CN113735733B

CN113735733B - Crystal polymorphs of N- [8- (2-hydroxybenzoyl) amino ] caprylic acid potassium and preparation method and application thereof

Info

Publication number: CN113735733B
Application number: CN202110838946.5A
Authority: CN
Inventors: 王宏阳; 江师月; 李尧; 潘海
Original assignee: Hangzhou Xianweida Biotechnology Co ltd
Current assignee: Hangzhou Xianweida Biotechnology Co ltd
Priority date: 2020-05-29
Filing date: 2020-12-31
Publication date: 2024-04-26
Anticipated expiration: 2040-12-31
Also published as: CN113735734A; CN113735734B; CN112661663B; CN113735733A; CN112661663A

Abstract

The application discloses a crystal polymorph of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate, which is a crystal form III, wherein the crystal form III at least has 2 theta degrees: an X-ray powder diffraction pattern of characteristic peaks expressed in 9.06+ -0.2, 23.30+ -0.2 and 21.44 + -0.2. The application also provides a crystal form IV, a crystal form I, a crystal form III and a preparation method of the crystal form IV. The N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph provided by the application has four crystal forms, has high solubility and strong stability, can more effectively deliver the medicine, increases the permeability of the delivered medicine in gastrointestinal tracts, and is favorable for preparing an oral preparation, so that the prevention and/or treatment medicine can be better delivered into the body to achieve the effect of improving the bioavailability.

Description

Crystal polymorphs of N- [8- (2-hydroxybenzoyl) amino ] caprylic acid potassium and preparation method and application thereof

The present application is a divisional application of a case with the application number 202011642226.3, wherein the application date is 12/31 in 2020, the invention name is N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph and a preparation method and application thereof.

Technical Field

The application relates to the field of chemical medicines, in particular to a N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph, a preparation method and application thereof.

Background

Macromolecular drugs such as polypeptides and proteins are often unstable to gastric acid due to large molecular weight and low fat solubility, can be destroyed by various digestive enzymes in the gastrointestinal tract, and cannot be smoothly absorbed by the intestinal tract after oral administration. In view of the above problems, attempts have been made to overcome the drug absorption disorder from various aspects, and besides some attempts have been made in terms of dosage form, gastrointestinal absorption promoters are often used to improve the biomembrane permeability of the drug, and although the absorption of the drug is increased, the absorption of endotoxin in the intestinal tract is also increased, and safety is lacking in long-term use.

U.S. Pat. No. 5,650,386, published in 1997, discloses a novel macromolecular drug delivery agent N- [8- (2-hydroxybenzoyl) amino ] caprylic acid (NAC for short) and its salts, the molecular formula of which is shown in formula (I). In particular, U.S. patent No. 8636996, published in 2009, discloses a polymorphic form, an amorphous form of monosodium N- [8- (2-hydroxybenzoyl) amino ] caprylate (SNAC for short), and a preparation method thereof, and the molecular formula is shown in formula (II).

SNAC is a novel amino acid derivative delivery agent. Recent researches show that the oral administration and the absorption of various protein medicine solutions such as heparin, human growth hormone and the like can be promoted without dosage form protection, but the oral administration and the absorption do not show obvious cytotoxicity. The bioavailability, solubility, and flowability of the different salt forms of the compounds may also vary. The same salt form has different crystal forms, and can have different crystal shapes, densities, hardness, colors, chemical stability, melting points, hygroscopicity, suspensibility, dissolution rate and other characteristics, and can directly or indirectly influence the capacity of the delivered medicine, so that the bioavailability, compressibility, stability and other aspects of the delivered medicine are different.

Disclosure of Invention

The application aims to provide an N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph, a preparation method and application thereof, a pharmaceutical composition and application thereof.

The technical scheme of the application is as follows:

1. A crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, characterized in that the crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is form I, said form I having at least 2Θ° as: x-ray powder diffraction pattern of characteristic peaks expressed in 7.83+ -0.2, 26.64 + -0.2 and 18.89+ -0.2.

2. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of item 1, wherein said crystalline form I further has at least the formula 2Θ°: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 5.24 + -0.2 and 21.59 + -0.2.

3. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of item 2, wherein form I further has at least the formula 2Θ°: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 13.02+ -0.2 and 24.29+ -0.2.

4. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of item 3, wherein said crystalline form I further has at least the formula 2Θ°: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 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 ] caprylate according to any one of claims 1 to 4, wherein the X-ray powder diffraction pattern of form I is as shown in figure 1.

6. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to any one of claims 1 to 4, wherein the melting point of form I is 163.1 ℃.

7. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to any one of claims 1 to 4, wherein the adsorbed water removal temperature of form I is 83.6 ℃.

8. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to any one of claims 1 to 4, wherein said form I loses 3.0% weight at 140 ℃.

9. A crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, characterized in that the crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is form II, said form II having at least 2Θ° of: x-ray powder diffraction patterns of characteristic peaks expressed in 24.76.+ -. 0.2, 6.73.+ -. 0.2 and 20.26.+ -. 0.2.

10. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 9, wherein said form II further has at least the formula 2Θ°: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 14.68+ -0.2 and 25.55+ -0.2.

11. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of item 10, wherein form II further has at least the formula 2Θ°: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 13.41 + -0.2 and 26.66 + -0.2.

12. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 11, wherein said form II further has at least the formula 2Θ°: an X-ray powder diffraction pattern of a characteristic peak indicated by one of 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.

13. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to item 9, wherein the X-ray powder diffraction pattern of form II is shown in figure 3.

14. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to any one of claims 9 to 13, wherein the melting point of form II is 162.5 ℃.

15. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to any one of claims 9 to 13, wherein the adsorbed water removal temperature of form II is 93 ℃.

16. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to any one of claims 9 to 13, wherein said form II loses weight 5.6% at 140 ℃.

17. A crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, characterized in that the crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is form III, said form III having at least 2Θ° of: an X-ray powder diffraction pattern of characteristic peaks expressed in 9.06+ -0.2, 23.30+ -0.2 and 21.44 + -0.2.

18. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 17, wherein said form III further has at least the formula 2Θ°: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 24.75+/-0.2 and 6.03+/-0.2.

19. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 18, wherein form III further has at least the following 2Θ°: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 21.20 + -0.2 and 17.06 + -0.2.

20. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to claim 19, wherein said form III further has an X-ray powder diffraction pattern of at least one characteristic peak represented by 2Θ° at ：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.

21. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to item 17, wherein the X-ray powder diffraction pattern of form III is shown in figure 5.

22. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to any one of claims 17 to 21, wherein the melting point of form III is 162.0 ℃.

23. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to any one of claims 17 to 21, wherein the adsorbed water removal temperature of form III is 94.5 ℃.

24. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate according to any one of claims 17 to 21, wherein said form III loses 6.1% weight at 140 ℃.

25. A crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, characterized in that the crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is form IV, said form IV having at least 2Θ° of: x-ray powder diffraction patterns of characteristic peaks expressed in 16.25+/-0.2, 6.8+/-0.2 and 22.08+/-0.2.

26. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 25, wherein form IV further has at least the formula 2Θ°: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 13.16+ -0.2 and 19.39+ -0.2.

27. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 26, wherein form IV further has at least the formula 2Θ°: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 18.35 + -0.2 and 9.68 + -0.2.

28. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of claim 27, wherein form IV further has at least the formula 2Θ°: an X-ray powder diffraction pattern of a characteristic peak represented by one of 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 ] caprylate according to item 25, wherein the X-ray powder diffraction pattern of form IV is shown in figure 7.

30. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of any one of claims 25 to 29, wherein the melting point of form IV is 163.8 ℃.

31. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of any one of claims 25 to 29, wherein the adsorbed water removal temperature of form IV is 96.1 ℃.

32. The crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of any one of claims 25 to 29, wherein said form IV loses 8.21% weight at 150 ℃.

