A co-crystal of mycophenolic acid medicine and its preparation and application

Abstract

The application belongs to the field of medicine and chemical industry, and discloses a mycophenolic acid medicine co-crystal and a preparation and application thereof. The co-crystal is prepared from mycophenolic acid and 4,4-bipyridine as raw materials. The co-crystal is a stoichiometric ratio diversity co-crystal. In the molecular structure of the co-crystal, the amount of substance of mycophenolic acid and 4,4-bipyridine is 1:1 or 2:1. The two kinds of mycophenolic acid medicine co-crystals prepared by a grinding method, a room temperature evaporation method or a slurry method are diversity co-crystals, and the diversity of the mycophenolic acid co-crystal has never been reported. The application solves the problems of poor stability and high hygroscopicity of mycophenolic acid, and the prepared co-crystal has low hygroscopicity and good stability.

Description

TECHNICAL FIELD

[0001] The present application relates to a mycophenolic acid pharmaceutical co-crystal, in particular to a mycophenolic acid pharmaceutical co-crystal and its preparation and application. BACKGROUND

[0002] Mycophenolic acid is an immunosuppressant, which plays an important role in transplant rejection and autoimmune diseases by inhibiting transplant rejection and antibody formation between foreign cells and antibodies. In addition, mycophenolic acid can also play an antiviral and antifungal, as well as antibacterial and antitumor role, and can enhance immune activity. Mycophenolic acid has high hygroscopicity and poor stability, and its clinical application is mainly its prodrug. After being absorbed and metabolized by the human body, mycophenolic acid with pharmacological activity is produced, and then its efficacy can be exerted. Therefore, there is an urgent need for an effective method to improve its inherent physicochemical properties.

[0003] As a new type of drug solid form, the pharmaceutical co-crystal combines the active pharmaceutical ingredient (API) with other physiologically acceptable acids, bases, salts, non-ionized compound molecules through non-covalent bonds in the same crystal lattice. At least one of the components of the pharmaceutical co-crystal is a molecular or ionic API, and each component is a solid at room temperature. The pharmaceutical co-crystal can improve the physical and chemical properties of the raw material without changing the chemical structure of the raw material.

[0004] So far, there has been no report on the synthesis of mycophenolic acid pharmaceutical co-crystal diversity. SUMMARY

[0005] The purpose of the present application is to provide a mycophenolic acid pharmaceutical co-crystal and its preparation and application, which solves the problems of poor stability and high hygroscopicity of mycophenolic acid. The co-crystal is a 1:1 co-crystal or a 2:1 co-crystal, which is a new structure with good stability and low hygroscopicity.

[0006] In order to achieve the above purpose, the present application provides a mycophenolic acid pharmaceutical co-crystal, which is prepared from mycophenolic acid and 4,4-bipyridine as raw materials. The co-crystal is a stoichiometric ratio diversity co-crystal, and in the molecular structure of the co-crystal, the amount of substance of mycophenolic acid and 4,4-bipyridine is 1:1 or 2:1.

[0007] The present application also provides a preparation method of the mycophenolic acid pharmaceutical co-crystal as described.

[0008] (1) mixing mycophenolic acid, 4,4-bipyridine and a solvent to obtain a mixture;

[0009] (2) grinding the mixture obtained in step (1) to obtain the mycophenolic acid pharmaceutical co-crystal; or

[0010] The mixture obtained in step (1) is shaken at 30-50℃, and solid and liquid are obtained by filtration, the obtained solid is dried to obtain the mycophenolic acid drug co-crystal; the obtained liquid is sealed and left with a small hole, and the crystal obtained after evaporation at room temperature is the mycophenolic acid drug co-crystal.

[0011] The solvent is acetonitrile or water.

[0012] Preferably, the mass ratio of mycophenolic acid and 4,4-bipyridine is (3-5) : 1.

[0013] Preferably, the shaking time is 20-40 hours.

[0014] Preferably, the grinding includes: grinding at a frequency of 15Hz±0.2Hz for 5-10min as a group, and the interval between two groups is 2-5min, and the total grinding time is 30min.

[0015] The application further provides a use of the mycophenolic acid drug co-crystal as described above in the preparation of immunosuppressive drugs.

