CN114380833B - Ketorolac and 4-pyridine carboxamide eutectic crystal and preparation method thereof - Google Patents
Ketorolac and 4-pyridine carboxamide eutectic crystal and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical eutectic, and provides a ketorolac and 4-pyridine carboxamide eutectic and a preparation method thereof, wherein the ketorolac and 4-pyridine carboxamide eutectic prepared by the invention uses Cu-K alpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 5.7+/-0.2 degrees, 6.6+/-0.2 degrees, 11.5+/-0.2 degrees, 13.4+/-0.2 degrees, 15.7+/-0.2 degrees, 17.5+/-0.2 degrees, 18.3+/-0.2 degrees and 27.4+/-0.2 degrees; the ketorolac and 4-pyridine carboxamide eutectic prepared by the method has the advantages of yield of more than 93%, purity of more than 99.80%, simple preparation method, easy control of crystallization process and good repeatability; compared with the prior ketorolac crystal form or ketorolac standard, the acid has higher solubility in phosphate buffer solution with pH of 6.8.
Description
Technical Field
The invention relates to the technical field of pharmaceutical co-crystals, in particular to a ketorolac and 4-pyridine carboxamide co-crystal and a preparation method and application thereof.
Background
Ketorolac (Ketorolac) is a non-steroidal anti-inflammatory drug with potent analgesic and moderate anti-inflammatory effects, which has analgesic effects equivalent to morphine and stronger than aspirin, indomethacin and naproxen. At present, there are many reports about ketorolac, mainly about preparation, physicochemical properties, pharmacological properties and the like, and few reports about crystal structures of ketorolac. The polymorphism of ketorolac, 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 researches on the solubility and stability of the crystal forms I-IV. The results show that the solubility of the crystal form I is highest, but about 3 hours are required for completely dissolving 10mg of the crystal form I in 1L of distilled water, and the crystal forms II to IV cannot be completely dissolved, especially the crystal form IV can be only dissolved for 64% after 5 hours; the crystal form I and the crystal form III have better stability, but the crystal transformation phenomenon occurs in the crystal form II and the crystal form IV. 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. But the solubility and stability of the existing crystal forms are still to be further improved.
4-Pyridine carboxamide is pyrazine derivative of nicotinamide, has selective antibacterial effect on human tubercle bacillus, low concentration antibacterial effect, high concentration antibacterial effect, and strong effect on bacteria with slow cell growth. The ketorolac and 4-pyridine carboxamide eutectic is prepared by a eutectic method, and can obviously improve the solubility, stability and other characteristics of the ketorolac, so that the purpose of improving the oral absorption effect of the ketorolac is achieved.
Disclosure of Invention
In view of the shortcomings of the prior art, the application provides a ketorolac and 4-pyridine carboxamide eutectic crystal.
Ketorolac as a pharmaceutical ingredient of the present invention, chemical name (+/-) -5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid, white crystalline or white powder, CAS number: 74103-06-3, the molecular formula is C 15H8D5NO3, and the structural formula is shown as a; the co-crystal former selected in the present invention is 4-pyridinecarboxamide, CAS number: 1453-82-3, the molecular formula is C 6H6N2 O, the structural formula is shown as b, the ketorolac prepared by the invention and 4-pyridine carboxamide are eutectic, and the crystal form contains one molecule of ketorolac and one molecule of 4-pyridine carboxamide.
According to a first aspect of the present invention, there is provided a co-crystal of ketorolac and 4-pyridinecarboxamide having characteristic peaks at 5.7±0.2°, 6.6±0.2°, 11.5±0.2°, 13.4±0.2°, 15.7±0.2°, 17.5±0.2°, 18.3±0.2°, 27.4±0.2° using Cu-kα radiation.
Preferably, the ketorolac is co-crystallized with 4-pyridinecarboxamide and the X-ray diffraction pattern expressed in 2 theta has a characteristic peak at 5.7±0.2°、6.6±0.2°、11.5±0.2°、13.4±0.2°、15.7±0.2°、17.5±0.2°、18.3±0.2°、19.9±0.2°、20.4±0.2°、21.7±0.2°、24.8±0.2°、25.5±0.2°、26.2±0.2°、26.3±0.2°、27.4±0.2°、37.8±0.2°、39.3±0.2° using Cu-ka radiation.
Preferably, the co-crystal of ketorolac and 4-pyridine carboxamide uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern as shown in figure 3.
