Nemategravir 4-dimethylaminopyridine eutectic crystal as well as preparation method and application thereof

Abstract

The invention discloses a nemategravir 4-dimethylaminopyridine eutectic crystal as well as a preparation method and application thereof. Specifically, the invention provides a eutectic crystal of a compound as shown in a formula I, and a preparation method and application of the eutectic crystal. The co-crystal has one or more advantages as follows: (1) the co-crystal has better solubility, is easier to preserve and is suitable for new drug development and industrial production; and (2) the process route is simple and the cost is low. # imgabs0 #

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technologies, and particularly to a nirmatrelvir 4-dimethylaminopyridine cocrystal, its preparation method, and its applications. Background Art

[0002] Nirmatrelvir, chemical name: (1R,2S,5S)-N-[(1S)-1-cyano-2-(2-oxopyrrolidin-3-yl)ethyl]-3-[(S)-3,3-dimethyl-2-(trifluoroacetamido)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, has the following structural formula:

[0003]

[0004] Nirmatrelvir is a 3CL protease inhibitor and plays an important role in the life cycle of many COVIDs. Its potential advantage is that it can act on all current COVID-19 variants. Moreover, its mechanism of action is significantly different from those of the approved anti-COVID-19 drugs remdesivir and molnupiravir, which inhibit COVID-19 by cleaving long polypeptide chains. Considering the great use of Nirmatrelvir in the treatment of COVID-19, it is necessary to study its crystal forms.

[0005] Patent CN114644681A discloses a nirmatrelvir isopropanol solvate crystal form and its preparation method, specifically discloses a nirmatrelvir isopropanol solvate crystal form and its preparation method. The original research company Pfizer's patent discloses two crystal forms, namely, the nirmatrelvir API crystal form and the methyl tert-butyl ether solvate, in WO2021250648A1. Zhong Jialiang et al. disclose a nirmatrelvir solvate, crystal form A, its preparation method, and its applications, specifically disclose an isobutyl acetate solvate, in patent CN116462735A. Shi Di'er et al. disclose a nirmatrelvir ethyl acetate solvate in the article (Acta Pharmaceutica Sinica 2023, 58(10): 3116-3122). Summary of the Invention

[0006] The technical problem to be solved by this invention is to provide a nirmatrelvir 4-dimethylaminopyridine cocrystal, its preparation method, and its applications. This cocrystal has good solubility and purity; the preparation method of this cocrystal is simple and low-cost, and is suitable for new drug development and industrial production.

[0007] The present invention provides a eutectic of a compound represented by Formula I, in which the molar ratio of nirmatrelvir to 4-dimethylaminopyridine is 1:1. The X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation has diffraction peaks at 7.162±0.2°, 11.519±0.2°, 11.978±0.2°, 12.199±0.2°, 13.502±0.2°, 14.361±0.2°, 15.182±0.2°, 15.481±0.2° and 15.718±0.2°.

[0008]

[0009] In some embodiments, the X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation may also have diffraction peaks at one or more of the following positions: 16.804±0.2°, 17.697±0.2°, 18.438±0.2°, 18.642±0.2°, 19.796±0.2°, 20.297±0.2°, 20.541±0.2°, 20.941±0.2° and 21.359±0.2°.

[0010] In some embodiments, the X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation may also have diffraction peaks at one or more of the following positions: 21.860±0.2°, 22.579±0.2°, 22.737±0.2°, 22.959±0.2°, 23.242±0.2°, 24.680±0.2°, 25.222±0.2°, 25.419±0.2° and 27.182±0.2°.

[0011] In some embodiments, the diffraction peak positions and relative peak heights of the X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation are shown in Table 1:

[0012] Table 1

[0013]

[0014]

[0015] In some embodiments, the diffraction peak positions, interplanar spacings, peak heights and relative peak heights of the X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation are shown in Table 2:

[0016] Table 2

[0017]

[0018]

[0019] In some embodiments, the eutectic uses Cu-Kα radiation, and the X-ray powder diffraction pattern represented by the 2θ angle has diffraction peak positions, interplanar spacings, peak heights, relative peak intensities, peak areas, relative peak areas, and full widths at half maximum as shown in Table 3:

[0020] Table 3

[0021]

[0022]

[0023] In some embodiments, the X-ray powder diffraction pattern of the eutectic represented by the 2θ angle using Cu-Kα radiation is substantially as Figure 2 shown.

