WO2022100395A1 - Baloxavir marboxil crystal form d and preparation method therefor - Google Patents

Abstract

Disclosed are a baloxavir marboxil crystal form D and a preparation method therefor. The baloxavir marboxil crystal form D is an anhydrous and solvent-free crystal form of baloxavir marboxil, and has characteristic diffraction peaks at diffraction angles 2θ of 4.5°, 8.8°, 10.8°, 13.2°, 14.3°, 14.8° and 16.2° under X-ray powder diffraction, wherein the test error is ± 0.2°. Research results of the present invention show that the crystal habit of the baloxavir marboxil crystal form D is an elongated needle-like crystal. A solvent is easily removed by means of vacuum drying. After drying, crystal particles with a purity of up to 99.5%, the limits of impurity residues and the solvent all meeting the quality standards of active pharmaceutical ingredients, and great stability, dispersibility, fluidity and compressibility can be obtained, and same are suitable for use as production raw materials of tablets. Moreover, the baloxavir marboxil crystal form D has better solubility than existing crystal forms in environments that simulate the pH of stomach and intestinal fluids, and is beneficial to the absorption and utilization of oral preparations.

Description

A kind of baloxavir dipivoxil crystal form D and preparation method thereof technical field

The invention relates to a baloxavir dipivoxil crystal form D and a preparation method thereof, belonging to the technical field of medicinal chemistry.

Background technique

Baloxavir Marboxil is a new anti-influenza drug developed by Shionogi, Japan, and its trade name is Xofluza. Xofluza is an innovative Cap-dependent endonuclease inhibitor and one of the few new oral drugs in the world that can inhibit the proliferation of influenza virus. It can target the key link of influenza virus replication and inhibit it from obtaining the 5' end of host mRNA from host cells. CAP structure, thereby inhibiting the transcription of the influenza virus's own mRNA, the drug was approved by Japan in February 2018 for the treatment of adult and pediatric patients with influenza A and B, and was approved by the FDA in October 2018 for the treatment of Uncomplicated acute influenza patients 12 years of age and older within 48 hours.

Baloxavir dipivoxil is a prodrug, which is hydrolyzed into the active substance baloxavir in the body, and their chemical structural formula is as follows:

According to the report of the existing literature, baloxavir dipivoxil is a polymorphic compound, such as: three crystal forms of Form I, Form II and Form III of baloxavir dipivoxil are disclosed in patent WO2018030463, wherein the Form I crystal form It is prepared in a mixed solution of dimethyl sulfoxide and water (see Example 10 therein), and the Form II crystal form is first dissolved in a mixed solution of acetonitrile (50 mL) and water (5 mL), and then replenished. Add 95mL water crystallization and obtain (detailed in the embodiment 21 wherein), the Form III crystal formation wherein is to use 40 times of methyl acetate to heat up and dissolve earlier, obtain by decompression concentration cooling crystallization (detailed in the embodiment 22 wherein) In addition, in patent CN201911140898.1, the Form A and Form B crystal forms of baloxavir dipivoxil are announced, and the Form A crystal form wherein is first used in good solvent (such as: dimethyl sulfoxide, dimethylformamide, Butyl formate, acetone) is dissolved at room temperature, and then at room temperature, a poor solvent (such as: ethanol, water, cyclohexane, isopropyl ether) is added dropwise to crystallize to obtain (details of the embodiment 1-4), wherein The Form B crystal form is first dissolved with acetonitrile, and then placed at room temperature to completely volatilize the acetonitrile to obtain; from the above existing research results, it can be known that the crystal form of baloxavir dipivoxil is very sensitive to solvents.

