Ketorolac tromethamine new crystal form and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to a novel crystal form of ketorolac tromethamine and a preparation method of the novel crystal form. In a powder diffraction pattern of ketorolac tromethamine, diffraction peaks exist at the positions of 2theta at 9.7 + / -0.2 degrees, 14.1 + / -0.2 degrees, 16.5 + / -0.2 degrees, 18.6 + / -0.2 degrees, 21.0 + / -0.2 degrees, 22.0 + / -0.2 degrees and 22.9 + / -0.2 degrees. The novel ketorolac tromethamine crystal form prepared by the invention is high in stability, good in stability and excellent in solubility, the preparation process is easy to industrialize, and the novel ketorolac tromethamine crystal form has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a new crystal form of ketorolac tromethamine and a preparation method thereof. Background Art

[0002] The compound involved in the present invention is a complex formed by (+ / -)-5-benzoyl-2,3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid and tris(hydroxymethyl)aminomethane, and the specific structural formula is shown in Formula 1: .

[0003] Ketorolac, that is, (+ / -)-5-benzoyl-2,3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid, and its tromethamine salt is a non-steroidal anti-inflammatory drug with good safety. It inhibits the synthesis of PG, has analgesic, anti-inflammatory, antipyretic effects and inhibits platelet aggregation. Its analgesic effect is similar to that of aspirin, and the analgesic effect after intramuscular injection is similar to that of a medium dose of morphine. Ketorolac tromethamine was developed by the American company Syntex Pharmaceuticals and was first launched in Spain in 1988. It was included in the European Pharmacopoeia and the British Pharmacopoeia in 1998 and has been launched in more than 20 countries such as the UK, Germany, France, and Spain. It is clinically used to relieve inflammation and pain caused by rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, etc., and is a safe and reliable drug for treating acute and chronic pain and anti-inflammation.

[0004] Most solid active pharmaceutical ingredients exhibit polymorphism. Different crystal forms of the same active pharmaceutical ingredient have significant differences in solubility, melting point, density, thermal stability, etc., thus affecting the stability, uniformity, bioavailability and safety of the drug. Therefore, in drug research and development, comprehensive and systematic polymorph screening and selection of dominant crystal forms for development are important research contents that cannot be ignored.

[0005] There is currently no relevant research report on the crystal form of ketorolac tromethamine. Ketorolac belongs to a polymorphic compound, and different ketorolac crystal forms have different stabilities, physical properties, solubilities, etc., and these properties can directly affect the stability and bioavailability of the active pharmaceutical ingredient and the preparation. However, the solubility and stability of the existing crystal forms still need to be further improved. Summary of the Invention

[0006] In view of the deficiencies of the prior art, the present invention provides a new crystal form of ketorolac tromethamine.

[0007] A new crystal form of ketorolac tromethamine has diffraction peaks at 9.7±0.2°, 14.1±0.2°, 16.5±0.2°, 18.6±0.2°, 21.0±0.2°, 22.0±0.2°, 22.9±0.2° as represented by 2θ in the X-ray powder diffraction spectrum.

[0008] The X-ray powder diffraction spectrum is represented by 2θ with diffraction peaks at 9.7±0.2°, 12.7±0.2°, 14.1±0.2°, 16.5±0.2°, 16.9±0.2°, 17.3±0.2°, 18.6±0.2°, 20.1±0.2°, 21.0±0.2°, 22.0±0.2°, 22.9±0.2°, 29.3±0.2°, 35.3±0.2°.

[0009] Preferably, the X-ray powder diffraction spectrum is represented by 2θ with diffraction peaks at 9.7±0.2°, 12.7±0.2°, 13.8±0.2°, 14.1±0.2°, 16.5±0.2°, 16.9±0.2°, 17.3±0.2°, 17.7±0.2°, 18.6±0.2°, 19.8±0.2°, 20.1±0.2°, 21.0±0.2°, 22.0±0.2°, 22.5±0.2°, 22.9±0.2°, 23.8±0.2°, 24.9±0.2°, 28.2±0.2°, 29.3±0.2°, 30.8±0.2°, 35.3±0.2°.

[0010] More preferably, the new crystalline form of ketorolac tromethamine has an Figure 1 X-ray powder diffraction pattern as shown. The specific X-ray diffraction data are shown in Table 1: Table 1 X-ray powder diffraction data of the new crystalline form of ketorolac tromethamine .

[0011] In the present invention, the X-ray powder diffraction test instrument and test conditions are as follows: PANalytical Empyrean X-ray powder diffractometer; copper target light source, flat sample stage, BBHD incident optical path, PLXCEL diffraction optical path, voltage 45 kv, current 40 mA, divergence slit 1 / 4°, anti-scattering slit 1°, Soller slit 0.04 rad, step size: 0.5 s, scanning range 3 - 50°.

