CN114276350B - Ketorolac and phenazine eutectic and preparation method thereof - Google Patents
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- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 title claims abstract description 99
- 229960004752 ketorolac Drugs 0.000 title claims abstract description 99
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 title claims abstract description 73
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 230000005496 eutectics Effects 0.000 title claims abstract description 19
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- 229910017541 Cu-K Inorganic materials 0.000 claims abstract description 6
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 14
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Abstract
The invention belongs to the technical field of pharmaceutical eutectic, and provides a ketorolac and phenazine eutectic and a preparation method thereof, wherein the ketorolac and phenazine eutectic prepared by the invention uses Cu-K alpha 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 ketorolac and phenazine prepared by the method has the advantages of high yield of 91% or more, high purity of 99.80%, simple preparation method, easy control of crystallization process, capability of obviously improving the stability and solubility of the ketorolac, better stability and higher solubility in different dissolution media compared with the existing crystal forms or ketorolac standard substances of the ketorolac.
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 useful in the treatment of moderate to severe pain, including post-operative and post-partum pain, and visceral pain associated with cancer, with good efficacy. Molecular weight 255.27, chemical name: (+/-) -5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid, having the structural formula:
ketorolac belongs to a polymorphic compound, and different ketorolac crystal forms have different stability, physical properties, solubility and the like, and the properties can directly influence the stability and bioavailability of raw materials and preparations. There are many reports concerning ketorolac at present, but there are few reports concerning its crystal structure. The 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 ketorolac crystal forms I, II, III and IV, and the solubility and stability of the existing crystal forms are further improved. The invention provides a ketorolac and phenazine cocrystal, which can obviously improve the solubility of ketorolac, and provides a basis for the ketorolac in the aspect of drug treatment, thereby better exerting the medicinal value of the ketorolac.
Disclosure of Invention
The invention aims to provide a ketorolac and phenazine eutectic crystal, and a preparation method and application thereof. The ketorolac and phenazine eutectic crystal provided by the invention combines two molecules of ketorolac in the crystal form of the ketorolac and phenazine eutectic with one molecule of phenazine, and the prepared ketorolac and phenazine eutectic has the advantages of good stability, high solubility, simple preparation method and the like, meets the medicinal requirements, and is suitable for medicine research. The specific technical scheme of the invention is as follows:
in one aspect, the invention provides a ketorolac-phenazine eutectic, which uses Cu-K alpha 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.
Preferably, the ketorolac and phenazine co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern 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 co-crystals use Cu-K alpha radiation, and the characteristic peaks conform to an X-ray powder diffraction pattern as shown in figure 1.
In a second aspect of the invention, there is provided a method of preparing a co-crystal of ketorolac and phenazine, the method comprising the steps of: adding ketorolac and phenazine into an organic solvent at room temperature, then carrying out ultrasonic treatment by using an ultrasonic instrument until the ketorolac and the phenazine are completely dissolved, filtering, placing the filtrate into an evaporator with a small-hole membrane seal, standing at room temperature for natural volatilization, filtering, and drying by using an oven to obtain ketorolac and phenazine cocrystal.
Preferably, the molar ratio of ketorolac to phenazine is 1:1 to 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 time of standing at room temperature and naturally volatilizing is 3-5 days; the temperature of the oven is 40-60 ℃; the drying time of the oven is 2-5 h.
In a third aspect the present application provides a pharmaceutical composition comprising a co-crystal of ketorolac and phenazine prepared as described above, together with other active ingredients which may be used in combination and/or with pharmaceutically acceptable adjuvant components thereof.
Confirmation of Crystal Structure
The X-ray powder diffraction test instrument and test conditions in the test of the ketorolac and phenazine co-crystal prepared by the invention are as follows: PANalytical Empyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction optical path: PLXCEL, voltage 45KV, current 40mA, divergence slit 1/4 degree, anti-scattering slit 1 degree, cable-stayed slit 0.04rad, counting time 0.5s per step, scanning range 3-50 degree.
Characteristic peaks in an X-ray diffraction diagram (Cu-K alpha) corresponding to ketorolac and phenazine cocrystal are shown in figure 1 and table 1 in detail.
TABLE 1 PXRD peaks for the co-crystals of ketorolac and phenazine
The ketorolac and phenazine provided by the invention are eutectic, and are subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffractometer and the testing conditions are as follows: the temperature 293 (2) K was measured using a XtaLAB Synergy X-ray single crystal diffractometer, and the data was collected and Lp corrected using CuKa radiation in an omega scan. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
Testing and analyzing the crystallographic data obtained by the co-crystal of ketorolac and phenazine prepared by the invention (table 2): the triclinic system has a space group of P-1 and unit cell parameters of:
α= 79.655 (2) °, β= 84.540 (2) °, γ= 81.129 (2) °, unit cell volume +.>
The ORTEP diagram of the ketorolac and phenazine co-crystal of the invention shows that two molecules of ketorolac are combined with one molecule of phenazine, as shown in fig. 2, and the unit cell stacking diagram is shown in fig. 3.
