Pyrimidine derivative meglumine salt and crystal forms thereof

Abstract

Disclosed for the first time are a pyrimidine derivative meglumine salt as shown below and crystal forms thereof. A series of the crystal forms exhibits good developability (such as stability, fluidity, compressibility, solubility, bioavailability, etc.), providing a variety of bulk drug options for subsequent drug development.

Description

A meglumine salt of a pyrimidine derivative and crystal forms thereof TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and relates to a meglumine salt of a pyrimidine derivative and crystal forms thereof, in particular to a meglumine salt of onradivir and crystal forms thereof and a preparation method. BACKGROUND

[0002] Influenza virus (IFV), also known as flu virus, is a segmented single-stranded negative-sense RNA virus that can cause epidemic cold in humans and animals. In recent years, the continuous occurrence of seasonal influenza and the occasional emergence of highly pathogenic influenza viruses (such as H1N1, H5N1 and H7N9) indicate the potential threat of influenza outbreak, and the prevention and control of influenza is important and urgent.

[0003] Current influenza treatment options include vaccination and chemotherapy and chemoprophylaxis with antiviral drugs. Antiviral drugs can also be used to treat influenza, among which neuraminidase inhibitors such as oseltamivir (Tamiflu) are the most widely used oral influenza antiviral drugs in clinical use, and are indicated for the treatment of influenza A and B in adults and children 1 year of age and older. However, through clinical observation, it has been found that drug-resistant virus strains have emerged for this type of neuraminidase inhibitor. In the field of anti-influenza virus, there is an urgent need for new anti-influenza virus drugs with novel mechanisms of action in clinical use, which can support the treatment of influenza A as a monotherapy, or be used for the prevention and treatment of influenza A by combination with other anti-influenza virus drugs with different mechanisms of action that are already on the market.

[0004] Onradivir, English name Onradivir, CAS: 2200336-20-3, its chemical name is: (2S, 3S)-3-[[6-cyclopropyl-5-fluoro-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic acid, and its structure is as shown below:

[0005] Onradivir is a small molecule RNA polymerase PB2 protein inhibitor for treating influenza A, and is intended to be used for the treatment of simple influenza A in adults in clinical use. Patent WO2018041263 discloses the structure of onradivir and its in vitro activity data, which shows that onradivir has a positive effect in the influenza virus replication inhibition test, and exhibits a significant therapeutic effect on the H1N1 mouse infection model of influenza A virus.

[0006] Patent WO2019170067 discloses a series of crystal forms, salt forms and crystal forms of salt forms of ondansetron, which have good stability and application prospect in production and clinic, and provide a variety of intermediate products and / or raw materials for the downstream process of bulk drug (such as preparation process) of pharmaceutical products.

[0007] Patent WO2021012864 discloses a series of ondansetron sodium salt crystal forms, which have improved solubility and stability compared with ondansetron free state.

[0008] The skilled person found that ondansetron free state has poor solubility and is difficult to dissolve in water, which affects the efficacy and clinical effect of the drug in clinical practice. Therefore, although there have been reports of ondansetron crystal forms, it is still necessary to develop more crystal forms, on the one hand to provide more ondansetron crystal forms for drug application, and on the other hand to develop ondansetron crystal forms that are more suitable for industrial production and have high economic benefits. Different crystal forms of the same drug have different characteristics in appearance, flowability, storage stability, solubility, melting point, density, thermal stability, chemical reactivity, optical and mechanical properties, etc., which can directly affect the stability, storage transfer, bioavailability, efficacy and safety of the drug, etc. and produce different effects.

[0009] At the same time, salt screening and crystal screening are one of the important links in drug development. For a specific compound, the advantages and disadvantages of the physicochemical properties of its free state, various salt forms and corresponding crystal forms are unknown. Based on further consideration of its drugability, finding suitable salt forms and their corresponding superior crystal forms provides a variety of intermediate products and / or raw material selection for subsequent drug development, which is of great significance to drug development. SUMMARY

[0010] The present application discloses meglumine salt of ondansetron (compound 1) for the first time, and provides crystal form I and amorphous form of compound 1 for the first time. The compound 1 crystal form has good drugability (such as stability, flowability, compressibility, solubility, bioavailability, etc.), provides a variety of raw material selection for subsequent drug development, and the preparation method is simple, the process stability is good, and it is suitable for drug development.

