Zolpidem salts and processes for their preparation

Abstract

The application belongs to the technical field of crystal form drug molecules, and relates to zolpidem salts, and a preparation method and application thereof. The application specifically provides zolpidem oxalate, zolpidem fumarate, zolpidem malonate and zolpidem-5-sulfosalicylate methanol compound. The method for preparing the zolpidem salt provided by the application is simple to operate, and the prepared crystal has high purity. The zolpidem salt provided by the application has good chemical stability and good solubility.

Description

Technical Field

[0001] This invention relates to the field of crystalline drug molecular technology, and particularly to the field of zolpidem crystalline technology, specifically zolpidem salts, their preparation methods, and applications. Background Technology

[0002] Zolpidem, chemical name: N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide, CAS number: 82626-48-0, its structural formula is shown below:

[0003]

[0004] Zolpidem is a non-benzodiazepine imidazopyridine short-acting sedative-hypnotic drug developed by Sanofi, France. It was first marketed in 1988 for the treatment of insomnia and brain disorders. Clinical trials have shown that zolpidem, as a new generation of hypnotics, is highly selective, has a short half-life (lasting only 1.6 hours), no rebound effect after discontinuation, few side effects, and no respiratory depression, making it one of the most popular sedative-hypnotic drugs currently available.

[0005] Currently, the main marketed zolpidem product is zolpidem tartrate. However, known zolpidem tartrate salts exhibit polymorphism (A, B, C, D, E, F, G, and H crystal forms), and these polymorphs can transform into each other under certain conditions. Therefore, preparing cocrystals or salts of zolpidem with similar pharmacodynamic effects can effectively avoid the problem of zolpidem polymorphism.

[0006] This invention provides a simple and easy-to-operate method for preparing high-purity zolpidem salts, providing a better basis for the application of zolpidem in drug therapy, thereby maximizing the medicinal value of zolpidem. Summary of the Invention

[0007] In view of the shortcomings of the prior art, the purpose of this invention is to provide zolpidem salt, its preparation method and its application.

[0008] In a first aspect, the present invention provides a zolpidem salt formed by combining zolpidem with an organic acid, wherein the organic acid is selected from oxalic acid, fumaric acid, malonic acid, and 5-sulfosalicylic acid.

[0009] Zolpidem Oxalate

[0010] The zolpidem oxalate of the present invention, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 7.02±0.2°, 12.07±0.2°, 14.00±0.2°, 16.00±0.2°, 19.42±0.2°, 21.63±0.2°, 23.31±0.2°, 25.87±0.2°, 27.84±0.2°, and 28.73±0.2°.

[0011] Preferably, the zolpidem oxalate, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 7.02±0.2°, 9.26±0.2°, 10.68±0.2°, 12.07±0.2°, 14.00±0.2°, 14.27±0.2°, 16.00±0.2°, 19.42±0.2°, 21.63±0.2°, 22.74±0.2°, 23.31±0.2°, 24.55±0.2°, 24.94±0.2°, 25.87±0.2°, 27.84±0.2°, 28.73±0.2°, 32.31±0.2°, 33.02±0.2°, and 37.70±0.2°.

[0012] Preferably, the zolpidem oxalate, when subjected to Cu-Kα radiation, exhibits characteristic peaks that conform to... Figure 1 The X-ray powder diffraction pattern shown or the detection data shown in Table 5 are as follows.

[0013] Preferably, the zolpidem oxalate, as detected by differential scanning calorimetry (DSC), exhibits an endothermic peak in the range of 137.03℃ to 284.29℃, with the peak value at 214.33℃.

[0014] The crystallographic parameters of the zolpidem oxalate are: orthorhombic crystal system, chiral space group P212121; unit cell parameters are: α = 90.00°, β = 90.00°, γ = 90.00°, unit cell volume

[0015] Zolpidem fumarate

[0016] A zolpidem fumarate, when irradiated with Cu-Kα, exhibits characteristic peaks at 7.41±0.2°, 10.86±0.2°, 18.37±0.2°, 18.52±0.2°, 19.38±0.2°, 21.58±0.2°, 25.20±0.2°, and 28.60±0.2° in its X-ray diffraction pattern (denoted as 2θ).

[0017] Preferably, the zolpidem fumarate, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 7.41±0.2°, 9.26±0.2°, 10.86±0.2°, 14.86±0.2°, 18.37±0.2°, 18.52±0.2°, 19.38±0.2°, 21.58±0.2°, 22.02±0.2°, 23.41±0.2°, 25.20±0.2°, 28.60±0.2°, 29.96±0.2°, and 33.25±0.2°.

[0018] Preferably, the zolpidem fumarate, when irradiated with Cu-Kα, exhibits characteristic peaks that conform to... Figure 5 The X-ray powder diffraction pattern shown or the detection data shown in Table 6 are as follows.

[0019] Preferably, the zolpidem fumarate, as detected by differential scanning calorimetry (DSC), exhibits an endothermic peak in the range of 203.83℃ to 235.00℃, with the peak value at 220.42℃.

[0020] The crystallographic parameters of the zolpidem fumarate are: orthorhombic crystal system, chiral space group P212121; unit cell parameters are: α = 90.00°, β = 90.00°, γ = 90.00°, unit cell volume

[0021] Zolpidem malonate

[0022] The zolpidem malonate of the present invention, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at 8.05±0.2°, 10.14±0.2°, 18.64±0.2°, 19.07±0.2°, 23.29±0.2°, and 26.04±0.2°.