TABLE 2 Kerolac and phenazine Co-crystals primary crystallographic data
The ketorolac and phenazine eutectic provided by the invention has the following TGA/DSC thermal analysis test conditions: METTLETOLEDO TGA/DSC3+ thermal analyzer, dynamic temperature section: 30-300 ℃, heating rate: 10 ℃/min, procedure gas N 2 Flow rate: 50ml/min, crucible: 40. Mu.L of an aluminum crucible is shown in FIG. 4.
The TGA/DSC test result of the ketorolac and phenazine cocrystal prepared by the invention is shown in figure 4, the DSC spectrum has an endothermic peak in the range of 165.72-173.24 ℃, and the peak value of the corresponding endothermic peak is 169.56 ℃; the thermogravimetric analysis (TGA) only has one weight loss step, which shows that the ketorolac and phenazine co-crystal has no solvent and stable structure.
The invention has the beneficial effects that:
1. the ketorolac and phenazine cocrystal prepared by the method can obviously improve the stability and solubility of the ketorolac, and has good stability and higher solubility in different dissolution media compared with the existing crystal forms of the ketorolac or ketorolac standard substances.
2. The preparation method is simple, the crystallization process is easy to control, and the reproducibility is good; the yield is high, the purity is high, the yield is more than 91.0%, the purity is more than 99.80%, and the method is suitable for industrial production.
Drawings
FIG. 1 is a PXRD pattern for a co-crystal of ketorolac and phenazine
FIG. 2 is an ORTEP plot of ketorolac co-crystals with phenazine
FIG. 3 is a unit cell stacking diagram of ketorolac and phenazine co-crystals
FIG. 4 is a TGA/DSC thermogram of ketorolac versus phenazine co-crystal
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The raw material sources are as follows: the ketorolac used in the experiment is prepared in a laboratory, the purity is more than 99%, and the sources and the specifications of the rest materials are all commercially available analytical purity or chemical purity.
Example 1:
25.5mg of ketorolac and 19.8mg of phenazine are added into 5mL of methanol, ultrasonic treatment is carried out until the mixture is completely dissolved by using an ultrasonic wave instrument, filtering is carried out, the filtrate is placed into an evaporator with a small pore membrane seal, standing and natural volatilizing are carried out for 3 days at 18 ℃, filtering is carried out, and drying is carried out for 2 hours at 50 ℃ in an oven, thus obtaining the ketorolac and phenazine eutectic with the yield of 93.5 percent and HPLC of 99.92 percent.
Example 2:
127.5mg of ketorolac and 117.0mg of phenazine are added into 8mL of methanol and 4mL of ethanol, ultrasonic treatment is carried out by an ultrasonic instrument until the mixture is completely dissolved, filtering is carried out, the filtrate is placed in an evaporator with a small-hole membrane seal, standing and natural volatilizing are carried out for 5 days at 15 ℃, filtering is carried out, and drying is carried out for 3 hours at 45 ℃ by an oven, thus obtaining ketorolac and phenazine eutectic with the yield of 93.1 percent and HPLC of 99.93 percent.
Example 3:
255.0mg of ketorolac and 180.0mg of phenazine are added into 12mL of acetone and 5mL of methanol, ultrasonic treatment is carried out until the mixture is completely dissolved by using an ultrasonic wave instrument, filtering is carried out, the filtrate is placed into an evaporator with a small pore membrane seal, standing and natural volatilizing are carried out for 4 days at 20 ℃, filtering is carried out, and drying is carried out for 2 hours by a baking oven at 60 ℃, thus obtaining ketorolac and phenazine eutectic with the yield of 92.7 percent and HPLC of 99.91 percent.
Example 4:
2.55g of ketorolac and 3.60g of phenazine are added into 50mL of methanol and 35mL of tetrahydrofuran, ultrasonic treatment is carried out until the mixture is completely dissolved by using an ultrasonic wave instrument, filtering is carried out, the filtrate is placed into an evaporator with a small pore membrane seal, standing and natural volatilizing are carried out for 3 days at 25 ℃, filtering is carried out, and drying is carried out for 5 hours by a baking oven at 40 ℃ to obtain the ketorolac and phenazine eutectic with the yield of 91.8 percent and the HPLC of 99.88 percent.
Example 5:
255.0mg of ketorolac and 144.0mg of phenazine are added into 30mL of acetonitrile, ultrasonic is used for complete dissolution, filtration is carried out, the filtrate is placed into an evaporator with a small pore membrane seal, standing and natural volatilizing are carried out for 2 days at 20 ℃, filtration is carried out, and drying is carried out for 3 hours at 55 ℃ to obtain the ketorolac and phenazine eutectic, the yield is 91.2 percent, and HPLC is 99.82 percent.
Stability test
1. Test materials: ketorolac and phenazine cocrystal and ketorolac standard prepared in examples 1-5.
2. The test method comprises the following steps: test is carried out by referring to the method of annex <9001 raw material medicine and preparation stability test guidelines > of the fourth part of Chinese pharmacopoeia (2015 edition), and high-temperature test conditions are as follows: 60 ℃; strong light irradiation test conditions: 4500lx±500lx; high humidity test conditions: the temperature is 25 ℃, and the relative humidity is 90% +/-5%. Purity was measured by HPLC, and three replicates were performed, respectively, and the results averaged.
