Monolavir crystal form VII and preparation method thereof

Abstract

The present invention discloses Monovir Form VII and a preparation method thereof, and belongs to the field of compound crystal forms. The X-ray powder diffraction spectrum of Monovir Form VII measured using Cu-Kα rays is shown in Figure 1. The Monovir Form VII is prepared by adding isobutanol to Monovir, dissolving it, and then using a cooling crystallization method or a solvent evaporation method to obtain Monovir Form VII crystals. The preparation process is simple, and the obtained crystal form has high purity. It is determined to be a new crystal form, Form VII, through the characterization of XRPD, X-ray single crystal diffraction, DSC, and TG.

Description

Technical Field

[0001] The present invention belongs to the field of compound crystal forms, and specifically relates to a monolavin crystal form VII and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Molnupiravir is a ribonucleoside analog jointly developed by Merck and Ridgeback. Molnupiravir was developed at Emory University in the United States. Initially used to treat equine encephalitis, it was later discovered in testing to be a broad-spectrum anti-RNA virus drug capable of preventing the replication of a variety of RNA viruses, including equine encephalitis virus, murine hepatitis virus (MHV), MERS, and 2019-nCoV.

[0004] There are currently seven patents related to the crystal forms of Monovir, covering a total of six crystal forms, including three solvates. The patent PCT / US2021 / 048054 of the original drug company Merck (MERCK) reports on the crystal form I, crystal form II and tetrahydrofuran solvate of Monovir. Patent CN114149476A reports on the crystal form I, crystal form II and crystal form III of Monovir. Patent CN113072606A reports on the crystal form I, crystal form II, ethanol solvate and isopropanol solvate of Monovir. The commercially available crystal form of Monovir is crystal form I, which is not conducive to the implementation and operation of the formulation process due to its poor fluidity.

[0005] It is well known that different crystalline forms of the same drug often have different physicochemical properties, such as solubility, dissolution rate, flowability, permeability, and stability. These physicochemical properties, in turn, affect the drug's bioavailability and therapeutic efficacy. This phenomenon is particularly evident in oral solid dosage forms, so the exploration and development of drug polymorphs is crucial. Currently, there are still few reports and numbers of crystalline forms of monoclad vir. Therefore, it is still necessary to develop new solid forms of monoclad vir to meet the needs of formulations and achieve good results in the pharmaceutical and drug administration stages. Summary of the Invention

[0006] In order to address the deficiencies of the prior art, the present invention aims to provide Monolavir Form VII and a preparation method thereof. The Monolavir Form VII provided by the present invention has better fluidity than the Monolavir raw material and meets the requirements of the formulation and production process.

[0007] One object of the present invention is to study, discover and provide a crystalline form of Monolavin, Form VII, by a crystallographic method.

[0008] The pure Monolavir crystal form VII provided by the present invention has an X-ray powder diffraction pattern as shown in FIG. Figure 1 As shown, the X-ray powder diffraction patterns using Cu-Kα radiation were expressed in 2θ angles at 8.66±1, 9.12±1, 10.69±1, 12.66±1, 13.07±1, 13.38±1, 15.36±1, 16.08±1, 16.31±1, 16.67±1, 17.37±1, 18.20±1, 18.29±1, 18.85±1, 19.17±1, 19.35±1, 20.09±1, and 2 The peaks are 0.74±1, 21.22±1, 21.48±1, 21.66±1, 22.96±1, 23.23±1, 23.76±1, 24.64±1, 24.97±1, 25.26±1, 25.74±1, 26.18±1, 26.33±1, 26.56±1, 26.95±1, 27.19±1, 27.60±1, 28.95±1, 29.20±1, and 29.34±1.

[0009] The present invention also uses X-ray single crystal diffraction to study and characterize Monolavin Form VII. The detection conditions are: room temperature 25°C using Cu Kα radiation to collect data, APEX3 Software Suite to restore and correct the data, and SHELXL to analyze and refine the structure.

