Crystalline form of 3-((L-valyl) amino))-3, 3-dideuterium-1-propanesulfonic acid, preparation method and uses thereof
11608314 · 2023-03-21
Assignee
Inventors
Cpc classification
A61P7/04
HUMAN NECESSITIES
C07C309/15
CHEMISTRY; METALLURGY
A61P25/28
HUMAN NECESSITIES
A61K31/205
HUMAN NECESSITIES
C07B2200/05
CHEMISTRY; METALLURGY
A61P9/14
HUMAN NECESSITIES
C07C309/15
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention relates to a crystalline form of compound 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid, preparation method and uses thereof.
Claims
1. A pharmaceutical composition comprising a crystalline form of compound 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid and a pharmaceutically acceptable carrier, wherein the crystalline form is characterized in that said crystalline form exhibits characteristic diffraction peaks at 2Θ diffraction angles of 9 0.1°, 11.0°, 14.6°, 15.6°, 16.3°, 17.5°, 18.2°, 19.1°, 20.7°, 22.2°, 22.7°, and 25.4° in an X-ray powder diffraction pattern using Cu-Kα as a radiation source, wherein 2Θ has an error range of ±0.2°.
2. The pharmaceutical composition as recited in claim 1, wherein said crystalline form exhibits characteristic diffraction peaks at 2Θ diffraction angles of 9.1°, 11.0°, 14.6°, 15.6°, 16.3°, 17.5°, 18.2°, 19.1°, 20.7°, 21.3°, 22.2°, 22.7°, 24.9°, 25.4°, 28.9°, 30.1°, 32.1°, and 34.2° in the X-ray powder diffraction pattern, wherein 20 has an error range of ±0.2°.
3. The pharmaceutical composition as recited in claim 1, wherein said crystalline form has an X-ray powder diffraction pattern as shown in
4. A pharmaceutical composition comprising a crystalline form of compound 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid and a pharmaceutically acceptable carrier, wherein the crystalline form is characterized in that said crystalline form exhibits characteristic diffraction peaks at 2Θ diffraction angles of 9 0.1°, 11.0°, 15.6°, 18.2°, 20.7°, and 22.2° in an X-ray powder diffraction pattern using Cu-Kα as a radiation source, wherein 2Θ has an error range of ±0.2°, wherein said crystalline form has a space group of P4.sub.32.sub.12, unit cell dimensions: a=11.1989(4) Å, α=90°, b=11.1989(4) Å, β=90°, c=18.2479(7) Å, γ=90°, Z=8, and has a unit cell volume of 2288.57(19) Å3.
5. The pharmaceutical composition as recited in claim 4, wherein said crystalline form belongs to a tetragonal system.
6. The pharmaceutical composition as recited in claim 5, wherein said crystalline form has a crystal size of 0.200×0.200×0.150 mm.sup.3.
7. The pharmaceutical composition as recited in claim 1, wherein said crystalline form has a melting point of 319° C. as measured by differential scanning calorimetry.
8. A method of treatment of Alzheimer's disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a crystalline form of compound 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid, wherein the crystalline form is characterized in that said crystalline form exhibits characteristic diffraction peaks at 2Θ diffraction angles of 9 0.1°, 11.0°, 15.6°, 18.2°, 20.7°, and 22.2° in an X-ray powder diffraction pattern using Cu-Kα as a radiation source, wherein 2Θ has an error range of ±0.2°.
9. The method as recited in claim 8, wherein said subject is an ApoE4 positive subject.
10. The method as recited in claim 8, wherein the crystalline form is characterized in that said crystalline form exhibits characteristic diffraction peaks at 2Θ diffraction angles of 9.1°, 11.0°, 14.6°, 15.6°, 16.3°, 17.5°, 18.2°, 19.1°, 20.7°, 22.2°, 22.7°, and 25.4° in the X-ray powder diffraction pattern, wherein 2Θ has an error range of ±0.2°.
