CN114573523A - Chlorzoxazone-2-indolecarboxylic acid eutectic crystal - Google Patents
Chlorzoxazone-2-indolecarboxylic acid eutectic crystal Download PDFInfo
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- TZFWDZFKRBELIQ-UHFFFAOYSA-N chlorzoxazone Chemical compound ClC1=CC=C2OC(O)=NC2=C1 TZFWDZFKRBELIQ-UHFFFAOYSA-N 0.000 claims description 26
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention belongs to the technical field of crystal form drug molecules, and particularly provides a chlorzoxazone-2-indolecarboxylic acid eutectic crystal. The chlorzoxazone-2-indolecarboxylic acid eutectic crystal prepared by the invention uses Cu-Kalpha radiation, and has characteristic peaks at 5.82 +/-0.2 degrees, 12.85 +/-0.2 degrees, 14.37 +/-0.2 degrees, 17.87 +/-0.2 degrees, 26.98 +/-0.2 degrees, 27.80 +/-0.2 degrees in an X-ray diffraction spectrogram expressed by 2 theta. The method for preparing the chlorzoxazone-2-indolecarboxylic acid eutectic is simple and convenient to operate, and the prepared crystal has high purity, better chemical stability in a solid state and better solubility. The invention has simple preparation process and better industrial application prospect.
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to the technical field of crystal forms of chlorzoxazone, and specifically relates to a chlorzoxazone-2-indolecarboxylic acid eutectic, and a preparation method and application thereof.
Background
The pharmaceutical co-crystal is a crystal formed by combining a pharmaceutical active ingredient with other substances according to a certain stoichiometric ratio under the action of hydrogen bonds or other non-covalent bonds. The hydrogen bond based molecular network bonding is the basis for the formation of the co-crystals. The combination of co-crystals is in a neutral state, relying on non-ionic bonding, which is a good choice when the active ingredient of the drug is a neutral molecule, the drug cannot be prepared in polymorphic form, amorphous form, or in solvent compounds and salts to improve the properties of the drug. The pharmaceutical co-crystal does not destroy the activity of the medicament in many times, and can improve the physical and chemical properties of the medicament, such as melting point, solubility, stability, dissolution rate, bioavailability and the like.
Chlorzoxazone (Chlorzoxazone), chemical name: 5-chloro-2-benzoxazolinone, english name: 5-chloro-2-benzoxazolinone. CAS number: 95-25-0, the structural formula is shown as follows:
chlorzoxazone is an oral potent muscle relaxant, developed by McNeil company in America, and marketed in the mid-sixties of the twentieth century, and is clinically used for lumbago, neuralgia, rheumatoid arthritis, acute and chronic soft tissue (muscle and ligament) sprain, contusion, post-exercise muscle soreness, and muscle spasm and chronic fasciitis caused by central neuropathy, and the total effective rate is as high as 98.59%. In addition, the Chinese medicinal composition has certain curative effect on muscle spasm caused by central neuropathy, chronic fasciitis and children's mental maldevelopment, and is one of the most widely used medicaments in clinical application at present.
The chlorzoxazone generally forms a compound preparation with the acetaminophen on the market, the compound process is complex, and even part of patients have allergy to the acetaminophen. In view of the defects, the invention provides a chlorzoxazone-2-indolecarboxylic acid eutectic form, thereby more efficiently exerting the medicinal value of chlorzoxazone.
Disclosure of Invention
The invention provides a simple and easy-to-operate method for preparing a high-purity co-crystal form of chlorzoxazone-2-indolecarboxylic acid, which provides a better basis for the application of chlorzoxazone in the aspect of drug co-therapy, thereby more efficiently exerting the medicinal value of chlorzoxazone.
One object of the present invention is to provide a co-crystal of chlorzoxazone-2-indolecarboxylic acid;
the specific technical content is as follows:
a chlorzoxazone-2-indolecarboxylic acid eutectic crystal uses Cu-Kalpha radiation, and has characteristic peaks at 5.82 +/-0.2 degrees, 12.85 +/-0.2 degrees, 14.37 +/-0.2 degrees, 17.87 +/-0.2 degrees, 26.98 +/-0.2 degrees, 27.80 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta.
Preferably, the chlorazoxazone-2-indolecarboxylic acid eutectic crystal 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 ° in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Ka radiation.
Preferably, the chlorzoxazone-2-indolecarboxylic acid eutectic is irradiated by Cu-Ka, and the characteristic peaks of the chlorzoxazone-2-indolecarboxylic acid eutectic accord with an X-ray powder diffraction spectrum and detection data shown in figure 1 and table 2.