[0011] Specifically, the meglumine salt of ombitasvir is obtained by the skilled person through multiple experiments. Ombitasvir is a pyrimidine derivative containing a carboxyl group, although it is understood in the art that ombitasvir can form a salt with conventional inorganic salts, such as sodium salt, but the expectation of whether it can form a salt with organic amine salt, such as meglumine salt, is unclear. In the prior art, the meglumine salt of a compound is also a common pharmaceutical salt. For Compound 1 of the present application, the skilled person found that it is difficult for meglumine to form a salt with ombitasvir when the initial crystal form screening was carried out by solution method and ball milling method. However, the skilled person surprisingly found that ombitasvir can form a salt with meglumine under specific conditions through multiple experiments; further experimental studies showed that the molar ratio of ombitasvir to meglumine in Compound 1 is 1:1, i.e. 1 molecule of ombitasvir and 1 molecule of meglumine are combined into a salt in a manner known in the art; the present application relates to a series of crystal forms of Compound 1, including but not limited to solvent-free and solvent-containing compounds of Compound 1, wherein the "solvent" in the "solvent-free and solvent-containing compounds" includes water and organic solvents, and the organic solvents are ethanol.

[0012] For the characterization of the crystal form of Compound 1, the skilled person in the art can understand that for a specific crystal form of a specific compound, due to the influence of instrument equipment, operation method, sample purity, human factors and the like in the characterization process, the 2θ angle of each diffraction peak in the X-ray powder diffraction pattern (XRPD) will have a certain fluctuation in repeated experiments, and the fluctuation range (error range) is usually ±0.2°; in addition, the skilled person in the art can also understand that the stability and repeatability of the diffraction peak will be affected by the 2θ angle, absorption intensity (peak height) and other factors of the comprehensive X-ray powder diffraction pattern; specifically, the stronger the absorption intensity, the better the separation, and the smaller the 2θ angle, the better the stability and repeatability of the diffraction peak, and the more it can be used to characterize the specific crystal form; and for the diffraction peak with larger 2θ angle and / or poorer separation and / or weaker relative intensity, it may have a larger fluctuation due to the influence of instrument equipment, operation method, sample purity, human factors and the like, and it may not appear repeatedly in repeated experiments, therefore, for the skilled person in the art, such absorption peak is not necessary for the characterization of the crystal form; more specifically, the present application follows the consensus of the crystal form characterization in the art, and the selection of the diffraction peak is comprehensively considered in terms of 2θ angle, absorption intensity (peak height) and other factors, and is grouped according to stability and repeatability. Therefore, the skilled person in the art can understand that the X-ray diffraction pattern of a crystal form in the present application does not have to be exactly the same as the X-ray diffraction pattern in the examples here. Any crystal form having a pattern identical or similar to the characteristic peaks in these patterns falls within the scope of the present application. The skilled person in the art can compare the patterns listed in the present application with the patterns of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

[0013] Those skilled in the art can also understand that, for the differential scanning calorimetry curve (DSC) and the thermogravimetric analysis curve (TGA) of the sample, the same batch and / or inter-batch samples will also be affected by the instrument equipment, detection conditions, detection personnel, etc. to cause fluctuations in the detection results, therefore, the present application complies with the consensus in the art for the characterization of crystal forms, and sets the fluctuation range of the starting point of the endothermic peak and the exothermic peak in the DSC spectrum to ±3°C, and sets the fluctuation range of the weight loss value in the TGA spectrum to ±1%.

[0014] Unless otherwise specified, "room temperature" in the present application refers to 25±5°C, and the thermogravimetric analysis curve (TGA) in the present application "does not show obvious weight loss" refers to weight loss ≤1% before the end of the detection temperature.

[0015] The first object of the present application is to provide a crystal form I of compound 1 and a preparation method thereof, which has good drugability.

