A co-crystal of ketorolac and piperazine and a method for preparing the same

Abstract

The present application belongs to the technical field of medicine crystallization, and particularly relates to a ketorolac and piperazine co-crystal crystal form and a preparation method thereof. The co-crystal has characteristic peaks at 8.0+ / -0.2°, 9.8+ / -0.2°, 13.5+ / -0.2°, 16.1+ / -0.2°, 17.0+ / -0.2°, 18.3+ / -0.2°, 19.5+ / -0.2°, 19.6+ / -0.2°, 19.9+ / -0.2° and 28.7+ / -0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation. The co-crystal preparation process is simple, the process is easy to control, the stability is good, the solubility of ketorolac in water is significantly improved, and under the condition of the same prescription, the tablet prepared by taking the co-crystal as an active ingredient has a faster dissolution rate and a higher dissolution degree, and is more suitable for being made into an oral preparation.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug crystallization, in particular to a ketorolac and piperazine co-crystal and a preparation method thereof. BACKGROUND

[0002] Ketorolac is a strong analgesic and moderate anti-inflammatory non-steroidal anti-inflammatory drug. The analgesic effect of ketorolac is equivalent to that of morphine, and is stronger than that of aspirin, indomethacin and naproxen. Ketorolac is almost insoluble in water. The currently marketed drug is ketorolac tromethamine, which is converted into ketorolac in vivo to exert efficacy. However, ketorolac tromethamine is unstable to light, heat, acid and base, and is prone to decarboxylation and oxidation to produce impurities, which to some extent affects the safety of clinical drug use.

[0003] At present, there are many reports about ketorolac, but most of them are about the preparation, derivatives, preparations, physicochemical properties and pharmacological properties of ketorolac. For example, Chinese patent CN108191876A discloses a synthesis process of ketorolac. The document "Solid Dispersion of Hydroxypropyl β-Cyclodextrin and Ketorolac: Enhancement of In-vitro Dissolution Rates, Improvement in Anti-inflammatory Activity and Reduction in Ulcerogenicity in Rats" uses β-cyclodextrin and ketorolac to prepare a solid dispersion to improve the solubility of ketorolac. However, the preparation process is complex, and the stability is poor.

[0004] Ketorolac exists in polymorphism, the literature Crystal Forms of Ketorolac (Arch Pharm Res, 2004, 27, 357-360) discloses the crystal form characterization data and preparation method of ketorolac crystal form I, crystal form II, crystal form III, crystal form IV, and the solubility and stability of crystal form I~IV are studied. The results show that the solubility of crystal form I is the highest, but 10 mg of crystal form I needs about 3 hours to completely dissolve in 1 L distilled water, crystal form II~IV cannot completely dissolve, especially crystal form IV, only 64% can be dissolved after 5 hours; crystal form I and crystal form III have good stability, but crystal form II and crystal form IV will appear crystal transformation phenomenon. The literature Crystal Structure of (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid, Ketorolac (Analytical Science, 2008, 24, 205-206) uses ethanol to dissolve and slowly evaporate to crystallize, and the obtained ketorolac crystal is characterized by crystallography, but the properties of the crystal are not studied. The literature "Resolution and Determination of Absolute Configuration of Photoactive Ketorolac Derivatives" discloses a ketorolac proline benzyl ester amide single crystal, but the physical and chemical properties thereof are not studied. Chinese patent CN110540542A discloses an S-ketorolac sodium salt and a preparation method thereof, but the yield of the obtained S-ketorolac sodium salt is low, which is not suitable for industrial production.

[0005] Overall, the solubility and stability of ketorolac prepared by the prior art still need to be further improved. The ketorolac and piperazine co-crystal prepared by the drug crystallization method can significantly improve the solubility and stability of ketorolac. SUMMARY

[0006] In view of the deficiencies of the prior art, the present application provides a ketorolac and piperazine co-crystal. Ketorolac as a drug component of the present application has a chemical name of (+ / -)-5-benzoyl-2,3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid, which is a white crystal or white powder. CAS number: 74103-06-3, molecular formula is C 15 H 13 NO3, the structural formula is shown as a, and the selected crystal former in the present application is piperazine, the molecular formula is C4H 10 N2, the structural formula is shown as b.

[0007]

[0008] The ketorolac and piperazine co-crystal has an X-ray diffraction spectrum with characteristic peaks at 8.0±0.2°, 9.8±0.2°, 13.5±0.2°, 16.1±0.2°, 17.0±0.2°, 18.3±0.2°, 19.5±0.2°, 19.6±0.2°, 19.9±0.2°, 28.7±0.2°, using Cu-Kα radiation, expressed in 2θ.