Preferably, the ketorolac and 4-pyridine carboxamide co-crystal have a molecular formula of C 21H19N3O4, and the crystallographic parameters are: monoclinic system, space group P2 1/n, unit cell parameters: α=90 °, β= 97.9100 (10) °, γ=90°, unit cell volume/>
The invention provides a preparation method of ketorolac and 4-pyridine carboxamide eutectic crystal, which comprises the following specific steps: adding ketorolac and 4-pyridine carboxamide into the organic solvent A, heating for dissolution, cooling for crystallization after solution clarification, filtering and drying to obtain ketorolac and 4-pyridine carboxamide eutectic.
Preferably, the organic solvent A is selected from one or two of methanol, ethanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile and water; further preferably, the organic solvent A is selected from one or two of methanol, acetone and acetonitrile.
Preferably, the molar feed ratio of the ketorolac to the 4-pyridine carboxamide is 1:1-2; further preferably, the molar feed ratio of ketorolac to 4-pyridine carboxamide is 1:1.0-1.5.
Preferably, the mass volume ratio of ketorolac to organic solvent A in the system is 3.2-6.4: 1, wherein the mass is in mg and the volume is in mL.
Preferably, the temperature of the dissolution heating is 40-60 ℃.
Preferably, the temperature reduction crystallization temperature is 0-30 ℃; further preferably, the temperature of the cooling crystallization is 10-30 ℃.
Preferably, the crystallization time is 12 to 72 hours.
Further preferably, the preparation method comprises the following steps: adding ketorolac and 4-pyridine carboxamide into an organic solvent A, heating to dissolve at 40-60 ℃, cooling to 10-30 ℃ for crystallization for 12-72 hours after solution is clarified, filtering, washing a filter cake, and drying to obtain a ketorolac and 4-pyridine carboxamide eutectic crystal form.
In a third aspect the application provides a pharmaceutical composition comprising a co-crystal of ketorolac and 4-pyridinecarboxamide according to the application and further comprising a pharmaceutically acceptable adjuvant component.
Preferably, the pharmaceutical composition of the present invention is prepared as follows: the compounds of the present invention are formulated into useful dosage forms by combining them with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques.
The fourth aspect of the invention also provides the application of the ketorolac and 4-pyridine carboxamide eutectic in preparing medicines for diminishing inflammation and easing pain.
Confirmation of Crystal Structure
Crystals meeting the specification size are selected from the prepared samples, and subjected to X-ray single crystal diffraction test analysis. X-ray crystal data were collected on a model XtaLAB Synergy of Japanese science, test temperature 293 (2) K, voltage 50kv, current 1mA, data were collected in omega scan mode with CuKa radiation and Lp correction was performed. 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.
The crystallography data of the ketorolac and 4-pyridine carboxamide eutectic crystal forms prepared by the invention are shown in table 1, and the crystallography parameters are as follows: monoclinic system, chiral space group: p2 1/n; the unit cell parameters are: α=90 °, β= 97.9100 (10) °, γ=90°, unit cell volume The ORTEP diagram (fig. 1) of the ketorolac and 4-pyridinecarboxamide co-crystals of the present invention shows that the crystalline form contains one molecule of ketorolac and one molecule of 4-pyridinecarboxamide. The hydrogen bond diagram of the ketorolac and 4-pyridine carboxamide eutectic is shown in figure 2.
TABLE 1 Keto-rolac and 4-Pyridinecarboxamide Co-Crystal Primary Crystal data
The X-ray powder diffraction test instrument and test conditions related in the invention: PANALYTICAL EMPYREAN X-ray powder diffractometer; cu-K alpha; sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; 1/4 of the divergent slit; an anti-scattering slit 1; a cable pull slit of 0.04rad; step size: 0.5s; scanning range: 3-50 deg.
According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 3 and Table 2.
TABLE 2 PXRD peaks for co-crystals of ketorolac and 4-pyridinecarboxamide
TGA/DSC thermal analysis tester and test conditions in the invention: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3+; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; program segment gas N 2; gas flow rate: 50mL/min; crucible: 40 μl of aluminum crucible.
The TGA/DSC test result of the ketorolac and 4-pyridine carboxamide eutectic prepared by the invention is shown in figure 4, the DSC spectrum shows an endothermic peak in the range of 186.47-205.28 ℃, and the peak value of the corresponding endothermic peak is 196.48 ℃; the thermogravimetric analysis (TGA) only has one weight loss step, which shows that the ketorolac and 4-pyridine carboxamide eutectic crystal has no solvent and stable structure.