33. A process for the preparation of a crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, comprising the steps of:

adding an organic solvent into a reaction container, stirring, then adding N- [8- (2-hydroxybenzoyl) amino ] caprylic acid, uniformly stirring, dropwise adding a potassium hydroxide solution, and concentrating after the dropwise addition is finished to obtain a crude product;

Adding an organic solvent into the crude product, pulping, filtering to obtain a filter cake, leaching the filter cake, and drying in a drying oven to obtain the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph.

34. The preparation method of the item 33, wherein the filter cake is dried in a drying oven after being rinsed, the drying temperature is 60-100 ℃ and the drying time is 30-40 h, and the crystal form I of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate is obtained; preferably, the drying comprises two steps, namely, drying at 60 ℃ for 16 hours, and then, carrying out nitrogen flattening on the system and drying at 100 ℃ for 24 hours again;

the crystal form I is the crystal form I of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate according to any one of the items 1 to 8.

35. The process of claim 33 wherein the filter cake is prepared as uniform particles and then the particles are dried in the drying oven, the dried particles are uniformly spread in a low temperature environment of 2-8 ℃ and allowed to stand for 2 days with a controlled relative humidity of 50% to form crystalline form III of N- [8- (2-hydroxybenzoyl) amino ] caprylic acid.

36. The method according to item 35, wherein the drying temperature of the pellets in the drying oven is 60 ℃ to 100 ℃ and the drying time is 30 to 40 hours; preferably, the drying is carried out in two steps, namely, the drying is carried out at 60 ℃ for 16 hours, and then the drying is carried out at 100 ℃ for 24 hours after nitrogen flattening.

37. The method of claim 35, wherein the filter cake is screened through a 20-24 mesh screen to obtain uniform particles;

The crystal form III is the crystal form III of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate according to any one of claims 17-24.

38. The method of any one of claims 33 to 37, wherein the organic solvent is isopropanol or acetone.

39. The method of any one of claims 33 to 37, wherein the concentration of potassium hydroxide in the solution is 40% to 90%, preferably the concentration of potassium hydroxide in the solution is 50%.

40. The process for preparing the catalyst according to any one of claims 33 to 37, wherein after adding N- [8- (2-hydroxybenzoyl) amino ] caprylic acid, the system is heated to 48 ℃ or higher, then potassium hydroxide solution is added dropwise, and after the completion of the dropwise addition, the reaction is carried out at a constant temperature for 0.5 to 2 hours;

Preferably, after adding N- [8- (2-hydroxybenzoyl) amino ] caprylic acid, the system is heated to 48-52 ℃, then potassium hydroxide solution is added dropwise, and after the dropwise addition, the reaction is carried out for 1h at a temperature.

41. The process of any one of claims 33 to 37, wherein the N- [8- (2-hydroxybenzoyl) amino ] caprylic acid and potassium hydroxide solution are added in a molar ratio of 1:1.

42. The process according to any one of claims 33 to 37, wherein the crude product is slurried with an organic solvent for a period of 0.5 to 1.5 hours, preferably 1 hour.

43. A process for the preparation of form I of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, characterized in that the form of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is heated to a temperature above at least 75 ℃ in addition to form I, to form I.

44. The process according to item 43, wherein the crystal form of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate other than crystal form I is at least one or two of crystal form II, crystal form III and crystal form IV.

45. The process of claim 43, wherein the crystalline form of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate other than crystalline form I is heated to above 75 ℃ under nitrogen to form crystalline form I of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate.

46. The process of claim 43 wherein form II of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is heated to 140 ℃ under nitrogen to form I of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate.

47. The process of claim 43 wherein form IV of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is heated to 110 ℃ under nitrogen to form I of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate.

48. A process for the preparation of crystalline form I of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, characterized in that the crystalline form of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is lyophilized to form crystalline form I, except for crystalline form I.

49. The process according to item 48, wherein the crystal form of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate other than crystal form I is at least one or two or more of crystal form II, crystal form III and crystal form IV.

50. The process of any one of claims 43-49, wherein form I is form I of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of any one of claims 1-8.

51. A process for the preparation of form II of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, characterized in that the potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is exposed to an environment having a relative humidity of 0-60% at room temperature for more than 24 hours in a crystalline form other than form II, to form said potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate.

52. The method of claim 51, wherein the relative humidity is 20%, 30%, 40%, 60% of the environment.

53. The process according to item 51, wherein the crystal form of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate other than crystal form II is at least one of crystal form I, crystal form III and crystal form IV.

54. The process of any one of claims 51-53, wherein form II is form II of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of any one of claims 9-16.

55. The preparation method of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal form IV is characterized by comprising the following steps:

Forming a gum-like substance in a relative humidity environment of greater than 80% for a crystalline form of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate other than form IV;

exposing the gum-like substance to an environment having a relative humidity of 20% -40% for more than 120 hours at room temperature to form IV.

56. The method according to item 55, wherein the crystal form other than form IV of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is at least one or two or more of form I, form II, and form III.

57. The method of preparing of item 55, wherein the gum-like substance is exposed to an environment having a relative humidity of 20%, 30%, or 40%, preferably the gum-like substance is exposed to an environment having a relative humidity of 40%.

58. The process of any one of claims 55-57 wherein form IV is form IV of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate of any one of claims 25-32.

59. A pharmaceutical composition comprising a crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate.

60. The pharmaceutical composition of claim 59, wherein the crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is one or at least two of form I, form II, form III, form IV.

61. The pharmaceutical composition according to any one of claims 59-60, wherein the pharmaceutical composition further comprises a prophylactic and/or therapeutic drug.

62. The pharmaceutical composition according to item 61, wherein the weight ratio of the crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate to the prophylactic and/or therapeutic agent is (20-60): 1, preferably the weight ratio of the crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate to the prophylactic and/or therapeutic agent in the pharmaceutical composition is 30:1.

63. The pharmaceutical composition of claim 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, thrombopoietin.

64. Use of a crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate or a pharmaceutical composition thereof in the preparation of a prophylactic and/or therapeutic medicament.

65. Use of a crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate or a pharmaceutical composition thereof for promoting drug delivery.

66. Use of a crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate or a pharmaceutical composition thereof in the manufacture of a medicament for the prevention and/or treatment of diabetes or diabetic complications or weight loss.

The N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph provided by the application has four crystal forms, has high solubility and strong stability, can more effectively deliver the medicine, increases the permeability of the delivered medicine in gastrointestinal tracts, and is favorable for preparing an oral preparation, so that the prevention and/or treatment medicine can be better delivered into the body to achieve the effect of improving the bioavailability. When used together with GLP-1r agonists, such as liraglutide, somalundide, etc., the effect of reducing blood sugar or body weight is significantly enhanced.

Drawings

The drawings are included to provide a better understanding of the application and are not to be construed as unduly limiting the application. Wherein:

FIG. 1 is an X-ray powder diffraction pattern of form I of PNAC prepared in example 1.

Fig. 2a is a DSC profile of form I of PNAC prepared in example 1.

FIG. 2b is a TGA profile of form I of PNAC prepared in example 1.

Fig. 3 is an X-ray powder diffraction pattern of form II of PNAC prepared in example 2.

Fig. 4a is a DSC profile of form II of PNAC prepared in example 2.

Fig. 4b is a TGA profile of form II of PNAC prepared in example 2.

Fig. 5 is an X-ray powder diffraction pattern of form III of PNAC prepared in example 3.

Fig. 6a is a DSC profile of form III of PNAC prepared in example 3.

Fig. 6b is a TGA profile of form III of PNAC prepared in example 3.

Fig. 7 is an X-ray powder diffraction pattern of form IV of PNAC prepared in example 4.

Fig. 8a is a DSC profile of form IV of PNAC prepared in example 4.

Fig. 8b is a TGA profile of form IV of PNAC prepared in example 4.