The inventor of this patent also found in the experiment that both Form II crystal form and Form III crystal form are unstable, and are easily converted into Form I crystal form during the crystallization process; The Form A and Form B crystal forms of Wei Dipivoxil have good stability under high temperature, high humidity and light conditions. However, by comparison, we found that the Form A crystal form is the Form I crystal form published in the patent WO2018030463, and The thermogravimetric analysis of Form B shows that it has a weight loss of about 0.5%. According to the patent, it is anhydrous, so this part of the weight loss indicates that Form B is a mixed crystal form mixed with solvates. And because Form B is obtained by volatilization and crystallization from the acetonitrile system, and acetonitrile belongs to the second-class solvent stipulated by ICH, the limit is lower, and on the other hand, mixed crystal will also affect the dissolution of the preparation, so the Form B in the form of acetonitrile solvate is It is impossible to be used as a medicine, and the preparation of Form B crystal form requires the natural volatilization of acetonitrile solution at room temperature for 3 to 4 days, which is definitely not possible in industrial production, and a large amount of acetonitrile solvent is volatilized into the air. It is beneficial to environmental protection, and when the equivalent weight is large, the degree of volatilization of the surface layer and the bottom layer of the solvent is different, and it is more likely to cause the problem that the solvent residue does not meet the requirements due to mixed crystals. Due to the above-mentioned reasons, the raw material used for oral preparations is still Form I crystal form (the same crystal form as Form A crystal form), but the crystal habit of the existing Form I crystal form is flaky, and the flaky crystal, in During the drying process, it is easy to wrap the solvent and agglomerate, which makes the material hard after drying, and the solvent residue is easy to exceed the standard. The impurities exceed the standard; in addition, after the material is agglomerated, the product has poor fluidity and needs to be physically pulverized to achieve the compressible particle size requirement, which has caused great difficulties in the production of oral pharmaceutical preparations. Therefore, there is an urgent need in the art to develop a new crystal form of baloxavir dipivoxil that is superior to the existing crystal form in terms of stability, solubility, fluidity, etc., to meet the industrial production requirements of oral baloxavir dipivoxil preparations.

SUMMARY OF THE INVENTION

In view of the above-mentioned problems and needs in the prior art, the object of the present invention is to provide a baloxavir dipivoxil crystal form D that is superior to the existing crystal form in terms of stability, solubility, fluidity, etc. Industrial production requirements for oral formulations of loxavir dipivoxil.

For realizing the above-mentioned purpose of the invention, the technical scheme adopted in the present invention is as follows:

The baloxavir dipivoxil crystal form D of the present invention is an anhydrous anhydrous ansolvate crystal form of baloxavir dipivoxil, and under X-ray powder diffraction, the diffraction angle 2θ is 4.5°, 8.8°, 10.8°, There are characteristic diffraction peaks at 13.2°, 14.3°, 14.8° and 16.2°, and the test error is ±0.2°.

Further, the baloxavir dipivoxil crystal form D of the present invention, under X-ray powder diffraction, has diffraction angles 2θ of 4.5°, 8.8°, 9.8°, 10.8°, 11.7°, 13.2°, 14.3° , 14.8°, 15.8°, 16.2°, 16.5°, 17.3°, 17.5°, 17.8°, 18.8°, 20.2°, 21.6°, 21.9°, 22.3°, 24.2°, 24.4°, 26.5°, 28.0°, 28.3 There are characteristic diffraction peaks at °, 29.7° and 31.5°, and the test error is ±0.2°.

Furthermore, the X-ray powder diffraction spectrum of the baloxavir dipivoxil crystal form D of the present invention is basically consistent with FIG. 4 .

Further, in the DSC spectrum of the baloxavir dipivoxil crystal form D described in the present invention, there is an endothermic peak at 235°C.

Furthermore, the DSC spectrum of the baloxavir dipivoxil crystal form D of the present invention is basically consistent with FIG. 5 .

Furthermore, the thermogravimetric analysis spectrum of baloxavir dipivoxil crystal form D according to the present invention is basically consistent with FIG. 6 .

A method for preparing baloxavir dipivoxil crystal form D of the present invention, comprising the following steps:

a) under the dissolving temperature of 20～50 ℃, the baloxavir dipivoxil raw material is dissolved in the mixed solvent formed by methylene chloride and the ester solvent by volume ratio of 1.0: (0.5～2.5), obtains a clear solution;

b) Then add n-heptane dropwise to the above system, stir to crystallize;

c) filter and collect the precipitated crystals;

d) The crystals obtained in step c) are vacuum-dried at 50-100° C. for 6-15 hours to obtain baloxavir dipivoxil crystal form D.

