Melogabalin-S-mandelic acid crystal form and preparation method thereof
By preparing the meregabalin-S-mandelic acid crystal form, the problem of impurities generated during the storage of meregabalin was solved, improving the solubility and stability of the drug and making it suitable for industrial production.
Patent Information
- Application Number
- CN202511050756.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-29
- Publication Date
- 2025-11-18
AI Technical Summary
In existing technologies, meregabrine generates various impurities during storage, affecting the safety, efficacy, stability, and controllability of the production process. Improving its stability and quality has become an urgent problem to be solved.
A melogabaline-S-mandelic acid crystal form was prepared by means of one molecule of melogabaline and one molecule of S-mandelic acid through a specific preparation method, including dissolution, heating, filtration, pH adjustment, cooling crystallization and vacuum drying steps, to form a crystal form with characteristic peaks in an X-ray diffraction pattern.
It improves the solubility and storage stability of melogabalin, reduces impurity content, enhances the consistency of drug quality and its antioxidant and anti-degradation properties, and is suitable for industrial production.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the technical field of pharmaceutical chemistry, and specifically relates to a meloxicam-S-mandelic acid crystal form and a preparation method thereof. BACKGROUND
[0002] Mirogabalin is a new type of selective alpha2delta-1 subunit modulator, which can reduce the release of excitatory neurotransmitters such as glutamate and substance P in the central nervous system by inhibiting the calcium ion influx of voltage-gated calcium channels, thereby relieving neuropathic pain. The drug was developed by Japan's First Sanjyo Corporation and approved in Japan on January 8, 2019. It is initially used for the treatment of peripheral neuropathic pain, including diabetic peripheral neuropathy and post-herpetic neuralgia. Subsequently, its indications have gradually expanded to central neuropathic pain. In clinical studies, mirogabalin has shown good efficacy and safety in Asian populations, especially in the treatment of diabetic peripheral neuropathy and post-herpetic neuralgia, with significantly better analgesic effect than placebo. In addition, mirogabalin also shows good efficacy in the treatment of neuropathic pain caused by lumbar spine disease, peripheral neuropathy caused by chemotherapy, and neuropathic pain caused by impaired liver and kidney function. It was approved in China in June 2024 for the treatment of diabetic peripheral neuropathic pain.
[0003] The marketed dosage form of mirogabalin is mirogabalin benzenesulfonate, with a CAS number of 1138245-21-2 and a chemical structure of C 18 H 25 NO5S, a molecular weight of 367.46. The drug is a white to slightly yellowish white powder, slightly soluble in 1,3-dimethyl-2-imidazolinone, methanol, ethanol and water, difficultly soluble in acetone, almost insoluble in acetonitrile, and extremely difficultly soluble in anisole and methyl tert-butyl ether. Mirogabalin benzenesulfonate has multiple chiral centers and unsaturated bonds, and multiple types of isomer (enantiomeric, diastereomeric, and double bond position isomer) impurities are generated during synthesis and storage. Different diastereomeric impurities are enantiomeric to each other, and different double bond position isomers are cis-trans isomers of each other.
[0004] The presence of impurities has a negative impact on various aspects of the drug, including safety, effectiveness, stability, and controllability of the production process. For example, impurities can affect the chemical stability of the drug, accelerating its degradation and thus shortening the shelf life of the drug. In addition, some impurities can be toxic, threatening the safety of drug use. At the same time, the presence of impurities reduces the purity of the drug, affecting the clinical efficacy. In the production process of mirogabalin benzenesulfonate, impurities can change the physicochemical properties of the drug, such as solubility and stability, thereby affecting the quality and effectiveness of the drug.
[0005] How to fundamentally solve the impurity problem of benzenesulfonic acid meloxicam during storage, improve the stability and quality of meloxicam, and provide a product with higher storage stability for clinical use has become a technical problem to be solved. SUMMARY
[0006] In view of the complex production process in the prior art, the present application provides a meloxicam-S-mandelic acid crystal form, which consists of one molecule of meloxicam and one molecule of S-mandelic acid as a basic structural unit. The crystal form of the present application improves the solubility, storage stability of meloxicam, reduces the impurity content, improves the quality of the product, and at the same time, the preparation method is simple and easy to operate, and has good application prospect in industrial production.