Fig. 9 is a graph showing the trend of the blood concentration of the intravenous administration group versus the administration time.

Fig. 10 is a graph showing the trend of the blood concentration of each group orally administered versus the administration time.

Fig. 11 is an XRPD pattern of solid state stability experiments for form II.

Fig. 12 is an XRPD pattern before and after milling experiments for form II.

Fig. 13 is an XRPD pattern before and after tabletting experiments for form II.

Fig. 14 is an XRPD pattern before and after jet milling experiments for form II.

Fig. 15 is an XRPD pattern of solid state stability experiments for form I.

Fig. 16 is an XRPD pattern before and after tabletting experiments for form I.

Fig. 17 is an XRPD pattern before and after jet milling experiments for form I.

Fig. 18 is an XRPD pattern before and after milling experiments for form I.

Fig. 19 is a graph showing the trend of the blood concentration of the intravenous administration group versus the administration time.

Fig. 20 is a graph showing the trend of the blood concentration of each group orally administered versus the administration time.

Detailed Description

Exemplary embodiments of the present application will now be described with reference to the accompanying drawings, in which various details of embodiments of the present application are included to facilitate understanding, and are to be considered merely exemplary. Accordingly, those of ordinary skill 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 application. To the extent that no conflict arises between a definition in this specification, the terms in this specification have the meanings commonly understood by those skilled in the art, but in the event of a conflict, the definition in this specification controls.

Potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate (PNAC for short), represented by formula (iii):

Powder diffraction by X-rays

X-ray powder diffraction (X-RayPowderDiffraction, XRPD) is commonly used for analysis of crystal structures. X-rays are electromagnetic waves that, when incident on a crystal, produce a periodically varying electromagnetic field in the crystal. Electrons and nuclei in atoms are caused to vibrate, and the vibration is negligible due to the mass of the nuclei. The vibrating electrons are the source of secondary X-rays, and the wavelength and the periodic phase are the same as those of the incident light. Based on the periodicity of the crystal structure, scattered waves of individual electrons in the crystal interfere with each other and overlap with each other, called diffraction. The directions in which the scattering wave circumferences coincide with each other are called diffraction directions, and diffraction lines are generated.

Instrument model: PANALYTICAL EMPYREAN and X' Pert3 ray powder diffraction analyzers;

rays: monochromatic Cu-ka radiation (λ=1.5406);

scanning mode: θ/2θ, scan range: 2-40 degrees;

voltage: 40KV, current: 40mA.

Thermogravimetric analysis

Thermogravimetric analysis (ThermogravimetricAnalysis, TGA) refers to a thermal analysis technique that measures the mass of a sample under test as a function of temperature at a programmed temperature, and is used to study the thermal stability and composition of materials. TGA is a relatively common detection means in both research and development and quality control. Thermogravimetric analysis is often used in combination with other analysis methods in actual material analysis to perform comprehensive thermal analysis and comprehensively and accurately analyze materials. The curve recorded by the thermogravimetric analyzer is called the TGA curve.

Instrument model: TAQ5000/Discovery 5500;

sweep gas: nitrogen gas;

the temperature rising mode is as follows: linearly heating;

temperature range: room temperature to 350 ℃.

Differential scanning calorimetric analysis

Differential Scanning Calorimeter (DSC), a technique for measuring the thermal flow rate of a sample relative to a reference over temperature or time under temperature program control. The curve recorded by a differential scanning calorimeter is called a DSC curve, and is generally characterized by W/g or mW/mg (i.e., the power flowing to each gram of sample) as an ordinate, and the temperature T or time T as an abscissa, various thermodynamic and kinetic parameters such as specific heat capacity, heat of reaction, heat of transformation, phase diagram, reaction rate, crystallization rate, polymer crystallinity, sample purity, etc. can be measured. The method has wide application temperature range (-175-725 ℃), high resolution and small sample consumption. Is suitable for inorganic matters, organic compounds and pharmaceutical analysis.

Instrument model: TAQ2000/Discovery 2500;

sweep gas: nitrogen gas;

the temperature rising mode is as follows: linearly heating;

Temperature range: 25-300 ℃.

The application provides a crystal polymorph of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate, which is a crystal form I with 2 theta degrees: x-ray powder diffraction pattern of characteristic peaks expressed in 7.83+ -0.2, 26.64 + -0.2 and 18.89+ -0.2.

In the present application, the crystalline form I has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 7.83+ -0.2, 26.64 + -0.2, 18.89+ -0.2 and 5.24+ -0.2.

In the present application, the crystalline form I has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 7.83+ -0.2, 26.64 + -0.2, 18.89+ -0.2 and 21.59+ -0.2.

In the present application, the crystalline form I has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 7.83+ -0.2, 26.64 + -0.2, 18.89+ -0.2, 5.24+ -0.2, 21.59+ -0.2.

In the present application, the crystalline form I has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 7.83.+ -. 0.2, 26.64.+ -. 0.2, 18.89.+ -. 0.2, 5.24.+ -. 0.2, 21.59.+ -. 0.2 and 24.29.+ -. 0.2.

In the present application, the crystalline form I has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 7.83+ -0.2, 26.64 + -0.2, 18.89+ -0.2, 5.24+ -0.2, 21.59+ -0.2, 13.02+ -0.2.

In the present application, the crystalline form I has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the crystalline form I has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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 and 6.61.+ -. 0.2.

In the present application, the crystalline form I has a2θ° of: an X-ray powder diffraction pattern of characteristic peaks expressed in 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, and 10.43+ -0.2.

In the present application, the crystalline form I has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the form I has an X-ray powder diffraction pattern having a characteristic peak, represented by 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.

In the present application, the X-ray powder diffraction pattern of form I is shown in fig. 1.

In the present application, the melting point of form I is 163.1 ℃.

In the present application, the adsorbed water removal temperature of form I was 83.6 ℃.

In the present application, form I loses 3.0% weight at 140 ℃.

The application provides a crystal polymorph of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate, which is a crystal form II, wherein the crystal form II at least has 2 theta degrees: x-ray powder diffraction patterns of characteristic peaks expressed in 24.76.+ -. 0.2, 6.73.+ -. 0.2 and 20.26.+ -. 0.2.

In the present application, the crystal form II has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 24.76.+ -. 0.2, 6.73.+ -. 0.2, 20.26.+ -. 0.2 and 14.68.+ -. 0.2.

In the present application, the crystal form II has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 24.76.+ -. 0.2, 6.73.+ -. 0.2, 20.26.+ -. 0.2 and 25.55.+ -. 0.2.

In the present application, the crystal form II has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 24.76.+ -. 0.2, 6.73.+ -. 0.2, 20.26.+ -. 0.2, 14.68.+ -. 0.2, 25.55.+ -. 0.2.

In the present application, the crystal form II has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 24.76.+ -. 0.2, 6.73.+ -. 0.2, 20.26.+ -. 0.2, 14.68.+ -. 0.2, 25.55.+ -. 0.2 and 13.41.+ -. 0.2.

In the present application, the crystal form II has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 24.76±0.2, 6.73±0.2, 20.26±0.2, 14.68±0.2, 25.55±0.2, 26.66±0.2.

In the present application, the crystal form II has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the crystal form II has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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, and 21.08±0.2.

In the present application, the crystal form II has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the crystal form II has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the form II has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form II has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form II has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form II has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form II has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form II has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form II has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the X-ray powder diffraction pattern of form II is shown in fig. 3.

In the present application, the melting point of form II is 162.5 ℃.

In the present application, the adsorbed water removal temperature of form II was 93 ℃.

In the present application, form II loses weight 5.6% at 140 ℃.

The application provides a crystal polymorph of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate, which is a crystal form III, wherein the crystal form III at least has 2 theta degrees: an X-ray powder diffraction pattern of characteristic peaks expressed in 9.06+ -0.2, 23.30+ -0.2 and 21.44 + -0.2.

