CN118063407A

CN118063407A - Riluzole-mandelic acid crystal form

Info

Publication number: CN118063407A
Application number: CN202211476777.6A
Authority: CN
Inventors: 刘忠; 翟立海; 郑家芳; 夏祥来; 张明明
Original assignee: Shandong New Time Pharmaceutical Co Ltd
Current assignee: Shandong New Time Pharmaceutical Co Ltd
Priority date: 2022-11-23
Filing date: 2022-11-23
Publication date: 2024-05-24

Abstract

The invention belongs to the technical field of crystal form drug molecules, and particularly relates to a riluzole-mandelic acid crystal form and a preparation method thereof. The riluzole-mandelic acid crystal form provided by the invention uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has diffraction peaks at 6.7+/-0.2 degrees, 18.0+/-0.2 degrees, 18.5+/-0.2 degrees, 19.4+/-0.2 degrees and 26.8+/-0.2 degrees; the preparation method of the riluzole-mandelic acid crystal form provided by the invention is simple and efficient, is suitable for industrial production, and the prepared crystal form has high purity, good stability and good pharmacokinetic properties.

Description

Riluzole-mandelic acid crystal form

Technical Field

The invention belongs to the technical field of crystal form drug molecules, and particularly relates to a riluzole-mandelic acid crystal form and a preparation method thereof.

Background

Riluzole (riluzole), chemical name 2-amino-6-trifluoro methoxy benzothiazole, molecular formula C ₈H₅F₃N₂ OS, molecular weight 234.01, white or white crystalline powder, its structural formula is:

Riluzole was first developed by the us sirofie company as a successful drug for the treatment of amyotrophic lateral sclerosis (ALS, fraudulence), approved for the first time in the us FDA and EMEA in the european union, formally marketed in the united states in the same year, and subsequently marketed in the united kingdom, france, germany, the netherlands, belgium, etc., and marketed in china 1999.

Riluzole is a glutamic acid antagonist, and is a sodium channel blocking benzothiazole anticonvulsant. Riluzole inhibits presynaptic release of glutamate and binds to the receptor preventing glutamate activation, and also inactivates potential-dependent sodium channels on nerve endings and cell bodies, stimulating G-protein dependent signaling processes. In vitro, riluzole protects cultured motor neurons from the toxic effects of glutamate activation and prevents neuronal death in ALS patients due to hypoxia or exposure to toxic factors in CSF.

Riluzole, however, is a poorly soluble compound with a solubility of about 0.3mg/mL at neutral pH, and its dissolution is the rate limiting step in the absorption and utilization of drugs in vivo, thereby limiting its use in formulations. In addition, while riluzole increases in solubility under acidic conditions (about 12mg/mL at pH 1.2), its chemical stability decreases dramatically. Therefore, increasing the solubility of riluzole is one of the bottlenecks in its related formulation development.

Since different crystal forms can directly influence the solubility, dissolution rate, bioavailability, action with a target point and the like of a drug in vivo, further influence the exertion of drug effect, and in view of the important therapeutic action of riluzole, although pharmaceutically acceptable riluzole has been marketed for many years, researches on dominant pharmaceutical crystal forms of riluzole have been reported to predict eutectic/salts of riluzole from a discontinuous .Hepatoprotective Cocrystals and Salts of Riluzole:Prediction,Synthesis,Solid State Characterization and Evaluation.Cryst.Growth Des.,2018,18(2),1047-1061. through a model, dissolution tests are carried out on 5 preferred eutectic and 2 salts, a series of eutectic/salts of riluzole are prepared by the same method as that of riluzole-syringic acid with the highest dissolution rate ;Non-classical synthons:Supramolecular recognition via S^…Ochalcogen bonding in the molecular complexes of riluzole.CHEM-EUR J.,2019,25(14),3591-3597. in phosphate buffer medium with pH of 6.8, but the solvent drop grinding method is not adopted to research ;Exploring Solid State Diversity and SolutionCharacteristics in a fluorine-containing drug Riluzole,Cryst.Growth Des.,2017,17(4),1938–1946. on the solubility and other properties of riluzole, wherein the solubility of riluzole-malonic acid crystal form is the highest.

