Drug-drug salt of CDK4 / 6 inhibitor and salicylic acid and application thereof

Abstract

The invention provides a medicine-medicine salt of a CDK4 / 6 inhibitor and salicylic acid, a crystal of the medicine-medicine salt, a preparation method of the crystal, a medicine composition containing the crystal and application of the medicine-medicine salt. In the medicine-medicine salt, the CDK4 / 6 inhibitor and a salicylic acid medicine are connected through an intermolecular ionic bond. The drug-drug salt obtained by the invention can realize the synergistic interaction of the CDK4 / 6 inhibitor and salicylic acid, improve the anti-tumor activity of the CDK4 / 6 inhibitor, improve the solubility of the CDK4 / 6 inhibitor, and improve the physical stability and bioavailability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a drug-drug salt of CDK4 / 6 inhibitor and salicylic acid, crystals of the drug-drug salt, preparation methods thereof, pharmaceutical compositions comprising the same, and their applications. Background Technology

[0002] In the field of drug development, the solubility of a drug is one of the key factors determining its oral absorption efficiency and bioavailability. Studies have shown that over 70% of marketed small-molecule chemical drugs suffer from insufficient solubility or limited dissolution, making solubility a significant bottleneck restricting in vivo absorption and clinical efficacy. For oral antitumor drugs, limited solubility not only reduces bioavailability and increases inter-individual variability, but also affects patient compliance and long-term medication safety.

[0003] Cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors are key cell cycle regulators that inhibit tumor cell proliferation by preventing tumor cells from transitioning from the G1 phase to the S phase. Currently, these drugs are primarily used to treat hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer, usually in combination with endocrine therapy, which can significantly prolong patient survival. However, the clinical application of CDK4 / 6 inhibitors is also accompanied by a series of adverse reactions, mainly including hematological toxicities such as neutropenia and thrombocytopenia, as well as non-hematological toxicities such as diarrhea, nausea, and fatigue. These adverse reactions are closely related to poor drug solubility and poor absorption. The molecular structure of a CDK4 / 6 inhibitor is shown in formula (I):

[0004] Ⅰ Currently, CDK4 / 6 inhibitors such as ribociclib, palbociclib, and abecilib, which are already on the market, all suffer from low solubility. Low solubility not only limits the drug's bioavailability, leading to unstable efficacy, but may also exacerbate gastrointestinal irritation and other side effects due to excessively high local concentrations or incomplete absorption, thus affecting its clinical efficacy and safety. Studies have shown that ribociclib bases have good water solubility (>2.4 mg / mL) in the low pH environment of the stomach (1.2-4.5), but its solubility decreases sharply (≤0.2 mg / mL) as the pH increases. This change in solubility may cause the drug to precipitate in the intestine, thereby affecting its absorption and bioavailability. Studies have shown that the absolute oral bioavailability of 600 mg ribociclib tablets is 65.8%. Similarly, palbociclib, a weak base drug, also exhibits significant pH dependence and is classified as a BCS class II drug. Palbociclib exhibits good water solubility at low pH levels (1.2-4.5), leading to significant gastric irritation and side effects such as nausea and vomiting. Conversely, palbociclib shows poor water solubility (2.9 μg / mL) at pH 6.8 and 7.4, potentially causing slow drug precipitation and dissolution in the intestines, thus affecting its absorption and bioavailability. Clinical studies have shown that the absolute bioavailability of palbociclib after oral administration is approximately 46%. Abecibide also exhibits a significant pH-dependent solubility, with extremely low solubility in basic water. However, in acidic environments, its solubility increases significantly due to protonation, facilitating drug dissolution in the stomach. As the drug enters the small intestine, the pH rises, causing abecibide's solubility to drop sharply, resulting in incomplete absorption and limited bioavailability (approximately 45%). This strong pH-dependent solubility variation is the main reason for its poor absorption and significant individual variability.

[0005] Salicylic acid, with the structural formula shown below, is an organic acid with antipyretic, anti-inflammatory, analgesic, and keratolytic effects. Clinically, it is widely used to treat inflammatory skin diseases such as acne and seborrheic dermatitis, as well as keratotic hyperplasia such as psoriasis, warts, corns, and calluses. As an over-the-counter topical medication, salicylic acid has advantages such as low price, ease of use, and low likelihood of dependence and bacterial resistance, making it a commonly used basic drug for inflammatory and keratotic skin diseases. Furthermore, salicylic acid has good water solubility at room temperature, with a solubility ≥2 mg / mL in water.

[0006]

[0007] Currently, improving the antitumor activity of CDK4 / 6 inhibitors, reducing their single-dose dosage, and improving their solubility in a neutral pH environment are urgent technical problems to be solved. Summary of the Invention

[0008] Objective of the Invention: To address the shortcomings of existing technologies, this invention provides a drug-drug salt of CDK4 / 6 inhibitor and salicylic acid, crystals of the drug-drug salt, its preparation method, pharmaceutical compositions comprising the same, and their applications. The CDK4 / 6 inhibitor drug-drug salt provided by this invention achieves synergistic effects between the CDK4 / 6 inhibitor and salicylic acid, increasing the antitumor activity of the CDK4 / 6 inhibitor, and exhibits high solubility and good stability, thereby improving bioavailability. Furthermore, its preparation method is simple, easily reproducible, and suitable for industrial production.

[0009] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: In a first aspect, the present invention provides a drug-drug salt of CDK4 / 6 inhibitor and salicylic acid, wherein the CDK4 / 6 inhibitor and salicylic acid are connected by intermolecular ionic bonds in the drug-drug salt.

[0010] As one implementation scheme, the CDK4 / 6 inhibitor is selected from ribociclib, palbociclib, and abecilib.

[0011] In one embodiment, in the drug-drug salt of CDK4 / 6 inhibitor and salicylic acid, the molar ratio of CDK4 / 6 inhibitor to salicylic acid is approximately 1:1.

[0012] As one implementation scheme, the drug-drug salt is ribociclib-salicylic acid drug-drug salt.

[0013] As one implementation, the ribociclib-salicylic acid drug-drug salt is wherein the molar ratio of ribociclib to salicylic acid is approximately 1:1.

[0014] As one implementation, the ribociclib-salicylic acid drug-drug salt is a crystal.

[0015] As one implementation scheme, the ribociclib-salicylic acid drug-drug salt crystal is a monoclinic crystal with space group P21 / c and cell parameters of: a=7.5027(2)Å, b=17.1408(5)Å, c=22.8591(7)Å, α=90°, β=93.342(2)°, γ=90°, and cell volume of 2934.73(15)Å. 3 ; As one implementation scheme, the single-crystal structure diagram of the ribociclib-salicylic acid drug-drug salt crystal is basically as follows: Figure 1 As shown.