[0016] The mycophenolic acid drug co-crystal and the preparation and application thereof solve the problems of poor stability and high hygroscopicity of mycophenolic acid, and have the following advantages:

[0017] 1. The two kinds of mycophenolic acid drug co-crystals prepared by the grinding method (if there is no solvent, the mycophenolic acid and 4,4-bipyridine cannot be directly ground to obtain the co-crystal), the room temperature evaporation method or the slurry method (if the shaking time is too long or too short, or the temperature is too high or too low, sometimes the target product cannot be synthesized) with mycophenolic acid and 4,4-bipyridine as raw materials are diversity co-crystals, specifically including 1:1 co-crystal and 2:1 co-crystal, and the diversity of mycophenolic acid drug co-crystals has never been reported.

[0018] 2. The mycophenolic acid drug co-crystals prepared by the application have low hygroscopicity and good stability.

[0019] 3. Compared with the prior art, the preparation method of the application is simple, easy to operate, and has low reaction temperature, and is environmentally friendly and pollution-free when water is used as the solvent, and has good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The PXRD graphs of the co-crystals prepared in examples 1, 2, 6 and 7 of the application, the simulated co-crystals, mycophenolic acid and 4,4-bipyridine.

[0021] Figure 2 The molecular structure diagram of the co-crystal prepared in example 2 of the application.

[0022] Figure 3 A co-crystal molecular structure diagram prepared for the present application example 7.

[0023] Figure 4 DSC spectra of co-crystals, mycophenolic acid and 4,4-bipyridine prepared for the present application examples 1, 2, 6 and 7, with temperature as abscissa and heat flow rate as ordinate.

[0024] Figure 5 Hygroscopicity curve spectra of co-crystals, mycophenolic acid and 4,4-bipyridine prepared for the present application examples 1, 2, 6 and 7. DETAILED DESCRIPTION

[0025] The technical solutions in the examples of the present application will be described clearly and completely below. Obviously, the described examples are only a part of the examples of the present application, but not all the examples. Based on the examples in the present application, all the other examples obtained by those skilled in the art without creative labor fall within the protection scope of the present application.

[0026] The chemical names and molecular formulas of the reagents used in the following examples are as follows:

[0027]

[0028] Example 1 (grinding method)

[0029] A preparation method of a mycophenolic acid drug co-crystal, the method comprising:

[0030] (1) 0.3361 g of mycophenolic acid, 0.1635 g of 4,4-bipyridine and 300 μL of acetonitrile were added into a grinding pot;

[0031] (2) 5 min as a group at a frequency of 15 Hz±0.2 Hz, with 2 min interval between two groups, repeated for 6 groups, a total of 30 min grinding, to obtain the co-crystal of the mycophenolic acid drug (1:1 co-crystal, the molar amount ratio of mycophenolic acid and 4,4-bipyridine is 1:1).

[0032] Example 2 (room temperature evaporation method)

[0033] A preparation method of a mycophenolic acid drug co-crystal, the method comprising:

[0034] (1) 1.0084 g of mycophenolic acid, 0.4916 g of 4,4-bipyridine and 40 mL of acetonitrile were added into a conical flask, and placed in a 30℃ shaking bed for 36 hours of shaking;

[0035] (2) After the end of the oscillation, filter the liquid into a flask, seal the flask with a sealing film, then use a fine needle to punch a hole in the sealing film, and place it at room temperature for slow evaporation for several days to obtain the mycophenolic acid drug co-crystal (1:1 co-crystal, the molar amount ratio of mycophenolic acid and 4,4-bipyridine is 1:1).

[0036] Example 3 (slurry method)

[0037] A preparation method of a mycophenolic acid drug co-crystal, the method comprising:

[0038] (1) 0.4087g of mycophenolic acid, 0.1990g of 4,4-bipyridine and 5mL of acetonitrile are added to a conical flask, which is placed in a 50℃ shaking bed and oscillated for 24 hours;

[0039] (2) After the end of the oscillation, filter the liquid into a flask, seal the flask with a sealing film, then use a fine needle to punch a hole in the sealing film, and place it at room temperature for slow evaporation for several days to obtain the mycophenolic acid drug co-crystal (1:1 co-crystal, the molar amount ratio of mycophenolic acid and 4,4-bipyridine is 1:1)

[0040] Example 4 (slurry method)

[0041] A preparation method of a mycophenolic acid drug co-crystal is basically the same as that of Example 3, with the difference being:

[0042] (1) 1.0084g of mycophenolic acid, 0.4916g of 4,4-bipyridine and 40mL of acetonitrile are added to a conical flask, which is placed in a 30℃ shaking bed and oscillated for 36 hours.