[0010] The pure Monolavir crystal form VII provided by the present invention has an X-ray single crystal diffraction pattern as shown in FIG. Figure 2 As shown, it has the following characteristics: an asymmetric unit of Monolavir crystal form VII contains a Monolavir molecule and an isobutanol molecule, which belongs to the orthorhombic crystal system P 212121 space group, and the unit cell parameters are α=β=γ=90°, the unit cell volume is The R factor is 0.0375.

[0011] The present invention also uses thermogravimetric analysis to study and characterize Monolavir Form VII. The detection conditions are: nitrogen purge, heating rate of 10°C / min.

[0012] The pure Monolavir crystal form VII provided by the present invention has a thermogravimetric analysis curve as shown in FIG. Figure 3 As shown, it has the following characteristics: when the temperature rises to 64.7°C, the sample loses 18.42% of its weight; when the temperature rises to 240.4°C, the sample loses 60.39% of its weight.

[0013] The present invention also uses differential scanning calorimetry to study and characterize Monolavir Form VII. The detection conditions are: nitrogen purge, heating rate of 10°C / min.

[0014] The pure Monolavir crystal form VII provided by the present invention has a differential scanning calorimetry analysis curve as shown in FIG. Figure 4 As shown, it has the following characteristics: the first endothermic peak appears at 63.1°C and the second endothermic peak appears at 158.9°C.

[0015] It is worth noting that for the X-ray powder diffraction pattern of the above-mentioned crystalline form, the characteristic peaks of the X-ray powder diffraction pattern may vary slightly between one machine and another, and between one sample and another. The values ​​may differ by about 1 unit, or about 0.8 units, or about 0.5 units, or about 0.3 units, or about 0.1 units. Therefore, the values ​​given cannot be regarded as absolute. Similarly, the values ​​given in the differential scanning calorimetry analysis curve of the above-mentioned crystalline form cannot be regarded as absolute.

[0016] The pure Monolavir crystal form VII provided by the present invention has a Fourier transform infrared spectrum as shown in FIG. Figure 5 shown.

[0017] For ground powders, the angle of repose is a characteristic parameter related to the friction between powders or the resistance to relative motion between powders. The smaller the angle of repose, the better the powder flowability. In order to quantitatively evaluate the powder flowability of the pure monolavin crystalline form VII provided by the present invention, the present invention measured the angle of repose values ​​of monolavin crystalline form VII and crystalline form I to compare the particle flow characteristics of different powders.

[0018] The powder fluidity test results of the pure Monovir Form VII provided by the present invention are shown in Table 1. The angle of repose of the Monovir Form VII provided by the present invention is less than 43°, which is much smaller than the 48.90° angle of repose corresponding to Form I. According to research, the angle of repose in the range of 41° to 45° can meet the requirements of the production process for powder fluidity. When the angle of repose exceeds 45°, the powder fluidity is very poor, and operations such as stirring and vibration must be performed during the production and preparation process, which makes it difficult to meet the requirements of the formulation and production process. Therefore, compared with Form I, the Monovir Form VII provided by the present invention significantly improves the powder fluidity, which is more conducive to subsequent industrial production and processing technology.

[0019] The present invention also provides a method for preparing the monolavir crystal form VII with high purity and without residual solvent.

[0020] The preparation method of the Monolavir Form VII provided by the present invention is to add isobutanol to Monolavir, dissolve it, and then obtain Monolavir Form VII crystals by cooling crystallization or solvent evaporation.

[0021] The present invention does not impose any restrictions on the amount of monolavin and isobutanol used. Monolavin Form VII crystals can be obtained by cooling crystallization or solvent evaporation. For example, the mass volume ratio of monolavin to isobutanol is 50-100 mg:3-5 mL. The mass volume ratio of the two can also be a ratio outside this range.