In the present application, the crystal form III has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 9.06±0.2, 23.30±0.2, 21.44 ±0.2, 24.75±0.2.

In the present application, the crystal form III has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 9.06+ -0.2, 23.30+ -0.2, 21.44 + -0.2 and 6.03+ -0.2.

In the present application, the crystal form III has a 2θ° of: an X-ray powder diffraction pattern of characteristic peaks expressed in 9.06+ -0.2, 23.30+ -0.2, 21.44 + -0.2, 24.75+ -0.2 and 6.03+ -0.2.

In the present application, the crystal form III has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 9.06±0.2, 23.30±0.2, 21.44 ±0.2, 24.75±0.2, 6.03±0.2, 21.20±0.2.

In the present application, the crystal form III has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 9.06±0.2, 23.30±0.2, 21.44 ±0.2, 24.75±0.2, 6.03±0.2, and 17.06±0.2.

In the present application, the crystal form III has a 2θ° of: an X-ray powder diffraction pattern of characteristic peaks expressed in 9.06+ -0.2, 23.30+ -0.2, 21.44 + -0.2, 24.75+ -0.2, 6.03+ -0.2, 21.20+ -0.2, and 17.06+ -0.2.

In the present application, the crystal form III has a 2θ° of: an X-ray powder diffraction pattern of characteristic peaks expressed in 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, and 21.75+ -0.2.

In the present application, the crystal form III has a2θ° of: an X-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the crystal form III has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the form III has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form III has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form III has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form III has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form III has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form III has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form III has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the X-ray powder diffraction pattern of form III is shown in fig. 5.

In the present application, the melting point of form III is 162.0 ℃.

In the present application, the adsorbed water removal temperature of form III was 94.5 ℃.

In the present application, form III loses 6.1% weight at 140 ℃.

The application provides a crystal polymorph of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate, which is a crystal form IV, wherein the crystal form IV at least has 2 theta degrees: x-ray powder diffraction patterns of characteristic peaks expressed in 16.25+/-0.2, 6.8+/-0.2 and 22.08+/-0.2.

In the present application, the crystal form IV has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 16.25+ -0.2, 6.8+ -0.2, 22.08+ -0.2, 13.16+ -0.2.

In the present application, the crystal form IV has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 16.25+ -0.2, 6.8+ -0.2, 22.08+ -0.2 and 19.39+ -0.2.

In the present application, the crystal form IV has a2θ° of: x-ray powder diffraction patterns of characteristic peaks expressed in 16.25+/-0.2, 6.8+/-0.2, 22.08+/-0.2, 13.16+/-0.2 and 19.39+/-0.2.

In the present application, the crystal form IV has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 16.25+ -0.2, 6.8+ -0.2, 22.08+ -0.2, 13.16+ -0.2, 19.39+ -0.2 and 18.35+ -0.2.

In the present application, the crystal form IV has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 16.25+ -0.2, 6.8+ -0.2, 22.08+ -0.2, 13.16+ -0.2, 19.39+ -0.2, 9.68+ -0.2.

In the present application, the crystal form IV has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the crystal form IV has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the crystal form IV has a 2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the crystal form IV has a2θ° of: x-ray powder diffraction pattern of characteristic peaks expressed in 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.

In the present application, the form IV has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form IV has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form IV has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form IV has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form IV has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form IV has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the form IV has an X-ray powder diffraction pattern having a characteristic peak expressed as 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.

In the present application, the X-ray powder diffraction pattern of form IV is shown in fig. 7.

In the present application, the melting point of form IV is 163.8 ℃.

In the present application, the adsorbed water removal temperature of form IV was 96.1 ℃.

In the present application, form IV loses 8.21% weight at 150 ℃.

The PNAC crystal forms I-IV provided by the application have good solubility, bioavailability and solid stability, and especially the bioavailability and solid stability of the crystal forms I and II are good.

The application provides a preparation method of a crystal form I of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate, which comprises the following steps:

Step one: adding an organic solvent into a reaction container, stirring, then adding N- [8- (2-hydroxybenzoyl) amino ] caprylic acid, uniformly stirring, dropwise adding a potassium hydroxide solution, and concentrating after the dropwise addition is finished to obtain a crude product;

Step two: adding an organic solvent into the crude product, pulping, filtering to obtain a filter cake, leaching the filter cake, and then placing the filter cake into a drying oven for drying at 60-100 ℃ for 30-40 h to obtain the crystal form I of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The drying temperature may be 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃ and 100 ℃. The drying time may be 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h.

Preferably, the drying is carried out in two steps, namely, the drying is carried out at 60 ℃ for 16 hours, and then the drying is carried out at 100 ℃ for 24 hours after nitrogen flattening.

In the present application, the organic solvent is isopropyl alcohol or acetone.

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

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

In the application, after N- [8- (2-hydroxybenzoyl) amino ] caprylic acid is added, the system is heated to more than 48 ℃, then potassium hydroxide solution is dripped, and after the dripping is finished, the temperature above 48 ℃ is kept for reaction for 0.5 to 2 hours.

Preferably, after adding N- [8- (2-hydroxybenzoyl) amino ] caprylic acid, the system is heated to 48-52 ℃, then potassium hydroxide solution is added dropwise, and after the dropwise addition, the temperature of 48-52 ℃ is kept for reaction for 1h.

The system temperature may be 48 ℃, 49 ℃, 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃.

The reaction time of the heat preservation can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h.

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

In the application, the time for adding the organic solvent into the crude product to pulp is 0.5h-1.5h, preferably 1h.

The time for pulping by adding the organic solvent into the crude product can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h and 2h.

The present application provides a second process for preparing form I of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate by heating the crystalline form of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, except for form I, to at least 75 ℃ to form I.

In the application, the crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except for crystal form I are at least one or more than two of crystal forms II, III and IV.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form I can be crystal form II.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form I can be crystal form III.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form I can be crystal form IV.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form I can be crystal form II and crystal form III.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form I can be crystal form II and crystal form IV.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form I can be crystal form III and crystal form IV.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form I can be crystal form II, crystal form III and crystal form IV.

In the application, the crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except the crystal form I are heated to above 75 ℃ under the protection of nitrogen for 0-300 min to form the crystal form I of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The heating temperature is preferably 110-140 ℃. The heating temperature may be 110 ℃, 115 ℃, 120 ℃, 125 ℃, 130 ℃, 135 ℃, 140 ℃.

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

In the present application, form II of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is heated to 140 ℃ under nitrogen to form I of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate.

In the present application, form IV of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate is heated to 110 ℃ under nitrogen to form I of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate.

The application provides a preparation method of a third crystal form I of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate, and the crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except the crystal form I are freeze-dried to form the crystal form I.

The application provides a preparation method of a crystal form III of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate, which comprises the following steps:

Step two: adding an organic solvent into the crude product, pulping, filtering to obtain a filter cake, preparing the filter cake into uniform particles, then placing the particles into a drying box for drying, uniformly spreading the dried particles in a low-temperature environment of 2-8 ℃, and standing for 2 days with the relative humidity controlled to be 50% to form the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal form III.

In the application, the filter cake is sieved by a 20-24-mesh sieve to obtain uniform particles.

In the application, the drying temperature is 60-100 ℃ and the drying time is 30-40 h. Preferably, the temperature of the drying may be 60 ℃, 65 ℃,70 ℃, 75 ℃, 80 ℃,85 ℃,90 ℃,95 ℃,100 ℃. The drying time may be 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h.

The application provides a preparation method of a crystal form II of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate, which is characterized in that the crystal form II of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except the crystal form II is exposed to a relative humidity environment with 0-60% at room temperature for more than 24 hours to form the crystal form II of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

In the present application, the relative humidity is 20%, 30%, 40%, 50%, 60% of the environment.

