A crystalline form of a compound and methods of making the same

Abstract

The application relates to a crystal form of a compound and a preparation method thereof. Specifically provided are crystal form I and crystal form II of a fumarate salt of [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridine-2-yl)-6-oxaspiro[4.5]decane-9-yl]ethyl})amine, the crystal form I has good crystal form stability, chemical stability, low hygroscopicity, and can be better used for production, storage and preparation processing; the crystal form II has good solubility and meets the requirements of a pharmaceutical preparation.

Description

[0001] This application claims priority to Chinese patent application CN202510559359.0, filed on April 30, 2025, and Chinese patent application CN 202511286982.X, filed on September 10, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to the crystal form of a compound and its preparation method. Background Technology

[0003] Oliceridine was approved by the FDA in August 2020 for postoperative analgesia. Its chemical name is [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospirocyclic[4.5]decane-9-yl]ethyl})amine fumarate. The free state of this compound is an oily liquid, and its structural formula is shown in Formula I.

[0004]

[0005] Formula I

[0006] Currently, no crystal forms of Formula I compounds have been reported in the literature. It is well known that the crystal form of a drug affects formulation quality and manufacturing processes. Research on drug crystal forms can provide references for formulation development, new drug formulation design, manufacturing process optimization, drug quality control, and clinical efficacy. Different crystal forms of the same drug may differ significantly in appearance, solubility, melting point, dissolution rate, and bioequivalence, thus affecting drug stability, bioavailability, and efficacy.

[0007] Therefore, it is necessary to study the crystal form of the compound of formula I and develop one or more crystal forms that are simple to prepare, have good solubility, high stability, high purity, are not easily hygroscopic, and are suitable for industrial production. Summary of the Invention

[0008] The present invention aims to provide a polymorph of [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospiro[4.5]decane-9-yl]ethyl})amine fumarate (compound of formula I), which has good crystal stability and chemical stability and can be better applied in clinical practice.

[0009] On one hand, the present invention provides a crystal form I of a compound of formula I, and obtains a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ by using Cu-Kα radiation.

[0010] Specifically, it exhibits three characteristic peaks at 10.14°, 21.81°, and 22.46°, with error ranges of ±0.3°, ±0.2°, or ±0.1°.

[0011] Specifically, it exhibits four characteristic peaks at 10.14°, 14.50°, 15.36°, and 17.74°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0012] Specifically, it exhibits five characteristic peaks at 10.14°, 15.36°, 17.74°, 21.81°, and 22.46°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0013] Specifically, it exhibits six characteristic peaks at 8.81°, 10.14°, 15.36°, 17.74°, 21.81°, and 22.46°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0014] Specifically, it exhibits seven characteristic peaks at 7.19°, 8.81°, 10.14°, 15.36°, 17.74°, 21.81°, and 22.46°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0015] Specifically, it exhibits 10 characteristic peaks at 7.19°, 8.81°, 10.14°, 14.10°, 15.36°, 16.20°, 17.74°, 18.47°, 21.81°, and 22.46°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0016] Specifically, it displays six characteristic peaks at 10.14°, 14.50°, 15.36°, 17.74°, 21.81°, and 22.46°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0017] Specifically, it displays 10 characteristic peaks at 10.14°, 14.10°, 14.50°, 15.36°, 16.20°, 17.74°, 18.47°, 21.81°, 22.46°, and 29.73°, with an error range of ±0.3°, ±0.2°, or ±1°.

[0018] Specifically, it displays 14 characteristic peaks at 8.81°, 10.14°, 14.10°, 14.50°, 15.36°, 16.20°, 17.15°, 17.74°, 18.47°, 21.12°, 21.81°, 22.46°, 24.90°, and 29.73°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0019] Specifically, it displays 15 characteristic peaks at 7.19°, 8.81°, 10.14°, 14.10°, 14.50°, 15.36°, 16.20°, 17.15°, 17.74°, 18.47°, 21.12°, 21.81°, 22.46°, 24.90°, and 29.73°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0020] Specifically, the powder X-ray diffraction pattern of crystal form I is basically as follows: Figure 1 As shown.

[0021] In a preferred embodiment of the present invention, the DSC melting endothermic peak value of crystal form I is selected from 175℃-185℃, preferably 181.3℃.

[0022] Specifically, the DSC melting endothermic peak value of crystal form I is selected from 176℃-184℃.

[0023] Specifically, the DSC melting endothermic peak value of crystal form I is selected from 176℃-183.7℃.

[0024] Specifically, the DSC melting endothermic peak value of crystal form I is selected from 178℃-183.7℃.