[0022] Preferably, the cooling crystallization method for preparing Monolavir Form VII comprises the following steps:

[0023] Isobutanol is added to Monolavir, the temperature is raised and stirred until the solution is clear, and then the temperature is slowly lowered to obtain Monolavir Form VII crystals.

[0024] Preferably, the heating device used for heating is an oil bath.

[0025] Preferably, the temperature is increased in a range of 60-80° C. More preferably, the temperature is increased to 70° C.

[0026] Preferably, the preparation of Monolavir Form VII by the solvent evaporation method comprises the following steps:

[0027] Isobutanol is added to Monolavir, the temperature is raised and stirred until the solution is clear, seed crystals are added, and the solvent is slowly evaporated to obtain Monolavir Form VII crystals.

[0028] Preferably, the seed crystals are selected from Monolavir Form VII obtained by cooling crystallization. Further preferably, complete and transparent Monolavir Form VII is selected as the seed crystals.

[0029] The preparation method of Monolavir Form VII of the present invention obtains a high-purity crystal form, and the X-ray powder diffraction spectrum characteristics and DSC characteristic patterns are consistent.

[0030] The beneficial effects of the present invention are:

[0031] From the above technical solution, it can be seen that the present invention discloses Monovir crystal form VII and a method for preparing Monovir crystal form VII. The X-ray powder diffraction spectrum of the crystal form of the present invention measured using Cu-Kα ray is as follows: Figure 1 As shown. The preparation of the Monovir crystal form VII is to add isobutanol to Monovir, dissolve it, and then use cooling crystallization or solvent evaporation to obtain Monovir crystal form VII crystals. The preparation process is simple, and the obtained crystal form has high purity. It is characterized by XRPD, X-ray single crystal diffraction, DSC, and TG, and is determined to be a new crystal form, crystal form VII. The powder flowability test found that the Monovir crystal form VII provided by the present invention has better flowability than the crystal form I, and can meet the requirements of the preparation and production process. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The accompanying drawings, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0033] Figure 1 is the XRPD pattern of Form VII;

[0034] Figure 2 This is the X-ray single crystal diffraction structure of Form VII;

[0035] Figure 3 is the thermogravimetric analysis (TG) diagram of Form VII;

[0036] Figure 4 is a differential scanning calorimetry (DSC) diagram of Form VII;

[0037] Figure 5 This is the Fourier transform infrared spectrum (FT-IR) of Form VII. DETAILED DESCRIPTION

[0038] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific examples. The following examples are merely illustrative and explain the present invention and should not be construed as limiting the scope of the invention. All techniques implemented based on the foregoing description of the present invention fall within the scope of the present invention. Unless otherwise indicated, the materials used in the present invention and the operating methods are well known in the art. The raw materials and solvents used in the present invention are all commercially available products or are prepared by known methods.

[0039] The detection instrument used in the present invention is:

[0040] 1. X-ray powder diffractometer

[0041] Model: SmartLab X-ray powder diffractometer produced by Japan Rigaku Corporation

[0042] Test conditions: room temperature 25°C, copper target, output power 9 kW, scanning range 5-40°, scanning speed 20° / min.

[0043] 2. X-ray single crystal diffractometer

[0044] Model: Smart-APEX II single crystal diffractometer produced by Bruker, Germany

[0045] Data were collected at room temperature (25°C) using Cu Kα radiation. APEX3 Software Suite was used for data reduction and correction, and SHELXL was used for structure analysis and refinement.

[0046] 3.DSC thermal analysis

[0047] Model: DSC 214Polyma thermal analyzer produced by NETZSCH, Germany

[0048] Test conditions: nitrogen purge, heating rate of 10°C / min.

[0049] 4. TG thermal analysis

[0050] Model: TG 209F3 Tarsus thermogravimetric analyzer produced by NETZSCH, Germany

[0051] Test conditions: nitrogen purge, heating rate of 10°C / min.