[0007] The technical scheme of the present application is as follows: a meloxicam-S-mandelic acid crystal form, the crystal form consists of one molecule of meloxicam and one molecule of S-mandelic acid as a basic structural unit, using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at least at 6.1±0.2°, 6.6±0.2°, 17.1±0.2°, 17.3±0.2°, 18.3±0.2°, 20.5±0.2°.
[0008] Preferably, the meloxicam-S-mandelic acid crystal form has characteristic peaks at least at 6.1±0.2°, 6.6±0.2°, 15.0±0.2°, 17.1±0.2°, 17.3±0.2°, 18.3±0.2°, 20.5±0.2°, 21.4±0.2°, 24.5±0.2° using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ.
[0009] Preferably, the meloxicam-S-mandelic acid co-crystal uses Cu-Kα radiation, and the characteristic peaks conform to the X-ray powder diffraction pattern as shown in Figure 1 .
[0010] Preferably, the meloxicam-S-mandelic acid crystal form has a molecular formula of C 20 H 27 NO5, and the crystallographic parameters are: monoclinic crystal system, space group P21, cell parameters: a=10.3729(3), b=6.4223(2), c=14.5936(4), α=90°, β=92.751(2)°, γ=90°, cell volume V=971.07(5).
[0011] The second aspect of the present application provides a preparation method of a meloxicam-S-mandelic acid crystal form, comprising the following steps:
[0012] S-mandelic acid is dissolved in a mixed solvent, then meloxicam is added, heated and stirred, filtered, pH regulator is added and stirring is continued, temperature is decreased to induce crystallization, filtered, washed with water, filtered, and vacuum dried to obtain the meloxicam-S-mandelic acid crystal form.
[0013] Preferably, in the preparation method, the molar ratio of meloxicam to S-mandelic acid is 1:0.8-3; further preferably, the molar ratio of meloxicam to S-mandelic acid is 1:2.
[0014] Preferably, the mass-volume ratio of meloxicam to the mixed solvent is 20.9:2-5, wherein the mass is in mg and the volume is in mL; further preferably, the mass-volume ratio of meloxicam to the mixed solvent is 20.9:3-4.
[0015] Preferably, in the preparation method, the mixed solvent is a mixed solvent of organic solvent A and organic solvent B, the organic solvent A is 1,3-dimethyl-2-imidazolidinone, and the organic solvent B is selected from one of ethanol, acetonitrile and water.
[0016] Further preferably, in the mixed solvent, the volume ratio of organic solvent A to organic solvent B is 4-7:1.
[0017] Preferably, in the preparation method, the heating temperature is 60-70℃; further preferably, the heating temperature is 65℃.
[0018] Preferably, in the preparation method, the pH regulator is a 1-2 mol / L hydrochloric acid or sulfuric acid solution, and the pH regulator is used to adjust the pH of the reaction solution to 5-6.
[0019] Preferably, in the preparation method, the pH regulator is added and stirring is continued for 1-2 h.
[0020] Preferably, in the preparation method, the temperature for temperature reduction and crystallization is 10-30℃.
[0021] Preferably, in the preparation method, the temperature for vacuum drying is 35-40℃, and the drying time is 3-5 h.
[0022] In the preparation method, the raw material meloxicam can be synthesized according to any method in the existing patent technology or purchased from a commercially available product.
[0023] In a third aspect of the present application, a pharmaceutical composition is provided, which contains the meloxicam-S-mandelic acid crystal form and other pharmaceutically acceptable components.
[0024] Confirmation of crystal structure
[0025] The X-ray crystal data of the meloxicam-S-mandelic acid crystal form of the present application in the test was collected on a Rigaku XtaLAB Synergy model instrument, at a test temperature of 293(2) K, with Cu-Ka radiation, in an omega scan mode, and Lp correction was performed. The structure was solved by direct method, and all non-hydrogen atoms were found by difference Fourier method, and all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least squares method.
[0026] The crystallographic data of the meloxicam-S-mandelic acid crystal form prepared in the present application (as shown in Table 1) is as follows: monoclinic crystal system, space group P21, cell parameters: a = 10.3729(3), b = 6.4223(2), c = 14.5936(4), α = 90°, β = 92.751(2)°, γ = 90°, cell volume V = 971.07(5).