[0016] As one embodiment, the powder X-ray diffraction pattern of the ribociclib-salicylic acid drug-drug salt crystal includes the following characteristic peaks at 2θ angles: 7.612°, 8.945°, 9.728°, 10.666°, 11.148°, 11.795°, 12.872°, 14.414°, 15.721°, 16.839°, 17.592°, 19.509°, 19.750°, 20.929°, 22.400°, 22.400°, and 27.318°, with a 2θ value accuracy of ±0.2°; As one embodiment, the powder X-ray diffraction pattern of the ribociclib-salicylic acid drug-drug salt crystal, expressed in terms of diffraction angle 2θ, is essentially as follows: Figure 3 As shown.

[0017] As one implementation, the infrared absorption spectrum of the ribociclib-salicylic acid drug-drug salt crystals, measured using KBr pellets, is at 3733.69 cm⁻¹. -l 3648.05 cm -l 3443.51 cm -l 3228.27 cm -l 2957.03 cm -l 1867.49 cm -l 1747.64 cm -l 1730.42 cm -l 1621.51 cm -l 1613.99 cm -l 1532.79 cm -l 1488.18 cm -l 1426.06 cm -l 1397.42 cm -l 1248.50 cm -l 1141.31 cm -l 931.48 cm -l 857.66 cm -l 760.63 cm -l 678.51 cm -l There is an absorption peak at that point.

[0018] As one implementation scheme, the differential scanning calorimetry curve of the ribociclib-salicylic acid drug-drug salt crystals has an endothermic peak at 262.3±1℃.

[0019] As one implementation scheme, the DSC spectrum of the ribociclib-salicylic acid drug-drug salt crystal is basically as follows: Figure 2 As shown (RBC-SA group).

[0020] As one implementation scheme, the thermogravimetric analysis curve of the ribociclib-salicylic acid drug-drug salt crystals shows weight loss starting at 254.5±1℃, corresponding to the melting and decomposition process of the ribociclib-salicylic acid drug-drug salt crystals.

[0021] As one implementation scheme, the TG spectrum of the ribociclib-salicylic acid drug-drug salt crystals is basically as follows: Figure 5 As shown.

[0022] As one implementation scheme, the drug-drug salt is palbociclib-salicylic acid drug-drug salt.

[0023] As one embodiment, the palbociclib-salicylic acid drug-drug salt is wherein the molar ratio of palbociclib to salicylic acid is approximately 1:1.

[0024] As one implementation, the palbociclib-salicylic acid drug-drug salt is in the form of crystals.

[0025] As one implementation scheme, the palbociclib-salicylic acid drug-drug salt crystal is a monoclinic crystal system with space group P 21 / n and cell parameters of a=8.44457(18), b=16.0686(4), c=20.5888(5), α=95.965(2), β=90, γ=90, and cell volume of 2778.62(11). As one implementation scheme, the single-crystal structure diagram of the palbociclib-salicylic acid drug-drug salt crystal is basically as follows: Figure 8 As shown.

[0026] As one embodiment, the powder X-ray diffraction pattern of the palbociclib-salicylic acid drug-drug salt crystal includes the following characteristic peaks at 2θ angles: 7.035°, 10.188°, 11.796°, 13.959°, 16.168°, 16.913°, 18.330°, 19.629°, 20.665°, 21.838°, 22.398°, 23.740°, 25.033°, 26.309°, 28.182°, and 30.587°, with a 2θ value accuracy of ±0.2°.

[0027] As one embodiment, the powder X-ray diffraction pattern of the palbociclib-salicylic acid drug-drug salt crystal, expressed in terms of diffraction angle 2θ, is essentially as follows: Figure 10 As shown.

[0028] As one embodiment, the infrared absorption spectrum of the palbociclib-salicylic acid drug-drug salt crystals, measured using KBr pellets, is at 3454.03 cm⁻¹. -l3427.67 cm -l 1704.83 cm -l 1629.62 cm -l 1575.62cm -l 1519.65 cm -l 1444.4 cm -l 1378.91 cm -l 1371.91 cm -l 1286.34cm -l 1139.77 cm -l 856.27cm -l 769.49 cm -l There is an absorption peak at that point.

[0029] As one implementation, the differential scanning calorimetry curve of the palbociclib-salicylic acid drug-drug salt crystals shows an endothermic peak at 256.4±1℃.

[0030] As one implementation scheme, the DSC spectrum of the palbociclib-salicylic acid drug-drug salt crystals is basically as follows: Figure 9 As shown (PAL-SA group).

[0031] As one implementation scheme, the thermogravimetric analysis curve of the palbociclib-salicylic acid drug-drug salt crystal shows significant weight loss at 243.3±1℃, corresponding to the melting and decomposition process of the palbociclib-salicylic acid drug-drug salt crystal.

[0032] As one implementation scheme, the TG curve of the palbociclib-salicylic acid drug-drug salt crystals is basically as follows: Figure 12 As shown.

[0033] As one implementation scheme, the drug-drug salt is abexilide-salicylic acid drug-drug salt.

[0034] As one implementation, the abecitabine-salicylic acid drug-drug salt is wherein the molar ratio of abecitabine to salicylic acid is approximately 1:1.

[0035] As one implementation, the abecitabine-salicylic acid drug-drug salt is a crystal.

[0036] As one embodiment, the abecicilline-salicylic acid drug-drug salt crystal is an orthorhombic crystal with space group Pna21 and cell parameters of: a=10.6092(1), b=13.6309(1), c=44.2976(5), α=90, β=90, γ=90, and cell volume of 6406.01(11). As one implementation scheme, the single-crystal structure diagram of the abecicilline-salicylic acid drug-drug salt crystal is basically as follows: Figure 15 As shown.

[0037] As one embodiment, the powder X-ray diffraction pattern of the abecicilline-salicylic acid drug-drug salt crystal includes the following characteristic peaks at 2θ angles: 6.749°, 7.951°, 10.666°, 11.888°, 12.949°, 13.165°, 15.860°, 17.419°, 18.236°, 19.894°, 20.575°, 21.456°, 22.778°, 22.898°, 24.340°, 24.796°, 25.925°, 27.488°, 28.954°, and 32.606°, with a 2θ value accuracy of ±0.2°.

