A CRYSTALLINE FORM OF 3- ((L-VALYL) AMINO) -1-PROPANESULFONIC ACID

Abstract

The present invention relates to a crystalline form of compound 3-((L-valyl)amino)-1-propanesulfonic acid, preparation method and uses thereof.

Claims

1. A crystalline form of 3-((L-valyl)amino)-1-propanesulfonic acid, characterized in that said crystalline form exhibits characteristic diffraction peaks at 2θ diffraction angles of 9.4°, 11.1°, 15.9°, 17.8°, 18.4°, 21.0°, and 22.5° in an X-ray powder diffraction pattern using Cu-Kα as a radiation source, wherein 2θ has an error range of ±0.2°, and a starting melt temperature of a differential scanning calorimetry curve of said crystalline form is about 301° C. or higher.

2. The crystalline form of claim 1, wherein the starting melt temperature of the differential scanning calorimetry curve of said crystalline form is about 301° C. to about 312° C.

3. The crystalline form of claim 1, wherein said crystalline form exhibits characteristic diffraction peaks at 2θ diffraction angles of 9.4°, 11.1°, 14.9°, 15.9°, 16.6°, 17.8°, 18.4°, 19.5°, 21.0°, 22.5°, 23.1°, and 25.7° in the X-ray powder diffraction pattern, wherein 2θ has an error range of ±0.2°.

4. The crystalline form of claim 1, wherein said crystalline form exhibits characteristic diffraction peaks at 2θ diffraction angles of 9.4°, 11.1°, 14.9°, 15.9°, 16.6°, 17.8°, 18.4°, 19.5°, 20.2°, 21.0°, 21.6°, 22.5°, 23.1°, 25.7°, 26.4°, 26.9°, 30.4°, 32.4°, and 34.5° in the X-ray powder diffraction pattern, wherein 2θ has an error range of ±0.2°.

5. The crystalline form of claim 1, wherein said crystalline form has an X-ray powder diffraction pattern as shown in FIG. 2.

6. The crystalline form of claim 1, wherein said crystalline form has a space group of P4.sub.32.sub.12, unit cell dimensions: a=1 1.1989(4) Å, α=90°, b=1 1.1988(4) Å, β=90°, c=18.2429(7) Å, γ=90°, Z=8, and has a unit cell volume of 2287.90(19) Å.sup.3.

7. The crystalline form of claim 6, wherein said crystalline form belongs to a tetragonal system.

8. The crystalline form of claim 7, wherein said crystalline form has a crystal size of 0.300×0.300×0.100 mm.sup.3.

9. A method for preparing the crystalline form of compound 3-((L-valyl)amino)-1-propanesulfonic acid of claim 1, characterized in that said method comprises the following steps: adding a solvent system to the compound 3-((L-valyl)amino)-1-propanesulfonic acid to obtain a clear solution, and volatilizing to dryness to obtain said crystalline form, wherein the step of adding the solvent system comprises: adding the solvent system consisting of a first solvent, wherein said first solvent is water; or adding the solvent system consisting of a first solvent and a second solvent, wherein said first solvent is firstly added, followed by said second solvent, wherein said first solvent is water, and said second solvent is selected from the group consisting of methanol or halogenated fatty alcohol; or adding the solvent system comprising or consisting of a first solvent, a second solvent, and a third solvent, wherein said first solvent is firstly added, sequentially followed by said second solvent and said third solvent, wherein said first solvent is water, and a combination of said second solvent/said third solvent is alcohols/ketones, alcohols/ethers, esters/nitriles, ketones/esters, or nitriles/N,N-dimethylformamide.

10. The method of claim 9, wherein: said alcohols are selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, pentanol, and hexanol; said ketones are selected from the group consisting of acetone, butanone, and 2-pentanone; said ethers are selected from the group consisting of ethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane; said esters are selected from the group consisting of ethyl formate, propyl formate, isopropyl formate, methyl acetate, ethyl acetate, and isopropyl acetate; and said nitriles are selected from the group consisting of acetonitrile, propionitrile, butyronitrile, and isobutyronitrile; or wherein the solvent system consisting of said first solvent and said second solvent is added to said compound, wherein said first solvent is firstly added, followed by said second solvent, wherein said first solvent is water, and said second solvent is selected from methanol or trifluoroethanol, or wherein the solvent system consisting of said first solvent, said second solvent and said third solvent is added to said compound, wherein said first solvent is firstly added, sequentially followed by said second solvent and said third solvent, wherein said first solvent is water, said second solvent is different from said third solvent, and a combination of said second solvent/said third solvent is ethanol/acetone, isopropanol/tetrahydrofiiran, ethyl acetate/acetonitrile, n-propanol/1,4-dioxane, acetone/isopropyl acetate, or acetonitrile/N,N-dimethylformamide, optionally wherein a volume ratio of said first solvent to said second solvent is 1:0.01-1:200 or 1:0.5-1:20, optionally wherein a volume ratio of said first solvent to said second solvent to said third solvent is 1:0.01-200:0.01-200 or 1:0.1-20:0.1-20.

11. (canceled)

12. (canceled)

13. The method of claim 9, wherein said clear solution is allowed to stand at room temperature or at a temperature of about 10-30° C. or at a crystallization temperature of about 20-60° C. or about 40-60° C. until it volatizes to dryness to obtain said crystalline form.

