N-[8-(2-hydroxybenzoyl)amino]potassium octanoate crystal polymorph, and preparation method and use thereof

Abstract

To provide a crystal polymorph of N-[8-(2-hydroxybenzoyl)amino]potassium octanoate.SOLUTION: The crystal polymorph of N-[8-(2-hydroxybenzoyl)amino]potassium octanoate is crystal Form I, which has at least an X-ray powder diffraction pattern with characteristic peaks represented by 2θ° of 7.83±0.2, 26.64±0.2 and 18.89±0.2. The crystal polymorph of N-[8-(2-hydroxybenzoyl)amino]potassium octanoate provided by the present application has four crystal forms, has high solubility and strong stability, delivers drugs more effectively, increases the permeability of the delivered drugs in the gastrointestinal tract, and is beneficial to the preparation of oral preparations, so that preventive and / or therapeutic drugs can be better delivered into the body to achieve the effect of improving the bioavailability.SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] [Technical field] The present application relates to the field of chemical medicine, in particular to potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorphs and their preparation methods and uses.

[0002] [Background technology] Polymer drugs such as peptide and protein drugs have large molecular weights, low lipid solubility, and are unstable to gastric acid, and can be destroyed by various digestive enzymes in the digestive tract, so they cannot enter the intestinal tract smoothly and be absorbed when administered orally. In response to the above problems, people have tried to overcome the drug absorption barrier in many ways, and in addition to some attempts at dosage forms, gastrointestinal absorption enhancers are often used to improve the biofilm permeability of drugs, which has increased the absorption of drugs, but also increased the absorption of intestinal toxins, and is lacking in safety for long-term use.

[0003] U.S. Patent No. 5,650,386, published in 1997, discloses a novel polymeric drug delivery agent, N-[8-(2-hydroxybenzoyl)amino]caprylic acid (abbreviated as NAC) and its salts, whose molecular formula is as shown in formula (I).In particular, U.S. Patent No. 8,636,996, published in 2009, discloses a crystalline polymorph, an amorphous form and a preparation method thereof of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylic acid (abbreviated as SNAC), whose molecular formula is as shown in formula (II). [ka]

[0004] SNAC is a novel amino acid derivative delivery agent. Recent studies have shown that it can promote the oral absorption of various protein drug solutions, such as heparin and human growth hormone, without dosage form protection, but no obvious cytotoxicity has been shown. The bioavailability, solubility, and fluidity of different salt forms of a compound are also different. Different crystal forms of the same salt form have different properties such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendability, and dissolution rate, which directly or indirectly affect the drug delivery ability and lead to differences in the bioavailability, compressibility, and stability of the delivered drug.

[0005] [Summary of the Invention] The object of the present application is to provide potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorphs and preparation methods and uses thereof, pharmaceutical compositions and uses thereof.

[0006] The technical proposal of this application is as follows: 1, at least 2θ°: 7.83±0.2, 26.64±0.2, and 18.89±0 A crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, characterized in that it is crystalline form I having a powder X-ray diffraction pattern with characteristic peaks represented by the formula: 2. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 1, wherein the crystalline form I further has a powder X-ray diffraction pattern having a characteristic peak represented by at least one of 2θ°: 5.24±0.2 and 21.59±0.2. 3. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 2, wherein the crystalline form I further has a powder X-ray diffraction pattern having a characteristic peak represented by at least one of 2θ°: 13.02±0.2 and 24.29±0.2. Item 4. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 3, wherein the crystalline form I further has a powder X-ray diffraction pattern having characteristic peaks represented by at least one of 2θ°: 6.61±0.2, 10.43±0.2, 31.63±0.2, and 37.00±0.2. 5. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 1 to 4, wherein the powder X-ray diffraction pattern of the crystalline form I is shown in FIG. 6. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 1 to 4, wherein the melting point of the crystalline form I is 163.1°C. 7. A crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 1 to 4, characterized in that the crystalline form I has an adsorbed water removal temperature of 83.6°C. 8. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 1 to 4, wherein the crystalline form I exhibits a weight loss of 3.0% at 140°C. 9. A crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, characterized in that it is crystalline form II having an X-ray powder diffraction pattern with characteristic peaks represented by at least the following angles 2θ: 24.76±0.2, 6.73±0.2, and 20.26±0.2. Item 10. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 9, wherein the crystalline form II further has a powder X-ray diffraction pattern having a characteristic peak represented by at least one of 2θ°: 14.68±0.2 and 25.55±0.2. Item 11. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 10, wherein the crystalline form II further has a powder X-ray diffraction pattern having a characteristic peak represented by at least one of 2θ°: 13.41±0.2 and 26.66±0.2. Item 12. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 11, wherein the crystalline form II further has a powder X-ray diffraction pattern having characteristic peaks represented by at least one of the following 2θ°: 21.08±0.2, 25.79±0.2, 28.47±0.2, 12.07±0.2, 15.38±0.2, 23.38±0.2, 29.48±0.2, 22.55±0.2, 27.79±0.2, and 8.91±0.2. 13. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 9, wherein the powder X-ray diffraction pattern of the crystalline form II is shown in FIG. 3. 14. The potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 9 to 13, characterized in that the melting point of the crystalline form II is 162.5°C. Crystal polymorphism of . 15. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 9 to 13, wherein the crystalline form II has an adsorbed water removal temperature of 93° C. 16. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 9 to 13, wherein the crystalline form II loses weight by 5.6% at 140°C. 17, a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, characterized in that it is crystalline form III having an X-ray powder diffraction pattern with characteristic peaks represented by at least the following angles 2θ: 9.06±0.2, 23.30±0.2, and 21.44±0.2. Item 18. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 17, characterized in that the crystalline form III further has a powder X-ray diffraction pattern having characteristic peaks represented by at least one of 2θ°: 24.75±0.2 and 6.03±0.2. Item 19. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 18, characterized in that the crystalline form III further has a powder X-ray diffraction pattern having a characteristic peak represented by at least one of 2θ°: 21.20±0.2 and 17.06±0.2. 20. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 19, wherein the crystalline form III further has a powder X-ray diffraction pattern having characteristic peaks represented by at least one of the following 2θ°: 21.75±0.2, 29.52±0.2, 22.15±0.2, 15.11±0.2, 28.47±0.2, 22.54±0.2, 30.71±0.2, 17.91±0.2, 15.64±0.2, and 26.49±0.2. 21. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 17, wherein the powder X-ray diffraction pattern of the crystalline form III is shown in FIG. 5. 22. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 17 to 21, wherein the melting point of the crystalline form III is 162.0°C. 23. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 17 to 21, characterized in that the crystalline form III has an adsorbed water removal temperature of 94.5°C. 24. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 17 to 21, wherein the crystalline form III loses weight by 6.1% at 140°C. 25, and being crystalline form IV having an X-ray powder diffraction pattern with characteristic peaks represented by at least the following angles 2θ: 16.25±0.2, 6.8±0.2, and 22.08±0.2. 26. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 25, wherein the crystalline form IV further has a powder X-ray diffraction pattern having a characteristic peak represented by at least one of 2θ°: 13.16±0.2 and 19.39±0.2. 27. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 26, characterized in that the crystalline form IV further has a powder X-ray diffraction pattern having a characteristic peak represented by at least one of 2θ°: 18.35±0.2 and 9.68±0.2. 28, the crystalline form IV has a 2θ° of at least: 15.92±0.2, 11.71±0.2 Item 28. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 27, further having a powder X-ray diffraction pattern having characteristic peaks represented by one of the following: 29.91±0.2, 23.04±0.2, 16.56±0.2, 23.5±0.2, 27.31±0.2, 19.74±0.2, 34.34±0.2, and 18.82±0.2. 29. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to item 25, wherein the powder X-ray diffraction pattern of the crystalline form IV is shown in FIG. 30. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 25 to 29, wherein the melting point of the crystalline form IV is 163.8°C. 31. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 25 to 29, wherein the crystalline form IV has an adsorbed water removal temperature of 96.1°C. 32. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 25 to 29, wherein the crystalline form IV loses weight by 8.21% at 150°C. 33. Add an organic solvent to a reaction vessel and stir, add N-[8-(2-hydroxybenzoyl)amino]octanoic acid and stir uniformly, add potassium hydroxide solution dropwise, and after the dropwise addition, concentrate to obtain a crude product; adding an organic solvent to the crude product, beating, and suction filtering to obtain a filter cake; rinsing the filter cake and drying it in a drying oven to obtain a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate; The method for preparing the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising: 34. Rinse the filter cake, put it into a drying oven, and dry it at 60°C to 100°C for 30 to 40 hours to obtain the crystal form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate; preferably, the drying is divided into two stages, firstly, dry it at 60°C for 16 hours, and then dry it at 100°C for 24 hours after replacing the system with nitrogen; Item 34. The method according to Item 33, wherein the crystalline form I is crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of Items 1 to 8. Item 35. The method according to item 33, further comprising: preparing the filter cake into uniform granules; placing the granules in the drying oven to dry; and spreading the dried granules uniformly in a low temperature environment of 2-8°C and keeping the granules at a controlled relative humidity of 50% for 2 days to form potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal form III. Item 36. The method according to item 35, wherein the drying temperature of the drying oven containing the granules is 60°C to 100°C, and the drying time is 30 to 40 hours. Preferably, the drying is divided into two stages, firstly drying at 60°C for 16 hours, and then drying at 100°C for 24 hours after replacing the system with nitrogen. 37. The filter cake is sieved through a 20-24 mesh sieve to obtain uniform particles; Item 36. The method according to Item 35, wherein the crystalline form III is crystalline form III of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of Items 17 to 24. 38. The method according to any one of items 33 to 37, wherein the organic solvent is isopropanol or acetone. 39. The method according to any one of items 33 to 37, wherein the concentration of the potassium hydroxide solution is 40% to 90%, preferably the concentration of the potassium hydroxide solution is 50%. 40. After adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid, Heat the mixture to 48°C or higher, add potassium hydroxide solution dropwise, and after the addition is complete, keep the mixture warm for 0.5 to 2 hours to react. Preferably, the method according to any one of Items 33 to 37, further comprising the steps of: adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid, raising the temperature of the system to 48° C. to 52° C.; adding the potassium hydroxide solution dropwise; and, after completion of the dropwise addition, maintaining the temperature for 1 hour to allow the reaction to proceed. 41. The method according to any one of items 33 to 37, wherein the molar ratio of the N-[8-(2-hydroxybenzoyl)amino]octanoic acid to the potassium hydroxide solution is 1:1. 42. The method according to any one of items 33 to 37, characterized in that the crude product is added with an organic solvent and then beaten for 0.5 to 1.5 hours, preferably 1 hour. 43. A method for preparing crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising heating a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I to at least 75°C to form crystalline form I. 44. The method according to item 43, wherein the crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I is at least one or more of crystalline forms II, III and IV. 45. The method according to item 43, characterized in that a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I is heated to 75°C or higher under the protection of nitrogen to form crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate. Item 46. The method according to item 43, characterized in that the crystal form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is heated to 140°C under the protection of nitrogen to form the crystal form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate. Item 47. The method according to item 43, characterized in that the crystalline form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is heated to 110°C under the protection of nitrogen to form crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate. 48. A method for preparing crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising freeze-drying a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I to form crystalline form I. Item 49. The method according to item 48, wherein the crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I is at least one or more of crystalline forms II, III and IV. 50. The preparation method according to any one of items 43 to 49, wherein the crystalline form I is crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 1 to 8. 51. A method for preparing crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising exposing a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form II to an environment having a relative humidity of 0-60% at room temperature for more than 24 hours to form crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate. 52. The preparation method according to item 51, characterized in that the relative humidity is 20%, 30%, 40%, or 60%. 53. The method according to item 51, wherein the crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form II is at least one or more of the crystalline forms I, III and IV. 54. The crystal form II is the crystal form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 9 to 16. 54. A preparation method according to any one of claims 51 to 53. 55, forming a gel-like substance from a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form IV in a relative humidity environment of more than 80%; and exposing the gel-like substance to an environment having a relative humidity of 20 to 40% at room temperature for 120 hours or more to form crystalline form IV. Item 56. The method according to item 55, wherein the crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form IV is at least one or more of crystalline forms I, II and III. 57. The method according to claim 55, characterized in that the gel-like substance is exposed to an environment having a relative humidity of 20%, 30%, or 40%, preferably the gel-like substance is exposed to an environment having a relative humidity of 40%. 58. The preparation method according to any one of items 55 to 57, wherein the crystalline form IV is crystalline form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of items 25 to 32. 59. A pharmaceutical composition comprising a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate. 60. The pharmaceutical composition according to item 59, characterized in that the crystalline polymorphism of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is one or at least two of crystalline form I, crystalline form II, crystalline form III, and crystalline form IV. 61. The pharmaceutical composition according to item 59 or 60, further comprising a prophylactic and / or therapeutic agent. 62. The pharmaceutical composition according to item 61, characterized in that the weight ratio of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorph to the prophylactic and / or therapeutic agent in the pharmaceutical composition is (20-60):1, preferably, the weight ratio of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorph to the prophylactic and / or therapeutic agent in the pharmaceutical composition is 30:1. 63. The pharmaceutical composition according to item 62, wherein the prophylactic and / or therapeutic agent is glucagon-like peptide-1, insulin, PYY, human amylin, heparin, human growth hormone, interferon, monoclonal antibody, protease inhibitor, or thrombopoietin. 64. Use of a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate or a pharmaceutical composition thereof in the preparation of a prophylactic and / or therapeutic drug. 65, Use of a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate or a pharmaceutical composition thereof in enhancing drug delivery. 66. Use of a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate or a pharmaceutical composition thereof in the preparation of a medicament for the prevention and / or treatment of diabetes or diabetic complications, or for weight loss (dieting).