[0025] Specifically, the DSC melting endothermic peak value of crystal form I can be 175℃, 175.1℃, 175.2℃, 175.3℃, 175.4℃, 175.5℃, 175.6℃, 175.7℃, 175.8℃, 175.9℃, 176.0℃, 176.1℃, 176.2℃, 176.3℃, 176.4℃, 176.5℃, 176.6℃, 176.7℃, 176.8℃, 176.9℃, 177.0℃, 177.1℃, 177.2℃, 177.3℃, 177.4℃, 177.5℃, 177.6℃, 177.7℃, 177.8℃, 177.9℃, 178.0℃, 178.1℃, 178.2℃, 178.3℃, 178.4℃, 178.5℃, 178.6℃, 178.7℃, 178.8℃, 178.9℃, 179.0℃, 179.1℃, 179.2℃, 179.3℃, 179.4℃, 179.5℃, 179.6℃, 179.7℃, 179.8℃ 179.9℃, 180.0℃, 180.1℃, 180.2℃, 180.3℃, 180.4℃, 180.5℃, 180.6℃, 180.7℃, 180.8℃, 180.9℃, 181.0℃, 181.1℃, 181.2℃, 181.3℃, 181.4℃, 181.5℃, 181.6℃, 181.7℃, 181.8℃, 181.9℃, 182.0℃, 182.1℃, 182.2℃, 182.3℃, 182.4℃ 182.5℃, 182.6℃, 182.7℃, 182.8℃, 182.9℃, 183.0℃, 183.1℃, 183.2℃, 183.3℃, ​​183.4℃, 183.5℃, 183.6℃, ​​183.7℃, 183.8℃, 183.9℃, 184.0℃, 184.1℃, 184.2℃, 184.3℃, 184.4℃, 184.5℃, 184.6℃, 184.7℃, 184.8℃, 184.9℃, 185.0℃.

[0026] In a preferred embodiment of the present invention, the crystal form I conforms to one or more of the following solid-state characteristics:

[0027] (I) Basically conforms Figure 1 Powder X-ray diffraction pattern;

[0028] (II) Basically conforms Figure 2 The DSC spectrum.

[0029] In another aspect, the present invention provides a method for preparing compound of formula I, crystal form I, wherein the method is selected from:

[0030] Method 1:

[0031] (1) Dissolve the compound of formula I in a solvent to obtain a solution containing the compound of formula I;

[0032] (2) Solvent removal method: Remove the solvent from the solution prepared in step (1) to obtain a precipitate;

[0033] The solvent is selected from one or more of alcohols, nitriles or water; the alcohol is preferably methanol, ethanol, isopropanol or n-propanol, and the nitrile is selected from acetonitrile.

[0034] In a further preferred embodiment of the present invention, the solvent is a mixed solvent, which is selected from n-propanol-water, methanol-water, ethanol-water (1:1), ethanol-water (2:1), 95% ethanol-water, and methanol-acetonitrile.

[0035] In a preferred embodiment of the present invention, the water content of the ethanol is ≤5% (v / v).

[0036] In a preferred embodiment of the present invention, step (1) further includes a heating process, wherein the heating temperature of the heating process is selected from the boiling point temperature of the solvent used in step (1) and is not higher than the boiling point temperature of the solvent used in step (1).

[0037] In a preferred embodiment of the present invention, the solvent removal method in step (2) is selected from the vacuum solvent removal method, and the vacuum solvent removal method is preferably the vacuum evaporation method. The vacuum solvent removal pressure is gradually reduced from 300 mbar to 10 mbar, and the temperature is increased from 20°C to 90°C.

[0038] In a preferred embodiment of the present invention, the solvent removal method in step (2) is selected from evaporation in a gas stream, wherein the gas stream is preferably an air stream or an inert gas stream, and the inert gas is preferably an argon and nitrogen stream.

[0039] Method 2:

[0040] After dissolving the compound of formula I in a good solvent, it is mixed with a poor solvent to obtain crystal I;

[0041] The good solvents are alcohols, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide; the poor solvents are nitrile compounds, C... 5-10 Saturated hydrocarbons, esters, and ethers; the alcohols are preferably methanol, ethanol, isopropanol, n-butanol, or n-propanol; the nitriles are selected from acetonitrile; and the C... 5-10 The saturated hydrocarbons are preferably cyclohexane, n-pentane, or n-heptane, the ethers are selected from methyl tert-butyl ether, isopropyl ether, and 1,4-dioxane, and the esters are preferably ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate.

[0042] In a preferred embodiment of the present invention, "mixing with a poor solvent" means adding a good solvent to a poor solvent or adding a poor solvent to a good solvent.

[0043] In a preferred embodiment of the invention, a drying gas flow condition is further included, wherein the drying gas flow is selected from argon, nitrogen, or air.

[0044] In another aspect, the present invention provides a crystal form II of a compound of formula I, and obtains a powder X-ray diffraction pattern expressed in terms of the diffraction angle 2θ using Cu-Kα radiation.

[0045] Specifically, it exhibits three characteristic peaks at 10.18°, 17.36°, and 23.76°, with error ranges of ±0.3°, ±0.2°, or ±0.1°.