[0023] Preferably, the zolpidem malonate, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 8.05±0.2°, 10.14±0.2°, 12.35±0.2°, 18.64±0.2°, 19.07±0.2°, 20.25±0.2°, 22.20±0.2°, 23.29±0.2°, 23.34±0.2°, 24.36±0.2°, 26.04±0.2°, 28.09±0.2°, 30.66±0.2°, and 33.74±0.2°.

[0024] Preferably, the zolpidem malonate, when irradiated with Cu-Kα, exhibits characteristic peaks that conform to... Figure 9 The X-ray powder diffraction pattern shown or the detection data shown in Table 7 are as follows.

[0025] Preferably, the zolpidem-malonate, as detected by differential scanning calorimetry (DSC), exhibits an endothermic peak in the range of 139.34℃ to 172.69℃, with a peak value at 155.19℃.

[0026] The crystallographic parameters of the zolpidem malonate are: orthorhombic crystal system, space group Pna21, and cell parameters are: α = 90.00°, β = 90.00°, γ = 90.00°, unit cell volume

[0027] Zolpidem-5-sulfosalicylate methanol complex

[0028] The zolpidem-5-sulfosalicylate methanol compound of the present invention exhibits characteristic peaks at 8.26±0.2°, 13.99±0.2°, 17.10±0.2°, 18.73±0.2°, 22.15±0.2°, 22.38±0.2°, 25.58±0.2°, and 34.19±0.2° in its X-ray diffraction pattern (denoted as 2θ) under Cu-Kα radiation.

[0029] Preferably, the zolpidem-5-sulfosalicylate methanol compound, when subjected to Cu-Kα radiation, exhibits an X-ray diffraction pattern (denoted as 2θ) at 7.99±0.2°, 8.26±0.2°, 8.55±0.2°, 11.00±0.2°, 12.13±0.2°, 13.99±0.2°, 15.48±0.2°, 15.99±0.2°, 16.80±0.2°, 17.10±0.2°, 17.65±0.2°, 18.73±0.2°, and 19.50±0.2°. Characteristic peaks are observed at 2°, 20.56±0.2°, 22.15±0.2°, 22.38±0.2°, 23.08±0.2°, 23.63±0.2°, 23.89±0.2°, 24.39±0.2°, 25.04±0.2°, 25.58±0.2°, 26.29±0.2°, 26.99±0.2°, 28.25±0.2°, 29.54±0.2°, 31.06±0.2°, 34.19±0.2°, and 45.69±0.2°.

[0030] Preferably, the zolpidem-5-sulfosalicylate methanol compound, when subjected to Cu-Kα radiation, exhibits characteristic peaks consistent with... Figure 13 The X-ray powder diffraction pattern shown or the detection data shown in Table 8 are as follows.

[0031] Preferably, the zolpidem-5-sulfosalicylate methanol compound exhibits two endothermic peaks as detected by differential scanning calorimetry (DSC): one endothermic peak ranges from 85.13℃ to 113.40℃, with a peak value at 100.38℃; the other endothermic peak ranges from 146.14℃ to 197.77℃, with a peak value at 183.05℃.

[0032] The crystallographic parameters of the zolpidem-5-sulfosalicylate methanol compound are: triclinic crystal system, chiral space group P-1; cell parameters are: α = 74.0660°, β = 89.9940°, γ = 87.9840°, cell volume

[0033] In a second aspect, the present invention provides a method for preparing the zolpidem salt.

[0034] The zolpidem salt of this invention can be prepared by the following method: for example, dissolving zolpidem and an organic acid in an organic solvent, heating to dissolve, clarifying the solution, cooling to crystallize, filtering and drying to obtain the zolpidem salt. The organic acid is selected from oxalic acid, fumaric acid, malonic acid, and 5-sulfosalicylic acid. The specific steps of the zolpidem salt preparation method are as follows:

[0035] Preparation of zolpidem oxalate

[0036] The zolpidem oxalate of the present invention can be prepared by the following method: for example, zolpidem and oxalic acid are dissolved in organic solvent A, heated to dissolve, the solution is clarified, cooled to crystallize, filtered and dried to obtain zolpidem oxalate.

[0037] The organic solvent A is selected from one or a mixture of at least two of acetone, methanol, ethanol, and acetonitrile.

[0038] Preferably, the organic solvent A is selected from one or both of acetone and methanol.

[0039] The molar ratio of zolpidem to oxalic acid is 1:0.9 to 1.2; preferably, the molar ratio of zolpidem to oxalic acid is 1:0.95 to 1.15.

[0040] The mass-to-volume ratio of zolpidem to organic solvent A in the system is 60:5 to 10, where mass is expressed in mg and volume in mL.

[0041] The melting and heating temperature is 40–55°C.

[0042] The cooling crystallization temperature is 0–30°C, and preferably, the cooling crystallization temperature is 10–25°C.

[0043] The crystallization time is 4 to 6 hours.

[0044] The drying temperature is 45–70°C, and the drying time is 8–12 hours.

[0045] The solvent for washing the filter cake is selected from acetone, methanol, ethanol, and acetonitrile.

[0046] Preparation of zolpidem fumarate

[0047] The zolpidem fumarate of the present invention can be prepared by the following method: for example, zolpidem and fumaric acid are dissolved in organic solvent B, heated to dissolve, the solution is clarified, cooled to crystallize, filtered and dried to obtain zolpidem fumarate.