Preferably, the chlorzoxazone-2-indolecarboxylic acid eutectic crystal has an endothermic peak detected by differential scanning thermal analysis (DSC), the temperature range is 156.76-193.43 ℃, the peak value of the endothermic peak is 183.88 ℃, and the endothermic peak is corresponding to the decomposition endothermic peak of chlorzoxazone-2-indolecarboxylic acid.
In a second aspect, the invention provides a method for preparing the co-crystal of chlorzoxazone-2-indolecarboxylic acid, which comprises the following steps:
dissolving the chlorzoxazone and the 2-indolecarboxylic acid in an organic solvent A, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain the chlorzoxazone-2-indolecarboxylic acid cocrystal.
The organic solvent A is selected from one or a mixed solvent of at least two of methanol, ethanol, acetone and isopropanol.
Preferably, the organic solvent A is one or two of methanol and ethanol.
The mol ratio of the chlorzoxazone to the 2-indolecarboxylic acid is 1: 0.87-1.22; preferably, the molar ratio of the chlorzoxazone to the 2-indolecarboxylic acid is 1: 0.92-1.11.
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.
The temperature for dissolving and heating is 40-55 ℃.
The cooling crystallization temperature is 0-30 ℃, and preferably, the cooling crystallization temperature is 5-20 ℃.
The crystallization time is 4-6 hours.
The drying temperature is 45-70 ℃, and the drying time is 8-12 hours.
Preferably, the preparation method comprises the following steps:
dissolving chlorzoxazone and 2-indolecarboxylic acid in an organic solvent A by heating at 40-55 ℃, stirring and refluxing for reaction for 1-2 hours, cooling to 5-20 ℃, crystallizing for 4-6 hours, filtering, washing a filter cake, and drying to obtain the chlorzoxazone-2-indolecarboxylic acid eutectic crystal.
The solvent for washing the filter cake is selected from one of acetone, methanol, ethanol and acetonitrile.
In a third aspect, the invention provides a pharmaceutical composition comprising the co-crystal of chlorzoxazone-2-indolecarboxylic acid prepared above, and other active ingredients and/or pharmaceutically acceptable auxiliary ingredients which can be used in combination.
Preferably, the other components include other active ingredients, excipients, fillers, etc. that may be used in combination.
Preferably, the pharmaceutical composition can be prepared into spray, tablets, capsules, powder injections, liquid injections and the like by using standard and conventional technologies.
In a fourth aspect, the application provides an application of a chlorzoxazone-2-indolecarboxylic acid eutectic as an active ingredient in preparation of analgesics.
Confirmation of the Crystal Structure
X-ray crystal data were collected on a jtaab Synergy model instrument, japan, testing temperature 293(2) K, irradiating with CuKa, collecting data in an omega scan fashion and Lp correction. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The crystallography parameters of the chlorzoxazone-2-indolecarboxylic acid eutectic prepared by the invention are tested and analyzed as follows: triclinic system, chiral space group is P-1; the unit cell parameters are:
a is 85.228(3) °, β is 87.044(3) °, γ is 67.178(3) °, unit cell volume
The molecular formula is as follows: c16H11ClN2O4Molecular weight: 330.72. the structure analysis ORTEP chart of the chlorzoxazone-2-indolecarboxylic acid eutectic of the invention shows that one molecule of chlorzoxazone and one molecule of 2-indolecarboxylic acid exist in the crystal, as shown in figure 3. The stacking diagram of the chlorzoxazone-2-indolecarboxylic acid eutectic crystal is shown in the attached figure 2.
TABLE 1 Main crystallographic data of Co-crystals of chlorzoxazone-2-indolecarboxylic acid
The X-ray powder diffraction test instrument and test conditions in the chlorzoxazone-2-indolecarboxylic acid eutectic crystal test are as follows: PANALYTIC EMPyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction path: PIXCEL, voltage 45KV, current 40mA, divergence slit 1/4 degrees, anti-divergence slit 1 degree, cable-stayed slit 0.04rad degree, counting time of each step 0.5s, and scanning range 3-50 degrees.
According to the crystallography data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in the attached figures 1 and 2 in detail.
TABLE 2 Clozazone-2-indolecarboxylic acid cocrystals dominant PXRD peaks
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns as described above.
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3 +; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; segment gas N2(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.