[0046] Specifically, it exhibits four characteristic peaks at 7.67°, 10.18°, 17.36°, and 23.76°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0047] Specifically, it exhibits five characteristic peaks at 10.18°, 16.02°, 17.36°, 22.50°, and 23.76°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0048] Specifically, it exhibits five characteristic peaks at 7.67°, 16.02°, 17.36°, 22.50°, and 23.76°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0049] Specifically, it exhibits seven characteristic peaks at 7.67°, 8.64°, 16.02°, 17.36°, 18.53°, 22.50°, and 23.76°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0050] Specifically, it exhibits seven characteristic peaks at 7.67°, 8.64°, 10.19°, 16.02°, 17.36°, 23.76°, and 24.69°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0051] Specifically, it exhibits nine characteristic peaks at 7.67°, 8.64°, 16.02°, 17.36°, 18.53°, 22.50°, 23.46°, 23.76°, and 24.69°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0052] Specifically, it exhibits 10 characteristic peaks at 7.67°, 8.64°, 10.19°, 16.02°, 17.36°, 18.53°, 22.50°, 23.46°, 23.76°, and 24.69°, with an error range of ±0.3°, ±0.2°, or ±1°.

[0053] Specifically, it exhibits 12 characteristic peaks at 7.67°, 8.64°, 10.18°, 16.02°, 17.36°, 18.53°, 19.39°, 21.84°, 22.50°, 23.46°, 23.76°, and 24.69°, with an error range of ±0.3°, ±0.2°, or ±0.1°.

[0054] In a preferred embodiment of the present invention, the crystal form II of the compound of formula I substantially conforms to Figure 5 Powder X-ray diffraction pattern.

[0055] On the other hand, the present invention provides a method for crystal form II, comprising the following steps:

[0056] (1) Dissolve [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospiro[4.5]decane-9-yl]ethyl})amine fumarate in a solvent to obtain a solution containing [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospiro[4.5]decane-9-yl]ethyl})amine fumarate; optionally, heating is performed during the dissolution process to aid dissolution;

[0057] (2) The obtained solution was cooled to -5℃ to 35℃ to prepare crystal form II, so that crystals precipitate out.

[0058] The solvent is selected from one or more of alcohols, esters, N-methylpyrrolidone, or dimethyl sulfoxide; the alcohols are preferably methanol, ethanol, isopropanol, n-butanol, or n-propanol, and the esters are preferably ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate.

[0059] In another aspect, the present invention also provides a pharmaceutical composition comprising one or more excipients, carriers, adjuvants, solvents, or combinations thereof of crystal form I or crystal form II.

[0060] In a preferred embodiment of the present invention, the active ingredient contains at least 50%-99% of crystal form I; preferably, it contains at least 70%-99% of said crystal form I; more preferably, it contains at least 90%-99% of crystal form I.

[0061] Specifically, the content of crystal form I in the active ingredient is 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0062] In a preferred embodiment of the present invention, the active ingredient contains at least 50%-99% of crystal form II; preferably, it contains at least 70%-99% of said crystal form II; more preferably, it contains at least 90%-99% of crystal form II.

[0063] Specifically, the content of crystal form II in the active ingredient is 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0064] In a preferred embodiment of the invention, the pharmaceutical composition may be administered via any suitable route, such as oral administration in capsule form, parenteral administration in injection form, topical administration in ointment or lotion form, rectal administration in suppository form, or transdermal administration in the form of a patch delivery system. In a preferred embodiment, the pharmaceutical composition is preferably administered orally.

[0065] Furthermore, the present invention also relates to the use of crystal forms I and II of the compounds of formula I described herein as medicines for treating and / or preventing pain and pain-related diseases, wherein the pain may be postoperative pain, cancer-related pain, neuropathic pain, traumatic pain, and pain caused by inflammation, etc.

[0066] Beneficial effects:

[0067] The compound of formula I prepared by this invention exhibits excellent hygroscopicity and solubility in its crystal form I. Under high humidity, high temperature, and light conditions, the crystal form does not transform into crystals and maintains high purity, demonstrating excellent physical and chemical stability, making it more suitable for production and storage. Furthermore, crystal form I exhibits good pharmacokinetics, meeting the requirements for oral administration. The preparation method of crystal form I in this invention is reproducible, has high purity, high yield, and is simple and readily available. Crystal form II exhibits good solubility, meeting the requirements for pharmaceutical formulations.

[0068] Terminology Explanation:

[0069] In the specification and claims of this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the invention, definitions and explanations of some related terms are provided below. Furthermore, in the event of any discrepancy between the definitions and explanations of terms provided herein and their commonly understood meanings by those skilled in the art, the definitions and explanations provided herein shall prevail.

[0070] In this invention, "crystal form I" refers to crystal form I of compound I, and "crystal form II" refers to crystal form II of compound I.