[0007] The potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorphs provided by the present application have four crystalline forms, which have high solubility and high stability, can deliver drugs more effectively, and can enhance the permeability of drugs delivered to the gastrointestinal tract, which is advantageous for the preparation of oral formulations, thereby achieving the effect of better delivering prophylactic and / or therapeutic drugs to the body and improving bioavailability.

[0008] The accompanying drawings are used for a better understanding of the present application and shall not be construed as constituting an undue limitation of the present application. [Brief description of the drawings]

[0009] [Figure 1] 1 is a powder X-ray diffraction pattern (powder X-ray diffraction spectrum) of the crystalline form I of PNAC prepared in Example 1. [Figure 2a] 1 is a DSC chart of the crystalline form I of PNAC prepared in Example 1. [Figure 2b] FIG. 1 is a TGA diagram of crystalline form I of PNAC prepared in Example 1. [Diagram 3] 1 is a powder X-ray diffraction pattern of PNAC crystal form II prepared in Example 2. [Figure 4a] 1 is a DSC chart of the crystal form II of PNAC prepared in Example 2. [Figure 4b] FIG. 2 is a TGA diagram of crystalline form II of PNAC prepared in Example 2. [Diagram 5] 1 is a powder X-ray diffraction pattern of crystalline form III of PNAC prepared in Example 3. [Figure 6a] 1 is a DSC chart of the crystalline form III of PNAC prepared in Example 3. [Figure 6b] FIG. 2 is a TGA diagram of crystalline form III of PNAC prepared in Example 3. [Figure 7] 1 is a powder X-ray diffraction pattern of crystalline form IV of PNAC prepared in Example 4. [Figure 8a] 1 is a DSC chart of the crystalline form IV of PNAC prepared in Example 4. [Figure 8b] FIG. 1 is a TGA diagram of crystalline form IV of PNAC prepared in Example 4. [Figure 9] FIG. 1 shows a time course of blood drug concentration versus administration time in the intravenous administration group. [Figure 10] FIG. 1 shows a graph showing changes in blood drug concentration versus administration time for each oral administration group. [Figure 11]1 is an XRPD spectrum of the solid stability experiment of crystalline form II. [Figure 12] 1 is an XRPD spectrum of crystalline form II before and after a polishing experiment. [Figure 13] 1 shows XRPD spectra of crystalline form II before and after tableting experiment. [Figure 14] 1 is an XRPD spectrum of crystalline form II before and after a jet milling experiment. [Figure 15] 1 is an XRPD spectrum of the solid stability experiment of crystalline form I. [Figure 16] 1 shows XRPD spectra of crystalline form I before and after tableting experiment. [Figure 17] 1 is an XRPD spectrum of Form I before and after a jet milling experiment. [Figure 18] 1 is an XRPD spectrum of crystalline form I before and after a polishing experiment. [Figure 19] FIG. 1 shows a time course of blood drug concentration versus administration time in the intravenous administration group. [Figure 20] FIG. 1 shows a graph showing changes in blood drug concentration versus administration time in each oral administration group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Exemplary embodiments of the present application are described below in conjunction with the accompanying drawings, which contain various details of the embodiments of the present application for ease of understanding, and should be considered as merely exemplary. Accordingly, those skilled in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the present application. Unless inconsistent with the definitions herein, the terms herein have the meanings generally understood by those skilled in the art, but in the event of any conflict, the definitions herein shall prevail.

[0011] Potassium N-[8-(2-hydroxybenzoyl)amino]octanoate (abbreviated as PNAC) is represented by the formula (III): [ka]

[0012] Powder X-ray diffraction X-ray powder diffraction (XRPD) is usually applied to the analysis of crystal structure. X-rays are a type of electromagnetic wave that, when incident on a crystal, It generates a periodically changing electromagnetic field within the atom. It vibrates the electrons and nuclei within the atom, but because the mass of the nuclei is so large, the vibrations can be ignored. The vibrating electrons are the wave source of the secondary X-rays, and their wavelength and phase are the same as the incident light. Based on the periodicity of the crystal structure, the scattered waves of each electron in the crystal interfere with each other and overlap, which is called diffraction. The direction in which the phases of the scattered waves match and reinforce each other is called the diffraction direction, and diffracted rays are generated. Instrument model: PANalytical Empyrean and X'Pert3 powder diffraction analyzers; Ray: Monochromatic Cu-Kα ray (λ=1.5406); Scan mode: θ / 2θ, scan range: 2~40°; Voltage: 40KV, Current: 40mA.

[0013] thermogravimetric analysis Thermogravimetric analysis (TGA) refers to a thermal analysis technique that measures the relationship between the mass of a test sample and the temperature change under program-controlled temperature, and is used to study the thermal stability and composition of materials. TGA is a detection method commonly used in research and development and quality control. Thermogravimetric analysis is often combined with other analytical methods in practical material analysis to perform comprehensive thermal analysis and analyze materials comprehensively and accurately. The curve recorded by a thermogravimetric analyzer is called a TGA curve. Device model:TA Q5000 / Discovery 5500; Purge gas: nitrogen; Heating method: Linear heating; Temperature range: room temperature to 350℃.

[0014] Differential scanning calorimetry Differential scanning calorimetry (DSC) is a technique that measures the heat flow of a sample relative to a reference substance as a function of temperature or time under the control of a temperature program. The curve recorded by a differential scanning calorimeter is called a DSC curve, and is generally plotted as W / g or mW / mg (i.e., output power per gram of sample) on the vertical axis and temperature T or time t on the horizontal axis. It can measure various thermodynamic and kinetic parameters such as specific heat capacity, heat of reaction, heat of transition, phase diagram, reaction rate, crystallization rate, polymer crystallinity, and sample purity. The method has a wide temperature range (-175 to 725 °C), high resolution, and low sample consumption. It is suitable for the analysis of inorganic substances, organic compounds, and drugs. Instrument model: TAQ2000 / Discovery 2500; Purge gas: nitrogen; Heating method: Linear heating; Temperature range: 25~300℃.