Although numerous riluzole co-crystals/salts have been disclosed in the prior literature, systematic studies on their crystalline forms are not comprehensive and remain to be perfected. Therefore, providing a new crystal form of riluzole with excellent stability and pharmacokinetic properties is a problem to be solved by those skilled in the art.

Disclosure of Invention

In view of the shortcomings of the prior art, the invention aims to provide a riluzole-mandelic acid crystal form and a preparation method thereof. The riluzole-mandelic acid crystal form provided by the invention has the advantages of good stability, good pharmacokinetic property, simplicity, easiness in obtaining and high patent medicine value.

In a first aspect of the invention, a crystal form of riluzole-mandelic acid is provided, wherein the molar ratio of riluzole to mandelic acid in the crystal unit of the co-crystal is 1:1.

A crystalline form of riluzole-mandelic acid, the co-crystal having characteristic peaks in terms of 2Θ, in an X-ray diffraction spectrum at 6.7 ± 0.2 °, 18.0 ± 0.2 °, 18.5 ± 0.2 °, 19.4 ± 0.2 °, 26.8 ± 0.2 ° using Cu-ka radiation.

Preferably, the co-crystal uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.7+/-0.2 degrees, 8.8+/-0.2 degrees, 15.4+/-0.2 degrees, 18.0+/-0.2 degrees, 18.5+/-0.2 degrees, 19.4+/-0.2 degrees, 23.0+/-0.2 degrees and 26.8+/-0.2 degrees.

Preferably, the co-crystal uses Cu-ka radiation and X-ray diffraction expressed in 2θ has characteristic peaks as shown in fig. 1.

Preferably, the riluzole-mandelic acid crystal form has a molecular formula of C ₁₆H₁₃F₃N₂O₄ S, and the crystallographic parameters are: monoclinic crystal system, space group is P21, unit cell parameterΑ=90 °, β= 104.8715 (6) °, γ=90°, unit cell volume/>

In another aspect, the invention provides a method for preparing the riluzole-mandelic acid crystal form, comprising the following steps: dissolving riluzole and mandelic acid in the mixed solvent, heating and stirring, filtering, cooling and standing, volatilizing and crystallizing, filtering and drying to obtain the final product.

Preferably, the mixed solvent is a mixed solvent of ethanol and other solvents, and the other solvents are ethyl acetate, acetonitrile, water, acetone or trifluoroethanol.

Further preferably, the mixed solvent is a mixed solvent of ethanol and acetone.

Preferably, the mass volume ratio of the riluzole to the mixed solvent is 15.7: 1-3, wherein the mass is in mg and the volume is in ml.

Further preferably, the mass-volume ratio of the riluzole to the mixed solvent is 15.7:1.2 to 1.5, wherein the mass is in mg and the volume is in ml.

Preferably, the volume ratio of the other solvents to ethanol in the mixed solvent is 1:1 to 2.

Preferably, the dosage mole ratio of the riluzole to the mandelic acid is 1:1.1-1.5.

Further preferably, the molar ratio of the riluzole to the mandelic acid is 1:1.2.

Preferably, the heating temperature is 50 to 70 ℃.

Preferably, the temperature of the cooling crystallization is 0-30 ℃.

Further preferably, the temperature of the cooling crystallization is 10-15 ℃.

Preferably, the crystallization time is 8-72 h.

Preferably, the drying temperature is 45-65 ℃.

Preferably, the drying time is 8 to 12 hours.

In a third aspect, the invention provides a pharmaceutical composition comprising the riluzole-mandelic acid crystalline form and a pharmaceutically acceptable additional component.

Such other components include other active ingredients, excipients, fillers, diluents, binders, disintegrants, lubricants, etc., which may be used in combination.