[0048] The organic solvent B is selected from one or a mixture of at least two of acetone, methanol, isopropanol, and acetonitrile.

[0049] Preferably, the organic solvent B is selected from one or both of acetone and methanol.

[0050] The molar ratio of zolpidem to fumaric acid is 1:0.85 to 1.35; preferably, the molar ratio of zolpidem to fumaric acid is 1:0.9 to 1.1.

[0051] The mass-to-volume ratio of fumaric acid and organic solvent B in the system is 6–10:1, where mass is expressed in mg and volume in mL.

[0052] The melting and heating temperature is 40–55°C.

[0053] The cooling crystallization temperature is 0–30°C, preferably 5–20°C.

[0054] The crystallization time is 4 to 6 hours.

[0055] The drying temperature is 45–70°C, and the drying time is 8–12 hours.

[0056] The solvent for washing the filter cake is selected from acetone, methanol, ethanol, and acetonitrile.

[0057] Preparation of zolpidem malonate

[0058] The zolpidem-malonate of the present invention can be prepared by the following method: for example, zolpidem and malonic acid are dissolved in organic solvent C, heated to dissolve, the solution is clarified, cooled to crystallize, filtered and dried to obtain zolpidem-malonate.

[0059] The organic solvent C is selected from one or a mixture of at least two of acetone, methanol, ethanol, and acetonitrile.

[0060] Preferably, the organic solvent C is selected from one or a mixture of two of acetone, methanol, and acetonitrile.

[0061] The molar ratio of zolpidem to malonic acid is 1:0.8 to 1.4; preferably, the molar ratio of zolpidem to malonic acid is 1:0.9 to 1.2.

[0062] The mass-to-volume ratio of malonic acid to organic solvent C in the system is 20:1 to 8, where mass is expressed in mg and volume in mL.

[0063] Preferably, the mass-to-volume ratio of malonic acid to organic solvent C in the system is 20:4 to 8, where the mass is expressed in mg and the volume in mL.

[0064] The volume ratio of acetone to organic solvent C in the system is 0.5:1.

[0065] The melting and heating temperature is 40–55°C.

[0066] The cooling crystallization temperature is 10-25°C, preferably 15-25°C.

[0067] The crystallization time is 4 to 6 hours.

[0068] The drying temperature is 45–70°C, and the drying time is 8–12 hours.

[0069] The solvent for washing the filter cake is selected from acetone, methanol, ethanol, and acetonitrile.

[0070] Preparation of zolpidem-5-sulfosalicylate methanol complex

[0071] The zolpidem of the present invention can be prepared by the following method: for example, zolpidem and 5-sulfosalicylic acid are dissolved in an organic solvent D, heated to dissolve, the solution is clarified, cooled to crystallize, filtered and dried to obtain the product.

[0072] The organic solvent D is selected from one or a mixture of at least two of methanol, ethanol, acetonitrile, acetone, and tetrahydrofuran.

[0073] Preferably, the organic solvent D is selected from one or a mixture of two of methanol, acetonitrile, and acetone.

[0074] The molar ratio of zolpidem to 5-sulfosalicylic acid is 1:0.7 to 1.4; preferably, the molar ratio of zolpidem to 5-sulfosalicylic acid is 1:0.8 to 1.2.

[0075] The mass-to-volume ratio of 5-sulfosalicylic acid and organic solvent D in the system is 6 to 15:1, where mass is expressed in mg and volume in mL.

[0076] The mass-to-volume ratio of 5-sulfosalicylic acid and organic solvent D in the system is 6 to 10:1, where mass is expressed in mg and volume in mL.

[0077] The volume ratio of methanol to organic solvent D in the system is 0.5:1.

[0078] The melting and heating temperature is 40–55°C.

[0079] The cooling crystallization temperature is 0–30°C, and preferably, the cooling crystallization temperature is 12–23°C.

[0080] The crystallization time is 3 to 5 hours.

[0081] The drying temperature is 40–65°C, and the drying time is 8–12 hours.

[0082] Zolpidem and 5-sulfosalicylic acid were dissolved in an organic solvent D containing methanol, heated to 40–55°C, stirred and refluxed for 1–2 hours, cooled to 12–23°C for 3–5 hours to crystallize, filtered, the filter cake was washed and dried to obtain zolpidem-5-sulfosalicylic acid methanol compound.

[0083] The solvent for washing the filter cake is selected from acetone, methanol, ethanol, and acetonitrile.

[0084] A third aspect of the present invention provides a pharmaceutical composition comprising the zolpidem oxalate, zolpidem fumarate, zolpidem malonate, and zolpidem-5-sulfosalicylate methanol complex prepared above, and containing other active ingredients that can be used in combination and / or pharmaceutically acceptable excipient components.

[0085] Preferably, the other components include other active ingredients, excipients, fillers, etc., that can be used in combination.

[0086] Preferably, the pharmaceutical composition can be formulated into sprays, tablets, capsules, powder injections, liquid injections, etc., using standard and conventional techniques.

[0087] In a fourth aspect, the present invention provides the use of zolpidem oxalate, zolpidem fumarate, zolpidem malonate, and zolpidem-5-sulfosalicylate methanol compound as active ingredients in the preparation of sedative-hypnotic drugs.

[0088] Confirmation of crystal structure

[0089] (1) X-ray single crystal diffraction test

[0090] The X-ray single-crystal diffraction instrument and testing conditions used for zolpidem salt in this invention are as follows: X-ray crystal data were collected on a Rigaku XtaLAB Synergy instrument in Japan, the testing temperature was 293(2) K, CuKa radiation was used, data were collected in ω-scan mode and Lp correction was performed. The structure was analyzed by direct method, all non-hydrogen atoms were identified by difference Fourier method, all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least squares method.

