnesium stearate were passed through an <NUM> mesh sieve. Prescribed amount of microcrystalline cellulose, lactose, sodium carboxymethyl starch, non-solvated crystal B and magnesium stearate were weighed and mixed uniformity. The mixture was filled into capsules to obtain the product.

Preparation process: Non-solvated crystal C of example <NUM> was pulverized and passed through a <NUM> mesh sieve, and microcrystalline cellulose, sodium carboxymethyl starch and talc powder were passed through an <NUM> mesh sieve. Prescribed amount of microcrystalline cellulose, sodium carboxymethyl starch and non-solvated crystal C were weighed and mixed uniformity. <NUM>% povidone K30 solution in ethanol was added in an appropriate amount, and the mixture was granulated and dried. Prescribed amount of talcum powder was added, and the mixture was mixed uniformity and tableted to obtain the product.

Claim 1:
A non-solvated crystal of N-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyquinoline-<NUM>-oxo)-<NUM>-naphthaleneformamide, wherein said non-solvated crystal is selected from non-solvated crystal A, non-solvated crystal B, and non-solvated crystal C, wherein
the X-ray powder diffraction pattern of said non-solvated crystal A has characteristic peaks at reflection angles 2θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; the X-ray powder diffraction pattern of said non-solvated crystal B has characteristic peaks at reflection angles 2θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>° and <NUM>°; and
the X-ray powder diffraction pattern of said non-solvated crystal C has characteristic peaks at reflection angles 2θ of <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM>°, <NUM> and <NUM>°.