A cabozantinib-succinate co-crystal and a preparation method thereof

Abstract

The application discloses a new ganbaxin-succinic acid co-crystal and a preparation method thereof. The method comprises the following steps: step 1, dissolving ganbaxin solid in solvent I; step 2, adding succinic acid solid into the solution obtained in step 1; step 3, heating the solution obtained in step 2 and keeping the temperature, and continuously stirring; step 4, filtering the clear solution obtained in step 3, and evaporating the filtrate; and step 5, drying the crystal obtained in step 5, and obtaining the ganbaxin-succinic acid co-crystal after drying. The solubility of the ganbaxin-succinic acid co-crystal obtained in water is 0.487 mg / mL, which is 10 times of that of the raw material medicine, and the water solubility of the ganbaxin-succinic acid co-crystal is much better than that of the original crystal.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical separation technology, and specifically relates to a new eutectic of glycyrrhizin and its crystallization preparation method. Background Technology

[0002] Climbazole (CAS number: 38083-17-9), also known as chloroether ketone, with the IUPAC name 1-(4-chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethyl-2-butanone, has the chemical formula C15H17ClN2O2 and a relative molecular mass of 292.76. Its structure is shown below. It appears as white or grayish-white crystals, sparingly soluble in water, but readily soluble in toluene and alcohols. The pharmaceutical form is a racemic compound composed of equimolar amounts of R- and S-climbazole.

[0003]

[0004] Climbazole is a classic imidazole antifungal agent with broad-spectrum bactericidal properties. Its bactericidal mechanism involves inhibiting the synthesis of lanosterol 14-α-demethylase in cytochrome P450 enzymes, thereby preventing ergosterol biosynthesis and increasing the fluidity of fungal cell membranes, thus inhibiting fungal growth. It is mainly used in anti-itch and anti-dandruff conditioning shampoos and conditioners, and can also be used in high-end detergents such as antibacterial soaps, shower gels, medicated toothpastes, and mouthwashes.

[0005] Co-crystallization is an effective method to both preserve pharmacological properties and improve the physicochemical properties of drugs. Ganbaosu, a promising local broad-spectrum antifungal drug, has long had its application scope and environmental friendliness limited by its poor water solubility. Therefore, it is necessary to study the co-crystallization of Ganbaosu. Succinic acid is mainly used as a precursor and intermediate for various drugs in the pharmaceutical industry, playing a crucial role, especially in the production of antibiotics, vitamins, and drugs for treating multiple sclerosis such as triamterene. Summary of the Invention

[0006] The purpose of this invention is to prepare a new eutectic of glycyrrhizin and succinic acid, which has higher water solubility and thermal stability compared with the original crystal form of glycyrrhizin.

[0007] To achieve the above objectives, the present invention provides a novel eutectic of glucomycin. The X-ray powder diffraction pattern of this crystal is as follows: at diffraction angles 2θ = 6.860 ± 0.2°, 11.581 ± 0.2°, 13.581 ± 0.2°, 14.419 ± 0.2°, 16.118 ± 0.2°, 18.078 ± 0.2°, 19.160 ± 0.2°, 20.602 ± 0.2°, 21.339 ± 0.2°, 21.739 ± 0.2°, 22.140 ± 0.2°, and 22.820 ± 0.2°. Characteristic peaks are observed at 23.059±0.2°, 23.281±0.2°, 25.920±0.2°, 26.420±0.2°, 27.139±0.2°, 27.360±0.2°, 28.600±0.2°, 29.079±0.2°, 29.299±0.2°, 30.241±0.2°, 32.319±0.2°, 33.018±0.2°, and 34.539±0.2°.

[0008] Preferably, the DSC-TG shows that the melting point of the new salt type is 107.07℃.

[0009] Preferably, the decomposition temperature is 170.16℃.

[0010] Preferably, the product is a white powder.

[0011] This invention also provides a method for preparing the above-mentioned galbac-succinate eutectic, comprising the following steps:

[0012] Step 1: Dissolve the solid glycyrrhizin in solvent I;

[0013] Step 2: Add solid succinic acid to the solution obtained in Step 1;

[0014] Step 3: Heat the solution obtained in Step 2 and maintain the temperature while continuously stirring;

[0015] Step 4: Filter the clear solution obtained in Step 3, and evaporate the filtrate;

[0016] Step 5: Dry the crystals obtained in Step 5 to obtain the ganbaosu-succinic acid eutectic.

