CN114573523A - Chlorzoxazone-2-indolecarboxylic acid eutectic crystal - Google Patents

Abstract

The invention belongs to the technical field of crystal drug molecules, and specifically provides a chlorzoxazone-2-indolecarboxylic acid co-crystal. The chlorzoxazone-2-indolecarboxylic acid co-crystal prepared by the present invention uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ is 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° have characteristic peaks. The method for preparing the chlorzoxazone-2-indolecarboxylic acid co-crystal provided by the invention is easy to operate, and the prepared crystal has high purity, good chemical stability in solid state, and good solubility. The preparation process of the invention is simple and has good industrial application prospect.

Description

A kind of chlorzoxazone-2-indolecarboxylic acid co-crystal

technical field

The invention relates to the technical field of crystal drug molecules, in particular to the technical field of chlorzoxazone crystal forms, in particular to a chlorzoxazone-2-indolecarboxylic acid co-crystal, a preparation method and application thereof.

Background technique

Drug co-crystals refer to crystals formed by the combination of active pharmaceutical ingredients and other substances in a certain stoichiometric ratio under the action of hydrogen bonds or other non-covalent bonds. The molecular network connection based on hydrogen bonding is the basis for the formation of co-crystals. The combination of co-crystals is in a neutral state and relies on non-ionic bonds. When the active ingredient of the drug is a neutral molecule, the drug cannot be improved by preparing polymorphic, amorphous, or solvated compounds and salts to improve drug properties. , the eutectic is a very good choice. In many cases, drug co-crystals not only do not destroy the activity of drugs, but also improve the physical and chemical properties of drugs such as melting point, solubility, stability, dissolution rate, and bioavailability.

Chlorzoxazone, chemical name: 5-chloro-2-benzoxazolinone, English name: 5-chloro-2-benzoxazolinone. CAS number: 95-25-0, its structural formula is as follows:

Chlorzoxazone is a powerful oral muscle relaxant, developed by McNeil Company in the United States and launched in the mid-1960s. It is clinically used for low back pain, neuralgia, rheumatoid arthritis, acute and chronic soft tissue ( Muscle, ligament) sprain, contusion, muscle soreness after exercise, muscle spasm and chronic fasciitis caused by central neuropathy, the total effective rate is as high as 98.59%. In addition, it has a certain curative effect on muscle spasm caused by central neuropathy, chronic fasciitis, and mental retardation in children. It is one of the most widely used drugs in clinical practice.

The marketed chlorzoxazone generally forms a compound preparation with acetaminophen, and the compounding process is relatively complicated, and even some patients are allergic to acetaminophen. In view of the above deficiencies, the present invention provides the form of chlorzoxazone-2-indolecarboxylic acid co-crystal, so that the medicinal value of chlorzoxazone can be exerted more efficiently.

SUMMARY OF THE INVENTION

The invention provides a simple and easy-to-operate method for preparing high-purity chlorzoxazone-2-indolecarboxylic acid co-crystal form, which provides a better basis for the application of chlorzoxazone in drug synergistic therapy, thereby improving the Efficiently exert the medicinal value of chlorzoxazone.

An object of the present invention is to provide a chlorzoxazone-2-indolecarboxylic acid co-crystal;

The specific technical content is as follows:

A chlorzoxazone-2-indolecarboxylic acid co-crystal, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ is 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° have characteristic peaks.

Preferably, the chlorzoxazone-2-indolecarboxylic acid co-crystal, using Cu-Kα radiation, has an X-ray diffraction pattern expressed in 2θ 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°, There is a characteristic peak at 40.12±0.2°.

Preferably, the chlorzoxazone-2-indolecarboxylic acid co-crystal uses Cu-Kα radiation, and its characteristic peaks conform to the X-ray powder diffraction patterns and detection data shown in Figure 1 and Table 2.

Preferably, the chlorzoxazone-2-indolecarboxylic acid co-crystal has an endothermic peak detected by differential scanning thermal analysis (DSC), the temperature range is 156.76-193.43°C, and the peak of the endothermic peak is 183.88°C , corresponding to the decomposition endothermic peak of chlorzoxazone-2-indolecarboxylic acid.