Compared with the currently reported ketorolac crystal forms, the ketorolac and 4-pyridine carboxamide eutectic prepared by the method has the following advantages:
(1) The ketorolac and 4-pyridine carboxamide eutectic crystal provided by the invention has higher solubility in phosphate buffer with pH of 6.8, and provides a reliable pharmaceutical active ingredient for preparing anti-inflammatory and analgesic drugs.
(2) The ketorolac and 4-pyridine carboxamide eutectic crystal provided by the invention has stable crystal structure, definite crystal form, definite main crystallographic parameters and definite atomic space position.
(3) The preparation method of the pharmaceutical co-crystal provided by the invention has the advantages of simple operation, easy control of crystallization process, good reproducibility, high yield, high purity, more than 93 percent, and purity higher than 99.80 percent, and is suitable for industrial production.
Drawings
FIG. 1 ORTEP spectra of ketorolac and 4-pyridinecarboxamide co-crystals.
FIG. 2 shows a hydrogen bonding diagram of ketorolac and 4-pyridinecarboxamide co-crystals.
Fig. 3 PXRD pattern of ketorolac co-crystal with 4-pyridinecarboxamide.
FIG. 4 TGA/DSC of a co-crystal of ketorolac and 4-pyridinecarboxamide.
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: ketorolac used in the experiment can be purchased and prepared by referring to the prior art, and the purity is more than 99%; the sources and specifications of the rest materials are all commercially available analytical purity or chemical purity.
Example 1:
255mg of ketorolac (1 mmoL) and 122mg of 4-pyridine carboxamide (1 mmoL) are dissolved in 40mL of acetone and 40mL of methanol, the solution is heated and dissolved at 40 ℃, the temperature is reduced to 10 ℃ after the solution is dissolved, the solution is stood for crystallization for 24 hours, the ketorolac and 4-pyridine carboxamide eutectic is obtained after filtration and drying, the yield is 96.8 percent, and HPLC:99.92%.
Example 2:
255mg of ketorolac (1 mmoL) and 146mg of 4-pyridine carboxamide (1.2 mmoL) are dissolved in 30mL of acetonitrile and 30mL of acetone, heated to 55 ℃ for dissolution, the solution is cooled to 15 ℃ after clarification, and is left to stand for crystallization for 48 hours, and the ketorolac and 4-pyridine carboxamide eutectic is obtained after filtration and drying, the yield is 98.2 percent, HPLC:99.96%.
Example 3:
255mg of ketorolac (1 mmoL) and 183mg of 4-pyridine carboxamide (1.5 mmoL) are dissolved in 40mL of acetonitrile, the solution is heated and dissolved at 60 ℃, the temperature is reduced to 30 ℃ after the solution is dissolved, the solution is stood for crystallization for 36 hours, the ketorolac and 4-pyridine carboxamide eutectic is obtained after filtration and drying, the yield is 98.0 percent, HPLC:99.93%.
Example 4:
255mg of ketorolac (1 mmoL) and 122mg of 4-pyridine carboxamide (1 mmoL) are dissolved in 40mL of ethanol, the solution is heated and dissolved at 50 ℃, the temperature is reduced to 15 ℃ after the solution is dissolved, the solution is stood still for crystallization for 12 hours, the ketorolac and 4-pyridine carboxamide eutectic is obtained after filtration and drying, the yield is 95.2 percent, and HPLC:99.83%.
Example 5:
128mg of ketorolac (0.5 mmoL) and 122mg of 4-pyridine carboxamide (1 mmoL) are dissolved in 22mL of ethyl acetate and 20mL of methanol, heated to 40 ℃ for dissolution, cooled to 0 ℃ after solution clarification, and left to stand for crystallization for 72 hours, filtered and dried to obtain ketorolac and 4-pyridine carboxamide eutectic, the yield is 94.5 percent, HPLC:99.86%.
Example 6:
255mg of ketorolac (1 mmoL) and 122mg of 4-pyridine carboxamide (1 mmoL) are dissolved in 18mL of isopropanol and 18mL of tetrahydrofuran, heated to 35 ℃ for dissolution, cooled to 0 ℃ after solution clarification, and left to stand for crystallization for 48 hours, filtered and dried to obtain ketorolac and 4-pyridine carboxamide eutectic, the yield is 93.1 percent, HPLC:99.80%.