11. The method as recited in claim 8, wherein the crystalline form is characterized in that said crystalline form exhibits characteristic diffraction peaks at 2Θ diffraction angles of 9.1°, 11.0°, 14.6°, 15.6°, 16.3°, 17.5°, 18.2°, 19.1°, 20.7°, 21.3°, 22.2°, 22.7°, 24.9°, 25.4°, 28.9°, 30.1°, 32.1°, and 34.2° in the X-ray powder diffraction pattern, wherein 2Θ has an error range of ±0.2°.
12. The method as recited in claim 8, wherein said crystalline form has an X-ray powder diffraction pattern as shown in
13. The method as recited in claim 8, wherein said crystalline form has a space group of P4.sub.32.sub.12, unit cell dimensions: a=11.1989(4) Å, α=90°, b=11.1989(4) Å, β=90°, c=18.2479(7) Å, γ=90°, Z=8, and has a unit cell volume of 2288.57(19) Å3.
14. The method as recited in claim 13, wherein said crystalline form belongs to a tetragonal system.
15. The method as recited in claim 14, wherein said crystalline form has a crystal size of 0.200×0.200×0.150 mm.sup.3.
16. The method as recited in claim 8, wherein said crystalline form has a melting point of 319° C. as measured by differential scanning calorimetry.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
(10) 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 18-25° C. and the percentage is expressed by weight. The experimental methods under specific conditions are not specified in the following examples, and they are carried out according to conventional procedures and conditions, or according to the product instructions.
Abbreviations
(11) DMSO Dimethyl sulfoxide DMF dimethylformamide DSC differential scanning calorimetry RH relative humidity XRD X-ray powder diffraction DCC N,N′-dicyclohexylcarbodiimide eq equivalent
(12) The X-ray powder diffraction (XRPD) test instrument involved herein is Bruker D8 Advance diffractometer; detection conditions: Cu Kα radiation with X-ray of 1.54 Å, 40 kV/40 mA; detection angle: 3-40° 20, scanning step: 0.02° 20; and scanning speed: 0.2 s.Math.step.sup.−1. Detection of environmental conditions: temperature=21° C., humidity=50%.
(13) 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.
(14) 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%.
(15) 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 150.00° C., and ramp 10.00° C./min to 350° C.
(16) The dynamic vapor sorption (DVS) instrument involved herein is Q5000TGA from TA Instruments; detection conditions: a platinum crucible, a protective atmosphere of nitrogen, a gas flow rate of 10 mL/min; and the following detection method: Equilibrate at at 25° C.; Humidity of 0%; Isothermal for 180 minutes; Abort next iso if weight (%)<0.0100 for 15.00 min; step humidity 10% every 120 min to 80.00%; Abort next iso if weight (%)<0.0100 for 15.00 min; step humidity 10% every 120 min to 0.00%. Determination criteria: Non-hygroscopic no more than 0.2% Slightly hygroscopic higher than 0.2%, but no more than 2.0% hygroscopic higher than 2%, but no more than 15% Extremely hygroscopic higher than 15%
Example 1
Preparation of an Amorphous Compound 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid
Step 1: Preparation of 3-amino-3,3-dideuterium-1-propanesulfonic acid sodium salt (1s)
(17) A solution of 3-hydroxypropanenitrile (26.0 g, 366 mmol, 1.0 eq.) in anhydrous THF (50 mL) was slowly added dropwise to a solution of LiAlD.sub.4 (10.0 g, 238 mmol, 0.65 eq.) in anhydrous THF (200 mL), and the reaction mixture was stirred overnight under reflux. After the reaction was cooled to room temperature, water (4.8 mL), a 15% NaOH aqueous solution (4.8 mL), and water (14.4 mL) were successively added for quenching, the mixture was stirred at room temperature for 2 hours, and then filtered to remove solid impurities. The filtrate was concentrated under reduced pressure and dried to give a red oily liquid which could be directly used in the next reaction step without purification.