14. The method of claim 9, wherein a mass-to-volume ratio of said compound to the total solvent is: 10 mg:0.05 ml-100 mg:250 ml or 100 mg:0.5 ml-100 mg:50 ml.

15.-19. (canceled)

20. A method for preparing the crystalline form of compound 3-((L-valyl)amino)-1-propanesulfonic acid of claim 1, characterized in that said method comprises the following steps: adding a solvent system to the compound 3-((Lvalyl)amino)-1-propanesulfonic acid to obtain a suspension solution, and stirring to obtain said crystalline form, wherein the step of adding the solvent system comprises: adding the solvent system consisting of a first solvent, wherein said first solvent is selected from a group consisting of ethanol, isopropanol, propanol, water-saturated secbutanol, or water-saturated esters solvent; or adding the solvent system consisting of a first solvent and a second solvent, wherein said first solvent is firstly added, followed by said second solvent, wherein said first solvent is different from said second solvent, and a combination of said first solvent/said second solvent is aromatics solvent/alcohols, alicyclic hydrocarbons solvent/alcohols, ethers/nitriles, alkanes solvent/halogenated alkanes solvent, or ethers/alcohols; or adding the solvent system comprising or consisting of a first solvent, a second solvent, and a third solvent, wherein said first solvent is firstly added, sequentially followed by said second solvent and said third solvent, wherein said third solvent is water, said first solvent is different from said second solvent, and a combination of said first solvent/said second solvent is alcohols/ketones, halogenated fatty alcohols/nitriles, alcohols/esters, ketones/nitriles, first ethers/second ethers, nitriles/nitromethane, alcohols/fatty acids, or ethers/esters.

21.-25. (canceled)

26. The method of claim 20, wherein said suspension solution is stirred to crystallize at a crystallization temperature of about 10-60° C.

27.-32. (canceled)

33. A method for preparing the crystalline form of compound 3-((L-valyl)amino)-1-propanesulfonic acid of claim 1, characterized in that said method comprises the following steps: adding a first solvent and a second solvent to the compound 3-((L-valyl)amino)-1-propanesulfonic acid to obtain a clear solution, adding a third solvent under stirring, and crystallizing to obtain said crystalline form, wherein a combination of said first solvent/said second solvent/said third solvent is alcohols/water/ketones, halogenated fatty alcohols/water/nitriles, ketones/water/alcohols, ethers/water/alcohols, alcohols/water/N,N-dimethylformamide, alcohols/water/ethers, first alcohols/water/second alcohols, or nitriles/water/fatty acids, wherein said first alcohols differ from said second alcohols.

34.-39. (canceled)

40. A method for preparing the crystalline form of compound 3-((L-valyl)amino)-1-propanesulfonic acid of claim 1, characterized in that said method comprises the following steps: adding a solvent to the compound 3-((L-valyl)amino)-1-propanesulfonic acid at a temperature of about 30-80° C. to obtain a clear solution, cooling, and crystallizing to obtain said crystalline form, wherein the step of adding said solvent comprises: firstly adding a first solvent, followed by sequentially adding a second solvent and a third solvent, wherein said first solvent is water or dimethyl sulfoxide, and a combination of said second solvent/said third solvent is alcohols/nitriles, alcohols/ethers, halogenated fatty acids/ketones, ketones/esters, halogenated alkanes/alcohols, ketones/aromatics, or nitriles/esters.

41. The method of claim 40, wherein said crystallizing is performed at a temperature of about −20-10° C.

42.-53. (canceled)

54. A pharmaceutical composition comprising the crystalline form of compound 3-((Lvalyl)amino)-1-propanesulfonic acid of claim 1, and a pharmaceutically acceptable carrier.

55.-60. (canceled)

61. A method of prevention or treatment of an amyloid-β related disease in a subject in need thereof comprising administrating to the subject a therapeutically effective amount of the crystalline form of 3-((L-valyl)amino)-1-propanesulfonic acid of claim 1.

62. The method of claim 61, wherein said amyloid-β related disease is Alzheimer's disease, mild cognitive impairment (MCI), Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, a degenerative dementia, a dementia of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or dementia associated with diffuse Lewy body type of Alzheimer's disease.

63. The method of claim 61, wherein said subject is an ApoE4 positive subject.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0087] FIG. 1 is an X-ray powder diffraction (XRD) pattern of an amorphous compound 3-((L-valyl)amino)-1-propanesulfonic acid in Example 1.

[0088] FIG. 2 is an X-ray powder diffraction (XRD) pattern of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 2 of the present invention.

[0089] FIG. 3 is a diagram showing the structure and atomic number of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid according to the present invention.

[0090] FIG. 4 is a unit cell packing diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid according to the present invention.

[0091] FIG. 5 illustrates differential scanning calorimetry (DSC) curves of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 2 of the present invention. In the DSC curves, the Crystalline Form I has a starting melt temperature of about 305° C. and a peak temperature of about 316° C. .

[0092] FIG. 6 is a thermogravimetric analysis diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 2 of the present invention, which shows that the crystalline form has a slow weight loss of about 0.5wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 307° C.

[0093] FIG. 7 is a PLM representation diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 2 of the present invention, which shows that the Crystalline Form I of the compound prepared in Example 2 is a granular crystalline form having good uniformity.