[0052] 5. FT-IR analysis

[0053] Model: Nicolet Nexus670 Fourier transform infrared spectrometer produced by Nicolet Corporation of the United States

[0054] Test conditions: room temperature 25°C, wave number 600-4000cm -1 , resolution 0.09cm -1 .

[0055] Example 1

[0056] Preparation and identification of Monolavir Form VII

[0057] At room temperature, accurately weigh 100.00 mg of Monovir sample and place it in a clean, transparent vial (volume 10 mL), and add 4 mL of isobutanol. Place a clean magnet in the vial containing the solution, heat it in an oil bath at 70°C, and stir at 500 rpm until the solution is completely clear. The glass bottle is then placed in a fume hood. After a period of natural cooling, cooling and crystallization can obtain Monovir Form VII with a purity of 100% and a yield of 64.2%. The obtained Monovir Form VII was tested by XRPD, X-ray single crystal diffraction, TG, DSC, and FT-IR.

[0058] like Figure 1As shown, the XRPD results showed that the diffraction angles (2θ angle) were 8.66±1, 9.12±1, 10.69±1, 12.66±1, 13.07±1, 13.38±1, 15.36±1, 16.08±1, 16.31±1, 16.67±1, 17.37±1, 18.20±1, 18.29±1, 18.85±1, 19.17±1, 19.35±1, 20.09±1, 20.74 There are characteristic peaks at 21.57±1, 24.71±1, 25.57±1, 26.18±1, 26.33±1, 26.56±1, 26.95±1, 27.19±1, 27.60±1, 28.95±1, 29.20±1, and 29.34±1.

[0059] like Figure 2 As shown, the X-ray single crystal diffraction results show that an asymmetric unit of Monolavir crystal form VII contains a Monolavir molecule and an isobutanol molecule, which belongs to the orthorhombic system P 212121 space group, and the unit cell parameters are α=β=γ=90°, the unit cell volume is The R factor is 0.0375.

[0060] like Figure 3 As shown, the TG results show that when the temperature rises to 64.7℃, the weight loss is 18.42%; when the temperature rises to 240.4℃, the weight loss is 60.39%.

[0061] like Figure 4 As shown in the DSC curve, the first endothermic peak appears at 63.1° C. and the second endothermic peak appears at 158.9° C. The second endothermic peak is a sharp endothermic peak.

[0062] like Figure 5 As shown, Monolavir Form VII has unique FT-IR peak characteristics at different wavelength positions.

[0063] Powder flowability test:

[0064] For ground powders, the angle of repose is a characteristic parameter related to the friction between powders or the resistance to relative motion between powders. The smaller the angle of repose, the better the powder fluidity.

[0065] After grinding the crystalline sample (Monolavir Form VII prepared in Example 1) into a powder, it was pre-sieved through a 0.45 mm pore size sieve. The powder flowability was then measured using the fixed funnel method. After the sample passes through the funnel, a powder cone is formed. The angle of repose α can be calculated by measuring the height of the powder cone.

[0066] The calculation formula is as follows: tan(α) = cone height / chassis radius.

[0067] The pure Monolavir crystal form VII provided by the present invention has good fluidity and can meet the requirements of formulation and production process. The test results are shown in Table 1.

[0068] Table 1 Repose angle measurement results

[0069] Components / Number of measurements 1 2 3 average value Monolavir crystal form I 48.24° 49.96° 48.49° 48.90° Monolavir Form VII 41.35° 42.92° 42.92° 42.40°

[0070] The test results show that the angle of repose of the Monovir Form VII provided by the present invention is less than 43°, which is much smaller than the 48.90° angle of repose corresponding to Form I. According to research, the angle of repose in the range of 41° to 45° can meet the requirements of the production process for powder fluidity. When the angle of repose exceeds 45°, the powder fluidity is very poor, and operations such as stirring and vibration must be performed during the production and preparation process, which makes it difficult to meet the requirements of the formulation and production process. Therefore, compared with Form I, the Monovir Form VII provided by the present invention significantly improves the powder fluidity, which is more conducive to subsequent industrial production and processing technology.