[0009] Preferably, the ketorolac and piperazine co-crystal has an X-ray diffraction spectrum with characteristic peaks at 8.0±0.2°, 9.8±0.2°, 12.5±0.2°, 13.5±0.2°, 16.1±0.2°, 17.0±0.2°, 18.3±0.2°, 19.5±0.2°, 19.6±0.2°, 19.9±0.2°, 20.2±0.2°, 20.3±0.2°, 23.1±0.2°, 24.2±0.2°, 25.7±0.2°, 28.7±0.2°, 32.1±0.2°, using Cu-Kα radiation, expressed in 2θ.

[0010] Preferably, the ketorolac and piperazine co-crystal has an X-ray powder diffraction spectrum as shown in the figure. Figure 1

[0011] Preferably, the ketorolac and piperazine co-crystal has a molecular formula of C 19 H 23 N3O3, and crystallographic parameters are as follows: orthorhombic system, space group P212121, cell parameters are as follows: α=90°, β=90°, γ=90°, cell volume

[0012] Preferably, the ketorolac and piperazine co-crystal has a DSC spectrum with an endothermic peak in the range of 164.66-198.34℃, and the peak value of the corresponding endothermic peak is 189.42℃.

[0013] In the second aspect of the present application, a preparation method of a ketorolac and piperazine co-crystal form is provided, and the specific steps include: mixing ketorolac and piperazine sufficiently, grinding to obtain a mixed powder; adding the mixed powder into a solvent, heating and stirring to dissolve, and then crystallizing after the solution is clarified, filtering and drying to obtain the ketorolac and piperazine co-crystal.

[0014] Preferably, the solvent is selected from one or more of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile and water; and more preferably, the solvent is selected from one or two of methanol, acetone and acetonitrile.

[0015] ​Preferably, the mass volume ratio of the ketorolac to the solvent is 4.0-6.5:1, wherein the mass is in mg and the volume is in ml.

[0016] Preferably, the molar ratio of the ketorolac to the piperazine is 1:1-2; further preferably 1:1.0-1.2.

[0017] Preferably, the temperature for the heating dissolution is 40-60℃; further preferably 50℃.

[0018] Preferably, the heating time is 1-3h.

[0019] Preferably, the crystallization time is 24-48h.

[0020] The third aspect of the present application provides a pharmaceutical composition comprising the ketorolac-piperazine co-crystal prepared above, and comprising other pharmaceutically acceptable components.

[0021] Preferably, the pharmaceutical composition of the present application is prepared by using standard and conventional techniques to combine the compound of the present application with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients to prepare a dosage form.

[0022] Preferably, the other pharmaceutically acceptable components include other active ingredients that can be used in combination, fillers, diluents, binders, disintegrants, lubricants, etc.; further preferably, the diluents are selected from one or more of starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol, sorbitol; the binders are selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium hydroxymethyl cellulose, ethyl cellulose and povidone; the disintegrants are selected from one or more of sodium carboxymethyl starch, low-substitution hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked povidone; the lubricants are selected from one or more of magnesium stearate, microfine silica, talc and sodium dodecyl sulfate.

[0023] Preferably, the pharmaceutical composition is a tablet, a capsule, a granule and a pill, etc.

[0024] The fourth aspect of the present application also provides the use of the ketorolac-piperazine co-crystal in the preparation of an anti-inflammatory analgesic drug.

[0025] Confirmation of the crystal structure

[0026] X-ray crystal data were collected on a Rigaku XtaLAB Synergy model instrument at a temperature of 293(2) K with Cu Ka radiation, in an omega scan mode and Lp correction. The structure was solved by direct methods, all non-hydrogen atoms were found by difference Fourier methods, all hydrogens on carbon and nitrogen were placed in calculated positions, and the structure was refined by least squares methods.

[0027] The crystallographic data of the prepared ketorolac and piperazine co-crystal crystalline form of the present application (as shown in Table 1) is as follows: its crystallographic parameters are: orthorhombic, space group P212121, cell parameters are: α = 90°, β = 90°, γ = 90°, cell volume

[0028] Table 1 Main crystallographic data of zolpidem-succinic acid co-crystal

[0029]

[0030]

[0031] The ORTEP diagram of the ketorolac and piperazine co-crystal of the present application shows that one molecule of ketorolac is combined with one molecule of piperazine in the crystalline form, as shown in the accompanying Figure 3 The hydrogen bond diagram of the ketorolac and piperazine co-crystal of the present application is shown in the accompanying Figure 4 According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in the accompanying Figure 1 and Table 2.