[0094] FIG. 8 is a FT-IR representation diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 2 of the present invention.

[0095] FIG. 9 illustrates differential scanning calorimetry (DSC) curves of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 6 of the present invention. In the DSC curves, the Crystalline Form I has a starting melt temperature of about 312° C. and a peak temperature of about 320° C.

[0096] FIG. 10 is a thermogravimetric analysis diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 6 of the present invention, which shows that the crystalline form has a slow weight loss of about 0.5wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 300° C.

[0097] FIG. 11 illustrates differential scanning calorimetry (DSC) curves of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 7 of the present invention. In the DSC curves, the Crystalline Form I has a starting melt temperature of about 308° C. and a peak temperature of about 317° C.

[0098] FIG. 12 is a thermogravimetric analysis diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 7 of the present invention, which shows that the crystalline form has a slow weight loss of about 1.4wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 302° C.

[0099] FIG. 13 illustrates differential scanning calorimetry (DSC) curves of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 8 of the present invention. In the DSC curves, the Crystalline Form I has a starting melt temperature of about 306° C. and a peak temperature of about 318° C.

[0100] FIG. 14 is a thermogravimetric analysis diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 8 of the present invention, which shows that the crystalline form has a slow weight loss of about 0.2wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 314° C.

[0101] FIG. 15 illustrates differential scanning calorimetry (DSC) curves of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 9 of the present invention. In the DSC curves, the Crystalline Form I has a starting melt temperature of about 301° C. and a peak temperature of about 312° C.

[0102] FIG. 16 is a thermogravimetric analysis diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 9 of the present invention, which shows that the crystalline form has a slow weight loss of about 1.2wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 303° C.

[0103] FIG. 17 illustrates differential scanning calorimetry (DSC) curves of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 14 of the present invention. In the DSC curves, the Crystalline Form I has a starting melt temperature of about 307° C. and a peak temperature of about 318° C. .

[0104] FIG. 18 is a thermogravimetric analysis diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 14 of the present invention, which shows that the crystalline form has a slow weight loss of about 0.5wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 310° C.

[0105] FIG. 19 illustrates differential scanning calorimetry (DSC) curves of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 24 of the present invention. In the DSC curves, the Crystalline Form I has a starting melt temperature of about 309° C. and a peak temperature of about 316° C.

[0106] FIG. 20 is a thermogravimetric analysis diagram of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 24 of the present invention, which shows that the crystalline form has a slow weight loss of about 0.6wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 317° C.

[0107] FIG. 21 is a blood concentration-time curve graph of the Crystalline Form I (No. S08S02S15a) of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 2 of the present invention.

[0108] FIG. 22 is a blood concentration-time curve graph of the Crystalline Form I (No. S08S04S22a) of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 7 of the present invention.

[0109] FIG. 23 is a blood concentration-time curve graph of the Crystalline Form I (No. S08S19S24a) of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 8 of the present invention.

[0110] FIG. 24 is a blood concentration-time curve graph of an amorphous form solid of Example 1 as a reference sample.

DETAILED DESCRIPTION

[0111] The present invention is further illustrated in detail by the following examples. Temperature is expressed in degrees Celsius. Unless stated otherwise, room temperature is in the range of 10-30° C. and the percentage is expressed by weight. In the following examples, the experimental methods without specific conditions are carried out according to conventional procedures and conditions, or according to the product instructions.

[0112] Abbreviations: [0113] DSC differential scanning calorimetry [0114] RH relative humidity [0115] XRD or XRPD X-ray powder diffraction [0116] DCC N,N′-dicyclohexylcarbodiimide [0117] eq equivalent

[0118] The X-ray powder diffraction (XRPD) test instrument involved herein is Bruker D8 Advance diffractometer; detection conditions: Cu Kα radiation with X-ray of 1.54Å, 40 kV/40 mA; detection angle: 3-40°2θ, scanning step: 0.02°2θ; and scanning speed: 0.2 s.step.sup.−1. Detection of environmental conditions: temperature=21° C., humidity=50%.

[0119] The X-ray single crystal diffraction analysis instrument involved herein is BrukerVenture; detection conditions: detection is carried out at a wavelength of 0.71073 Å at a temperature of 180 K.

[0120] The differential scanning calorimetry (DSC) instrument is the Q200 DSC instrument from TA Instruments; detection conditions: an aluminum crucible (with cover, but without perforation), a protective atmosphere of nitrogen, a gas flow rate of 40 mL/min, and the following common detection method: equilibrate at 20° C., and ramp rate of 10° C./min to 340° C. Detection of environmental conditions: temperature=20° C., humidity=56%.

[0121] The thermogravimetric analyzer (TGA) involved herein is Q500TGA from TA Instruments; detection conditions: a platinum crucible, a protective atmosphere of nitrogen, a gas flow rate of 40 mL/min; and the following detection method: a Hi-Res sensitivity of 3.0, ramp 10.00° C./min, res 5.0 to 120.00° C., and ramp 10.00° C./min to 350° C.