[0038] As one embodiment, the powder X-ray diffraction pattern of the abecicilline-salicylic acid drug-drug salt crystal, expressed in terms of diffraction angle 2θ, is essentially as follows: Figure 17 As shown.

[0039] As one embodiment, the infrared absorption spectrum of the abecicilline-salicylic acid drug-drug salt crystals, measured using KBr pellets, is at 3234.81 cm⁻¹. -l 3226.26 cm -l 3089.53 cm -l 1635.40cm -l 1585.26cm -l 1531.26 cm -l 1484.98cm -l 1456.05cm -l 1434.88 cm -l 1400.12cm -l 1349.98cm -l 1292.12cm -l 1245.84cm -l 1151.32 cm -l 1066.48cm -l 860.13 cm -l 809.99 cm -l 759.84 cm -l 667.27cm -l There is an absorption peak at that point.

[0040] As one implementation, the differential scanning calorimetry curve of the abecicilline-salicylic acid drug-drug salt crystals shows an endothermic peak at 228.9±1℃.

[0041] As one implementation scheme, the DSC spectrum of the abecicilline-salicylic acid drug-drug salt crystal is basically as follows: Figure 16 As shown (ABE-SA group).

[0042] As one implementation scheme, the thermogravimetric analysis curve of the abecitabine-salicylic acid drug-drug salt crystals shows weight loss starting at 228.4±1℃, corresponding to the melting and decomposition process of the abecitabine-salicylic acid drug-drug salt crystals.

[0043] As one implementation scheme, the TG curve of the abecicilline-salicylic acid drug-drug salt crystal is basically as follows: Figure 19 As shown.

[0044] Secondly, the present invention provides a method for preparing the above-mentioned CDK4 / 6 inhibitor and salicylic acid drug-drug salt, the preparation method including solution method and liquid-assisted grinding method.

[0045] As a specific implementation plan, the solution method includes the following steps: The CDK4 / 6 inhibitor was added to an organic solvent to obtain system A; Salicylic acid was added to an organic solvent and mixed to obtain system B; Mix system A and system B to obtain system C, and let it stand; Filter, wash, collect filter cake, and dry to obtain the drug-drug salt of CDK4 / 6 inhibitor and salicylic acid; As one implementation scheme, in step 1), the organic solvent is selected from halogenated alkyl solvents or alcohol solvents.

[0046] As one implementation, in step 2), the organic solvent is selected from one or more of ketone solvents, alcohol solvents, alkyl nitrile solvents, haloalkyl solvents, alkyl sulfoxide solvents, or cyclic ether solvents.

[0047] As one embodiment, in step 2), the organic solvent is selected from one or more of the following: C1-C6 ketone solvents, C1-C6 alcohol solvents, C1-C6 alkyl nitrile solvents, C1-C6 haloalkyl solvents, C1-C6 alkyl sulfoxide solvents, or C1-C6 cyclic ether solvents.

[0048] As one implementation, in step 2), the organic solvent is selected from one or more of acetone, methanol, ethanol, isopropanol, chloroform, acetonitrile, ethyl acetate, or dimethyl sulfoxide.

[0049] In one implementation scheme, in step 2), the organic solvent is selected from methanol or acetonitrile.

[0050] As one implementation scheme, in step 3), the total mass ratio of CDK4 / 6 inhibitor and salicylic acid to the total volume ratio of solvent in system C is 4-6 mg / ml.

[0051] As one implementation scheme, in step 3), the molar ratio of CDK4 / 6 inhibitor to salicylic acid is 1:1.

[0052] As one implementation scheme, in step 3), the standing conditions are: standing at 10-28℃ for 4-156 hours.

[0053] As a specific implementation scheme, the liquid-assisted grinding method includes the following steps: Take the CDK4 / 6 inhibitor and salicylic acid, and add them to the container; Add organic solvent and ball mill; After obtaining the sample, it is dried to obtain the drug-drug salt of CDK4 / 6 inhibitor and salicylic acid; As one implementation scheme, in step 1), the molar ratio of the CDK4 / 6 inhibitor to salicylic acid is 1:1.

[0054] In one implementation scheme, in step 2), the organic solvent is selected from alcohol solvents.

[0055] As one implementation, in step 2), the organic solvent is selected from C1-C6 alcohol solvents.

[0056] In one implementation scheme, in step 2), the organic solvent is selected from ethanol.

[0057] As one implementation scheme, in step 2), the ball milling conditions are: ball milling at a frequency of 15-25 Hz for 3-15 minutes.

[0058] Thirdly, the present invention provides a pharmaceutical composition comprising the CDK4 / 6 inhibitor and a drug-drug salt or crystals thereof of salicylic acid.

[0059] Fourthly, the present invention provides the use of the CDK4 / 6 inhibitor and salicylic acid drug-drug salt, or crystals thereof, or drug composition thereof, in the preparation of antitumor drugs.

[0060] As one implementation scheme, the tumor is selected from breast cancer, ovarian cancer, bladder cancer, non-small cell lung cancer, recurrent brain metastases, squamous cell carcinoma, or central nervous system tumors.

[0061] As one implementation scheme, the tumor is selected from breast cancer.

[0062] Beneficial effects: Compared with the prior art, the present invention has the following advantages: 1. The drug-drug salt of CDK4 / 6 inhibitor and salicylic acid provided by the present invention can achieve synergistic effect between CDK4 / 6 inhibitor and salicylic acid, thereby improving the anti-tumor activity of CDK4 / 6 inhibitor; 2. The drug-drug salt of CDK4 / 6 inhibitor and salicylic acid provided by the present invention can improve the solubility of CDK4 / 6 inhibitor, increase bioavailability, and has excellent physical stability.

[0063] 3. The method for preparing CDK4 / 6 inhibitors and salicylic acid drug-drug salts provided by this invention is simple to operate, has low energy consumption, is easy to repeat, has good product reproducibility, and high yield, making it suitable for industrial production.

[0064] Terminology Definitions and Explanations In the specification and claims of this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this disclosure, definitions and explanations of some related terms are provided below. Furthermore, in the event of any discrepancy between the definitions and explanations of terms provided herein and their commonly understood meanings by those skilled in the art, the definitions and explanations provided herein shall prevail.

[0065] The term "about" is used in this application to mean approximately, around, roughly, or approximately. When the term "about" is used in conjunction with a numerical range, the range is modified by expanding the upper and lower limits of the stated numerical range. Unless otherwise stated, the term "about" is used herein to modify the upper and lower limits of the stated value by a numerical value with a 10% deviation.