[0032] Table 2 PXRD peaks of ketorolac and piperazine co-crystal

[0033]

[0034]

[0035] The TGA / DSC thermal analysis tester and test conditions in the present application: TGA / DSC thermal analyzer: METTLER TOLEDO TGA / DSC 3+ ; dynamic temperature range: 30-300℃; heating rate: 10℃ / min; program gas: N2; gas flow: 50mL / min; crucible: aluminum crucible 40μl.

[0036] The TGA / DSC test results of the prepared ketorolac and piperazine co-crystal of the present application are as follows: Figure 2As shown in the DSC spectrum, an endothermic peak appears in the range of 164.66-198.34 °C, and the peak value of the endothermic peak is 189.42 °C. The thermal gravimetric analysis (TGA) only has one weight loss step, indicating that the ketoprofen and piperazine co-crystal does not have a solvent, and the structure is stable.

[0037] The ketoprofen and piperazine co-crystal provided by the present application has the following advantages over the existing ketoprofen crystal form:

[0038] (1) The HPLC purity of the ketoprofen and piperazine co-crystal crystal form is still higher than 99% after high temperature test and high humidity environment placement, and the crystal form does not change after 6 months of storage under accelerated conditions, and the stability is good.

[0039] (2) The solubility of the ketoprofen crystal form in water is significantly improved, and the dissolution rate of the tablet prepared by using the same prescription as the active ingredient is faster, the dissolution is higher, and it is more suitable for oral preparation.

[0040] (3) The preparation method is simple to operate, the crystallization process is easy to control, the reproducibility is good, and it is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 . PXRD spectrum of ketoprofen and piperazine co-crystal.

[0042] Figure 2 . PXRD spectrum of ketoprofen and piperazine co-crystal.

[0043] Figure 3 . ORTEP diagram of ketoprofen and piperazine co-crystal.

[0044] Figure 4 . Hydrogen bond diagram of ketoprofen and piperazine co-crystal. DETAILED DESCRIPTION

[0045] The present application will be further illustrated by the following examples, which should be correctly understood: the examples of the present application are only used to illustrate the present application, and are not limited to the present application, so that the simple improvement of the present application under the premise of the method of the present application is within the scope of the present application. The raw materials and reagents used in the present application are commercially available.

[0046] Example 1

[0047] After mixing 255.27 mg of ketoprofen and 86.13 mg of piperazine, grinding, adding the mixed powder into 40 mL of acetone, ultrasonic assisted dissolution, then heating and stirring at 40 °C for 2 h, filtering, and the filtrate was placed at room temperature for 36 h to crystallize. After the crystal was precipitated, the crystal was filtered and dried to obtain the ketoprofen and piperazine co-crystal, with a yield of 86.3% and HPLC purity of 99.91%.

[0048] Example 2

[0049] The ketorolac and piperazine were mixed and ground, the mixed powder was added into 40 mL acetonitrile, and then was ultrasonically dissolved. The mixture was stirred at 50°C for 2 hours, and then was filtered. The filtrate was left to stand at room temperature for 36 hours to crystallize. After the crystals were precipitated, the crystals were filtered and dried to obtain the ketorolac and piperazine co-crystal, with a yield of 88.2% and HPLC of 99.84%.

[0050] Example 3

[0051] The ketorolac and piperazine were mixed and ground, the mixed powder was added into 20 mL acetone and 20 mL methanol, and then was ultrasonically dissolved. The mixture was stirred at 50°C for 3 hours, and then was filtered. The filtrate was left to stand at room temperature for 24 hours to crystallize. After the crystals were precipitated, the crystals were filtered and dried to obtain the ketorolac and piperazine co-crystal, with a yield of 82.6% and HPLC of 99.86%.

[0052] Example 4

[0053] The ketorolac and piperazine were mixed and ground, the mixed powder was added into 60 mL methanol, and then was ultrasonically dissolved. The mixture was stirred at 50°C for 1 hour, and then was filtered. The filtrate was left to stand at room temperature for 48 hours to crystallize. After the crystals were precipitated, the crystals were filtered and dried to obtain the ketorolac and piperazine co-crystal, with a yield of 83.7% and HPLC of 99.83%.