(18) The oily liquid (10.0 g, 128 mmol, 1.0 eq.) was dissolved in 100 mL of a chloroform solution and stirred in ice bath, and dichlorosulfoxide (18.2 g, 154 mmol, 1.2 eq.) was added thereto dropwise slowly. The reaction mixture was stirred overnight under reflux and the solvent was removed in a rotary evaporator, followed by concentration to give a black mixture. Purification by column chromatography gave 3-chloro-1,1-dideuterium-1-propylamine hydrochloride as a white solid (10.8 g, 64.4%).
(19) The 3-chloro-1,1-dideuterium-1-propylamine hydrochloride (10.0 g, 76.3 mmol, 1.0 eq.) was dissolved in water (50 mL) and stirred, and Na.sub.2SO.sub.3 (9.61 g, 76.3 mmol, 1.0 eq.) was added thereto. The mixture was stirred overnight under reflux, and the solvent was distilled off in a rotary evaporator to give a white solid. The white solid was added into a concentrated hydrochloric acid, solid (sodium chloride) was removed through filtration, and the filtrate was concentrated under reduced pressure and dried to give a white solid, which was then recrystallized (with water-ethanol) and dried to give a white solid 3-amino-3,3-dideuterium-1-propanesulfonic acid (1) (9.5 g, 88.3%). .sup.1H NMR (500 MHz, D.sub.2O): δ ppm 2.15 (t, J=7.5 Hz, 2H), 3.07 (t, J=7.5 Hz, 2H); .sup.13C NMR (125 MHz, D.sub.2O): δ ppm 22.21, 37.74 (in, CD.sub.2), 47.87; m/z (ES−) 140.0 (M-H).
(20) The 3-amino-3,3-dideuterium-1-propanesulfonic acid was dissolved in 10 mL of water and equimolar amounts of sodium hydroxide was added thereto. The mixture was stirred at room temperature for 10 minutes, and then concentrated to dryness under reduced pressure to give a white solid 1s.
Step 2: Preparation of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid
(21) The 3-amino-3,3-dideuterium-1-propanesulfonic acid sodium salt is (1.63 g, 10.0 mmol, 1.0 eq) and N-tert-butoxycarbonyl-L-valine (2.60 g, 12.0 mmol, 1.2 eq.) were dissolved in anhydrous DMF (20 mL) After DCC (2.47 g, 12.0 mmol, 1.2 eq.) and HOBt (1.35 g, 10.0 mmol, 1.0 eq.) were added under ice bath conditions, the mixture was stirred overnight at room temperature. After water (2 mL) was added, the stirring was continued for 1 hour, the insoluble solids were removed through filtration, the filtrate was concentrated under reduced pressure to give a white solid crude. The solid was dissolved in water (20 mL) and extracted twice with ethyl acetate, the aqueous phase was concentrated under reduced pressure and then purified by column chromatography to give a while solid sodium 3-((N-tert-butoxycarbonyl-L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid (3.2 g, 88.3%). The while solid (3.2 g, 8.83 mmol, 1.0 eq.) was dissolved in a 1N HCl solution (30 mL), stirred at 50° C. for 2 h, and concentrated under reduced pressure. The solid was dissolved in water (10 mL); after the Amberlite IR120 H-type ion exchange resins were added, stirring was conducted for 2 minutes; and the resins were removed through filtration. The ion exchange process was repeated, the filtrate was concentrated to dryness under reduced pressure to give an amorphous solid 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid (1.87 g, 88.1%). .sup.1H NMR (500 MHz, D.sub.2O): δ ppm 0.92-1.06 (m, 6H) 1.98 (t, J=7.5 Hz, 2H), 2.17-2.21 (m, 1H), 2.95 (t, J=8.0 Hz, 2H), 3.76 (d, J=6.5 Hz, 1H); .sup.13C NMR (125 MHz, D.sub.2O): δ ppm 17.01, 17.57, 23.73, 29.80, 48.40, 58.78, 169.18; m/z (ES) 239.1 (M-H).
