Crystal form of salt of propofol derivative as well as preparation method and application of crystal form

Abstract

The invention belongs to the technical field of chemical medicines, and particularly relates to a crystal form of a salt of a propofol derivative as well as a preparation method and application thereof. The invention provides a crystal form of a compound A or a hydrate, an organic solvate or an organic solvate of the hydrate of the compound A with a structure shown as a formula I. The stability and the safety of the crystal form are greatly improved, and the crystal form has important significance for improving the medicine quality. # imgabs0 #

Description

[0001] This application claims the following priority:

[0002] CN202410035663.0, application date 2024.01.10. Technical Field

[0003] The invention belongs to the technical field of chemical medicine, and in particular relates to a crystal form, a preparation method and an application of a salt of a propofol derivative. Background Art

[0004] The polymorphism of drugs can affect the chemical stability, melting point, dissolution rate, and pharmacokinetics of drugs. The differences in pharmacological / toxic effects of different crystal forms have attracted increasing attention in recent years (see Li Lin et al. Synthesis of the antiallergic drug rupatifene fumarate and preparation and characterization of its crystal form A [J]. Chinese Journal of Medicinal Chemistry, 2020, 30(07): 405-409.). For example, the experimental results disclosed by Liu Kaihang in his master's thesis "Screening, preparation, characterization and pharmacokinetic study of polymorphs of tasimelteon" pointed out that the IC50 values ​​of crystal forms I and II of tasimelteon for C6 cell lines were 110 and 190 μg / mL, respectively, and the IC50 values ​​of the two for U87 cells were 131 and 191 μg / mL, respectively. The difference in cytotoxicity between the two was attributed to their different dissolution rates and ultimately to their different stacking methods. Therefore, different crystal forms of the same compound may have pharmacodynamic / toxicological differences.

[0005] CN116023284B discloses a series of pharmaceutically acceptable salts of propofol derivatives. The present invention further studies the preferred phosphate and citrate salts thereof and finds that the stability and safety of the product prepared by the method disclosed in CN116023284B need to be further improved. Summary of the invention

[0006] The object of the present invention is to provide a crystalline form of a pharmaceutically acceptable salt of 2,6-diisopropylphenyl (R)-4-(dimethylamino)-2-fluorobutyrate, wherein the stability and safety of the crystalline form are greatly improved.

[0007] The technical solution of the present invention is:

[0008] A compound A having a structure as shown in formula I or a hydrate, an organic solvate or a crystalline form of an organic solvate of the hydrate,

[0009]

[0010] In one aspect, preferably, the crystalline form is selected from:

[0011] The XRPD pattern of Compound A hemihydrate expressed in 2θ angles has characteristic absorption at 3.8°±0.2°, 11.2°±0.2°, 18.9°±0.2°, 22.5°±0.2° and 15.1°±0.2°.

[0012] The XRPD pattern of compound A expressed in 2θ angle has characteristic absorption at 3.7°±0.2°, 11.1°±0.2°, 15.0°±0.2°, 20.4°±0.2° and 11.2°±0.2°.

[0013] The XRPD pattern of the isopropanol solvate of Compound A expressed in 2θ has characteristic absorption at 21.1°±0.2°, 18.3°±0.2°, 9.3°±0.2°, 5.4°±0.2° and 3.7°±0.2°,

[0014] The XRPD pattern of Compound A hemihydrate expressed in 2θ has characteristic absorption at 3.5°±0.2°, 14.1°±0.2°, 13.4°±0.2°, 13.6°±0.2° and 17.9°±0.2, and

[0015] The XRPD pattern of Compound A expressed in 2θ has one of the characteristic crystalline forms at 3.7°±0.2°, 11.0°±0.2°, 16.8°±0.2°, 22.0°±0.2° and 13.2°±0.2°.

[0016] Further preferably, the crystal form is selected from:

[0017] The XRPD pattern of Compound A hemihydrate expressed in 2θ is a crystalline form with characteristic absorption at 3.8°±0.2°, 11.2°±0.2°, 18.9°±0.2°, 22.5°±0.2°, 15.1°±0.2°, 25.4°±0.2°, 18.7°±0.2°, 24.9°±0.2°, 18.5°±0.2° and 20.8°±0.2°,

[0018] The XRPD pattern of compound A expressed in 2θ angles has characteristic absorption at 3.7°±0.2°, 11.1°±0.2°, 13.6°±0.2°, 15.0°±0.2°, 20.4°±0.2°, 11.2°±0.2°, 18.0°±0.2°, 18.8°±0.2°, 17.9°±0.2° and 22.7°±0.2°,