A second aspect of the present invention provides a method for preparing the chlorzoxazone-2-indolecarboxylic acid co-crystal, the method comprising the following steps:

Chlorzoxazone and 2-indolecarboxylic acid are dissolved in organic solvent A, heated to dissolve, after the solution is clarified, cooled for crystallization, filtered and dried to obtain a co-crystal of chlorzoxazone-2-indolecarboxylic acid.

The organic solvent A is selected from one of methanol, ethanol, acetone, and isopropanol or a mixed solvent of at least two or more.

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

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

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

The temperature of the dissolving heating is 40-55°C.

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

The crystallization time is 4 to 6 hours.

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

Preferably, the preparation method comprises the following steps:

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

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

A third aspect of the present invention provides a pharmaceutical composition, comprising the chlorzoxazone-2-indolecarboxylic acid co-crystal prepared above, and containing other active ingredients and/or pharmaceutically acceptable adjuvant components that can be used in combination .

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

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

The fourth aspect of the present application provides the use of a chlorzoxazone-2-indolecarboxylic acid co-crystal as an active ingredient in preparing an analgesic.

Confirmation of crystal structure

The X-ray crystallographic data were collected on Rigaku XtaLAB Synergy model instrument, the test temperature was 293(2) K, irradiated with CuKa, and the data were collected by ω scanning and Lp correction was performed. The structure was analyzed by direct method, all non-hydrogen atoms were found by difference Fourier method, and all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least square method.

α＝85.228(3)°，β＝87.044(3)°，γ＝67.178(3)°，晶胞体积

分子式：C₁₆H₁₁C_lN₂O₄，分子量：330.72。本发明的氯唑沙宗-2-吲哚甲酸共晶的结构解析ORTEP图表明，该晶体存在一分子氯唑沙宗，一分子2-吲哚甲酸，如附图3所示。本发明的氯唑沙宗-2-吲哚甲酸共晶的堆积图，如附图2所示。Test and analyze the chlorzoxazone-2-indolecarboxylic acid co-crystal prepared by the present invention, its crystallographic parameters are: triclinic crystal system, chiral space group is P-1; unit cell parameters are:

α=85.228(3)°, β=87.044(3)°, γ=67.178(3)°, unit cell volume

Molecular formula: C ₁₆ H ₁₁ C _l N ₂ O ₄ , molecular weight: 330.72. The structure analysis ORTEP diagram of the chlorzoxazone-2-indolecarboxylic acid co-crystal of the present invention shows that there are one molecule of chlorzoxazone and one molecule of 2-indolecarboxylic acid in the crystal, as shown in FIG. 3 . The stacking diagram of the chlorzoxazone-2-indolecarboxylic acid co-crystal of the present invention is shown in accompanying drawing 2 .

Table 1 Main crystallographic data of chlorzoxazone-2-indolecarboxylic acid co-crystal

The X-ray powder diffraction test instrument and test conditions in the chlorzoxazone-2-indolecarboxylic acid co-crystal test of the present invention are: PANalytical Empyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction optical path: PIXCEL, voltage 45KV, current 40mA, divergence slit 1/4°, anti-scatter slit 1°, Sora slit 0.04rad, counting time per step 0.5s, scanning range 3～50 °.

According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are shown in Figures 1 and 2.

Table 2 Main PXRD peaks of chlorzoxazone-2-indolecarboxylic acid co-crystal

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

TGA/DSC thermal analysis tester and test conditions in the present invention: TGA/DSC thermal analyzer: METTLER TOLEDOTGA/DSC3+; dynamic temperature section: 30-300°C; heating rate: 10°C/min; program gas N ₂ ; gas Flow rate: 50 mL/min; crucible: 40 μl of aluminum crucible.

The differential scanning calorimetry (DSC) results of the chlorzoxazone-2-indolecarboxylic acid co-crystal prepared by the method of the present invention are shown in Figure 4, and the chlorzoxazone-2-indolecarboxylic acid co-crystal is Differential scanning calorimetry (DSC) detected an endothermic peak with a temperature range of 156.76-193.43℃, and the peak of the endothermic peak was at 183.88℃, corresponding to the decomposition endothermic peak of chlorzoxazone-2-indolecarboxylic acid. Its thermogravimetric analysis (TGA) has only one weight loss step, which can correspond well with DSC. The chlorzoxazone-2-indolecarboxylic acid has the DSC/TGA spectrum shown in FIG. 4 .