[0122] The polarization microscope (PLM) graph involved herein is derived from an XP-500E heating stage polarization microscope (from Shanghai Changfang Optical instrument Co., Ltd.). A small amount of powder samples were taken and placed on a glass slide, a little mineral oil was added dropwise to the glass slide to better disperse the powder samples, and a cover glass was taken to cover the glass slide. Then, a sample was placed on an object stage of the XP-500E heating stage polarization microscope, and an appearance of the sample was observed at an appropriate amplification factor selected and photographed.

[0123] The Fourier Transform infrared (FT-IR) spectrometer involved herein is Bruker Tensor 27 (control software/analysis software: OPUS); detecton method: an ATR method; collected wavelength range: 600-4000 cm.sup.−1; scanning time: 32 s; and a resolution ratio: 4 cm.sup.−1.

EXAMPLE 1

Preparation of 3-((L-valyl)amino)-1-propanesulfonic acid

[0124] 1 g of 3((L-valypamino)-1-propanesulfonic acid was dissolved in 5 mL water and subjected to concentration under reduced pressure to obtain 1 g of an amorphous solid compound.

[0125] The X-ray powder diffraction (XRD) pattern of the amorphous solid is as shown in FIG. 1.

EXAMPLE 2

Preparation of the Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid

[0126] A solvent system of water/ethanol/acetone (1.0 mL/2.0 mL/2.0 mL) having a total volume of 5.0 mL was added to 100 mg of the amorphous solid compound of 3-((L-valyl)amino)-1-propanesulfonic acid obtained according to Example 1, wherein solvents were added in the sequence of water (i.e., a first solvent), ethanol (i.e., a second solvent), and acetone (i.e., a third solvent) to obtain a clear solution, and after filtration the filtrate was placed at room temperature (crystallization temperature) and naturally evaporated to dryness to obtain 95 mg of granular crystals, i.e., the Crystalline Form I, having a yield of 95% and a purity of greater than 99%.

EXAMPLE 3

Determination of Characterization of Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid Obtained According to Example 2

[0127] 1. X-Ray Powder Diffraction of the Crystalline Form I

[0128] The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters. The result is shown in FIG. 2, and those specific data are shown in Table 1:

TABLE-US-00001 TABLE 1 Data related to X-ray powder diffraction in FIG. 2 Peak Height Peak Area Peak 2θ diffraction Interplanar Peak Relative Peak Relative No. angle (°) Spacing (Å) Height Intensity (I %) Area Intensity (I %) 1 9.38 9.421 409 41.3 2512 45.6 2 11.294 7.8278 991 100 5505 100 3 14.894 5.9432 78 7.9 483 8.8 4 15.939 5.5557 312 31.5 2032 36.9 5 16.658 5.3175 107 10.8 799 14.5 6 17.804 4.9778 570 57.5 3125 56.8 7 18.465 4.8011 614 62 3258 59.2 8 19.473 4.5547 122 12.3 630 11.4 9 20.285 4.3743 30 3 88 1.6 10 21.098 4.2075 467 47.1 2616 47.5 11 21.659 4.0997 79 8 919 16.7 12 22.539 3.9416 884 89.2 4966 90.2 13 23.033 3.8582 580 58.5 3276 59.5 14 25.192 3.5321 81 8.2 542 9.8 15 25.668 3.4677 306 30.9 2570 46.7 16 26.429 3.3695 61 6.2 416 7.6 17 26.901 3.3116 166 16.8 1116 20.3 18 29.204 3.0554 112 11.3 1051 19.1 19 30.427 2.9354 143 14.4 1264 23 20 32.367 2.7637 164 16.5 1369 24.9 21 33.04 2.7089 100 10.1 543 9.9 22 33.381 2.682 40 4 436 7.9 23 34.445 2.6015 95 9.6 856 15.5 24 35.265 2.5429 51 5.1 314 5.7 25 36.205 2.479 47 4.7 339 6.2 26 37.241 2.4124 86 8.7 248 4.5 27 38.885 2.3141 67 6.8 506 9.2

[0129] 2. X-Ray Single Crystal Diffraction Analysis of Said Crystalline Form I

[0130] The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters. The results are shown below and in Tables 2-3 and FIGS. 3-4.

[0131] The compound 3-((L-valyl)amino)-1-propanesulfonic acid according to the present invention has the molecular formula of C.sub.8H.sub.18N.sub.2O.sub.4S, a molecular weight of 238.30, a density of 1.384 Mg/m.sup.3, F(000)=1024. The Crystalline Form I is a white crystal and has a crystal size of 0.300×0.300×0.100 mm.sup.3. The Crystalline Form I belongs to a tetragonal system and has a space group of P4.sub.32.sub.12. The unit cell dimensions measured at a wavelength of 0.71073 Å at a temperature of 180 K are as follows: [0132] a=11.1988(4) Å, α=90°, b=11.1988(4) Å, β=90°, c=18.2429(7) Å, γ=90°, Z=8, unit cell volume of 2287.90(19) Å.sup.3.

