Method for treating nemategravir crystals

Abstract

The invention provides a method for treating a nemategravir crystal. The method comprises the step of contacting nemategravir to be treated with water vapor to obtain a nemategravir Form 1 crystal. According to the method provided by the invention, the nematevir solid containing the Form 4 mixed crystal can be converted into the single nematevir Form 1 crystal, and the method is simple to operate, free of material loss and suitable for industrial mass production.

Description

Technical field:

[0001] The present application relates to the field of medical technology, and in particular to a method for processing Namatevir crystals. Background technology:

[0002] Nirmatrelvir, chemical name: (1R, 2S, 5S)-N-[(1S)-1-cyano-2-(2-oxo-pyrrolidin-3-yl)ethyl]-3-[(S)-3,3-dimethyl-2-(trifluoroacetamido)butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-amide, the structural formula is as follows:

[0003]

[0004] Nematevir is one of the main ingredients of Paxlovid, an anti-COVID-19 drug developed by Pfizer of the United States. Paxlovid is an oral small molecule drug for the treatment of COVID-19. It is used to treat adult patients with mild to moderate COVID-19 who have high risk factors for progression to severe illness, such as advanced age, chronic kidney disease, diabetes, cardiovascular disease, chronic lung disease and other high risk factors for severe illness.

[0005] Pfizer mentioned the crystal forms of Nematevir in patent document WO2021250648A1. Nematevir exists in Form 1, Form 2, Form 4 and Form 5, among which Form 2 is a methyl tert-butyl ether solvate; Form 1 is the current pharmaceutical crystal form, which is obtained by crystallizing Form 2 in isopropyl acetate and n-heptane; Form 4 is obtained by crystallizing Form 1; Form 5 is an amorphous compound.

[0006] According to WO2021250648A1, it is known that the Form 1 crystal of Namatevir can be obtained by slurrying in 12 times the volume of water at 5°C for 21 days, filtering and drying to obtain the Form 4 crystal of Namatevir. According to the actual research of the inventors, it was found that during the conventional preparation, storage or processing (such as micronization) of Form 1 of Namatevir, mixed crystals of Form 1 and Form 4 will appear. As we all know, mixed crystals will seriously affect the efficacy of the drug. Summary of the invention:

[0007] In order to solve the above-mentioned mixed crystal problem, the present invention provides a method for treating Namatevir crystals, comprising contacting the Namatevir solid to be treated with water vapor to obtain Namatevir Form 1 crystals.

[0008] The present invention also provides a method for preparing Namatevir crystals, comprising the following steps: contacting the Namatevir solid to be treated with water vapor to obtain Namatevir Form 1 crystals.

[0009] According to a preferred embodiment of the present invention, the namatevir solid to be treated is a micronized product, preferably D90≤60μm, more preferably D90≤20μm, and even more preferably D90≤12μm, such as 10μm, 6μm, 5μm, etc.

[0010] According to a preferred embodiment of the present invention, the namatevir solid to be treated is form 4, or a mixture of form 1 and form 4.

[0011] The Namatevir form 1 and form 4 crystals are both crystals defined in WO2021250648A1.

[0012] According to a preferred embodiment of the present invention, the X-ray diffraction pattern of the namatevir solid to be treated contains, in addition to the characteristic peak of form I, a characteristic peak at 12.2°±0.2°, for example, a relative intensity range of 2% to 100% is displayed at 12.2°±0.2°.

[0013] According to a preferred embodiment of the present invention, the crystals in the Namatevir solid to be treated have X-ray powder diffraction values ​​as shown in Table 1, Table 3 or Table 5.

[0014] According to a preferred embodiment of the present invention, the treated Namatevir Form 1 crystals do not have a diffraction peak at 12.2°±0.2° in the X-ray diffraction spectrum.

[0015] According to a preferred embodiment of the present invention, the treated Namatevir form 1 crystals have X-ray powder diffraction values ​​as shown in Table 2, Table 4 or Table 6.

[0016] According to a preferred embodiment of the present invention, the water vapor can be provided by a water vapor generator, or by placing water in a drying oven and providing it by vacuuming;

[0017] According to a preferred embodiment of the present invention, the namatevir solid to be treated is contacted with water vapor under heating conditions, preferably heated to 35-80°C, such as 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 70°C, 80°C, or a range of any two values ​​therein, such as between 40 and 60°C.

[0018] According to a preferred embodiment of the present invention, when the Nematevir solid to be treated contacts with water vapor, the Nematevir solid is in a closed or relatively closed environment.

[0019] According to a preferred embodiment of the present invention, when the Namatevir solid to be treated contacts water vapor, the relative humidity of the system is above 35%, preferably above 50%, and further preferably above 75%.

