CN114276350A - Ketorolac and phenazine eutectic crystal and preparation method thereof - Google Patents
Ketorolac and phenazine eutectic crystal and preparation method thereof Download PDFInfo
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- CN114276350A CN114276350A CN202011054911.4A CN202011054911A CN114276350A CN 114276350 A CN114276350 A CN 114276350A CN 202011054911 A CN202011054911 A CN 202011054911A CN 114276350 A CN114276350 A CN 114276350A
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Abstract
The invention belongs to the technical field of pharmaceutical co-crystals, and provides a ketorolac and phenazine co-crystal and a preparation method thereof, wherein the prepared ketorolac and phenazine co-crystal uses Cu-Kalpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 6.2 +/-0.2 degrees, 6.6 +/-0.2 degrees, 8.2 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.5 +/-0.2 degrees and 16.4 +/-0.2 degrees; the prepared ketorolac and phenazine eutectic has the advantages of yield of more than 91 percent, purity of more than 99.80 percent, simple preparation method, easy control of crystallization process, and capability of obviously improving the stability and solubility of the ketorolac, and compared with the existing crystal form of the ketorolac or a ketorolac standard product, the prepared ketorolac and phenazine eutectic has better stability and higher solubility in different dissolving media.
Description
Technical Field
The invention relates to the technical field of pharmaceutical co-crystals, in particular to a ketorolac and phenazine co-crystal and a preparation method and application thereof.
Background
Ketorolac (Ketorolac) is a potent analgesic, moderately anti-inflammatory non-steroidal anti-inflammatory drug used to treat moderate to severe pain, including post-operative and post-partum pain, as well as visceral pain associated with cancer, with superior efficacy. Molecular weight 255.27, chemical name: (+/-) -5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid, of the formula:
ketorolac belongs to a polycrystalline compound, different ketorolac crystal forms have different stability, physical properties, solubility and the like, and the properties can directly influence the stability and bioavailability of bulk drugs and preparations. At present, more reports are related to ketorolac, but the reports on the crystal structure of ketorolac are less. The Crystal form of Ketorolac has polymorphism, and the article Crystal Forms of Ketorolac (Arch Pharm Res,2004,27,357-360) discloses Crystal form characterization data and preparation methods of Crystal Forms I, II, III and IV of Ketorolac, and the solubility and stability of the existing Crystal Forms need to be further improved. The invention provides a co-crystal of ketorolac and phenazine, which can obviously improve the solubility of ketorolac and provide a basis for ketorolac in the aspect of drug treatment, thereby better exerting the medicinal value of ketorolac.
Disclosure of Invention
The invention aims to provide a ketorolac and phenazine eutectic and a preparation method and application thereof. The ketorolac and phenazine eutectic crystal provided by the invention has the advantages of good stability, high solubility, simple and convenient preparation method and the like, meets the medicinal requirements, and is suitable for pharmaceutical research. The specific technical scheme of the invention is as follows:
according to the ketorolac and phenazine eutectic provided by the invention, Cu-Kalpha radiation is used, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 6.2 +/-0.2 degrees, 6.6 +/-0.2 degrees, 8.2 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.5 +/-0.2 degrees and 16.4 +/-0.2 degrees.
Preferably, the ketorolac and phenazine eutectic crystal uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.2 +/-0.2 degrees, 6.6 +/-0.2 degrees, 8.2 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.5 +/-0.2 degrees, 16.4 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.8 +/-0.2 degrees, 29.09 +/-0.2 degrees, 29.8 +/-0.2 degrees, 34.0 +/-0.2 degrees, 38.3 +/-0.2 degrees and 41.9 +/-0.2 degrees.
Preferably, the ketorolac and phenazine eutectic uses Cu-Ka radiation, and the characteristic peak of the eutectic accords with an X-ray powder diffraction pattern shown in figure 1.
In a second aspect of the present invention, a method for preparing a co-crystal of ketorolac and phenazine is provided, which includes the following steps: adding ketorolac and phenazine into an organic solvent at room temperature, performing ultrasonic treatment by using an ultrasonic instrument until the ketorolac and the phenazine are completely dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at room temperature for natural volatilization, filtering, and drying in an oven to obtain the co-crystal of the ketorolac and the phenazine.
Preferably, the molar ratio of ketorolac to phenazine is 1: 1-2; more preferably, the molar ratio of ketorolac to phenazine is 1: 1.1 to 1.3.
