CN116804038A - Monolavir crystal form VII and its preparation method - Google Patents
Monolavir crystal form VII and its preparation method Download PDFInfo
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Abstract
本发明公开了莫诺拉韦晶型Ⅶ及其制备方法，属于化合物晶型领域。所述莫诺拉韦晶型Ⅶ使用Cu‑Kα射线测量得到的X‑射线粉末衍射谱图如图1所示。所述莫诺拉韦晶型Ⅶ的制备为向莫诺拉韦中加入异丁醇，溶解后利用冷却结晶法或溶剂挥发法得到莫诺拉韦晶型Ⅶ晶体。制备工艺过程简单，且获得的晶型纯度高，经XRPD、X射线单晶衍射、DSC、TG的表征，确定为一种新的晶型，晶型Ⅶ。
The invention discloses monogravir crystal form VII and a preparation method thereof, and belongs to the field of compound crystal forms. The X-ray powder diffraction spectrum of the monogravir crystal form VII measured using Cu-Kα rays is shown in Figure 1. The monogravir crystal form VII is prepared by adding isobutanol to monogravir, and after dissolving, the monogravir crystal form VII crystal is obtained by using a cooling crystallization method or a solvent evaporation method. The preparation process is simple, and the purity of the obtained crystal form is high. After characterization by XRPD, X-ray single crystal diffraction, DSC, and TG, it was determined to be a new crystal form, Form VII.
Description
Technical Field
The invention belongs to the field of compound crystal forms, and particularly relates to a minora-vir crystal form VII and a preparation method thereof.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Mo Nuola the name of Ware (English: molnupiravir) is a ribonucleoside analogue developed by the company Mitsadone and Ridgeback in combination. Mo Nuola is born at the university of Emerri in the United states, and this drug was originally used in the treatment of equine encephalitis, and it was later found in the test that Mo Nuola is a broad spectrum anti-RNA virus drug that is capable of preventing replication of a variety of RNA viruses, including equine encephalitis virus, murine Hepatitis Virus (MHV), MERS, 2019-nCOV, and the like.
There are seven patents currently on the Mo Nuola crystal form of the weber, containing a total of six crystal forms, three of which are solvates. PCT/US2021/048054, patent No. US2021/048054, by the Protect company, mitsadone (MERCK), reports form I, form II and tetrahydrofuran solvates of Mo Nuola. Patent CN114149476a reports Mo Nuola of the crystals of the arms i, ii and iii. Patent CN113072606a reports Mo Nuola of the crystalline form i, form ii, ethanol solvate and isopropanol solvate of the wir. Mo Nuola Wei Shi the sold crystal form is the crystal form I, and the poor fluidity is unfavorable for the implementation and operation of the preparation process.
It is well known that different crystal forms of the same drug often have different physicochemical properties, such as: solubility, dissolution rate, flowability, permeability, stability, etc., which in turn affect the bioavailability and therapeutic effect of the drug. This phenomenon is particularly evident in the case of oral solid preparations, and therefore, the search and development of polymorphic forms of a drug has become critical. The report and quantity of the crystal form of Mo Nuola is still small, so that new solid forms of the morolavir still need to be developed to meet the requirements of the preparation, and therefore, good effects are achieved in the pharmaceutical and administration stages.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a Mo Nuola crystal form VII of the Weather and a preparation method thereof. Compared with Mo Nuola of the raw material of the weber, the Mo Nuola weber crystal form VII provided by the invention has better fluidity, and meets the requirements of preparation and production processes.
It is an object of the present invention to investigate, discover and provide the crystalline form vii of minora via a crystallographic approach.
The X-ray powder diffraction of the pure Mo Nuola Wer crystal form VII provided by the invention is shown in a figure 1, cu-K alpha radiation is used, and the X-ray powder diffraction is represented by angles of 2 theta 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, 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, 26.35+/-1, 27.35+/-1, 29+/-1, and 28.35+/-1.
The invention also adopts X-ray single crystal diffraction to research and characterize Mo Nuola Wer crystal form VII. The detection conditions are as follows: data were collected using Cu ka radiation at 25 ℃ at room temperature, reduced and corrected using APEX3 Software Suite, SHELXL to resolve and refine the structure.