[0071] The "alcohols" mentioned in this invention refer to one or more "hydroxyl groups" replacing "C". 1-6 A group derived from one or more hydrogen atoms on an alkyl group, wherein the "C" 1-6 "alkyl" refers to a saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. Specific examples of "alcohols" include but are not limited to methanol, ethanol, n-propanol, or isopropanol.

[0072] The "esters" mentioned in this invention refer to compounds with fewer than 15 carbon atoms formed by the reaction of organic acids with alcohols or phenols and the loss of water, or lower ester compounds containing the functional group -C(O)O- and having fewer than 15 carbon atoms. Specific examples include, but are not limited to, ethyl acetate, dimethyl phthalate, butyl acetate, or propyl acetate.

[0073] The "ethers" mentioned in this invention refer to chain or cyclic compounds containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include, but are not limited to, diethyl ether, isopropyl ether, propylene glycol methyl ether, tetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane.

[0074] The "halogenated hydrocarbons" mentioned in this invention refer to one or more "halogen atoms" replacing "C". 1-6 A group derived from one or more hydrogen atoms on an alkyl group, wherein the "C" 1-6 "Alkyl" as defined above, specific examples include but are not limited to: chloromethane, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.

[0075] The "ketones" mentioned in this invention refer to compounds in which a carbonyl group (-C(O)-) is attached to two hydrocarbon groups. Depending on the hydrocarbon groups in the molecule, ketones can be classified into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones, and unsaturated ketones. Specific examples include, but are not limited to: acetone, butanone (e.g., 2-butanone), pentanone (e.g., pentan-2-one, pentan-3-one), hexanone (e.g., hexan-2-one or hexan-3-one), acetophenone, methyl isobutyl ketone, or methyl pyrrolidone.

[0076] The "nitrile" mentioned in this invention refers to one or more "cyano" groups replacing "C". 1-6 A group derived from one or more hydrogen atoms on an alkyl group, wherein the "C" 1-6 As defined above, "alkyl" refers to a group in which a carbon atom and a nitrogen atom are connected by a triple bond, with the chemical formula -CN. Specific examples include, but are not limited to, acetonitrile or propionitrile.

[0077] The "saturated hydrocarbon" mentioned in this invention refers to C5-10 Chain or cyclic alkanes are compounds in which all carbon atoms in the molecule are linked by single bonds and the remaining valence bonds are combined with hydrogen. Specific examples include, but are not limited to, n-pentane, n-hexane, cyclohexane, or n-heptane.

[0078] The "mixed solvent" mentioned in this invention refers to a solvent formed by mixing one or more different types of solvents in a certain proportion, wherein the certain proportion is 0.05:1 to 1:0.05, preferably 1:1, 1:2, 1:3, 1:4, 1:5, 1:8, or 1:10.

[0079] The "precipitant" mentioned in this invention refers to an "antisolvent" or "anti-solvent," meaning that when separating or removing a certain component, the substance is dissolved in a suitable solvent beforehand, and a solvent that is insoluble with the component to be separated is added; the precipitant is miscible with the solvent of the compound shown in Formula I.

[0080] The good solvent is a solvent that has good solubility for the compound of this application, and the poor solvent is a solvent that has poor solubility or is insoluble in the compound of this application.

[0081] The "boiling point" mentioned in this invention refers to the boiling point or azeotropic point of a pure solvent or a mixed solvent.

[0082] The "powder X-ray diffraction pattern or PXRD" described in this invention refers to the PXRD pattern obtained when X-rays are incident on an atomic surface of a crystal or part of a crystal sample with a lattice spacing of d at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) with a grazing angle θ.

[0083] The “2θ or 2θ angle” mentioned in this invention refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree. The error range of 2θ is ±0.1 to ±0.5, preferably ±0.1 to ±0.3, and more preferably ±0.2.

[0084] The "interplanar spacing or interplanar spacing (d-value)" described in this invention refers to the use of three non-parallel unit vectors a, b, and c to connect adjacent points in a space lattice. These vectors divide the lattice into juxtaposed parallelepiped units, known as the interplanar spacing. The space lattice is divided according to these defined parallelepiped unit lines, resulting in a linear grid called a space lattice or crystal lattice. Lattice and crystal lattice respectively use geometric points and lines to reflect the periodicity of a crystal structure. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is Å or angstrom.

[0085] The "differential scanning calorimetry (DSC)" described in this invention determines the transition temperature when a crystal absorbs or releases heat due to changes in its crystal structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point can be within about 5°C, typically within about 3°C, in consecutive analyses. When describing a compound as having a given DSC peak or melting point, this refers to ±5°C of that DSC peak or melting point. This temperature variation is also "substantially" taken into account. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0086] The term "treatment" refers to any indication of successful treatment or improvement of an injury, disease, lesion, or condition, including any objective or subjective parameters, such as the elimination, relief, or reduction of symptoms, or making the patient more tolerant of the injury, lesion, or condition; slowing the rate of degeneration or worsening; making the final outcome of degeneration less likely to cause debilitating effects; or improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0087] The term “treatment” and its related expressions include prevention of disease, lesion, ailment or illness (e.g., prevention of the development of one or more symptoms of the disease, ailment or illness described herein).