Preferably, the mass volume ratio of the ketorolac to the organic solvent is 5-30: 1, wherein mass is in mg and volume is in mL; more preferably, the mass volume ratio of the ketorolac to the organic solvent is 5-15: 1, wherein the mass is in mg and the volume is in mL.
Preferably, the organic solvent is one or a combination of several of methanol, ethanol, acetone, acetonitrile and tetrahydrofuran; more preferably, the organic solvent is one or two of methanol, ethanol and acetone.
Preferably, the standing at room temperature is carried out for 3-5 days for natural volatilization; the temperature of the oven is 40-60 ℃; and the drying time of the oven is 2-5 h.
A third aspect of the present application provides a pharmaceutical composition comprising a co-crystal of ketorolac and phenazine prepared as described above, and further active ingredients and/or pharmaceutically acceptable auxiliary components thereof, which may be used in combination.
Confirmation of the Crystal Structure
The X-ray powder diffraction test instrument and test conditions in the ketorolac and phenazine eutectic test prepared by the invention are as follows: PANALYTIC EMPyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction path: PLXCEL, 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.
The characteristic peaks in the X-ray diffraction pattern (Cu-Ka) corresponding to the ketorolac and phenazine eutectic are detailed in figure 1 and table 1.
TABLE 1 Kellorolac and phenazine cocrystals dominant PXRD peaks
The ketorolac and phenazine eutectic provided by the invention is subjected to X-ray single crystal diffraction test analysis. The related X-ray single crystal diffraction instrument and test conditions are as follows: chemistry xtlab Synergy X-ray single crystal diffractometer, test temperature 293(2) K, use CuKa radiation, collect data in omega scan mode and perform 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.
Crystallographic data obtained by testing and analyzing the ketorolac and phenazine eutectic prepared by the invention (table 2) are as follows: triclinic, space group P-1, cell parameters:
a is 79.655(2) °, β is 84.540(2) °, γ is 81.129(2) °, unit cell volume
The ORTEP diagram of the ketorolac and phenazine co-crystal of the present invention shows that two molecules of ketorolac bind to one molecule of phenazine, as shown in fig. 2, and the unit cell stacking diagram is shown in fig. 3.
TABLE 2 ketorolac and phenazine cocrystals data for primary crystallography
The TGA/DSC thermal analysis test conditions of the ketorolac and phenazine eutectic disclosed by the invention are as follows: METTLETOLEDO TGA/DSC3+ thermal analyzer, dynamic temperature profile: 30-300 ℃, heating rate: 10 ℃/min, program segment gas N2Flow rate: 50ml/min, crucible: aluminum crucible 40. mu.L, as shown in FIG. 4.
The TGA/DSC test result of the ketorolac and phenazine eutectic prepared by the invention is shown in figure 4, the DSC graph has an endothermic peak within the range of 165.72-173.24 ℃, and the peak value corresponding to the endothermic peak is 169.56 ℃; the thermogravimetric analysis (TGA) only has one weight loss step, which shows that the ketorolac and phenazine eutectic has no solvent and stable structure.
The invention has the beneficial effects that:
1. the ketorolac and phenazine eutectic prepared by the invention can obviously improve the stability and solubility of ketorolac, has good stability compared with the existing crystal form of ketorolac or a ketorolac standard product, and has higher solubility in different dissolution media.
2. The preparation method is simple, the crystallization process is easy to control, and the reproducibility is good; high yield and purity, the yield is more than 91.0 percent, the purity is higher than 99.80 percent, and the method is suitable for industrial production.
Drawings
FIG. 1 is a PXRD diagram of ketorolac and phenazine co-crystal
FIG. 2 is an ORTEP diagram of a co-crystal of ketorolac and phenazine
FIG. 3 is a graph of the unit cell stacking of a co-crystal of ketorolac and phenazine
FIG. 4 is a TGA/DSC thermogram of a co-crystal of ketorolac and phenazine
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.
The raw material sources are as follows: the ketorolac used in the experiment is self-made in a laboratory, the purity is more than 99 percent, and the sources and specifications of the rest materials are all market analytical purity or chemical purity.