[0016] Specifically, the crystal form I of the aforementioned compound 1 has stably appearing diffraction peaks at 2θ of 8.1, 16.4, 17.8, 18.9, 22.3 and 25.1 (±0.2°) in the XRPD spectrum.

[0017] Further, the crystal form I of the aforementioned compound 1 has diffraction peaks at 2θ of 9.5, 11.5, 13.3, 19.9, 20.4, 26.0 and 26.9 (±0.2°) in the XRPD spectrum.

[0018] Further, in some schemes of the present application, the crystal form I of the aforementioned compound 1 has the diffraction peak conditions of the crystal form I of compound 1 as shown in the following table:

[0019] Further, in some schemes of the present application, the crystal form I of the aforementioned compound 1 has an XRPD spectrum substantially as shown in FIG. 1.

[0020] The crystal form I of the aforementioned compound 1 has an endothermic peak starting point at 205.56±3°C in the differential scanning calorimetry curve (DSC).

[0021] Further, in some schemes of the present application, the crystal form I of the aforementioned compound 1 has a DSC spectrum substantially as shown in FIG. 2.

[0022] The crystal form I of the aforementioned compound 1 does not show obvious weight loss at 105°C in the thermogravimetric analysis curve (TGA), and further, the weight loss at 105°C is 0.69±1%.

[0023] Further, in some schemes of the present application, the crystal form I of the aforementioned compound 1 has a TGA spectrum substantially as shown in FIG. 3.

[0024] Further, the crystalline form I of compound 1 of the present application is substantially free of crystallization water, and is in an anhydrous form.

[0025] The preparation method of the crystalline form I of compound 1 of the present application, in which ethanol is used as the solvent, first dissolves onladivir at 60-70℃, then adds meglumine, and obtains after stirring and cooling. The mass-volume ratio of onladivir to the solvent (ethanol) is 1:6-16; preferably 1:7-14.

[0026] The preparation method of the crystalline form I of compound 1 has stable process, mild reaction conditions, and raw materials are easy to obtain, and can be used for large-scale industrial production of the crystalline form I of compound 1.

[0027] The second object of the present application is to provide an amorphous form of compound 1 and a preparation method thereof, which has good drug properties.

[0028] For the characterization of the amorphous form of compound 1, it is well known to those skilled in the art that amorphous form belongs to a thermodynamic high-energy state, and is a thermodynamic metastable structure. The basic particles constituting the compound are randomly arranged in three-dimensional space. X-ray powder diffraction (XRPD) is one of the most intuitive ways to judge the amorphous form. Specifically, when the compound exists in an amorphous form, its XRPD pattern usually shows no sharp diffraction peak, i.e. there is no characteristic diffraction peak in the XRPD spectrum, or there is one or several broad and flat diffraction peaks (commonly referred to as "steamed bun peaks" in the industry). Those skilled in the art can understand that the broad and flat diffraction peak in the amorphous XRPD spectrum is relative to the narrow and sharp diffraction peak in the crystalline XRPD spectrum. Generally speaking, the broad and flat diffraction peak in the amorphous XRPD spectrum can span up to 5° or even more.

[0029] Specifically, the amorphous form of the aforementioned compound 1 has no characteristic sharp peak in the XRPD spectrum. Further, the XRPD spectrum of the amorphous form of the compound 1 has two broad peaks between 5°-15° and 15°-25°.

[0030] Further, in some schemes of the present application, the XRPD spectrum of the amorphous form of the aforementioned compound 1 is substantially as shown in Figure 5.

[0031] The amorphous form of the aforementioned compound 1 has a weight loss of 4.37±1% at 105±3℃ in the thermal gravimetric analysis curve (TGA).

[0032] Further, in some schemes of the present application, the TGA spectrum of the amorphous form of the aforementioned compound 1 is substantially as shown in Figure 6.

[0033] The present application also provides the use of the crystalline form I of compound 1 in the preparation of amorphous compound 1.