[0019] The XRPD pattern of the isopropanol solvate of Compound A expressed in 2θ angles is a crystalline form with characteristic absorption at 21.1°±0.2°, 18.3°±0.2°, 9.3°±0.2°, 5.4°±0.2°, 3.7°±0.2°, 21.2°±0.2°, 24.8°±0.2°, 18.6°±0.2°, 22.6°±0.2° and 12.2°±0.2°,

[0020] a crystalline form having characteristic absorptions at 3.5°±0.2°, 14.1°±0.2°, 13.4°±0.2°, 13.6°±0.2°, 17.9°±0.2°, 10.9°±0.2°, 10.6°±0.2°, 21.3°±0.2°, 11.1°±0.2° and 19.7°±0.2° as represented by the XRPD pattern of Compound A hemihydrate expressed in 2θ, and

[0021] Compound A is one of the crystalline forms having characteristic absorptions at 3.7°±0.2°, 11.0°±0.2°, 16.8°±0.2°, 22.0°±0.2°, 13.2°±0.2°, 19.3°±0.2°, 12.6°±0.2°, 21.4°±0.2°, 20.8°±0.2° and 23.9°±0.2° in the XRPD pattern with 2θ angles.

[0022] Another aspect of the present invention provides a method for preparing the above-mentioned crystal form, wherein the preparation method is one selected from recrystallization, slurrying and spray drying.

[0023] More preferably, the recrystallization of the present invention is carried out in a water-ethanol mixed solvent, the slurrying is carried out in ethyl acetate or isopropanol, and the spray drying is carried out in acetonitrile.

[0024] More preferably, the volume ratio of water to ethanol in the water-ethanol mixed solvent is 1:1-3.

[0025] Further preferably, the specific operation of the pulping is: adding the raw materials into an organic solvent to prepare a suspension, stirring at 4-25° C. for 1-7 days, filtering and collecting the sample, and vacuum drying to constant weight to obtain the product.

[0026] More preferably, the concentration of the suspension is 40-60 mg / mL.

[0027] Another aspect of the present invention provides a freeze-dried powder for injection consisting of the aforementioned crystal form.

[0028] Another aspect of the present invention provides use of the aforementioned crystal form in the preparation of anesthetic analgesics.

[0029] Drug polymorphism is an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, crystal stability, chemical stability, storage stability, and bioavailability, and may have great differences, which will have different effects on the storage, transfer, application, stability, and efficacy of the drug. The present invention obtains a new crystal form of a salt of a propofol derivative through a large number of creative studies. Compared with the raw material drug, the stability and safety of each crystal form provided by the present invention are greatly improved, and the solubility in the four media is significantly higher than that of the raw material drug, which is of great significance for improving the quality of drugs.

[0030] Compared with the prior art, the present invention has the following advantages:

[0031] (1) The present invention provides a plurality of crystal forms of salts of propofol derivatives, including crystal form I, crystal form II, crystal form III, crystal form IV, and crystal form V. The results of the solubility study of the crystal forms show that the solubility of each crystal form of the present invention in four media is significantly higher than that of raw material A, which indicates that each crystal form of the present invention has good solubility.

[0032] (2) The stability study of the crystal forms showed that when placed under experimental conditions of illumination (cold white light, 5000 Lux ± 500 Lux; closed cup) and 60°C (closed cup) for 5 days and 10 days respectively, the crystal forms remained unchanged and the purity of the compound changed slightly. This indicates that the crystal forms of the present invention have good physical and chemical stability, and can effectively avoid crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and efficacy.

[0033] (3) The preparation methods of the various crystal forms provided by the present invention are simple, easy to operate, and easy to implement industrially.

[0034] (4) The neurotoxicity study results of the crystal forms show that the safety of the crystal forms provided by the present invention is greatly improved compared with the raw material drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 is the XRPD pattern of Form I;

[0036] Figure 2 It is the DSC and TGA overlay of Form I;

[0037] Figure 3 is the XRPD pattern of Form II;

[0038] Figure 4 It is the DSC and TGA overlay of Form II;

[0039] Figure 5 is the XRPD pattern of Form III;

[0040] Figure 6is the XRPD pattern of Form IV;

[0041] Figure 7 It is the DSC and TGA superposition diagram of Form IV;

[0042] Figure 8 is the XRPD pattern of Form V;

[0043] Fig. 9 This is the XRPD overlay of Form II under various conditions in the stability test. DETAILED DESCRIPTION

[0044] The present invention is further illustrated below through the description of specific implementation modes, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0045] In the crystal form screening work carried out in cooperation with a well-known domestic CRO, the applicant evaluated more than ten crystal forms (including hydrates, organic solvates or organic solvates of hydrates) of the prepared raw material A from the aspects of solubility, stability, re-dissolution time, cytotoxicity, etc., and disclosed the dominant crystal forms and their test results as specific embodiments of the present invention.