The pure Mo Nuola crystal form VII of the invention has the X-ray single crystal diffraction shown in figure 2 and has the following characteristics: mo Nuola an asymmetric unit of the crystal form VII of the virus comprises a molecule of morolavir and an molecule of isobutanol, which belong to the orthorhombic system P2 1 2 1 2 1 Space group, unit cell parameters are α=β=γ=90°, unit cell volume is +.>The R factor is 0.0375.
The invention also adopts a thermogravimetric analysis method to research and characterize Mo Nuola the crystal form VII. The detection conditions are as follows: nitrogen purging, and heating rate is 10 ℃/min.
The thermogravimetric analysis curve of the pure Mo Nuola Wer crystal form VII provided by the invention is shown in figure 3, and the pure Mo Nuola Wer crystal form VII has the following characteristics: the sample lost weight at 18.42% when the temperature was raised to 64.7 ℃; when the temperature was raised to 240.4 ℃, the sample lost weight of 60.39%.
The invention also uses differential scanning calorimetry to study and characterize Mo Nuola Wer form VII. The detection conditions are as follows: nitrogen purging, and heating rate is 10 ℃/min.
The differential scanning calorimetric analysis curve of the pure Mo Nuola Wer crystal form VII provided by the invention is shown in figure 4, and the pure Mo Nuola Wer crystal form VII has the following characteristics: the first endothermic peak appears at 63.1℃and the second endothermic peak appears at 158.9 ℃.
It is noted that for the X-ray powder diffraction patterns of the crystalline forms described above, there may be slight variations in the characteristic peaks of the X-ray powder diffraction patterns between one machine and another and between one sample and another, the values of which may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by about 0.3 units, or by about 0.1 units, and thus the values given cannot be considered absolute. Also, the values given in the differential scanning calorimetry graphs of the above-described crystal forms cannot be considered absolute.
The Fourier infrared spectrum of the pure Mo Nuola Wer crystal form VII provided by the invention is shown in figure 5.
For the ground powder, the repose angle is a characteristic parameter related to the friction force between the powder or the relative motion resistance between the powder, and the smaller the repose angle is, the better the powder flowability is. In order to quantitatively evaluate the powder flowability of the pure Mo Nuola Wer crystal form VII provided by the invention, the invention determines the repose angle values of Mo Nuola Wer crystal form VII and crystal form I so as to compare the particle flow characteristics of different powders.
The powder flowability detection result of the pure Mo Nuola weber crystal form VII provided by the invention is shown in table 1, and the repose angle of the Mo Nuola weber crystal form VII provided by the invention is smaller than 43 degrees and is far smaller than 48.90 degrees corresponding to the crystal form I. According to the research, the repose angle can meet the requirement of the production process on the powder flowability in the range of 41-45 degrees. When the repose angle exceeds 45 degrees, the powder has poor fluidity, and operations such as stirring and vibration must be performed in the production and preparation process, so that the preparation and production process requirements are difficult to meet. Therefore, compared with the crystal form I, the Mo Nuola Wer crystal form VII provided by the invention obviously improves the powder fluidity, and is more beneficial to subsequent industrial production and processing technology treatment.
The invention also provides a preparation method of the Mo Nuola-Weather crystal form VII, which has high purity and does not contain residual solvent.
The preparation method of the Mo Nuola-Weir crystal form VII provided by the invention comprises the steps of adding isobutanol into Mo Nuola-Weir, dissolving, and obtaining Mo Nuola-Weir crystal form VII crystals by a cooling crystallization method or a solvent volatilization method.
The dosage of the Mo Nuola-type crystal form VII of the pyrrosia is not limited, and Mo Nuola-type crystal form VII of the pyrrosia can be obtained by a cooling crystallization method or a solvent volatilization method. For example, the mass volume ratio of Mo Nuola to isobutanol is 50-100mg:3-5mL, the mass-volume ratio of the two can be the ratio outside the range.
Preferably, the preparation of Mo Nuola of the crystal form VII of the Weather by adopting a cooling crystallization method comprises the following steps:
and adding isobutanol into Mo Nuola, heating and stirring until the solution is clear, and slowly cooling to obtain Mo Nuola crystal form VII crystals of the vir.
Preferably, the heating device for heating is an oil bath.
Preferably, the temperature rising interval of the temperature rising is 60-80 ℃. Further preferably, the temperature is raised to 70 ℃.