Solubility test
1. Test materials: the ketorolac prepared in examples 1-6 was co-crystallized with 4-pyridinecarboxamide and a ketorolac standard.
2. The test method comprises the following steps: solubility tests refer to the content of the Chinese pharmacopoeia (2015 edition). The corresponding crystals were produced by the method of examples 1 to 6, respectively, by weighing 10mL of medium (pH 7.0 water, pH2.0 hydrochloric acid solution, pH6.8 phosphate buffer) into a penicillin bottle, adding an excessive amount of the drug, sealing the penicillin bottle, placing in a 37℃water bath, stirring at constant temperature for 1 hour, filtering with a 0.2 μm filter membrane, measuring peak areas of the respective filtrates at 313nm wavelength, respectively, and calculating the solubility by testing 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 3.
TABLE 3 solubility of ketorolac and 4-pyridinecarboxamide co-crystals in different media
Through experiments, the ketorolac and 4-pyridine carboxamide eutectic prepared in the embodiments 1-6 of the invention have similar solubility effects, and compared with a ketorolac standard (ketorolac crystal form I) and other ketorolac crystal forms, the solubility of the ketorolac and 4-pyridine carboxamide eutectic in phosphate buffer with pH of 6.8 is obviously improved, and the ketorolac and 4-pyridine carboxamide eutectic has important significance for improving bioavailability and drug effect of the ketorolac.
Claims (9)
1. A ketorolac and 4-pyridinecarboxamide co-crystal, characterized in that Cu-ka radiation is used, and an X-ray diffraction pattern expressed in 2Θ has characteristic peaks at 5.7±0.2°, 6.6±0.2°, 11.5±0.2°, 13.4±0.2°, 15.7±0.2°, 17.5±0.2°, 18.3±0.2°, 27.4±0.2°.
2. The co-crystal of ketorolac and 4-pyridinecarboxamide according to claim 1 wherein the X-ray diffraction spectrum expressed in 2Θ has a characteristic peak at 5.7±0.2°、6.6±0.2°、11.5±0.2°、13.4±0.2°、15.7±0.2°、17.5±0.2°、18.3±0.2°、19.9±0.2°、20.4±0.2°、21.7±0.2°、24.8±0.2°、25.5±0.2°、26.2±0.2°、26.3±0.2°、27.4±0.2°、37.8±0.2°、39.3±0.2° using Cu-ka radiation.
3. The co-crystal of ketorolac and 4-pyridinecarboxamide according to claim 1 wherein the X-ray diffraction expressed in 2Θ using Cu-ka radiation has a characteristic peak as shown in figure 3.
4. The co-crystal of ketorolac and 4-pyridinecarboxamide according to claim 1 wherein the crystallographic parameters are: monoclinic system, chiral space group: p2 1/n; the unit cell parameters are a= 16.6650 (2) a, b=4.250 a, c= 25.9822 (3) a, α=90 °, β= 97.9100 (10) °, γ=90°, and unit cell volume v= 1822.71 (3) a 3.
5. The method for preparing the co-crystal of ketorolac and 4-pyridinecarboxamide according to any one of claims 1 to 4, wherein the specific preparation steps include: adding ketorolac and 4-pyridine carboxamide into the organic solvent A, heating for dissolution, cooling for crystallization after solution clarification, filtering and drying to obtain ketorolac and 4-pyridine carboxamide eutectic; the organic solvent A is selected from one or a combination of methanol, ethanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile and water.
6. The method for preparing a co-crystal of ketorolac and 4-pyridinecarboxamide according to claim 5, wherein the molar ratio of ketorolac to 4-pyridinecarboxamide is 1:1-2.
7. The method for preparing the ketorolac and 4-pyridinecarboxamide eutectic according to claim 5, wherein the mass-volume ratio of ketorolac to organic solvent A is 3.2-6.4: 1, wherein the mass is in mg and the volume is in mL.
8. The method for preparing ketorolac and 4-pyridinecarboxamide according to claim 5, wherein the temperature of the heating dissolution is 40-60 ℃; the crystallization temperature is 0-30 ℃; the crystallization time is 12-72 hours.
9. The pharmaceutical composition is characterized by comprising the ketorolac and 4-pyridine carboxamide eutectic crystal and other pharmaceutically acceptable auxiliary material components.
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