(22) The X-ray powder diffraction (XRD) pattern of the amorphous solid is as shown in
Example 2
Preparation of the Crystalline Form of 3-((l-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid
(23) 3 g of the amorphous solid of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid as prepared in Example 1 was dissolved in 10 mL water and heated to 60° C. to give a clear solution which was then stirred, and 100 mL of ethanol was added thereto. The mixture was cooled to room temperature and stirred for 1 hour; crystals were precipitated, filtered, and dried to give white crystals of 2.6 g with a purity of 100%, which white crystals were of Crystalline Form A.
Example 3
Characterization of Crystalline Form A of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid According to the Present Example 2
(24) 1. X-Ray Powder Diffraction of Said Crystalline Form A
(25) The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters. The result is shown in
(26) TABLE-US-00001 TABLE 1 Data related to X-ray powder diffraction in FIG. 2 Peak Peak 2θ Height Area diffraction Interplanar Relative Relative Peak angle Spacing Peak Intensity Peak Intensity No. (°) (Å) Height (I %) Area (I %) 1 9.061 9.7514 1700 100.0 13990 100.0 2 10.991 8.0435 584 34.4 4944 35.3 3 11.981 7.3809 54 3.2 393 2.8 4 13.581 6.5145 34 2.0 141 1.0 5 14.585 6.0683 216 12.7 1654 11.8 6 15.629 5.6651 862 50.7 7426 53.1 7 16.320 5.4268 327 19.2 2577 18.4 8 17.505 5.0621 836 49.2 7558 54.0 9 18.156 4.8820 1203 70.8 11764 84.1 10 19.108 4.6408 343 20.2 2893 20.7 11 19.973 4.4419 136 8.0 1185 8.5 12 20.703 4.2867 1049 61.7 8827 63.1 13 21.294 4.1691 218 12.8 1768 12.6 14 22.183 4.0040 863 50.8 9017 64.5 15 22.734 3.9081 1020 60.0 9964 71.2 16 24.908 3.5718 137 8.1 1880 13.4 17 25.397 3.5042 854 50.2 9604 68.6 18 26.128 3.4078 159 9.4 1327 9.5 19 26.704 3.3355 152 8.9 1851 13.2 20 28.893 3.0876 272 16.0 2340 16.7 21 30.118 2.9647 418 24.6 4039 28.9 22 30.612 2.9181 57 3.4 335 2.4 23 31.677 2.8223 62 3.6 670 4.8 24 32.088 2.7870 338 19.9 3467 24.8 25 32.708 2.7357 80 4.7 539 3.9 26 33.079 2.7058 88 5.2 857 6.1 27 34.180 2.6211 209 12.3 2239 16.0 28 34.893 2.5692 78 4.6 936 6.7 29 35.865 2.5018 74 4.4 761 5.4 30 36.944 2.4311 115 6.8 1137 8.1 31 37.672 2.3858 100 5.9 919 6.6 32 38.602 2.3304 117 6.9 1271 9.1
(27) 2. X-Ray Single Crystal Diffraction Analysis of Said Crystalline Form A
(28) 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
(29) The compound 3-((L-valyl)amino)-3,3-dideuterium-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 1.383 Mg/m.sup.3, F(000)=1024. Said Crystalline Form A is a white crystal, has a crystal size of 0.200×0.200×0.150 mm.sup.3 Said Crystalline Form A 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 180K are as follows:
(30) a=11.1989(4) Å, α=90°, b=11.1989(4) Å, β=90°, c=18.2479(7) Å, γ=90°, Z=8, unit cell volume of 2288.57(19) Å3.