[0043] Example 5 (slurry method)

[0044] A preparation method of a mycophenolic acid drug co-crystal is basically the same as that of Example 3, with the difference being:

[0045] (1) 40mL of acetonitrile is replaced by 5mL of water.

[0046] Example 6 (grinding method)

[0047] A preparation method of a mycophenolic acid drug co-crystal is basically the same as that of Example 1, with the difference being:

[0048] (1) The mass of mycophenolic acid and 4,4-bipyridine is 0.2422g and 0.0592g respectively;

[0049] (2) Grind at a frequency of 15Hz±0.2Hz for 10min, repeat for 2 groups with an interval of 5min, a total of 30min, to obtain the mycophenolic acid drug co-crystal (2:1 co-crystal, the molar amount ratio of mycophenolic acid and 4,4-bipyridine is 2:1).

[0050] Example 7 (room temperature evaporation method)

[0051] The preparation method of a mycophenolic acid drug cocrystal is basically the same as that in Example 2, except that:

[0052] (1) The masses of mycophenolic acid and 4,4-bipyridine were 1.0086 g and 0.4912 g, respectively;

[0053] (2) Same as step (2) of Example 2, to obtain the cocrystal of the mycophenolic acid drug (2:1 cocrystal, the molecular weight ratio of mycophenolic acid and 4,4-bipyridine is 2:1).

[0054] Example 8 (Grinding Method)

[0055] The preparation method of a mycophenolic acid drug cocrystal is basically the same as that in Example 1, except that:

[0056] (1) Replace 300 μL of acetonitrile with 40 μL of water.

[0057] Example 9 (Room Temperature Volatilization Method)

[0058] The preparation method of a mycophenolic acid drug cocrystal is basically the same as that in Example 2, except that:

[0059] (1) Replace 40 mL of acetonitrile with 4 mL of water.

[0060] Experiment 1: Detection of Drug Eutectic Structure

[0061] 1. X-ray powder diffraction for detecting drug eutectics

[0062] X-ray powder diffractometer (Rigaku, Japan, model D / max-2500), current 15mA, voltage 40kV, scan rate 8° / min, scan range 5-50°, wavelength 0.15406nm, Cu Kα emission target.

[0063] like Figure 1 The figures show the PXRD patterns of the eutectic, simulated eutectic, mycophenolic acid, and 4,4-bipyridine prepared in Examples 1, 2, 6, and 7 of this invention. A 1:1 eutectic refers to a molar ratio of mycophenolic acid to 4,4-bipyridine of 1:1; a 2:1 eutectic refers to a molar ratio of mycophenolic acid to 4,4-bipyridine of 2:1. Figure 1It can be seen that the diffraction angles (2θ) of the mycophenolic acid-4,4-bipyridine 2:1 eutectic are 6.922°, 9.799°, 10.398°, 10.862°, 12.003°, 12.419°, 13.939°, 14.301°, 15.202°, ​​17.024°, 18.204°, 19.421°, 19.98°, 20.238°, 21.837°, 22.079°, 22.302°, 23.118°, 23.398°, 23.782°, and 24.4°. Characteristic peaks are present at 21°, 24.801°, 25.537°, 25.758°, 26.022°, 26.36°, 26.557°, 27.639°, 29.699°, and 30.282° (the characteristic peaks at 6.922°, 9.799°, 10.398°, 12.003°, and 17.024° are all newly appearing), while the characteristic peaks at 7.78°, 9.48°, 13.54°, and 16.26° (mycophenolic acid) and at 12.78° (4,4-bipyridine) completely disappear.

[0064] The diffraction angles (2θ) of the mycophenolic acid-4,4-bipyridine 1:1 eutectic were 5.978°, 9.82°, 10.776°, 11.979°, 12.222°, 12.698°, 14.238°, 15.96°, 16.298°, 16.541°, 17.12°, 17.784°, 18.701°, 19.719°, 20.001°, 20.202°, ​​20.623°, and 21.621°. Characteristic peaks were observed at 22.439°, 23.902°, 24.198°, 24.959°, 25.382°, 28.041°, 28.383°, and 28.62° (the characteristic peaks at 5.978°, 9.82°, 11.979°, and 17.12° were newly appearing), while the characteristic peaks at 7.78°, 9.48°, and 13.54° (mycophenolic acid) and at 14.7° (4,4-bipyridine) completely disappeared. Furthermore, the PXRD pattern of the experimentally prepared sample was basically consistent with the single-crystal simulated spectrum and showed no impurity peaks, indicating that the prepared sample had high purity.