[0034] The preparation method of the amorphous compound 1 of the present application is to heat the crystalline form of compound 1 to 60-75℃ to dissolve in water and ethanol as mixed solvents, and then to obtain by concentrating and drying. The mass-volume ratio (g / ml) of the crystalline form I of compound 1 and the mixed solvents is 1:14-48; preferably 1:34-38; more preferably 1:30-36; and the volume ratio of water and ethanol is 1:3-7; preferably 1:3.5-6.0; more preferably 5-6 to ensure complete dissolution of the material.

[0035] The preparation method of the amorphous compound 1 is stable in process, mild in reaction condition, and the raw materials are easy to obtain, which can be used for large-scale industrial production of amorphous compound 1.

[0036] The third object of the present application is to provide a raw material drug containing at least one of the crystalline form I and the amorphous form of compound 1. Based on the beneficial effects of the crystalline form I and the amorphous form of compound 1 of the present application, the raw material drug containing the crystalline form also embodies the beneficial effects (such as stability, water solubility, etc.) basically consistent with the crystalline form. Specifically, the raw material drug can be compound 1 (i.e. ondansetron meglumine salt), or ondansetron and / or other salt forms of ondansetron, which are common pharmaceutical salts in the art, including but not limited to salts with bases such as potassium salt, calcium salt, magnesium salt, triethylamine salt, etc., and salts with acids such as hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; more specifically, the mass percentage of compound 1 in the raw material drug is any value between 0.01 and 99.99%, further, the mass percentage of compound 1 in the raw material drug is any value between 1.00 and 99.00%.

[0037] The fourth object of the present application is to provide a pharmaceutical composition composed of the aforementioned raw material drug and pharmaceutically acceptable excipients, which include but are not limited to at least one of fillers, binders, disintegrants, etc.; specifically, based on the beneficial effects of the crystalline form I and the amorphous form of compound 1 of the present application, the beneficial effects are ultimately reflected in the pharmaceutical composition; more specifically, the mass percentage of the aforementioned raw material drug in the pharmaceutical composition is any value between 1.00 and 99.00%, further, the mass percentage of the aforementioned raw material drug in the pharmaceutical composition is any value between 5.00 and 95.00%, and more further, the mass percentage of the aforementioned raw material drug in the pharmaceutical composition is any value between 10.00 and 90.00%.

[0038] The fifth object of the present application is to provide the use of the compound 1 crystalline form I and amorphous in the preparation of anti-influenza virus drugs. Further, the use of the compound 1 crystalline form I and amorphous in the preparation of drugs for treating influenza or influenza caused by highly pathogenic avian influenza virus. Further, the use of the compound 1 crystalline form I and amorphous in the preparation of anti-influenza A virus drugs.

[0039] In summary, the compound 1 crystalline form I and amorphous of the present application has a certain drug prospect, therefore, if the detection means proves that the compound 1 crystalline form I and amorphous exist in the aforementioned bulk drug and / or pharmaceutical composition, it should be regarded as using the compound 1 crystalline form I and amorphous provided by the present application. In addition to the aforementioned X-ray powder diffraction, the detection means can further include differential scanning calorimetry (DSC), infrared spectroscopy (IR), Raman spectroscopy (Raman), solid-state nuclear magnetic resonance (SSNMR) and other detection methods which can be used alone or in combination to prove the use of the compound 1 crystalline form I or amorphous of the present application, and the influence of pharmaceutical excipients and the like can be removed by methods commonly used by those skilled in the art, such as difference mapping method.

[0040] The present application has the following advantages and beneficial effects relative to the prior art:

[0041] 1. A compound 1, which is the meglumine salt of ombitasvir, is first disclosed, which has advantages in solubility and stability beyond the reasonable prediction of those skilled in the art.

[0042] 2. A compound 1 crystalline form I and a preparation method thereof are first disclosed, which has relatively optimal physical and chemical stability and has a considerable drug prospect;

[0043] 3. A compound 1 amorphous and a preparation method thereof are first disclosed, which has relatively optimal stability and has a considerable drug prospect;

[0044] 4. A bulk drug is provided, which contains at least one of the compound 1 crystalline form I and amorphous of the present application, and the bulk drug embodies the beneficial effects substantially consistent with the compound 1 crystalline form I and amorphous of the present application.