[0015] The present application provides a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate being crystalline form I, the crystalline form I having an X-ray powder diffraction pattern with characteristic peaks represented by at least the following angles 2θ: 7.83±0.2, 26.64±0.2, and 18.89±0.2.

[0016] In the present application, said crystalline form I has an X-ray powder diffraction pattern with characteristic peaks represented by the following angles 2θ: 7.83±0.2, 26.64±0.2, 18.89±0.2, 5.24±0.2.

[0017] In the present application, the crystalline form I has the following molecular weight distributions at 2θ°: 7.83±0.2, 26.64±0.2, 1 It has a powder X-ray diffraction pattern with characteristic peaks represented by: 8.89±0.2, 21.59±0.2.

[0018] In the present application, said crystalline form I has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 7.83±0.2, 26.64±0.2, 18.89±0.2, 5.24±0.2, 21.59±0.2.

[0019] In the present application, said crystalline form I has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 7.83±0.2, 26.64±0.2, 18.89±0.2, 5.24±0.2, 21.59±0.2, 24.29±0.2.

[0020] In the present application, said crystalline form I has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 7.83±0.2, 26.64±0.2, 18.89±0.2, 5.24±0.2, 21.59±0.2, 13.02±0.2.

[0021] In the present application, said crystalline form I has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 7.83±0.2, 26.64±0.2, 18.89±0.2, 5.24±0.2, 21.59±0.2, 13.02±0.2, 24.29±0.2.

[0022] In the present application, said crystalline form I has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 7.83±0.2, 26.64±0.2, 18.89±0.2, 5.24±0.2, 21.59±0.2, 13.02±0.2, 24.29±0.2, 6.61±0.2.

[0023] In the present application, said crystalline form I has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 7.83±0.2, 26.64±0.2, 18.89±0.2, 5.24±0.2, 21.59±0.2, 13.02±0.2, 24.29±0.2, 6.61±0.2, 10.43±0.2.

[0024] In the present application, said crystalline form I has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 7.83±0.2, 26.64±0.2, 18.89±0.2, 5.24±0.2, 21.59±0.2, 13.02±0.2, 24.29±0.2, 6.61±0.2, 10.43±0.2, 31.63±0.2.

[0025] In the present application, said crystalline form I has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 7.83±0.2, 26.64±0.2, 18.89±0.2, 5.24±0.2, 21.59±0.2, 13.02±0.2, 24.29±0.2, 6.61±0.2, 10.43±0.2, 31.63±0.2, 37.00±0.2.

[0026] In the present application, the powder X-ray diffraction pattern of the crystalline form I is shown in FIG.

[0027] In the present application, the melting point of crystalline form I is 163.1°C.

[0028] In the present application, the adsorbed water removal temperature of crystalline form I is 83.6°C.

[0029] In the present application, crystalline form I loses weight by 3.0% at 140°C.

[0030] The present application provides a crystal polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, The crystalline polymorph of ruthenium is crystalline Form II, said crystalline Form II having an X-ray powder diffraction pattern with characteristic peaks represented at least by the following angles 2θ: 24.76±0.2, 6.73±0.2, and 20.26±0.2.

[0031] In the present application, said crystalline form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following 2θ degrees: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2.

[0032] In the present application, said crystalline form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 25.55±0.2.

[0033] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2.

[0034] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2.

[0035] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 26.66±0.2.

[0036] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2.

[0037] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2.

[0038] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2, 25.79±0.2.

[0039] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2, 25.79±0.2, 28.47±0.2.

[0040] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2, 25.79±0.2, 28.47±0.2, 12.07±0.2.

[0041] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2, 25.79±0.2, 28.47±0.2, 12.07±0.2, 15.38±0.2.

[0042] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2, 25.79±0.2, 28.47±0.2, 12.07±0.2, 15.38±0.2, 23.38±0.2.

[0043] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2, 25.79±0.2, 28.47±0.2, 12.07±0.2, 15.38±0.2, 23.38±0.2, 29.48±0.2.

[0044] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2, 25.79±0.2, 28.47±0.2, 12.07±0.2, 15.38±0.2, 23.38±0.2, 29.48±0.2, 22.55±0.2.

[0045] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2, 25.79±0.2, 28.47±0.2, 12.07±0.2, 15.38±0.2, 23.38±0.2, 29.48±0.2, 22.55±0.2, 27.79±0.2.

[0046] In the present application, said crystalline Form II has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 13.41±0.2, 26.66±0.2, 21.08±0.2, 25.79±0.2, 28.47±0.2, 12.07±0.2, 15.38±0.2, 23.38±0.2, 29.48±0.2, 22.55±0.2, 27.79±0.2, 8.91±0.2.

[0047] In the present application, the powder X-ray diffraction pattern of the crystalline form II is shown in FIG.

[0048] In the present application, the melting point of crystalline form II is 162.5°C.

[0049] In the present application, the adsorbed water removal temperature of crystalline form II is 93°C.

[0050] In the present application, crystalline form II loses weight by 5.6% at 140°C.

[0051] The present application provides a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate being crystalline form III, the crystalline form III having a molecular weight of at least 2θ°:9.06 The compound has an X-ray powder diffraction pattern with characteristic peaks represented by the formulas: 23.30±0.2, 23.30±0.2, and 21.44±0.2.

[0052] In the present application, said crystalline form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2.

[0053] In the present application, said crystalline form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 6.03±0.2.

[0054] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2.

[0055] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2.

[0056] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 17.06±0.2.

[0057] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2.

[0058] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2.

[0059] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2, 29.52±0.2.

[0060] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2, 29.52±0.2, 22.15±0.2.

[0061] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2, 29.52±0.2, 22.15±0.2, 15.11±0.2.

[0062] In the present application, the crystalline form III has a 2θ° of 9.06±0.2, 23.30±0.2 , 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2, 29.52±0.2, 22.15±0.2, 15.11±0.2, 28.47±0.2.

[0063] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2, 29.52±0.2, 22.15±0.2, 15.11±0.2, 28.47±0.2, 22.54±0.2.

[0064] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2, 29.52±0.2, 22.15±0.2, 15.11±0.2, 28.47±0.2, 22.54±0.2, 30.71±0.2.

[0065] In the present application, said crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2, 29.52±0.2, 22.15±0.2, 15.11±0.2, 28.47±0.2, 22.54±0.2, 30.71±0.2, 17.91±0.2.

[0066] In the present application, the crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2, 29.52±0.2, 22.15±0.2, 15.11±0.2, 28.47±0.2, 22.54±0.2, 30.71±0.2, 17.91±0.2, 15.64±0.2.

[0067] In the present application, the crystalline Form III has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 9.06±0.2, 23.30±0.2, 21.44±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2, 17.06±0.2, 21.75±0.2, 29.52±0.2, 22.15±0.2, 15.11±0.2, 28.47±0.2, 22.54±0.2, 30.71±0.2, 17.91±0.2, 15.64±0.2, 26.49±0.2.

[0068] In the present application, the powder X-ray diffraction pattern of the crystalline form III is shown in FIG.

[0069] In the present application, the melting point of crystalline form III is 162.0°C.

[0070] In the present application, the adsorbed water removal temperature of crystalline form III is 94.5°C.

[0071] In the present application, crystalline form III loses weight by 6.1% at 140°C.

[0072] The present application provides a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate being crystalline form IV, the crystalline form IV having characteristic peaks represented by at least 2θ°: 16.25±0.2, 6.8±0.2, and 22.08±0.2. It has a powder X-ray diffraction pattern.

[0073] In the present application, said crystalline form IV has an X-ray powder diffraction pattern with characteristic peaks represented by the following angles 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2.

[0074] In the present application, said crystalline form IV has an X-ray powder diffraction pattern with characteristic peaks represented by the following angles 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 19.39±0.2.

[0075] In the present application, said crystalline form IV has an X-ray powder diffraction pattern having characteristic peaks represented by the following angles 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2.

[0076] In the present application, said crystalline form IV has an X-ray powder diffraction pattern with characteristic peaks represented by the following angles 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2.

[0077] In the present application, said crystalline form IV has an X-ray powder diffraction pattern with characteristic peaks represented by the following angles 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 9.68±0.2.

[0078] In the present application, said crystalline form IV has an X-ray powder diffraction pattern with characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2.

[0079] In the present application, said crystalline form IV has an X-ray powder diffraction pattern with characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2, 15.92±0.2.

[0080] In the present application, said crystalline form IV has an X-ray powder diffraction pattern with characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2, 15.92±0.2, 11.71±0.2.

[0081] In the present application, said crystalline Form IV has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2, 15.92±0.2, 11.71±0.2, 29.91±0.2.

[0082] In the present application, said crystalline Form IV has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2, 15.92±0.2, 11.71±0.2, 29.91±0.2, 23.04±0.2.

[0083] In the present application, the crystalline form IV has the following 2θ°: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9 It has a powder X-ray diffraction pattern having characteristic peaks represented by: 0.68±0.2, 15.92±0.2, 11.71±0.2, 29.91±0.2, 23.04±0.2, 16.56±0.2.

[0084] In the present application, the crystalline form IV has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2, 15.92±0.2, 11.71±0.2, 29.91±0.2, 23.04±0.2, 16.56±0.2, 23.5±0.2.

[0085] In the present application, the crystalline form IV has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2, 15.92±0.2, 11.71±0.2, 29.91±0.2, 23.04±0.2, 16.56±0.2, 23.5±0.2, 27.31±0.2.

[0086] In the present application, the crystalline form IV has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2, 15.92±0.2, 11.71±0.2, 29.91±0.2, 23.04±0.2, 16.56±0.2, 23.5±0.2, 27.31±0.2, 19.74±0.2.

[0087] In the present application, the crystalline form IV has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2, 15.92±0.2, 11.71±0.2, 29.91±0.2, 23.04±0.2, 16.56±0.2, 23.5±0.2, 27.31±0.2, 19.74±0.2, 34.34±0.2.