[0065] 2. Detection of the molecular structure of drug cocrystals

[0066] Using a Bruker D8 diffractometer, at room temperature, with Mo Kα radiation SCXRD analysis was performed on the PZA-MMA eutectic. Cell refinement and data simplification were performed using Bruker SAINT software, and the crystal structure was refined on F2 using the full matrix least squares method with SHELXL.

[0067] like Figure 2The diagram shows the molecular structure of the eutectic prepared in Example 2 of this invention. It contains one mycophenolic acid molecule and one 4,4-bipyridine molecule. The 1:1 eutectic of mycophenolic acid and 4,4-bipyridine (1:1 eutectic means the molar ratio of mycophenolic acid to 4,4-bipyridine is 1:1) exhibits triclinic crystal symmetry, space group P-1, and cell parameters of [value missing]. α = 113.410(5)°, β = 93.114(4)°, γ = 99.049(4)°, and the unit cell volume is The molecular formula is C 54 H 56 N4O 12 .

[0068] like Figure 3 The diagram shows the eutectic molecular structure prepared in Example 7 of this invention. It contains two mycophenolic acid molecules and one 4,4-bipyridine molecule. The 2:1 eutectic of mycophenolic acid and 4,4-bipyridine (2:1 eutectic means the molar ratio of mycophenolic acid to 4,4-bipyridine is 2:1) exhibits monoclinic crystal system symmetry, space group P121 / c1, and cell parameters are shown below. α = 90°, β = 95.574(2)°, γ = 90°, and the unit cell volume is The molecular formula is C 22 H 24 NO.6.

[0069] Combination Figures 1 to 3 This proves that the mycophenolic acid drug eutectic of the present invention belongs to a new crystalline phase, and the synthesized eutectic has high purity.

[0070] Experimental Example 2: Characterization of Drug Cocrystallization

[0071] 1. Instruments for characterizing drug cocrystals

[0072] Thermal analysis of mycophenolic acid, 4,4-bipyridine, and two ratios of mycophenolic acid-4,4-bipyridine eutectics was performed using a TA instrument DSC 2500 module (differential scanning calorimeter); nitrogen was used as the protective gas; the temperature range was 30-200℃, the heating rate was 8℃·min⁻¹, and the sample mass was 3 mg.

[0073] Figure 4 The images show the DSC spectra of the eutectic, mycophenolic acid, and 4,4-bipyridine prepared in Examples 1, 2, 6, and 7 of this invention. The horizontal axis represents temperature, and the vertical axis represents heat flow rate. A 1:1 eutectic refers to a molar ratio of mycophenolic acid to 4,4-bipyridine of 1:1; a 2:1 eutectic refers to a molar ratio of mycophenolic acid to 4,4-bipyridine of 2:1. Figure 4The differential scanning calorimetry (DSC) spectrum of the 1:1 eutectic of mycophenolic acid and 4,4-bipyridine shows an endothermic peak at 126.49 ± 0.2 °C, while the DSC spectrum of the 2:1 eutectic of mycophenolic acid and 4,4-bipyridine shows an endothermic peak at 141.16 ± 0.3 °C. Therefore, the endothermic peak positions of the two eutectics are different, which, combined with... Figures 2 to 3 The different molar ratios of mycophenolic acid molecules and 4,4-bipyridine molecules in the 1:1 and 2:1 eutectic structures demonstrate that mycophenolic acid and 4,4-bipyridine produced a new crystalline phase, synthesizing eutectics with diverse stoichiometric ratios, namely 1:1 and 2:1 eutectics, and all of these eutectics had high purity.

[0074] Experiment Example 3: Stability Performance Testing

[0075] A constant temperature and humidity chamber (LHS-80HC-Ⅱ, Shanghai Yiheng Scientific Instruments Co., Ltd.) was used to determine the eutectic and active pharmaceutical ingredient by setting the humidity to 75%RH and the temperature to 298.15K.