[0088] An example of an "effective amount" is an amount sufficient to treat, prevent, or reduce one or more symptoms of a disease; it may also be called a "therapeutic effective amount." A "preventive effective amount" of a drug is an amount that, when administered to a subject, will have the expected preventive effect, such as preventing or delaying the onset or recurrence of injury, disease, lesion, or disorder, or reducing the likelihood of the onset (or recurrence) of injury, disease, lesion, or disorder, or its symptoms. A single dose may not produce complete prevention, and may only occur after a series of doses. Therefore, a preventive effective amount can be administered in one or more doses. Attached Figure Description

[0089] Figure 1 The PXRD pattern is for crystal form I.

[0090] Figure 2 This is the DSC spectrum of crystal form I.

[0091] Figure 3 The PXRD patterns of crystal form I over 10 days are shown.

[0092] Figure 4The PXRD patterns of crystal form I after ball milling for 30 min and 2 h are shown.

[0093] Figure 5 The PXRD pattern is for crystal form II.

[0094] Figure 6 The PXRD pattern of crystal form II after 60℃ (10 days), 92.5% humidity (10 days), and 10 days of light exposure.

[0095] Figure 7 PXRD patterns of crystal form II after 3 months of accelerated processing and 3 months of long-term processing. Detailed Implementation

[0096] The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the nature and scope of the present invention.

[0097] Test conditions of the instruments used in the experiment:

[0098] 1. Powder X-ray Diffraction (PXRD) pattern

[0099] Instrument model: Bruker D8 Focus powder X-ray diffractometer.

[0100] Powder X-ray parameters: Cu / Kα (λ=1.540598Å).

[0101] Voltage: 40 kilovolts (kV).

[0102] Current: 40 milliamperes (mA).

[0103] Scan range: from 3.0 to 40 degrees.

[0104] Scan step size: 0.02 degrees.

[0105] Scanning speed: 0.5 seconds / step.

[0106] 2. Differential Scanning Calorimeter (DSC) thermal analysis method

[0107] Instrument model: Netzsch DSC 3500 Sirius differential scanning calorimeter (Germany).

[0108] Purging gas: Nitrogen.

[0109] Heating rate: 10.0 K / min.

[0110] Temperature range: 30℃-200℃.

[0111] 3. Chromatographic conditions

[0112]

[0113] 4. Reagents used in the experiment

[0114]

[0115] Example 1

[0116] Weigh approximately 0.5 g of compound I and dissolve it completely in 1.5 mL of methanol at 65 °C. Then, quickly pour in approximately 40 mL of methyl tert-butyl ether. A large amount of white solid precipitates. Allow the suspension to settle, filter, wash, and dry in a forced-air environment at 60 °C to obtain crystal form I. Its powder X-ray diffraction pattern is shown below. Figure 1 Its DSC spectrum is shown in Figure 2 During the DSC heating process, the endothermic peak begins at 178℃, terminates at 183.7℃, and reaches a peak temperature of 181.3℃. This crystal form is defined as crystal form I, and its characteristic peak positions and interplanar spacing are shown in the table below:

[0117] Characteristic peak positions and interplanar spacing of crystal form I

[0118]

[0119] Example 2

[0120] Weigh 0.1 g of compound I into a large test tube, add 2 mL of methanol, shake thoroughly to dissolve, and then place it in a parallel reaction apparatus to remove the solvent. At the end of the experiment, collect the solid to obtain crystal form I.

[0121] Example 3

[0122] Weigh about 0.5 g of compound I, add 10 mL of ethanol and dissolve it completely at 65 °C, then quickly pour in about 50 mL of n-propyl acetate. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air dryer at 60 °C to obtain crystal form I.

[0123] Example 4

[0124] Weigh about 0.5 g of compound I, add 2 mL of dimethyl sulfoxide and dissolve it completely at 65 °C. Then quickly pour in about 30 mL of isopropyl ether. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air environment at 60 °C to obtain crystal form I.

[0125] Example 5

[0126] Weigh about 0.5 g of compound I, add 2 mL of N,N-dimethylformamide and dissolve it completely at 65°C. Then quickly pour in about 40 mL of methyl ether. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air dryer at 60°C to obtain crystal form I.

[0127] Example 6

[0128] Weigh about 0.5 g of compound I, add 10 mL of n-propanol and dissolve it completely at 65 °C. Then quickly pour in about 50 mL of ethyl acetate. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air environment at 60 °C to obtain crystal form I.

[0129] Example 7

[0130] Weigh about 0.5 g of compound I, add 10 mL of ethanol and dissolve it completely at 65 °C, then quickly pour in about 50 mL of n-hexane. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air environment at 60 °C to obtain crystal form I.