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

In the application, the crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except for crystal form II are at least one or more than two of crystal form I, crystal form III and crystal form IV.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form II can be crystal form I.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form II can be crystal form III.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form II can be crystal form IV.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form II can be crystal form I and crystal form III.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form II can be crystal form I and crystal form IV.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form II can be crystal form III and crystal form IV.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form II can be crystal form I, crystal form III and crystal form IV.

The application provides a preparation method of a N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal form IV, which comprises the following steps:

In the application, the crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form IV are at least one or more than two of crystal form I, crystal form II and crystal form III.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form IV can be crystal form I.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form IV may be crystal form II.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form IV may be crystal form III.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form IV can be crystal form I and crystal form III.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form IV can be crystal form I and crystal form II.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form IV can be crystal form III and crystal form II.

The crystal forms of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate except crystal form IV can be crystal form I, crystal form II and crystal form III.

In the present application, the gum-like substance is exposed to an environment having a relative humidity of 20%, 30% or 40%, preferably the gum-like substance is exposed to an environment having a relative humidity of 40%.

In the present application, forms other than form IV are left to stand in a relative humidity environment of greater than 80% for at least two days to form a gum-like substance. The time of the placement may be 48h, 50h, 55h, 60h, 65h, 72h, etc.

The gum-like substance may be exposed to an environment having a relative humidity of 20% to 40% at room temperature, form IV may be formed for 120h、121h、122h、123h、124h、125h、126h、127h、128h、129h、130h、131h、132h、133h、134h、135h、136h、137h、138h、139h、140h or the like.

The application provides a pharmaceutical composition comprising a crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate.

The pharmaceutical composition further comprises a prophylactic and/or therapeutic agent, which may be glucagon-like peptide-1 (abbreviated as GLP-1), insulin, PYY, human amylin, heparin, human growth hormone, interferon, monoclonal antibody, protease inhibitor, thrombopoietin.

In the application, the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph in the medicine composition is one or more than two of crystal form I, crystal form II, crystal form III and crystal form IV.

The pharmaceutical composition comprises a crystal form I of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises a crystal form II of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises a crystal form III of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises crystal form IV of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises a crystal form I and a crystal form II of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises a crystal form I and a crystal form III of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises a crystal form I and a crystal form IV of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises a crystal form II and a crystal form III of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises a crystal form II and a crystal form IV of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises a crystal form III and a crystal form IV of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises crystal form I, crystal form II and crystal form III of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises crystal form II, crystal form III and crystal form IV of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises crystal form I, crystal form III and crystal form IV of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

The pharmaceutical composition comprises crystal form I, crystal form II, crystal form III and crystal form IV of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate.

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

In the present application, the pharmaceutical composition may have a weight ratio of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate crystal polymorph to prophylactic and/or therapeutic agent of 30:1.

The weight ratio of the N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph and the prophylactic and/or therapeutic medicine in the medicine 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、60:1.

The pharmaceutical composition may be a tablet.

The application provides an N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph or application of its pharmaceutical composition in preparing preventive and/or therapeutic medicines.

The application provides a use of a crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate or a pharmaceutical composition thereof in promoting drug delivery.

The application provides an application of N- [8- (2-hydroxybenzoyl) amino ] potassium octoate crystal polymorph or a pharmaceutical composition thereof in preparing medicines for preventing and/or treating diabetes or diabetic complications.

Preventive and/or therapeutic drug

Prophylactic and/or therapeutic agents refer to agents that, by use, achieve the purpose of avoiding, curing, alleviating, altering, treating, ameliorating, improving or affecting a condition (e.g., a disease), symptoms of a disease, or susceptibility to a disease.

The prophylactic and/or therapeutic agent may be a protein; a polypeptide; a peptide; a hormone; polysaccharides, mucopolysaccharides and specific mixtures of mucopolysaccharides; a carbohydrate; a lipid; polar small organic molecules (i.e., polar organic molecules having a molecular weight of 500 daltons or less); other organic compounds; and specific compounds which do not pass through the gastrointestinal mucosa itself (only through the portion of the dose administered) and/or are susceptible to cleavage by acid and enzyme activity in the gastrointestinal tract; or any combination thereof.

The prophylactic and/or therapeutic agent may be one that includes (but is not limited to) the following: including their synthetic, natural or recombinant origin: growth hormone, including human growth hormone (hGH), recombinant human growth hormone (rhGH), bovine growth (hGH), bovine growth hormone and porcine growth hormone; growth hormone releasing hormone; growth hormone releasing factor (e.g., GRF analog g); interferons, including α, β, and γ; interleukin 1; interleukin 2; insulin, including porcine, bovine, human and human recombinant insulin, optionally with counter ions including zinc, sodium, calcium and ammonium; insulin-like growth factors, including IGF-l; heparin, including unfractionated heparin, heparin analogues, dermatan, chondroitin, low molecular weight heparin, very low molecular weight heparin, and ultra low molecular weight heparin; calcitonin, including salmon, eel, pig and human calcitonin; erythropoietin; atrial natriuretic peptide; an antigen; a monoclonal antibody; somatostatin; protease inhibitors; corticotropin, gonadotropin releasing hormone; oxytocin; luteinizing hormone releasing hormone; egg-stimulating hormone; glucocerebrosidase; thrombopoietin; febuxostat; prostaglandins; cyclosporine; vasopressin; sodium cromoglycate (cromoglycate sodium or cromoglycate disodium (disodium chromoglycate)); vancomycin; deferoxamine (DFO); bisphosphonates, including ibandronate, alendronate, tiludronate, etidronate, clodronate, pamidronate, olpadronate, and ibandronate, and pharmaceutically acceptable salts thereof (e.g., sodium ibandronate); gallium salts (such as gallium nitrate, gallium nitrate nonahydrate, and gallium maltolate); acyclovir and its pharmaceutically acceptable salts (e.g., acyclovir sodium); parathyroid hormone (PTH), including fragments thereof; antimigraine agents such as BIBN-4096BS and other calcitonin gene-related protein antagonists; antimicrobial agents, including antibiotics (including bactericidal, lipopeptidic and cyclic peptide antibiotics that act on gram positive bacteria, including daptomycin), antibacterial and antifungal agents; a vitamin; analogs, fragments, mimetics, or polyethylene glycol (PEG) modified derivatives of these compounds; or any combination thereof.

Preferred agents of the application are peptides and proteins which are difficult to be taken orally into the intestine for absorption, and common agents include insulin, monoclonal antibodies, heparin, glucagon-like peptide, PYY, human amylin, human growth hormone, interferon, protease inhibitors, thrombopoietin, and the like, including analogues, fragments, mimetics and polyethylene glycol modified derivatives thereof.

Insulin

Insulin is a protein hormone secreted by islet beta cells within the pancreas by stimulation with endogenous or exogenous substances such as glucose, lactose, ribose, arginine, glucagon, and the like. Insulin is the only hormone in the body that reduces blood glucose while promoting glycogen, fat, protein synthesis. Exogenous insulin is mainly used for diabetes treatment. All crystalline forms of insulin in the present application include, but are not limited to, naturally occurring insulin and synthetic insulin crystalline forms. Because of the ease of oral administration, subcutaneous injections are still the dominant route today.

PYY

PYY is secreted postprandially by endocrine cells distal to the gastrointestinal tract and acts on satiety of hypothalamic signaling. Recent studies have shown that obese subjects have lower fasting and postprandial levels of PYY, which may be responsible for their high appetite and food consumption. When administered intravenously, it inhibits appetite and food intake in lean and obese subjects. Other peptides from the Pancreatic Peptide (PP) family, such as PYY fragments (e.g., PYY [3-36 ]) and other PYY agonists, can also suppress appetite. However, its oral activity is essentially negligible due to its low absorption and rapid degradation in the gastrointestinal tract.

Glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1 for short) is a brain intestinal peptide secreted by ileum endocrine cells, and is currently mainly used as a target for the action of type 2 diabetes drugs. GLP-1 can inhibit gastric emptying and reduce intestinal peristalsis, so that the food intake can be controlled, and the weight can be reduced. However, since GLP-1 is a polypeptide, oral administration is easily degraded and it is difficult to reach the intestinal tract.