[0020] According to a preferred embodiment of the present invention, pure form I can be obtained by contacting the treated Namatevir solid with water vapor; after the treatment, it can be further dried and then cooled to a suitable temperature for discharge.

[0021] According to a preferred embodiment of the present invention, the contact time with water vapor depends on the situation, for example, more than 0.5 hours, for example, 1 hour, 2 hours, 5 hours, 10 hours, 24 hours, or 48 hours or the range therebetween or greater than the above time.

[0022] The third aspect of the present invention provides a method for treating Namatevir crystals, comprising the following steps: placing the Namatevir solid to be treated and a certain amount of water separately in the same vacuum dryer, and both the material and the water are exposed in the dryer, opening the vacuum and heating for a period of time to obtain Namatevir Form 1 crystals.

[0023] The definitions of the Namatevir solid to be treated and the treated Namatevir Form 1 crystals are as described above.

[0024] The solid Namatevir to be treated is preferably placed in a flat manner.

[0025] According to a preferred embodiment of the present invention, the vacuum dryer is a DZF, YZG or FZG series vacuum dryer.

[0026] According to a preferred embodiment of the present invention, the certain amount of water is placed in another container separately and openly, and is not in direct contact with the material. The inventors found that without placing additional water, the mixed crystal containing form 4 cannot be successfully converted to form 1. However, there is no strict restriction on the amount of water placed in the step (a). According to the present invention, those skilled in the art can determine the appropriate amount through routine experiments, such as ensuring that the system still contains additional water before the crystal transformation is completed; after the crystal transformation is completed, whether the system still contains additional water is not affected. According to a preferred embodiment of the present invention, the amount of water used can be, for example, 0.01 to 1000 times the weight of the solid of Namatevir to be treated, such as 0.04 times, 0.4 times, 1 times, 10 times, 100 times, 1000 times or any range thereof, such as 0.04 to 1 times.

[0027] According to a preferred embodiment of the present invention, the method is heated in a vacuum dryer, and the preferred heating temperature is 35-80°C, for example 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 70°C, 80°C, or a range of any two values ​​therein, for example, between 40 and 60°C; the preferred vacuum degree is ≥0.03MPa, for example 0.04MPa, 0.05MPa, 0.055MPa, 0.06MPa, 0.065MPa, 0.07MPa, 0.075MPa, 0.08MPa, 0.085MPa, 0.09MPa, 0.095MPa, 0.1Mpa and a range of any two values ​​or greater than any one of the above values, for example, 0.055MPa to 0.095MPa.

[0028] The heating time in the vacuum dryer may be, as appropriate, for example, more than 0.5 hour, 1 hour, 2 hours, 5 hours, 10 hours, 24 hours, or 48 hours or a range therebetween or longer than the above time.

[0029] The present invention completes the phase change by contacting with water vapor under heating conditions. After the phase change is completed, it can be further dried; then cooled, for example, cooled to a temperature of 15 to 30° C., or cooled to room temperature before discharging.

[0030] The innovation of the present invention is that the inventor unexpectedly discovered that by treating Namatevir with water vapor, preferably contacting with water vapor under heating conditions, Namatevir containing Form 4 mixed crystals can be converted into Form 1 single crystals. This method is simple to operate, and there is no material loss during the crystal conversion process. It has strong practical application value and is suitable for large-scale industrial production. Description of the drawings:

[0031] Attached Figure 1 : X-ray powder diffraction pattern corresponding to Table 1 of Example 1.

[0032] Attached Figure 2 : X-ray powder diffraction pattern corresponding to Table 2 of Example 1. DETAILED DESCRIPTION

[0033] The detection method using X-ray powder diffraction of the present invention is as follows:

[0034] X-ray diffractometer: X'Pert Pro MPD;

[0035] Light tube type: Empytean XRD Tube Cu LFF HR;

[0036] Voltage and current: 45kV, 40mA;

[0037] Goniometer: PW3050 / 60 vertical goniometer, radius 240mm;

[0038] Slit: FDS = 2°, ASS = 1 / 2°, Mask = 15 mm, DASS = 5.0 mm;

[0039] Detector: X'Celerator super energy detector;

[0040] Scan mode: continuous scan;

[0041] Step size: 0.00167°;

[0042] Scanning range: 3.0-50.0°;

[0043] Counting time per step: 50s.

[0044] Particle size test method:

[0045] Malvern Mastersizer 2000, wet method.

[0046] Preparation example:

[0047] According to the example of PCT patent WO2021250648A1 (recrystallization of Example 13; producing solid form 1), namatevir form I was prepared in isopropyl acetate and heptane, and then air flow pulverization was performed to obtain the namatevir solid to be treated in Example 1 and Example 2.