[0131] Example 8

[0132] Weigh about 0.5 g of compound I, add 2 mL of N,N-dimethylacetamide and dissolve it completely at 65 °C. Then add it dropwise into a beaker containing about 40 mL of methyl tert-butyl ether. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air environment at 60 °C to obtain crystal form I.

[0133] Example 9

[0134] Weigh about 0.5 g of compound I, add 8 mL of 95% ethanol and dissolve it completely at 65°C. Then add it dropwise into a beaker containing about 50 mL of isobutyl acetate. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air environment at 60°C to obtain crystal form I.

[0135] Example 10

[0136] Weigh about 0.5 g of compound I, add 2 mL of dimethyl sulfoxide and dissolve it completely at 65 °C. Then add it dropwise into a beaker containing about 50 mL of methyl tert-butyl ether. A large amount of white solid precipitates out. Let the suspension stand to settle, and solid precipitates out. Filter, wash, and dry in a forced air at 60 °C to obtain crystal form I.

[0137] Example 11

[0138] Weigh about 0.5 g of compound I, add 1.5 mL of methanol and dissolve it completely at 65 °C. Then add it dropwise into a beaker containing about 40 mL of ethyl acetate. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air environment at 60 °C to obtain crystal form I.

[0139] Example 12

[0140] Weigh about 0.5 g of compound I, add 10 mL of ethanol and dissolve it completely at 65 °C. Then add it dropwise into a beaker containing about 50 mL of cyclohexane. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air environment at 60 °C to obtain crystal form I.

[0141] Example 13

[0142] Weigh about 0.5 g of compound I, add 10 mL of n-propanol and dissolve it completely at 65 °C. Then add it dropwise into a beaker containing about 60 mL of butyl acetate. A large amount of white solid precipitates out. Let the suspension stand to settle, filter, wash, and dry in a forced-air dryer at 60 °C to obtain crystal form I.

[0143] Example 14

[0144] Weigh 0.5 g of compound (I) into a test tube, add 5 mL of a mixed solution of N-methylpyrrolidone-butyl acetate (volume ratio 2:3), and heat at 65 °C to completely dissolve the sample. Seal the tube and allow it to stand at room temperature. After the solid precipitates, filter, wash, and dry in a forced-air environment at 60 °C to obtain crystal form II. Its powder X-ray diffraction pattern is shown in [Figure number missing]. Figure 5 The positions of its characteristic peaks and interplanar spacings are shown in Table 2 below:

[0145] Peak position and interplanar spacing of crystal form II

[0146]

[0147] Example 15

[0148] Weigh 0.5 g of compound (I) into a test tube, add 4.5 mL of N-methylpyrrolidone-isopropyl acetate (volume ratio 1:2), and heat at 65 °C to completely dissolve the sample. Seal the tube and let it stand at room temperature. After the solid precipitates, filter, wash, and dry at 60 °C to obtain crystal form II.

[0149] Example 16

[0150] Weigh 0.5 g of compound (I) into a test tube, add 1.5 mL of N-methylpyrrolidone-n-butanol (volume ratio 2:1), and heat at 65 °C to completely dissolve the sample. Seal the tube and let it stand at room temperature. After the solid precipitates, filter, wash, and dry at 60 °C to obtain crystal form II.

[0151] Example 17

[0152] Weigh 0.5 g of compound (I) into a test tube, add 3 mL of N-methylpyrrolidone-isobutyl acetate (volume ratio 1:2), and heat at 65 °C to completely dissolve the sample. Seal the tube and let it stand at room temperature. After the solid precipitates, filter, wash, and dry at 60 °C to obtain crystal form II.

[0153] Example 18: Stability test of compound of formula I in crystal form I and crystal form II

[0154] (1) High temperature experiment

[0155] Samples of compound I in crystal form I and crystal form II were placed in clean petri dishes and incubated at 60°C for 10 days. Samples were taken on days 0, 5, and 10. PXRD analysis was then performed.

[0156] (2) High humidity test

[0157] Samples of compound I in crystal form I and crystal form II were placed in clean petri dishes and stored at a relative humidity of 92.5% for 10 days. Samples were taken on day 0, day 5, and day 10 for PXRD analysis.

[0158] (3) Light Illumination Experiment

[0159] Samples of compound I (crystal form I and crystal form II) were placed in clean petri dishes, spread evenly, and then placed in a light box (illuminance 5000 lx) for 10 days. Samples were taken on days 0, 5, and 10 for PXRD analysis. Specific experimental results are as follows:

[0160] Experiment on factors affecting the crystal form of compound I

[0161]

[0162] Formula I Compound Crystal Form II Influencing Factors Test

[0163]

[0164] (4) Accelerated testing

[0165] The samples were placed in double-layered pharmaceutical sealed bags, with an outer layer of aluminum-plastic packaging, and placed at 40℃ / 75%RH. Samples were taken once each at the end of January and March to detect changes in crystal form.