Human amylin

Human amylin (hIAPP) is a polypeptide hormone composed of 37 amino acids synthesized and secreted by islet cells, and synergistically regulates sugar homeostasis with insulin, glucagon and the like. The physiological and pharmacological functions of hIAPP monomers are as follows: 1) Affecting insulin and glucagon secretion; 2) Delaying gastric emptying and reducing postprandial blood glucose; 3) Elevation of renin and angiotensin II, regulation of kidney growth; 4) Raising aldosterone and reducing blood calcium;

5) Adjusting bone density; 6) Vasodilating and regulating hemodynamics; 7) Regulate immune effects. hIAPP monomers can induce regulatory T cell differentiation, thereby regulating inflammatory responses and secretion of immune factors. The hIAPP has potential application prospect in the prevention and treatment of diseases such as obesity, diabetes, autoimmune diseases, osteoporosis and the like.

Pharmaceutical composition

The pharmaceutical composition may include pharmaceutically acceptable excipients in addition to PNAC and the prophylactic and/or therapeutic agents of the present application, which may be non-toxic fillers, stabilizers, diluents, carriers, solvents or other formulation excipients. For example, diluents, excipients, such as microcrystalline cellulose, mannitol, and the like; fillers such as starch, sucrose, etc.; binders such as starch, cellulose derivatives, alginates, gelatin and/or polyvinylpyrrolidone; disintegrants, such as calcium carbonate and/or sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants such as cetyl alcohol; carriers, solvents such as water, physiological saline, kaolin, bentonite, and the like; lubricants such as talc, calcium/magnesium stearate, polyethylene glycol, and the like. In addition, the pharmaceutical composition of the present application is preferably an injection.

Pharmaceutical compositions in solid form are preferred and they can be formulated into solid dosage forms. The solid dosage form may be a capsule, tablet or granule, such as a powder or a sachet. The powder may be an encapsulated agent that is mixed with a liquid and applied. The solid dosage form may also be a topical delivery system, such as an ointment, cream, or semi-solid. Contemplated solid dosage forms may include sustained or controlled release systems. Preferably the solid dosage form is a dosage form for oral administration.

The powder may be packaged into capsules or compressed into tablets, used in powder form or incorporated into ointments, creams or semisolids. Methods for forming solid dosage forms are well known in the art.

PNAC of the present application may be used as a delivery agent in pharmaceutical compositions.

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

Following administration, the active agent in the unit dosage form is absorbed into the circulation. The bioavailability of an active agent is readily assessed by measuring known pharmacological activity in the blood (e.g., increased clotting time due to heparin or decreased calcium circulation levels due to calcitonin). Or the circulating level of the active agent itself may be measured directly.

Delivery system

The amount of prophylactic and/or therapeutic drug (which may be referred to as an active agent) used in the pharmaceutical compositions of the present application is an effective amount to achieve the purpose of the active agent for the target indication. The amount of active agent in the composition is generally a pharmacologically, biologically, therapeutically or chemically effective amount. However, the amount may be less than when the composition is used in a unit dosage form, as the unit dosage form may contain multiple delivery agent compound/active agent compositions or may contain divided pharmacologically, biologically, therapeutically or active effective amounts. The total effective amount may be administered in cumulative units that together contain an effective amount of the active agent.

The total amount of active agent used can be determined by methods well known to those skilled in the art. However, because the compositions of the present application may deliver an active agent more effectively than other compositions or compositions containing an active agent alone, lower amounts of biological or chemical active agents than are used in existing unit dosage forms or delivery systems may be administered to a subject while still achieving the same blood and/or therapeutic effects.

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

The compounds and compositions of the application are useful for administering biologically or chemically active agents to any animal, including (but not limited to): birds, such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and in particular humans; and insects.

These compounds and compositions are particularly advantageous for delivering chemical or biological agents that might otherwise be destroyed or have reduced activity prior to the event that the agent reaches the target area (i.e., the area where the agent is released from the delivery composition) and within the animal to which they are administered. In particular, the compounds and compositions of the present application are useful for oral administration of active agents, especially those that are not commonly delivered orally or those that require enhanced delivery.

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 use of a delivery agent. Delivery may be improved by delivering more active agent over a period of time, or delivering active agent over a specific period of time (such as faster action or delayed delivery) or over a period of time (such as sustained delivery).

Examples

The experimental methods used in the following examples are conventional methods, if no special requirements are imposed.

Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.

Example 1

NAC of N- [8- (2-hydroxybenzoyl) amino ] caprylic acid is prepared by the method described in example 1 of International patent application WO2008/028859

Preparation PNAC Crystal form I

To a 50L reactor was added isopropanol (22070.0 ml,4.0 vol), and NAC (5518 g,1.0 eq) was added with stirring. The system was warmed to 50℃and a 50% potassium hydroxide solution (1304.0 g,1.0 eq) was added dropwise to the system. After the dripping, the system becomes clear and transparent yellow solution, and the reaction is carried out for 1h at the temperature of 50 ℃. The reaction solution was concentrated in portions at 40℃to give a crude product having a pale orange color.

The crude product was slurried in isopropanol (19310.0 ml,3.5 vol) for 1h. The system was suction filtered and the filter cake rinsed with isopropyl alcohol (2760.0 ml,0.5 vol). Transferring the filter cake into a vacuum drying oven, flatly pressing a drying system by nitrogen, drying for 16 hours at 60 ℃, transferring the filter cake into the vacuum drying oven again, and drying for 24 hours at 100 ℃. After the completion of the drying, 4.52kg of a total product was obtained, and the yield was 72.8%, which was an off-white powdery solid.

According to measurement, the product is in a crystal form I, the XRPD and TGA/DSC of the crystal form I are respectively shown in figures 1-2 b, PNAC is in the crystal form I, wherein the characteristic XRPD peak (characterized by degrees 2 theta) of the crystal form I is shown in the following table 1:

Table 1 shows characteristic XRPD peaks for form I (characterized by degrees 2. Theta.)

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A DSC profile (fig. 2 a) shows that form I starts to exhibit a melting endotherm at 195.5 ℃ with a peak value of 163.1 ℃; the DSC (FIG. 2 a) and TGA (FIG. 2 b) profiles combined revealed that form I was anhydrous.

Example 2

Preparation PNAC Crystal form II

And (3) contacting PNAC crystal form I prepared in the example 1 with an environment with 60% relative humidity at room temperature, and standing for more than 24 hours to obtain the product.

The product was determined to be form II, the XRPD, TGA/DSC of which are shown in figures 3-4b, respectively, wherein the characteristic XRPD peaks (characterized by °2θ) for form II are shown in table 2 below:

table 2 shows characteristic XRPD peaks for form II (characterized by °2θ)

A DSC profile (fig. 4 a) shows that form II starts to exhibit a melting endotherm at 157.1 ℃ with a peak at 162.5 ℃; the DSC (FIG. 4 a) and TGA (FIG. 4 b) profiles combined revealed form II as a 1/3 hydrate.

Example 3

Preparation PNAC Crystal form III

The crude product was slurried in isopropanol (19310.0 ml,3.5 vol) for 1h. Filtering the system to obtain a filter cake, sieving the filter cake with a 24-mesh sieve to prepare uniform particles, transferring the particles into a vacuum drying oven for drying, carrying out nitrogen flat pressing on the drying system, drying at 60 ℃ for 16 hours, transferring the dried particles into the vacuum drying oven again at 100 ℃ for 24 hours to obtain particles which are uniformly spread in a low-temperature environment at 5 ℃, and controlling the relative humidity to be 50% for 2 days to obtain the product.

The product was determined to be form III, with XRPD, TGA/DSC of form III shown in figures 5-6b, respectively, wherein the characteristic XRPD peaks (characterized by °2θ) of form III are shown in table 3 below:

table 3 shows characteristic XRPD peaks for form III (characterized by degrees 2. Theta.)