[0091] The crystallographic data of zolpidem oxalate prepared in this invention were tested and analyzed. Its crystallographic parameters are: orthorhombic crystal system, chiral space group P212121; unit cell parameters are: α = 90.00°, β = 90.00°, γ = 90.00°, unit cell volume The molecular formula is: C 21 H 23 N3O5, molecular weight: 397.42. See Table 1 for details.

[0092] Table 1. Main crystallographic data of zolpidem oxalate

[0093]

[0094]

[0095] The structural analysis of zolpidem oxalate of the present invention shows that the crystal contains one molecule of zolpidem and one molecule of oxalic acid, as shown in the attached diagram. Figure 3 As shown. A packing diagram of the zolpidem oxalate of the present invention is attached. Figure 2 As shown.

[0096] The crystallographic data of the zolpidem fumarate prepared in this invention were tested and analyzed. Its crystallographic parameters are: orthorhombic crystal system, chiral space group P212121; unit cell parameters are: α = 90.00°, β = 90.00°, γ = 90.00°, unit cell volume The molecular formula is: C 23 H 25 N3O5, molecular weight: 423.47. See Table 2 for details.

[0097] Table 2. Main crystallographic data of zolpidem fumarate

[0098]

[0099]

[0100] The structural analysis of the zolpidem fumarate of this invention shows that the crystal contains one molecule of zolpidem and one molecule of fumaric acid, as shown in the attached diagram. Figure 7 As shown. A packing diagram of the zolpidem fumarate of the present invention is attached. Figure 6 As shown.

[0101] The crystallographic data of the zolpidem malonate prepared in this invention were tested and analyzed. Its crystallographic parameters are: orthorhombic crystal system, space group Pna21, and cell parameters are: α = 90.00°, β = 90.00°, γ = 90.00°, unit cell volume The molecular formula is: C 22 H 24 N3O5, molecular weight: 410.44. See Table 3 for specific results.

[0102] Table 3. Main crystallographic data of zolpidem malonate

[0103]

[0104]

[0105] The structural analysis photograph of the zolpidem malonic acid salt of the present invention shows that the crystal contains one molecule of zolpidem and one molecule of malonic acid, as shown in the attached image. Figure 11 As shown. A packing diagram of the zolpidem malonate of the present invention is attached. Figure 10 As shown.

[0106] The crystallographic data of the zolpidem-5-sulfosalicylate methanol complex prepared in this invention were tested and analyzed. Its crystallographic parameters are: triclinic system, chiral space group P-1; unit cell parameters are: α = 74.0660°, β = 89.9940°, γ = 87.9840°, cell volume The molecular formula is: C 27 H 31 N3O8S, molecular weight: 557.61. See Table 4 for details.

[0107] Table 4. Main crystallographic data of zolpidem-5-sulfosalicylate methanol complex

[0108]

[0109]

[0110] The crystal structure analysis of the zolpidem-5-sulfosalicylic acid methyl ester compound of the present invention shows that the crystal contains one molecule of zolpidem, one molecule of 5-sulfosalicylic acid, and one molecule of methanol, as shown in the attached figure. Figure 15 As shown. A packing diagram of the zolpidem-5-sulfosalicylate methanol compound of the present invention is attached. Figure 14 As shown.

[0111] (2) X-ray powder diffraction detection

[0112] The X-ray powder diffraction instrument and testing conditions used for zolpidem salt described in this invention are as follows: PANalyticalEmpyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction light path: PIXCEL, voltage 45KV, current 40mA, divergence slit 1 / 4°, anti-scattering slit 1°, Solar slit 0.04rad, counting time per step 0.5s, scanning range 3~50°.

[0113] The characteristic peaks in the main X-ray powder diffraction (Cu-Kα) patterns of zolpidem oxalate are shown in Table 5.

[0114] Table 5. Major PXRD peaks of zolpidem oxalate

[0115]

[0116]

[0117] The characteristic peaks in the main X-ray powder diffraction pattern (Cu-Kα) of zolpidem fumarate are shown in Table 6.

[0118] Table 6. Major PXRD peaks of zolpidem fumarate

[0119]

[0120] The characteristic peaks in the main X-ray powder diffraction pattern (Cu-Kα) of zolpidem malonate are shown in Table 7.

[0121] Table 7. Major PXRD peaks of zolpidem malonate

[0122]

[0123]

[0124] The characteristic peaks in the main X-ray powder diffraction (Cu-Kα) pattern of zolpidem-5-sulfosalicylate methanol compound are shown in Table 8.

[0125] Table 8. Main PXRD peaks of zolpidem-5-sulfosalicylate methanolic compound composition

[0126]

[0127]

[0128] All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns as described above.

[0129] (3) TGA / DSC analysis

[0130] The TGA / DSC thermal analysis instrument and test conditions in this invention are as follows: TGA / DSC thermal analyzer: METTLER TOLEDOTGA / DSC3+; dynamic temperature range: 30~300℃; heating rate: 10℃ / min; program segment: gas N2; gas flow rate: 50mL / min; crucible: aluminum crucible 40μl.