TABLE-US-00002 TABLE 2 Atomic coordinates (×10.sup.4) and equivalent isotropic displacement parameters (Å.sup.2 × 10.sup.3) of Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid x y z U(eq) S(1) 4282(1) 6791(1) 1087(1) 16(1) O(1) 3036(1) 6442(1) 1154(1) 27(1) O(2) 4639(1) 7029(1)  335(1) 23(1) O(3) 4616(1) 7782(1) 1564(1) 28(1) O(4) 8934(1) 5299(1) 2681(1) 23(1) N(1) 8400(1) 4697(2) 1541(1) 19(1) N(2) 11162(1)  5927(1) 2107(1) 16(1) C(1) 5126(2) 5544(2) 1385(1) 22(1) C(2) 6471(2) 5727(2) 1331(1) 19(1) C(3) 7121(2) 4670(2) 1676(1) 23(1) C(4) 9192(2) 4988(2) 2054(1) 16(1) C(5) 10494(2)  4864(2) 1822(1) 15(1) C(6) 11039(2)  3698(2) 2121(1) 19(1) C(7) 10259(2)  2622(2) 1935(1) 26(1) C(8) 12309(2)  3520(2) 1835(1) 31(1)

TABLE-US-00003 TABLE 3 Hydrogen coordinates (×10.sup.4) and equivalent isotropic displacement parameters (Å.sup.2 × 10.sup.3) of Crystalline Form I of 3-((L-valyl)amino)-1-propanesulfonic acid x y z U(eq) H(1A) 8662 4512 1101 23 H(2A) 11787 6091 1805 25 H(2B) 11439 5767 2566 25 H(2C) 10663 6569 2125 25 H(1B) 4917 5368 1902 26 H(1C) 4901 4840 1087 26 H(2D) 6698 6472 1587 23 H(2E) 6706 5803 810 23 H(3A) 6978 4673 2212 28 H(3B) 6787 3919 1476 28 H(5A) 10540 4857 1274 18 H(6A) 11080 3766 2667 23 H(7B) 9482 2706 2177 39 H(7C) 10650 1891 2107 39 H(7A) 10144 2579 1403 39 H(8C) 12807 4196 1987 46 H(8A) 12295 3472 1299 46 H(8B) 12639 2779 2037 46

[0133] 3. Differential Scanning Calorimetry (DSC) of the Crystalline Form I

[0134] The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters. The results are shown in FIG. 5. In the DSC curves, its starting melt temperature is about 305° C., and the peak temperature is about 316° C.

[0135] 4. Thermogravimetric Analysis (TGA) of the Crystalline Form I

[0136] The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters. The results are shown in FIG. 6. The TGA diagram shows that the crystalline form has a slow weight loss of about 0.5wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 307° C.

[0137] 5. Polarization Microscope (PLM) Detection Method of the Crystalline Form I

[0138] The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters (ocular lens times=10 times, objective lens times=4 times etc.). The results are shown in FIG. 7. The PLM graph shows that the compound crystals prepared in Example 2 are granular crystals having good uniformity.

[0139] 6. FT-IR Representation Diagram of the Crystalline Form I

[0140] The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters. The results are shown in FIG. 8.

EXAMPLE 4

Preparation of a Crystalline Form of 3-((L-valyl)amino)-1-propanesulfonic acid

[0141] About 100 mg of the solid of 3((L-valyl)amino)-1-propanesulfonic acid obtained according to Example 1 was taken, and used to prepare the crystalline form of 3-((L-valyl)amino)-1-propanesulfonic acid according to the method of Example 2, except that the solvent system (a first solvent/a second solvent/a third solvent) of water/ethanol/acetone (1 mL/2 mL/1 mL) having a total volume of 4 mL was used.

[0142] 95 mg of white crystals were obtained with a yield of 95% and a purity of greater than 99%, and was Crystalline Form I as characterized by XRD (not shown).

EXAMPLE 5

Preparation of a Crystalline Form of 3-((L-valyl)amino)-1-propanesulfonic acid

[0143] About 100 mg of the solid of 3-((L-valyl)amino)-1-propanesulfonic acid in Example 1 was taken, and used to prepare the crystalline form of 3-((L-valyl)amino)-1-propanesulfonic acid according to the method of Example 2, except that the solvent system (a first solvent/a second solvent/a third solvent) of water/ethanol/acetone (1 mL/1 mL/2 mL) having a total volume of 4 mL was used.

[0144] 95 mg of white crystals were obtained with a yield of 95% and a purity of greater than 99%, and was Crystalline Form I as characterized by XRD (not shown).

EXAMPLES 6-9

[0145] Preparation of crystalline forms of 3-((L-valyl)amino)-1-propanesulfonic acid under different conditions by reference to the method of Example 2 was investigated, and results were shown in Table 4 below.

TABLE-US-00004 TABLE 4 The results of preparation of crystalline forms of 3-((L- valyl)amino)-1-propanesulfonic acid of examples 6-9 Solvent System Amount of Amount of (First Solvent/ Solvents Amorphous Second Solvent/ (v/v(ml/ml) Solid of Crystallization optional Third or v/v/v, Example 1 Temperature Crystal Crystalline Examples Solvent) (ml/ml/ml)) (mg) (° C.) Morphology Form 6 Water/Trifluoroethanol 0.2/0.8 10 Room Slices Crystalline Temperature Form I 7 Water/Isopropanol/ 0.2/0.2/0.6 10 Room Slices Crystalline Tetrahydrofuran Temperature Form I 8 Water/Ethyl acetate/ 0.2/0.2/0.6 10 Room Bulks Crystalline Acetonitrile Temperature Form I 9 Water/N-propanol/1,4- 0.2/0.2/0.2 10 50° C. Fine Crystalline dioxane Powder Form I

[0146] The crystal sample prepared in Examples 6-9 and the crystal sample in Example 2 have the same or similar XRD pattern (not shown), indicating that the sample of Examples 6-9 and the sample of Example 2 belong to the same crystalline form.