A DSC profile (fig. 6 a) shows that form III starts to exhibit a melting endotherm at 156.6 ℃ with a peak at 162.0 ℃; the DSC (FIG. 6 a) and TGA (FIG. 6 b) profiles combined revealed that form III was a 1/2 hydrate.

Example 4

Preparation PNAC Crystal form IV

Form I PNAC prepared in example 1 was placed under room temperature conditions in contact with 80% relative humidity for 3 days to form a gum-like material, which was exposed to an environment with 40% relative humidity for 5 days to form a product.

The product was determined to be form IV, with XRPD, TGA/DSC of form IV shown in figures 7-8b, respectively, wherein the characteristic XRPD peaks (characterized by °2θ) of form IV are shown in table 4 below:

Table 4 shows the characteristic XRPD peaks for form IV (characterized by degrees 2. Theta.)

A DSC profile (fig. 8 a) shows that form IV has a melting endotherm peak at 163.8 ℃; the DSC (FIG. 8 a) and TGA (FIG. 8 b) profiles combined revealed form IV as the 1 hydrate.

Experimental example

SNAC：

Characterization ofSNAC in tablets (developed by the danish pharmaceutical corporation, norand nod) was found to be the same as form I in patent WO 2005107462. SNAC herein is thus prepared by the preparation method of SNAC form I of example 1 in reference patent WO 2005107462. SNACs in the following examples were all prepared by this method.

Form I (PNAC-I) was prepared as described in example 1.

Form II (PNAC-II) was prepared as described in example 2.

Form III (PNAC-III) was prepared as described in example 3.

Form IV (PNAC-IV) was prepared as in example 4.

Experimental example 1 PNAC stability of solutions in aqueous solution of different Crystal forms

The PNAC crystal form I-IV samples prepared in the previous examples and the SNAC crystal form I samples prepared in the previous examples are respectively dissolved in purified water, and are respectively placed at 4 ℃ and at room temperature, the change condition of the solution is observed, and the stability difference of different salt forms and different crystal forms in aqueous solution under the condition of high concentration (500 mg/mL) is compared, so that the results are shown in Table 5 (the dissolution of the sample PNAC crystal form I-IV and the solution placement process are not different).

TABLE 5 solubility of PNAC different crystal forms under different dissolution conditions

As can be seen from table 5, after SNAC was dissolved at 4 ℃, the solution started to have floc at 0.5h, and the fluidity of the solution gradually deteriorated over time, until larger white particles were precipitated in the 2h solution; flocs also appear when SNAC solution is left to stand for 1h at elevated temperature to room temperature, and increase in flocs becomes cloudy for 2 h. The PNAC I-IV dissolved solution prepared by the method can not generate a small amount of fine filament floccules when being placed at the bottom of 1h at 4 ℃ until the state of the solution changes little after 2 h; a small amount of floc will appear after 2h of solution at room temperature. This shows that under the same conditions, PNAC I-IV of the present application is superior to SNAC in solution stability at high concentrations (500 mg/mL).

Experimental example 2 Effect of different crystalline forms of PNAC on the bioavailability of GLP-1 drug in beagle dogs

The preparation method of GLP-1 drug M4 (M4 for short) is disclosed in patent application WO2019201328.

The preparation of the combination oral tablets is described in WO2012080471 in example 1. Wherein the delivery agent (SNAC, PNAC-I, PNAC-II) binds to M4, respectively. The combined oral tablet prepared by combining SNAC and M4 is snac+m4. PNAC-I in combination with M4 the combined oral tablet was PNAC-I+M4. The PNAC-II and M4 combined oral tablet is PNAC-II+M4.

In the combination oral tablet: the M4 content was 10mg and the delivery agent content was 100mg.

Prescription of intravenous injection M4: m4 was dissolved in 8mM phosphate buffer pH7.2 to give a final M4 concentration of 1mg/mL.

28 Beagle dogs, 9-12kg, were selected and were male and divided into 4 groups, wherein the first group was single intravenous injection of M4 (0.05 mg/kg, n=4), the second group was single oral snac+m4 (1 tablet, n=8), the third group was single oral PNAC-i+m4 (1 tablet, n=8), the fourth group was single oral PNAC-ii+m4 (1 tablet, n=8), and the effect of different crystal forms of PNAC on the bioavailability of M4 in beagle dogs was compared.

The beagle dogs were fasted for no water at night before the oral administration group, the tablets were taken with 10ml of water (quantitative) after the administration of the day, the dogs were fed back after 4 hours, and blood concentration at different time points and the calculated exposure AUC _last in animals were measured by blood sampling according to the blood sampling protocol of table 6, and specific results are shown in tables 7, 8 and 9 and fig. 9 and 10.

Table 6 shows a blood sampling protocol

Group of	Blood collection time point
		Intravenous injection M4 group	0 Hours prior to dosing, 0.5, 1, 3, 6, 12, 24, 48, 72, 96, 144, and 192 hours post dosing;
Oral administration group	0 Hours before administration, 1.5, 3, 8, 24, 48, 72, 96 hours after administration

Note that: at least 500 μl of plasma at each time point

Table 7 is a summary of blood concentration at various time points in the intravenous administration group

Table 8 shows a summary of blood concentration at various time points for each group of oral administration

Table 9 comparative summary of the in vivo exposure (AUC _last) of each group of drugs to animals

As can be seen from the data in tables 7-9, the absolute bioavailability of the single oral SNAC group was 0.88%, while the absolute bioavailability of the single oral PNAC-II group was 1.28%, the absolute bioavailability of the single oral PNAC-I group was 1.11%, and the bioavailability of the PNAC group was significantly higher than that of the SNAC group.

Compared with the single oral SNAC group, the single oral PNAC-II group has the absolute bioavailability improved by 45.5 percent, and the single oral PNAC-I group has the absolute bioavailability improved by 26.1 percent.

Experimental example 3 Effect of different amounts and different crystalline forms of PNAC on the bioavailability of GLP-1 drugs in beagle dogs

The preparation of the combination oral tablets is described in WO2012080471 in example 1. Wherein the delivery agent (SNAC, PNAC-I, PNAC-II) binds to M4, respectively. The combined oral tablet prepared by combining SNAC and M4 is snac+m4.PNAC-I in combination with M4 the combined oral tablet was PNAC-I+M4. The combined oral tablet prepared by PNAC-II in combination with M4 is PNAC-II+M4.

In combination oral tablets, each tablet of ingredient: m4 content was 10mg and delivery agent content was 300mg and 450mg, respectively.

28 Beagle dogs, 9-15kg, were selected and were male and divided into 7 groups of 4, and the effect of PNAC different crystal forms on the bioavailability of M4 in beagle dogs was compared. Wherein the grouping information is as follows in table 10.

The beagle dogs were fasted and not disabled the evening before the group was orally administered, the tablets were taken with 10ml of water (quantitative) after the day of administration, the dogs were fed back after 4 hours, and blood concentration at different time points was measured by blood sampling according to the blood sampling protocol of table 11 and the exposure AUC _last in animals was calculated, and specific results are shown in tables 12 to 14 and fig. 19 and 20.

Table 10 is grouping information

Group of	Route of administration	Dosage for administration	Number of animals (Only)
				M4	i.v.	0.05mg/kg	4
SNAC(300mg)+M4	p.o.	300+10Mg tablet 1 tablet	4
				SNAC(450mg)+M4	p.o.	450+10Mg tablet 1 tablet	4
PNAC-Ⅰ(300mg)+M4	p.o.	300+10Mg tablet 1 tablet	4
				PNAC-Ⅰ(450mg)+M4	p.o.	450+10Mg tablet 1 tablet	4
PNAC-IⅠ(300mg)+M4	p.o.	300+10Mg tablet 1 tablet	4
				PNAC-IⅠ(450mg)+M4	p.o.	450+10Mg tablet 1 tablet	4

Table 11 shows a blood sampling protocol

Note that: at least 500 μl plasma was used at each time point.