[0131] The differential scanning calorimetry (DSC) results of the zolpidem oxalate prepared by the method described in this invention are as follows: Figure 4 As shown, zolpidem oxalate exhibited an endothermic peak in the temperature range of 137.03℃ to 284.29℃, with a peak value at 214.33℃, as detected by differential scanning calorimetry (DSC). Its thermogravimetric analysis (TGA) showed only one weight loss step, which corresponded well with the DSC results. The zolpidem oxalate exhibited the following properties... Figure 4 The DSC / TGA spectrum shown.

[0132] The differential scanning calorimetry (DSC) results of the zolpidem fumarate prepared by the method described in this invention are as follows: Figure 8 As shown, zolpidem fumarate exhibited an endothermic peak at 203.83℃–235.00℃, with a peak value at 220.42℃, as detected by differential scanning calorimetry (DSC). Its thermogravimetric analysis (TGA) showed only one weight loss step, which corresponded well with the DSC results. The zolpidem fumarate exhibited the following characteristics: Figure 8 The DSC / TGA spectrum shown.

[0133] The differential scanning calorimetry (DSC) results of the zolpidem malonate prepared by the method described in this invention are as follows: Figure 12 As shown, zolpidem malonate exhibited an endothermic peak at 139.34℃ to 172.69℃, with a peak value at 155.19℃, as detected by differential scanning calorimetry (DSC). The zolpidem malonate contains... Figure 12 The DSC / TGA spectrum shown.

[0134] The differential scanning calorimetry (DSC) results of the zolpidem-5-sulfosalicylate methanol complex prepared by the method described in this invention are as follows: Figure 16As shown, the zolpidem-5-sulfosalicylate methanol compound exhibited two endothermic peaks as detected by differential scanning calorimetry (DSC): one endothermic peak ranged from 85.13℃ to 113.40℃, with a peak at 100.38℃; the other endothermic peak ranged from 146.14℃ to 197.77℃, with a peak at 183.05℃. Its thermogravimetric analysis (TGA) showed only one weight loss step, which corresponded well with the DSC results. The zolpidem-5-sulfosalicylate methanol compound exhibited the following characteristics: Figure 16 The DSC / TGA spectrum shown.

[0135] The method for preparing zolpidem salt provided by this invention is simple to operate, and the prepared crystals have high purity. The zolpidem salt provided by this invention has good chemical stability in the solid state and good solubility. Attached Figure Description

[0136] Figure 1 X-ray powder diffraction pattern of zolpidem oxalate.

[0137] Figure 2 : Stacking diagram of zolpidem oxalate.

[0138] Figure 3 ORTEP plot of zolpidem oxalate.

[0139] Figure 4 Differential scanning calorimetry (DSC) curve of zolpidem oxalate.

[0140] Figure 5 X-ray powder diffraction pattern of zolpidem fumarate.

[0141] Figure 6 : Stacking diagram of zolpidem fumarate.

[0142] Figure 7 ORTEP plot of zolpidem fumarate.

[0143] Figure 8 Differential scanning calorimetry (DSC) curve of zolpidem fumarate.

[0144] Figure 9 X-ray powder diffraction pattern of zolpidem malonate.

[0145] Figure 10 Stacking diagram of zolpidem malonate.

[0146] Figure 11 ORTEP plot of zolpidem malonate.

[0147] Figure 12 Differential scanning calorimetry (DSC) curve of zolpidem malonate.

[0148] Figure 13 X-ray powder diffraction pattern of zolpidem-5-sulfosalicylate methanol compound.

[0149] Figure 14 Packing diagram of zolpidem-5-sulfosalicylate methanol compound.

[0150] Figure 15 ORTEP diagram of zolpidem-5-sulfosalicylate methanol compound.

[0151] Figure 16 Differential scanning calorimetry (DSC) curve of zolpidem-5-sulfosalicylate methanol compound. Detailed implementation method:

[0152] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0153] Preparation of zolpidem oxalate

[0154] Example 1

[0155] 159 mg of zolpidem and 46.5 mg of oxalic acid were added to 18.5 mL of acetone, heated to 45 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 10–15 °C, and allowed to stand for crystallization for 5 hours. The mixture was filtered, the filter cake was washed with acetonitrile, and dried under vacuum at 50 °C for 10 hours to obtain zolpidem oxalate with a yield of 96.79% and a purity of 99.95%.

[0156] Example 2

[0157] 280.5 mg zolpidem and 78 mg oxalic acid were added to 23.5 mL of methanol, heated to 40 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours. After slowly cooling to 15–20 °C, the mixture was allowed to stand at a controlled temperature for 6 hours to crystallize. The crystals were filtered, the filter cake was washed with acetone, and dried under vacuum at 45 °C for 8 hours to obtain zolpidem oxalate. The yield was 90.27% and the purity was 99.94%.

[0158] Example 3

[0159] 116.5 mg of zolpidem and 40 mg of oxalic acid were added to 20 mL of a mixed solvent (10 mL of methanol and 10 mL of acetonitrile). The mixture was heated to 50 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours. After slowly cooling to 8–18 °C, the mixture was allowed to stand at a controlled temperature for 4 hours to crystallize. The crystals were filtered, the filter cake was washed with ethanol, and the mixture was dried under vacuum at 60 °C for 12 hours to obtain zolpidem oxalate. The yield was 93.25% and the purity was 99.93%.

[0160] Example 4

[0161] 310 mg of zolpidem and 82 mg of oxalic acid were added to 31 mL of a mixed solvent (16 mL of acetone and 15 mL of ethanol), heated to 55 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 13–18 °C, and allowed to stand for crystallization for 5 hours. The crystals were filtered, washed with methanol, and dried under vacuum at 65 °C for 11 hours to obtain zolpidem oxalate, with a yield of 84.36% and a purity of 99.91%.