[0088] In the present application, the crystalline form IV has an X-ray powder diffraction pattern having characteristic peaks represented by the following degrees 2θ: 16.25±0.2, 6.8±0.2, 22.08±0.2, 13.16±0.2, 19.39±0.2, 18.35±0.2, 9.68±0.2, 15.92±0.2, 11.71±0.2, 29.91±0.2, 23.04±0.2, 16.56±0.2, 23.5±0.2, 27.31±0.2, 19.74±0.2, 34.34±0.2, 18.82±0.2.

[0089] In the present application, the powder X-ray diffraction pattern of the crystalline form IV is shown in FIG.

[0090] In the present application, the melting point of crystalline form IV is 163.8°C.

[0091] In the present application, the adsorption water removal temperature of crystalline form IV is 96.1°C.

[0092] In the present application, crystalline form IV loses 8.21% weight at 150°C.

[0093] The crystal forms I to IV of PNAC provided in the present application all have good solubility, bioavailability and solid-state stability, and in particular, the bioavailability and solid-state stability of crystal forms I and II are superior.

[0094] This application takes the following steps: Step 1: Add organic solvent to the reaction vessel and stir to remove N-[8-(2-hydroxybenzoyl) adding 1,2-diamino-1,2-phenyl-octanoic acid to the mixture, stirring the mixture until uniform, adding potassium hydroxide solution dropwise, and concentrating the mixture after the completion of the dropwise addition to obtain a crude product; and Step 2: adding an organic solvent to the crude product, beating and suction filtering to obtain a filter cake, rinsing the filter cake, and then drying it in a drying oven at a drying temperature of 60°C to 100°C for 30 to 40 hours to obtain crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate; The present invention provides a method for preparing the crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising:

[0095] The drying temperature may be 60° C., 65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 95° C., or 100° C. The drying time may be 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, or 40 hours.

[0096] Preferably, the drying is divided into two stages, first drying at 60° C. for 16 hours, then drying at 100° C. for 24 hours after flushing the system with nitrogen.

[0097] In the present application, the organic solvent is isopropanol or acetone.

[0098] In the present application, the concentration of the potassium hydroxide solution is 40% to 90%, and preferably the concentration of the potassium hydroxide solution is 50%.

[0099] The concentration of the potassium hydroxide solution may be 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%.

[0100] In the present invention, after adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid, the temperature in the system is raised to 48°C or higher, and potassium hydroxide solution is added dropwise. After completion of the dropwise addition, the reaction is allowed to proceed for 0.5 to 2 hours while maintaining the temperature at 48°C or higher.

[0101] Preferably, after adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid, the temperature inside the system is raised to 48°C to 52°C, potassium hydroxide solution is added dropwise, and after completion of the dropwise addition, the reaction is carried out for 1 hour while maintaining the temperature at 48°C to 52°C.

[0102] The temperature in the system may be 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, or 55°C.

[0103] The incubation reaction time may be 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, or 2 hours.

[0104] In the present application, the molar ratio of said N-[8-(2-hydroxybenzoyl)amino]octanoic acid to potassium hydroxide is 1:1.

[0105] In the present application, the time for adding the organic solvent to the crude product and beating it is 0.5 to 1.5 hours, preferably 1 hour.

[0106] The time for adding the organic solvent to the crude product and beating it may be 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, or 2 hours.

[0107] The present application provides a second method for preparing crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, which comprises heating a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I to at least 75° C. to form crystalline form I.

[0108] In the present application, the crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form I is at least one or more of crystalline form II, crystalline form III and crystalline form IV.

[0109] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form I may be the crystalline form II.

[0110] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form I may be crystalline form III.

[0111] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form I may be the crystalline form IV.

[0112] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form I may be crystalline form II or crystalline form III.

[0113] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form I may be crystalline form II or crystalline form IV.

[0114] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form I may be crystalline form III or crystalline form IV.

[0115] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form I may be crystalline form II, crystalline form III, or crystalline form IV.

[0116] In the present application, a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I is heated to 75°C or higher for 0-300 minutes under the protection of nitrogen to form crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.

[0117] The heating temperature is preferably 110 to 140° C. The heating temperature may be 110° C., 115° C., 120° C., 125° C., 130° C., 135° C., or 140° C.

[0118] The heating time is 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 140 minutes, 145 minutes, 150 minutes, 155 minutes, 160 minutes, , 165 minutes, 170 minutes, 175 minutes, 180 minutes, 185 minutes, 190 minutes, 195 minutes, 200 minutes, 205 minutes, 210 minutes, 210 minutes, 220 minutes, 225 minutes, 230 minutes, 235 minutes, 240 minutes, 245 minutes, 250 minutes, 255 minutes, 260 minutes, 265 minutes, 270 minutes, 275 minutes, 280 minutes, 285 minutes, 290 minutes, 295 minutes, 300 minutes.

[0119] In the present application, the crystal form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is heated to 140° C. under the protection of nitrogen to obtain N-[8-(2-hydroxybenzoyl)amino]octanoate. The crystal form I of potassium octanoate is formed.

[0120] In the present application, potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline form IV is heated to 110° C. under the protection of nitrogen to form potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline form I.

[0121] The present application provides a third method for preparing potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline form I, which comprises freeze-drying a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than Form I to form Form I.

[0122] In the present application, the crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form I is at least one or more of crystalline form II, crystalline form III and crystalline form IV.

[0123] This application takes the following steps: Step 1: adding an organic solvent to a reaction vessel and stirring, adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid and stirring uniformly, dropping potassium hydroxide solution, and concentrating after dropping to obtain a crude product; and Step 2: adding an organic solvent to the crude product, beating and suction filtering to obtain a filter cake, preparing the filter cake into uniform granules, and then putting the granules into the drying oven to dry, and then spreading the dried granules uniformly in a low temperature environment of 2-8°C and placing them under a controlled relative humidity of 50% for 2 days to form the crystal form III of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate. The present invention provides a method for preparing crystalline form III of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising:

[0124] In the present application, the filter cake is sieved through a 20-24 mesh sieve to obtain uniform particles.

[0125] In the present application, the drying temperature is 60° C. to 100° C., and the drying time is 30 to 40 hours. Preferably, the drying temperature may be 60° C., 65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 95° C., or 100° C. The drying time may be 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, or 40 hours.

[0126] Preferably, the drying is divided into two stages, first drying at 60° C. for 16 hours, then drying at 100° C. for 24 hours after flushing the system with nitrogen.

[0127] In the present application, the organic solvent is isopropanol or acetone.

[0128] In the present application, the concentration of the potassium hydroxide solution is 40% to 90%, and preferably the concentration of the potassium hydroxide solution is 50%.

[0129] The concentration of the potassium hydroxide solution may be 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%.

[0130] In the present invention, after adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid, the temperature in the system is raised to 48°C or higher, and potassium hydroxide solution is added dropwise. After completion of the dropwise addition, the reaction is allowed to proceed for 0.5 to 2 hours while maintaining the temperature at 48°C or higher.

[0131] Preferably, after adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid The temperature inside the system is raised to 48°C to 52°C, and the potassium hydroxide solution is added dropwise. After the addition is complete, the reaction is carried out for 1 hour while maintaining the temperature at 48°C to 52°C.

[0132] The temperature in the system may be 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, or 55°C.

[0133] The temperature holding reaction time may be 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, or 2 hours.

[0134] In the present application, the molar ratio of said N-[8-(2-hydroxybenzoyl)amino]octanoic acid to potassium hydroxide is 1:1.

[0135] In the present application, the time for adding the organic solvent to the crude product and beating it is 0.5 to 1.5 hours, preferably 1 hour.

[0136] The time for adding the organic solvent to the crude product and beating it may be 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, or 2 hours.

[0137] The present application provides a method for preparing crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising exposing a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form II to an environment having a relative humidity of 0 to 60% at room temperature for 24 hours or more to form crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.

[0138] In this application, the relative humidity is 20%, 30%, 40%, and 60%.

[0139] In the present application, the time for forming crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate can be 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, etc.

[0140] In the present application, the crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form II is at least one or more of crystalline form I, crystalline form III and crystalline form IV.

[0141] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form II may be the crystalline form I.

[0142] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form II may be the crystalline form III.

[0143] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form II may be the crystalline form IV.

[0144] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form II may be the crystalline form I or the crystalline form III.

[0145] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form II may be the crystalline form I or the crystalline form IV.

[0146] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form II may be crystalline form III or crystalline form IV.

[0147] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form II may be crystalline form I, crystalline form III, or crystalline form IV.

[0148] The present application, forming a gel-like substance from a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form IV in a relative humidity environment of greater than 80%; exposing the gelatinous material to a 20-40% relative humidity environment at room temperature for 120 hours or more to form crystalline form IV; The present invention provides a method for preparing crystalline form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising:

[0149] In the present application, the crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form IV is at least one or more of the crystalline form I, the crystalline form II and the crystalline form III.

[0150] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form IV may be the crystalline form I.

[0151] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form IV may be the crystalline form II.

[0152] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form IV may be the crystalline form III.

[0153] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form IV may be the crystalline form I or the crystalline form III.

[0154] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form IV may be the crystalline form I or the crystalline form II.

[0155] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form IV may be the crystalline form III or the crystalline form II.

[0156] The crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystalline form IV may be the crystalline form I, the crystalline form II, or the crystalline form III.

[0157] In the present application, the gel material is exposed to an environment having a relative humidity of 20%, 30%, or 40%, and preferably, the gel material is exposed to an environment having a relative humidity of 40%.

[0158] In the present application, the crystalline form other than crystalline form IV is left in a relative humidity environment of more than 80% for at least 2 days or more to form a gel-like substance, and the leaving time may be 48 hours, 50 hours, 55 hours, 60 hours, 65 hours, 72 hours, etc.

