A cloxazone-nicotinic acid co-crystal

Abstract

The application belongs to the technical field of crystal form drug molecules, and specifically provides a clozaparide-nicotinic acid co-crystal. The prepared clozaparide-nicotinic acid crystal uses Cu-K alpha radiation, and the X-ray diffraction spectrum expressed in 2 theta has characteristic peaks at 4.47+ / -0.2°, 8.78+ / -0.2°, 8.99+ / -0.2°, 13.30+ / -0.2°, 13.52+ / -0.2°, 18.08+ / -0.2°, 19.33+ / -0.2° and 48.49+ / -0.2°. The method for preparing the clozaparide-nicotinic acid co-crystal is simple to operate, 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-nicotinic 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 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, and is one of the most widely used drugs in clinical application.

[0006] Nicotinic acid belongs to vitamin B3, also known as niacin, anti-leprosy factor, molecular formula: C6H5NO2, chemical name 3-pyridine carboxylic acid, white or slightly yellow crystal, is one of the 13 essential vitamins for the human body, and belongs to vitamin B group. Nicotinic acid can affect the hematopoietic process, promote iron absorption and blood cell production; maintain the normal function of the skin and the secretion of the digestive glands; improve the excitability of the central nervous system and the function of the cardiovascular system, the reticuloendothelial system and the endocrine system.

[0007] The marketed chlorzoxazone is generally formed into a compound preparation with acetaminophen, and the compound process is relatively complex, and even some patients have an allergic reaction to acetaminophen. In view of the above shortcomings, the present application provides a chlorzoxazone-nicotinic acid co-crystal form, so as to more efficiently exert the medicinal value of chlorzoxazone. SUMMARY

[0008] The present application provides a simple and easy to operate method for preparing high purity clozapine-nicotinic acid co-crystal, which provides better basis for the application of clozapine in drug synergistic therapy, so as to more efficiently exert the medicinal value of clozapine.

[0009] An object of the present application is to provide a clozapine-nicotinic acid co-crystal.

[0010] The specific technical content is as follows:

[0011] A clozapine-nicotinic acid co-crystal, using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 4.47±0.2°, 8.78±0.2°, 8.99±0.2°, 13.30±0.2°, 13.52±0.2°, 18.08±0.2°, 19.33±0.2°, 48.49±0.2°.

[0012] Preferably, the clozapine-nicotinic acid co-crystal, using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 4.47±0.2°, 8.78±0.2°, 8.99±0.2°, 13.30±0.2°, 13.52±0.2°, 14.53±0.2°, 15.22±0.2°, 18.08±0.2°, 19.33±0.2°, 20.98±0.2°, 22.66±0.2°, 23.96±0.2°, 24.44±0.2°, 25.57±0.2°, 27.28±0.2°, 29.59±0.2°, 30.06±0.2°, 37.67±0.2°, 43.81±0.2°, 48.49±0.2°.

[0013] Preferably, the clozapine-nicotinic acid co-crystal, using Cu-Kα radiation, the characteristic peaks thereof conform to the X-ray powder diffraction spectrum and detection data shown in Table 1 and Table 2. Figure 1

[0014] Preferably, the clozapine-nicotinic acid co-crystal is detected by differential scanning calorimetry (DSC) to have two endothermic peaks, the first endothermic peak has an onset point at 148.38℃, and the second endothermic peak has an onset point at 208.64℃.

[0015] The second aspect of the present application provides a method for preparing the clozapine-nicotinic acid co-crystal, which comprises the following steps:

[0016] The clozapine and nicotinic acid are dissolved in an organic solvent A, heated and dissolved, the solution is clarified, then cooled and crystallized, filtered and dried to obtain the clozapine-nicotinic acid co-crystal.

[0017] ​The organic solvent A is selected from one or more of acetone, methanol, isopropanol, acetonitrile or a mixture thereof.

[0018] Preferably, the organic solvent A is selected from one or both of methanol and acetone.

[0019] The molar ratio of the chlorzoxazone to the nicotinic acid is 1:0.90-1.20; preferably, the molar ratio of the chlorzoxazone to the nicotinic acid is 1:0.95-1.1.

[0020] The mass-volume ratio of the chlorzoxazone and the organic solvent A in the system is 10-25:1, wherein the mass is in mg and the volume is in mL.