The results of a Differential Scanning Calorimetry (DSC) curve of the chlorzoxazone-2-indolecarboxylic acid eutectic prepared by the method are shown in figure 4, the chlorzoxazone-2-indolecarboxylic acid eutectic is detected to have an endothermic peak through Differential Scanning Calorimetry (DSC), the temperature range is 156.76-193.43 ℃, the peak value of the endothermic peak is 183.88 ℃, and the endothermic peak is correspondingly the decomposition endothermic peak of chlorzoxazone-2-indolecarboxylic acid. The thermogravimetric analysis (TGA) only has one weight loss step and can well correspond to DSC. The chlorzoxazone-2-indolecarboxylic acid exists in a DSC/TGA pattern as shown in figure 4.
The method for preparing the chlorzoxazone-2-indolecarboxylic acid eutectic is simple and convenient to operate, the prepared crystal is high in purity, and the chlorzoxazone-2-indolecarboxylic acid eutectic provided by the invention has good chemical stability and good solubility in a solid state.
Drawings
FIG. 1: x-ray powder diffraction pattern of the chlorzoxazone-2-indolecarboxylic acid co-crystal.
FIG. 2: stacking diagram of the chlorzoxazone-2-indolecarboxylic acid eutectic.
FIG. 3: ORTEP diagram of eutectic of chlorzoxazone-2-indolecarboxylic acid.
FIG. 4: a Differential Scanning Calorimetry (DSC) curve of the eutectic of chlorzoxazone-2-indolecarboxylic acid.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
Adding 100.0mg of chlorzoxazone and 95.13mg of 2-indolecarboxylic acid into 8mL of methanol, heating to 50 ℃, stirring for dissolving, carrying out reflux reaction for 1 hour, slowly cooling to 10-15 ℃, standing at a controlled temperature for 5 hours for crystallization, filtering, washing a filter cake with acetone, and carrying out vacuum drying at 55 ℃ for 10 hours to obtain the chlorzoxazone-2-indolecarboxylic acid with the yield of 97.81% and the purity of 99.98%.
Example 2
Adding 99.8mg of chlorzoxazone and 99.59mg of 2-indolecarboxylic acid into 15mL of ethanol, heating to 45 ℃, stirring for dissolving, carrying out reflux reaction for 1 hour, slowly cooling to 5-10 ℃, standing at a controlled temperature for crystallization for 5 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 45 ℃ for 8 hours to obtain the chlorzoxazone-2-indolecarboxylic acid eutectic crystal with the yield of 97.27% and the purity of 99.97%.
Example 3
169.57mg of chlorzoxazone and 158.45mg of 2-indolecarboxylic acid are added into 18mL of mixed solvent (9mL of methanol and 9mL of acetone), heated to 52 ℃, stirred and dissolved, refluxed for 2 hours, slowly cooled to 15-20 ℃, kept at a controlled temperature, kept stand for crystallization for 4 hours, filtered, washed with acetonitrile to obtain a filter cake, and dried in vacuum at 65 ℃ for 11 hours to obtain the chlorzoxazone-2-indolecarboxylic acid eutectic crystal, wherein the yield is 95.76%, and the purity is 99.96%.
Example 4
Adding 110.5mg of chlorzoxazone and 125.70mg of 2-indolecarboxylic acid into 12mL of isopropanol, heating to 55 ℃, stirring for dissolving, carrying out reflux reaction for 1 hour, slowly cooling to 8-15 ℃, standing at controlled temperature for crystallization for 6 hours, filtering, washing a filter cake with methanol, and carrying out vacuum drying at 60 ℃ for 9 hours to obtain the chlorzoxazone-2-indolecarboxylic acid eutectic with yield of 95.43% and purity of 99.95%.
Example 5
Adding 80.9mg of chlorzoxazone and 61.5mg of 2-indolecarboxylic acid into 4mL of acetone, heating to 35 ℃, stirring for dissolving, carrying out reflux reaction for 1 hour, slowly cooling to 0-5 ℃, standing at controlled temperature for crystallization for 3 hours, filtering, washing a filter cake with methanol, and carrying out vacuum drying at 40 ℃ for 7 hours to obtain the chlorzoxazone-2-indolecarboxylic acid eutectic crystal, wherein the yield is 78.19% and the purity is 99.92%.
Example 6
66.2mg of chlorzoxazone and 81.79mg of 2-indolecarboxylic acid are added into 21mL of mixed solvent (11mL of methanol and 10mL of ethanol), heated to 50 ℃, stirred and dissolved, refluxed for 2 hours, slowly cooled to 20-30 ℃, kept at a controlled temperature, kept stand for crystallization for 7 hours, filtered, washed by acetonitrile to obtain a filter cake, and dried in vacuum for 14 hours at 75 ℃ to obtain the chlorzoxazone-2-indolecarboxylic acid eutectic crystal, wherein the yield is 91.42%, and the purity is 99.90%.