[0012] Test method: Fill the ground sample (100 mg) in the groove of the glass plate. After leveling its plane with the glass surface using a cover glass, place the sample in the PANalytical X-ray powder diffractometer, use a copper X-ray source with 40 kV and 40 mA, the scanning range is 0 - 50 (2theta), and the scanning speed is 8° / minute. The scanning error is usually ±0.2 degrees (2θ).

[0013] The present invention also provides a method for preparing the new crystal form of ketorolac, which is specifically prepared by the following steps: adding ketorolac to water, refluxing for 1 h, filtering by suction, adding organic solvent A to the solid, slowly heating and dissolving, adding tromethamine for crystallization, rotary evaporation, adding organic solvent B to the solid, heating under reflux for 2 h, cooling and filtering by suction, and drying to obtain the target product.

[0014] The organic solvent A is one of methanol, ethanol, acetone, tetrahydrofuran, and acetonitrile; preferably, the organic solvent A is ethanol.

[0015] The feeding ratio of the crude ketorolac: organic solvent A: organic solvent B is 1:1 - 5:5 - 15, m / V / V, where the mass m of the crude ketorolac is in g and the volume V of the solvent is in mL.

[0016] Preferably, the ratio is 1:1.5 - 2:4 - 8.

[0017] The organic solvent B is one of ethanol, acetone, n - heptane, petroleum ether, n - hexane, and methyl tert - butyl ether; preferably, the organic solvent B is acetone.

[0018] The heating temperature is 40 - 90 °C; preferably, the heating temperature is 60 - 80 °C.

[0019] The stirring time is 1 - 8 h; preferably, the stirring time is 2 - 4 h.

[0020] The present invention also provides the use of the new crystal form of ketorolac tromethamine, which can be used as a non - steroidal anti - inflammatory drug.

[0021] The present invention also provides a pharmaceutical composition, which contains an active ingredient of the new crystal form of ketorolac within a safe and effective amount range and a pharmaceutically acceptable carrier.

[0022] "Safe and effective amount" means that the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1 - 2000 mg of the active ingredient per dose, more preferably, contains 10 - 200 mg of the active ingredient per dose. Preferably, the "per dose" is one tablet.

[0023] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers, wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0024] There is no particular limitation on the mode of administration of the active ingredient or pharmaceutical composition of the present invention. Representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc. The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0025] Compared with the prior art, the main advantages of the new crystal form provided by the present invention are: 1. The product is a new crystal form of tromethamine ketorolac, with excellent physicochemical properties and good stability; 2. The preparation method is simple and easy to operate, suitable for industrial production; 3. The crystal form product is stable and can significantly improve the solubility of this product. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 : X-ray powder diffraction pattern of the new crystal form of ketorolac. DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention will be further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are only given for the purpose of illustrating the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope claimed by the present invention. Example 1

[0028] 10.00 g of ketorolac was added to a reaction flask, 30 mL of water was added, refluxed for 1 h, filtered by suction, 30 mL of ethanol was added to the solid, slowly heated to 45 - 50 °C to dissolve, tromethamine was added for crystallization, spun dry, 100 mL of acetone was added to the solid, heated under reflux for 2 h, cooled and filtered by suction, and dried to obtain 13.43 g of tromethamine ketorolac crystals, with a yield of 91.04%. After measurement, its X-ray powder diffraction pattern is Figure 1 substantially the same. Example 2

[0029] Add 10.00 g of ketorolac into a flask, add 30 mL of water, reflux for 1 h, filter by suction, add 20 mL of methanol to the solid, slowly heat to 45 - 50 °C to dissolve, add trometamol for crystallization, spin dry, add 100 mL of acetone to the solid, heat under reflux for 2 h, cool down and filter by suction, dry to obtain 12.53 g of ketorolac trometamol crystals, with a yield of 84.93%. After determination, its X-ray powder diffraction pattern is consistent with Figure 1 basically the same. Example 3

[0030] Add 10.00 g of ketorolac into a flask, add 30 mL of water, reflux for 1 h, filter by suction, add 30 mL of ethanol to the solid, slowly heat to 45 - 50 °C to dissolve, add trometamol for crystallization, spin dry, add 100 mL of ethanol to the solid, heat under reflux for 2 h, cool down and filter by suction, dry to obtain 10.96 g of ketorolac trometamol crystals, with a yield of 74.29%. After determination, its X-ray powder diffraction pattern is consistent with Figure 1 basically the same. Example 4