Table 12 shows the summary of blood concentration at different time points in intravenous administration group

Table 13 is a summary of blood concentration at various time points for each group of oral administration

Table 14 comparison summary of the in vivo exposure (AUC _last) of each group of drugs in animals

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As can be seen from Table 14, the absolute bioavailability of the single oral SNAC (300 mg) group was 0.70%, the single oral SNAC (450 mg) group was 0.80%, the single oral PNAC-II group (300 mg) was 1.20%, the single oral PNAC-II group (450 mg) was 1.92%, the single oral PNAC-I group (300 mg) was 1.01%, the single oral PNAC-I group (450 mg) was 1.72%, all significantly higher than SNAC, while PNAC increased significantly with increasing content.

Compared with the single oral SNAC (300 mg), the single oral PNAC-II (300 mg) group has 71 percent of absolute bioavailability, and the single oral PNAC-I (300 mg) group has 44 percent of absolute bioavailability; compared with the single oral SNAC (450 mg), the single oral PNAC-II (450 mg) group has 140 percent of absolute bioavailability, and the single oral PNAC-I (450 mg) group has 115 percent of absolute bioavailability.

From the single drug, compared with the single oral SNAC (450 mg) group, the single oral SNAC (300 mg) group has the advantages that the absolute bioavailability is only improved by 14%, the bioavailability between the two groups is not greatly different, and the combination shows that the content of SNAC in the drug has no effect on the absolute bioavailability. Compared with the single oral PNAC-II (450 mg) group, the single oral PNAC-II (300 mg) group has the absolute bioavailability improved by 60%; the absolute bioavailability of the single oral PNAC-I (300 mg) group was improved by 70% compared to the single oral PNAC-I (450 mg) group. In combination with the absolute bioavailability of the single oral PNAC-ii and PNAC-I (100 mg) groups of example 2, it was further demonstrated that the absolute bioavailability of PNAC of the application increased significantly with increasing content in the drug and an unexpected improvement in quality occurred.

Experimental example 4

PNAC solid stability test of Crystal form II

The form II prepared in example 2 was divided into three groups, the first group was left to stand at 60 ℃ for 24 hours, giving solid samples. The second group was left to stand at 40℃and a relative humidity of 75% for two weeks to obtain solid samples. The third group was left to stand at 25 ℃ with a relative humidity of 60% for 2 weeks to give solid samples, which were then evaluated for physical and chemical stability by XRPD and HPLC tests, respectively.

The HPLC test is to set the purity of the crystal form II obtained in example 2 as a reference sample to 100area% and the relative purity=hplc purity/reference sample purity. In the HPLC test method, a C18 reversed phase chromatographic column with a column length of 150mm is used, a mobile phase is an acetonitrile-water+0.05% trifluoroacetic acid system, the flow rate is 1.2ml/min, sample injection detection is carried out under the condition of detector wavelength UV-215nm, and the main peak purity is calculated according to a normalization method.

After testing, the reference samples were found to have a relative purity of 100% by HPLC after being placed in different environments for a set period of time. The XRPD pattern after the experiment is shown in fig. 11, which is identical to the characteristic peaks of the reference sample, and it is known that the crystal form is unchanged in the solid state stability experiment.

The solid state stability test of PNAC form I was performed using the same procedure as described above, and the results are shown in fig. 15.

Experimental example 5

Stability experiments during formulation

The form II obtained in example 2 was divided into three groups, and the first group was manually ground for 10 minutes to obtain solid samples. The second group was tabletted (pressure 3 kilonewtons) on form II to obtain solid samples. And the third group carries out jet milling (sample injection pressure is 0.4 megapascals and milling pressure is 0.2 megapascals) on the crystal form II to obtain a solid sample. And three groups of solid samples were XRPD characterized to assess their physical stability. The specific results are shown in FIGS. 12-14.

As can be seen from fig. 12-14, the crystal form II of the sample was unchanged after grinding, tabletting and air-jet milling.

Stability experiments during PNAC, form I, form II, form III, form IV formulations were performed using the same procedure as described above, and the results are shown in table 15.

The XRPD characterization results for form I of PNAC are shown in FIGS. 16-18, and it can be seen from FIGS. 16-18 that the form I is unchanged after grinding, tabletting and air-jet milling.

Table 15 shows the results of stability experiments for PNAC different crystal forms

From the above table, PNAC form I and form II are stable, and form I will be transformed only when left in an environment exceeding 60% rh for a long period of time, and form II is stable under whatever conditions were tested.

Although the embodiments of the present application have been described above in connection with the above, the present application is not limited to the above-described specific embodiments and fields of application, which are merely illustrative, instructive, and not restrictive. Those skilled in the art, having the benefit of this disclosure, may effect numerous forms of the application without departing from the scope of the application as claimed.

Claims

1. A pharmaceutical composition, wherein the pharmaceutical composition comprises a derivative of a GLP-1 (7-37) analogue and a crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, the crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate being form I;

the crystal form I at least has 2 theta degrees: an X-ray powder diffraction pattern of characteristic peaks expressed in 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;

The derivative of the GLP-1 (7-37) analog is N- ε ³⁰ - [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) -4(s) -carboxybutyrylamino ] ethoxy) ethoxy ] acetamido) ethoxy ] acetyl ] (Val ⁸Glu²²Lys³⁰Arg^26,34 -GLP-1 (7-37)) peptide.

2. The pharmaceutical composition of claim 1, wherein the crystalline form I further has at least a 2Θ° of: an X-ray powder diffraction pattern of characteristic peaks expressed in one of 6.61.+ -. 0.2, 10.43.+ -. 0.2, 31.63.+ -. 0.2 and 37.00.+ -. 0.2.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the X-ray powder diffraction pattern of form I is as in figure 1.

4. The pharmaceutical composition according to claim 1 or 2, wherein the melting point of form I is 163.1 ℃.

5. The pharmaceutical composition according to claim 1 or 2, wherein the adsorbed water removal temperature of form I is 83.6 ℃.

6. The pharmaceutical composition according to claim 1 or 2, wherein the crystalline form I loses 3.0% weight at 140 ℃.

7. The pharmaceutical composition according to claim 1 or 2, wherein the composition is a tablet.

8. The pharmaceutical composition according to claim 1 or 2, wherein the composition is an oral tablet.

9. A pharmaceutical composition, wherein the pharmaceutical composition comprises a derivative of a GLP-1 (7-37) analogue and a crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate, the crystalline polymorph of potassium N- [8- (2-hydroxybenzoyl) amino ] caprylate being form II;

The crystal form II at least has 2 theta degrees: an X-ray powder diffraction pattern of characteristic peaks expressed in 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;

10. The pharmaceutical composition of claim 9, wherein the form II further has at least a2Θ° of: an X-ray powder diffraction pattern of a characteristic peak indicated by one of 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.

11. The pharmaceutical composition according to claim 9 or 10, wherein the X-ray powder diffraction pattern of form II is as in figure 3.

12. The pharmaceutical composition according to claim 9 or 10, wherein the melting point of form II is 162.5 ℃.

13. The pharmaceutical composition according to claim 9 or 10, wherein the adsorbed water removal temperature of form II is 93 ℃.

14. The pharmaceutical composition of claim 9 or 10, wherein the crystalline form II loses weight 5.6% at 140 ℃.

15. The pharmaceutical composition according to claim 9 or 10, wherein the composition is a tablet.

16. The pharmaceutical composition according to claim 9 or 10, wherein the composition is an oral tablet.

17. Use of a pharmaceutical composition according to any one of claims 1-16 for the preparation of a prophylactic and/or therapeutic medicament.

18. Use of a pharmaceutical composition according to any one of claims 1-16 for the manufacture of a medicament for the prevention and/or treatment of diabetes or diabetic complications or weight loss.