(31) TABLE-US-00002 TABLE 2 Atomic coordinates (×10.sup.4) and equivalent isotropic displacement parameters (Å.sup.2 × 10.sup.3) of Crystalline Form A of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid x y z U(eq) S(1) 4285(1) 6792(1) 1087(1) 16(1) O(1) 3039(1) 6443(1) 1155(1) 27(1) O(2) 4642(1) 7029(1) 336(1) 22(1) O(3) 4620(2) 7782(2) 1564(1) 28(1) O(4) 8939(1) 5298(1) 2682(1) 23(1) N(1) 8402(2) 4698(2) 1544(1) 19(1) N(2) 11164(2) 5926(2) 2107(1) 16(1) C(1) 5128(2) 5545(2) 1385(1) 21(1) C(2) 6471(2) 5727(2) 1330(1) 19(1) C(3) 7121(2) 4672(2) 1679(1) 23(1) C(4) 9194(2) 4989(2) 2056(1) 16(1) C(5) 10496(2) 4865(2) 1822(1) 15(1) C(6) 11040(2) 3698(2) 2120(1) 19(1) C(7) 10260(2) 2623(2) 1935(1) 27(1) C(8) 12308(2) 3521(2) 1836(2) 31(1)
(32) TABLE-US-00003 TABLE 3 Hydrogen coordinates (×10.sup.4) and equivalent isotropic displacement parameters (Å.sup.2 × 10.sup.3) of Crystalline Form A of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid x y z U(eq) H(1A) 8663 4513 1104 23 H(2A) 11789 6090 1804 25 H(2B) 11443 5766 2565 25 H(2C) 10666 6568 2125 25 H(1B) 4920 5370 1902 26 H(1C) 4903 4841 1088 26 H(2D) 6699 6475 1584 23 H(2E) 6706 5798 809 23 H(3A) 6977 4681 2215 28 H(3B) 6787 3920 1482 28 H(5A) 10540 4859 1275 18 H(6A) 11080 3765 2666 23 H(7B) 9481 2709 2174 40 H(7C) 10649 1892 2109 40 H(7A) 10149 2577 1403 40 H(8C) 12806 4198 1988 46 H(8A) 12296 3472 1300 46 H(8B) 12638 2781 2038 46
(33) 3. Differential Scanning Calorimetry (DSC) of Said Crystalline Form a
(34) The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters. The results are shown in
(35) 4. Thermogravimetric Analysis (TGA) of Said Crystalline Form A
(36) The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters. The results are shown in
(37) 5. Dynamic Vapor Sorption (DVS) Analysis of Said Crystalline Form A
(38) The determination was carried out using the aforementioned instruments, determination methods, operating conditions, and parameters. The results are shown in
Example 4
Preparation of a crystalline form of 3-((1-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid
(39) About 100 mg of the solid of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid as prepared in Example 1 was taken, and a crystalline form of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid was prepared according to the method of Example 2, except that 0.5 mL of water and 20 mL of ethanol were used.
(40) 95 mg of white crystals were obtained with a purity of 100%, and was Crystalline Form A as characterized by XRD.
Example 5
Preparation of a Crystalline Form of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid
(41) About 100 mg of the solid of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid as prepared in Example 1 was taken, and a crystalline form of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid was prepared according to the method of Example 2, except that 1 mL of water and 100 mL of ethanol were used.
(42) 95 mg of white crystals were obtained with a purity of 100%, and was Crystalline Form A as characterized by XRD.
Examples 6-40
(43) Preparation of crystalline forms of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid under different conditions by reference to the method of Example 2 was investigated, the resulting crystalline forms were characterized by XRD, and results were shown in Table 4 below.
