A clozapine-2-indolecarboxylic acid co-crystal

Abstract

The application belongs to the technical field of crystal form drug molecules, and specifically provides a clozapine-2-indole carboxylic acid co-crystal. The prepared clozapine-2-indole carboxylic acid co-crystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 5.82±0.2°, 12.85±0.2°, 14.37±0.2°, 17.87±0.2°, 26.98±0.2° and 27.80±0.2°. The method for preparing the clozapine-2-indole carboxylic acid co-crystal is simple in operation, the prepared crystal has high purity, good chemical stability in a solid state and good solubility. The preparation process is simple, and the application has good industrial application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of crystal form drug molecules, in particular to the technical field of chlorzoxazone crystal forms, and specifically to a chlorzoxazone-2-indole carboxylic acid co-crystal, a preparation method and application thereof. BACKGROUND

[0002] A drug co-crystal refers to a crystal formed by a combination of a pharmaceutically active ingredient and other substances in a certain stoichiometric ratio under the action of hydrogen bonds or other non-covalent bonds. The molecular network linking mode based on hydrogen bonds is the basis for the formation of co-crystals. The combination of co-crystals is in a neutral state and relies on non-ionic bond combination. When the pharmaceutically active ingredient is a neutral molecule, the drug cannot be improved in terms of drug properties by preparing polymorphs, amorphous substances, or preparing solvent compounds and salts, and co-crystals are a very good choice. In many cases, a drug co-crystal not only does not destroy the activity of the drug, but also improves the melting point, solubility, stability, dissolution rate and bioavailability of the drug.

[0003] Chlorzoxazone, chemical name: 5-chloro-2-benzoxazolinone, English name: 5-chloro-2-benzoxazolinone. CAS No. 95-25-0, its structural formula is as follows:

[0004]

[0005] Chlorzoxazone is a strong oral muscle relaxant developed by McNeil Company in the United States and marketed in the mid-1960s. It is clinically used for lumbar pain, neuralgia, rheumatoid arthritis, acute and chronic soft tissue (muscle, ligament) sprain, contusion, post-exercise muscle soreness, muscle spasm caused by central nervous system disease and chronic fasciitis, with a total effective rate of up to 98.59%. In addition, it has certain effect on muscle spasm caused by central nervous system disease and chronic fasciitis, and poor intelligence development in children. It is one of the most widely used drugs in clinical application.

[0006] The marketed chlorzoxazone is generally formed into a compound preparation with acetaminophen, and the compound process is relatively complex. In addition, some patients have an allergic reaction to acetaminophen. In view of the above shortcomings, the present application provides a chlorzoxazone-2-indole carboxylic acid co-crystal, so as to more efficiently exert the medicinal value of chlorzoxazone. SUMMARY

[0007] The present application provides a simple and easy-to-operate method for preparing high-purity chlorzoxazone-2-indole carboxylic acid co-crystal crystal form, which provides a better basis for the application of chlorzoxazone in drug synergistic therapy, so as to more efficiently exert the medicinal value of chlorzoxazone.

[0008] An object of the present application is to provide a clozapine-2-indolecarboxylic acid co-crystal.

[0009] The specific technical content is as follows:

[0010] A clozapine-2-indolecarboxylic acid co-crystal, using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 5.82±0.2°, 12.85±0.2°, 14.37±0.2°, 17.87±0.2°, 26.98±0.2°, 27.80±0.2°.

[0011] Preferably, the clozapine-2-indolecarboxylic acid co-crystal, using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 5.82±0.2°, 12.85±0.2°, 13.53±0.2°, 14.37±0.2°, 17.47±0.2°, 17.87±0.2°, 19.65±0.2°, 24.91±0.2°, 26.27±0.2°, 26.98±0.2°, 27.80±0.2°, 29.19±0.2°, 29.60±0.2°, 40.12±0.2°.

[0012] Preferably, the clozapine-2-indolecarboxylic acid co-crystal, using Cu-Kα radiation, the characteristic peaks thereof are consistent with the X-ray powder diffraction spectrum and detection data shown in Table 1 and Table 2. Figure 1

[0013] Preferably, the clozapine-2-indolecarboxylic acid co-crystal is detected by differential scanning calorimetry (DSC) to have an endothermic peak in the temperature range of 156.76-193.43℃, and the peak value of the endothermic peak is at 183.88℃, corresponding to the decomposition endothermic peak of clozapine-2-indolecarboxylic acid.