[0027] Table 1 Main crystallographic data of meloxicam-S-mandelic acid crystal form
[0028]
[0029]
[0030] The ORTEP diagram of the meloxicam-S-mandelic acid crystal form of the present application shows that one molecule of meloxicam and one molecule of S-mandelic acid are contained in the crystal form, as shown in Figure 1. Figure 2 The hydrogen bond diagram of the meloxicam-S-mandelic acid of the present application is shown in Figure 2. According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in Figure 3 and Table 2. Figure 3 Figure 1
[0031] Table 2 PXRD peaks of meloxicam-S-mandelic acid crystal form
[0032]
[0033]
[0034] The meloxicam-S-mandelic acid crystal form samples prepared in Examples 1-5 in the specific embodiments of the present application all have the same crystallographic parameters and X-ray powder diffraction spectra as described above.
[0035] The meloxicam-S-mandelic acid crystal form of the present application is tested by TGA / DSC thermal analysis under the following conditions: Mettler-Toledo TGA / DSC thermal analyzer (model: TGA / DSC 3P evo), sample weight: 5-10 mg, heating rate: 10°C / min, temperature range: 25-300°C, nitrogen flow rate: 50 mL / min. 3+ ), dynamic temperature range: 30-300℃, heating rate: 10℃ / min, program gas N2, flow rate: 50 mL / min, crucible: aluminum crucible 40 μL.
[0036] The TGA / DSC test result of the meloxicam-S-mandelic acid crystal form prepared by the method of the present application is shown in the following table: Figure 4 As shown: there is a strong endothermic peak at 149.43-158.50℃, which is the melting point of the meloxicam-S-mandelic acid co-crystal.
[0037] Compared with the prior art, the present application has the following technical effects:
[0038] 1. The meloxicam-S-mandelic acid crystal form obtained by the present application has high dissolution rate and stability, reduces impurity content, improves product quality, and enhances stability and consistency during storage and transportation;
[0039] 2. The crystal form obtained by the present application is more uniform during storage, and has higher antioxidant and anti-degradation properties than the marketed meloxicam benzenesulfonate;
[0040] 3. The preparation method of the crystal form of the present application is simple and easy to operate, and has good prospects for industrialized production. BRIEF DESCRIPTION OF DRAWINGS
[0041] Figure 1 . PXRD spectrum of meloxicam-S-mandelic acid crystal form.
[0042] Figure 2 . ORTEP diagram of meloxicam-S-mandelic acid crystal form.
[0043] Figure 3 . Hydrogen bond diagram of meloxicam-S-mandelic acid crystal form.
[0044] Figure 4 . DSC-TGA diagram of meloxicam-S-mandelic acid crystal form. DETAILED DESCRIPTION
[0045] The following specific embodiments are listed to further illustrate the present application, but in no way limit the scope of the present application. Those skilled in the art can make various modifications or improvements based on the basic idea of the present application, as long as they do not deviate from the basic idea of the present application, and are within the scope of the present application.
[0046] Example 1
[0047] S- mandelic acid was dissolved in mixed solvent (1,3-dimethyl-2-imidazolidinone 3.2 mL, ethanol 0.8 mL), then 20.9 mg of milnacian was added, heated and stirred at 65°C, filtered, the pH of the reaction solution was adjusted to 5 using 1 mol / L hydrochloric acid solution, continued to stir for 1 h, cooled to 10-12°C, and crystallized, filtered, washed with water three times, filtered, and dried at 35-40°C under vacuum for 4 h to obtain the milnacian-S-mandelic acid crystal form, with a yield of 97.2% and a purity of 99.97%.
[0048] Example 2
[0049] S- mandelic acid was dissolved in mixed solvent (1,3-dimethyl-2-imidazolidinone 3.2 mL, ethanol 0.8 mL), then 20.9 mg of milnacian was added, heated and stirred at 65°C, filtered, the pH of the reaction solution was adjusted to 5 using 1 mol / L hydrochloric acid solution, continued to stir for 1 h, cooled to 10-12°C, and crystallized, filtered, washed with water three times, filtered, and dried at 35-40°C under vacuum for 4 h to obtain the milnacian-S-mandelic acid crystal form, with a yield of 97.2% and a purity of 99.97%.