The preparation method of the pharmaceutical composition comprises the following steps: the crystalline form of riluzole-mandelic acid of the present invention is formulated into a useful dosage form in combination with other pharmaceutically acceptable ingredients using standard and conventional techniques.

Dosage forms of the pharmaceutical composition include, but are not limited to, tablets, capsules, granules and pills.

Crystal structure confirmation:

X-ray crystal data in the riluzole-mandelic acid crystal form test are collected on a Japanese society XtaLAB Synergy model instrument, the test temperature 293 (2) K is radiated by Cu-Ka, and the data are collected in an omega scanning mode and corrected by Lp. 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 crystallographic data of the crystal form of the riluzole-mandelic acid prepared by the invention: monoclinic crystal system, space group is P21, unit cell parameterΑ=90 °, β= 104.8715 (6) °, γ=90°, unit cell volume/>The specific results are shown in Table 1.

TABLE 1 riluzole-mandelic acid Crystal form main crystallographic data

The ORTEP diagram of the crystalline form of riluzole-mandelic acid of the present invention shows that the crystalline form contains one molecule of riluzole and one molecule of mandelic acid, as shown in fig. 2. The stacking chart of the riluzole-mandelic acid crystal forms of the invention is shown in figure 3. According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figures 1 and 2.

TABLE 2 principal X-ray powder diffraction characteristic peaks of riluzole-mandelic acid crystalline form

Compared with the prior art, the invention has the technical effects that:

(1) The riluzole-mandelic acid crystal form provided by the invention has good pharmacokinetic properties, has very strong pharmaceutical value, and is beneficial to improving clinical curative effect;

(2) The riluzole-mandelic acid crystal form has good stability, and is suitable for manufacturing and long-term storage of pharmaceutical preparations;

(3) The preparation method has the advantages of simple preparation process, easy control of crystallization process, good reproducibility and higher product yield, and is suitable for industrial production.

Drawings

Fig. 1: x-ray powder diffraction pattern of riluzole-mandelic acid crystalline form;

Fig. 2: ORTEP diagram of riluzole-mandelic acid crystalline form;

Fig. 3: a plot of riluzole-mandelic acid crystalline form.

Detailed Description

The invention is further illustrated by the following description of specific embodiments with the understanding that: the examples of the present invention are merely illustrative of the present invention and are not intended to be limiting. Therefore, simple modifications to the invention, which are within the scope of the claimed invention, are possible with the method of the invention.

Example 1

468.4Mg of riluzole and 365.2mg of mandelic acid are added into a mixed solvent of 15ml of acetone and 25ml of ethanol, water bath heating and stirring are carried out at 60 ℃, filtering is carried out, standing, volatilizing and crystallizing are carried out at 10-15 ℃ for 8h, filtering is carried out, drying is carried out at 50-55 ℃ for 8h, thus obtaining riluzole-mandelic acid crystal form, the yield is 96.2%, and the HPLC purity is 99.87%.

Example 2

468.4Mg of riluzole and 334.7mg of mandelic acid are added into a mixed solvent of 10ml of acetone and 20ml of ethanol, the mixed solvent is heated and stirred in a water bath at 50 ℃, filtered, kept stand at 20-25 ℃ for volatilization and crystallization for 72h, filtered, dried at 45-50 ℃ for 12h, and the riluzole-mandelic acid crystal form is obtained, the yield is 93.0%, and the HPLC purity is 99.76%.

Example 3

468.4Mg of riluzole and 456.4mg of mandelic acid are added into a mixed solvent of 45ml of trifluoroethanol and 45ml of ethanol, the mixed solvent is heated and stirred in a water bath at 70 ℃, filtered, kept stand at 0-5 ℃ for volatilization and crystallization for 24 hours, filtered, dried at 60-65 ℃ for 10 hours, and the riluzole-mandelic acid crystal form is obtained, the yield is 92.3%, and the HPLC purity is 99.70%.