[0066] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. Attached Figure Description

[0067] Figure 1 This is a single-crystal structure diagram of ribociclib-salicylic acid drug-drug salt; Figure 2 DSC diagram of ribociclib-salicylic acid drug-drug salt crystals; Figure 3 PXRD pattern of ribociclib-salicylic acid drug-drug salt crystals; Figure 4 The IR spectrum of ribociclib-salicylic acid drug-drug salt crystals; Figure 5 The TG spectrum of ribociclib-salicylic acid drug-drug salt crystals; Figure 6 X-ray powder diffraction pattern for long-term stability test of ribociclib-salicylic acid drug-drug salt crystals; Figure 7 X-ray powder diffraction pattern of ribociclib-salicylic acid drug-drug salt crystals in accelerated stability test; Figure 8 This is a single-crystal structure diagram of palbociclib-salicylic acid drug-drug salt; Figure 9 DSC diagram of palbociclib-salicylic acid drug-drug salt crystals; Figure 10 PXRD pattern of palbociclib-salicylic acid drug-drug salt crystals; Figure 11 IR spectroscopy of palbociclib-salicylic acid drug-drug salt crystals; Figure 12 The TG spectrum of palbociclib-salicylic acid drug-drug salt crystals; Figure 13 X-ray powder diffraction pattern for long-term stability experiment of palbociclib-salicylic acid drug-drug salt crystals; Figure 14 X-ray powder diffraction pattern of palbociclib-salicylic acid drug-drug salt crystals in accelerated stability test; Figure 15 This is a single-crystal structure diagram of abexicillin-salicylic acid drug-drug salt; Figure 16 DSC diagram of abexicillin-salicylic acid drug-drug salt crystals; Figure 17 PXRD pattern of abecicilline-salicylic acid drug-drug salt crystals; Figure 18 IR spectroscopy of abexicillin-salicylic acid drug-drug salt crystals; Figure 19 The TG spectrum of abexicillin-salicylic acid drug-drug salt crystals; Figure 20 X-ray powder diffraction pattern for long-term stability experiment of abexicillin-salicylic acid drug-drug salt crystals; Figure 21 X-ray powder diffraction pattern of abexicillin-salicylic acid drug-drug salt crystals in accelerated stability experiment; Figure 22 The equilibrium solubility results of CDK4 / 6 inhibitor-salicylic acid drug-drug salt crystals in pH buffer solution; Detailed Implementation

[0068] The invention can be better understood from the following embodiments. However, the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0069] In the following examples, "PM" refers to a mixture of two single drugs physically mixed in a 1:1 molar ratio, such as... Figure 2 The RBC-SA-PM group represents the physical mixing of drug RBC and drug SA in a 1:1 molar ratio. Figure 9 The PAL-SA-PM group represents the physical mixing of drug PAL and drug SA in a 1:1 molar ratio. Figure 16 The ABE-SA-PM group represents the physical mixing of drug ABE and drug SA in a molar ratio of 1:1.

[0070] The instruments used in this invention for detecting the structure and properties of drug-drug salt crystals are as follows: The single-crystal X-ray diffractometer, detector model: Rigaku HyPix, uses a nitrogen atmosphere, low temperature 100K detection, stone mill monochromator, copper target X-ray, wavelength of 0.154178 Å; Bruker Apex2 CCD diffractometer, stone mill monochromator, molybdenum target X-ray, wavelength of 0.71073 Å.

[0071] Differential scanning calorimeter, Netzsch DSC 200F3, Germany. This invention uses a nitrogen atmosphere and a heating rate of 10K / min. X-ray powder diffractometer, manufactured by Panaco GmbH, Netherlands, model X'Pert PRO MPD, Cu-K(α), tube voltage 40kV, tube current 40mA, scanning speed 2° / min, 2θ range 3-60°; (4) Fourier transform infrared spectrometer, manufactured by Bruker GmbH, Germany, model Vertex 70, with an absorbance range of 4000–500 cm⁻¹. -l ; (5) Thermogravimetric analyzer, Netzsch TG 209F3, Germany. This invention uses a nitrogen atmosphere. The test temperature range is selected from room temperature to 800℃ (inclusive). The test mode is selected as heating curve. The specific test temperature range is 30~350 (℃). The heating rate is 10℃ / min.

[0072] Example 1: Preparation and Characterization of Rebociclib-Salicylic Acid Drug-Drug Salt Crystals (RBC-SA)

[0073] 1) Solution preparation 217.3 mg (0.5 mmol) of ribociclib was dissolved in 15 mL of dichloromethane, and 69.1 mg (0.5 mmol) of salicylic acid was dissolved in 8 mL of methanol. The two systems were then mixed in a test tube and allowed to stand at 20 ± 5 °C for 2 days. A solid precipitated out, which was filtered, washed with methyl tert-butyl ether, dried under vacuum, and collected to give 229.3 mg of the title compound. The product obtained is ribociclib-salicylic acid drug-drug salt crystals.

[0074] The single-crystal X-ray diffraction results of the drug-drug salt crystals obtained in Example 1 are as follows: Figure 1 As shown in the table below, the single-crystal data are as follows:

[0075] The differential thermal (DSC) spectrum of the ribociclib-salicylic acid drug-drug salt crystals obtained in Example 1 is shown below. Figure 2 As shown, the melting point of the drug-drug salt crystals is different from that of the active pharmaceutical ingredient and the co-formed drug. There is a single endothermic peak at 262.3℃, which proves that a new phase is formed.

[0076] The powder X-ray diffraction (PXRD) pattern of the ribociclib-salicylic acid drug-drug salt crystals obtained in Example 1 is shown below. Figure 3 As shown, characteristic peaks are observed at diffraction angles 2θ of 7.612°, 8.945°, 9.728°, 10.666°, 11.148°, 11.795°, 12.872°, 14.414°, 15.721°, 16.839°, 17.592°, 19.509°, 19.750°, 20.929°, 22.400°, 22.400°, and 27.318°, indicating the formation of a new crystalline phase. The XRPD diffraction peak parameters are shown in the table below.

[0077]

[0078] The infrared spectrum (IR) of the ribociclib-salicylic acid drug-drug salt crystals obtained in Example 1 is as follows: Figure 4 As shown: Due to intermolecular ionic interactions, the -NH- groups in ribociclib and the -COOH groups in the co-formed drug exhibit red shifts or blue shifts in the IR spectrum of ribociclib drug-drug salt crystals, at 3733.69 cm⁻¹. -l 3648.05 cm -l 3443.51 cm -l 3228.27 cm -l 2957.03 cm -l 1867.49 cm -l 1747.64 cm -l1730.42 cm -l 1621.51 cm -l 1613.99 cm -l 1532.79 cm -l 1488.18 cm -l 1426.06 cm -l 1397.42 cm -l 1248.50 cm -l 1141.31 cm -l 931.48 cm -l 857.66 cm -l 760.63 cm -l 678.51 cm -l The presence of a characteristic absorption peak further confirms the formation of ribociclib-salicylic acid drug-drug salt crystals.