In step a), the dissolving temperature is preferably 20-40°C, and preferably 25-35°C.

In step a), the type of the baloxavir dipivoxil raw material is not limited, and it can be amorphous or any known crystal form or a mixture thereof.

In step a), the mass volume ratio of the baloxavir dipivoxil raw material and the mixed solvent is 1 gram: (8～15) milliliters, preferably 1 gram: (8～12) milliliters, and 1 gram: (8～12) milliliters. Grams: 10ml is optimal.

In step a), the volume ratio of the dichloromethane to the ester solvent in the mixed solvent is preferably 1.0:(0.8-1.2), and is the best at 1.0:1.0.

In step a), described ester solvent is selected from at least one in methyl benzoate, ethyl benzoate, methyl formate, ethyl formate, isopropyl formate, butyl formate, butyl acetate, with Any one selected from methyl benzoate, methyl formate and ethyl formate is the best.

In step b), the ratio of the volume of n-heptane used to the volume of the mixed solvent used in step a) is (1-1.2):1, with 1:1 being the best.

In step d), the vacuum drying conditions are preferably drying at 70-90°C for 6-10 hours, and optimally drying at 60-80°C for 6-8 hours.

Compared with the prior art, the present invention has the following significant beneficial effects:

The research results of the present invention show that the crystal form D of baloxavir dipivoxil described in the present invention is an anhydrous and solvent-free crystal form, the crystal habit of the crystal form is a slender needle-like crystal, and the solvent is easily removed by vacuum drying. It can obtain crystal particles with a purity of up to 99.5%, the residual impurities and solvent limits are in line with the API quality standards, and the stability, dispersibility, fluidity and compressibility are very good crystal particles, which are very suitable as raw materials for tablet production; and , the baloxavir dipivoxil crystal form D of the present invention has better solubility than the existing crystal form in the pH environment simulating gastric and intestinal juice, which is very beneficial to the absorption and utilization of oral preparations; Compared with the existing known crystal forms, the loxavir dipivoxil crystal form D has various excellent properties that are more suitable for oral preparations, and has produced significant progress and unexpected technical effects compared with the prior art.

Description of drawings

Fig. 1 is the X-ray powder diffraction pattern (XRPD) of the crystal form C described in Example 1;

Fig. 2 is the differential scanning calorimetry analysis spectrum (DSC) of crystal form C described in embodiment 1;

Fig. 3 is the thermogravimetric analysis data (TGA) of crystal form C described in embodiment 1;

Figure 4 is the X-ray powder diffraction pattern (XRPD) of Form D described in Example 1;

5 is a differential scanning calorimetry (DSC) spectrum of Form D described in Example 1;

Fig. 6 is the thermogravimetric analysis data (TGA) of crystal form D described in Example 1;

Fig. 7 is the X-ray powder diffraction pattern (XRPD) of known crystal form I;

Fig. 8 is the XRPD contrast spectrum of the stability experiment of crystal form D described in Example 4;

Fig. 9 is the crystal habit photo of crystal form D described in this application;

Figure 10 is a photograph of the crystal habit of the known Form I.

Detailed ways

In the following examples, unless otherwise specified, the described test method is usually carried out under conventional conditions or conditions suggested by the manufacturer, and the indicated raw materials and reagents can be obtained by commercially available methods.