3. Test results: the test results are shown in Table 3.
TABLE 3 stability test determination of ketorolac and phenazine cocrystals
Through experiments, the ketorolac and phenazine prepared in the embodiments 1-5 of the invention have high eutectic purity, and the sample has small purity change under high temperature, high humidity and strong light conditions, thus having remarkable stability. In addition, the ketorolac and phenazine cocrystal prepared by the method is respectively stored for 60 days under the conditions of relative humidity of 75+/-5% and 25 ℃, the purity of the ketorolac and phenazine cocrystal is reduced slightly compared with that of a ketorolac standard substance, and PXRD and DSC analysis show that the crystal form is stable and no crystal transformation phenomenon occurs.
Solubility test
1. Test materials: ketorolac and phenazine cocrystal and ketorolac standard prepared in examples 1-5.
2. The test method comprises the following steps: solubility tests refer to the content of the Chinese pharmacopoeia (2015 edition). The co-crystals of ketorolac and phenazine were produced by the method of examples 1 to 5, respectively, 10mL of medium (pH 7.0 water, pH1.0 hydrochloric acid solution, pH6.8 phosphate buffer) was measured in a vial, an excessive amount of the drug was added, the vial was sealed and stirred in a 37℃water bath at constant temperature for 1 hour, filtered through a 0.2 μm filter membrane, and the peak areas of the filtrate were measured at 313nm wavelength, respectively, and the solubility was calculated by measuring the peak areas of the standard control.
The liquid phase detection method comprises the following steps: 1mL of filtrate is taken, a solvent (0.1% phosphoric acid water: acetonitrile=7:3) is added, diluted to a scale, uniformly shaken, filtered, and 10 mu L of a sample solution is precisely measured, injected into a liquid chromatograph and calculated according to an area normalization method.
3. Test results: the solubility test results are shown in Table 4.
TABLE 4 solubility of ketorolac and phenazine co-crystals in different media
Through experiments, the ketorolac and phenazine cocrystals prepared in the embodiments 1-5 have similar solubility effects, have higher solubility in three media of pH7.0 water, pH1.0 hydrochloric acid solution and pH6.8 phosphate buffer solution compared with a ketorolac standard (ketorolac crystal form I), and have important significance for improving the bioavailability and the drug effect of the ketorolac.
Claims (9)
1. The ketorolac and phenazine cocrystal is characterized in that Cu-K alpha radiation is used for the ketorolac and phenazine cocrystal, 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.
2. The ketorolac and phenazine co-crystal according to claim 1, wherein the ketorolac and phenazine co-crystal has 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° using Cu-ka radiation.
3. The ketorolac and phenazine co-crystal according to claim 1, wherein the ketorolac and phenazine co-crystal uses Cu-ka radiation and has a characteristic peak conforming to an X-ray powder diffraction pattern as shown in figure 1.
4. The ketorolac to phenazine co-crystal of claim 1, wherein the crystallographic parameters of the ketorolac to phenazine co-crystal are: the triclinic system has a space group of P-1 and unit cell parameters of:a=4.30390(10) Å，b=13.7671(3) Å，c= 14.6552 (3) a, α= 79.655 (2) °, β= 84.540 (2) °, γ= 81.129 (2) °, unit cell volumeV=841.98(3)Å 3 。
5. A method for preparing a co-crystal of ketorolac and phenazine according to any one of claims 1 to 4, comprising the steps of: adding ketorolac and phenazine into an organic solvent at room temperature, then carrying out ultrasonic treatment by using an ultrasonic instrument until the ketorolac and the phenazine are completely dissolved, filtering, placing the filtrate into an evaporator with a small-hole membrane seal, standing at room temperature for natural volatilization, filtering, and drying by using an oven to obtain ketorolac and phenazine eutectic; wherein the organic solvent is one or a combination of a plurality of methanol, ethanol, acetone, acetonitrile and tetrahydrofuran.
6. The method for preparing a ketorolac and phenazine co-crystal according to claim 5, wherein the molar ratio of ketorolac to phenazine is 1:1 to 2.
7. The method for preparing ketorolac and phenazine cocrystal according to claim 5, wherein the mass-volume ratio of ketorolac to organic solvent is 5-30: 1, wherein the mass is in mg and the volume is in mL.
8. The method for preparing ketorolac and phenazine cocrystal according to claim 5, wherein the time of standing and naturally volatilizing at room temperature is 3-5 days; the temperature of the oven is 40-60 ℃; the drying time of the oven is 2-5 h.
9. The pharmaceutical composition is characterized by comprising ketorolac, phenazine cocrystal 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 |
|---|
| Crystal forms of Ketorolac;Sohn, Young-Taek等;Archives of Pharmacal Research;第27卷(第3期);全文 * |
| Crystal Structure of (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid, Ketorolac;Jerry P. JASINSKI等;ANALYTICAL SCIENCES;第24卷;全文 * |
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