[0054] Example 5

[0055] The ketorolac and piperazine were mixed and ground, the mixed powder was added into 20 mL ethanol and 20 mL methanol, and then was ultrasonically dissolved. The mixture was stirred at 50°C for 2 hours, and then was filtered. The filtrate was left to stand at room temperature for 48 hours to crystallize. After the crystals were precipitated, the crystals were filtered and dried to obtain the ketorolac and piperazine co-crystal, with a yield of 78.6% and HPLC of 99.85%.

[0056] Example 6

[0057] The ketorolac and piperazine were mixed and ground, the mixed powder was added into 20 mL tetrahydrofuran and 20 mL water, and then was ultrasonically dissolved. The mixture was stirred at 50°C for 2 hours, and then was filtered. The filtrate was cooled at 10-15°C for 48 hours to crystallize. After the crystals were precipitated, the crystals were filtered and dried to obtain the ketorolac and piperazine co-crystal, with a yield of 72.5% and HPLC of 99.82%.

[0058] Example 7

[0059] Dissolve 255.27 mg of ketorolac in 40 mL of methanol, filter, then let crystals precipitate at room temperature, after the crystals precipitate, filter and dry to obtain a ketorolac crystal form, with a yield of 64.50% and a purity of 99.89%.

[0060] Comparative Example 1

[0061] Dissolve 255.27 mg of ketorolac in 40 mL of methanol, filter, then let crystals precipitate at room temperature, after the crystals precipitate, filter and dry to obtain a ketorolac crystal form, with a yield of 64.50% and a purity of 99.89%.

[0062] Comparative Example 2 Ketorolac Crystal Form I

[0063] Dissolve 255.27 mg of ketorolac in 40 mL of methanol, filter, then let crystals precipitate at room temperature, after the crystals precipitate, filter and dry to obtain a ketorolac crystal form, with a yield of 64.50% and a purity of 99.89%.

[0064] Verification Example

[0065] 1. Stability Test

[0066] (1) Test materials: the ketorolac and piperazine co-crystal prepared in Example 1, the crystal form of Comparative Example 1, and the crystal form of Comparative Example 2.

[0067] (2) Test method: The test was performed according to the method of <9001 Raw Materials and Preparation Stability Test Guidelines> in Appendix IV of the Chinese Pharmacopoeia (2020 Edition), high temperature test conditions: 60℃; strong light irradiation test conditions: 4500lx±500lx; high humidity test conditions: temperature 25℃, relative humidity 90%±5%. Purity was detected by HPLC method, and three parallel tests were performed, and the average value was taken.

[0068] (3) Test results: The test results are shown in Table 3.

[0069] Table 3 Determination results of stability test

[0070]

[0071] Note: The ketorolac and piperazine co-crystal prepared in the example of the present application has the same stability as the crystal form of Example 1.

[0072] The experimental results show that the ketorolac and piperazine co-crystal prepared in the present application has high purity, and the sample purity changes little under high temperature, high humidity, and strong light conditions, and has good stability. In addition, the ketorolac and piperazine co-crystal prepared in the present application is stored at a relative humidity of 75±5% and a temperature of 25℃ for 60 days, and its PXRD shows that the crystal form is stable and no crystal transformation occurs.

[0073] 2. Solubility test

[0074] (1) Test material: ketoprofen and piperazine co-crystal prepared in Example 1, Form 1 of Comparative Example 1, and Form 2 of Comparative Example 2.

[0075] (2) Test method: The solubility test was performed according to the relevant content of Chinese Pharmacopoeia (2020 edition). 900 ml of medium (water) was weighed into a reaction bottle, and an excess amount of the drug was added. The reaction bottle was sealed and placed in a 37°C water bath for constant temperature stirring for 1 hour. The filtrate was filtered through a 0.2 μm filter membrane, and the absorbance was measured at a wavelength of 313 nm. The solubility was calculated by comparing the absorbance of the test standard with that of the control.

[0076] (3) Test results: The solubility test results are shown in Table 4.

[0077] Table 4 Solubility of different ketoprofen crystal forms in water

[0078] Sample Solubility (mg / mL) Ketorolac prepared in Example 1 with piperazine co-crystal 0.96 Crystalline form of Comparative Example 1 0.15 Crystalline form of Comparative Example 2 0.10

[0079] Note: The ketoprofen and piperazine co-crystal prepared in the present application has the same solubility as the Form 1 crystal of Example 1.