[0159] The time for exposing the gelatinous substance to an environment having a relative humidity of 20-40% at room temperature to form crystalline form IV may be 120 hours, 121 hours, 122 hours, 123 hours, 124 hours, 125 hours, 126 hours, 127 hours, 128 hours, 129 hours, 130 hours, 131 hours, 132 hours, 133 hours, 134 hours, 135 hours, 136 hours, 137 hours, 138 hours, 139 hours, 140 hours, etc.

[0160] The present application provides pharmaceutical compositions comprising crystalline polymorphs of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.

[0161] The pharmaceutical composition may further comprise a prophylactic and / or therapeutic agent, which may be glucagon-like peptide-1 (simply referred to as GLP-1), insulin, PYY, human amylin, heparin, human growth hormone, interferon, monoclonal antibodies, protease inhibitors, and / or thrombopoietin.

[0162] In the present application, the crystalline polymorphism of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate in the pharmaceutical composition is at least one or more of crystalline form I, crystalline form II, crystalline form III and crystalline form IV.

[0163] The pharmaceutical composition comprises crystalline Form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.

[0164] The pharmaceutical composition comprises potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline Form II.

[0165] The pharmaceutical composition comprises potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline Form III.

[0166] The pharmaceutical composition comprises potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline Form IV.

[0167] The pharmaceutical composition comprises potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, crystalline form I and crystalline form II.

[0168] The pharmaceutical composition comprises potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, crystalline form I and crystalline form III.

[0169] The pharmaceutical composition comprises potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, crystalline form I and crystalline form IV.

[0170] The pharmaceutical composition comprises potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, crystalline form II and crystalline form III.

[0171] The pharmaceutical composition comprises potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, crystalline form II and crystalline form IV.

[0172] The pharmaceutical composition comprises potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, crystalline form III and crystalline form IV.

[0173] The pharmaceutical compositions include potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, Form I, Form II, and Form III.

[0174] The pharmaceutical compositions include potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, Form II, Form III, and Form IV.

[0175] The pharmaceutical compositions include potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, Form I, Form III, and Form IV.

[0176] The pharmaceutical compositions include potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, Form I, Form II, Form III, and Form IV.

[0177] In the present application, the weight ratio of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorph to the prophylactic and / or therapeutic agent in the pharmaceutical composition may be (20-60:1).

[0178] In the present application, the weight ratio of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorph to the prophylactic and / or therapeutic agent in the pharmaceutical composition may be 30:1.

[0179] The weight ratio of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorph to the prophylactic and / or therapeutic agent in the pharmaceutical composition can be 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, or 60:1.

[0180] The pharmaceutical composition may be a tablet.

[0181] The present application provides the use of a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate or a pharmaceutical composition thereof in the preparation of a prophylactic and / or therapeutic drug.

[0182] The present application provides the use of a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate or a pharmaceutical composition thereof in enhancing drug delivery.

[0183] The present application provides use of a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate or a pharmaceutical composition thereof in the preparation of a medicament for the prevention and / or treatment of diabetes or diabetic complications.

[0184] Prophylactic and / or therapeutic agents Prophylactic and / or therapeutic agents refer to agents that can be used to accomplish the purpose of preventing, curing, alleviating, mitigating, altering, treating, ameliorating, improving, or affecting a condition (such as a disease), symptoms of a disease, or susceptibility to a disease.

[0185] The prophylactic and / or therapeutic agents may be proteins, polypeptides, peptides, hormones, polysaccharides, mucopolysaccharides, and certain mixtures of mucopolysaccharides, carbohydrates, lipids, small polar organic molecules (i.e., polar organic molecules having a molecular weight of 500 Daltons or less), other organic compounds, and certain compounds that do not themselves cross the gastrointestinal mucosa (only a portion of an administered dose does pass through) and / or are susceptible to cleavage by acid and enzymatic activity in the gastrointestinal tract, or any combination thereof.

[0186] Prophylactic and / or therapeutic agents include growth hormones, including human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth hormone (hGH), bovine and porcine growth hormone; growth hormone releasing hormone; growth hormone releasing factors (e.g., GRF analog g); interferons, including alpha, beta, and gamma; interleukin 1; interleukin 2; insulin, including porcine, bovine, human insulin, and human recombinant insulin, which may include counterions such as zinc, sodium, calcium, and ammonium; insulin-like growth factors, including IGF-1; unfractionated heparin, heparin analogs, dermatan, chondroitin, and the like. Heparins, including heparin, low molecular weight heparin, very low molecular weight heparin, and very low molecular weight heparin; calcitonins, including salmon, eel, porcine, and human calcitonin; erythropoietin; atrial natriuretic peptide; antigens; monoclonal antibodies; somatostatin; protease inhibitors; corticotropin, gonadotropin-releasing hormone; oxytocin; luteinizing hormone-releasing hormone; follicle-stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim; prostaglandins; cyclosporine; vasopressin; cromolyn sodium (cromolyn sodium or disodium cromoglycate chromoglycate); vancomycin; deferoxamine (DFO); bisphosphonates, including acid salts of ibandronate, alendronate, tiludronate, etidronate, clodronate, pamidronate, opadronate, and icadronate, and pharmaceutically acceptable salts thereof (e.g., ibandronate sodium); gallium salts (such as gallium nitrate, gallium nitrate nonahydrate, gallium maltolate, and the like); acyclovir and its pharmaceutically acceptable salts (such as acyclovir sodium); parathyroid hormone (PTH), including fragments thereof; antimigraine medications, such as BIBN-4096BS and other calcitonin gene-related protein antagonists; antimicrobials, including antibiotics (including bactericidal agents acting against gram-positive bacteria, including daptomycin, lipopeptide and cyclic peptide antibiotics), antibacterial and antifungal agents; vitamins;These may include, but are not limited to, analogs, fragments, mimetics, or polyethylene glycol (PEG) modified derivatives of these compounds; or any combination thereof, including their synthetic, natural, or recombinant origins;

[0187] Preferred drugs in the present application are polypeptide and protein drugs that are poorly absorbed and poorly absorbed in the intestinal tract when administered orally, and common drugs include insulin, monoclonal antibodies, heparin, glucagon-like peptides, PYY, human amylin, human growth hormone, interferons, protease inhibitors, thrombopoietin, and the like, including their analogs, fragments, mimetics, and polyethylene glycol-modified derivatives.

[0188] Insulin Insulin is a protein hormone secreted by the islet β cells of the pancreas when stimulated by endogenous or exogenous substances such as glucose, lactose, ribose, arginine, and glucagon. Insulin is the only hormone that can lower blood glucose levels in the body, while promoting the synthesis of glycogen, fat, and protein. Exogenous insulin is mainly used to treat diabetes. All crystalline forms of insulin in this application include, but are not limited to, naturally occurring insulin and crystalline forms of synthetic insulin. Subcutaneous injection is still the main method of administration, as oral administration is prone to degradation.

[0189] PYY PYY is secreted from endocrine cells in the distal gastrointestinal tract after a meal and acts on satiety signals in the hypothalamus. Recent studies have shown that obese individuals have lower fasting and postprandial PYY levels, which may explain their increased appetite and food consumption. When administered intravenously, it suppresses appetite and food intake in lean and obese individuals. Other peptides in the pancreatic peptide (PP) family, such as PYY fragments (e.g., PYY[3-36]), and other PYY agonists, can also suppress appetite. However, it is poorly absorbed in the gastrointestinal tract and is rapidly degraded. Therefore, its oral activity is almost negligible.

[0190] Glucagon-like peptide-1 Glucagon-like peptide-1 (GLP-1) is a type of brain-gut peptide secreted from ileal endocrine cells and is mainly used as a target for type 2 diabetes treatment. GLP-1 can inhibit gastric emptying and reduce intestinal peristalsis, which helps control food intake and reduce weight. However, since GLP-1 is a polypeptide, oral administration is easily degraded and does not easily reach the intestinal tract.

[0191] Human amylin Human amylin (hIAPP) is a 37-amino acid polypeptide hormone synthesized and secreted by pancreatic islet cells, which cooperates with insulin and glucagon to regulate glucose homeostasis. The physiological and pharmacological functions of hIAPP monomer are: 1) affecting insulin and glucagon secretion; 2) delaying gastric emptying and lowering postprandial blood glucose; 3) increasing renin and angiotensin II and regulating kidney growth; 4) increasing aldosterone and reducing blood calcium; 5) regulating bone density; 6) dilating blood vessels and regulating hemodynamics; 7) regulating immune effects. hIAPP monomer can induce and regulate T cell differentiation, thereby regulating inflammatory responses and the secretion of immune factors. hIAPP may have potential applications in the prevention and treatment of obesity, diabetes, autoimmunity, osteoporosis, and other diseases.

[0192] Pharmaceutical Compositions In addition to the PNAC and prophylactic and / or therapeutic agent described in the present application, the pharmaceutical composition may also contain pharma- ceutically acceptable additives, which may be non-toxic fillers, stabilizers, diluents, carriers, solvents or other formulation additives. For example, diluents and excipients such as microcrystalline cellulose and mannitol; fillers such as starch and sucrose; binders such as starch, cellulose derivatives, alginates, gelatin, and / or polyethylene pyrrolidone; disintegrants such as calcium carbonate and / or sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; carriers and solvents such as water, saline, kaolin, and bentonite; and lubricants such as talc, calcium / magnesium stearate, and polyethylene glycol. The pharmaceutical composition of the present application is preferably an injection.

[0193] The pharmaceutical compositions are preferably solid form pharmaceutical compositions, which can be formulated as solid dosage forms. The solid dosage forms can be capsules, tablets, or granules, such as powders or sachets. The powders can be put into sachets (microcapsules) for mixing with liquid and administering. The solid dosage forms can also be topical delivery systems, such as ointments, creams, or semisolids. Possible solid dosage forms can include sustained or controlled release systems. Preferably, the solid dosage forms are for oral administration.