[0045] 5. A pharmaceutical composition is provided, which is composed of the bulk drug of the present application and pharmaceutically acceptable excipients, and has the beneficial effects substantially consistent with the compound 1 crystalline form I and amorphous of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1: XRPD spectrum of compound 1 crystalline form I.

[0047] Figure 2: DSC pattern of Compound 1 Form I.

[0048] Figure 3: TGA pattern of Compound 1 Form I.

[0049] Figure 4: XRPD comparison pattern of Compound 1 Form I.

[0050] Figure 5: XRPD pattern of Compound 1 amorphous.

[0051] Figure 6: TGA pattern of Compound 1 amorphous.

[0052] Figure 7: NMR hydrogen spectrum detection pattern of Compound 1 Form I.

[0053] Figure 8: NMR hydrogen spectrum detection pattern of Compound 1 amorphous. DETAILED DESCRIPTION

[0054] The present application will be further described in conjunction with the following examples and drawings, but the embodiments of the present application are not limited thereto.

[0055] Detection conditions

[0056] X-ray powder diffraction

[0057] X-ray powder diffractometer: Bruker D8 Advance; 2 theta scanning angle: from 3° to 45°; scanning step: 0.02°;

[0058] Exposure time: 0.2 seconds; light tube voltage and current: 40KV, 40mA.

[0059] Differential scanning calorimetry analysis

[0060] Differential scanning calorimeter: TA Instruments Q2000 FC100; heating rate: 10℃ / min;

[0061] Detection method: after the sample is accurately weighed, it is placed in a DSC Tzero sample pan and heated to 350℃, and the nitrogen blowing speed in the furnace is 50mL / min.

[0062] Thermogravimetric analysis

[0063] Thermogravimetric analyzer: thermogravimetric / differential thermal simultaneous measurement system, model: DTG-60AH;

[0064] TGA / DTA detection parameters: heating rate 10℃ / min, target temperature 800℃, holding time 0min; nitrogen (purity greater than 99.99%), flow rate 50mL / min. Sample processing process: take about 2-10mg sample, put into alumina crucible, and start detection after the weight display value is stable.

[0065] NMR analysis:

[0066] NMR instrument: Bruker AVANCE III HD; probe: 5mm CPTCI 1H-13C / 15N / D Z-GRD Z117768 / 0031;

[0067] Experiment type: 1H NMR, sampling parameters: PULPROG = zg30; TD = 65536; NS = 8

[0068] Example 1 Preparation method of ombitasvir

[0069] Ombitasvir was prepared according to the method disclosed in Example 4 of the reference patent WO2018041263.

[0070] Example 2 Preparation method of compound 1 crystal form I

[0071] Take 15.0 g of ombitasvir, add 120 ml of ethanol, stir and warm to 65℃, add 6.06 g of meglumine to dissolve, then stir for 10 min, and cool to room temperature (25℃) naturally under stirring, solid precipitates, continue to stir for 1 h to make the solid precipitate completely, suction filtration, and vacuum drying of half of the solid to obtain white solid 9.87 g, which is compound 1 crystal form I, the XRPD spectrum thereof is shown in Figure 1, the DSC spectrum thereof is shown in Figure 2, and the TGA spectrum thereof is shown in Figure 3.

[0072] Example 3 Preparation method of compound 1 crystal form I

[0073] Take 15.0 g of ombitasvir, add 150 ml of ethanol, stir and warm to 70℃, add 6.06 g of meglumine to dissolve, then stir for 15 min, and cool to room temperature (25℃) naturally under stirring, solid precipitates, continue to stir for 1 h to make the solid precipitate completely, suction filtration, and vacuum drying to obtain white solid, which is compound 1 crystal form I, and the comparison of the XRPD spectrum of the obtained crystal form I is shown in Figure 4.

[0074] Example 4 Preparation method of compound 1 amorphous

[0075] Take half of the white solid (9.9 g, dry basis) obtained after suction filtration in the preparation of Example 2, add 300 ml of ethanol, stir and warm to 70℃, then add 50 ml of water to dissolve completely, and concentrate to dryness at 60-70℃ to obtain solid 8.76 g, the XRPD spectrum thereof is shown in Figure 5, and the TGA spectrum thereof is shown in Figure 6.