(44) TABLE-US-00004 TABLE 4 Amount Amount Amount of of the of the Amorphous First Second Solid of Crystallization First Solvent Solvent Example 1 Temperature Crystalline Examples Solvent (mL) Second Solvent (mL) (g) (° C.) Form 6 Water 0.056 Methanol 3 0.01 60 Crystalline Form A 7 Water 0.056 N-propanol 3 0.01 60 Crystalline Form A 8 Water 0.056 Isopropanol 3 0.01 60 Crystalline Form A 9 Water 0.056 Ethylene glycol 3 0.01 60 Crystalline Form A 10 Water 0.056 glycerin 3 0.01 60 Crystalline Form A 11 Water 0.056 Benzyl alcohol 3 0.01 60 Crystalline Form A 12 Water 0.056 Trifluoroethanol 3 0.01 60 Crystalline Form A 13 Water 0.056 Acetonitrile 3 0.01 60 Crystalline Form A 14 Water 0.056 Ethyl acetate 3 0.05 40 Crystalline Form A 15 Water 0.056 Isopropyl acetate 3 0.05 40 Crystalline Form A 16 Water 0.1 Acetone 2 0.01 25 Crystalline Form A 17 Water 0.1 Butanone 2 0.01 25 Crystalline Form A 18 Water 0.1 Methyl tert-butyl 10 0.01 25 Crystalline ether Form A 19 Water 0.056 Tetrahydrofuran 3 0.01 60 Crystalline Form A 20 Water 0.056 1,4-dioxane 3 0.01 60 Crystalline Form A 21 Water 0.05 Trifluoroethanol 1 0.015 40 Crystalline Form A 22 Water 0.1 Toluene 20 0.015 40 Crystalline Form A 23 Water 0.056 Acetic acid 4 0.01 60 Crystalline Form A 24 Water 0.1 Dimethyl sulfoxide 5 0.1 40 Crystalline Form A 25 Water 0.056 N,N- 3 0.01 60 Crystalline dimethylformamide Form A 26 Water 0.056 N,N- 4 0.01 60 Crystalline dimethylacetamide Form A 27 Water 1 Trifluoroacetate 20 0.01 60 Crystalline Form A 28 Water 0.5 N-butanol 20 0.1 60 Crystalline Form A 29 Water 0.5 Tert-butanol 20 0.1 60 Crystalline Form A 30 DMSO 1 Methanol 20 0.01 60 Crystalline Form A 31 DMSO 1 Ethanol 20 0.01 60 Crystalline Form A 32 DMSO 1 Isopropanol 20 0.01 60 Crystalline Form A 33 DMSO 1 Acetone 5 0.01 60 Crystalline Form A 34 DMSO 1 Butanone 5 0.01 60 Crystalline Form A 35 DMSO 1 Isopropyl acetate 4 0.01 60 Crystalline Form A 36 DMSO 1 Tetrahydrofuran 5 0.01 60 Crystalline Form A 37 DMSO 1 Acetonitrile 4 0.01 60 Crystalline Form A 38 DMSO 1 Toluene 5 0.01 60 Crystalline Form A 39 DMSO 1 N-butanol 5 0.01 40 Crystalline Form A 40 DMSO 1 Tert-butanol 5 0.01 40 Crystalline Form A
Examples 41-46
(45) About 10 mg of the amorphous solid of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid as prepared in Example 1 was taken, and preparation of crystalline forms of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid under different conditions was investigated using the slurry crystallization method at room temperature by reference to the principle of Example 2. Specifically, about 10 mg of said amorphous solid was taken and dissolved in said first solvent; the second solvent was added thereto to obtain a suspension, which was stirred at room temperature for 3 days; and the slurry suspension was centrifuged to obtain crystals. The results for characterization by XRD are shown in Table 5 below.
(46) TABLE-US-00005 TABLE 5 Amount of Amount of the First the Second Crystalline Examples First Solvent Solvent (mL) Second Solvent Solvent (mL) Form 41 Water 0.05 Methanol 1.0 Crystalline Form A 42 Water 0.1 Ethanol 2.0 Crystalline Form A 43 Water 0.1 Isopropanol 2.0 Crystalline Form A 44 Water 0.1 Acetone 2.0 Crystalline Form A 45 Water 0.05 Tetrahydrofuran 2.0 Crystalline Form A 46 Water 0.05 Acetonitrile 2.0 Crystalline Form A
Examples 47-50
(47) About 10 mg of the amorphous solid of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid as prepared in Example 1 was taken, and preparation of crystalline forms of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid under different conditions was investigated using the slurry crystallization method at high temperature by reference to the principle of Example 2. Specifically, about 10 mg of said amorphous solid was taken and dissolved in said first solvent; the second solvent was added thereto to obtain a suspension, which was stirred at 40° C. for 3 days; and the slurry suspension was centrifuged to obtain crystals. The results for characterization by XRD are shown in Table 6 below.