[0021] The temperature of the dissolution heating is 40-55℃.

[0022] The temperature of the cooling and crystallization is 0-30℃, preferably 5-20℃.

[0023] The crystallization time is 4-6 hours.

[0024] The drying temperature is 45-70℃ and the drying time is 8-12 hours.

[0025] Preferably, the preparation method comprises the following steps:

[0026] The chlorzoxazone and the nicotinic acid are dissolved in the organic solvent A, heated and dissolved at 40-55℃, stirred and refluxed for 1-2 hours, cooled to 5-20℃ for 4-6 hours of crystallization, filtered, the filter cake is washed and dried to obtain the chlorzoxazone-nicotinic acid co-crystal.

[0027] The solvent for washing the filter cake is selected from one of acetone, methanol, ethanol and acetonitrile.

[0028] The third aspect of the present application provides a pharmaceutical composition comprising the chlorzoxazone-nicotinic acid co-crystal prepared as described above, and containing other active ingredients and / or pharmaceutically acceptable excipient components that can be used in combination.

[0029] Preferably, the other components include other active ingredients, excipients, fillers, etc. that can be used in combination.

[0030] Preferably, the pharmaceutical composition can be prepared into a spray, a tablet, a capsule, a powder injection, a liquid injection, etc. using standard and conventional techniques.

[0031] The fourth aspect of the present application provides the use of the chlorzoxazone-nicotinic acid co-crystal as an active ingredient for the preparation of an analgesic.

[0032] Confirmation of the crystal structure

[0033] X-ray crystal data were collected on a Rigaku XtaLAB Synergy model instrument at a temperature of 293(2) K with Cu Ka radiation, in an omega scan mode and Lp correction. The structure was solved by direct methods, all non-hydrogen atoms were found by difference Fourier methods, all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least squares method.

[0034] The prepared chlorzoxazone-nicotinic acid co-crystal was tested and analyzed, and the crystallographic parameters thereof are as follows: tetragonal system, chiral space group Pna21; cell parameters are as follows: α = 90.00°, β = 90.00°, γ = 90.00°, cell volume Molecular formula: C 26 H 20 Cl2N4O8, molecular weight: 587.36. The ORTEP diagram of the structure analysis of the chlorzoxazone-nicotinic acid co-crystal of the present application shows that two molecules of chlorzoxazone and two molecules of nicotinic acid exist in the crystal, as shown in the accompanying Figure 3 The packing diagram of the chlorzoxazone-nicotinic acid co-crystal of the present application is shown in the accompanying Figure 2 .

[0035] Table 1 Main crystallographic data of chlorzoxazone-nicotinic acid

[0036]

[0037]

[0038] The X-ray powder diffraction testing instrument and testing conditions of the chlorzoxazone-nicotinic acid co-crystal of the present application in the test are as follows: PANalytical Empyrean X-ray powder diffraction instrument; 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°, Soller slit 0.04 rad, counting time of each step 0.5s, scanning range 3-50°.

[0039] According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in the accompanying Figure 1 and 2 .

[0040] Table 2 Main PXRD peaks of chlorzoxazone-nicotinic acid co-crystal

[0041]

[0042]

[0043] All the samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction spectra as described above.

[0044] The TGA / DSC thermal analyzer and test conditions in the application: TGA / DSC thermal analyzer: METTLER TOLEDO TGA / DSC3+; dynamic temperature section: 30-300℃; heating rate: 10℃ / min; program section gas: N2; gas flow: 50mL / min; crucible: aluminum crucible 40μl.

[0045] The results of the differential scanning calorimetry curve (DSC) of the clozapine-nicotinic acid co-crystal prepared by the method are shown in Figure 4 The clozapine-nicotinic acid co-crystal is detected by differential scanning calorimetry (DSC) to appear two endothermic peaks, the first endothermic peak has an onset point at 148.38℃, which corresponds to the melting point of the clozapine-nicotinic acid co-crystal, and the second endothermic peak has an onset point at 208.64℃, which corresponds to the decomposition endothermic peak of the clozapine-nicotinic acid co-crystal. The thermogravimetric analysis (TGA) only has one weight loss step, which can well correspond to the DSC. The clozapine-nicotinic acid co-crystal has the DSC / TGA spectrum as shown in Figure 4

[0046] The method for preparing the clozapine-nicotinic acid co-crystal provided by the application is simple to operate, and the prepared crystal has high purity. The clozapine-nicotinic acid co-crystal provided by the application has good chemical stability in a solid state and good solubility. BRIEF DESCRIPTION OF DRAWINGS

[0047] Figure 1 : X-ray powder diffraction spectrum of the clozapine-nicotinic acid co-crystal.