[0024] In some embodiments, the eutectic is orthorhombic, with a space group of P212121 and lattice parameters of α = 90.00°, β = 90.00°, and γ = 90.00°, and its unit cell volume is

[0025] In some embodiments, for the eutectic, the first endothermic peak in the differential scanning calorimetry analysis graph appears at 184.14 °C ± 3 °C, and the peak value of the endothermic peak appears at 190.73 °C ± 3 °C.

[0026] In some embodiments, the differential scanning calorimetry analysis graph of the eutectic is substantially as Figure 3 shown.

[0027] In some embodiments, for the eutectic, weight loss begins at 125 °C ± 3 °C in the thermogravimetric analysis graph.

[0028] In some embodiments, for the eutectic, 19.50% weight loss occurs at 260 °C ± 3 °C in the thermogravimetric analysis graph.

[0029] In some embodiments, for the eutectic, decomposition begins at 260 °C ± 3 °C and is complete at 350 °C ± 3 °C in the thermogravimetric analysis graph.

[0030] In some embodiments, the thermogravimetric analysis graph of the eutectic is substantially as Figure 3 shown.

[0031] The present invention also provides a method for preparing the eutectic, comprising crystallizing nirmatrelvir in a solvent to obtain the eutectic; wherein, the solvent is 4-dimethylaminopyridine, a mixed solvent of 4-dimethylaminopyridine and methyl acetate, or a mixed solvent of 4-dimethylaminopyridine and isopropyl acetate.

[0032] In some embodiments, in the preparation method, the mass ratio of nirmatrelvir to 4-dimethylaminopyridine is 1:(0.1 - 0.5), preferably 1:0.2, 1:0.25 or 1:0.3.

[0033] In some embodiments, in the preparation method, the mass-to-volume ratio of 4-dimethylaminopyridine to methyl acetate is (5 - 15) g / mL, preferably 8 g / mL, 9.25 g / mL or 10 g / mL.

[0034] In some embodiments, in the preparation method, the nirmatrelvir 4-dimethylaminopyridine cocrystal can be prepared by conventional operations in the art, preferably by heating and dissolving, and the temperature of the heating is preferably 40 - 50 °C.

[0035] In some embodiments, in the preparation method, filtration can be performed after the dissolution, and the filtration can be a conventional operation in the art, preferably normal pressure and room temperature filtration.

[0036] In some embodiments, the crystallization method is natural evaporation crystallization or cooling crystallization.

[0037] In some embodiments, in the preparation method, the crystallization method can be a conventional method for such operations in the art, preferably natural evaporation crystallization or cooling crystallization.

[0038] In some embodiments, in the preparation method, the natural evaporation crystallization method can be natural evaporation crystallization after naturally cooling to room temperature after heating and dissolving; the cooling crystallization can be crystallization after cooling to room temperature after heating and dissolving.

[0039] In some embodiments, in the preparation method, the crystallization time is 2 - 150 h, preferably 110 - 120 h or 2 - 6 h.

[0040] In some embodiments, in the preparation method, the post-treatment steps after crystallization include: filtration and drying.

[0041] In some embodiments, in the post-treatment steps, the filtration can be the conventional conditions and operations for such operations in the art, preferably normal temperature and normal pressure filtration; the drying can be the conventional conditions and operations for such operations in the art, preferably normal temperature and normal pressure drying.

[0042] In some embodiments, add nirmatrelvir and 4-dimethylaminopyridine to methyl acetate according to a molar ratio of 1:1, heat to 40 - 50 °C and stir to dissolve, filter, naturally evaporate the filtrate until white crystalline solids appear, filter the crystals, and dry, then it is done.

[0043] In some embodiments, nirmatrelvir and 4-dimethylaminopyridine are added to isopropyl acetate in a molar ratio of 1:1, heated to 40-50 °C and stirred until dissolved, filtered, the filtrate is naturally evaporated until white crystalline solid appears, the crystals are filtered and dried, and that's it.