Example 1:
adding 25.5mg of ketorolac and 19.8mg of phenazine into 5mL of methanol, performing ultrasonic treatment by using an ultrasonic instrument until the ketorolac and the phenazine are completely dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 18 ℃ for natural volatilization for 3 days, filtering, and drying in an oven at 50 ℃ for 2 hours to obtain the ketorolac and phenazine eutectic crystal, wherein the yield is 93.5%, and the HPLC (high performance liquid chromatography) is 99.92%.
Example 2:
adding 127.5mg of ketorolac and 117.0mg of phenazine into 8mL of methanol and 4mL of ethanol, performing ultrasonic treatment by using an ultrasonic instrument until all the ketorolac and the phenazine are dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 15 ℃ for natural volatilization for 5 days, filtering, and drying in an oven at 45 ℃ for 3 hours to obtain the ketorolac and phenazine eutectic crystal, wherein the yield is 93.1%, and the HPLC (high performance liquid chromatography) is 99.93%.
Example 3:
adding 255.0mg of ketorolac and 180.0mg of phenazine into 12mL of acetone and 5mL of methanol, performing ultrasonic treatment by using an ultrasonic instrument until all the ketorolac and the phenazine are dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 20 ℃ for natural volatilization for 4 days, filtering, and drying in an oven at 60 ℃ for 2 hours to obtain the ketorolac and phenazine eutectic crystal, wherein the yield is 92.7%, and the HPLC (high performance liquid chromatography) is 99.91%.
Example 4:
adding 2.55g of ketorolac and 3.60g of phenazine into 50mL of methanol and 35mL of tetrahydrofuran, performing ultrasonic treatment by using an ultrasonic instrument until all the ketorolac and the phenazine are dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 25 ℃ for natural volatilization for 3 days, filtering, and drying in an oven at 40 ℃ for 5 hours to obtain the ketorolac and phenazine eutectic crystal, wherein the yield is 91.8%, and the HPLC (high performance liquid chromatography) is 99.88%.
Example 5:
adding 255.0mg of ketorolac and 144.0mg of phenazine into 30mL of acetonitrile, performing ultrasonic treatment by using an ultrasonic instrument until the ketorolac and the phenazine are completely dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 20 ℃ for natural volatilization for 2 days, filtering, and drying in an oven at 55 ℃ for 3 hours to obtain the ketorolac and phenazine eutectic crystal, wherein the yield is 91.2%, and the HPLC is 99.82%.
Stability test
1. Test materials: the ketorolac and phenazine co-crystals and ketorolac standards prepared in examples 1-5.
2. The test method comprises the following steps: the test is carried out according to the method of appendix <9001 raw material medicament and preparation stability test guiding principle > in the fourth part of Chinese pharmacopoeia (2015 edition), and the high-temperature test conditions are as follows: 60 ℃; conditions of the intense light irradiation test: 4500lx ± 500 lx; high humidity test conditions: the temperature is 25 ℃ and the relative humidity is 90% +/-5%. The purity was checked by HPLC and three replicates were performed, with the results averaged.
3. And (3) test results: the test results are shown in Table 3.
TABLE 3 stability test results for co-crystals of ketorolac and phenazine
Tests prove that the ketorolac and phenazine eutectic prepared in the embodiments 1 to 5 of the invention has high purity, and the purity of the sample is slightly changed under the conditions of high temperature, high humidity and strong light, so that the ketorolac and phenazine eutectic has remarkable stability. In addition, the ketorolac and phenazine eutectic prepared by the invention is stored for 60 days under the conditions of relative humidity of 75 +/-5% and 25 ℃, the purity of the ketorolac and phenazine eutectic is reduced very little relative to a ketorolac standard product, and PXRD and DSC analysis show that the crystal form is stable and no crystal transformation phenomenon occurs.
Solubility test
1. Test materials: the ketorolac and phenazine co-crystals and ketorolac standards prepared in examples 1-5.
2. The test method comprises the following steps: the solubility test is referred to the contents of the Chinese pharmacopoeia (2015 edition). The co-crystals of ketorolac and phenazine were produced by amplification according to the methods of examples 1-5, 10mL of media (pH7.0 water, pH1.0 hydrochloric acid solution, pH6.8 phosphate buffer) were measured into penicillin bottles, respectively, the excess drug was added, the vials were sealed and placed in a 37 ℃ water bath and stirred at constant temperature for 1 hour, filtered through a 0.2 μm filter, the filtrate was taken and the peak areas at 313nm wavelength were measured, respectively, and the solubility was calculated by measuring the peak area of the standard control.