Example 4

468.4Mg of riluzole and 365.2mg of mandelic acid are added into a mixed solvent of 15ml of ethyl acetate and 20ml of ethanol, the mixed solvent is heated and stirred in a water bath at 50 ℃, filtered, kept stand at 0-5 ℃ for volatilization and crystallization for 12 hours, filtered, dried at 50-55 ℃ for 8 hours, and the riluzole-mandelic acid crystal form is obtained, the yield is 95.1%, and the HPLC purity is 99.71%.

Example 5

468.4Mg of riluzole and 395.6mg of mandelic acid are added into a mixed solvent of 15ml of acetone and 30ml of ethanol, the mixed solvent is heated and stirred in a water bath at 60 ℃, filtered, kept stand at 10-15 ℃ for volatilizing and crystallizing for 8 hours, filtered, dried at 45-50 ℃ for 12 hours, and the riluzole-mandelic acid crystal form is obtained, the yield is 94.5%, and the HPLC purity is 99.82%.

Example 6

468.4Mg of riluzole and 608.6mg of mandelic acid are added into a mixed solvent of 20ml of acetone and 35ml of ethanol, water bath heating and stirring are carried out at 60 ℃, filtering is carried out, standing, volatilizing and crystallizing are carried out at 10-15 ℃, filtering is carried out, drying is carried out at 45-50 ℃ for 12 hours, thus obtaining riluzole-mandelic acid crystal form, the yield is 86.3%, and the HPLC purity is 99.61%.

Comparative example 1

Adding 58.5mg of riluzole and 26.0mg of malonic acid into a mortar, dropwise adding methanol, grinding for 15min, dropwise adding methanol, continuously grinding for 15min, air-drying at room temperature, adding methanol, crystallizing at room temperature to obtain riluzole-malonic acid crystal form, wherein the HPLC purity is 98.42%.

Comparative example 2

Adding 58.5mg of riluzole and 28.0mg of sorbic acid into a mortar, dropwise adding methanol, grinding for 15min, dropwise adding methanol, continuously grinding for 15min, air-drying at room temperature, adding toluene, crystallizing at room temperature to obtain riluzole-sorbic acid crystal form, and carrying out HPLC (high performance liquid chromatography) purity of 98.12%.

Comparative example 3

Adding 58.5mg of riluzole and 49.3mg of syringic acid into a mortar, dropwise adding methanol, grinding for 30min, and air-drying to obtain a riluzole-syringic acid crystal form, wherein the HPLC purity is 99.75%.

Comparative example 4

58.5Mg of riluzole and 53.0mg of 3,4, 5-trimethoxybenzoic acid are added into a mortar, a mixed solution of methanol and ethanol is added dropwise, the mixture is ground into slurry, then the mixed solution of methanol and ethanol is added for crystallization at room temperature, and after standing for 2 weeks, the riluzole-trimethoxybenzoic acid crystal form is obtained, and the HPLC purity is 99.28%.

Comparative example 5

Adding 58.5mg of riluzole and 29.5mg of succinic acid into a mortar, dropwise adding a mixed solution of methanol and ethanol, grinding to slurry, adding the mixed solution of methanol and ethanol, crystallizing at room temperature, and standing for 2 weeks to obtain a crystal form of riluzole and succinic acid, wherein the HPLC purity is 99.73%.

Comparative example 6

Adding 58.5mg riluzole into a mortar, adding L-glutamic acid and D-glutamic acid, dropwise adding methanol, grinding, dropwise adding methanol at intervals of 5min, grinding for 20min, standing at room temperature, and crystallizing to obtain the rilu Lujing type with HPLC purity of 99.05%.

Verification embodiment

1. Solubility of

Respectively weighing 10ml of water Yu Xilin bottles, adding excessive sample to be tested, sealing the penicillin bottles, placing the penicillin bottles in a constant-temperature water bath at 25 ℃ for stirring for 1 hour, filtering the penicillin bottles by a filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 270nm, and the solubility (converted to riluzole) was calculated by measuring the absorbance of the standard control. The results are shown in Table 3.

TABLE 3 solubility test results

As can be seen from table 3, the solubility of the riluzole-mandelic acid crystalline form of the present invention is superior to the dominant crystalline form reported in the prior art.