[0044] The present invention also provides the use of the cocrystal of the compound shown in Formula I in the preparation of anti-COVID-19 drugs.

[0045] The crystal forms of the present invention can be identified by one or several solid-state analysis methods, such as X-ray powder diffraction, single-crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric curve, etc. Those skilled in the art know that the peak intensity and / or peak situation of X-ray powder diffraction may vary due to different experimental conditions. At the same time, due to the different precisions of instruments, the measured 2θ values will have an error of about ±0.2°. And the relative intensity value of the peak depends more on certain properties of the measured sample, such as the crystal size and purity. Despite experimental errors, instrumental errors, and preferred orientation, etc., those skilled in the art can still obtain sufficient information to distinguish each crystal form from the X-ray powder diffraction data provided in this application. In DSC measurement, according to the heating rate, crystal shape, purity, and other measurement parameters, the initial temperature, maximum temperature, and heat of fusion data of the measured endothermic peak all have a certain degree of variability.

[0046] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0047] The reagents and raw materials used in the present invention are all commercially available.

[0048] The positive and progressive effects of the present invention are as follows:

[0049] 1. The nirmatrelvir 4-dimethylaminopyridine cocrystal provided in this application has good solubility, is easier to store, and is suitable for new drug development and industrial production.

[0050] 2. The preparation method of the nirmatrelvir 4-dimethylaminopyridine cocrystal of this application has a simple process route and low cost, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 It is the unit cell diagram of the nirmatrelvir 4-dimethylaminopyridine cocrystal prepared in Example 1;

[0052] Figure 2 It is the measured and simulated X-ray powder diffraction patterns of the nirmatrelvir 4-dimethylaminopyridine cocrystal prepared in Example 1;

[0053] Figure 3Differential scanning calorimetry curve and thermogravimetric analysis curve of the nirmatrelvir 4-dimethylaminopyridine cocrystal prepared in Example 1;

[0054] Figure 4 1H-NMR spectrum of the nirmatrelvir 4-dimethylaminopyridine cocrystal prepared in Example 1;

[0055] Figure 5 Regression equation graph of the relationship between concentration and peak area in the equilibrium solubility test;

[0056] Figure 6 Intrinsic dissolution curve. Detailed implementation manners

[0057] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0058] It should be understood that slightly different melting point readings may be given by using different types of equipment or different measurement conditions. The melting points of different crystal forms are affected by the sample weight, heating rate, particle size, and calibration and maintenance of the testing equipment. The provided values cannot be taken as absolute values.

[0059] It should be understood that slightly different XRPD patterns and peaks may be given by using different types of equipment or different measurement conditions. The patterns, peaks, and relative intensities of each diffraction of different crystal forms are affected by the pretreatment method of the sample, scanning speed, particle size, and calibration and maintenance of the testing equipment. The provided values cannot be taken as absolute values.

[0060] Detection methods:

[0061] 1. Single crystal X-ray diffraction

[0062] Instrument: SMART APEX-II (Bruker, Germany)

[0063] Wavelength:

[0064] Target: Cu-Kα radiation

[0065] Detector: Bruker APEX-II CCD

[0066] 2. Powder X-ray diffraction

[0067] Instrument: D8 Advance X-ray diffractometer (Bruker, Germany)

[0068] Wavelength:

[0069] Target: Cu-Kα radiation

[0070] Tube voltage: 40 kV

[0071] Tube current: 40 mA

[0072] Step size: 0.02°

[0073] Scanning speed: 16° / min

[0074] 3. Differential scanning calorimetry

[0075] Instrument: TA Q2000 differential scanning calorimeter (TA, USA)

[0076] Temperature range: 30 - 300 °C

[0077] Heating rate: 10 °C / min

[0078] 4. Thermogravimetric analysis

[0079] Instrument: TA Q500 thermogravimetric analyzer (TA, USA)