The liquid phase detection method comprises the following steps: taking 1mL of filtrate, adding a solvent (0.1% phosphoric acid water: acetonitrile: 7:3) to dilute to a scale, shaking up, filtering, precisely measuring 10 mu L of sample solution, injecting into a liquid chromatograph, and calculating according to an area normalization method.
3. And (3) test results: the results of the solubility test are shown in Table 4.
TABLE 4 solubility of Co-crystals of ketorolac and phenazine in different media
Tests prove that the co-crystals of ketorolac and phenazine prepared in the embodiments 1 to 5 of the invention have similar solubility effects, and have higher solubility in three media, namely water with pH of 7.0, hydrochloric acid solution with pH of 1.0 and phosphate buffer solution with pH of 6.8, compared with a ketorolac standard substance (ketorolac crystal form I), and have important significance for improving the bioavailability and the drug effect of ketorolac.
Claims (10)
1. A ketorolac and phenazine eutectic is characterized in that the ketorolac and phenazine eutectic uses Cu-Ka radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.2 +/-0.2 degrees, 6.6 +/-0.2 degrees, 8.2 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.5 +/-0.2 degrees, and 16.4 +/-0.2 degrees.
2. The ketorolac and phenazine co-crystal of claim 1, wherein the ketorolac and phenazine co-crystal has an X-ray diffraction pattern expressed in 2 Θ using Cu-ka radiation with characteristic peaks at 6.2 ± 0.2 °, 6.6 ± 0.2 °, 8.2 ± 0.2 °, 12.8 ± 0.2 °, 13.5 ± 0.2 °, 16.4 ± 0.2 °, 19.8 ± 0.2 °, 20.8 ± 0.2 °, 29.09 ± 0.2 °, 29.8 ± 0.2 °, 34.0 ± 0.2 °, 38.3 ± 0.2 °, 41.9 ± 0.2 °.
3. The ketorolac and phenazine co-crystal of claim 1, wherein the ketorolac and phenazine co-crystal uses Cu-ka radiation with characteristic peaks according to the X-ray powder diffraction pattern shown in figure 1.
4. The ketorolac and phenazine cocrystal of claim 1 wherein the crystallographic parameters of the ketorolac and phenazine cocrystal are: triclinic, space group P-1, cell parameters:
a is 79.655(2) °, β is 84.540(2) °, γ is 81.129(2) °, unit cell volume
5. A method for preparing a co-crystal of ketorolac and phenazine according to any one of claims 1 to 4, characterized in that it comprises the following steps: adding ketorolac and phenazine into an organic solvent at room temperature, performing ultrasonic treatment by using an ultrasonic instrument until the ketorolac and the phenazine are completely dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at room temperature for natural volatilization, filtering, and drying in an oven to obtain the ketorolac and phenazine eutectic crystal.
6. The method of claim 5, wherein the molar ratio of ketorolac to phenazine is from 1: 1 to 2.
7. The method for preparing the ketorolac and phenazine eutectic crystal according to claim 5, wherein the mass-to-volume ratio of the ketorolac to the organic solvent is 5-30: 1, wherein the mass is in mg and the volume is in mL.
8. The method of claim 5, wherein the organic solvent is one or more selected from the group consisting of methanol, ethanol, acetone, acetonitrile, and tetrahydrofuran.
9. The method for preparing the ketorolac and phenazine eutectic crystal according to claim 5, wherein the natural volatilization time of the ketorolac and phenazine eutectic crystal after standing at room temperature is 3-5 days; the temperature of the oven is 40-60 ℃; and the drying time of the oven is 2-5 h.
10. A pharmaceutical composition is characterized by comprising a ketorolac and phenazine eutectic crystal and pharmaceutically acceptable auxiliary materials.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013283A1 (en) * | 1992-12-17 | 1994-06-23 | Sepracor Inc. | Antipyretic and analgesic methods and compositions containing optically pure r-ketorolac |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013283A1 (en) * | 1992-12-17 | 1994-06-23 | Sepracor Inc. | Antipyretic and analgesic methods and compositions containing optically pure r-ketorolac |
Non-Patent Citations (2)
| Title |
|---|
| JERRY P. JASINSKI等: "Crystal Structure of (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid, Ketorolac", ANALYTICAL SCIENCES * |
| SOHN, YOUNG-TAEK等: "Crystal forms of Ketorolac", ARCHIVES OF PHARMACAL RESEARCH * |
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