[0014] The second aspect of the present application provides a method for preparing the clozapine-2-indolecarboxylic acid co-crystal, which comprises the following steps:

[0015] The clozapine and 2-indolecarboxylic acid are dissolved in an organic solvent A, heated and dissolved, and then the solution is cooled to crystallize, filtered and dried to obtain the clozapine-2-indolecarboxylic acid co-crystal.

[0016] The organic solvent A is selected from one or more of methanol, ethanol, acetone, and isopropanol.

[0017] Preferably, the organic solvent A is selected from one or both of methanol and ethanol.

[0018] ​The molar ratio of the chlorzoxazone to 2-indolecarboxylic acid is 1:0.87-1.22; preferably, the molar ratio of the chlorzoxazone to 2-indolecarboxylic acid is 1:0.92-1.11.

[0019] The mass-volume ratio of the 2-indolecarboxylic acid to the organic solvent A in the system is 5-13:1, wherein the mass is in mg and the volume is in mL.

[0020] The temperature of the dissolution heating is 40-55°C.

[0021] The temperature of the cooling and crystallization is 0-30°C, preferably, the temperature of the cooling and crystallization is 5-20°C.

[0022] The crystallization time is 4-6 hours.

[0023] The drying temperature is 45-70°C, and the drying time is 8-12 hours.

[0024] Preferably, the preparation method comprises the following steps:

[0025] The chlorzoxazone and the 2-indolecarboxylic acid are heated and dissolved in the organic solvent A at 40-55°C, stirred and refluxed for 1-2 hours, cooled to 5-20°C for 4-6 hours of crystallization, filtered, the filter cake is washed, and dried to obtain the chlorzoxazone-2-indolecarboxylic acid co-crystal.

[0026] The solvent for washing the filter cake is selected from one of acetone, methanol, ethanol and acetonitrile.

[0027] The third aspect of the present application provides a pharmaceutical composition comprising the chlorzoxazone-2-indolecarboxylic acid co-crystal prepared above, and containing other active ingredients and / or formulation-acceptable auxiliary components that can be used in combination.

[0028] Preferably, the other components include other active ingredients, excipients, fillers, etc. that can be used in combination.

[0029] Preferably, the pharmaceutical composition can be prepared into sprays, tablets, capsules, powder injections, liquid injections, etc. using standard and conventional techniques.

[0030] The fourth aspect of the present application provides the use of the chlorzoxazone-2-indolecarboxylic acid co-crystal as an active ingredient in the preparation of analgesics.

[0031] Confirmation of the crystal structure

[0032] X-ray crystal data were collected on a Rigaku XtaLAB Synergy instrument at a test temperature of 293(2) K using CuKa radiation. Data were collected in ω-scan mode and Lp correction was performed. The structure was resolved using the direct method, and all non-hydrogen atoms were identified using the difference Fourier method. Hydrogen atoms on all carbon and nitrogen atoms were obtained by theoretical hydrogenation. The structure was refined using the least squares method.

[0033] The chlorzoxazone-2-indolecarboxylic acid eutectic prepared in this invention was tested and analyzed. Its crystallographic parameters are: triclinic system, chiral space group P-1; cell parameters are: α = 85.228(3)°, β = 87.044(3)°, γ = 67.178(3)°, cell volume Molecular formula: C 16 H 11 C l N₂O₄, molecular weight: 330.72. The ORTEP diagram of the chlorzoxazone-2-indolecarboxylic acid eutectic structure of this invention shows that the crystal contains one molecule of chlorzoxazone and one molecule of 2-indolecarboxylic acid, as shown in the attached diagram. Figure 3 As shown. The packing diagram of the chlorzoxazone-2-indolecarboxylic acid eutectic of the present invention is attached. Figure 2 As shown.

[0034] Table 1. Main crystallographic data of chlorzoxazone-2-indolecarboxylic acid eutectic.

[0035]

[0036]

[0037] The X-ray powder diffraction test instrument and test conditions for the chlorzoxazone-2-indolecarboxylic acid eutectic test described in this invention are as follows: PANalytical Empyrean 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°.

[0038] Based on crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 1 and 2 .

[0039] Table 2. Major PXRD peaks of chlorzoxazone-2-indolecarboxylic acid cocrystal.

[0040]

[0041]

[0042] All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns as described above.

[0043] 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.