[0080] Temperature range: 30 - 350 °C

[0081] Heating rate: 10 °C / min

[0082] 5. Nuclear magnetic resonance spectrometer

[0083] Instrument: 600 MHz nuclear magnetic resonance spectrometer (Bruker, Germany)

[0084] Solution: DMSO-d6

[0085] 6. High performance liquid chromatograph

[0086] Instrument: U3000 high performance liquid chromatograph (Thermo Fisher)

[0087] Chromatographic column: CHIRALCEL OD-RH HPLC column (Daicel, 4.6 mm × 150 mm, 5 μm)

[0088] Detection wavelength: 220 nm

[0089] Mobile phase: water: acetonitrile = 67:33

[0090] Flow rate: 1 mL / min

[0091] 7. Dissolution tester

[0092] Instrument: Agilent Technologies 708-DS (Japan)

[0093] Sampling Station: Agilent Technologies 850-DS (Japan)

[0094] 8. Particle Size Analyzer

[0095] Instrument: HELOS (H4605) & OASISDRY / L, R5

[0096] Analysis Software: PAQXOS 5.0.5

[0097] Trigger Conditions: Start when Copt ≥ 0.5; Valid test when 0.5% ≤ Copt ≤ 5%; End when 1s Copt ≤ 0.5% or 60s actual time

[0098] Dispersion Method: Injector pressure 1 bar, VIBRI vacuum 32.00 mbar, Injection rate 30%, Lift height 0.5 mm

[0099] Example 1

[0100] Preparation of Nirmatrelvir 4-Dimethylaminopyridine Cocrystal

[0101] The crystalline form of nirmatrelvir API was synthesized and characterized by crystal structure according to the method disclosed by Jiang et al. in (Reaction Chemistry & Engineering. Synthesis and crystal characteristics of nirmatrelvir. 2023, 8: 1747-1759). Among them, the crystalline form of nirmatrelvir is a solvent-free crystalline form.

[0102] 15 mg of nirmatrelvir API (purity 98.43%) and 3.7 mg of 4-dimethylaminopyridine were dissolved in 0.4 mL of methyl acetate, heated and stirred at 40 - 50 °C for 10 min to dissolve, filtered, and the filtrate was allowed to evaporate naturally at room temperature. After 5 days, white blocky crystals appeared, which is nirmatrelvir 4-dimethylaminopyridine cocrystal. The crystal form yield was 99.8%, and the purity measured by HPLC reached 99.95%.

[0103] The single crystal sample obtained in Example 1 was determined by single crystal X-ray diffraction, and the obtained sample was the co-crystal molecular structure diagram, as Figure 1 shown.

[0104] It is composed of 1 molecule of nirmatrelvir and 1 molecule of 4-dimethylaminopyridine. It is an orthorhombic crystal, its space group is P212121, and its unit cell parameters are α = 90.00°, β = 90.00° and γ = 90.00°, and its unit cell volume is

[0105] After the sample of Example 1 was ground, it was determined by X-ray powder diffraction pattern. The X-ray powder diffraction pattern and the single crystal simulated powder pattern are as Figure 2 shown. The specific data of the X-ray powder diffraction expressed in 2θ angle are shown in Table 4. It was confirmed that there was no crystal form transformation before and after the sample was ground, and the measured pattern was consistent with the single crystal diffraction simulated pattern, indicating that nirmatrelvir 4-dimethylaminopyridine is a pure crystal form.

[0106] Table 4

[0107]

[0108]

[0109] The hydrogen spectrum of the sample of Example 1 was measured as Figure 4 shown. The specific information of the hydrogen spectrum is as follows:

[0110] 1 H NMR(600MHz,DMSO-d6)δ9.40(s,1H),9.01(s,1H),7.66(s,1H),4.97(ddd,J=10.8,8.5,5.1Hz,1H),4.41(s,1H),4.15(s,1H),3.91(dd,J=10.4,5.5Hz,1H),3.79(s,2H),3.69(d,J=10.4Hz,1H),3.14(t,J=9.1Hz,1H),3.04(td,J=9.3,7.1Hz,1H),2.44–2.34(m,1H),2.19–2.04(m,2H),2.01(s,3H),1.85(s,1H),1.76–1.64(m,2H),1.57(dd,J=7.6,5.5Hz,1H),1.32(d,J=7.6Hz,1H),1.03(s,3H),0.98(s,9H),0.88(s,6H),0.85(s,3H)[nirmatrelvir];8.10(dd,2H),6.58(dd,2H),2.93(s,6H)[4-dimethylaminopyridine]. The NMR data indicate that the molar ratio of nirmatrelvir API and 4-dimethylaminopyridine is 1:1.