[0147] The DSC curves (see FIG. 9) of the crystal sample of Example 6 show that the starting melt temperature is about 312° C., the peak temperature is about 320° C., and its TGA diagram (see FIG. 10) indicates that the crystalline form has a slow weight loss of about 0.5wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 300° C.

[0148] The DSC curves (see FIG. 11) of the crystal sample (No. S08S04S22a) of Example 7 show that the starting melt temperature is about 308° C., the peak temperature is about 317° C., and its TGA diagram (see FIG. 12) indicates that the crystalline form has a slow weight loss of about 1.4wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 302° C.

[0149] The DSC curves (see FIG. 13) of the crystal sample (No. S08S19S24a) of Example 8 show that the starting melt temperature is about 306° C., the peak temperature is about 318° C., and its TGA diagram (see FIG. 14) indicates that the crystalline form has a slow weight loss of about 0.2wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 314° C.

[0150] The DSC curves (see FIG. 15) of the crystal sample of Example 9 show that the starting melt temperature is about 301° C., the peak temperature is about 312° C., and its TGA diagram (see FIG. 16) indicates that the crystalline form has a slow weight loss of about 1.2wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 303° C.

EXAMPLE 10

[0151] Water having a total volume of 0.2 mL was added to 10 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid prepared in Example 1 to obtain a clear solution, and after filtration the filtrate was placed at room temperature (crystallization temperature) and naturally evaporated to dryness to obtain 9 mg of granular crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 90% and a purity of greater than 99%.

EXAMPLE 11

[0152] A solvent system of water/methanol (0.2 mL/0.8 mL) having a total volume of 1.0 mL was added to 10 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid obtained according to Example 1, wherein solvents were added in the sequence of water (i.e., a first solvent) and methanol (i.e., a second solvent) to obtain a clear solution, and the filtrate after filtration was placed at room temperature (crystallization temperature) and naturally evaporated to dryness to obtain 9 mg of granular crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 90% and a purity of greater than 99%.

EXAMPLE 12

[0153] A solvent system (a first solvent/a second solvent/a third solvent) of water/acetone/isopropyl acetate (0.2 mL/0.6 mL/0.2 mL) having a total volume of 1.0 mL was added to 10 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid obtained according to Example 1, wherein solvents were added in the sequence of water (i.e., the first solvent), acetone (i.e., the second solvent), and isopropyl acetate (i.e., the third solvent) to obtain a clear solution, and the filtrate after filtration was placed at a temperature of 50° C. and evaporated to dryness to obtain 8 mg of granular crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 80% and a purity of greater than 99%.

EXAMPLE 13

[0154] A solvent system (a first solvent/a second solvent/a third solvent) of water/acetonitrile/N,N-dimethylformamide (0.2 mL/0.4 mL/0.2 mL) having a total volume of 0.8 mL was added to 10 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid obtained according to Example 1, wherein solvents were added in the sequence of water (i.e., the first solvent), acetonitrile (i.e., the second solvent), and N,N-dimethylformamide (i.e., the third solvent) to obtain a clear solution, and the filtrate after filtration was placed at a temperature of 50° C. and evaporated to dryness to obtain 8 mg of granular crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 80% and a purity of greater than 99%.

EXAMPLE 14

[0155] A solvent system of trifluoroethanol/acetonitrile/water (2.0 mL/2.0 mL/0.02 mL) having a total volume of 4.02 mL was added to 10 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid obtained according to Example 1, wherein solvents were added in the sequence of trifluoroethanol (i.e., the first solvent), acetonitrile (i.e., the second solvent), and water (i.e., the third solvent) to obtain a suspension solution which was stirred for 5 days at room temperature, and the resulting crystal slurry was subjected to centrifugal filtration, washing, and drying to obtain 8 mg of fine granular crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 80% and a purity of greater than 99%.

[0156] The DSC curves (see FIG.17) of the resulting crystal sample indicate that the starting melt temperature is about 307° C., and the peak temperature is about 318° C. The TGA diagram (see FIG.18) thereof shows that the crystalline form has a slow weight loss of about 0.5wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 310° C.

EXAMPLES 15-23

[0157] Preparation of crystalline forms of 3-((L-valyl)amino)-1-propanesulfonic acid under different conditions by reference to the method of Example 14 was investigated, and results were shown in Table 5 below.

TABLE-US-00005 TABLE 5 The results of preparation of crystalline forms of 3-((L- valyl)amino)-1-propanesulfonic acid of examples 15-23 Amount of Solvent System (First Amount of Solvents Amorphous Solid Solvent/Second Solvent/ (v/v(ml/ml) or v/v/v, of Example 1 Crystalline Examples Third Solvent) (ml/ml/ml)) (mg) Form 15 Methanol/Acetone/Water 2.0/2.0/0.2 15 Crystalline Form I 16 N-propanol/Isopropyl Acetate/ 2.0/2.0/0.3 10 Crystalline Water Form I 17 Acetone/Acetonitrile/Water 2.0/2.0/0.2 10 Crystalline Form I 18 Tetrahydrofuran/Methyl tert- 2.0/1.0/0.2 10 Crystalline butyl ether/Water Form I 19 Acetomtrile/Nitromethane/Water 2.0/1.0/0.1 10 Crystalline Form I 20 Water-saturated Sec-butanol 2.0 10 Crystalline Form I 21 Toluene/N-butanol 1.0/1.0 10 Crystalline Form I 22 Methylcyclohexane/Isopropanol 1.0/1.0 10 Crystalline Form I 23 ethanol 2   10 Crystalline Form I

[0158] The crystal sample prepared in Examples 15-23 is the Crystalline Form I as characterized by XRD (not shown).