[0162] Example 5

[0163] 96.5 mg zolpidem and 34 mg oxalic acid were added to 13 mL of ethanol, heated to 42 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours, slowly cooled to 8–13 °C, and allowed to stand at a controlled temperature for 5 hours to crystallize. The mixture was filtered, the filter cake was washed with methanol, and dried under vacuum at 55 °C for 9 hours to obtain zolpidem oxalate with a yield of 88.76% and a purity of 99.90%.

[0164] Example 6

[0165] 234 mg of zolpidem and 55 mg of oxalic acid were added to 15.5 mL of acetonitrile, heated to 35 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours, slowly cooled to 0–5 °C, and allowed to stand for crystallization for 7 hours. The mixture was filtered, the filter cake was washed with acetone, and dried under vacuum at 40 °C for 13 hours to obtain zolpidem oxalate, with a yield of 69.21% and a purity of 97.88%.

[0166] Example 7

[0167] 127.5 mg zolpidem and 49 mg oxalic acid were added to 23.5 mL of methanol, heated to 55 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 31–36 °C, and allowed to stand for crystallization for 3 hours. The mixture was filtered, the filter cake was washed with acetonitrile, and dried under vacuum at 75 °C for 7 hours to obtain zolpidem oxalate with a yield of 82.19% and a purity of 97.86%.

[0168] Preparation of zolpidem fumarate

[0169] Example 8

[0170] 181.5 mg zolpidem and 68.5 mg fumaric acid were added to 11.5 mL of methanol, heated to 50 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 5–10 °C, and allowed to stand for crystallization for 5 hours. The mixture was filtered, the filter cake was washed with ethanol, and dried under vacuum at 60 °C for 10 hours to obtain zolpidem fumarate, with a yield of 94.97% and a purity of 99.96%.

[0171] Example 9

[0172] 297 mg of zolpidem and 101 mg of fumaric acid were added to 14.5 mL of a mixed solvent (7 mL of methanol and 7.5 mL of acetone), heated to 40 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours. After slowly cooling to 10–15 °C, the mixture was allowed to stand at a controlled temperature for 4 hours to crystallize. The crystals were then filtered, the filter cake was washed with acetonitrile, and dried under vacuum at 45 °C for 8 hours to obtain zolpidem fumarate, with a yield of 83.11% and a purity of 99.95%.

[0173] Example 10

[0174] 326 mg of zolpidem and 135.5 mg of fumaric acid were added to 17 mL of a mixed solvent (9 mL of methanol and 8 mL of isopropanol), heated to 45 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours. After slowly cooling to 15–20 °C, the mixture was allowed to stand at a controlled temperature for 6 hours to crystallize. The crystals were then filtered, washed with acetone, and dried under vacuum at 50 °C for 9 hours to obtain zolpidem fumarate, with a yield of 91.13% and a purity of 99.94%.

[0175] Example 11

[0176] 153.5 mg zolpidem and 50 mg fumaric acid were added to 5.5 mL of isopropanol, heated to 52 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 20–25 °C, and allowed to stand for 6 hours to crystallize. The mixture was filtered, the filter cake was washed with methanol, and dried under vacuum at 65 °C for 11 hours to obtain zolpidem fumarate, with a yield of 76.91% and a purity of 99.93%.

[0177] Example 12

[0178] 85.5 mg zolpidem and 44 mg fumaric acid were added to 4.5 mL of acetonitrile, heated to 48 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 18–23 °C, and allowed to stand for crystallization for 5 hours. The mixture was filtered, the filter cake was washed with ethanol, and dried under vacuum at 70 °C for 10 hours to obtain zolpidem fumarate, with a yield of 86.43% and a purity of 99.91%.

[0179] Example 13

[0180] 215 mg zolpidem and 57 mg fumaric acid were added to 11.5 mL of acetone, heated to 35 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours. After slowly cooling to 0–5 °C, the mixture was allowed to stand at a controlled temperature for 7 hours to crystallize. The mixture was then filtered, the filter cake was washed with acetonitrile, and dried under vacuum at 40 °C for 13 hours to obtain zolpidem fumarate, with a yield of 60.23% and a purity of 99.88%.

[0181] Example 14

[0182] 113.5 mg of zolpidem and 60 mg of fumaric acid were added to 5.5 mL of methanol, heated to 55 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 31–36 °C, and allowed to stand for crystallization for 3 hours. The mixture was filtered, the filter cake was washed with ethanol, and dried under vacuum at 75 °C for 7 hours to obtain zolpidem fumarate, with a yield of 80.29% and a purity of 99.85%.

[0183] Preparation of zolpidem malonate

[0184] Example 15

[0185] 61.5 mg of zolpidem and 21 mg of malonic acid were added to 4 mL of a mixed solvent (2 mL of acetonitrile and 2 mL of acetone), heated to 50 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 15–20 °C, and allowed to stand at a controlled temperature for 6 hours to crystallize. The crystals were filtered, the filter cake was washed with acetone, and dried under vacuum at 50 °C for 8 hours to obtain zolpidem malonic acid salt, with a yield of 97.91% and a purity of 99.92%.