[0194] The powder can be encapsulated or compressed into tablets, used in powder form, or incorporated into ointments, creams, or semi-solids. Methods of forming solid dosage forms are well known in the art.

[0195] The PNAC in this application can be used as a delivery agent in a pharmaceutical composition.

[0196] The amount of delivery agent in the solid dosage form is a delivery effective amount, which can be determined for any particular compound or biologically or chemically active agent by methods well known to those of skill in the art.

[0197] After administration, the active agent in the unit dosage form is absorbed into the circulation. The bioavailability of the active agent is The activity of an active agent is readily assessed by assaying for a known pharmacological activity in the blood (e.g., increasing blood clotting time with heparin or decreasing circulating calcium levels with calcitonin). Alternatively, circulating levels of the active agent itself can be measured directly.

[0198] Delivery System The amount of prophylactic and / or therapeutic agent (sometimes called active agent) used in the pharmaceutical composition of the present application is an amount effective to achieve the purpose of the active agent for the target indication. The active agent is generally used in the composition in a pharmacologically, biologically, therapeutically or chemically effective amount. However, this amount may be lower than the dose when the composition is used in a unit dosage form, because the unit dosage form may contain multiple delivery agent compound / active agent compositions or may contain a pharmacologically, biologically, therapeutically or active effective amount per dose. The total effective amount may be administered in cumulative units that contain an effective amount of the active agent in total.

[0199] The total amount of active agent used can be determined by methods known to those skilled in the art, but because the compositions of the present application can deliver the active agent more effectively than other compositions or compositions containing only the active agent, it is possible to administer to a subject less of the biologically or chemically active agent used in existing unit dosage forms or delivery systems while achieving the same blood levels and / or therapeutic effect.

[0200] The delivery agents disclosed herein facilitate the delivery of biologically and chemically active agents, particularly to the oral, sublingual, buccal, intraduodenal, intracolonic, rectal, vaginal, mucosal, pulmonary, intranasal, and ocular systems.

[0201] The compounds and compositions of the present application are used to administer biologically or chemically active agents to any animal, including, but not limited to, mammals, such as birds, such as chickens, rodents, cows, pigs, dogs, cats, primates, and especially humans, and insects.

[0202] These compounds and compositions are particularly advantageous for the delivery of chemically or biologically active agents that are destroyed or have reduced activity due to the conditions that the active agent encounters before reaching the target area (i.e., the area of ​​the delivery composition where the active agent is released) and within the animal body to which they are administered. In particular, the compounds and compositions of the present application are used for the oral administration of active agents, especially those that are not normally delivered orally or for which enhanced delivery is desired.

[0203] The compositions comprising the compounds and active agents have utility in delivering the active agent to a selected biological system and increasing or enhancing the bioavailability of the active agent over delivery of the active agent without the delivery agent. Delivery can be improved by delivering more active agent over a period of time, or by delivering the active agent over a particular period of time, such as a faster acting or delayed delivery, or over a period of time, such as sustained delivery. [Example]

[0204] The experimental methods used in the following examples are conventional methods unless otherwise stated. Materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.

[0205] [Example 1] N-[8-(2-hydroxybenzoyl)amino]octanoic acid, NAC, was prepared by following the method of Example 1 of International Patent Application WO2008 / 028859.

[0206] Preparation of PNAC Crystal Form I Add isopropanol (22070.0 ml, 4.0 vol) to a 50 L reactor and stir. Stirring was started, and NAC (5518 g, 1.0 equivalent) was added. The system was heated to 50°C, and the prepared 50% potassium hydroxide solution (1304.0 g, 1.0 eq) was added dropwise to the system. After the addition, the system became a transparent yellow solution, and the reaction was carried out for 1 hour while keeping the temperature at 50°C. The reaction solution was concentrated in batches at 40°C, and the color of the obtained crude product was pale orange yellow. The combined crude product was added to isopropanol (19310.0 ml, 3.5 vol) and beaten for 1 hour. The system was suction filtered and the filter cake was rinsed with isopropanol (2760.0 ml, 0.5 vol). The filter cake was transferred to a vacuum drying oven, the drying system was flushed with nitrogen, and dried at 60° C. for 16 hours, then transferred to a vacuum drying oven and dried at 100° C. for 24 hours. After drying was completed, a total of 4.52 kg of product was obtained, which was an off-white powdery solid in nature. The yield was 72.8%. After measurement, the product is crystalline form I, and the XRPD and TGA / DSC of crystalline form I are shown in Figures 1-2b, respectively. PNAC is crystalline form I, and the characteristic XRPD peaks (characterized in °2θ) of crystalline form I are shown in Table 1 below.

[0207] [Table 1]

[0208] The DSC spectrum (Fig. 2a) shows that the melting endotherm peak of crystalline form I begins to appear at 195.5 °C and peaks at 163.1 °C. Both the DSC (Fig. 2a) and TGA (Fig. 2b) spectra indicate that crystalline form I is anhydrous.

[0209] [Example 2] Preparation of PNAC Crystal Form II The PNAC crystal form I prepared in Example 1 was exposed to an environment of 60% relative humidity at room temperature for more than 24 hours to obtain a product. The product was determined to be crystalline form II. The XRPD and TGA / DSC of the product are shown in Figures 3-4b, respectively, and the characteristic XRPD peaks (characterized by °2θ) of crystalline form II are shown in Table 2 below.

[0210] [Table 2]

[0211] The DSC spectrum (Fig. 4a) shows that the melting endotherm peak of crystalline form II begins to appear at 157.1 C and peaks at 162.5 C. The combination of DSC (Fig. 4a) and TGA (Fig. 4b) spectra indicates that crystalline form II is a 1 / 3 hydrate.

[0212] [Example 3] N-[8-(2-hydroxybenzoyl)amino]octanoic acid, NAC, was prepared by following the method of Example 1 of International Patent Application WO2008 / 028859.

[0213] Preparation of PNAC Crystal Form III Isopropanol (22070.0 ml, 4.0 vol) was added to a 50 L reactor, stirring was started, and NAC (5518 g, 1.0 eq) was added. The system was heated to 50°C, and the prepared 50% potassium hydroxide solution (1304.0 g, 1.0 eq) was added dropwise to the system. After the addition, the system became a transparent yellow solution, and the reaction was carried out for 1 hour while keeping the temperature at 50°C. The reaction solution was concentrated in batches at 40°C, and the color of the obtained crude product was pale orange yellow. The crude product was combined and added to isopropanol (19310.0ml, 3.5vol) and beaten for 1 hour. The system was suction filtered to obtain a filter cake, which was sieved through a 24 mesh sieve to make uniform granules, transferred to a vacuum drying oven, the drying system was replaced with nitrogen, and dried at 60°C for 16 hours, then transferred to a vacuum drying oven and dried at 100°C for 24 hours. The obtained granules were spread evenly in a low temperature environment at 5°C and placed in a controlled relative humidity of 50% for 2 days to obtain the product. The product was determined to be crystalline form III. The XRPD and TGA / DSC of crystalline form III are shown in Figures 5-6b, respectively, and the characteristic XRPD peaks (characterized by °2θ) of crystalline form III are shown in Table 3 below.

[0214] [Table 3]

[0215] The DSC spectrum (Figure 6a) shows that the melting endotherm peak of crystalline form III begins at 156.6° C. and peaks at 162.0° C. The combination of the DSC (Figure 6a) and TGA (Figure 6b) spectra indicates that crystalline form III is a hemihydrate.

[0216] [Example 4] Preparation of PNAC crystal form IV The PNAC crystal form I prepared in Example 1 was exposed to an environment of 80% relative humidity at room temperature and allowed to stand for 3 days to form a gel-like substance, which was then exposed to an environment of 40% relative humidity and allowed to stand for 5 days to obtain a product. The product was determined to be crystalline form IV. XRPD and TGA / DS of crystalline form IV Form IV and Form C are shown in Figures 7-8b, respectively, and the characteristic XRPD peaks (characterized by °2θ) of crystalline form IV are shown in Table 4 below.

[0217] [Table 4]

[0218] The DSC spectrum (Figure 8a) shows that the melting endotherm peak of crystalline form IV begins to appear at 163.8° C. The combination of the DSC (Figure 8a) and TGA (Figure 8b) spectra indicates that crystalline form IV is a hydrate.

[0219] [Experimental Example] SNAC: Characterization of SNAC in Rybelsus® tablets (developed by Danish pharmaceutical company Novo Nordisk) revealed that it was identical to crystalline form I in patent WO2005107462. Therefore, the SNAC herein was prepared by referring to the preparation method of SNAC crystalline form I in Example 1 of patent WO2005107462. All SNAC in the following examples was prepared by this method. Crystalline form I (PNAC-I) was prepared in Example 1. Crystalline form II (PNAC-II) was prepared in Example 2. Crystalline form III (PNAC-III) was prepared in Example 3. Crystalline form IV (PNAC-IV) was prepared in Example 4.

[0220] [Experimental Example 1: Solution stability test of different crystal forms of PNAC in aqueous solution] The samples of PNAC crystal forms I to IV prepared in the above examples and the sample of SNAC crystal form I prepared above were dissolved in purified water, respectively, and placed under two conditions of 4°C and room temperature, respectively, to observe the changes in the solutions, and the differences in stability under high concentration (500 mg / mL) conditions of different salt forms and different crystal forms in aqueous solutions were compared. The results are shown in Table 5 (there was no difference in the dissolution and solution standing processes of sample PNAC crystal forms I to IV).