(48) TABLE-US-00006 TABLE 6 Amount of Amount of the First the Second Crystalline Examples First Solvent Solvent (mL) Second Solvent Solvent (mL) Form 47 Water 0.05 Trifluoroethanol 1.0 Crystalline Form A 48 Water 0.1 N-propanol 2.0 Crystalline Form A 49 Water 0.1 1,4-dioxane 2.0 Crystalline Form A 50 Water 0.1 Acetonitrile 2.0 Crystalline Form A
Examples 51-55
(49) About 10 mg of the amorphous solid of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid as prepared in Example 1 was taken, and preparation of crystalline forms of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid under different conditions was investigated using the volatile crystallization method at room temperature. Specifically, about 10 mg of said amorphous solid was taken, said first solvent and second solvent were added thereto to obtain a clear solution, and the filtrate after filtration was placed at room temperature and naturally evaporated to dryness. The results for characterization by XRD are shown in Table 7 below.
(50) TABLE-US-00007 TABLE 7 Amount of Amount of the First the Second Examples First Solvent Solvent (mL) Second Solvent Solvent (mL) Crystalline Form 51 Water 0.05 Methanol 0.4 Crystalline Form A 52 Water 0.2 Ethanol 0.4 Crystalline Form A 53 Water 0.2 Acetone 0.2 Crystalline Form A 54 Water 0.2 Tetrahydrofuran 0.4 Crystalline Form A 55 Water 0.15 Acetonitrile 0.2 Crystalline Form A
Examples 56-60
(51) About 10 mg of the amorphous solid of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid as prepared in Example 1 was taken, and preparation of crystalline forms of 3-((L-valyl)amino)-3,3-dideuterium-1-propanesulfonic acid under different conditions was investigated using the volatile crystallization method at high temperature. Specifically, about 10 mg of said amorphous solid was taken, said first solvent and second solvent were added thereto to obtain a clear solution, and the filtrate after filtration was placed at room temperature and naturally evaporated to dryness. The results for characterization by XRD are shown in Table 8 below.
(52) TABLE-US-00008 TABLE 8 Amount of Amount of the First the Second Examples First Solvent Solvent (mL) Second Solvent Solvent (mL) Crystalline Form 56 Water 0.1 Methanol 0.4 Crystalline Form A 57 Water 0.1 Trifluoroethanol 0.4 Crystalline Form A 58 Water 0.1 Isopropanol 0.3 Crystalline Form A 59 Water 0.1 1,4-dioxane 0.3 Crystalline Form A 60 Water 0.1 Acetonitrile 0.3 Crystalline Form A
Example 61
(53) Stability Test of the Crystalline Form a According to the Present Invention
(54) 1. Detection Method Sample and experimental preparation: the Crystalline Form A as prepared in Example 2 was taken as a sample; a proper amount of the sample was weighted and placed on a watch glass to form a thin layer of about 3-5 mm in thickness. Experimental conditions: conventional (sealed and kept in darkness at 25° C.), long-term (uncovered and kept in darkness with −60% RH at 25° C.), and accelerated (uncovered and kept in darkness with −75% RH at 40° C.) conditions. Detection time: Day 0, Day 10. Detected items: crystalline forms (XRD test), and melting points (DSC test).
(55) Results: Crystalline form: no change was detected in Crystalline Form A within 10 days under conventional, long-term and accelerated conditions. The specific results are shown in
(56) As can be seen from the above, said Crystalline Form A is the most stable crystalline form at room temperature, and no change has been detected in the crystalline form (by XRD detection) or in its melting point (by DSC detection) within 10 days under long-term and accelerated conditions. It can be seen from the above data that the crystalline form has excellent stability, better meets the quality requirements of pharmaceutical production, and is easy to store for long periods.
(57) The present invention is not limited by the examples shown and described above, but may vary within the scope of the claims.