[0076] Example 5 Preparation method of compound 1 amorphous

[0077] Take the white solid obtained after filtration in the preparation of Example 3 (9.8g of dry product), add 300ml of ethanol and 50ml of water, stir to dissolve completely at 70°C, and concentrate to dryness at 60-70°C to obtain 8.58g of solid, which is amorphous Compound 1, and the obtained solid has the same crystal form as the product of Example 4.

[0078] Example 6 Study on the possibility of forming a salt of ombitasvir and meglumine

[0079] 1) Solution method: about 30mg of ombitasvir was weighed into a solution, respectively, in an appropriate amount of ethanol, ethyl acetate, ethylene glycol dimethyl ether and tetrahydrofuran solvent, about two equivalents of meglumine was added, and stirring was carried out at room temperature, and whether solid was precipitated (solution suspension method) was observed. If solid was precipitated, it was centrifuged and dried at room temperature under vacuum. If no solid was precipitated after stirring the solution for 48h, the solution was cooled in a refrigerator at 5-15°C, and whether solid was precipitated (cooling crystallization method) was observed. If solid was precipitated, it was centrifuged and dried at room temperature under vacuum. If no solid was precipitated by cooling crystallization, a poor solvent n-hexane was gradually added dropwise at room temperature, and stirring was carried out overnight until turbidity was produced, and then it was centrifuged and dried at room temperature under vacuum (salting-out crystallization method).

[0080] 2) Ball milling method: about 200mg of ombitasvir was physically mixed with 1 equivalent of meglumine, 100uL of ethanol was added, and solid-phase reaction was carried out in a planetary ball mill (30Hz, 30min).

[0081] The solid obtained by the above screening method was characterized, and the results are shown in the following table:

[0082] Table 1 Study on the salt formation of ombitasvir and meglumine

[0083] From the results in Table 1 above, it can be seen that the salt formation of ombitasvir and meglumine was not achieved by the conventional solution method and ball milling method, and the salt formation between ombitasvir and meglumine was difficult to predict.

[0084] Example 7 Preparation of ombitasvir meglumine salt crystal form I under different conditions

[0085] About 2g of ombitasvir and an equivalent amount of meglumine were weighed into a reaction bottle, 20ml of the corresponding solvent was added, stirring was carried out at a specific temperature for 1h, and the state of the final sample was observed after cooling to room temperature.

[0086] Table 2 Screening of ombitasvir meglumine salt preparation process

[0087] From the above table, under the same conditions, ondansetron and meglumine failed to obtain ondansetron meglumine salt in tetrahydrofuran, acetonitrile, acetone, ethyl acetate, ethylene glycol dimethyl ether and mixed solvents of ethanol and water with a volume ratio of 3:1 and 2:1 (samples 1-7), but ondansetron meglumine salt can be obtained using single ethanol as a solvent (samples 8-10). At the same time, the stirring temperature also has an effect on the ondansetron and meglumine salt formation, and although ondansetron meglumine salt can be obtained at a lower temperature of 50°C (sample 8) and a higher temperature of 75°C (sample 10), the crystal form is a mixed crystal and the quality is slightly poor, and at a lower temperature, the solid is not fully precipitated and is in a slurry state.

[0088] Example 8 Salt analysis of compound 1 crystal form I and amorphous form

[0089] 1) The contents of ondansetron and meglumine in the crystal form I obtained in Example 2 and the amorphous form obtained in Example 4 were detected respectively, and the salt formation ratio was calculated. The detection results are shown in Table 3 below:

[0090] Table 3 Contents of ondansetron and meglumine in compound 1

[0091] Conclusion: From the data in the table, the molar ratio of ondansetron to meglumine in the ondansetron meglumine salt crystal form I and amorphous form prepared in the present application is close to the theoretical salt formation ratio of 1 / 1. Considering the detection error and other reasons, and the acid-base salt formation ratio is generally an integer multiple, therefore, the salt formation ratio of the crystal form 1 and amorphous form of compound 1 obtained in the present application is 1:1.

[0092] 2) The crystal form I obtained in Example 2 and the amorphous form obtained in Example 4 were detected by nuclear magnetic resonance respectively,

[0093] Figure 7 is a nuclear magnetic hydrogen spectrum detection diagram of the crystal form I of compound 1, and Figure 8 is a nuclear magnetic hydrogen spectrum detection diagram of the amorphous form of compound 1. In the detection spectrum diagram of the crystal form I, there is an ondansetron structural fragment N-CH- at about δ4.71, the integral number is 1.00, and there is a meglumine fragment terminal hydroxyethyl HO-CH2CH at about δ3.75, the integral number is 1.01, and the nuclear magnetic integral ratio is 1:1.01, which is consistent with the structure of target compound 1. In the detection spectrum diagram of the amorphous form, there is an ondansetron structural fragment N-CH- at about δ4.71, the integral number is 1.04, and there is a meglumine fragment terminal hydroxyethyl HO-CH2, the integral number is 1.96, and the nuclear magnetic integral ratio is 1.04:1.96, which is consistent with the structure of target compound 1. Therefore, the salt formation ratio of the crystal form 1 and amorphous form of compound 1 obtained in the present application is 1:1.

[0094] Example 9 Related substance detection of compound 1 crystal form I and amorphous form

[0095] The crystal form I obtained in Example 2 and the amorphous obtained in Example 4 were subjected to related substance analysis to investigate the related substance of Compound 1, and the results showed that the total impurity content of the crystal form I was 0.344%, and the total impurity content of the amorphous was 0.512%. The related substances of the crystal form I and the amorphous of Compound 1 obtained in the application meet the quality control requirements (total impurity content ≤2.0%), and have no obvious influence on the stability of the main component ombitasvir.

[0096] Example 10 Solubility analysis of crystal form

[0097] Ombitasvir sodium salt was prepared according to the method disclosed in Example 1 of the patent WO2021012864.

[0098] Ombitasvir sodium salt crystal form I was prepared according to the method disclosed in Example 2 of the patent WO2021012864.

[0099] Ombitasvir sodium salt crystal form II was prepared according to the method disclosed in Example 5 of the patent WO2021012864.

[0100] Ombitasvir sodium salt crystal form III was prepared according to the method disclosed in Example 6 of the patent WO2021012864.

[0101] Experimental operation: The equilibrium solubility of Compound 1 crystal form I and amorphous and ombitasvir sodium salt crystal forms I-III was detected in pH 6.8 phosphate buffer, respectively. The solubility detection method: high performance liquid chromatography, chromatographic conditions: column: octadecylsilane bonded silica gel as the filling agent (ACE Excel 3C18-AR, 4.6mmx150mm, 3μm); detector: UV detector (detection wavelength 260nm); mobile phase: mobile phase A: 0.05% formic acid solution (V / V); mobile phase B: methanol; isocratic elution; column temperature: 40℃; flow rate and injection volume: 1.0ml / min; 10μl. The detection results are shown in Table 4.

[0102] Table 4 Investigation of solubility of samples in pH 6.8 medium

[0103] Note: The detection data is the average of three parallel tests.

[0104] Conclusion: From the data in the above table, it can be seen that the solubility of ombitasvir in pH 6.8 system is poor. After forming a salt with sodium hydroxide or meglumine, the solubility can be increased. In terms of improving the solubility of ombitasvir in free state, the solubility of the meglumine salt crystal form and the amorphous of the application is better than that of the ombitasvir sodium salt crystal form.

[0105] In repeated experiments, the solubility of ombitasvir meglumine salt of the application in pH 6.8 system showed a better trend than that of sodium salt crystal form.

[0106] Example 11 Mechanical stability investigation

[0107] Operation: Different crystal form samples were applied with pressure of 500N and 2000N respectively for tabletting, and then XRPD analysis was carried out to see whether crystal form change occurred, and the results are shown in Table 5 below:

[0108] Table 5 Crystal form after tabletting under different pressure

[0109] From the above table, after tabletting under pressure of 500N and 2000N, the ondansetron meglumine salt crystal form I and amorphous of the application did not change. It can be seen that the ondansetron meglumine salt crystal form of the application has good mechanical pressure stability, so that the quality of the drug is controllable during production and storage.