[0050] Example 3
[0051] S- mandelic acid was dissolved in mixed solvent (1,3-dimethyl-2-imidazolidinone 3.2 mL, ethanol 0.8 mL), then 20.9 mg of milnacian was added, heated and stirred at 65°C, filtered, the pH of the reaction solution was adjusted to 5 using 1 mol / L hydrochloric acid solution, continued to stir for 1 h, cooled to 10-12°C, and crystallized, filtered, washed with water three times, filtered, and dried at 35-40°C under vacuum for 4 h to obtain the milnacian-S-mandelic acid crystal form, with a yield of 97.2% and a purity of 99.97%.
[0052] Example 4
[0053] S- mandelic acid was dissolved in mixed solvent (1,3-dimethyl-2-imidazolidinone 3.2 mL, ethanol 0.8 mL), then 20.9 mg of milnacian was added, heated and stirred at 65°C, filtered, the pH of the reaction solution was adjusted to 5 using 1 mol / L hydrochloric acid solution, continued to stir for 1 h, cooled to 10-12°C, and crystallized, filtered, washed with water three times, filtered, and dried at 35-40°C under vacuum for 4 h to obtain the milnacian-S-mandelic acid crystal form, with a yield of 97.2% and a purity of 99.97%.
[0054] Example 5
[0055] S-mandelic acid was dissolved in mixed solvent (1,3-dimethyl-2-imidazolidinone 3.2 mL, ethanol 0.8 mL), then 20.9 mg of memantine was added, heated and stirred at 65 ℃, filtered, cooled and crystallized at 10-12 ℃, filtered, and dried at 35-40 ℃ under vacuum for 4 h to obtain memantine-S-mandelic acid crystal form, with a yield of 76.5% and a purity of 99.95%.
[0056] Comparative Example 1
[0057] Memantine (8.0 g) was dissolved in anisole (156 mL), and then benzenesulfonic acid (6.29 g) dissolved in anisole (20 mL) was added dropwise thereto at a controlled dropping speed, with a dropping time of 2 h; after the addition was completed, anisole (8 mL) was added to the suspension, and the mixture was stirred at room temperature for 1.5 h; then acetone (40 mL) was added, and the mixture was further stirred for 1.5 h, and then cooled to 2 ℃; the suspension was filtered, the separated solid was washed with cooled acetone (28 mL), and dried under reduced pressure to obtain the desired benzenesulfonic acid memantine crystal form I, with a yield of 93.9% and a purity of 99.93%.
[0058] Verification Example
[0059] Experimental Example 1: Solubility Investigation
[0060] The solubility of the memantine crystal forms obtained in Experimental Example 1 and Comparative Example 1 in water was determined by the following method: 10 mL of water was taken in a vial, and an excess amount of the sample to be tested was added, the vial was sealed, and placed in a 25 ℃ constant-temperature water bath for stirring for 24 h, then filtered through a 0.45 μm filter membrane, and the filtrate was determined for the content of the sample in the saturated solution by high performance liquid chromatography.
[0061] The results show that the solubility of the memantine-S-mandelic acid crystal form prepared in the application is 16.2 mg / mL, while the solubility of the benzenesulfonic acid memantine crystal form I obtained in Comparative Example 1 is 5.35 mg / mL. It can be seen that the solubility of the memantine-S-mandelic acid crystal form prepared in the application is significantly improved compared with the benzenesulfonic acid memantine crystal form I.
[0062] Experimental Example 2: Stability Investigation of Crystal Form
[0063] The related substance content of the memantine crystal forms obtained in Experimental Example 1 and Comparative Example 1 after open storage for 10 days under high temperature (60 ℃), high humidity (25 ℃, relative humidity 90±5%), and strong light irradiation (irradiance 4500±500 lx) conditions was determined, and the experimental results are shown in Table 2.
[0064] Table 2: Stability test results of samples
[0065]
[0066] The results show that the meloxicam-S-mandelic acid crystal form prepared in the application has lower related substance content and better stability in high temperature, high humidity and strong light irradiation experiments; and the stability of the benzenesulfonic acid meloxicam-crystal form I obtained in the comparative example is poor.
[0067] Example 3 investigates the stability of the crystal form in forced degradation test
[0068] The investigation of the stability of the meloxicam crystal form obtained in Example 1 and Comparative Example 1 in the forced degradation test is helpful to evaluate the changes in the physical and chemical properties of the drug under extreme conditions, guide the optimization of the formula and process, and ensure the safety and effectiveness of the drug during storage and use, which is an important part of drug research and development and quality control.