[0048] Figure 2 : Packing diagram of the clozapine-nicotinic acid co-crystal.

[0049] Figure 3 : ORTEP diagram of the clozapine-nicotinic acid co-crystal.

[0050] Figure 4 : Differential scanning calorimetry curve (DSC) of the clozapine-nicotinic acid co-crystal. DETAILED DESCRIPTION

[0051] The application will be further described by examples, and it should be understood that the examples of the application are only used to illustrate the application, and are not a limitation of the application, so that the simple improvement of the application under the premise of the method of the application is within the scope of the application.

[0052] Example 1

[0053] ​Add 169.57 mg of clozapine and 123.11 mg of nicotinic acid into 11.3 mL of methanol, heat to 50°C, stir to dissolve, reflux for 1 hour, slowly cool to 5-10°C, control temperature and stand for crystallization for 5 hours, filter, wash the filter cake with methanol, and dry under vacuum at 60°C for 10 hours to obtain clozapine-nicotinic acid, with a yield of 97.77% and a purity of 99.97%.

[0054] Example 2

[0055] Add 100 mg of clozapine and 76.33 mg of nicotinic acid into 10 mL of acetone, heat to 52°C, stir to dissolve, reflux for 1 hour, slowly cool to 5-10°C, control temperature and stand for crystallization for 5 hours, filter, wash the filter cake with acetonitrile, and dry under vacuum at 50°C for 10 hours to obtain clozapine-nicotinic acid, with a yield of 96.67% and a purity of 99.95%.

[0056] Example 3

[0057] Add 263.45 mg of clozapine and 210.52 mg of nicotinic acid into 13 mL of mixed solvent (6 mL of methanol and 7 mL of acetone), heat to 50°C, stir to dissolve, reflux for 1 hour, slowly cool to 8-15°C, control temperature and stand for crystallization for 4 hours, filter, wash the filter cake with ethanol, and dry under vacuum at 45°C for 8 hours to obtain clozapine-nicotinic acid, with a yield of 96.12% and a purity of 99.94%.

[0058] Example 4

[0059] Add 144 mg of clozapine and 115.72 mg of nicotinic acid into 10.5 mL of isopropyl alcohol, heat to 55°C, stir to dissolve, reflux for 1 hour, slowly cool to 10-15°C, control temperature and stand for crystallization for 6 hours, filter, wash the filter cake with acetone, and dry under vacuum at 50°C for 9 hours to obtain clozapine-nicotinic acid, with a yield of 95.76% and a purity of 99.93%.

[0060] Example 5

[0061] Add 80 mg of clozapine and 49.18 mg of nicotinic acid into 11.42 mL of acetonitrile, heat to 35°C, stir to dissolve, reflux for 2 hours, slowly cool to 0-5°C, control temperature and stand for crystallization for 5 hours, filter, wash the filter cake with methanol, and dry under vacuum at 40°C for 7 hours to obtain clozapine-nicotinic acid, with a yield of 82.49% and a purity of 99.89%.

[0062] Example 6

[0063] Put 339.14 mg of clozapine, 320.09 mg of nicotinic acid into 13 mL of methanol, heat to 55 DEG C, stir to dissolve, reflux for 2 hours, slowly cool to 20-30 DEG C, control temperature and stand for 5 hours, filter, wash the filter cake with ethanol, and dry at 75 DEG C under vacuum for 14 hours to obtain the clozapine-nicotinic acid co-crystal, with a yield of 90.97% and a purity of 99.88%.

[0064] Stability test

[0065] The clozapine-nicotinic acid co-crystal prepared in Examples 1-6 is subjected to an accelerated test, and is placed in a constant temperature and humidity incubator at 40±2 DEG C and RH 75±5% for 6 months, and samples are taken at the end of 0, 1, 2, 3 and 6 months for testing appearance, related substances, content and loss on drying. The results are shown in Table 3.