The parameters of X-ray powder diffraction are as follows (XRPD):

X-ray powder diffractometer: Brucker D8 advance X-ray powder diffractometer;

X-ray reflection parameters: copper target

Scan at room temperature:

Voltage: 40 kilovolts (kv);

Current: 40 milliamps (mA);

Scan Mode: Continuous;

Scanning range: 2.0 to 35.0 degrees;

Step size: 0.020°;

Measurement time per step: 0.1 sec/step;

Differential scanning calorimetry (DSC) analysis method parameters are as follows:

Differential Scanning Calorimetry (DSC) instrument: TA Q2000;

Temperature range: room temperature～250℃;

Scanning speed: 10℃/min;

Protective gas: nitrogen, 50 ml/min;

Thermogravimetric analysis (TGA) parameters are as follows:

Thermogravimetric analysis (TGA) instrument: TGA55 type;

Temperature range: room temperature～300℃;

Scanning speed: 10℃/min;

Protective gas: nitrogen, 60 ml/min.

Example 1

At room temperature, 10.0 g of baloxavir dipivoxil was dissolved in a mixed solvent of 50 mL of dichloromethane and 50 mL of methyl benzoate, and then 100 mL of n-heptane was added dropwise, stirred and crystallized for 1 hour, filtered, and the filter cake used Rinse with n-heptane, the obtained crystal is referred to as crystal form C in the present application, and its XRPD spectrum is shown in Figure 1. It can be seen from Figure 1 that the 2θ of the X-ray powder diffraction pattern of the crystal form C is at 4.0± 0.2°, 8.0±0.2°, 11.1±0.2°, 11.4±0.2°, 12.0±0.2°, 13.2±0.2°, 13.6±0.2°, 14.1±0.2°, 14.3±0.2°, 16.1±0.2°, 16.3± Featured at 0.2°, 17.9±0.2°, 20.2±0.2°, 20.8±0.2°, 23.9±0.2°, 24.3±0.2°, 24.5±0.2°, 25.6±0.2°, 28.5±0.2° and 32.6±0.2° peak.

Fig. 2 is a differential scanning calorimetry spectrum of the crystal form C, and it can be seen from Fig. 2 that the crystal form C has endothermic peaks at 90-100°C and 235°C.

Fig. 3 is the thermogravimetric analysis spectrum of the crystal form C. It can be seen from Fig. 3 that the crystal form C has a weight loss of 8.0-11.0% at 90-100°C, indicating that the crystal form C is baloxavir dipivoxil The solvate of methyl benzoate, wherein the content of methyl benzoate is 8.0-11.0%.

The obtained crystal form C was dried in a vacuum drying oven at 80 ° C for 6 hours to obtain 9.2 g of solid. Its XRPD spectrum is shown in Figure 4, that is: the diffraction angles 2θ are 4.5°, 8.8°, 9.8° °, 10.8°, 11.7°, 13.2°, 14.3°, 14.8°, 15.8°, 16.2°, 16.5°, 17.3°, 17.5°, 17.8°, 18.8°, 20.2°, 21.6°, 21.9°, 22.3°, There are characteristic diffraction peaks at 24.2°, 24.4°, 26.5°, 28.0°, 28.3°, 29.7° and 31.5°, and the test error is ±0.2°. The application records the crystal form obtained after drying as crystal form D.

Fig. 5 is the differential scanning calorimetry spectrum of the crystal form D, as can be seen from Fig. 5: the crystal form D has an endothermic peak at 235°C; Fig. 6 is the thermogravimetric analysis spectrum of the crystal form D , it can be seen from Figure 6 that the crystal form D is an anhydrous and solvent-free crystal form.

Example 2

At room temperature, 10.0 g of baloxavir dipivoxil was dissolved in a mixed solvent of 50 mL of dichloromethane and 50 mL of ethyl formate, then 100 mL of n-heptane was added dropwise, stirred and crystallized for 1 hour, filtered, and the filter cake was washed with n-heptane. Rinse with heptane, and then vacuum dry at 60 °C for 8 hours to obtain 9.6 g of solid. Its XRPD spectrum is basically consistent with Figure 4, its differential scanning calorimetry spectrum is basically consistent with Figure 5, and its thermogravimetric analysis spectrum The figure is basically consistent with FIG. 6, which is the crystal form D described in this application.