[0069] During the storage of benzenesulfonic acid meloxicam, degradation impurities such as the following structure may be produced, therefore, the stability of the newly prepared crystal form in the forced degradation test is investigated:
[0070]
[0071] Acid degradation test: take about 20 mg of the test sample, place it in a 10 mL volumetric flask, add 1 mL of 0.1 mol / L HCl aqueous solution, place it for 3 h, then add 0.1 mol / L NaOH aqueous solution to adjust the pH to about 7, dilute to the mark with blank solvent, shake well, and take it as the acid degradation sample to determine the related substance content.
[0072] Alkaline degradation test: take about 20 mg of the test sample, place it in a 10 mL volumetric flask, add 1 mL of 0.1 mol / L NaOH aqueous solution, place it for 3 h, then add 0.1 mol / L HCl aqueous solution to adjust the pH to about 7, dilute to the mark with blank solvent, shake well, and take it as the alkaline degradation sample to determine the related substance content.
[0073] Oxidative degradation test: take about 20 mg of the test sample, place it in a 10 mL volumetric flask, add 1 mL of 1% H2O2 solution, dilute to the mark with blank solvent, shake well, and take it as the oxidative degradation sample to determine the related substance content.
[0074] Table 2 Stability test results of the samples
[0075]
[0076] The results show that, under the forced degradation condition, compared with the benzenesulfonic acid meloxicam-Form I obtained in Comparative Example 1, the meloxicam-S-mandelic acid crystal form prepared in the application exhibits excellent stability, which can effectively guarantee the quality of the drug during storage and transportation, reduce the influence of environmental factors on the stability of the drug, thereby facilitating the extension of the effective period of the product.
Claims
1. A melogabalin-S-mandelic acid crystal form, characterized in that, The crystal form consists of a basic structural unit composed of one molecule of melogabalin and one molecule of S-mandelic acid.
2. The crystal form as described in claim 1, characterized in that, The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 6.1±0.2°, 6.6±0.2°, 17.1±0.2°, 17.3±0.2°, 18.3±0.2°, and 20.5±0.2°.
3. The crystal form as described in claim 1, characterized in that, The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 6.1±0.2°, 6.6±0.2°, 15.0±0.2°, 17.1±0.2°, 17.3±0.2°, 18.3±0.2°, 20.5±0.2°, 21.4±0.2°, and 24.5±0.2°.
4. The crystal form as described in claim 1, characterized in that, The crystal form was subjected to Cu-Kα radiation, and its characteristic peaks corresponded to the X-ray powder diffraction pattern shown in Figure 1.
5. The crystal form as described in claim 1, characterized in that, The molecular formula of the crystal form is C 20 H 27 NO5 has the following crystallographic parameters: monoclinic crystal system, space group P21, cell parameters: a = 10.3729(3), b = 6.4223(2), c = 14.5936(4), α = 90°, β = 92.751(2)°, γ = 90°, and cell volume V = 971.07(5).
6. A method for preparing the crystal form as described in claim 1, characterized in that, The method includes the following steps: dissolving S-mandelic acid in a mixed solvent, then adding melogabalin, heating and stirring, filtering, adding a pH adjuster and continuing to stir, cooling to crystallize, filtering, washing with water, filtering again, and vacuum drying to obtain melogabalin-S-mandelic acid crystal form.
7. The method as described in claim 6, characterized in that, In the method, the molar ratio of melogabalin to S-mandelic acid is 1:0.8-3.
8. The method as described in claim 6, characterized in that, In the method, the mass-to-volume ratio of melogabalin to the mixed solvent is 20.9:2-5, where mass is expressed in mg and volume in mL.
9. The method as described in claim 6, characterized in that, In the method, the mixed solvent is a mixture of organic solvent A and organic solvent B, wherein organic solvent A is 1,3-dimethyl-2-imidazolinone, and organic solvent B is selected from ethanol, acetonitrile, and water.
10. The method as described in claim 6, characterized in that, In the method, the pH adjuster is a 1-2 mol / L hydrochloric acid or sulfuric acid solution, and the pH of the reaction solution is adjusted to 5-6 using the pH adjuster.