Preferably, the preparation of Mo Nuola of the weber form vii by solvent evaporation comprises the steps of:
and adding isobutanol into Mo Nuola, heating and stirring until the solution is clear, adding seed crystals, and slowly volatilizing the solvent to obtain Mo Nuola crystal form VII crystals.
Preferably, the seed crystal is selected from Mo Nuola crystal form VII prepared by a cooling crystallization method. Further preferably, the fully transparent Mo Nuola Wer form VII is selected as seed.
The preparation method of Mo Nuola Wer crystal form VII of the invention has high purity of the crystal form, consistent X-ray powder diffraction spectrum characteristics and DSC characteristic patterns,
the beneficial effects of the invention are as follows:
according to the technical scheme, the invention discloses Mo Nuola and Mo Nuola crystal forms VII and preparation methods thereof. The X-ray powder diffraction pattern of the crystal form obtained by Cu-K alpha ray measurement is shown in figure 1. The Mo Nuola-Weir crystal form VII is prepared by adding isobutanol into Mo Nuola-Weir, dissolving, and obtaining Mo Nuola-Weir crystal form VII crystals by a cooling crystallization method or a solvent volatilization method. The preparation process is simple, the purity of the obtained crystal form is high, and the crystal form is determined to be a new crystal form, namely a crystal form VII through the characterization of XRPD, X-ray single crystal diffraction, DSC and TG. Powder flowability test shows that the Mo Nuola-Weir crystal form VII provided by the invention has better flowability compared with the crystal form I, and can meet the requirements of preparation and production process.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is an XRPD pattern for form VII;
FIG. 2 is an X-ray single crystal diffraction structure of form VII;
FIG. 3 is a thermogravimetric analysis (TG) plot of form VII;
FIG. 4 is a Differential Scanning Calorimetric (DSC) plot of form VII;
FIG. 5 is a Fourier infrared (FT-IR) diagram of form VII.
Detailed Description
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments. The following examples are given by way of illustration and explanation of the present invention and should not be construed as limiting the scope of the invention in any way, as long as the techniques implemented based on the foregoing are within the scope of the invention. Unless otherwise indicated, the materials and methods of operation used in the present invention are well known in the art. The starting materials and solvents used in the present invention are commercially available or may be prepared by known methods.
The detection instrument used in the invention comprises:
1. x-ray powder diffractometer
Model: smartLab X-ray powder diffractometer manufactured by Japanese Physics company
Test conditions: the room temperature is 25 ℃, the output power of the copper target is 9kW, the scanning range is 5-40 degrees, and the scanning speed is 20 degrees/min.
2. X-ray single crystal diffractometer
Model: smart-APEX II single crystal diffractometer manufactured by Bruce Corp
Test conditions: data were collected using Cu ka radiation at 25 ℃ at room temperature, reduced and corrected using APEX3 Software Suite, SHELXL to resolve and refine the structure.
3. DSC thermogram
Model: DSC 214Polyma thermal analyzer manufactured by German Chi-resistant company
Test conditions: nitrogen purging, and heating rate is 10 ℃/min.
4. TG thermal analysis
Model: TG 2099F3 Tarsus thermogravimetric analyzer produced by German resistant company
Test conditions: nitrogen purging, and heating rate is 10 ℃/min.
5. FT-IR analysis
Model: nicolet Nexus670 Fourier infrared spectrometer manufactured by Nikriging company of America
Test conditions: room temperature 25 deg.c and wave number 600-4000cm -1 Resolution of 0.09cm -1 。
Example 1
Preparation and identification of Mo Nuola Wer crystal form VII
100.00mg of a sample of minora-vir was accurately weighed at room temperature and placed in a clean, clear vial (10 mL in volume) and 4mL of isobutanol was added. Placing the cleaned magnet into a small bottle containing the solution, heating in an oil bath at 70deg.C, and stirring at 500rpm until the solution is completely clear. And then placing the glass bottle in a fume hood, naturally cooling for a period of time, and cooling and crystallizing to obtain Mo Nuola-Wer crystal form VII, wherein the purity is 100%, and the yield is 64.2%. The obtained Mo Nuola Wer form VII was subjected to XRPD, X-ray single crystal diffraction, TG, DSC and FT-IR tests.