EXAMPLE 24

[0159] A solvent system of n-heptane/chloroform (1.0 mL/1.0 mL) having a total volume of 2 mL was added to 10 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid obtained according to Example 1, wherein solvents were added in the sequence of n-heptane (i.e., the first solvent) and chloroform (i.e., the second solvent) to obtain a suspension solution which was stirred for 5 days at a temperature of 40° C., and the resulting crystal slurry was subjected to centrifugal filtration, washing, and drying to obtain 9 mg of fine granular crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 90% and a purity of greater than 99%.

[0160] The DSC curves (see FIG. 19) of the resulting crystal sample indicate that the starting melt temperature is about 309° C., and the peak temperature is about 316° C. The TGA diagram (see FIG. 20) thereof shows that the crystalline form has a slow weight loss of about 0.6wt % before about 120° C., showing that it is an anhydrate; and the decomposition temperature is about 317° C.

EXAMPLES 25-31

[0161] Preparation of crystalline forms of 3-((L-valyl)amino)-1-propanesulfonic acid under different conditions by reference to the method of Example 24 was investigated, and results were shown in Table 6 below.

TABLE-US-00006 TABLE 6 The results of preparation of crystalline forms of 3-((L- valyl)amino)-1-propanesulfonic acid of examples 25-31 Amount of Solvent System (First Amount of Solvents Amorphous Solid Solvent/Second Solvent/ (v/v(ml/ml) or v/v/v, of Example 1 Crystalline Examples optional Third Solvent) (ml/ml/ml)) (mg) Form 25 Water-saturated Ethyl Acetate 2.0 15 Crystalline Form I 26 Isopropanol 2.0 10 Crystalline Form I 27 Ethanol/Butanone/Water 2.0/2.0/0.2 10 Crystalline Form I 28 N-butanol/Acetic Acid/Water 2.0/2.0/0.1 10 Crystalline Form I 29 1,4-dioxane/Isopropyl acetate/ 2.0/2.0/0.2 10 Crystalline Water Form I 30 Isopropyl Ether/Acetonitrile 1.0/1.0 10 Crystalline Form I 31 Tetrahydrofuran/Methanol 1.0/1.0 10 Crystalline Form I

[0162] The crystal sample prepared in Examples 25-31 is the Crystalline Form I as characterized by XRD (not shown).

EXAMPLE 32

[0163] A solvent system of methanol/water/acetone (0.09 mL/0.09 mL/4.0 mL) having a total volume of 4.18 mL was added to 10 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid obtained according to Example 1, wherein solvents were added in the sequence of methanol (i.e., the first solvent) and water (i.e., the second solvent) to obtain a clear solution, and acetone (i.e., the third solvent) was slowly added during stirring. Stirring continues for 3 min after precipitation of the solid, and the resulting crystal slurry was subjected to centrifugal filtration, washing, and drying to obtain 9 mg of crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 90% and a purity of greater than 99%.

EXAMPLES 33-40

[0164] Preparation of crystalline forms of 3-((L-valyl)amino)-1-propanesulfonic acid under different conditions by reference to the method of Example 32 was investigated, and results were shown in Table 7 below.

TABLE-US-00007 TABLE 7 The results of preparation of crystalline forms of 3-((L- valyl)amino)-1-propanesulfonic acid of examples 33-40 Amount of Solvent System (First Amount of Solvents Amorphous Solid Solvent/Second Solvent/ (v/v(ml/ml) or v/v/v, of Example 1 Crystalline Examples optional Third Solvent) (ml/ml/ml)) (mg) Form 33 Trifluoroethanol/Water/Acetonitrile 0.09/0.09/2.0 10 Crystalline Form I 34 N-propanol/Water/Tetrahydrofuran 0.09/0.09/2.0 10 Crystalline Form I 35 acetone/Water/Isopropanol 0.09/0.09/2.0 10 Crystalline Form I 36 Tetrahydrofuran/Water/N-butanol 0.09/0.09/2.0 10 Crystalline Form I 37 ethanol/Water/N,N-dimethylformamid 0.09/0.09/5.0 10 Crystalline Form I 38 Isopropanol/Water/1,4-dioxane 0.09/0.09/2.0 10 Crystalline Form I 39 1,4-dioxane/Water/ethanol 0.09/0.09/5.0 10 Crystalline Form I 40 Acetonitrile/Water/Acetic Acid 0.09/0.09/5.0 10 Crystalline Form I

[0165] The crystal sample prepared in Examples 33-40 is the Crystalline Form I as characterized by XRD (not shown)

EXAMPLE 41

[0166] To 15 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid in Example 1 a solvent system of water/ethanol/1,4-dioxane (0.2 mL/1.0 mL/0.8 mL) having a total volume of 2 mL was added at a temperature of 60° C., wherein solvents were added in the sequence of water (i.e., the first solvent), ethanol (i.e., the second solvent), and 1,4-dioxane (i.e., the third solvent) to obtain a clear solution, which was then placed in ice-salt baths and stirred.