[0079] The TG curve of the ribociclib-salicylic acid drug-drug salt crystals obtained in Example 1 is shown below. Figure 5 The diagram shows the weight loss starting at 262.3±1℃, corresponding to the melting and decomposition process of ribociclib-salicylic acid drug-drug salt crystals. (From...) Figure 5 Thermogravimetric analysis data of ribociclib and salicylic acid drug-drug salt crystals show that ribociclib and the co-formed drug do not have solvent weight loss peaks before their respective melting points, indicating that they do not contain solvent. After the temperature reaches the corresponding melting point range, the sample begins to decompose gradually.

[0080] 2) Preparation by liquid-assisted grinding method 217.3 mg (0.5 mmol) of ribociclib and 69.1 mg (0.5 mmol) of salicylic acid were added to a container, followed by the addition of 3 ml of ethanol. The container was then ball-milled at 15-25 Hz for 3-15 min. The resulting solid was vacuum-dried and collected to yield 0.26 g of the title compound. The product obtained is ribociclib-salicylic acid drug-drug salt crystals.

[0081] The differential thermal analysis (DSC) data of the obtained ribociclib-salicylic acid drug-drug salt crystals were the same as the melting point of the ribociclib-salicylic acid drug-drug salt crystals obtained by the solution method, which proved the formation of ribociclib-salicylic acid drug-drug salt crystals.

[0082] Example 2 Preparation and characterization of palbociclib-salicylic acid drug-drug salt crystals (PAL-SA)

[0083] 1) Solution preparation 223.75 mg (0.5 mmol) of palbociclib was dissolved in 12 mL of dichloromethane, and 69.1 mg (0.5 mmol) of salicylic acid was dissolved in 5 mL of methanol. The two systems were then mixed in a test tube and allowed to stand at 20 ± 5 °C for 7 days. Crystals precipitated, which were filtered, washed with methyl tert-butyl ether, dried under vacuum, and collected to give 251.8 mg of the title compound. The product obtained is palbociclib-salicylic acid drug-drug salt crystals.

[0084] The single-crystal X-ray diffraction results of the drug-drug salt crystals obtained in Example 2 are as follows: Figure 8 As shown in the table below.

[0085]

[0086] The differential thermal (DSC) spectrum of the palbociclib-salicylic acid drug-drug salt crystals obtained in Example 2 is shown below. Figure 9 As shown, the melting point of the drug-drug salt crystals is different from that of the active pharmaceutical ingredient and the co-formed drug. There is a single endothermic peak at 260.9℃, which proves that a new phase is formed.

[0087] The powder X-ray diffraction (PXRD) pattern of the palbociclib-salicylic acid drug-drug salt crystals obtained in Example 2 is shown below. Figure 10 As shown, characteristic peaks are present at diffraction angles 2θ of 7.035°, 10.188°, 11.796°, 13.959°, 16.168°, 16.913°, 18.330°, 19.629°, 20.665°, 21.838°, 22.398°, 23.740°, 25.033°, 26.309°, 28.182°, and 30.587°, indicating the formation of a new crystalline phase. The XRPD diffraction peak parameters are shown in the table below.

[0088]

[0089] The infrared spectrum (IR) of the palbociclib-salicylic acid drug-drug salt crystals obtained in Example 2 is as follows: Figure 11 As shown: Due to intermolecular ionic interactions, the -NH- groups in palbociclib and the -COOH groups in the co-formed drug exhibit red shifts or blue shifts in the IR spectrum of palbociclib drug-drug salt crystals, at 3454.03 cm⁻¹. -l 3427.67 cm -l 1704.83cm -l 1629.62 cm -l 1575.62cm -l 1519.65 cm -l 1444.4 cm -l1378.91 cm -l 1371.91 cm -l 1286.34cm -l 1139.77 cm -l 856.27cm -l 769.49 cm -l The presence of a characteristic absorption peak further confirms the formation of palbociclib-salicylic acid drug-drug salt crystals.

[0090] The TG curve of the palbociclib-salicylic acid drug-drug salt crystals obtained in Example 2 is shown below. Figure 12 The diagram shows the weight loss starting at 256.4±1℃, corresponding to the melting and decomposition process of palbociclib-salicylic acid drug-drug salt crystals. (From...) Figure 12 Thermogravimetric analysis data of palbociclib and salicylic acid drug-drug salt crystals show that palbociclib and the co-formed drugs have no solvent weight loss peaks before their respective melting points, indicating that they do not contain solvent. After the temperature reaches the corresponding melting point range, the sample begins to decompose gradually.

[0091] 2) Preparation by liquid-assisted grinding method 223.75 mg (0.5 mmol) of palbociclib and 69.1 mg (0.5 mmol) of salicylic acid were added to a container, followed by the addition of 3 ml of ethanol or acetonitrile. The container was then ball-milled at 15-25 Hz for 3-15 min. The resulting solid was vacuum-dried and collected to yield 0.30 g of the title compound. The product obtained is palbociclib-salicylic acid drug-drug salt crystals.

[0092] The differential thermal analysis (DSC) data of the obtained palbociclib-salicylic acid drug-drug salt crystals were the same as the melting point of the palbociclib-salicylic acid drug-drug salt crystals obtained by the solution method, which proved the formation of palbociclib-salicylic acid drug-drug salt crystals.

[0093] Example 3 Preparation and Characterization of Abecilibalycinate-Salicylic Acid Drug-Drug Salt Crystals (ABE-SA)

[0094] 1) Solution preparation 253.3 mg (0.5 mmol) of abexicillin was dissolved in 18 mL of methanol, and 69.1 mg (0.5 mmol) of salicylic acid was dissolved in 10 mL of isopropanol. The two systems were then mixed in a test tube and allowed to stand at 20 ± 5 °C for 3 days. Crystals precipitated, which were filtered, washed with methyl tert-butyl ether, dried under vacuum, and the crystals were collected to give 268.5 mg of the title compound. The product obtained is abexicillin-salicylic acid drug-drug salt crystals.