[0071] Example 2

[0072] Preparation and identification of Monolavir Form VII

[0073] At room temperature, accurately weigh 100.00 mg of monolavir sample into a clean, transparent vial (volume 10 mL) and add 5 mL of isobutanol. Place a clean magnet in the vial containing the solution, heat it in a 60°C oil bath, and stir at 500 rpm until the solution is completely clear. Then, place the glass bottle in a fume hood and allow it to cool naturally for a period of time. Cool and crystallize to obtain monolavir Form VII.

[0074] The obtained Monolavin Form VII crystals were subjected to XRPD testing, and the results were consistent with those of Figure 1 The results were consistent and confirmed to be Monolavir crystal form VII.

[0075] Example 3

[0076] Preparation and identification of Monolavir Form VII

[0077] At room temperature, accurately weigh 100.00 mg of monolavir sample into a clean, transparent vial (volume 10 mL) and add 4 mL of isobutanol. Place a clean magnetic rod in the vial containing the solution, heat it in an 80°C oil bath, and stir at 500 rpm until the solution is completely clear. Then, place the glass bottle in a fume hood and allow it to cool naturally for a period of time. Cool and crystallize to obtain monolavir Form VII.

[0078] The obtained Monolavin Form VII crystals were subjected to XRPD testing, and the results were consistent with those of Figure 1 The results were consistent and confirmed to be Monolavir crystal form VII.

[0079] Example 4

[0080] Preparation and identification of Monolavir Form VII

[0081] At room temperature, accurately weigh 50.00 mg of monolavir sample into a clean, transparent vial (10 mL volume) and add 3 mL of isobutanol. Place a clean magnetic rod in the vial containing the solution, heat it in a 70°C oil bath, and stir at 500 rpm until the solution is completely clear. Then, place the glass bottle in a fume hood and allow it to cool naturally for a period of time. Cool and crystallize to obtain monolavir Form VII.

[0082] The obtained Monolavin Form VII crystals were subjected to XRPD testing, and the results were consistent with those of Figure 1 The results were consistent and confirmed to be Monolavir crystal form VII.

[0083] Example 5

[0084] Preparation and identification of Monolavir Form VII

[0085] At room temperature, accurately weigh 100.00 mg of monolavir sample into a clean, transparent vial (volume 10 mL) and add 5 mL of isobutanol. Place a clean magnetic rod in the vial containing the solution, heat it in a 70°C oil bath, and stir at 500 rpm until the solution is completely clear. Then, place the glass bottle in a fume hood and allow it to cool naturally for a period of time. Cool and crystallize to obtain monolavir Form VII.

[0086] The obtained Monolavin Form VII crystals were subjected to XRPD testing, and the results were consistent with those of Figure 1 The results were consistent and confirmed to be Monolavir crystal form VII.

[0087] Example 6

[0088] Preparation of Monolavir Form VII

[0089] At room temperature, accurately weigh 50.00 mg of Monolavir sample and place it in a clean, transparent vial (volume 10 mL), and add 4 mL of isobutanol. A clean magnetic particle is placed in the vial containing the solution, stirred at 500 rpm for 30 minutes, and filtered to obtain a clear solution. The seed crystals are then placed in the vial and placed in a fume hood. After 2 days of volatilization, Monolavir Form VII is obtained with a purity of 100% and a yield of 60.4%. The seed crystals are selected from the Monolavir Form VII crystals obtained in Example 1, and complete, transparent crystals are selected as seed crystals.

[0090] The obtained Monolavin Form VII crystals were subjected to XRPD testing, and the results were consistent with those of Figure 1 The results were consistent and confirmed to be Monolavir crystal form VII.