The method for preparing the chlorzoxazone-2-indolecarboxylic acid co-crystal provided by the invention is easy to operate, and the prepared crystal has high purity, and the chlorzoxazone-2-indolecarboxylic acid co-crystal provided by the invention has better performance in solid state. chemical stability and good solubility.

Description of drawings

Figure 1: X-ray powder diffraction pattern of chlorzoxazone-2-indolecarboxylic acid co-crystal.

Figure 2: Packing diagram of chlorzoxazone-2-indolecarboxylic acid co-crystals.

Figure 3: ORTEP profile of chlorzoxazone-2-indolecarboxylic acid co-crystal.

Figure 4: Differential Scanning Calorimetry (DSC) graph of chlorzoxazone-2-indolecarboxylic acid co-crystal.

Detailed ways

The present invention will be further illustrated by the following examples. It should be understood correctly that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, under the premise of the method of the present invention, a simple improvement of the present invention is made. All belong to the protection scope of the present invention.

Example 1

100.0 mg of chlorzoxazone and 95.13 mg of 2-indolecarboxylic acid were added to 8 mL of methanol, heated to 50 °C with stirring to dissolve, refluxed for 1 hour, slowly cooled to 10 to 15 °C, and allowed to stand for crystallization under temperature control for 5 hours. Filtration, washing the filter cake with acetone, and vacuum drying at 55° C. for 10 h to obtain chlorzoxazone-2-indolecarboxylic acid with a yield of 97.81% and a purity of 99.98%.

Example 2

99.8mg of chlorzoxazone and 99.59mg of 2-indolecarboxylic acid were added to 15mL of ethanol, heated to 45°C with stirring to dissolve, refluxed for 1 hour, slowly cooled to 5-10°C, and allowed to stand for crystallization under temperature control for 5 hours , filtered, the filter cake was washed with ethanol, and vacuum-dried at 45°C for 8 h to obtain chlorzoxazone-2-indolecarboxylic acid co-crystal with a yield of 97.27% and a purity of 99.97%.

Example 3

169.57mg of chlorzoxazone and 158.45mg of 2-indolecarboxylic acid were added to 18mL of mixed solvent (9mL of methanol and 9mL of acetone), heated to 52°C with stirring to dissolve, refluxed for 2 hours, slowly cooled to 15-20°C, The temperature was controlled to stand for crystallization for 4 hours, filtered, and the filter cake was washed with acetonitrile, and vacuum-dried at 65°C for 11 hours to obtain a co-crystal of chlorzoxazone-2-indolecarboxylic acid with a yield of 95.76% and a purity of 99.96%.

Example 4

110.5mg of chlorzoxazone and 125.70mg of 2-indolecarboxylic acid were added to 12mL of isopropanol, heated to 55°C with stirring to dissolve, refluxed for 1 hour, slowly cooled to 8-15°C, and allowed to stand for crystallization under temperature control. After 6 hours, filter, wash the filter cake with methanol, and vacuum dry at 60° C. for 9 hours to obtain chlorzoxazone-2-indolecarboxylic acid co-crystal with a yield of 95.43% and a purity of 99.95%.

Example 5

80.9mg of chlorzoxazone and 61.5mg of 2-indolecarboxylic acid were added to 4mL of acetone, heated to 35°C with stirring to dissolve, refluxed for 1 hour, slowly cooled to 0-5°C, and allowed to stand for crystallization under temperature control for 3 hours , filtered, the filter cake was washed with methanol, and vacuum-dried at 40° C. for 7 h to obtain a co-crystal of chlorzoxazone-2-indolecarboxylic acid with a yield of 78.19% and a purity of 99.92%.

Example 6

66.2mg of chlorzoxazone and 81.79mg of 2-indolecarboxylic acid were added to 21mL of mixed solvent (11mL of methanol and 10mL of ethanol), heated to 50°C, stirred and dissolved, refluxed for 2 hours, slowly cooled to 20～30°C, The temperature was controlled to stand for crystallization for 7 hours, filtered, and the filter cake was washed with acetonitrile, and vacuum-dried at 75°C for 14 hours to obtain a co-crystal of chlorzoxazone-2-indolecarboxylic acid with a yield of 91.42% and a purity of 99.90%.