[0017] Preferably, the ratio of the solid gluconol to solvent I is 90 mg / ml to 100 mg / ml. The gluconol used in the initial reactants of this invention is a gluconol product existing in the prior art and commercially available. The solute-solvent ratio of the initial reactants in this invention, converted to gluconol monomer form, is that the mass-to-volume ratio of gluconol to solvent in the gluconol solution obtained in step 1 is 0.09 g:1 ml to 0.10 g:1 ml. More preferably, the ratios are 0.090 g:1 mL, 0.091 g:1 mL, 0.092 g:1 mL, 0.093 g:1 mL, 0.094 g:1 mL, 0.095 g:1 mL, 0.096 g:1 mL, 0.097 g:1 mL, 0.098 g:1 mL, 0.099 g:1 mL, and 0.10 g:1 mL.

[0018] In any of the above-mentioned preferred embodiments, in step 1, the solvent I includes at least one of ethanol and methanol, and is more preferably ethanol.

[0019] In any of the above-mentioned embodiments, in step 1, the temperature at which the galangal solid dissolves in solvent I is 30–50°C. More preferably, it is 30, 35, 40, 45, or 50°C or a range thereof, and even more preferably 35 or 40°C or a range thereof.

[0020] Preferably, in step 2, the molar ratio of succinic acid solid to galangal solid is 1:1.8 to 1:2.2. The succinic acid used in the initial reactants of this invention is a succinic acid product existing in the prior art and can be commercially available. Preferably, the ratio is 1:1.8, 1:2.0, 1:2.1, 1:2.2, or a range thereof. More preferably, the molar ratio of succinic acid solid to galangal solid is 1:1.8, 1:2.0, or a range thereof.

[0021] In any of the above-mentioned embodiments, the solution heating temperature in step 3 is preferably 30–50°C. More preferably, it is 30, 35, 40, 45, or 50°C or a range thereof. More preferably, it is 35 or 40°C or a range thereof.

[0022] Preferably, in step 3, the stirring rate is 100–200 rpm. More preferably, it is 100, 150, or 200 rpm or a range thereof. More preferably, it is 150 or 170 rpm or a range thereof.

[0023] In any of the above-mentioned preferred embodiments, in step 3, the constant temperature time is 3 to 5 hours, preferably 3, 3.5, 4, 4.5, 5 hours and the range therebetween, and more preferably 3.5, 4 hours and the range therebetween.

[0024] In any of the above-mentioned embodiments, in step 4, the evaporation temperature of the solution is 0–15°C, preferably 0, 5, 10, 15°C or a range thereof. More preferably, it is 4°C.

[0025] In any of the above-mentioned preferred embodiments, in step 4, the evaporation time of the solution is 3 to 7 days, preferably 3, 4, 5, 6, or 7 days or a range thereof. More preferably, it is 4 or 5 days or a range thereof.

[0026] In any of the above-mentioned preferred embodiments, in step 5, the crystal drying temperature is 40-50°C, preferably 40, 45, 50°C or a range thereof, and more preferably 50°C.

[0027] Preferably, in step 5, the drying time is 3 to 4 hours. More preferably, it is 3.5 to 4 hours or a range thereof.

[0028] In any of the above-mentioned preferred embodiments, in step 5, the drying conditions are a vacuum or a nitrogen environment, and more preferably a nitrogen environment.

[0029] In the method described in this invention, the crystallization method is evaporation crystallization.

[0030] The chemical stability of the succinic acid-glucopyranoic acid crystals prepared in this invention was investigated. During storage at 40℃±2℃ and RH75±5% for 56 days, the color, purity, and morphology of the product remained unchanged, indicating good chemical stability of the crystal form. The results are shown in Table 1.

[0031] Table 1. Chemical stability study of the ganbaosu-succinic acid eutectic crystal of the present invention.