[0091] Example 7

[0092] Preparation of Monolavir Form VII

[0093] At room temperature, accurately weigh 100.00 mg of Monolavir sample and place it in a clean, transparent vial (volume 10 mL), and add 4 mL of isobutanol. A clean magnetic particle is placed in the vial containing the solution, stirred at 500 rpm for 30 minutes, and filtered to obtain a clear solution. The seed crystals are then placed in the vial and placed in a fume hood. After 2 days of volatilization, Monolavir Form VII is obtained with a purity of 100% and a yield of 54.8%. The seed crystals are selected from the Monolavir Form VII crystals obtained in Example 1, and complete, transparent crystals are selected as seed crystals.

[0094] The obtained Monolavin Form VII crystals were subjected to XRPD testing, and the results were consistent with those of Figure 1 The results were consistent and confirmed to be Monolavir crystal form VII.

[0095] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A method for preparing Monolavir crystal form VII, characterized in that: The monolavin crystal form VII uses Cu-Kα radiation and expresses X-ray powder diffraction at 2θ angles of 8.66±1, 9.12±1, 10.69±1, 12.66±1, 13.07±1, 13.38±1, 15.36±1, 16.08±1, 16.31±1, 16.67±1, 17.37±1, 18.20±1, 18.29±1, 18.85±1, 19.17±1, 19.35±1, 20.09± 1, 20.74±1, 21.22±1, 21.48±1, 21.66±1, 22.96±1, 23.23±1, 23.76±1, 24.64±1, 24.97±1, 25.26±1, 25.74±1, 26.18±1, 26.33±1, 26.56±1, 26.95±1, 27.19±1, 27.60±1, 28.95±1, 29.20±1, 29.34±1 with characteristic peaks; The thermogravimetric analysis curve of the Monolavin Form VII shows that when heated to 64.7°C, the weight loss is 18.42%; when heated to 240.4°C, the weight loss is 60.39%; The unit cell parameters of Monolavin Form VII are a=9.0428 (7) Å, 11.0073 (9) Å, 20.3884 (17) Å, α=β=γ=90°, and the unit cell volume is 2029.4 (3) Å. 3 , R factor is 0.0375; The preparation method of the Monolavir Form VII is as follows: adding isobutanol to Monolavir, dissolving the monolavir, and then using a cooling crystallization method or a solvent evaporation method to obtain Monolavir Form VII crystals.

2. The method for preparing Monolavir crystal form VII according to claim 1, wherein: The differential scanning calorimetry analysis curve of the Monolavir crystal form VII shows a first endothermic peak at 63.1°C and a second endothermic peak at 158.9°C.

3. The method for preparing Monolavir crystal form VII according to claim 1, wherein: The cooling crystallization method for preparing Monolavir Form VII comprises the following steps: Isobutanol is added to Monolavir, the temperature is raised and stirred until the solution is clear, and then the temperature is slowly lowered to obtain Monolavir Form VII crystals.

4. The method for preparing Monolavir crystal form VII according to claim 3, wherein: The mass volume ratio of monovaccin to isobutanol is 50-100 mg: 3-5 mL.

5. The method for preparing Monolavir crystal form VII according to claim 3, wherein: The heating device used for heating is an oil bath.

6. The method for preparing Monolavir crystal form VII according to claim 3, wherein: The heating range is 60-80°C.

7. The method for preparing Monolavir crystal form VII according to claim 3, wherein: The temperature is raised to 70°C.

8. The method for preparing Monolavir crystal form VII according to claim 1, wherein: The preparation of Monolavir Form VII by the solvent evaporation method comprises the following steps: Isobutanol is added to Monolavir, the temperature is raised and stirred until the solution is clear, seed crystals are added, and the solvent is slowly evaporated to obtain Monolavir Form VII crystals.

9. The method for preparing Monolavir crystal form VII according to claim 8, wherein: The seed crystals are selected from Monolavir crystal form VII prepared by cooling crystallization method.

10. The method for preparing Monolavir crystal form VII according to claim 9, wherein: Select complete and transparent Monolavir Form VII as the seed crystal.

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