[0221] [Table 5]

[0222] As can be seen from Table 5, after SNAC was dissolved at 4°C, flocs began to appear in the solution at 0.5 hours, the fluidity of the solution gradually decreased with time, and large white particles precipitated in the solution at 2 hours. When the temperature was raised to room temperature, flocs also appeared in the solution after the SNAC solution was left for 1 hour, and the flocs increased and the solution became turbid at 2 hours. In contrast, when the solution of PNAC I to IV prepared in this application was left at 4°C for 1 hour, a small amount of thread-like flocs appeared at the bottom, and the state of the solution did not change much until 2 hours. When left at room temperature for 2 hours, a small amount of flocs appeared in the solution. This indicates that under the same conditions, the solution stability of PNAC I to IV of this application is superior to SNAC under high concentration (500 mg / mL) conditions.

[0223] [Experimental Example 2: Effect of different crystal forms of PNAC on the bioavailability of GLP-1 drugs in beagle dogs] For the preparation method of GLP-1 drug M4 (abbreviated as M4), please refer to patent application WO2019201328. For the preparation method of the composite oral tablet, please refer to the preparation method in Example 1 of Patent WO2012080471. Each of the delivery agents (SNAC, PNAC-I, PNAC-II) is combined with M4. The composite oral tablet that combines SNAC and M4 is SNAC+M4. The composite oral tablet that combines PNAC-I and M4 is PNAC-I+M4. The composite oral tablet that combines PNAC-II and M4 is PNAC-II+M4. In the combined oral tablet, the content of M4 was 10 mg and the content of the delivery agent was 100 mg. Formulation of M4 for intravenous injection: M4 was dissolved in 8 mM, pH 7.2 phosphate buffer to a final concentration of 1 mg / mL. Twenty-eight male beagle dogs weighing 9-12 kg were divided into four groups. Group 1 was administered a single dose of M4 (0.05 mg / kg, N=4) by intravenous injection, group 2 was administered a single dose of SNAC+M4 (1 tablet, N=8), group 3 was administered a single dose of PNAC-I+M4 (1 tablet, N=8), and group 4 was administered a single dose of PNAC-II+M4 (1 tablet, N=8) to compare the effects of different crystalline forms of PNAC on the bioavailability of M4 in beagle dogs. The beagle dogs in the oral administration group were fasted the night before and allowed to drink water. After administration on the same day, the tablets were taken with 10 ml of water (quantitatively), and food was resumed 4 hours later. Then, blood samples were taken according to the blood sampling scheme in Table 6 to measure the blood drug concentration at different time points and the exposure amount in the animal body AUC last The specific results are shown in Tables 7, 8, and 9, and Figures 9 and 10.

[0224] [Table 6]

[0225] [Table 7]

[0226] [Table 8]

[0227] [Table 9]

[0228] As can be seen from the calculation of the data in Tables 7 to 9, the absolute bioavailability of the single oral administration group of SNAC was 0.88%, the absolute bioavailability of the single oral administration group of PNAC-II was 1.28%, and the absolute bioavailability of the single oral administration group of PNAC-I was 1.11%, and the bioavailability of the two PNAC groups was significantly higher than that of the SNAC group. Compared with the single oral dose of SNAC, the absolute bioavailability of the single oral dose of PNAC-II increased by 45.5% and that of the single oral dose of PNAC-I increased by 26.1%.

[0229] [Experimental Example 3: Effects of different contents and different crystal forms of PNAC on the bioavailability of GLP-1 drugs in beagle dogs] For the preparation method of GLP-1 drug M4 (abbreviated as M4), please refer to patent application WO2019201328. For the preparation method of the composite oral tablet, please refer to the preparation method in Example 1 of Patent WO2012080471. Each of the delivery agents (SNAC, PNAC-I, PNAC-II) is combined with M4. The composite oral tablet that combines SNAC and M4 is SNAC+M4. The composite oral tablet that combines PNAC-I and M4 is PNAC-I+M4. The composite oral tablet that combines PNAC-II and M4 is PNAC-II+M4. In the composite oral tablet, the content of M4 in each tablet was 10 mg, and the contents of the delivery agents were 300 mg and 450 mg, respectively. Formulation of M4 for intravenous injection: M4 was dissolved in 8 mM, pH 7.2 phosphate buffer to a final concentration of 1 mg / mL. Twenty-eight male beagle dogs weighing 9-15 kg were divided into seven groups, with four dogs in each group, to compare the effects of different crystalline forms of PNAC on the bioavailability of M4 in beagle dogs. The group information is shown in Table 10 below. The beagle dogs in the oral administration group were fasted the night before and allowed to drink water. After administration on the same day, the tablets were taken with 10 ml of water (quantitatively), and food was resumed 4 hours later. Then, blood samples were taken according to the blood sampling scheme in Table 11 to measure the blood drug concentration at different time points and the exposure amount in the animal body AUC last The specific results are shown in Tables 12 to 14 and Figures 19 and 20.

[0230] [Table 10]

[0231] [Table 11]

[0232] [Table 12]

[0233] [Table 13]

[0234] [Table 14]

[0235] As can be seen from Table 14, the absolute bioavailability of the single oral administration group of SNAC (300 mg) was 0.70%, the absolute bioavailability of the single oral administration group of SNAC (450 mg) was 0.80%, the absolute bioavailability of the single oral administration group of PNAC-II (300 mg) was 1.20%, the absolute bioavailability of the single oral administration group of PNAC-II (450 mg) was 1.92%, the absolute bioavailability of the single oral administration group of PNAC-I (300 mg) was 1.01%, and the absolute bioavailability of the single oral administration group of PNAC-I (450 mg) was 1.72%, all of which were significantly higher than SNAC, and the PNAC absolute bioavailability increased significantly with increasing content. Compared with the single oral administration of SNAC (300 mg), PNAC-II (300 mg) The absolute bioavailability of the single oral dose of PNAC-II (450 mg) was increased by 140% and that of the single oral dose of PNAC-I (450 mg) was increased by 115% compared to the single oral dose of SNAC (450 mg). From the perspective of a single drug, the absolute bioavailability of the single oral administration group of SNAC (300 mg) was increased by only 14% compared with the single oral administration group of SNAC (450 mg), and there was no significant difference in the bioavailability between the two groups. In other words, the content of SNAC in the drug had little effect on the absolute bioavailability. Compared with the single oral administration group of PNAC-II (450 mg), the absolute bioavailability of the single oral administration group of PNAC-II (300 mg) was increased by 60%. Compared with the single oral administration group of PNAC-I (450 mg), the absolute bioavailability of the single oral administration group of PNAC-I (300 mg) was increased by 70%. Combining the absolute bioavailability of the single oral administration groups of PNAC-II and PNAC-I (100 mg) in Example 2, it could be further verified that with an increase in the content of the present PNAC in the drug, the absolute bioavailability increased significantly, and there was an unexpected qualitative improvement.

[0236] [Experimental Example 4] Solid-state stability experiments of PNAC crystal form II The crystalline form II prepared in Example 2 was divided into three groups. The first group was left at 60° C. for 24 hours to obtain a solid sample. The second group was left at 40° C. and 75% relative humidity for two weeks to obtain a solid sample. The third group was left at 25° C. and 60% relative humidity for two weeks to obtain a solid sample. Each of the three solid samples was evaluated for physical and chemical stability by XRPD and HPLC tests. Here, the HPLC test means that the crystalline form II obtained in Example 2 is used as a reference sample, and the purity obtained by HPLC purity test is 100 area%, and the relative purity is HPLC purity / reference sample purity. In the HPLC test method, a C18 reverse phase chromatographic column with a column length of 150 mm is used, and an acetonitrile-water+0.05% trifluoroacetic acid system is used as the mobile phase, and the sample is injected at a flow rate of 1.2 ml / min, and the detection is performed under the condition of a detector wavelength of UV-215 nm, and the purity of the main peak is calculated according to the normalization method. After the test, the reference samples were placed in different environments for a certain period of time, and the measured HPLC relative purity was found to be 100%. The XRPD overlay after the experiment is shown in Figure 11, which is exactly the same as the characteristic peaks of the reference samples, indicating that none of the crystal forms have changed in the solid stability experiment. The solid state stability experiment of PNAC crystal form I was carried out using the same method as above, and the results are shown in FIG.

[0237] [Experimental Example 5] Stability testing in formulations The crystalline form II obtained in Example 2 was divided into three groups. In the first group, the crystalline form II was manually ground for 10 minutes to obtain solid samples. In the second group, the crystalline form II was compressed into tablets (pressure 3 kN) to obtain solid samples. In the third group, the crystalline form II was subjected to jet milling (injection pressure 0.4 MPa, grinding pressure 0.2 MPa) to obtain solid samples. The solid samples of the three groups were characterized by XRPD and the physical stability was evaluated. Specific results are shown in Figures 12 to 14. From Figures 12-14, it can be seen that after grinding, tableting, and jet milling of crystalline form II, the crystalline form of the sample did not change. Using the same method as above, stability tests during the preparation process of PNAC crystalline form I, crystalline form II, crystalline form III and crystalline form IV were carried out, and the results are shown in Table 15. The XRPD characterization results of PNAC crystalline form I are shown in Figures 16 to 18. From Figures 16 to 18, it can be seen that after grinding, tableting, and jet milling of crystalline form I, the crystalline form of the sample did not change.

[0238] [Table 15]

[0239] As can be seen from the results in the table above, PNAC Form I and Form II are very stable, Form I only crystallizes when placed in an environment above 60% RH for a long period of time, while Form II is stable regardless of the conditions under test.

[0240] Although the embodiments of the present application have been described above, the present application is not limited to the above specific embodiments and application fields, and the above specific embodiments are merely illustrative, instructive, and not restrictive. Those skilled in the art can also create many forms under the teachings of this specification without departing from the scope of protection of the claims of this application, all of which belong to the protection of this application.

Claims

1. A crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, characterized in that it is crystalline form I having an X-ray powder diffraction pattern with characteristic peaks represented by at least 2θ°: 7.83±0.2, 26.64±0.2, and 18.89±0.

2.

2. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 1, characterized in that the crystalline form I further has a powder X-ray diffraction pattern having characteristic peaks represented by at least one of the following 2θ degrees: 5.24±0.2 and 21.59±0.

2.

3. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 2, characterized in that the crystalline form I further has a powder X-ray diffraction pattern having characteristic peaks represented by at least one of the following 2θ degrees: 13.02±0.2 and 24.29±0.

2.

4. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 3, characterized in that the crystalline form I further has an X-ray powder diffraction pattern having characteristic peaks represented by at least one of the following 2θ°: 6.61±0.2, 10.43±0.2, 31.63±0.2, and 37.00±0.

2.

5. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 1 to 4, characterized in that the powder X-ray diffraction pattern of the crystalline form I is shown in Figure 1.

6. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 1 to 4, characterized in that the melting point of the crystalline form I is 163.1°C.

7. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 1 to 4, characterized in that the adsorbed water removal temperature of the crystalline form I is 83.6°C.

8. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 1 to 4, characterized in that the crystalline form I loses weight by 3.0% at 140°C.

9. A crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, characterized in that it is crystalline form II having an X-ray powder diffraction pattern with characteristic peaks represented by at least the following 2θ°: 24.76±0.2, 6.73±0.2, and 20.26±0.

2.

10. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 9, characterized in that the crystalline form II further has an X-ray powder diffraction pattern having characteristic peaks represented by at least one of the following 2θ degrees: 14.68±0.2 and 25.55±0.

2.

11. The crystalline form II further has a powder X-ray diffraction pattern having characteristic peaks represented by at least one of the following 2θ degrees: 13.41±0.2 and 26.66±0.

2. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 10.

12. 12. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 11, characterized in that the crystalline form II further has an X-ray powder diffraction pattern having characteristic peaks represented by at least one of the following angles 2θ: 21.08±0.2, 25.79±0.2, 28.47±0.2, 12.07±0.2, 15.38±0.2, 23.38±0.2, 29.48±0.2, 22.55±0.2, 27.79±0.2, and 8.91±0.

2.

13. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 9, characterized in that the powder X-ray diffraction pattern of the crystalline form II is shown in FIG.

14. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 9 to 13, characterized in that the melting point of the crystalline form II is 162.5°C.

15. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 9 to 13, characterized in that the crystalline form II has an adsorbed water removal temperature of 93°C.

16. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 9 to 13, characterized in that the crystalline form II loses 5.6% at 140°C.

17. A crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, characterized in that it is crystalline form III having an X-ray powder diffraction pattern with characteristic peaks represented by at least the following 2θ degrees: 9.06±0.2, 23.30±0.2, and 21.44±0.

2.

18. 18. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 17, characterized in that the crystalline form III further has an X-ray powder diffraction pattern having characteristic peaks represented by at least one of the following 2θ degrees: 24.75±0.2 and 6.03±0.

2.

19. 19. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 18, characterized in that the crystalline form III further has an X-ray powder diffraction pattern having characteristic peaks represented by at least one of the following 2θ degrees: 21.20±0.2 and 17.06±0.

2.

20. 20. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 19, wherein the crystalline Form III further has an X-ray powder diffraction pattern having characteristic peaks represented by at least one of the following angles 2θ: 21.75±0.2, 29.52±0.2, 22.15±0.2, 15.11±0.2, 28.47±0.2, 22.54±0.2, 30.71±0.2, 17.91±0.2, 15.64±0.2, and 26.49±0.

2.

21. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 17, characterized in that the powder X-ray diffraction pattern of the crystalline form III is shown in FIG.

22. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 17 to 21, characterized in that the melting point of the crystalline form III is 162.0°C.

23. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 17 to 21, characterized in that the crystalline form III has an adsorbed water removal temperature of 94.5°C.

24. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 17 to 21, characterized in that the crystalline form III loses 6.1% at 140°C.

25. A crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, characterized in that it is crystalline form IV having an X-ray powder diffraction pattern with characteristic peaks represented by at least the following 2θ degrees: 16.25±0.2, 6.8±0.2, and 22.08±0.

2.

26. 26. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 25, wherein the crystalline form IV further has an X-ray powder diffraction pattern having characteristic peaks represented by at least one of the following 2θ degrees: 13.16±0.2 and 19.39±0.

2.

27. 27. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 26, wherein the crystalline form IV further has an X-ray powder diffraction pattern having characteristic peaks represented by at least one of the following 2θ degrees: 18.35±0.2 and 9.68±0.

2.

28. 28. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate of claim 27, wherein the crystalline form IV further has an X-ray powder diffraction pattern having characteristic peaks represented by at least one of the following degrees 2θ: 15.92±0.2, 11.71±0.2, 29.91±0.2, 23.04±0.2, 16.56±0.2, 23.5±0.2, 27.31±0.2, 19.74±0.2, 34.34±0.2, and 18.82±0.

2.

29. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to claim 25, characterized in that the powder X-ray diffraction pattern of the crystalline form IV is shown in FIG.

30. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 25 to 29, characterized in that the melting point of the crystalline form IV is 163.8°C.

31. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 25 to 29, characterized in that the crystalline form IV has an adsorbed water removal temperature of 96.1°C.

32. The crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 25 to 29, characterized in that the crystalline form IV loses 8.21% at 150°C.

33. adding an organic solvent to a reaction vessel and stirring the mixture; adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid and stirring the mixture to homogeneity; dropping a potassium hydroxide solution; and concentrating the mixture to obtain a crude product after the dropping is completed; adding an organic solvent to the crude product, beating and suction filtering to obtain a filter cake; rinsing the filter cake and drying it in a drying oven to obtain a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate; The method for preparing the crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is characterized in that it comprises:

34. The filter cake is rinsed and placed in a drying oven for drying at a temperature of 60°C to 100°C for 30 to 40 hours to obtain the crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate; preferably, the drying is divided into two stages, firstly drying at 60°C for 16 hours, then drying at 100°C for 24 hours after replacing the system with nitrogen; The preparation method according to claim 33, characterized in that the crystalline form I is crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 1 to 8.

35. preparing the filter cake into uniform granules, putting the granules into the drying oven to dry, spreading the dried granules uniformly in a low temperature environment of 2-8°C and keeping the relative humidity controlled at 50% for 2 days to form potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline form III; The drying temperature of the drying oven in which the granules are placed is 60° C. to 100° C., and the drying time is 30 to 40 hours. Preferably, the drying is divided into two stages, first drying at 60° C. for 16 hours, then drying at 100° C. for 24 hours after replacing the system with nitrogen, and sieving the filter cake through a 20-24 mesh sieve to obtain uniform particles; The preparation method according to claim 33, characterized in that the crystalline form III is potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 17 to 24.

36. The preparation method according to any one of claims 33 to 35, characterized in that the organic solvent is isopropanol or acetone, and the concentration of the potassium hydroxide solution is 40% to 90%, preferably the concentration of the potassium hydroxide solution is 50%.

37. After adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid, the temperature in the system is raised to 48°C or higher, and potassium hydroxide solution is added dropwise. After the dropwise addition is completed, the system is kept warm for 0.5 to 2 hours to react. Preferably, after adding N-[8-(2-hydroxybenzoyl)amino]octanoic acid, the temperature in the system is raised to 48° C. to 52° C., a potassium hydroxide solution is added dropwise, and after the dropwise addition is completed, the reaction is allowed to proceed by keeping the temperature for 1 hour. The molar ratio of the N-[8-(2-hydroxybenzoyl)amino]octanoic acid to the potassium hydroxide solution is 1:1; The process according to any one of claims 33 to 35, characterized in that the crude product is mixed with an organic solvent and then beaten for 0.5 to 1.5 hours, preferably 1 hour.

38. heating a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I to at least 75° C. to form crystalline form I; The crystal form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystal form I is at least one or two of crystal forms II, III and IV. That's all. A method for preparing crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising heating a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I to 75°C or higher under the protection of nitrogen to form crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.

39. The preparation method according to claim 38, characterized in that the crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is heated to 140° C. under the protection of nitrogen to form crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.

40. The preparation method according to claim 38, characterized in that the crystalline form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is heated to 110° C. under the protection of nitrogen to form crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.

41. freeze-drying a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form I to form crystalline form I; The crystal form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystal form I is at least one or more of crystal form II, crystal form III and crystal form IV, A method for preparing crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, characterized in that the crystalline form I is crystalline form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 1 to 8.

42. A method for preparing crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising exposing a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form II to an environment having a relative humidity of 0 to 60% at room temperature for 24 hours or more to form crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate.

43. The relative humidity is 20%, 30%, 40%, or 60%. The crystal form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystal form II is at least one or more of the crystal forms I, III and IV; The preparation method according to claim 42, characterized in that the crystalline form II is crystalline form II of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 9 to 16.

44. forming a gel-like material from a crystalline form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than crystalline form IV in a relative humidity environment of greater than 80%; exposing the gelled material to an environment having a relative humidity of 20-40% at room temperature for at least 120 hours to form crystalline form IV; The crystal form of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate other than the crystal form IV is at least one or more of the crystal forms I, II and III; A method for preparing crystalline form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, characterized in that the crystalline form IV is the crystalline form IV of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate according to any one of claims 25 to 32.

45. A pharmaceutical composition comprising a crystalline polymorph of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, The pharmaceutical composition, wherein the crystalline polymorphism of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is one or at least two of crystalline form I, crystalline form II, crystalline form III, and crystalline form IV.

46. The pharmaceutical composition further comprises a prophylactic and / or therapeutic agent, The pharmaceutical composition according to claim 45, wherein the weight ratio of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorph to the prophylactic and / or therapeutic agent in the pharmaceutical composition is (20-60):1, preferably the weight ratio of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline polymorph to the prophylactic and / or therapeutic agent in the pharmaceutical composition is 30:

1.

47. The pharmaceutical composition of claim 46, wherein the prophylactic and / or therapeutic agent is glucagon-like peptide-1, insulin, PYY, human amylin, heparin, human growth hormone, interferon, monoclonal antibody, protease inhibitor, or thrombopoietin.

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