[0032] 7 days 14 days 21 days 28 days 42 days 56 days Properties White powder White powder White powder White powder White powder White powder purity 99.8％ 99.8％ 99.8％ 99.8％ 99.8％ 99.8％

[0033] The solubility of the active pharmaceutical ingredient (API) crystal form and the new cocrystal was investigated by placing ganbaosu and ganbaosu-succinic acid cocrystal in water at 25°C. The results are as follows: Figure 3 As shown, the solubility of the crystalline form of ganbaosu raw material in water is 0.04595 mg / mL, while the solubility of the ganbaosu-succinic acid cocrystal in water is 0.487 mg / mL, which is 10 times that of the raw material. This shows that the water solubility of the ganbaosu-succinic acid cocrystal is much better than that of the original crystalline form. Attached Figure Description

[0034] Figure 1 X-ray powder diffraction pattern of the glycoside-succinic acid eutectic in preferred embodiment 1 of the present invention.

[0035] Figure 2 DSC-TG analysis chromatogram of the glycoside-succinic acid eutectic in preferred embodiment 1 of the present invention.

[0036] Figure 3Dissolution curves of the eutectic and original crystal forms of glycyrrhizic acid-succinic acid eutectic in preferred embodiment 1 of the present invention. Detailed Implementation

[0037] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0038] Example 1

[0039] 0.270 g of ganbaosu solid was dissolved in 3.0 ml of methanol at 35 °C, and 0.054 g of succinic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 35 °C for 3.5 h. The mixture was then filtered, and the filtrate was placed in an environment of 4 °C for atmospheric pressure evaporation. After evaporation for 4 days, the resulting crystals were dried in a nitrogen drying oven at 50 °C. The final ganbaosu-succinic acid eutectic crystal product was obtained after drying.

[0040] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 6.860±0.2°, 11.581±0.2°, 13.581±0.2°, 14.419±0.2°, 16.118±0.2°, 18.078±0.2°, 19.160±0.2°, 20.602±0.2°, 21.339±0.2°, 21.739±0.2°, 22.140±0.2°, and 22.820±0.2°. Characteristic peaks were observed at 23.059±0.2°, 23.281±0.2°, 25.920±0.2°, 26.420±0.2°, 27.139±0.2°, 27.360±0.2°, 28.600±0.2°, 29.079±0.2°, 29.299±0.2°, 30.241±0.2°, 32.319±0.2°, 33.018±0.2°, and 34.539±0.2°. DSC-TG results showed a melting temperature of 107.07℃ and a decomposition temperature of 170.16℃. The product was a white powder with a purity of 99.8% and a process yield of 91%.

[0041] Example 2

[0042] 0.276 g of ganbaosu solid was dissolved in 3.0 ml of ethanol at 35 °C, and 0.056 g of succinic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 35 °C for 3.5 h. The mixture was then filtered, and the filtrate was placed in an environment of 4 °C for atmospheric pressure evaporation. After evaporation for 5 days, the resulting crystals were dried in a nitrogen drying oven at 50 °C. The final ganbaosu-succinic acid eutectic crystal product was obtained after drying.

[0043] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 6.860±0.2°, 11.581±0.2°, 13.581±0.2°, 14.419±0.2°, 16.118±0.2°, 18.078±0.2°, 19.160±0.2°, 20.602±0.2°, 21.339±0.2°, 21.739±0.2°, 22.140±0.2°, and 22.820±0.2°. Characteristic peaks were observed at 23.059±0.2°, 23.281±0.2°, 25.920±0.2°, 26.420±0.2°, 27.139±0.2°, 27.360±0.2°, 28.600±0.2°, 29.079±0.2°, 29.299±0.2°, 30.241±0.2°, 32.319±0.2°, 33.018±0.2°, and 34.539±0.2°. DSC-TG results showed a melting temperature of 107.07℃ and a decomposition temperature of 170.16℃. The product was a white powder with a purity of 99.7% and a process yield of 89%.

[0044] Example 3

[0045] 0.300 g of ganbaosu solid was dissolved in 3.0 ml of methanol at 40 °C, and 0.061 g of succinic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 40 °C for 4.0 h. The mixture was then filtered, and the filtrate was placed in an environment of 4 °C for atmospheric pressure evaporation. After evaporation for 4 days, the resulting crystals were dried in a nitrogen drying oven at 50 °C. The final ganbaosu-succinic acid eutectic crystal product was obtained after drying.