Stability test

The chlorzoxazone-2-indolecarboxylic acid co-crystals prepared in Examples 1 to 6 of the present invention were subjected to an accelerated test, and placed in a constant temperature and humidity incubator at 40±2° C.; , At the end of 1, 2, 3 and 6 months, take samples to check the appearance, related substances, content and loss on drying. The results are shown in Table 3.

Table 3 Accelerated test results of chlorzoxazone-2-indolecarboxylic acid co-crystals

Accelerated tests show that the chlorzoxazone-2-indolecarboxylic acid co-crystal of the present invention has relatively stable physical and chemical properties, no obvious decrease in purity, and less increase in impurity content.

Solubility test

For the specific solubility test, refer to the Chinese Pharmacopoeia 2015 and accurately weigh the chlorzoxazone-2-indolecarboxylic acid co-crystals of 1 to 6 in the embodiment in excess, place them in a small cillin bottle, and add DMSO and pH 1.0 hydrochloric acid solution respectively. , water, prepare a saturated solution of chlorzoxazone, shake well to dissolve, and filter. According to UV-Vis spectrophotometry (general rule 0401), measure the absorbance at the wavelength of 270nm to calculate its solubility. The test results are shown in Table 4.

Table 4 Solubility of chlorzoxazone-2-indolecarboxylic acid co-crystals

It is known through experiments that all chlorzoxazone-2-indolecarboxylic acid co-crystals prepared by the scheme of the present invention can achieve similar solubility effects and have better solubility.

Claims (10)

1. a co-crystal of chlorzoxazone-2-indolecarboxylic acid, characterized in that, using Cu-Kα radiation, the X-ray diffraction pattern represented by 2θ is 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° have characteristic peaks. 2. chlorzoxazone-2-indolecarboxylic acid co-crystal as claimed in claim 1, is characterized in that, using Cu-Kα radiation, the X-ray diffraction pattern represented by 2θ is at 5.82±0.2°, 12.85±0.2° degrees °, 29.60±0.2°, and characteristic peaks at 40.12±0.2°. 3. chlorzoxazone-2-indolecarboxylic acid co-crystal as claimed in claim 1, is characterized in that, uses Cu-Kα radiation, its characteristic peak conforms to the X-ray powder diffraction pattern shown in Fig. 1 and table 2 and Test data. 4. chlorzoxazone-2-indolecarboxylic acid co-crystal as claimed in claim 1, is characterized in that, the crystallographic parameter of described chlorzoxazone-2-indolecarboxylic acid co-crystal is: triclinic crystal system, the chiral space group is P-1; the unit cell parameters are:

α=85.228(3)°, β=87.044(3)°, γ=67.178(3)°, unit cell volume

5. a preparation method of the chlorzoxazone-2-indolecarboxylic acid co-crystal described in any one of claims 1～4, the method comprises the following steps: Chlorzoxazone and 2-indolecarboxylic acid are dissolved in organic solvent A, heated to dissolve, after the solution is clarified, cooled for crystallization, filtered and dried to obtain a co-crystal of chlorzoxazone-2-indolecarboxylic acid. 6. the preparation method of chlorzoxazone-2-indolecarboxylic acid co-crystal as claimed in claim 5, is characterized in that, described organic solvent A is selected from one of methanol, ethanol, acetone, isopropanol or At least two or more mixed solvents; preferably, the organic solvent A is selected from one or both of methanol and ethanol. 7. the preparation method of chlorzoxazone-2-indolecarboxylic acid co-crystal as claimed in claim 5, is characterized in that, the mol ratio of described chlorzoxazone and 2-indolecarboxylic acid is 1:0.87～1.22 ; Preferably, the molar ratio of chlorzoxazone and 2-indolecarboxylic acid is 1:0.92～1.11. 8. the preparation method of chlorzoxazone-2-indolecarboxylic acid co-crystal as claimed in claim 5, is characterized in that, in described system, the mass volume ratio of 2-indolecarboxylic acid and organic solvent A is 5～13 : 1, where the mass is in mg and the volume is in mL. 9. A pharmaceutical composition, characterized in that it comprises the co-crystal of chlorzoxazone-2-indolecarboxylic acid according to any one of claims 1 to 4 and contains other active ingredients and/or preparations that can be used in combination Scientifically acceptable excipient components. 10. The application of the chlorzoxazone-2-indolecarboxylic acid co-crystal described in claims 1 to 4 as an active ingredient for the preparation of analgesics.

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