[0166] (5) Long-term test

[0167] The samples were placed in double-layered pharmaceutical sealed bags, with an outer layer of aluminum-plastic packaging, and placed at 25℃ / 60%RH. Samples were taken once each at the end of January and March to detect changes in crystal form.

[0168] The results of accelerated and long-term experiments are as follows:

[0169] Accelerated testing and long-term testing

[0170]

[0171] In summary, crystal form I remained stable under conditions of high temperature (60℃, 10 days), relative humidity (92.5%, 10 days), and light exposure (5000 lx, 10 days). It remained stable under accelerated and long-term conditions, and no changes in crystal form were observed.

[0172] Crystal form II transforms into crystal form I under high temperature (60℃, 10 days) and high humidity (92.5%, 10 days), and partial transformation into crystal form I is achieved under light exposure of 5000 lx (10 days). See attached diagram. Figure 6 ; Accelerated transformation to crystal form I under accelerated 3-month and long-term 3-month conditions, see appendix. Figure 7 .

[0173] Example 19: Hygroscopicity Investigation

[0174] (1) Hygroscopicity test method

[0175] 1. Take a dry, stoppered glass weighing bottle and place it in a constant temperature desiccator at 25℃±1℃ (with a saturated ammonium chloride solution at the bottom) one day before the test (set the temperature to 25℃±1℃ and the relative humidity to 80%±2%), and accurately weigh it (m1).

[0176] 2. Take an appropriate amount of the test sample of crystal form I and crystal form II of compound (I), spread it evenly in the weighing bottle above, the thickness of the test sample is generally about 1 mm, and accurately weigh it (m2).

[0177] 3. Leave the weighing bottle open and place it, along with the cap, under the above-mentioned constant temperature and humidity conditions for 24 hours.

[0178] 4. Close the weighing bottle cap and accurately weigh the contents (m3).

[0179] Weight gain percentage =

[0180] (2) Results of hygroscopicity test: Crystal form I is non-hygroscopic, while crystal form II is hygroscopic.

[0181]

[0182] Example 20: Pressure-induced crystal transformation experiment

[0183] To comprehensively investigate the existence of polymorphic substances of Formula I compounds, a physical lattice destruction method was used to examine the effect of pressure changes on crystal form I of Formula I compounds.

[0184] (1) Experimental conditions: Weigh about 1 g of the sample of compound I crystal form I and place it in the agate mortar of the ball mill. Set the ball mill speed to 400 r / min. After grinding for 30 min, stop for 10 min. Perform PXRD detection at different time points of grinding. Grind for 2 h and observe the crystal form transformation each time.

[0185] (2) Results: After ball milling, the crystal form of the compound of formula I remained unchanged, indicating that crystal form I is stable to pressure. The PXRD pattern of the milled crystal form is shown in [reference needed]. Figure 4 .

[0186] Example 21: Solubility Test

[0187] The solubility of crystal form I and crystal form II under different conditions was investigated. The solubility was detected by HPLC, and the results are as follows:

[0188]

[0189] Example 22: Pharmacokinetic Experiment

[0190] Objective: To investigate the pharmacokinetic characteristics of compound I (crystal form I) in beagle dogs after oral administration.

[0191] Methods: Three healthy adult male Beagle dogs were used in this study. All dogs were fasted overnight before administration. 2 mg / kg of compound I (crystal form I) was administered orally. Blood samples were collected before administration and at 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 7 h, 10 h, and 24 h after administration. The concentration of compound I in Beagle dog plasma was analyzed using LC-MS / MS. The non-compartmental model (NCA) method of WinNonlin software was used to analyze the plasma concentration data, calculate pharmacokinetic parameters, and investigate the metabolic characteristics of compound I in vivo. Results are as follows:

[0192]

[0193] The results showed that compound I of formula I, crystal form I, has good pharmacokinetic properties and is suitable for oral administration.

[0194] It should be understood that the present invention is not limited to the above embodiments. The embodiments and other contents described in the specification are only for illustrating the principles of the present invention. Various non-substantial changes and modifications without departing from the concept of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospirocyclic[4.5]decane-9-yl]ethyl})amine fumarate crystal form I, characterized in that, Powder X-ray diffraction patterns, expressed in terms of diffraction angle 2θ, were obtained using Cu-Kα radiation. Characteristic peaks, also expressed in terms of 2θ, were observed at 10.14°, 15.36°, 17.74°, 21.81°, and 22.46°, with an error range of ±0.2° for each characteristic peak's 2θ value. The powder X-ray diffraction pattern of crystal form I shows characteristic peaks at 8.81°, 10.14°, 15.36°, 17.74°, 18.47°, 21.81°, and 22.46°, expressed in 2θ angles, with an error range of ±0.2° for each characteristic peak; or The powder X-ray diffraction pattern of crystal form I shows characteristic peaks represented by 2θ angles at 7.19°, 8.81°, 10.14°, 14.10°, 15.36°, 16.20°, 17.74°, 18.47°, 21.81°, and 22.46°, where the error range of the 2θ value for each characteristic peak is ±0.2°; or The powder X-ray diffraction pattern of crystal form I shows characteristic peaks at 7.19°, 8.81°, 10.14°, 14.10°, 14.50°, 15.36°, 16.20°, 17.15°, 17.74°, 18.47°, 21.12°, 21.81°, 22.46°, 24.90°, and 29.73°, with an error range of ±0.2° for the 2θ value of each characteristic peak.