[0046] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 6.860±0.2°, 11.581±0.2°, 13.581±0.2°, 14.419±0.2°, 16.118±0.2°, 18.078±0.2°, 19.160±0.2°, 20.602±0.2°, 21.339±0.2°, 21.739±0.2°, 22.140±0.2°, and 22.820±0.2°. Characteristic peaks were observed at 23.059±0.2°, 23.281±0.2°, 25.920±0.2°, 26.420±0.2°, 27.139±0.2°, 27.360±0.2°, 28.600±0.2°, 29.079±0.2°, 29.299±0.2°, 30.241±0.2°, 32.319±0.2°, 33.018±0.2°, and 34.539±0.2°. DSC-TG results showed a melting temperature of 107.07℃ and a decomposition temperature of 170.16℃. The product appeared as a white powder with a purity of 99.6% and a process yield of 89%.

[0047] Example 4

[0048] 0.300 g of ganbaosu solid was dissolved in 3.0 ml of ethanol at 40 °C, and 0.067 g of succinic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 40 °C for 4.0 h. The mixture was then filtered, and the filtrate was placed in an environment of 4 °C for atmospheric pressure evaporation. After evaporation for 5 days, the resulting crystals were dried in a nitrogen drying oven at 50 °C. The final ganbaosu-succinic acid eutectic crystal product was obtained after drying.

[0049] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 6.860±0.2°, 11.581±0.2°, 13.581±0.2°, 14.419±0.2°, 16.118±0.2°, 18.078±0.2°, 19.160±0.2°, 20.602±0.2°, 21.339±0.2°, 21.739±0.2°, 22.140±0.2°, and 22.820±0.2°. Characteristic peaks were observed at 23.059±0.2°, 23.281±0.2°, 25.920±0.2°, 26.420±0.2°, 27.139±0.2°, 27.360±0.2°, 28.600±0.2°, 29.079±0.2°, 29.299±0.2°, 30.241±0.2°, 32.319±0.2°, 33.018±0.2°, and 34.539±0.2°. DSC-TG results showed a melting temperature of 107.07℃ and a decomposition temperature of 170.16℃. The product was a white powder with a purity of 99.7% and a process yield of 90%.

[0050] Example 5

[0051] 0.285 g of ganbaosu solid was dissolved in 3.0 ml of methanol at 35 °C, and 0.064 g of succinic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 35 °C for 3.5 h. The mixture was then filtered, and the filtrate was placed in an environment of 4 °C for atmospheric pressure evaporation. After evaporation for 5 days, the resulting crystals were dried in a nitrogen drying oven at 50 °C. The final ganbaosu-succinic acid eutectic crystal product was obtained after drying.

[0052] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 6.860±0.2°, 11.581±0.2°, 13.581±0.2°, 14.419±0.2°, 16.118±0.2°, 18.078±0.2°, 19.160±0.2°, 20.602±0.2°, 21.339±0.2°, 21.739±0.2°, 22.140±0.2°, and 22.820±0.2°. Characteristic peaks were observed at 23.059±0.2°, 23.281±0.2°, 25.920±0.2°, 26.420±0.2°, 27.139±0.2°, 27.360±0.2°, 28.600±0.2°, 29.079±0.2°, 29.299±0.2°, 30.241±0.2°, 32.319±0.2°, 33.018±0.2°, and 34.539±0.2°. DSC-TG results showed a melting temperature of 107.07℃ and a decomposition temperature of 170.16℃. The product was a white powder with a purity of 99.8% and a process yield of 91%.

[0053] Example 6

[0054] The chemical properties of the ganbaosu-succinic acid eutectic products obtained in Examples 1-5, namely the ganbaosu-succinic acid eutectic crystals of the present invention, were tested.

[0055] 1) The chemical stability of the ganbaosu-succinic acid eutectic crystal prepared in this invention was investigated. During storage at 40℃±2℃ and RH75±5% for 56 days, the color, purity, and morphology of the product remained unchanged, indicating that the crystal form has good chemical stability. The results are shown in Table 2.

[0056] Table 2. Chemical stability study of the ganbaosu-succinic acid eutectic described in this invention.