[0095] The single-crystal X-ray diffraction results of the drug-drug salt crystals obtained in Example 3 are as follows: Figure 15 As shown in the table below.

[0096]

[0097] The differential thermal (DSC) spectrum of the abexicillin-salicylic acid drug-drug salt crystals obtained in Example 3 is shown below. Figure 16 As shown, the melting point of the drug-drug salt crystals is different from that of the active pharmaceutical ingredient and the co-formed drug. There is a single endothermic peak at 228.9℃, which proves that a new phase is formed.

[0098] The powder X-ray diffraction (PXRD) pattern of the abexicillin-salicylic acid drug-drug salt crystals obtained in Example 3 is shown below. Figure 17 As shown, characteristic peaks are present at diffraction angles 2θ of 6.749°, 7.951°, 10.666°, 11.888°, 12.949°, 13.165°, 15.860°, 17.419°, 18.236°, 19.894°, 20.575°, 21.456°, 22.778°, 22.898°, 24.340°, 24.796°, 25.925°, 27.488°, 28.954°, and 32.606°, indicating the formation of a new crystalline phase. The XRPD diffraction peak parameters are shown in the table below.

[0099]

[0100] The infrared spectrum (IR) of the abecitabine-salicylic acid drug-drug salt crystals obtained in Example 3 is as follows: Figure 18 As shown: Due to intermolecular ionic interactions, the -NH- groups in abexicillin and the -COOH groups in the co-formed drug exhibit red shifts or blue shifts in the IR spectrum of abexicillin drug-drug salt crystals, at 3234.81 cm⁻¹. -l 3226.26 cm -l 3089.53cm -l 1635.40cm -l 1585.26cm -l 1531.26 cm -l 1484.98cm -l 1456.05cm -l 1434.88 cm -l 1400.12cm -l 1349.98cm -l 1292.12 cm -l 1245.84cm -l 1151.32 cm-l 1066.48cm -l 860.13cm -l 809.99 cm -l 759.84 cm -l 667.27cm -l The presence of a characteristic absorption peak further confirms the formation of abecicilline-salicylic acid drug-drug salt crystals.

[0101] The TG curve of the abexicillin-salicylic acid drug-drug salt crystals obtained in Example 3 is shown below. Figure 19 The diagram shows the weight loss starting at 228.4±1℃, corresponding to the melting and decomposition process of abexicillin-salicylic acid drug-drug salt crystals. (From...) Figure 19 Thermogravimetric analysis data of abexicillin and salicylic acid drug-drug salt crystals show that there are no solvent weight loss peaks before the corresponding melting point of abexicillin and the co-formed drug, indicating that there is no solvent in them. After the temperature reaches the corresponding melting point, the sample begins to decompose gradually.

[0102] 2) Preparation by liquid-assisted grinding method 253.3 mg (0.5 mmol) of abexicillin and 69.1 mg (0.5 mmol) of salicylic acid were added to a container, followed by the addition of 3 ml of ethanol. The container was then ball-milled at 15-25 Hz for 3-15 min. The resulting solid was vacuum-dried and collected to yield 0.38 g of the title compound. The product obtained is abexicillin-salicylic acid drug-drug salt crystals.

[0103] The differential thermal analysis (DSC) data of the obtained abexicillin-salicylic acid drug-drug salt crystals were the same as the melting point of the abexicillin-salicylic acid drug-drug salt crystals obtained by the solution method, which proved the formation of abexicillin-salicylic acid drug-drug salt crystals.

[0104] Example 4: Equilibrium Solubility Experiment

[0105] Excess CDK4 / 6 inhibitor and the resulting drug-drug salt crystals were placed in 20 mL glass tubes, and 5 mL of pH 7.4 phosphate buffer and pH 6.8 phosphate buffer were added respectively. The mixture was shaken thoroughly for 24 h at 37 ℃ and 100 rpm in a constant temperature shaker. The supernatant was filtered through a 0.45 μm organic membrane filter, and the collected filtrate was analyzed by Shimadzu liquid chromatography. The column chromatography used was a Shim-pack VP-ODS C18 (4.6 × 250 mm, 5.0 μm, Shimadzu), with a column temperature of 40 ℃. Mobile phase A was 1 / 1000 formic acid in water at a ratio of 1000:1, and mobile phase B was methanol-acetonitrile (50:50). The flow rate was 1 mL / min, the injection volume was 10 μL, and the detection wavelength was 237 nm.

[0106] Record the peak area and substitute it into the standard curve to calculate the equilibrium solubility, as follows: Figure 22 As shown, in pH 7.4 phosphate buffer solution, the solubility of ribociclib is 0.1122 mg / ml; the solubility of ribociclib in ribociclib-salicylic acid drug-drug salt crystals is 0.1508 mg / ml; the solubility of palbociclib is 0.0125 mg / ml; the solubility of palbociclib in palbociclib-salicylic acid drug-drug salt crystals is 0.0768 mg / ml; the solubility of abexicillin is 0.0095 mg / ml; and the solubility of abexicillin in abexicillin-salicylic acid drug-drug salt crystals is 1.2610 mg / ml. The results showed that the solubility of the obtained ribociclib-salicylic acid drug-drug salt crystals was 1.34 times higher than that of ribociclib, the solubility of palbociclib-salicylic acid drug-drug salt crystals was 6.12 times higher than that of palbociclib, and the solubility of abecitabine-salicylic acid drug-drug salt crystals was 131.90 times higher than that of abecitabine. In a pH 6.8 phosphate buffer solution, the solubility of ribociclib is 0.0156 mg / ml; the solubility of ribociclib in ribociclib-salicylic acid drug-drug salt crystals is 0.1567 mg / ml; the solubility of palbociclib is 0.0441 mg / ml; the solubility of palbociclib in palbociclib-salicylic acid drug-drug salt crystals is 0.1058 mg / ml; the solubility of abexicillin is 0.4252 mg / ml; and the solubility of abexicillin in abexicillin-salicylic acid drug-drug salt crystals is 1.2993 mg / ml. The results showed that the solubility of the obtained ribociclib-salicylic acid drug-drug salt crystals was 10.02 times higher than that of ribociclib, the solubility of palbociclib-salicylic acid drug-drug salt crystals was 2.40 times higher than that of palbociclib, and the solubility of abecitabine-salicylic acid drug-drug salt crystals was 3.06 times higher than that of abecitabine.