[0044] The differential scanning calorimetry (DSC) results of the chlorzoxazone-2-indolecarboxylic acid eutectic prepared by the method described in this invention are as follows: Figure 4 As shown, the chlorzoxazone-2-indolecarboxylic acid eutectic, detected by differential scanning calorimetry (DSC), exhibited an endothermic peak ranging from 156.76 to 193.43 °C, with a peak value at 183.88 °C, corresponding to the endothermic decomposition peak of chlorzoxazone-2-indolecarboxylic acid. Its thermogravimetric analysis (TGA) showed only one weight loss step, which corresponded well with the DSC results. The chlorzoxazone-2-indolecarboxylic acid exhibited the following characteristics: Figure 4 The DSC / TGA spectrum shown.

[0045] The method for preparing chlorzoxazone-2-indolecarboxylic acid cocrystal provided by this invention is simple to operate and produces crystals with high purity. The chlorzoxazone-2-indolecarboxylic acid cocrystal provided by this invention has good chemical stability in the solid state and good solubility. Attached Figure Description

[0046] Figure 1 X-ray powder diffraction pattern of chlorzoxazone-2-indolecarboxylic acid eutectic.

[0047] Figure 2 Packing diagram of chlorzoxazone-2-indolecarboxylic acid eutectic.

[0048] Figure 3 ORTEP diagram of chlorzoxazone-2-indolecarboxylic acid eutectic.

[0049] Figure 4 Differential scanning calorimetry (DSC) curve of chlorzoxazone-2-indolecarboxylic acid eutectic. Detailed Implementation

[0050] 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.

[0051] Example 1

[0052] 100.0 mg chlorzoxazone and 95.13 mg 2-indolecarboxylic acid were added to 8 mL of methanol, heated to 50 °C and stirred to dissolve. The mixture was refluxed for 1 hour, then 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 acetone, and dried under vacuum at 55 °C for 10 hours to obtain chlorzoxazone-2-indolecarboxylic acid with a yield of 97.81% and a purity of 99.98%.

[0053] Example 2

[0054] 99.8 mg of chlorzoxazone and 99.59 mg of 2-indolecarboxylic acid were added to 15 mL of ethanol, heated to 45 °C and stirred to dissolve. The mixture was refluxed for 1 hour, then 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 45 °C for 8 hours to obtain chlorzoxazone-2-indolecarboxylic acid cocrystals with a yield of 97.27% and a purity of 99.97%.

[0055] Example 3

[0056] 169.57 mg of chlorzoxazone and 158.45 mg of 2-indolecarboxylic acid were added to 18 mL of a mixed solvent (9 mL of methanol and 9 mL of acetone), heated to 52 °C and stirred to dissolve. The mixture was refluxed for 2 hours, then slowly cooled to 15–20 °C and allowed to stand for crystallization for 4 hours. The crystals were filtered, washed with acetonitrile, and dried under vacuum at 65 °C for 11 hours to obtain chlorzoxazone-2-indolecarboxylic acid eutectic with a yield of 95.76% and a purity of 99.96%.

[0057] Example 4

[0058] 110.5 mg of chlorzoxazone and 125.70 mg of 2-indolecarboxylic acid were added to 12 mL of isopropanol, heated to 55 °C and stirred to dissolve. The mixture was refluxed for 1 hour, then slowly cooled to 8–15 °C and allowed to stand for 6 hours to crystallize. The crystals were filtered, washed with methanol, and dried under vacuum at 60 °C for 9 hours to obtain chlorzoxazone-2-indolecarboxylic acid eutectic with a yield of 95.43% and a purity of 99.95%.

[0059] Example 5

[0060] 80.9 mg of chlorzoxazone and 61.5 mg of 2-indolecarboxylic acid were added to 4 mL of acetone, heated to 35 °C and stirred to dissolve. The mixture was refluxed for 1 hour, then slowly cooled to 0–5 °C and allowed to stand for crystallization for 3 hours. The crystals were filtered, washed with methanol, and dried under vacuum at 40 °C for 7 hours to obtain chlorzoxazone-2-indolecarboxylic acid cocrystals with a yield of 78.19% and a purity of 99.92%.

[0061] Example 6

[0062] 66.2 mg of chlorzoxazone and 81.79 mg of 2-indolecarboxylic acid were added to 21 mL of a mixed solvent (11 mL of methanol and 10 mL of ethanol), heated to 50 °C and stirred to dissolve. The mixture was refluxed for 2 hours, then slowly cooled to 20–30 °C and allowed to stand for crystallization for 7 hours. The crystals were filtered, washed with acetonitrile, and dried under vacuum at 75 °C for 14 hours to obtain chlorzoxazone-2-indolecarboxylic acid eutectic with a yield of 91.42% and a purity of 99.90%.