Example 3

10.0g of baloxavir dipivoxil, 40mL of dichloromethane and 50mL of methyl formate were added to the reaction flask, the temperature was raised to 35°C to dissolve, then 100mL of n-heptane was added dropwise, stirred and crystallized for 1 hour, and then cooled to 20°C left and right, stirring and filtering, the filter cake was rinsed with n-heptane, and then vacuum-dried at 80 ° C for 6 hours to obtain 9.5 g of solid, the XRPD spectrum of which was basically consistent with Figure 4, and the differential scanning calorimetry spectrum was as shown in Figure 4. 5 is basically the same, and its thermogravimetric analysis spectrum is basically the same as Figure 6, which is the crystal form D described in this application.

Example 4: Stability Test

According to the guiding principles of the stability test of pharmaceutical preparations, the crystal form D (prepared from Examples 1-3) described in this application and the known crystal form I (prepared with reference to Example 10 in patent WO2018030463) are prepared, and their XRPD spectra are shown in the figure 7, which is basically consistent with Figure 3 in WO2018030463) to conduct experiments on influencing factors, including high temperature test, high humidity test and strong light irradiation test, to investigate the stability conditions affecting its crystal form:

High temperature test: Take appropriate amount of crystal form D and crystal form I samples respectively, lay them flat in a weighing bottle, and place them in a constant temperature and humidity box at 70°C and RH75% for 10 days. Take about 100 mg of the above samples, and use powder X-ray Its crystal form was tested by powder diffraction (XRPD), and the results are shown in Table 1 and Figure 8;

High humidity test: Take appropriate amount of crystal form D and crystal form I samples respectively, lay them flat in a weighing bottle, and place them in a constant temperature and humidity box at 25°C and RH 92.5% for 10 days. Take about 100 mg of the above samples and use powder X - XRPD testing its crystal form, the results are shown in Table 1 and Figure 8;

Illumination test: Take appropriate amount of samples of crystal form D and crystal form I respectively, spread them into weighing bottles, and put them in a constant temperature and humidity box (25°C) with visible light 4500Lux ± 500Lux (VIS) and ultraviolet light 1.7W*h/m2 (UV). ℃, RH 60% ± 5%) for 10 days, take about 100 mg of the above sample, use powder X-ray powder diffraction (XRPD) to test its crystal form, the results are shown in Table 1 and Figure 8.

Table 1 Stability test results

Sample crystal form	Form D	Form I
High temperature (70℃, RH75%, 10 days)	still in form D	still in form I
High humidity (25℃, RH 92.5%, 10 days)	still in form D	still in form I
Light (10 days)	still in form D	still in form I

It can be seen from Table 1 and Figure 8 that the crystal form D described in the present application has the same stability as the crystal form I.

Example 5: Solubility Test

Prepare the following solution with reference to the appendix of the Japanese Pharmacopoeia:

pH 1.2 solution: take 2.0 g of sodium chloride, dissolve it in an appropriate amount of water, add 7 mL of hydrochloric acid, add water to dilute to 1000 mL, and mix well to get it;

pH4.0 solution: mix 0.05mol/L acetic acid solution and 0.05mol/L sodium acetate solution in a ratio of 16.4:3.6 to obtain;

Phosphate buffer at pH 6.8: Take 1.7 g of potassium dihydrogen phosphate and 1.775 g of anhydrous disodium hydrogen phosphate, add water to dissolve and dilute to 1000 mL.

Take an appropriate amount of crystal form D and crystal form I samples respectively, and dissolve them with pH1.2 solution, pH4.0 solution, pH6.8 phosphate buffer solution to make a saturated solution, then centrifuge, and carry out HPLC content analysis on the supernatant, Calculate the corresponding solubility. The specific experimental results are shown in Table 2.

Table 2 Solubility test results

Sample crystal form	Form D	Form I
PH1.2, 37℃	22.68μg/mL	20.6μg/mL
PH4.0, 37℃	24.98μg/mL	19.3μg/mL
PH6.8, 37℃	23.54μg/mL	18.9μg/mL

It can be seen from the results shown in Table 2: the baloxavir dipivoxil crystal form D described in this application has a solubility better than the existing crystal form I in the pH environment of simulating gastrointestinal fluid, which is very beneficial to the absorption and utilization of oral preparations. .