[0111] The differential scanning calorimetry diagram of the sample of Example 1 is as Figure 3 shown. It can be seen from Figure 3 that the first endothermic peak of the eutectic appears at 184.14 °C, and the peak value of the endothermic peak appears at 190.73 °C.

[0112] The thermogravimetric analysis diagram of the sample of Example 1 is as Figure 3As shown, the eutectic starts to lose weight at 125°C, loses 19.50% of its weight at 260°C, and exactly loses all of the 4-dimethylaminopyridine in the eutectic at this point, indicating that the molar ratio of 4-dimethylaminopyridine to nirmatrelvir in the eutectic is 1:1; it starts to decompose at 260°C and decomposes completely at 350°C.

[0113] Example 2

[0114] Preparation of nirmatrelvir 4-dimethylaminopyridine eutectic

[0115] The crystal form of nirmatrelvir raw material drug was synthesized and characterized by crystal structure according to the method disclosed by Jiang et al. in (Reaction Chemistry & Engineering. Synthesis and crystal characteristics of nirmatrelvir. 2023, 8: 1747-1759). Among them, the crystal form of nirmatrelvir is a solvent-free crystal form.

[0116] Dissolve 15 mg of nirmatrelvir raw material drug (the same as in Example 1) (purity 98.43%) and 3.7 mg of 4-dimethylaminopyridine in 0.4 mL of isopropyl acetate solvent, heat and stir to dissolve clear at 40-50°C, stir at room temperature for 2 hours, filter after a white suspension appears, and dry at 25°C at room temperature. The yield is 99.2%, and the purity measured by HPLC is 99.90%. The obtained crystal form was detected by X-ray powder diffraction, and the X-ray powder diffraction pattern is basically consistent with Figure 2 The results are basically the same, and the characteristic peak positions are shown in Table 4.

[0117] Example 3

[0118] The inventors studied and compared the crystal forms of nirmatrelvir isobutyl acetate solvate, nirmatrelvir isopropanol solvate, nirmatrelvir ethyl acetate solvate, nirmatrelvir methyl tert-butyl ether solvate, the raw crystal form of nirmatrelvir and the nirmatrelvir 4-dimethylaminopyridine eutectic crystal form of this application.

[0119] Test samples:

[0120] The crystal form of nirmatrelvir raw material drug was synthesized according to the method disclosed by Jiang et al. in (Reaction Chemistry & Engineering. Synthesis and crystal characteristics of nirmatrelvir. 2023, 8: 1747-1759) and was confirmed as the nirmatrelvir raw material drug crystal form in the article by XRPD;

[0121] The isobutyl acetate solvate crystal form of nirmatrelvir was prepared by the method of patent CN116462735A and confirmed by XRPD to be the isobutyl acetate solvate crystal form of nirmatrelvir in patent CN116462735A;

[0122] The isopropyl alcohol solvate crystal form of nirmatrelvir was prepared by the preparation method in patent CN114644681A and confirmed by XRPD to be the isopropyl alcohol solvate crystal form of nirmatrelvir prepared in patent CN114644681A;

[0123] The methyl tert-butyl ether solvate crystal form of nirmatrelvir was prepared by the preparation method in patent WO2021250648A1 and confirmed by XRPD to be the methyl tert-butyl ether solvate crystal form of nirmatrelvir prepared in patent WO2021250648A1;

[0124] The ethyl acetate solvate crystal form of nirmatrelvir was prepared by the preparation method of Stier et al. in the article (Acta Pharmaceutica Sinica 2023, 58(10): 3116 - 3122). The purity of the nirmatrelvir raw material used was 98.43%; it was confirmed by XRPD to be the ethyl acetate solvate crystal form of nirmatrelvir prepared in the article.