[0076] Prepare pre-weighed, labeled small beakers. Place 0.03 g of mycophenolic acid, the two mycophenolic acid-4,4-bipyridine cocrystals and 4,4-bipyridine ligands from Examples 1 and 2 into the beakers respectively. Place the beakers open in a constant temperature and humidity chamber at 75% RH (relative humidity of air) / 25°C for one month. Record the changes in sample weight at fixed time intervals to investigate the stability of the samples under high humidity conditions.

[0077] Figure 5 The images show the hygroscopic curves of the eutectic, mycophenolic acid, and 4,4-bipyridine prepared in Examples 1, 2, 6, and 7 of this invention. A 1:1 eutectic refers to a molar ratio of mycophenolic acid to 4,4-bipyridine of 1:1; a 2:1 eutectic refers to a molar ratio of mycophenolic acid to 4,4-bipyridine of 2:1. Figure 5 It can be seen that at 75% RH / 25℃, mycophenolic acid is more hygroscopic than the two mycophenolic acid-4,4-bipyridine cocrystals. The hygroscopicity ranking of the two mycophenolic acid-4,4-bipyridine cocrystals is as follows: 1∶1 cocrystal < 2∶1 cocrystal. Therefore, both mycophenolic acid-4,4-bipyridine cocrystals exhibit low hygroscopicity and are more stable, demonstrating better stability.

[0078] Although the present invention has been described in detail through the preferred embodiments above, it should be understood that the above description should not be considered as a limitation of the present invention. Various modifications and substitutions to the present invention will be apparent to those skilled in the art after reading the above description. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims

1. A co-crystal of mycophenolic acid drug, characterized in that, The co-crystal is prepared from mycophenolic acid and 4,4-bipyridine, and the co-crystal is a diversity co-crystal, in the molecular structure of the co-crystal, the substance amount of mycophenolic acid and 4,4-bipyridine is 1:1 or 2:1; When the amount of substance of mycophenolic acid and 4,4-bipyridine is 1:1, the obtained co-crystal is a 1:1 co-crystal, which exhibits triclinic symmetry, the space group is P-1, the cell parameter values are a = 8.9513(11) Å, b = 16.424(2) Å, c = 18.273(2) Å, α = 113.410(5) °, β = 93.114(4) °, γ = 99.049(4) °, and the cell volume is 2414.3(5) Å 3 , the molecular formula is C 54 H 56 N4O 12 ; When the amount of substance of mycophenolic acid and 4,4-bipyridine is 2:1, the obtained co-crystal is a 2:1 co-crystal, which exhibits monoclinic symmetry, the space group is P1 21 / c1, the cell parameter values are a = 9.0636(4) Å, b = 25.5022(12) Å, c = 8.6257(4) Å, α = 90°, β = 95.574(2) °, γ = 90°, and the cell volume is 1984.33(16) Å 3 , the molecular formula is C 22 H 24 NO6.

2. A process for the preparation of a co-crystal of mycophenolic acid drug as claimed in claim 1, characterized in that, The method comprises: (1) mixing mycophenolic acid, 4,4-bipyridine and a solvent to obtain a mixture; The mass ratio of mycophenolic acid and 4,4-bipyridine is (3-5):1; (2) grinding the mixture obtained in step (1) to obtain the co-crystal of the mycophenolic acid drug; Or, placing the mixture obtained in step (1) in 30-50 DEG C and oscillating, filtering to obtain solid and liquid, drying the obtained solid to obtain the co-crystal of the mycophenolic acid drug; sealing the obtained liquid and leaving a small hole, and placing it at room temperature to volatilize to obtain crystals, which are the co-crystal of the mycophenolic acid drug; The solvent is acetonitrile or water.

3. A process for the preparation of a co-crystal of mycophenolic acid drug as claimed in claim 2, wherein, The oscillation time is 20-40 hours.

4. The process for preparing mycophenolic acid pharmaceutical co-crystal as claimed in claim 2, wherein, The grinding comprises: Grinding at a frequency of 15 Hz±0.2 Hz for 5-10 min as a group, and the interval between two groups is 2-5 min, and the total grinding time is 30 min.

5. Use of the co-crystal of the mycophenolic acid drug according to claim 1 in the preparation of immunosuppressive drugs.

Images