[0046] Example 1. Preparation methods and structure confirmation of each crystal form

[0047] The preparation methods of the various crystal forms described in the present invention and the specific structure confirmation results are shown in Table 1.

[0048] Table 1 Preparation methods of various crystal forms described in the present invention and specific structural confirmation results

[0049]

[0050]

[0051]

[0052]

[0053] Note:

[0054] The raw material A described in Table 1 is the phosphate of 2,6-diisopropylphenyl (R)-4-(dimethylamino)-2-fluorobutyrate (raw material A) prepared by the method disclosed in CN116023284B.

[0055] The XRPD detection conditions are as follows:

[0056] Testing instrument: Rigaku SmartLab SE;

[0057] Detection conditions: X-ray tube voltage 40 kV, X-ray tube current 40 mA, scanning range 3-40° (2θ), step size 0.02°, scanning speed 5° / min.

[0058] Testing basis: Appendix IXF X-ray powder diffraction method of the People's Republic of China (Part II, 2010 edition).

[0059] Example 2 Solubility study of crystal form

[0060] Take appropriate amount of crystal forms I to IV or raw material A and shake in biological media (FaSSIF, FeSSIF and FaSSGF) and water at 37°C for 24 hours for solubility test. Weigh 30 mg of sample into a sample bottle, and then add 3 mL of three media and water to form a suspension. All suspensions were shaken at 200 rpm at 37°C, and observed, sampled and the filtrate was tested for solubility at 0.5, 2 and 24 hours. The results are shown in Table 2.

[0061] Table 2: Solubility study results of crystal forms

[0062]

[0063]

[0064] As shown in Table 2, the solubility of each crystal form of the present invention in the four media is significantly higher than that of raw material A. The solubility described in Table 2 is determined by HPLC, wherein the HPLC conditions are shown in Table 3.

[0065] Table 3 HPLC conditions

[0066]

[0067]

[0068] Example 3 Stability Study of Crystalline Form

[0069] Take appropriate amounts of Forms I to IV or raw material A and place them under three conditions: illumination (cold white light, 5000Lux±500Lux; closed), 60°C (closed) and 25°C / 90%RH (open) for 5 days (5D) and 10 days (10D). The solid samples after placement were subjected to XRPD (conditions are the same as in Example 1) and HPLC tests (conditions are the same as in Example 2) to analyze the crystal stability and chemical stability. The results are shown in Table 4, where the XRPD superposition diagram of Form II under various conditions in the stability test is shown in Table 4. Fig. 9 .

[0070] Table 4 Results of stability study of crystal forms

[0071]

[0072]

[0073] Note: NA in the table means not determined.

[0074] As shown in Table 4, the crystal form of the present invention has good stability under conditions other than room temperature and high temperature, and the crystal form stability and chemical stability are significantly better than those of raw material A.

[0075] Among the tested crystal forms, the XRPD superposition diagrams of crystal form II under various conditions in the stability test are shown in Fig. 9 .

[0076] Example 4 Neurotoxicity Study of Crystalline Form

[0077] The neurotoxicity of the crystalline form of the present invention and raw material A at a final concentration of 1 mg / mL was investigated using the method disclosed by Ren Jie et al. in the article "Sulforaphane and its derivative BSFN induce apoptosis of SH-SY5Y cells by activating the PI3K / Akt pathway" (Source: Chinese Journal of Pharmaceutical Sciences, 2014, 49(20): 1813-1819). The results are shown in Table 5.

[0078] Table 5 Neurotoxicity results of the crystal form of the present invention and raw material A at a final concentration of 1 mg / mL

[0079]

[0080]

[0081] Note:

[0082] *The statistical function provided by Microsoft Excel 2010 was used for analysis. SS means the difference compared with the API is statistically significant; NSS means the difference is not statistically significant.

[0083] Example 5 Preparation Example

[0084] Take an appropriate amount of each of the crystal forms I to V, prepare it with water for injection to a concentration of 10 mg / mL, filter it aseptically, and dispense it into vials, 10 mL per bottle. After freeze-drying, seal the bottle and check for leaks.

[0085] XRPD detection showed that the above-mentioned crystal forms did not undergo any changes in crystal form during the freeze-drying process.