2. Stability test

The influence factor test is carried out by referring to the guidance method (light 4500lx, high temperature 60 ℃ C., high humidity 92.5%) related to stability investigation in the fourth section of Chinese pharmacopoeia, the purity detection is carried out by HPLC method, and the result is shown in Table 4.

TABLE 4 influence factor test results

3. Pharmacokinetic experiments

180-220G healthy male Wistar rats were randomly divided into 7 groups of 5 animals each, placed under constant environmental conditions (22±1 ℃,55±10% rh,12h light-dark cycle), and allowed free food and water intake. And respectively adding the riluzole crystal forms into 0.5% methyl cellulose aqueous solution to obtain the drug administration liquid. The samples were collected from the posterior venous plexus of the rat eye socket at pre-dose, after-dose, at 0.25h, 0.50h, 1.0h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h, 12.0h and 24.0h, respectively, before-dose, after-dose, 0.25h, 0.50h, 1.0h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h and 24.0h, after-dose, in microcentrifuge tubes containing sodium citrate (3.8% w/v) as an anticoagulant, and after centrifugation at 4℃for 10min, the plasma was subjected to HPLC analysis.

HPLC conditions: agilentC18 reverse phase chromatography column, 4.6 mm. Times.50 mm,5mm; mobile phase 25mMKH ₂PO₄ solution (pH adjusted to 3.5 with orthophosphoric acid): methanol=30:70 v/v; a detection wavelength of 263nm; the flow rate was 1ml/min.

TABLE 5 pharmacokinetic parameters of riluzole

From the above data, the riluzole-mandelic acid of the present invention has good solubility, stability and pharmacokinetic properties compared to the dominant crystalline forms reported in the prior art.

Claims

1. A crystalline form of riluzole-mandelic acid, characterized in that the molar ratio of riluzole to mandelic acid in the crystal units of the crystalline form is 1:1.

2. The crystalline riluzole-mandelic acid form according to claim 1, characterized in that the X-ray diffraction spectrum expressed in 2Θ has characteristic peaks at 6.7 ± 0.2 °, 18.0 ± 0.2 °, 18.5 ± 0.2 °, 19.4 ± 0.2 °, 26.8 ± 0.2 ° using Cu-ka radiation.

3. The crystalline riluzole-mandelic acid form according to claim 1, characterized in that the X-ray diffraction spectrum expressed in 2Θ has characteristic peaks at 6.7±0.2°, 8.8±0.2°, 15.4±0.2°, 18.0±0.2°, 18.5±0.2°, 19.4±0.2°, 23.0±0.2°, 26.8±0.2° using Cu-ka radiation.

4. The crystalline riluzole-mandelic acid form according to claim 1, characterized in that the X-ray diffraction expressed in 2Θ using Cu-ka radiation has a characteristic peak as shown in fig. 1.

5. The crystalline riluzole-mandelic acid form according to claim 1, characterized in that the crystallographic parameters of the crystalline form are: monoclinic crystal system, space group is P21, unit cell parameterΑ=90 °, β= 104.8715 (6) °, γ=90°, unit cell volume/>

6. The process for the preparation of crystalline riluzole-mandelic acid according to any one of claims 1 to 5, comprising the steps of: dissolving riluzole and mandelic acid in the mixed solvent, heating and stirring, filtering, cooling and standing, volatilizing and crystallizing, filtering and drying to obtain the final product.

7. The method according to claim 6, wherein the mixed solvent is a mixed solvent of ethanol and other solvents, and the other solvents are ethyl acetate, acetonitrile, water, acetone, or trifluoroethanol.

8. The preparation method according to claim 6, wherein the mass-to-volume ratio of the riluzole to the mixed solvent is 15.7:1-3, wherein the mass is in mg and the volume is in ml.

9. The method according to claim 6, wherein the heating temperature is 50 to 70 ℃.

10. The method according to claim 6, wherein the temperature-lowering crystallization temperature is 0 to 30 ℃.