As shown in FIG. 1, XRPD results demonstrate that peaks at diffraction angles (2-theta 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 are characteristic.
As shown in FIG. 2, the X-ray single crystal diffraction result shows that one asymmetric unit of Mo Nuola Wer crystal form VII comprises one molecular of Munolamine and one molecular of isobutanol, which belongs to orthorhombic system P2 1 2 1 2 1 Space group, unit cell parameters areα=β=γ=90°, unit cell volume isThe R factor is 0.0375.
As shown in fig. 3, TG results indicate that the weight loss was 18.42% when the temperature was raised to 64.7 ℃; when the temperature was raised to 240.4 ℃, the weight loss was 60.39%.
As shown in FIG. 4, the DSC curve shows a first endotherm at 63.1℃and a second endotherm at 158.9 ℃. The second one is a sharp endothermic peak.
As shown in fig. 5, mo Nuola wei form vii has unique FT-IR peak position characteristics at different wavelength positions.
Powder flowability test:
for the ground powder, the repose angle is a characteristic parameter related to the friction force between the powder or the relative motion resistance between the powder, and the smaller the repose angle is, the better the powder flowability is.
After grinding the crystal sample (Mo Nuola Wer form VII prepared in example 1) into a powder, it was previously passed through a sieve having a pore size of 0.45 mm. Then, the powder fluidity is measured by a fixed funnel method, and a powder cone is formed after the sample passes through the funnel. The angle of repose α can be calculated by measuring the height of the powder cone.
The calculation formula is as follows: tan (α) =cone height/chassis radius.
The pure Mo Nuola crystal form VII of the invention has better fluidity and can meet the requirements of preparation and production process. The test results are shown in Table 1.
TABLE 1 measurement results of repose angle
| Component/number of measurements | 1 | 2 | 3 | Average value of |
| Mo Nuola Wer Crystal form I | 48.24° | 49.96° | 48.49° | 48.90° |
| Mo Nuola A-V crystal form VII | 41.35° | 42.92° | 42.92° | 42.40° |
Test results show that the repose angle of the Mo Nuola Wer crystal form VII provided by the invention is smaller than 43 degrees and is far smaller than 48.90 degrees corresponding to the crystal form I. According to the research, the repose angle can meet the requirement of the production process on the powder flowability in the range of 41-45 degrees. When the repose angle exceeds 45 degrees, the powder has poor fluidity, and operations such as stirring and vibration must be performed in the production and preparation process, so that the preparation and production process requirements are difficult to meet. Therefore, compared with the crystal form I, the Mo Nuola Wer crystal form VII provided by the invention obviously improves the powder fluidity, and is more beneficial to subsequent industrial production and processing technology treatment.
Example 2
Preparation and identification of Mo Nuola Wer crystal form VII
100.00mg of a sample of minora-vir was accurately weighed at room temperature and placed in a clean, clear vial (volume 10 mL) and 5mL of isobutanol was added. Placing the cleaned magnet into a small bottle containing the solution, heating in an oil bath at 60 ℃, and stirring at 500rpm until the solution is completely clear. And then placing the glass bottle in a fume hood, naturally cooling for a period of time, and cooling and crystallizing to obtain the Mo Nuola-Wer crystal form VII.
The obtained Mo Nuola-Weather crystal form VII crystals were subjected to XRPD testing, and the results are consistent with FIG. 1 and are determined to be Mo Nuola-Weather crystal form VII.
Example 3
Preparation and identification of Mo Nuola Wer crystal form VII
100.00mg of a sample of minora-vir was accurately weighed at room temperature and placed in a clean, clear vial (10 mL in volume) and 4mL of isobutanol was added. Placing the cleaned magnet into a small bottle containing the solution, heating in an oil bath at 80 ℃, and stirring at 500rpm until the solution is completely clear. And then placing the glass bottle in a fume hood, naturally cooling for a period of time, and cooling and crystallizing to obtain the Mo Nuola-Wer crystal form VII.
The obtained Mo Nuola-Weather crystal form VII crystals were subjected to XRPD testing, and the results are consistent with FIG. 1 and are determined to be Mo Nuola-Weather crystal form VII.