In addition, take appropriate amount of crystal form D and crystal form I samples respectively, magnify 100 times under the microscope to observe their crystal habits and find out:

Fig. 9 is the crystal habit photo of the crystal form D described in the application, as can be seen from Fig. 9: the crystal habit of the crystal form D described in the present application is a slender needle-like crystal, and the particle dispersibility is good, indicating that it has good fluidity and compressibility, very suitable for use as a raw material for tablets;

Fig. 10 is the crystal habit photo of the known crystal form I, as can be seen from Fig. 10: the crystal habit of crystal form I is flaky, and the flaky crystal, in the process of baking the material, is easy to wrap the solvent and agglomerate, resulting in baking After drying, the material is hard, and the solvent residue is easy to exceed the standard. It often takes a long time to dry to reach the solvent limit. If the drying time is too long, it is easy to cause the degradation of impurities to exceed the standard. In addition, after the material is agglomerated, the product has poor fluidity and needs to be physically crushed. Reaching the particle size requirement causes trouble to the production and preparation of tablets, and is not an ideal raw material for tablet preparation.

Finally, it should be pointed out here that the above are only some preferred embodiments of the present invention, and should not be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art according to the above-mentioned contents of the present invention All belong to the protection scope of the present invention.

Claims (10)

1. A baloxavir dipivoxil crystal form D, which is an anhydrous ansolvate crystal form of baloxavir , 13.2°, 14.3°, 14.8° and 16.2° have characteristic diffraction peaks, and the test error is ±0.2°.
2. The baloxavir dipivoxil crystal form D according to claim 1, characterized in that: under X-ray powder diffraction, the diffraction angles 2θ are 4.5°, 8.8°, 9.8°, 10.8°, 11.7°, 13.2° , 14.3°, 14.8°, 15.8°, 16.2°, 16.5°, 17.3°, 17.5°, 17.8°, 18.8°, 20.2°, 21.6°, 21.9°, 22.3°, 24.2°, 24.4°, 26.5°, 28.0 There are characteristic diffraction peaks at °, 28.3°, 29.7° and 31.5°, and the test error is ±0.2°.
3. The baloxavir dipivoxil crystal form D according to claim 1, characterized in that: in the DSC spectrum of the baloxavir dipivoxil crystal form D, there is an endothermic peak at 235°C.
4. A method for preparing the baloxavir dipivoxil crystal form D of claim 1, wherein the method comprises the steps:

   a) under the dissolving temperature of 20～50 ℃, the baloxavir dipivoxil raw material is dissolved in the mixed solvent formed by methylene chloride and the ester solvent by volume ratio of 1.0: (0.5～2.5), obtains a clear solution;

   b) Then add n-heptane dropwise to the above system, stir to crystallize;

   c) filter and collect the precipitated crystals;

   d) The crystals obtained in step c) are vacuum-dried at 50-100° C. for 6-15 hours to obtain baloxavir dipivoxil crystal form D.
5. The method according to claim 4, characterized in that: in step a), the dissolving temperature is 20-40°C.
6. The method according to claim 4, characterized in that: in step a), the form of the baloxavir dipivoxil raw material is amorphous or any known crystal form or a mixture thereof.
7. The method according to claim 4, wherein: in step a), the mass volume ratio of the baloxavir dipivoxil raw material and the mixed solvent is 1 gram: (8～15) milliliters.
8. The method according to claim 4, wherein in step a), the volume ratio of dichloromethane to ester solvent in the mixed solvent is 1.0:(0.8～1.2).
9. method according to claim 4, is characterized in that: in step a), described ester solvent is selected from methyl benzoate, ethyl benzoate, methyl formate, ethyl formate, isopropyl formate, formic acid At least one of butyl ester and butyl acetate.
10. The method according to claim 4, wherein: in step b), the ratio of the volume of n-heptane used to the volume of the mixed solvent used in step a) is (1～1.2):1.

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