[0186] Example 16

[0187] 190.5 mg of zolpidem and 77 mg of malonic acid were added to 23 mL of a mixed solvent (11.5 mL of methanol and 11.5 mL of acetone), heated to 45 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours, slowly cooled to 20–25 °C, and allowed to stand for crystallization for 5 hours. The mixture was filtered, the filter cake was washed with methanol, and dried under vacuum at 55 °C for 12 hours to obtain zolpidem malonic acid salt with a yield of 95.48% and a purity of 99.91%.

[0188] Example 17

[0189] 278 mg of zolpidem and 85 mg of malonic acid were added to 4 mL of a mixed solvent (2 mL of ethanol and 2 mL of acetone), heated to 55 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours, slowly cooled to 13–18 °C, and allowed to stand at a controlled temperature for 4 hours to crystallize. The crystals were filtered, washed with acetonitrile, and dried under vacuum at 70 °C for 11 hours to obtain zolpidem malonic acid salt, with a yield of 83.89% and a purity of 99.90%.

[0190] Example 18

[0191] 118 mg of zolpidem and 56 mg of malonic acid were added to 22 mL of a mixed solvent (11 mL of methanol and 11 mL of acetone), heated to 40 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 10–15 °C, and allowed to stand at a controlled temperature for 6 hours to crystallize. The crystals were filtered, washed with ethanol, and dried under vacuum at 65 °C for 10 hours to obtain zolpidem malonic acid salt, with a yield of 91.42% and a purity of 99.89%.

[0192] Example 19

[0193] 334 mg of zolpidem and 90.5 mg of malonic acid were added to 32 mL of a mixed solvent (16 mL of acetonitrile and 16 mL of acetone), heated to 52 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 17–22 °C, and allowed to stand at a controlled temperature for 4 hours to crystallize. The crystals were filtered, washed with acetone, and dried under vacuum at 45 °C for 9 hours to obtain zolpidem malonic acid salt, with a yield of 72.17% and a purity of 99.88%.

[0194] Example 20

[0195] 201 mg of zolpidem and 48 mg of malonic acid were added to 21 mL of a mixed solvent (10.5 mL of methanol and 10.5 mL of acetone), heated to 35 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 2–7 °C, and allowed to stand at a controlled temperature for 3 hours to crystallize. The mixture was then filtered, the filter cake was washed with ethanol, and dried under vacuum at 40 °C for 7 hours to obtain zolpidem malonic acid salt, with a yield of 62.45% and a purity of 97.85%.

[0196] Example 21

[0197] 163 mg of zolpidem and 83 mg of malonic acid were added to 29 mL of a mixed solvent (14.5 mL of acetonitrile and 14.5 mL of acetone), heated to 55 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours, slowly cooled to 26–30 °C, and allowed to stand at a controlled temperature for crystallization for 7 hours. The crystals were filtered, washed with methanol, and dried under vacuum at 75 °C for 13 hours to obtain zolpidem malonic acid salt, with a yield of 82.17% and a purity of 97.83%.

[0198] Preparation of zolpidem-5-sulfosalicylate methanol complex

[0199] Example 22

[0200] 193 mg of zolpidem and 160 mg of 5-sulfosalicylic acid were added to 27 mL of a mixed solvent (13.5 mL of methanol and 13.5 mL of acetonitrile). The mixture was heated to 50 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour. After slowly cooling to 12–17 °C, the mixture was allowed to stand at a controlled temperature for 4 hours to crystallize. The crystals were filtered, and the filter cake was washed with ethanol. The mixture was then dried under vacuum at 60 °C for 10 hours to obtain zolpidem-5-sulfosalicylic acid methanol compound with a yield of 95.32% and a purity of 99.93%.

[0201] Example 23

[0202] 246.5 mg of zolpidem and 163 mg of 5-sulfosalicylic acid were added to 20 mL of a mixed solvent (10 mL of methanol and 10 mL of ethanol), heated to 40 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours. After slowly cooling to 17–23 °C, the mixture was allowed to stand at a controlled temperature for 3 hours to crystallize. The crystals were filtered, the filter cake was washed with acetone, and dried under vacuum at 45 °C for 12 hours to obtain zolpidem-5-sulfosalicylic acid methanol compound with a yield of 74.13% and a purity of 99.92%.

[0203] Example 24

[0204] 371 mg of zolpidem and 214.5 mg of 5-sulfosalicylic acid were added to 22 mL of a mixed solvent (11 mL of methanol and 11 mL of tetrahydrofuran). The mixture was heated to 45 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours. After slowly cooling to 5–10 °C, the mixture was allowed to stand at a controlled temperature for crystallization for 5 hours. The crystals were filtered, and the filter cake was washed with acetonitrile. The mixture was then dried under vacuum at 55 °C for 11 hours to obtain zolpidem-5-sulfosalicylic acid methanol compound with a yield of 62.39% and a purity of 99.91%.

[0205] Example 25

[0206] 98.5 mg of zolpidem and 98 mg of 5-sulfosalicylic acid were added to 8 mL of a mixed solvent (4 mL of methanol and 4 mL of acetonitrile). The mixture was heated to 55 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour. After slowly cooling to 15–20 °C, the mixture was allowed to stand at a controlled temperature for 4 hours to crystallize. The crystals were filtered, the filter cake was washed with ethanol, and the mixture was dried under vacuum at 65 °C for 9 hours to obtain zolpidem-5-sulfosalicylic acid methanol compound with a yield of 90.21% and a purity of 99.90%.