[0125] Investigation conditions: 1. Equilibrium solubility test

[0126] The equilibrium solubility test measures the concentration of a compound when the solution and the solid are in equilibrium when there is an excess of solid in the saturated solution, which is a dynamic equilibrium process of solid dissolution and precipitation from the solution. It can be used to evaluate the solubility of drugs in vitro.

[0127] Accurately weigh 100.0 mg of the sample (purity 98.43%) and add it to screw-cap test tubes containing 20 mL of pH 1.2 HCl medium (simulating gastric juice) and neutral phosphate buffer saline medium (pH 6.8) respectively. Stir the suspension at 100 rpm, and the water bath temperature is 37°C. After 3 days, collect 1 mL of the solution from each test tube and dilute it to 10 mL. Take aliquots (2 mL), filter through a 0.45 μm membrane filter, and analyze using HPLC, and then conduct the solubility test in triplicate.

[0128] Standard curve: Weigh accurately 10.0 mg of the sample (purity 98.43%) and add it to a 10 mL volumetric flask. Then dilute it to a stock solution of 1.00 mg / mL with acetonitrile and water in a ratio of 1:1. Dilute the stock solution with acetonitrile to standard working solutions with concentrations of 0.00625 mg / ml, 0.0125 mg / ml, 0.025 mg / mL, 0.05 mg / ml, 0.1 mg / mL, and 0.2 mg / ml. Using acetonitrile as the blank control, record the regression equation for the relationship between the concentration (mg / mL) and the peak area (mAu·min).

[0129] Experimental results and discussion: The linear regression equation is Y = 0.1183 + 91.15224X, R 2 = 0.99995, as Figure 5 shown. The solubility data of nirmatrelvir isobutyl acetate solvate crystal form, nirmatrelvir isopropyl alcohol solvate crystal form, nirmatrelvir methyl tert-butyl ether solvate crystal form, nirmatrelvir ethyl acetate solvate crystal form, nirmatrelvir API crystal form, and nirmatrelvir 4-dimethylaminopyridine cocrystal form after three days are shown in Table 5.

[0130] Table 5

[0131]

[0132] As can be seen from Table 5, the nirmatrelvir 4-dimethylaminopyridine cocrystal form has good solubility at both pH 1.2 and 6.8, which are 1.09 mg / ml and 1.11 mg / ml respectively. The nirmatrelvir API crystal form has low solubility at both pH 1.2 and 6.8, which are 0.81 and 0.78 mg / ml respectively. The solubility of the other solvates is close to that of the API crystal form and is not as good as that of the nirmatrelvir 4-dimethylaminopyridine cocrystal prepared in this application.

[0133] Investigation conditions: 2. Intrinsic dissolution test

[0134] Intrinsic dissolution measurement is very important in the development process of chemical drugs because it can predict potential bioavailability problems.

[0135] Powder samples (100 mg of nirmatrelvir API crystal form, 100 mg of nirmatrelvir isobutyl acetate solvate crystal form, 100 mg of nirmatrelvir isopropyl alcohol solvate crystal form, 100 mg of nirmatrelvir methyl tert-butyl ether solvate crystal form, 100 mg of nirmatrelvir ethyl acetate solvate crystal form, and 100 mg of nirmatrelvir 4-dimethylaminopyridine cocrystal form) were pressed into a steel cylinder (cylinder diameter 6.0 mm). The dissolution medium was 1000 mL of deionized water. Thirteen sampling time points were set at 3 min, 5 min, 7 min, 10 min, 15 min, 20 min, 25 min, 30 min, 45 min, 60 min, 90 min, and 120 min. The water bath temperature was maintained at 37 ± 0.2 °C. Each time 2 mL of the sample was taken, and the same volume of the dissolution medium was replenished simultaneously. Insoluble particles were filtered out with a 0.45 μm membrane, and the same volume of the dissolution medium was replenished simultaneously. 1 mL of the mother liquor was taken and added to 0.5 mL of acetonitrile solution to prepare the injection solution. After the solution was filtered, it was detected by a high-performance liquid chromatograph, and the concentration of the drug at each time point was calculated according to the standard curve. A total of 3 groups of parallel experiments were carried out.