[0110] Example 12 Flowability investigation

[0111] Appropriate amounts of ondansetron free form and prepared meglumine salt crystal form and sodium salt crystal form samples were taken respectively, and the powder bulk density was determined by the graduated cylinder knocking method, and the results are shown in Table 6 below:

[0112] Table 6 Flowability investigation of samples

[0113] Ondansetron free form product is extremely hydrophobic and has extremely poor flowability, which brings great difficulty to formulation development. By salifying with meglumine or sodium salt, the flowability of ondansetron can be significantly improved. From the data in the above table, the bulk density of ondansetron meglumine salt crystal form I is greater than that of ondansetron free form, which reflects that the flowability is significantly improved, and is not inferior to sodium salt crystal form I.

[0114] From the above, the ondansetron meglumine salt and its crystal form I and amorphous form are prepared by specific conditions, and the crystal form has stability, solubility and flowability, etc. effects, which provides a variety of intermediate products and / or raw materials for the large-scale production of bulk drug and the downstream process of pharmaceutical products (such as formulation process).

[0115] The above examples are the preferred embodiments of the present application, but the embodiments of the present application are not limited by the above examples, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application are equivalent replacement methods, and are all included in the protection scope of the present application.

Claims

1. A crystalline Form I of Compound 1 characterized by, The XRPD pattern of the crystalline Form I of the compound 1 has diffraction peaks at 8.1, 16.4, 17.8, 18.9, 22.3 and 25.1 (±0.2°) of 2 theta; further, the XRPD pattern of the crystalline Form I of the compound 1 has diffraction peaks at 9.5, 11.5, 13.3, 19.9, 20.4, 26.0 and 26.9 (±0.2°) of 2 theta; 2. The crystalline Form I of the compound 1 according to claim 1, characterized in that, The XRPD diffraction peaks of the crystalline Form I of the compound 1 include the data as shown in the following table: ; further, the crystalline Form I of Compound 1 has a DSC pattern substantially as shown in Figure 2.

3. The crystalline Form I of the compound 1 according to claim 1 or 2, characterized in that, The DSC pattern of the crystalline Form I of Compound 1 has an endothermic peak starting point at 205.56±3°C; further, the DSC pattern of the crystalline Form I of Compound 1 has a DSC pattern substantially as shown in Figure 2.

4. The crystalline Form I of compound 1 according to any one of claims 1-3, characterized in that, The TGA pattern of the crystalline Form I of Compound 1 has a weight loss of 0.69±1% at 105±3°C; further, the TGA pattern of the crystalline Form I of Compound 1 has a TGA pattern substantially as shown in Figure 3.

5. Amorphous form of Compound 1 characterized by, the amorphous XRPD pattern of the compound 1 has no sharp diffraction peaks; further, the amorphous XRPD pattern of the compound 1 has two broad peaks between 5°-15° and 15°-25° in 2Θ; further, the amorphous XRPD pattern of the compound 1 is substantially as shown in Figure 5; 6. The amorphous form of compound 1 according to claim 5, characterized in that, The TGA pattern of the amorphous of Compound 1 has a weight loss of 4.37±1% before 105±3°C; further, the TGA pattern of the amorphous of Compound 1 has a TGA pattern substantially as shown in Figure 6.

7. A raw material drug comprising Compound 1 and / or ombitasvir and / or other salt forms of ombitasvir, characterized in that, The drug substance comprises at least one crystalline form or amorphous form of Compound 1 according to any one of claims 1 to 6; 8. A pharmaceutical composition, characterized by, The pharmaceutical composition consists of the drug substance of claim 7 and pharmaceutically acceptable excipients, which include at least one of a filler, a binder, a disintegrant, a lubricant.

9. Use of the crystalline Form I or amorphous of Compound 1 according to any one of claims 1-6 in the preparation of an anti-influenza virus drug.

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