[0080] The experimental results show that the ketoprofen and piperazine co-crystal prepared in the present application has a significantly improved solubility in water compared to other ketoprofen crystal forms, which helps to improve its bioavailability.

[0081] 3. Dissolution test of oral preparation

[0082] Ketoprofen and piperazine co-crystal, Form 1 of Comparative Example 1, and Form 2 of Comparative Example 2 were used as active ingredients to prepare 100 tablets (10 mg / tablet) according to the following method:

[0083] Weight component (%): ketoprofen 1 g, lactose 9 g, sodium carboxymethyl starch 1.8 g, magnesium stearate 0.18 g, and silicon dioxide 0.05 g.

[0084] Preparation method: The active ingredient was sieved through an 80 mesh sieve, then mixed with other excipients, and then compressed into tablets.

[0085] Dissolution test: The tablets prepared above were tested according to the dissolution test method (2015 edition, Part 4, General Rule 0931, Second Method for Dissolution Test). The dissolution medium was 600 mL of water, the rotation speed was 50 r / min, and the operation was carried out according to the method. The cumulative dissolution at different times was measured at 5, 10, 15, 30, 45, and 60 min. The dissolution results are shown in Table 5.

[0086] Table 5 Cumulative dissolution of tablets prepared from different crystal forms

[0087]

[0088]

[0089] The results show that ketorolac and piperazine co-crystal is more suitable for oral preparation than other ketorolac crystal forms because the dissolution rate and dissolution degree of the common tablet prepared from ketorolac and piperazine co-crystal are higher.

Claims

1. A ketorolac co-crystal with piperazine, characterized in that, The eutectic was subjected to Cu-Kα radiation, and its X-ray diffraction pattern, expressed in 2θ, showed characteristic peaks at 8.0±0.2°, 9.8±0.2°, 13.5±0.2°, 16.1±0.2°, 17.0±0.2°, 18.3±0.2°, 19.5±0.2°, 19.6±0.2°, 19.9±0.2°, and 28.7±0.2°.

2. The ketorolac and piperazine co-crystal as described in claim 1, characterized in that, The eutectic was subjected to Cu-Kα radiation, and its X-ray diffraction pattern, expressed in 2θ, showed characteristic peaks at 8.0±0.2°, 9.8±0.2°, 12.5±0.2°, 13.5±0.2°, 16.1±0.2°, 17.0±0.2°, 18.3±0.2°, 19.5±0.2°, 19.6±0.2°, 19.9±0.2°, 20.2±0.2°, 20.3±0.2°, 23.1±0.2°, 24.2±0.2°, 25.7±0.2°, 28.7±0.2°, and 32.1±0.2°.

3. The ketorolac and piperazine co-crystal as described in claim 1, characterized in that, The eutectic was irradiated with Cu-Kα radiation, and its characteristic peaks conformed to the X-ray powder diffraction pattern shown in Figure 1.

4. The ketorolac and piperazine co-crystal as described in claim 1, characterized in that, The eutectic belongs to an orthorhombic crystal system with space group P212121. Its cell parameters are: a = 7.18970(10) Å, b = 13.9887(2) Å, c = 17.7645(3) Å, α = 90°, β = 90°, γ = 90°, and cell volume V = 1786.66(5) Å. 3 .

5. A method for preparing the ketorolac and piperazine co-crystal according to any one of claims 1-4, characterized in that, The process includes the following steps: thoroughly mixing ketorolac and piperazine, grinding them to obtain a mixed powder; adding the mixed powder to a solvent, heating and stirring to dissolve it, clarifying the solution, allowing it to stand at room temperature to crystallize, filtering and drying to obtain a ketorolac-piperazine cocrystal.

6. The preparation method according to claim 5, characterized in that, The mass-to-volume ratio of the ketorolac to the solvent is 4.0–6.5:1, where the mass is expressed in mg and the volume in mL.

7. The preparation method according to claim 5, characterized in that, The solvent is selected from one or more of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, and water.

8. The preparation method according to claim 5, characterized in that, The molar ratio of ketorolac to piperazine is 1:1 to 2.

9. The preparation method according to claim 5, characterized in that, The molar ratio of ketorolac to piperazine is 1:1.0 to 1.

2.

10. The preparation method according to claim 5, characterized in that, The heating and melting temperature is 40–60°C.

11. The preparation method according to claim 5, characterized in that, The heating and melting temperature is 50°C.

12. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the ketorolac and piperazine cocrystal as described in any one of claims 1-3 and other pharmaceutically acceptable excipients.

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