[0136] The intrinsic dissolution value was calculated according to formula (1):

[0137] G = (dw / dt) / S (1)

[0138] In the formula: G is the intrinsic dissolution value (μg / min / cm 2 ); dw is the change in drug dissolution (μg); dt represents the change in time (min); S represents the compressed surface area (cm 2 ).

[0139] The results are shown in Table 6 and Figure 6 as follows.

[0140] Table 6

[0141]

[0142] As can be seen from Table 6, the lowest intrinsic dissolution value of the nirmatrelvir API crystal form was 0.002 mg / min / cm 2 , the intrinsic dissolution value of the nirmatrelvir isobutyl acetate solvate crystal form was 0.0865 mg / min / cm 2 , the intrinsic dissolution value of the nirmatrelvir isopropyl alcohol solvate crystal form was 0.0897 mg / min / cm 2 , the intrinsic dissolution value of the nirmatrelvir methyl tert-butyl ether solvate crystal form was 0.1161 mg / min / cm 2 , the intrinsic dissolution value of the nirmatrelvir ethyl acetate solvate crystal form was 0.0615 mg / min / cm 2。The highest intrinsic dissolution rate of the nirmatrelvir 4-dimethylaminopyridine co-crystal form is 0.1478 mg / min / cm 2 , which is 73 times that of the API crystal form. The order of their intrinsic dissolution rates is: nirmatrelvir 4-dimethylaminopyridine co-crystal form > nirmatrelvir methyl tert-butyl ether solvate crystal form > nirmatrelvir isopropanol solvate crystal form > nirmatrelvir isobutyl acetate solvate crystal form > nirmatrelvir API crystal form. Generally, the nirmatrelvir 4-dimethylaminopyridine co-crystal form is considered to have a higher bioavailability.

[0143] Investigation conditions: 3. Particle size distribution test

[0144] Particle morphology and particle size can affect the rearrangement and interaction mode of powder particles in the tablet press die, and thus determine the final properties of the powder. Particle morphology will affect the mode of particle rearrangement in the plane and determine the type of particle bonding, such as interlocking or bonding in the form of solid bridges. During the compression process of drug powder particles, particle shape and surface roughness will affect the tableting performance of the powder. The friction and adhesion between irregularly shaped particles with a rough surface are enhanced, resulting in enhanced tableting performance of the powder.

[0145] The obtained samples of nirmatrelvir 4-dimethylaminopyridine co-crystal form, nirmatrelvir methyl tert-butyl ether solvate crystal form, nirmatrelvir isopropanol solvate crystal form, nirmatrelvir isobutyl acetate solvate crystal form, and nirmatrelvir API crystal form were ground and passed through a 300-mesh sieve, and then tested on a HELOS (H4605) & OASISDRY / L laser particle size analyzer. Each sample was tested in parallel three times. Using a pressure of 1 bar, a vacuum of 32 mbar, an injection rate of 30%, the test was started when Copt≥0.5%, and the data between 0.5%≤Copt≤5% of the effective test were taken, and D 10 , D 50 , D 90 were used to evaluate the particle size distribution.

[0146] Table 7

[0147]

[0148] Note: "**" represents the RSD of the results of three parallel tests for each sample.

[0149] As can be seen from Table 7, the D 10 of the 4-dimethylaminopyridine co-crystal form is 4.90±0.06 μm, the D 50 is 19.65±1.68 μm, and the D 90 is 224.08±5.03 μm, having a relatively uniform powder particle size. During the compression process of drug powder particles, it enhances the tableting performance of the powder and is more conducive to the tableting process of the preparation.