[0048] According to the embodiment of PCT patent WO2021250648A1 (recrystallization of Example 13; producing solid form 1), namatevir form I was prepared in isopropyl acetate and heptane, and then air flow milling was performed to obtain a micropowder sample, and the micropowder sample was slurried in 5-10°C water for 1 day to obtain the namatevir solid to be treated in Example 3.

[0049] Example 1

[0050] 100 g of the solid Namatevir to be treated (D90 is 6 μm, X-ray powder diffraction data are shown in Table 1, wherein the 12.2° angle is the characteristic peak of Form 4, with a relative intensity of 15.3%, see also Appendix Figure 1 ) was laid flat in a glass dish with a diameter of 20 cm, the glass dish was covered with filter paper, the glass dish was placed on the upper layer of a DZF-6050 vacuum oven, a glass dish with a diameter of 20 cm was placed on the lower layer, and 100 g of water was added thereto without sealing. The oven temperature was set to 45°C, the vacuum degree was 0.095 MPa, and vacuum drying was performed for 2 hours. Cooled to room temperature, the material was taken out, and the crystal form was detected. The data is shown in Table 2. The 12.2° angle disappeared, which is a single crystal form of Namatevir Form 1. See also Appendix Figure 2 .

[0051] Table 1

[0052]

[0053] Table 2

[0054]

[0055] Example 2

[0056] 5kg of the solid Namatevir to be treated (D90 is 5μm, X-ray powder diffraction data is shown in Table 3, wherein the relative intensity at 12.2° angle is 10.1%) is laid flat on a stainless steel tray with a size of 640mm*460mm, the tray is covered with a polyester cover cloth, and the tray is placed on the top layer of the YZG-1400 vacuum oven, and a stainless steel tray with a size of 640mm*460mm is placed on the bottom layer, and 2kg of water is added thereto without sealing. The oven temperature is set to 60°C, the vacuum degree is 0.085MPa, and vacuum drying is performed for 20 hours. After cooling to room temperature, the material is taken out and the crystal form is detected. The data is shown in Table 4, and the 12.2° angle disappears, which is a single Form 1 crystal form.

[0057] Table 3

[0058]

[0059]

[0060] Table 4

[0061]

[0062] Example 3

[0063] 5 kg of the to-be-treated solid namatevir 3 (D90 is 10 μm, X-ray powder diffraction data is shown in Table 5, where the 12.2° angle is the characteristic peak relative intensity of crystal form 4 of 100%) was laid flat on a stainless steel tray with a size of 640 mm * 460 mm, the tray was covered with a polyester cover cloth, and the tray was placed on the top layer of the FZG-10 vacuum oven, and a stainless steel tray with a size of 640 mm * 460 mm was placed on the bottom layer, and 0.2 kg of water was added thereto without sealing. The oven temperature was set to 40 ° C, the vacuum degree was 0.055 MPa, and vacuum drying was performed for 48 hours. After cooling to room temperature, the material was taken out and the crystal form was detected. The data is shown in Table 6, which is a single Form 1 crystal form.

[0064] Table 5

[0065]

[0066] Table 6

[0067]

[0068]

Claims

1. A method for treating Namatevir crystals, comprising contacting the Namatevir solid to be treated with water vapor to obtain Namatevir Form 1 crystals.

2. A method for treating Namatevir crystals, comprising placing the Namatevir solid to be treated and a certain amount of water separately in the same vacuum dryer, and the material and water are both exposed in the dryer, opening the vacuum and heating for a period of time to obtain Namatevir Form 1 crystals.

3. The method according to any one of claims 1 or 2, wherein the namatevir solid to be treated is a micronized product, preferably with D90 ≤ 60 μm, more preferably D90 ≤ 20 μm, and even more preferably D90 ≤ 12 μm.

4. The method according to any one of claims 1 or 2, wherein the namatevir solid to be treated is form 4, or a mixture of form 1 and form 4.

5. The method according to any one of claims 1 or 2, wherein the X-ray diffraction pattern of the namatevir solid to be treated contains a form 4 characteristic peak located at 12.2°±0.2°.

6. The method according to claim 1, when the Namatevir solid to be treated contacts with water vapor, the relative humidity in the system is above 35%, preferably above 50%, and further preferably above 75%.

7. The method according to claim 1, comprising contacting the solid Namatevir to be treated with water vapor under heating conditions.

8. The method according to claim 2 or 7, wherein the heating temperature is 35 to 80°C, preferably 40 to 60°C.

9. The method according to claim 8, wherein the heating time in said step is 0.5 hours or more, preferably 2 hours or more, and more preferably 2 to 48 hours.

10. The method according to claim 2, wherein the amount of water used is 0.01 to 1000 times, preferably 0.04 to 1 times, of the weight of the solid namatevir to be treated, and further, the vacuum degree is ≥ 0.03 MPa, preferably 0.055 MPa to 0.095 MPa.

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