Stability test
Carrying out an accelerated test on the chlorzoxazone-2-indolecarboxylic acid eutectic crystal prepared in the embodiment 1-6 of the invention, and placing the eutectic crystal at 40 +/-2 ℃; and (3) sampling and inspecting the appearance, related substances, content and drying weight loss at the end of 0, 1, 2, 3 and 6 months in a constant-temperature and constant-humidity incubator with RH75 +/-5 percent for 6 months. The results are shown in Table 3.
TABLE 3 accelerated test results of Co-crystals of chlorzoxazone-2-indolecarboxylic acid
Accelerated tests show that the chlorzoxazone-2-indolecarboxylic acid eutectic crystal has stable physical and chemical properties, the purity is not obviously reduced, and the impurity content is slightly increased.
Solubility test
In the specific solubility test, referring to Chinese pharmacopoeia 2015, the chlorzoxazone-2-indolecarboxylic acid eutectic excess amount of 1-6 in the embodiment is respectively and precisely weighed, placed in a vial, and added with DMSO, hydrochloric acid solution with pH of 1.0 and water respectively to prepare a chlorzoxazone saturated solution, shaken up to dissolve and filtered. The solubility was calculated by measuring the absorbance at a wavelength of 270nm by UV-visible spectrophotometry (general rule 0401). The test results are shown in Table 4.
TABLE 4 solubility of Co-crystals of chlorzoxazone-2-indolecarboxylic acid
Experiments show that all the chlorzoxazone-2-indolecarboxylic acid eutectic crystals prepared by the scheme of the invention can achieve similar solubility effect and have better solubility.
Claims (10)
1. The chlorzoxazone-2-indolecarboxylic acid eutectic crystal is characterized in that an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation has characteristic peaks at 5.82 +/-0.2 degrees, 12.85 +/-0.2 degrees, 14.37 +/-0.2 degrees, 17.87 +/-0.2 degrees, 26.98 +/-0.2 degrees and 27.80 +/-0.2 degrees.
2. The co-crystal of chlorzoxazone-2-indolecarboxylic acid of claim 1, characterised by an X-ray diffraction pattern using Cu-ka radiation expressed in terms of 2 Θ 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 °.
3. The co-crystal of chlorzoxazone-2-indolecarboxylic acid of claim 1 where the characteristic peaks, using Cu-ka radiation, follow the X-ray powder diffraction pattern and detection data shown in figure 1 and table 2.
4. The co-crystal of chlorzoxazone-2-indolecarboxylic acid of claim 1 where the crystallographic parameters of the co-crystal of chlorzoxazone-2-indolecarboxylic acid are: triclinic system, chiral space group is P-1; the unit cell parameters are:
a is 85.228(3) °, β is 87.044(3) °, γ is 67.178(3) °, unit cell volume
5. A preparation method of the chlorzoxazone-2-indolecarboxylic acid eutectic crystal of any one of claims 1-4, which comprises the following steps:
dissolving the chlorzoxazone and the 2-indolecarboxylic acid in an organic solvent A, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain the chlorzoxazone-2-indolecarboxylic acid cocrystal.
6. The method for preparing the co-crystal of chlorzoxazone-2-indolecarboxylic acid according to claim 5, wherein the organic solvent A is selected from one or a mixture of at least two of methanol, ethanol, acetone and isopropanol; preferably, the organic solvent A is one or two of methanol and ethanol.
7. The preparation method of the chlorzoxazone-2-indolecarboxylic acid eutectic crystal of claim 5, wherein the molar ratio of chlorzoxazone to 2-indolecarboxylic acid is 1: 0.87-1.22; preferably, the molar ratio of the chlorzoxazone to the 2-indolecarboxylic acid is 1: 0.92-1.11.
8. The preparation method of the chlorzoxazone-2-indolecarboxylic acid eutectic crystal of claim 5, wherein the mass-to-volume ratio of 2-indolecarboxylic acid to organic solvent A in the system is 5-13: 1, wherein the mass is in mg and the volume is in mL.
9. A pharmaceutical composition, which comprises the co-crystal of chlorzoxazone-2-indolecarboxylic acid according to any one of claims 1-4, and further comprises other active ingredients and/or pharmaceutically acceptable auxiliary components that can be used in combination.
10. Use of the co-crystal of chlorzoxazone-2-indolecarboxylic acid as claimed in claims 1-4 as an active ingredient for the preparation of analgesics.
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