[0107] Example 5 Stability Experiment

[0108] Long-term stability tests were conducted on the obtained CDK4 / 6 inhibitor and salicylic acid drug-drug salt crystals using a constant temperature and humidity chamber. The crystals were stored for 4 weeks at 25±2℃ and 60±5% relative humidity, and samples were taken at 0 days, 2 weeks, and 4 weeks for X-ray powder diffraction analysis. (See relevant spectra...) Figure 6 , Figure 13 and Figure 20 As shown in the figure, the X-ray powder diffraction pattern remains unchanged, indicating that the crystal structure has not changed and its thermal stability is good.

[0109] Accelerated stability tests were conducted on the obtained CDK4 / 6 inhibitor and salicylic acid drug-drug salt crystals using a constant temperature and humidity chamber. The crystals were stored for 4 weeks at 40±2℃ and 75±5% relative humidity, and samples were taken at 0 days, 2 weeks, and 4 weeks for X-ray powder diffraction analysis. (See relevant spectra...) Figure 7 , Figure 14 and Figure 21 As shown in the figure, the X-ray powder diffraction pattern remains unchanged, indicating that the crystal structure has not changed and its wet stability is good.

[0110] Example 6: Determination of Antitumor Activity

[0111] To investigate the antitumor effects of CDK4 / 6 inhibitors and salicylic acid drug-drug salts, the MTT assay was used to detect the cytotoxic activity of compounds RBC, PAL, ABE, SA, RBC-SA, PAL-SA, and ABE-SA drug-drug salts against breast cancer MDA-MB-231 cells. Cells were cultured in RPMI 1640 (Biological Industries, Israel) containing 10% fetal bovine serum (Gibco, Brazil) and a mixture of 1% penicillin or streptomycin. Furthermore, MDA-MB-231 cells were cultured at 37 °C in a humidified incubator with 5% CO2 at a density of 5000 cells / well. Subsequently, 50 μL of DMSO solution containing different concentrations of RBC, PAL, ABE, SA, RBC-SA, PAL-SA, and ABE-SA drug-drug salt crystals (0, 0.01, 0.1, 1, 10, 100 μM) was added to each well, and the cells were incubated at 37°C for 72 hours. Then, 50 μL of MTT (2 mg / mL) was added to each well, and the cells were incubated for another 4 hours. Afterward, the liquid in each well was removed, and 150 μL of DMSO was added. The absorbance (OD value) at 490 nm was measured using a microplate reader (Biotek, SYNERGY HTX, VT, USA). Three parallel experiments were set up for each group, and the IC50 value (half-maximal inhibitory concentration) was fitted according to the dose-dependent relationship using Graphpad Prism software. The results are shown in Table 1.

[0112] Table 1: IC50 of CDK4 / 6 inhibitors and SA drug-drug salts on breast cancer MDA-MB-231 cell line 50 result

[0113] The CDK4 / 6 inhibitor and salicylic acid drug-drug salt crystals provided by this invention can be used to prepare drugs for the prevention and / or treatment of cancer, and have broad application prospects.

[0114] In summary, this invention utilizes a suitable CDK4 / 6 inhibitor and salicylic acid to form drug-drug salt crystals. The preparation method is simple, reproducible, and yields high efficiency. The resulting CDK4 / 6 inhibitor drug-drug salt crystals improve the physicochemical properties and pharmacological activity of the CDK4 / 6 inhibitor while also enhancing its solubility and exhibiting excellent physical stability. The synergistic antitumor effect of the CDK4 / 6 inhibitor and salicylic acid enhances antitumor performance, facilitating the development of pharmaceutical formulations and promoting the widespread application of CDK4 / 6 inhibitors in the pharmaceutical field.

[0115] The embodiments of the present invention have been described in detail above with reference to specific examples. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A drug-drug salt prepared from a CDK4 / 6 inhibitor and salicylic acid, characterized in that, The CDK4 / 6 inhibitor is linked to salicylic acid by intermolecular ionic bonds; preferably, the CDK4 / 6 inhibitor is selected from ribociclib, palbociclib, and abemaciclib.

2. The drug-drug salt prepared from the CDK4 / 6 inhibitor and salicylic acid according to claim 1, characterized in that, The drug-drug salt mentioned is ribociclib-salicylic acid drug-drug salt; Alternatively, the drug-drug salt is a ribociclib-salicylic acid drug-drug salt, wherein the molar ratio of ribociclib to salicylic acid is approximately 1:1; Alternatively, the drug-drug salt is ribociclib-salicylic acid drug-drug salt crystals; Alternatively, the drug-drug salt is a ribociclib-salicylic acid drug-drug salt crystal, wherein the crystal is monoclinic, space group P21 / c, and the cell parameters are: a=7.5027(2)Å, b=17.1408(5)Å, c=22.8591(7)Å, α=90°, β=93.342(2)°, γ=90°, and the cell volume is 2934.73(15)Å. 3 ; Alternatively, the drug-drug salt is a ribociclib-salicylic acid drug-drug salt crystal, and the powder X-ray diffraction pattern of the crystal includes the following characteristic peaks at 2θ angles: 7.612°, 8.945°, 9.728°, 10.666°, 11.148°, 11.795°, 12.872°, 14.414°, 15.721°, 16.839°, 17.592°, 19.509°, 19.750°, 20.929°, 22.400°, 22.400°, and 27.318°, with a 2θ value accuracy of ±0.2°; Alternatively, the drug-drug salt is ribociclib-salicylic acid drug-drug salt crystal, and the infrared absorption spectrum of the crystal is at 3733.69 cm⁻¹. -l 3648.05 cm -l 3443.51 cm -l 3228.27 cm -l 2957.03 cm -l 1867.49cm -l 1747.64 cm -l 1730.42 cm -l 1621.51 cm -l 1613.99 cm -l 1532.79 cm -l 1488.18 cm -l 1426.06 cm -l 1397.42 cm -l 1248.50 cm -l 1141.31 cm -l 931.48 cm -l 857.66 cm -l 760.63 cm -l 678.51 cm -l There is an absorption peak at this point; Alternatively, the drug-drug salt is ribociclib-salicylic acid drug-drug salt crystal, the differential scanning calorimetry curve of the crystal has an endothermic peak at 262.3±1℃, and the thermogravimetric analysis curve shows significant weight loss from 254.5±1℃.