[0207] Example 26

[0208] 129 mg of zolpidem and 149 mg of 5-sulfosalicylic acid were added to 10 mL of a mixed solvent (5 mL of methanol and 5 mL of acetone), heated to 41 °C and stirred to dissolve. The mixture was then heated under reflux for 2 hours. After slowly cooling to 3–8 °C, the mixture was allowed to stand at a controlled temperature for 5 hours to crystallize. The crystals were then filtered, washed with acetonitrile, and dried under vacuum at 45 °C for 8 hours to obtain zolpidem-5-sulfosalicylic acid methanol compound with a yield of 89.32% and a purity of 99.87%.

[0209] Example 27

[0210] 160 mg of zolpidem and 80 mg of 5-sulfosalicylic acid were added to 16 mL of a mixed solvent (8 mL of methanol and 8 mL of tetrahydrofuran). The mixture was heated to 30 °C and stirred to dissolve. The mixture was then heated under reflux for 3 hours. After slowly cooling to 0–5 °C, the mixture was allowed to stand at a controlled temperature for 6 hours to crystallize. The crystals were filtered, and the filter cake was washed with acetone. The mixture was then dried under vacuum at 35 °C for 13 hours to obtain zolpidem-5-sulfosalicylic acid methanol compound with a yield of 50.11% and a purity of 98.79%.

[0211] Example 28

[0212] 267.5 mg of zolpidem and 332 mg of 5-sulfosalicylic acid were added to 21 mL (10.5 mL of methanol and 10.5 mL of acetonitrile), heated to 55 °C and stirred to dissolve. The mixture was then heated under reflux for 1 hour, slowly cooled to 32–37 °C, and allowed to stand for crystallization for 2 hours. The mixture was filtered, the filter cake was washed with ethanol, and dried under vacuum at 70 °C for 7 hours to obtain a zolpidem-zolpidem-5-sulfosalicylic acid methanol complex with a yield of 80.54% and a purity of 98.21%.

[0213] Stability test

[0214] The zolpidem salts prepared in Examples 1, 8, 15, and 22 of this invention were subjected to accelerated testing and placed in a constant temperature and humidity incubator at 40±2℃ and RH 75±5% for 6 months. Samples were taken at the end of 1, 2, 3, and 6 months to test appearance, related substances, and purity. The results are shown in Table 9.

[0215] Table 9. Accelerated test results of zolpidem salt

[0216]

[0217] Accelerated testing showed that the zolpidem salt of the present invention has relatively stable physicochemical properties, and the purity of zolpidem salt did not decrease significantly, while the increase in impurity content was minimal.

[0218] Solubility test

[0219] The specific solubility test was conducted according to the Chinese Pharmacopoeia 2015. Excess zolpidem salts from Examples 1, 8, 15, and 22 were accurately weighed and placed in small vials. Hydrochloric acid solution (pH 1.0) and water were added respectively to prepare saturated zolpidem solutions. The solutions were shaken well to dissolve and then filtered. The solubility was calculated by measuring the absorbance at a wavelength of 270 nm using ultraviolet-visible spectrophotometry (General Rule 0401). The test results are shown in Table 10.

[0220] Table 10 Solubility of zolpidem salts

[0221]

[0222] Experiments have shown that all zolpidem salts prepared according to the present invention can achieve similar solubility effects and have good solubility.

Claims

1. A salt of Zolpidem, characterized in that, The zolpidem salt is formed from the combination of zolpidem and an organic acid, wherein the organic acid is selected from oxalic acid; the zolpidem oxalate salt has an X-ray diffraction pattern expressed in degrees 2-theta using Cu-Ka radiation having characteristic peaks at 7.02±0.2°, 12.07±0.2°, 14.00±0.2°, 16.00±0.2°, 19.42±0.2°, 21.63±0.2°, 23.31±0.2°, 25.87±0.2°, 27.84±0.2°, 28.73±0.2°; differential scanning calorimetry (DSC) analysis shows an endothermic peak in the range of 137.03-284.29°C, with a peak value at 214.33°C; the crystallographic parameters are: orthorhombic crystal system, chiral space group P212121; the unit cell parameters are: a = 5.33790(10) Å, b = 10.9174(2) Å, c = 33.4544(6) Å, α = 90.00°, β = 90.00°, γ = 90.00°, unit cell volume V = 1949.59(6) Å 3 .

2. The salt of zolpidem according to claim 1, characterized in that, The zolpidem salt is one selected from the group consisting of the zolpidem oxalate salt, and the characteristic peaks thereof are consistent with the X-ray powder diffraction pattern shown in Figure 1 or the detection data shown in Table 5 using Cu-Ka radiation.

3. The process for preparing a salt of Zolpidem according to any one of claims 1 to 2, characterized in that, The preparation of the zolpidem salt comprises the following steps: The zolpidem and oxalic acid are dissolved in an organic solvent A, heated and dissolved, and then the solution is cooled to precipitate crystals, filtered and dried to obtain the zolpidem oxalate salt, wherein the organic solvent A is selected from one or a mixture of at least two of acetone, methanol, ethanol and acetonitrile; the molar ratio of the zolpidem to the oxalic acid is 1:0.9-1.2; the heating and dissolving temperature is 40-50°C; the cooling and crystallization temperature is 0-30°C; and the drying temperature is 45-70°C.

4. The method for preparing zolpidem according to claim 3, characterized in that, The molar ratio of the zolpidem to the oxalic acid is 1:0.95-1.

15.

5. The use of the zolpidem salt as claimed in claims 1-2 as an active ingredient for preparing a sedative and hypnotic drug.

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