[0031] Add 10.00 g of ketorolac into a reaction flask, add 30 mL of water, reflux for 1 h, filter by suction, add 50 mL of ethanol to the solid, slowly heat to 45 - 50 °C to dissolve, add trometamol for crystallization, spin dry, add 100 mL of acetone to the solid, heat under reflux for 2 h, cool down and filter by suction, dry to obtain 12.85 g of ketorolac trometamol crystals, with a yield of 87.11%. After determination, its X-ray powder diffraction pattern is consistent with Figure 1 basically the same. Example 5

[0032] Add 10.00 g of ketorolac into a reaction flask, add 30 mL of water, reflux for 1 h, filter by suction, add 30 mL of ethanol to the solid, slowly heat to 45 - 50 °C to dissolve, add trometamol for crystallization, spin dry, add 50 mL of methanol to the solid, heat under reflux for 2 h, cool down and filter by suction, dry to obtain 12.37 g of ketorolac trometamol crystals, with a yield of 83.85%. After determination, its X-ray powder diffraction pattern is consistent with Figure 1 basically the same. Example 6

[0033] Add 10.00 g of ketorolac into a reaction flask, add 30 mL of water, reflux for 1 h, filter by suction, add 60 mL of acetone to the solid, slowly heat to 45 - 50 °C to dissolve, add trometamol for crystallization, spin dry, add 100 mL of acetone to the solid, heat under reflux for 2 h, cool down and filter by suction, dry to obtain 14.21 g of ketorolac trometamol crystals, with a yield of 96.32%. After determination, its X-ray powder diffraction pattern is consistent with Figure 1 basically the same. Example 7

[0034] Add 10.00 g of ketorolac to a reaction flask, add 30 mL of water, reflux for 1 h, filter by suction. Add 60 mL of acetone to the solid, slowly heat to 45 - 50 °C to dissolve, add trometamol for crystallization, spin dry. Add 100 mL of ethanol to the solid, heat under reflux for 2 h, cool down and filter by suction, dry to obtain 13.03 g of ketorolac trometamol crystals, with a yield of 88.32%. After determination, its X-ray powder diffraction pattern is Figure 1 substantially the same.

Claims

1. A new crystal form of ketorolac tromethamine, characterized in that: The X-ray powder diffraction pattern is expressed by 2θ as having diffraction peaks at 9.7±0.2°, 14.1±0.2°, 16.5±0.2°, 18.6±0.2°, 21.0±0.2°, 22.0±0.2°, and 22.9±0.2°.

2. The new crystalline form of ketorolac tromethamine according to claim 1, characterized in that The X-ray powder diffraction pattern is expressed by 2θ with diffraction peaks at 9.7±0.2°, 12.7±0.2°, 14.1±0.2°, 16.5±0.2°, 16.9±0.2°, 17.3±0.2°, 18.6±0.2°, 20.1±0.2°, 21.0±0.2°, 22.0±0.2°, 22.9±0.2°, 29.3±0.2°, and 35.3±0.2°.

3. The new crystal form of ketorolac tromethamine according to claim 1, characterized in that The new crystal form has an X-ray powder diffraction pattern as shown in FIG1 .

4. A method for preparing a new crystal form of ketorolac tromethamine, characterized in that: The preparation method is prepared by the following steps: adding ketorolac to water, refluxing for 1 hour, filtering with suction, adding organic solvent A to the solid, slowly heating to dissolve, adding tromethamine to crystallize, spin drying, adding organic solvent B to the solid, heating and refluxing for 2 hours, cooling and filtering with suction, and drying to obtain the target product.

5. The method for preparing the new crystal form of ketorolac tromethamine according to claim 4, characterized in that: The organic solvent A is one of methanol, ethanol, acetone, tetrahydrofuran and acetonitrile.

6. The method for preparing the new crystal form of ketorolac tromethamine according to claim 4, characterized in that: The feed ratio of the crude ketorolac product: organic solvent A: organic solvent B is 1:1-5:5-15, m / V / V, wherein the mass m of the crude ketorolac product is measured in g, and the volume V of the solvent is measured in mL.

7. The method for preparing the new crystal form of ketorolac tromethamine according to claim 4, characterized in that: The organic solvent B is one of ethanol, acetone, n-heptane, petroleum ether, n-hexane, and methyl tert-butyl ether.

8. The method for preparing the new crystal form of ketorolac tromethamine according to claim 4, characterized in that: The heating temperature is 40-90°C.

9. A use of the new crystalline form of ketorolac tromethamine as described in claims 1-3, characterized in that: Use as a nonsteroidal anti-inflammatory drug.

10. A pharmaceutical composition, characterized in that The composition comprises the new crystal form of ketorolac tromethamine as described in any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

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