3. The drug-drug salt prepared from the CDK4 / 6 inhibitor and salicylic acid according to claim 1, characterized in that, The drug-drug salt mentioned is palbociclib-salicylic acid drug-drug salt; Alternatively, the drug-drug salt is a palbociclib-salicylic acid drug-drug salt, wherein the molar ratio of palbociclib to salicylic acid is approximately 1:1; Alternatively, the drug-drug salt is palbociclib-salicylic acid drug-drug salt crystal; Alternatively, the drug-drug salt is a palbociclib-salicylic acid drug-drug salt crystal, the crystal being monoclinic with space group P 21 / n, and cell parameters being: a=8.44457(18), b=16.0686(4), c=20.5888(5), α=95.965(2), β=90, γ=90, and cell volume being 2778.62(11); Alternatively, the drug-drug salt is a palbociclib-salicylic acid drug-drug salt crystal, and the powder X-ray diffraction pattern of the crystal includes the following characteristic peaks at 2θ angles: 7.035°, 10.188°, 11.796°, 13.959°, 16.168°, 16.913°, 18.330°, 19.629°, 20.665°, 21.838°, 22.398°, 23.740°, 25.033°, 26.309°, 28.182°, and 30.587°, with a 2θ value accuracy of ±0.2°; Alternatively, the drug-drug salt is palbociclib-salicylic acid drug-drug salt crystal, the infrared absorption spectrum of which is at 3454.03 cm⁻¹. -l 3427.67 cm -l 1704.83 cm -l 1629.62 cm -l 1575.62cm -l 1519.65 cm -l 1444.4 cm -l 1378.91 cm -l 1371.91 cm -l 1286.34cm -l 1139.77 cm -l 856.27cm -l 769.49 cm -l There is an absorption peak at this point; Alternatively, the drug-drug salt is palbociclib-salicylic acid drug-drug salt crystal, the differential scanning calorimetry curve of the crystal has an endothermic peak at 256.4±1℃, and the thermogravimetric analysis curve shows significant weight loss from 243.3±1℃.

4. The drug-drug salt prepared from the CDK4 / 6 inhibitor and salicylic acid according to claim 1, characterized in that, The drug-drug salt mentioned is abecicilline-salicylic acid drug-drug salt; Alternatively, the drug-drug salt is abexicillin-salicylic acid drug-drug salt, wherein the molar ratio of abexicillin to salicylic acid is approximately 1:1; Alternatively, the drug-drug salt is abexilide-salicylic acid drug-drug salt crystal; Alternatively, the drug-drug salt is abexicillin-salicylic acid drug-drug salt crystal, the crystal is orthorhombic, space group is Pna21, and the cell parameters are: a=10.6092(1), b=13.6309(1), c=44.2976(5), α=90, β=90, γ=90, and the cell volume is 6406.01(11); Alternatively, the drug-drug salt is abexicillin-salicylic acid drug-drug salt crystal, and the powder X-ray diffraction pattern of the crystal includes the following characteristic peaks at 2θ angles: 6.749°, 7.951°, 10.666°, 11.888°, 12.949°, 13.165°, 15.860°, 17.419°, 18.236°, 19.894°, 20.575°, 21.456°, 22.778°, 22.898°, 24.340°, 24.796°, 25.925°, 27.488°, 28.954°, and 32.606°, with a 2θ value accuracy of ±0.2°; Alternatively, the drug-drug salt is abexilide-salicylic acid drug-drug salt crystal, the infrared absorption spectrum of which is at 3234.81 cm⁻¹. -l 3226.26 cm -l 3089.53 cm -l 1635.40cm -l 1585.26cm -l 1531.26 cm -l 1484.98cm -l 1456.05cm -l 1434.88 cm -l 1400.12cm -l 1349.98cm -l 1292.12 cm -l 1245.84cm -l 1151.32 cm -l 1066.48cm -l 860.13 cm -l 809.99 cm -l 759.84 cm -l 667.27cm -l There is an absorption peak at this point; Alternatively, the drug-drug salt is abexilide-salicylic acid drug-drug salt crystal, the differential scanning calorimetry curve of which has an endothermic peak at 228.9±1℃, and the thermogravimetric analysis curve shows weight loss starting from 228.4±1℃.

5. A method for preparing a drug-drug salt made from a CDK4 / 6 inhibitor and salicylic acid according to any one of claims 1-4, characterized in that, The preparation method includes a solution method or a liquid-assisted grinding method; The solution method includes the following steps: The CDK4 / 6 inhibitor was added to an organic solvent to obtain system A; Salicylic acid was added to an organic solvent and mixed to obtain system B; Mix system A and system B to obtain system C, and let it stand; Filter, wash, collect filter cake, and dry to obtain the drug-drug salt of CDK4 / 6 inhibitor and salicylic acid; Preferably, in step 1), the organic solvent is selected from halogenated alkyl solvents or alcohol solvents; Preferably, in step 2), the organic solvent is selected from one or more of ketone solvents, alcohol solvents, alkyl nitrile solvents, haloalkyl solvents, alkyl sulfoxide solvents, or cyclic ether solvents; or, the organic solvent is selected from one or more of C1-C6 ketone solvents, C1-C6 alcohol solvents, C1-C6 alkyl nitrile solvents, C1-C6 haloalkyl solvents, C1-C6 alkyl sulfoxide solvents, or C1-C6 cyclic ether solvents; or, the organic solvent is selected from one or more of acetone, methanol, ethanol, isopropanol, chloroform, acetonitrile, ethyl acetate, or dimethyl sulfoxide; or, the organic solvent is selected from methanol or acetonitrile. Preferably, in step 3), in system C, the total mass ratio of CDK4 / 6 inhibitor and salicylic acid to the total volume ratio of solvent is 4-6 mg / ml, and the molar ratio of CDK4 / 6 inhibitor to salicylic acid is 1:1; the standing conditions are: standing at 10-28℃ for 4-156 h. The liquid-assisted grinding method includes the following steps: Take the CDK4 / 6 inhibitor and salicylic acid, and add them to the container; Add organic solvent and ball mill; After obtaining the sample, it is dried to obtain the drug-drug salt of CDK4 / 6 inhibitor and salicylic acid; Preferably, in step 1), the molar ratio of the CDK4 / 6 inhibitor to salicylic acid is 1:1; Preferably, in step 2), the organic solvent is selected from alcohol solvents; or, the organic solvent is selected from C1-C6 alcohol solvents; or, the organic solvent is selected from ethanol. Preferably, in step 2), the ball milling conditions are: ball milling at a frequency of 15-25 Hz for 3-15 minutes.

6. A pharmaceutical composition comprising a drug-drug salt of a CDK4 / 6 inhibitor according to any one of claims 1-4 and salicylic acid.

7. The use of the CDK4 / 6 inhibitor of any one of claims 1-4 and the drug-drug salt of salicylic acid, and the composition of claim 5, in the preparation of an antitumor drug.

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