[0063] Stability test

[0064] The chlorzoxazone-2-indolecarboxylic acid eutectic prepared in Examples 1-6 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 0, 1, 2, 3, and 6 months to test the appearance, related substances, content, and loss on drying. The results are shown in Table 3.

[0065] Table 3. Accelerated test results of chlorzoxazone-2-indolecarboxylic acid cocrystal.

[0066]

[0067]

[0068] Accelerated testing showed that the chlorzoxazone-2-indolecarboxylic acid eutectic of the present invention has relatively stable physicochemical properties, with no significant decrease in purity and only a slight increase in impurity content.

[0069] Solubility test

[0070] For specific solubility tests, in accordance with the Chinese Pharmacopoeia 2015, excess chlorzoxazone-2-indolecarboxylic acid cocrystals from Examples 1-6 were accurately weighed and placed in small vials. DMSO, hydrochloric acid solution at pH 1.0, and water were added respectively to prepare saturated chlorzoxazone solutions. The solutions were then shaken to dissolve and 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 4.

[0071] Table 4. Solubility of chlorzoxazone-2-indolecarboxylic acid eutectic

[0072]

[0073] Experiments have shown that all chlorzoxazone-2-indolecarboxylic acid eutectics prepared by the present invention can achieve similar solubility effects and have good solubility.

Claims

1. A chlorzoxazone-2-indolecarboxylic acid eutectic, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at 5.82±0.2°, 12.85±0.2°, 14.37±0.2°, 17.87±0.2°, 26.98±0.2°, and 27.80±0.2°.

2. The chlorzoxazone-2-indolecarboxylic acid eutectic as described in claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, shows characteristic peaks at 5.82±0.2°, 12.85±0.2°, 13.53±0.2°, 14.37±0.2°, 17.47±0.2°, 17.87±0.2°, 19.65±0.2°, 24.91±0.2°, 26.27±0.2°, 26.98±0.2°, 27.80±0.2°, 29.19±0.2°, 29.60±0.2°, and 40.12±0.2°.

3. The chlorzoxazone-2-indolecarboxylic acid eutectic as described in claim 1, characterized in that, Using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction patterns and detection data shown in Figure 1 and Table 2.

4. The chlorzoxazone-2-indolecarboxylic acid eutectic as described in claim 1, characterized in that, The crystallographic parameters of the chlorzoxazone-2-indolecarboxylic acid eutectic are: triclinic system, chiral space group P-1; cell parameters are: a=7.3241(2)Å, b=7.3871(3)Å, c=14.5803(5)Å, α=85.228(3) °, β=87.044(3) °, γ=67.178(3) °, cell volume V=724.41(5)Å3.

5. A method for preparing the chlorzoxazone-2-indolecarboxylic acid eutectic according to any one of claims 1 to 4, the method comprising the following steps: Chlorzoxazone and 2-indolecarboxylic acid were dissolved in organic solvent A, heated to dissolve, and after the solution became clear, it was cooled to crystallize, filtered and dried to obtain chlorzoxazone-2-indolecarboxylic acid cocrystals; wherein, the organic solvent A was selected from one or a mixture of at least two of methanol, ethanol, acetone and isopropanol.

6. The method for preparing chlorzoxazone-2-indolecarboxylic acid eutectic as described in claim 5, characterized in that, The organic solvent A is selected from one or both of methanol and ethanol.

7. The method for preparing chlorzoxazone-2-indolecarboxylic acid eutectic as described in claim 5, characterized in that, The molar ratio of chlorzoxazone to 2-indolecarboxylic acid is 1:0.87~1.

22.

8. The method for preparing chlorzoxazone-2-indolecarboxylic acid eutectic as described in claim 5, characterized in that, The molar ratio of chlorzoxazone to 2-indolecarboxylic acid is 1:0.92~1.

11.

9. The method for preparing chlorzoxazone-2-indolecarboxylic acid eutectic as described in claim 5, characterized in that, The mass-to-volume ratio of 2-indolecarboxylic acid and organic solvent A is 5 to 13:1, where the mass is expressed in mg and the volume in mL.

10. A pharmaceutical composition, characterized in that, The product comprises any one of the chlorzoxazone-2-indolecarboxylic acid cocrystals according to claims 1 to 4 and contains other active ingredients that can be used in combination and / or pharmaceutically acceptable excipient components.

11. The use of chlorzoxazone-2-indolecarboxylic acid cocrystal as an active ingredient in the preparation of analgesics according to any one of claims 1 to 4.

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