[0066] Table 3: Accelerated test results of the clozapine-nicotinic acid co-crystal

[0067]

[0068]

[0069] The accelerated test shows that the clozapine-nicotinic acid co-crystal of the application is stable in terms of physicochemical properties, and the purity of clozapine does not decrease significantly, and the impurity content increases less.

[0070] Solubility test

[0071] The solubility test is specifically referred to the Chinese Pharmacopoeia 2015. Excess clozapine-nicotinic acid co-crystal of Examples 1-6 is precisely weighed, placed in a small Westlin bottle, and DMSO solution, pH 1.0 hydrochloric acid solution and water are added to prepare a clozapine saturated solution, which is shaken and dissolved, and filtered. The absorbance is measured at a wavelength of 270 nm by UV-visible spectrophotometry (General Rule 0401) to calculate the solubility. The test results are shown in Table 4.

[0072] Table 4: Solubility of the clozapine-nicotinic acid co-crystal

[0073]

[0074] It is found through the test that all the clozapine-nicotinic acid co-crystals prepared by the scheme of the application can achieve similar solubility effects and have good solubility.

Claims

1. A co-crystal of clozapine-nicotinic acid, characterized by, X-ray diffraction spectrum using Cu-Kα radiation has characteristic peaks at 4.47±0.2°, 8.78±0.2°, 8.99±0.2°, 13.30±0.2°, 13.52±0.2°, 18.08±0.2°, 19.33±0.2°, 48.49±0.2°.

2. The chlorzoxazone-nicotinic acid co-crystal of claim 1, wherein, X-ray diffraction spectrum using Cu-Kα radiation has characteristic peaks at 4.47±0.2°, 8.78±0.2°, 8.99±0.2°, 13.30±0.2°, 13.52±0.2°, 14.53±0.2°, 15.22±0.2°, 18.08±0.2°, 19.33±0.2°, 20.98±0.2°, 22.66±0.2°, 23.96±0.2°, 24.44±0.2°, 25.57±0.2°, 27.28±0.2°, 29.59±0.2°, 30.06±0.2°, 37.67±0.2°, 43.81±0.2°, 48.49±0.2°.

3. The chlorzoxazone-nicotinic acid co-crystal of claim 1, wherein, X-ray powder diffraction spectrum using Cu-Kα radiation has characteristic peaks as shown in Figure 1.

4. The chlorzoxazone-nicotinic acid co-crystal of claim 1, wherein, The crystallographic parameters of the chlorzoxazone-nicotinic acid co-crystal are: tetragonal crystal system, chiral space group Pna21; cell parameters are: a = 12.5626(2) Å, b = 5.38860(10) Å, c = 39.1343(6) Å, a = 90.00°, β = 90.00°, γ = 90.00°, cell volume V = 2649.19(8) Å 3 .

5. A process for the preparation of cloxazone-nicotinic acid co-crystal according to any one of claims 1 to 4, characterized in that, The specific preparation steps include: chlorzoxazone and nicotinic acid are dissolved in an organic solvent A, heated and dissolved, the solution is clear, then cooled to crystallize, filtered and dried to obtain chlorzoxazone-nicotinic acid co-crystal; The organic solvent A is selected from one or a mixture of more than two of acetone, methanol, isopropanol and acetonitrile; the molar ratio of chlorzoxazone to nicotinic acid is 1:0.90-1.20; the temperature of heating and dissolving is 40-55°C; the temperature of cooling and crystallizing is 0-30°C.

6. The process for preparing cloxazone-nicotinic acid co-crystal as claimed in claim 5 wherein, The organic solvent A is selected from one or both of methanol and acetone.

7. The process for preparing cloxazone-nicotinic acid co-crystal as claimed in claim 5 wherein, The molar ratio of chlorzoxazone to nicotinic acid is 1:0.95-1.

1.

8. The process for preparing cloxazone-nicotinic acid co-crystal as claimed in claim 5, wherein, The mass-volume ratio of chlorzoxazone to organic solvent A is 10-25:1, wherein the mass is in mg and the volume is in mL.

9. A pharmaceutical composition comprising the chlorzoxazone-nicotinic acid co-crystal of any one of claims 1-4 and containing other active ingredients and / or formulation-acceptable auxiliary components that can be used in combination.

10. Use of the chlorzoxazone-nicotinic acid co-crystal of any one of claims 1-4 as an active ingredient for preparing an analgesic drug.

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