2. The crystal form I according to claim 1, characterized in that, The powder X-ray diffraction pattern of crystal form I is basically shown in Figure 1.

3. Crystal form I according to claim 1, characterized in that, The melting endothermic peak of the DSC of crystal form I is selected from 175℃-185℃, preferably 181.3℃; preferably, the DSC spectrum of crystal form I is basically as shown in Figure 2.

4. A [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospiro[4.5]decane-9-yl]ethyl})amine fumarate crystal form II, characterized in that, Powder X-ray diffraction patterns, expressed in terms of diffraction angle 2θ, were obtained using Cu-Kα radiation. Characteristic peaks, also expressed in terms of 2θ, were observed at 7.67°, 16.02°, 17.36°, 22.50°, and 23.76°, with an error range of ±0.2° for each characteristic peak's 2θ value. The powder X-ray diffraction pattern of crystal form II shows characteristic peaks at 7.67°, 8.64°, 16.02°, 17.36°, 18.53°, 22.50°, and 23.76°, expressed in 2θ angles, with an error range of ±0.2° for each characteristic peak; or The powder X-ray diffraction pattern of crystal form II shows characteristic peaks at 7.67°, 8.64°, 16.02°, 17.36°, 18.53°, 22.50°, 23.46°, 23.76°, and 24.69°, expressed in 2θ angles, with an error range of ±0.2° for each characteristic peak; or The powder X-ray diffraction pattern of crystal form II shows characteristic peaks at 7.67°, 8.64°, 10.18°, 16.02°, 17.36°, 18.53°, 19.39°, 21.84°, 22.50°, 23.46°, 23.76°, and 24.69°, expressed in 2θ angles, with an error range of ±0.2° for each characteristic peak.

5. The crystal form II according to claim 4, characterized in that, The powder X-ray diffraction pattern of crystal form II is basically shown in Figure 5.

6. A method for preparing crystal form I as described in any one of claims 1-3, characterized in that, Includes the following steps: (1) Dissolve [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospiro[4.5]decane-9-yl]ethyl})amine fumarate in a solvent to obtain a solution containing [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospiro[4.5]decane-9-yl]ethyl})amine fumarate; (2) Remove the solvent from the solution prepared in step (1) by solvent removal method to obtain a precipitate; The solvent is selected from one or more of alcohols, nitriles, or water; the alcohol is preferably methanol, ethanol, isopropanol, or n-propanol, and the nitrile is selected from acetonitrile.

7. A method for preparing crystal form I as described in any one of claims 1-3, characterized in that, Includes the following steps: [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospiro[4.5]decane-9-yl]ethyl})amine fumarate was dissolved in a good solvent and then mixed with a poor solvent to obtain crystal I; The good solvent is an alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide; the bad solvent is a nitrile, C5-10 saturated hydrocarbon, ester, or ether; the alcohol is preferably methanol, ethanol, isopropanol, n-butanol, or n-propanol; the nitrile is selected from acetonitrile; the C5-10 saturated hydrocarbon is preferably cyclohexane, n-pentane, or n-heptane; the ether is selected from methyl tert-butyl ether, isopropyl ether, or 1,4-dioxane; the ester is preferably ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate; wherein, mixing with the bad solvent refers to adding a good solvent to the bad solvent or vice versa.

8. A method for preparing crystal form II as described in any one of claims 4-5, characterized in that, Includes the following steps: (1) Dissolve [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospiro[4.5]decane-9-yl]ethyl})amine fumarate in a solvent to obtain a solution containing [(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxospiro[4.5]decane-9-yl]ethyl})amine fumarate; optionally, heating is performed during the dissolution process to aid dissolution; (2) The obtained solution was cooled to -5℃ to 35℃ to prepare crystal form II, so that crystals precipitate out. The solvent is selected from one or more of alcohols, esters, N-methylpyrrolidone, or dimethyl sulfoxide; the alcohols are preferably methanol, ethanol, isopropanol, n-butanol, or n-propanol, and the esters are preferably ethyl acetate, n-propyl acetate, isopropyl acetate, or isobutyl acetate.

9. A pharmaceutical composition comprising the crystal form of any one of claims 1 to 5, one or more excipients, a carrier, an adjuvant, a solvent, or a combination thereof.

10. Use of the crystal form according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing pain.

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