Claims

1. A eutectic of a compound represented by Formula I, characterized in that, In the eutectic, the molar ratio of nirmatrelvir to 4-dimethylaminopyridine is 1:

1. The X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation has diffraction peaks at 7.162±0.2°, 11.519±0.2°, 11.978±0.2°, 12.199±0.2°, 13.502±0.2°, 14.361±0.2°, 15.182±0.2°, 15.481±0.2° and 15.718±0.2°; 2. The eutectic according to claim 1, wherein The X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation also has diffraction peaks at one or more of the following positions: 16.804±0.2°, 17.697±0.2°, 18.438±0.2°, 18.642±0.2°, 19.796±0.2°, 20.297±0.2°, 20.541±0.2°, 20.941±0.2° and 21.359±0.2°.

3. The eutectic according to claim 2, characterized in that, The X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation also has diffraction peaks at one or more of the following positions: 21.860±0.2°, 22.579±0.2°, 22.737±0.2°, 22.959±0.2°, 23.242±0.2°, 24.680±0.2°, 25.222±0.2°, 25.419±0.2° and 27.182±0.2°.

4. The eutectic according to claim 3, characterized in that, The X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation, the positions and relative intensities of the diffraction peaks are shown in the following table:

5. The eutectic according to claim 4, characterized in that, The eutectic uses Cu-Kα radiation The X-ray powder diffraction pattern represented by 2θ angle, the positions of the diffraction peaks, interplanar spacings, peak heights, relative intensities of peak heights, peak areas, relative intensities of peak areas and full widths at half maximum are shown in the following table:

6. The eutectic according to claim 1, characterized in that, The eutectic satisfies one or more of the following conditions: 1) For the eutectic, its X-ray powder diffraction pattern represented by 2θ angle using Cu-Kα radiation is basically as shown in Figure 2; 2) For the eutectic, the first endothermic peak in the differential scanning calorimetry analysis diagram appears at 184.14℃±3℃, and the peak value of the endothermic peak appears at 190.73℃±3℃; 3) For the eutectic, weight loss starts at 125℃±3℃ in the thermogravimetric analysis diagram; and 4) For the eutectic, 19.50% weight loss occurs at 260℃±3℃ in the thermogravimetric analysis diagram.

7. The eutectic according to claim 1, wherein The eutectic satisfies one or more of the following conditions: 1) The eutectic is orthorhombic, with a space group of P212121 and lattice parameters of α = 90.00°, β = 90.00°, and γ = 90.00°, and its unit cell volume is 2) For the eutectic, its differential scanning calorimetry analysis diagram is basically as shown in Figure 3; and 3) For the eutectic, its thermogravimetric analysis diagram is basically as shown in Figure 3.

8. A method for preparing a eutectic as described in any one of claims 1-7, characterized in that, Nirmatrelvir is crystallized in a solvent to obtain the eutectic; wherein, the solvent is 4-dimethylaminopyridine, a mixed solvent of 4-dimethylaminopyridine and methyl acetate, or a mixed solvent of 4-dimethylaminopyridine and isopropyl acetate.

9. The method for preparing a eutectic according to claim 8, wherein The preparation method of the eutectic satisfies one or more of the following conditions: 5) The mass ratio of the nirmatrelvir to the 4-dimethylaminopyridine is 1:(0.1 - 0.5), preferably 1:0.2, 1:0.25 or 1:0.3; 6) The mass-volume ratio of the 4-dimethylaminopyridine to the methyl acetate is (5 - 15) g / mL, preferably 8 g / mL, 9.25 g / mL or 10 g / mL; 7) The mass-volume ratio of the 4-dimethylaminopyridine to the isopropyl acetate is (5 - 15) g / mL, preferably 8 g / mL, 9.25 g / mL or 10 g / mL; 8) The cocrystal is prepared by heating and dissolving, and the temperature of the heating is preferably 40 - 50 °C; 9) The way of crystal precipitation is natural evaporation crystallization or cooling crystallization; the way of natural evaporation crystallization can be natural evaporation crystallization after naturally cooling to room temperature after heating and dissolving; the cooling crystallization can be crystallization after cooling to room temperature after heating and dissolving; and 10) After the crystallization, the following post-treatment steps are further included: filtration and drying; the filtration can be filtration under normal temperature and pressure; the drying can be drying under normal temperature and pressure.

10. Use of a cocrystal according to any one of claims 1 - 7 in the preparation of an anti-COVID-19 drug.

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