Claims

1. A compound A having a structure as shown in formula I or a hydrate, an organic solvate or a crystalline form of an organic solvate of a hydrate, 2. The crystal form according to claim 1, characterized in that The crystal form is selected from: The XRPD pattern of Compound A hemihydrate expressed in 2θ angles has characteristic absorption at 3.8°±0.2°, 11.2°±0.2°, 18.9°±0.2°, 22.5°±0.2° and 15.1°±0.2°. The XRPD pattern of compound A expressed in 2θ angle has characteristic absorption at 3.7°±0.2°, 11.1°±0.2°, 15.0°±0.2°, 20.4°±0.2° and 11.2°±0.2°. The XRPD pattern of the isopropanol solvate of Compound A expressed in 2θ has characteristic absorption at 21.1°±0.2°, 18.3°±0.2°, 9.3°±0.2°, 5.4°±0.2° and 3.7°±0.2°, The XRPD pattern of Compound A hemihydrate expressed in 2θ has characteristic absorption at 3.5°±0.2°, 14.1°±0.2°, 13.4°±0.2°, 13.6°±0.2° and 17.9°±0.2, and The XRPD pattern of Compound A expressed in 2θ has one of the characteristic crystalline forms at 3.7°±0.2°, 11.0°±0.2°, 16.8°±0.2°, 22.0°±0.2° and 13.2°±0.2°.

3. The crystal form according to claim 2, characterized in that: The crystal form is selected from: The XRPD pattern of Compound A hemihydrate expressed in 2θ is a crystalline form with characteristic absorption at 3.8°±0.2°, 11.2°±0.2°, 18.9°±0.2°, 22.5°±0.2°, 15.1°±0.2°, 25.4°±0.2°, 18.7°±0.2°, 24.9°±0.2°, 18.5°±0.2° and 20.8°±0.2°, The XRPD pattern of compound A expressed in 2θ angles has characteristic absorption at 3.7°±0.2°, 11.1°±0.2°, 13.6°±0.2°, 15.0°±0.2°, 20.4°±0.2°, 11.2°±0.2°, 18.0°±0.2°, 18.8°±0.2°, 17.9°±0.2° and 22.7°±0.2°, The XRPD pattern of the isopropanol solvate of Compound A expressed in 2θ angles is a crystalline form with characteristic absorption at 21.1°±0.2°, 18.3°±0.2°, 9.3°±0.2°, 5.4°±0.2°, 3.7°±0.2°, 21.2°±0.2°, 24.8°±0.2°, 18.6°±0.2°, 22.6°±0.2° and 12.2°±0.2°, a crystalline form having characteristic absorptions at 3.5°±0.2°, 14.1°±0.2°, 13.4°±0.2°, 13.6°±0.2°, 17.9°±0.2°, 10.9°±0.2°, 10.6°±0.2°, 21.3°±0.2°, 11.1°±0.2° and 19.7°±0.2° as represented by the XRPD pattern of Compound A hemihydrate expressed in 2θ, and Compound A is one of the crystalline forms having characteristic absorptions at 3.7°±0.2°, 11.0°±0.2°, 16.8°±0.2°, 22.0°±0.2°, 13.2°±0.2°, 19.3°±0.2°, 12.6°±0.2°, 21.4°±0.2°, 20.8°±0.2° and 23.9°±0.2° in the XRPD pattern with 2θ angles.

4. The method for preparing a crystal form according to any one of claims 1 to 3, characterized in that: The preparation method is one selected from recrystallization, beating and spray drying.

5. The method for preparing the crystal form according to claim 4, characterized in that: The recrystallization is carried out in a water-ethanol mixed solvent, the beating is carried out in ethyl acetate or isopropanol, and the spray drying is carried out in acetonitrile.

6. The method for preparing the crystal form according to claim 4, characterized in that: The volume ratio of water to ethanol in the water-ethanol mixed solvent is 1:1-3.

7. The method for preparing the crystal form according to claim 4, characterized in that: The specific operation of the pulping is: adding the raw materials into an organic solvent to prepare a suspension, stirring at 4-25° C. for 1-7 days, filtering and collecting the sample, and vacuum drying to constant weight to obtain the product.

8. The method for preparing the crystal form according to claim 7, characterized in that: The concentration of the suspension is 40-60 mg / mL.

9. A freeze-dried powder for injection consisting of the crystal form according to any one of claims 1 to 3.

10. Use of the crystal form according to any one of claims 1 to 3 in the preparation of anesthetic analgesics.

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