[0167] After precipitation of the solid, the resulting crystal slurry was subjected to centrifugal filtration, washing, and drying to obtain 13 mg of crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 87% and a purity of greater than 99%.

EXAMPLE 42

[0168] To 15 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid in Example 1 a solvent system of water/isopropanol/tetrahydrofuran (0.2 mL/1.0 mL/0.6 mL) having a total volume of 1.8 mL was added at a temperature of 60° C., wherein solvents were added in the sequence of water (i.e., the first solvent), isopropanol (i.e., the second solvent), and tetrahydrofuran (i.e., the third solvent) to obtain a clear solution, which was then placed in ice-salt baths and stirred. After precipitation of the solid, the resulting crystal slurry was subjected to centrifugal filtration, washing, and drying to obtain 14 mg of crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 93% and a purity of greater than 99%.

EXAMPLES 43-48

[0169] Preparation of crystalline forms of 3-((L-valyl)amino)-1-propanesulfonic acid under different conditions by reference to the method of Example 41 was investigated, and results were shown in Table 8 below.

TABLE-US-00008 TABLE 8 The results of preparation of crystalline forms of 3-((L- valyl)amino)-1-propanesulfonic acid of examples 43-48 Amount of Solvent System (First Amount of Solvents Amorphous Solid Solvent/Second Solvent/ (v/v(ml/ml) or v/v/v, of Example 1 Crystalline Examples optional Third Solvent) (ml/ml/ml)) (mg) Form 43 Water/Methanol/Acetonitrile 0.2/1.0/1.0 15 Crystalline Form I 44 Water/Trifluoroethanol/Acetone 0.2/1.0/1.0 15 Crystalline Form I 45 Water/Acetone/Ethyl Acetate 0.2/0.6/0.4 15 Crystalline Form I 46 Dimethyl Sulfoxide/Chloroform/N- 1.0/1.0/1.0 15 Crystalline butanol Form I 47 Dimethyl Sulfoxide/Butanone/ 1.0/1.0/1.0 15 Crystalline Toluene Form I 48 Dimethyl Sulfoxide/Acetonitrile/ 1.0/2.0/2.0 15 Crystalline Isopropyl Acetate Form I

EXAMPLE 49

[0170] 10 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid in Example 1 was taken and placed in a centrifuge tube, 0.05 mL of water was added, and then the solution was allowed to stand in an atmosphere of tetrahydrofuran to precipitate a solid to obtain 9 mg of crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 90% and a purity of greater than 99%.

EXAMPLE 50

[0171] 10 mg of the amorphous solid of 3-((L-valyl)amino)-1-propanesulfonic acid in Example 1 was taken and placed in a centrifuge tube, 0.05 mL of water was added, and then the solution was allowed to stand in an atmosphere of methanol to precipitate a solid to obtain 9 mg of crystals, i.e., the Crystalline Form I as characterized by XRD (not shown), having a yield of 90% and a purity of greater than 99%.

EXAMPLE 51

Pharmacokinetics Comparative Analysis

[0172] By means of a pharmacokinetics comparative experiment, the pharmacodynamics feature of the crystalline form I provided herein after administration is compared with that of the amorphous solid of Example 1 as a reference sample.

[0173] Experimental Method:

[0174] SD rats (all male, weight of 260-280 g) were randomizely grouped, each group of 3 animals. The medication group received the crystalline form compound (No. S08S02S15a) of the Example 2, the crystalline form compound (No. S08S04S22a) of the Example 7, and the crystalline form compound (No. S08S19S24a) of the Example 8, respectively, and the control group received the reference sample (the amorphous solid of Example 1). The animals were fasted for 12 hours before administration, and the dosage of administration was 133 mg/kg. The corresponding medications were administered by intragastric administration using a solid capsule administration system (Size 9el Rat Box+Foam+Funnel+Syringe). Rat plasma samples were collected before administration, and 0.08, 0.16, 0.33, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after administration, respectively. After heparin tube anticoagulation, centrifugation was performed at 5000 rpm for 10 min at a temperature of 4° C. A plasma supernatant sample was taken and subjected to protein precipitation using methanol, and then, the medication concentration in the plasma was monitored by LC/MS2. A blood concentration-time curve is plotted for the results, as shown in FIGS. 21-24.

[0175] As can be seen from FIGS. 21-24, as compared with the reference sample, the compound of the Crystalline Form I provided herein is capable of improving medication dissolution. Without being bound by theory, the inventor believes that during capsule intragastric administration, the medication of the crystalline form I provided herein can effectively improve the maximum blood concentration Cmax, exposure AUC, half-life period T.sub.½, etc., and has certain advantages in medication dissolution, due to physical properties such as crystal form, particle size, and uniformity, which are different from and superior to those of the amorphous solid.

[0176] The present invention is not limited by the examples shown and described above, but may vary within the scope of the claims.

[0177] Unless defined otherwise or the context clearly dictates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention.