CN114507266A - Molnupiravir crystal form and preparation method thereof - Google Patents
Molnupiravir crystal form and preparation method thereof Download PDFInfo
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- CN114507266A CN114507266A CN202210078070.3A CN202210078070A CN114507266A CN 114507266 A CN114507266 A CN 114507266A CN 202210078070 A CN202210078070 A CN 202210078070A CN 114507266 A CN114507266 A CN 114507266A
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention discloses a Molnupriver crystal form and a preparation method of the Molnupriver crystal form, and the Molnupriver single crystal is firstly measured by an X-ray single crystal diffraction method to be composed of Molnupriver molecules and ethanol molecules, so that the real three-dimensional structure of four chiral centers in the Molnupriver molecules is accurately shown. The Molnnupiravir crystal has moderate granularity, excellent fluidity and purity, and is suitable for being used as a raw material medicament for producing a prodrug or a medicinal preparation of the Molnnupiravir crystal.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a Molnopiravir crystal form and a preparation method thereof.
Background
The Molnupiravir chemical name is: ((2R,3S,4R,5R) -3, 4-dihydro-5- (4- (hydroxyamino) -2-oxopyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) methylisobutyl ester, of the formula:
molnupiravir is a highly potent orally bioavailable form of a ribonucleoside analog that was developed by the emerica drug innovation corporation (DRIVE) of emerica university and later developed by both the default santo and the ridge biotheratics. Is a prodrug of N4-hydroxycytidine, is converted into an active component of N4-hydroxycytidine in vivo, and plays an antiviral role by introducing replication errors during the replication of viral RNA. Preclinical studies have shown that Molnupiravir is active against the most common SARS-CoV-2 variant and inhibits viral replication.
On 4/11/2021, Molnupiravir was approved by the british pharmaceutical and health care authority (MHRA) for the treatment of light and medium covd-19 adult patients at risk of developing moderate and severe covd-19. The oral small molecule new crown specific medicine is the first approved oral small molecule new crown specific medicine in the world.
On 23/12/2021, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authority (EUA) to Molnupiravir of Merck for treating adult mild-to-moderate new-crown patients who were positive in direct detection of SARS-CoV-2 virus and had a high risk of developing severe cases including hospitalization or death.
With the development and research of drugs, the research of crystal forms is more and more emphasized. Different crystal forms can affect the dissolution and absorption of the medicine in vivo, and further affect the clinical curative effect and safety of the medicine. Therefore, it is particularly important to study the crystal form of the polymorphic drug. In the existing patent, only the patent with the application number of 202110055824.9 reports the crystalline form A of Molnnupiravir, but the crystalline form A has poor fluidity and is not beneficial to the operation of a preparation process.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a Molnupravir crystal form and a preparation method thereof.
The purpose of the invention is realized by the following technical scheme:
a crystalline form of Molnupiravir having characteristic peaks in the following positions by X-ray diffraction: 8.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.3 +/-0.2 degrees, 20.7 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.3 +/-0.2 degrees, 22.6 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.8 +/-0.2 degrees, 26.3 +/-0.2 degrees, 26.8 +/-0.2 degrees, 27.1 +/-0.2 degrees, 27.5 +/-0.2 degrees, 28.8 +/-0.2 degrees, 29.4 +/-0.2 degrees.
Preferably, the Theta value of the X-ray powder diffraction pattern 2 has characteristic peaks at 8.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 20.9 +/-0.2 degrees, 22.6 +/-0.2 degrees, 24.7 +/-0.2 degrees and 2 degrees, and the peak value is strong.
Preferably, the crystal form belongs to an orthorhombic system, the space group is P2(1)2(1), and the unit cell parameters are as follows: a-8.7253(8) a, b-11.7496(11) a, c-18.2220(17) a, α = β = γ =90.00 °, temperature 298K, unit cell volume V-1868.1(3) a3The number of asymmetric units Z =4 in the unit cell.
Preferably, the differential scanning calorimetry of the crystalline form has a peak at 140-146 ℃.
Preferably, the Molnnupiravir single crystal is observed under a polarization microscope as a columnar crystal with a rectangular external shape.
Preferably, the preparation method of any one of the above Molnupiravir crystal forms comprises the following steps:
s1, dissolution of Molnopiravir
Mixing the Molnupriver and an ethanol solvent, and fully dissolving to obtain a Molnupriver alcohol solution, wherein the ethanol solvent does not contain water;
s2, crystallization
And crystallizing the Molnupriver alcoholic solution, and carrying out solid-liquid separation to obtain the required Molnupriver single crystal.
Preferably, in S1, Molnupiravir and an ethanol solvent are mixed and heated to 30 to 60 ℃ to be sufficiently dissolved.
Preferably, in S1, the dissolving temperature of Molnupiravir in an ethanol solvent is 40 to 60 ℃, and stirring is performed during the dissolving process.
Preferably, the concentration of the Molnupravir alcohol solution formed after dissolution in S1 is 20 mg/mL-100 mg/mL, preferably 40 mg/mL-70 mg/mL.
Preferably, in S2, the crystallization method is crystallization by a temperature difference method, cooling to-2 to 5 ℃ for crystallization, wherein the crystallization time is 0.5 to 36 hours, and performing solid-liquid separation to obtain crystals of a desired crystal form, wherein the crystals do not contain crystal water.
Preferably, in S2, the crystallization method is to perform crystallization by using a gas phase volatilization method to obtain a single crystal, the temperature is 25 to 40 ℃, preferably 25 ℃, and the volatilization time is 2 to 5 days, so as to finally obtain the required Molnupiravir single crystal.
Preferably, in S2, the crystallization method is gradient temperature increase crystallization, the Molnupiravir alcoholic solution is placed in a reaction kettle, the temperature increase and decrease rate, the temperature gradient at 20 ℃, 50 ℃ and 20 ℃, and the time gradients for 2h, 2h and 20h are set correspondingly, and the Molnupiravir is subjected to single crystal culture, so as to obtain the desired Molnupiravir single crystal.
The beneficial effects of the invention are: according to the invention, the Molnopiravir single crystal is firstly measured by an X-ray single crystal diffraction method to be composed of Molnopiravir molecules and ethanol molecules, and the real three-dimensional structure of four chiral centers in the Molnopiravir molecules is accurately shown. The Molnnupiravir crystal has moderate granularity, excellent fluidity and purity, and is suitable for being used as a raw material medicament for producing a prodrug or a medicinal preparation of the Molnnupiravir crystal.
Drawings
FIG. 1 is a schematic diagram of temperature gradient culture conditions of a crystal form according to an embodiment of the present invention;
FIG. 2 is a schematic view of the crystalline form of Molnupiarvir of the present invention viewed under a polarizing microscope;
FIG. 3 is a schematic view of the crystalline form of Molnupiarvir of the present invention observed under a polarizing microscope;
FIG. 4 is an X-ray single crystal diffraction structure of the crystalline form of Molnupiarvir of the present invention;
FIG. 5 is an X-ray diffraction pattern of the crystalline form of Molnupravir of the present invention;
FIG. 6 is a DSC of crystalline form of Molnupriarvir of the present invention;
FIG. 7 is a DSC of crystalline form of Molnupiarvir of the invention;
FIG. 8 is a schematic view of a crystalline form of Molnupiarvir of the present invention viewed under a polarizing microscope;
FIG. 9 is a DSC of a Molnbupiravir drug substance of the invention;
FIG. 10 is an X-ray diffraction pattern of a Molnuprairir drug substance of the present invention;
fig. 11 is a schematic view of a Molnupiravir drug substance of the invention observed under a polarizing microscope.
Detailed Description
The conception, the specific structure and the technical effects of the present invention will be further described in conjunction with the accompanying drawings to fully understand the objects, the features and the effects of the present invention.
Among the types and test conditions of the X-ray powder diffractometer, the X-ray single crystal diffractometer, the differential scanning calorimetry and the polarization microscope apparatus, the types and test conditions of the X-ray powder diffractometer and the polarization microscope apparatus are as follows:
name of experimental instrument: x-ray diffractometer (XRD) (Rigaku Japan Ulima IV)
And (3) testing conditions are as follows: scanning mode 2Theta/Theta, Scanning mode continuous Scanning, tube pressure 40KV, tube current 40mA, and Scanning range 3-60 degrees; the step size is 0.02 °.
The related X-ray single crystal diffractometer has the following instrument models and test conditions:
name of experimental instrument: x-ray single crystal diffractometer (Smart-APEX II type, Bruk, Germany);
and (3) testing conditions are as follows: the diffraction measurement equipment type CCD area detector, method phi and omega scans, radiation type Mo-Ka, wavelength 0.71073A.
The model of Differential Scanning Calorimetry (DSC) instrument and the test conditions are as follows:
name of experimental instrument: TA differential scanning calorimetry (Discovery).
And (3) testing conditions are as follows: using a sealed disk apparatus, the instrument was purged with nitrogen at 50 mL/min. Data were collected between room temperature and 180 ℃ at a heating rate of 10 ℃/min.
The model of the polarizing microscope instrument and the test conditions are as follows:
name of experimental instrument: polarization microscope (Axiolabal) from Zeiss.
And (3) testing conditions are as follows: polarizing condition, 5 times of objective lens and 10 times of ocular lens
Example 1
Weighing Molnopiravir 500mg in a conical flask, dropwise adding absolute ethyl alcohol for 1 mL/time until the solution is transparent, performing ultrasonic treatment for 2min to completely dissolve the Molnopiravir to obtain a 20mg/mL Molnopiravir alcoholic solution, sealing with a preservative film, pricking holes, and slowly volatilizing the ethyl alcohol for 4 days at room temperature to finally obtain a Molnopiravir monocrystal.
The Molnupiravir single crystal is colorless and transparent needle-shaped, and is observed as a rectangular columnar crystal under a polarizing microscope as shown in fig. 2, and the crystal has extinction property when observed under polarized light, and shows different colors with the change of angles. The crystal state is different from the known crystal form, namely the crystal form of the bulk drug, and is shown in figure 11.
An X-ray single crystal diffraction structure of the new crystal form of Molnupiravir is shown in fig. 4, and the new crystal form of Molnupiravir is determined by an X-ray single crystal diffraction method to be composed of Molnupiravir molecules and ethanol molecules, the crystal form belongs to an orthorhombic system, the space group is P2(1)2(1), the cell parameters are a-8.7253(8) a, b-11.7496(11) a, c-18.2220(17) a, α = β = γ =90.00 °, temperature 298K, and the cell volume is V-1868.1(3) a3The number of asymmetric units in the unit cell Z = 4.
An X-ray single crystal diffraction pattern of Molnupiravir single crystal is shown in fig. 5. The X-ray diffraction has characteristic peaks at the following positions: 8.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.3 +/-0.2 degrees, 20.7 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.3 +/-0.2 degrees, 22.6 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.8 +/-0.2 degrees, 26.3 +/-0.2 degrees, 26.8 +/-0.2 degrees, 27.1 +/-0.2 degrees, 27.5 +/-0.2 degrees, 28.8 +/-0.2 degrees, 29.4 +/-0.2 degrees. Different from the known crystal form, namely the crystal form X-ray diffraction pattern (figure 10) of the bulk drug, the compound has characteristic diffraction peaks at 6.54 +/-0.2 degrees, 9.79 +/-0.2 degrees, 13.09 +/-0.2 degrees, 16.38 +/-0.2 degrees, 17.20 +/-0.2 degrees, 18.10 +/-0.2 degrees, 20.62 +/-0.2 degrees, 21.33 +/-0.2 degrees and 28.08 +/-0.2 degrees.
After testing, in this example, a DSC chart of the synthesized crystal form of the present invention is shown in fig. 6, a melting point is 145.7 ℃, which is different from a melting point of Molnupiravir raw material, a melting point of the bulk drug is 159.7 ℃, and a DSC chart of the bulk drug is shown in fig. 10. The difference of the crystal forms can also be judged by the difference of the melting points.
Example 2
Weighing 400mg of Molnupriver raw material medicine into a reaction kettle, dropwise adding 10mL of absolute ethyl alcohol to form Molnupriver alcohol solution with the concentration of 100mg/mL, then placing the reaction kettle into a drying oven, setting the temperature rising and reducing rate, the temperature gradient of 20 ℃, 50 ℃ and 20 ℃, correspondingly setting the time gradients of 2h, 2h and 20h, specifically setting the culture conditions as shown in figure 1, carrying out single crystal culture on the Molnupriver, and finally obtaining the Molnupriver single crystal.
The Molnnupiravir single crystal is colorless and transparent, is observed as an oblique rectangular columnar crystal under a polarizing microscope as shown in figure 3, and when a crystal sample is placed on a stage and rotated for 360 degrees, the crystal shows temporary disappearance and twinkling.
After testing, in this example, a DSC chart of the synthesized crystal form of the present invention is shown in fig. 7, a melting point is 145.7 ℃, which is different from a melting point of Molnupiravir raw material, a melting point of the bulk drug is 159.7 ℃, and a DSC chart of the bulk drug is shown in fig. 9. Different crystal forms have different melting points, so that the crystal form of the invention is different from the crystal form of the Molnnupiravir raw material.
Example 3
Weighing 400mg of Molnupravir raw material medicine into a conical flask with a plug, adding 15mL of ethanol solvent, mixing, and heating the solution to 40 ℃ to fully dissolve the Molnupravir raw material medicine to obtain an alcoholic solution of the Molnupravir. Then the solution is placed at the room temperature of 25 ℃ for 5 hours, and finally the solution is placed in a refrigerator at the temperature of 4 ℃ for 24 hours to obtain colorless transparent crystals.
The Molnupiravir crystal is a rhombic columnar crystal observed by polarization as shown in fig. 8, and when a crystal sample is placed on a stage and rotated for 360 degrees, the crystal shows temporary disappearance and glittering and shows extinction.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (8)
1. A crystalline form of Molnupiravir, characterized in that: the X-ray diffraction of the crystal form has characteristic peaks at the following positions: 8.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.3 +/-0.2 degrees, 20.7 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.3 +/-0.2 degrees, 22.6 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.8 +/-0.2 degrees, 26.3 +/-0.2 degrees, 26.8 +/-0.2 degrees, 27.1 +/-0.2 degrees, 27.5 +/-0.2 degrees, 28.8 +/-0.2 degrees, 29.4 +/-0.2 degrees.
2. A crystalline form of Molnupiravir as claimed in claim 1, wherein: the Theta value of an X-ray powder diffraction pattern 2 is 8.9 degrees +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 20.9 +/-0.2 degrees, 22.6 +/-0.2 degrees, 24.7 +/-0.2 degrees and 2 degrees, and the peak value is strong.
3. A crystalline form of Molnupiravir as claimed in claim 1, wherein: the crystal form belongs to an orthorhombic system, the space group is P2(1), 2, (1), 2 and 1, and the unit cell parameters are as follows: a-8.7253(8) A, b-11.7496(11) A, c-18.2220(17) A, α = β = γ =90.00 DEG, temperature 298K, unit cell volume V-1868.1(3) A3The number of asymmetric units Z =4 in the unit cell.
4. A crystalline form of Molnupiravir as claimed in claim 1, wherein: the differential scanning calorimetry of the crystal form has a peak at 140-146 ℃.
5. A crystalline form of Molnupiravir as claimed in claim 1, wherein: the appearance of the Molnnupiravir single crystal is rectangular columnar crystal observed under a polarization microscope.
6. The method of any one of claims 1-5, wherein the crystalline form of Molnnupiravir comprises: the method comprises the following steps: dissolving the Molnopiravir in absolute ethyl alcohol, heating to 30-60 ℃, fully dissolving to obtain a Molnopiravir alcohol solution with the concentration of 20-100 mg/mL, and performing single crystal culture by using a gas phase volatilization method or a temperature difference method or a gradient heating method to finally obtain the required Molnopiravir single crystal.
7. The method of claim 6, wherein the crystalline form of Molnupiravir comprises: when the crystallization is carried out by using a temperature difference method, cooling the Molnnapiarvir alcoholic solution to-2-5 ℃ for crystallization, wherein the crystallization time is 0.5-36 hours, and carrying out solid-liquid separation to obtain a crystal with a new crystal form.
8. The method of claim 6, wherein the crystalline form of Molnupiravir comprises: when a gradient heating method is adopted for crystallization, the method comprises the following steps of placing the Molnopiravir alcoholic solution in a reaction kettle, setting the heating and cooling rates, the temperature gradient of 20 ℃, 50 ℃ and 20 ℃, correspondingly setting the time gradients of 2h, 2h and 20h, carrying out single crystal culture on the Molnopiravir, and finally obtaining the required Molnopiravir single crystal.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111372592A (en) * | 2017-12-07 | 2020-07-03 | 埃默里大学 | N4-hydroxycytidine and derivatives and antiviral uses related thereto |
| CN112608357A (en) * | 2020-12-21 | 2021-04-06 | 杭州科巢生物科技有限公司 | Preparation method of antiviral drug Molnbupiravir |
| 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 |
| CN113307834A (en) * | 2021-04-23 | 2021-08-27 | 安徽贝克联合制药有限公司 | Polymorphic substance of ribonucleoside analogue, preparation method and application thereof |
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- 2022-01-24 CN CN202210078070.3A patent/CN114507266A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111372592A (en) * | 2017-12-07 | 2020-07-03 | 埃默里大学 | N4-hydroxycytidine and derivatives and antiviral uses related thereto |
| CN112608357A (en) * | 2020-12-21 | 2021-04-06 | 杭州科巢生物科技有限公司 | Preparation method of antiviral drug Molnbupiravir |
| 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 |
| CN113307834A (en) * | 2021-04-23 | 2021-08-27 | 安徽贝克联合制药有限公司 | Polymorphic substance of ribonucleoside analogue, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| INESH J. PAYMODE ET AL.: "Toward a Practical, Two-Step Process for Molnupiravir from Cytidin", 《ORG. PROCESS RES. DEV.》 * |
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