Example 4
Preparation and identification of Mo Nuola Wer crystal form VII
At room temperature, a 50.00mg sample of minora-vir was accurately weighed into a clean, clear vial (10 mL in volume) and 3mL of isobutanol was added. Placing the cleaned magnet into a small bottle containing the solution, heating in an oil bath at 70deg.C, and stirring at 500rpm until the solution is completely clear. And then placing the glass bottle in a fume hood, naturally cooling for a period of time, and cooling and crystallizing to obtain the Mo Nuola-Wer crystal form VII.
The obtained Mo Nuola-Weather crystal form VII crystals were subjected to XRPD testing, and the results are consistent with FIG. 1 and are determined to be Mo Nuola-Weather crystal form VII.
Example 5
Preparation and identification of Mo Nuola Wer crystal form VII
100.00mg of a sample of minora-vir was accurately weighed at room temperature and placed in a clean, clear vial (volume 10 mL) and 5mL of isobutanol was added. Placing the cleaned magnet into a small bottle containing the solution, heating in an oil bath at 70deg.C, and stirring at 500rpm until the solution is completely clear. And then placing the glass bottle in a fume hood, naturally cooling for a period of time, and cooling and crystallizing to obtain the Mo Nuola-Wer crystal form VII.
The obtained Mo Nuola-Weather crystal form VII crystals were subjected to XRPD testing, and the results are consistent with FIG. 1 and are determined to be Mo Nuola-Weather crystal form VII.
Example 6
Preparation of Mo Nuola Wer Crystal form VII
At room temperature, a 50.00mg sample of minora-vir was accurately weighed into a clean, clear vial (10 mL in volume) and 4mL of isobutanol was added. The vial with the solution was placed in a cleaned magnet, stirred at 500rpm for 30 minutes and filtered to give a clear solution. The seed crystal was then placed in a vial and placed in a fume hood, after 2 days of volatilization, mo Nuola Wer form VII was obtained in a purity of 100% and a yield of 60.4%. The seed crystal was selected from the Mo Nuola Wer crystal form VII crystals prepared in example 1, and the complete transparent crystal was selected as the seed crystal.
The obtained Mo Nuola-Weather crystal form VII crystals were subjected to XRPD testing, and the results are consistent with FIG. 1 and are determined to be Mo Nuola-Weather crystal form VII.
Example 7
Preparation of Mo Nuola Wer Crystal form VII
100.00mg of a sample of minora-vir was accurately weighed at room temperature and placed in a clean, clear vial (10 mL in volume) and 4mL of isobutanol was added. The vial with the solution was placed in a cleaned magnet, stirred at 500rpm for 30 minutes and filtered to give a clear solution. Then the seed crystal is put into a small bottle and placed in a fume hood, and after 2 days of volatilization, mo Nuola of the crystal form VII of the Weather is obtained, the purity is 100%, and the yield is 54.8%. The seed crystal was selected from the Mo Nuola Wer crystal form VII crystals prepared in example 1, and the complete transparent crystal was selected as the seed crystal.
The obtained Mo Nuola-Weather crystal form VII crystals were subjected to XRPD testing, and the results are consistent with FIG. 1 and are determined to be Mo Nuola-Weather crystal form VII.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778387A (en) * | 2021-01-15 | 2021-05-11 | 杭州科巢生物科技有限公司 | Molnupiravir crystal form A and preparation method thereof |
| CN114507266A (en) * | 2022-01-24 | 2022-05-17 | 海门品尚医药科技有限公司 | A kind of Molnupiravir crystal form and preparation method thereof |
| US20220185840A1 (en) * | 2020-12-10 | 2022-06-16 | Optimus Drugs (P) Ltd | Pharmaceutical polymorphs of molnupiravir |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20220185840A1 (en) * | 2020-12-10 | 2022-06-16 | Optimus Drugs (P) Ltd | Pharmaceutical polymorphs of molnupiravir |
| CN112778387A (en) * | 2021-01-15 | 2021-05-11 | 杭州科巢生物科技有限公司 | Molnupiravir crystal form A and preparation method thereof |
| CN114507266A (en) * | 2022-01-24 | 2022-05-17 | 海门品尚医药科技有限公司 | A kind of Molnupiravir crystal form and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| PEIZHUO HAN 等: "Polymorphs and Solvates of Molnupiravir: Crystal Structures and Solid Forms Transformation Analysis", CRYST. GROWTH DES., vol. 24, 28 May 2024 (2024-05-28), pages 4758 * |
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