[0057]

[0058] 2) such as Figure 1 The image shows the X-ray powder diffraction pattern of the ganbaosu-succinic acid eutectic obtained in Example 1, and the X-ray powder diffraction patterns of the ganbaosu-succinic acid eutectic obtained in Examples 1-5. Figure 1 Therefore, it will not be provided again here.

[0059] 3) The galbac-succinic acid eutectic crystal obtained in this invention was subjected to DSC-TG analysis. The specific method for DSC-TG analysis is a conventional method in the prior art. The DSC-TG analysis chromatogram of the galbac-succinic acid eutectic crystal obtained in Example 1 is shown below. Figure 2As shown, the DSC analysis chromatogram indicates a melting temperature of 107.07℃ and a decomposition temperature of 170.16℃. The information in the figure confirms that the ganbaosu-succinic acid eutectic obtained in the examples is stable. The results of Examples 1-5 are consistent, and images are not repeated here.

[0060] 4) Figure 3 The figures show the dissolution curves of the ganbaosu-succinic acid cocrystal and the original crystal form obtained in Example 1. The solubility of the ganbaosu active pharmaceutical ingredient (API) in water is 0.04595 mg / mL, while the solubility of the ganbaosu-succinic acid cocrystal is 0.487 mg / mL, which is 10 times that of the API. This demonstrates that the water solubility of the ganbaosu-succinic acid cocrystal is significantly better than that of the original crystal form. The results of Examples 1-5 are consistent, and images are not repeated here. It is evident that the water solubility of the ganbaosu-succinic acid cocrystal is significantly better than that of the original crystal form.

[0061] The present invention will be described more clearly and completely through the following embodiments, but the described examples are only a part of the embodiments of the present invention, and not all of them. The embodiments are provided to help understand the present invention and should not be construed as limiting the scope of protection of the present invention.

[0062] The crystal form of the glycopyrrolidone-succinic acid eutectic and its preparation method disclosed and proposed in this invention can be implemented by those skilled in the art by appropriately changing the raw materials, process parameters, and other aspects, based on the content of this document. The methods and products of this invention have been described through preferred embodiments. Those skilled in the art can obviously modify or appropriately change and combine the methods and products described herein without departing from the content, spirit, and scope of this invention to achieve the technology of this invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included within the spirit, scope, and content of this invention.

Claims

1. A novel eutectic crystal of glycyrrhizin-succinic acid, characterized in that, The X-ray powder diffraction pattern of the crystal is observed at diffraction angles 2θ = 6.860 ± 0.2°, 11.581 ± 0.2°, 13.581 ± 0.2°, 14.419 ± 0.2°, 16.118 ± 0.2°, 18.078 ± 0.2°, 19.160 ± 0.2°, 20.602 ± 0.2°, 21.339 ± 0.2°, 21.739 ± 0.2°, 22.140 ± 0.2°, and 22.820 ± 0.2°. Characteristic peaks are observed at 23.059±0.2°, 23.281±0.2°, 25.920±0.2°, 26.420±0.2°, 27.139±0.2°, 27.360±0.2°, 28.600±0.2°, 29.079±0.2°, 29.299±0.2°, 30.241±0.2°, 32.319±0.2°, 33.018±0.2°, and 34.539±0.2°.

2. The crystal as described in claim 1, characterized in that, The melting point of the crystal is 107.07℃.

3. The method for preparing the crystal as described in claim 1 or 2, comprising the following steps: Step 1: Dissolve the solid glyphosate in solvent I; solvent I is ethanol and / or methanol; Step 2: Add solid succinic acid to the solution obtained in Step 1; Step 3: Heat the solution obtained in Step 2 to 30-50°C and maintain this temperature while continuously stirring; Step 4: Filter the clear solution obtained in Step 3, and evaporate the filtrate; the evaporation temperature of the solution is 0-15℃, and the evaporation time is 3-7 days; Step 5: Dry the crystals obtained in Step 5 to obtain the ganbaosu-succinic acid eutectic.

4. The preparation method according to claim 3, characterized in that, In step 1, the mass-to-volume ratio of the ganbaosu solid to solvent I is 90 mg / ml to 100 mg / ml.

5. The preparation method according to claim 4, characterized in that, In step 1, the temperature at which the solid ganbaosu dissolves in solvent I is 30–50°C.

6. The preparation method according to claim 3, characterized in that, In step 2, the molar ratio of the succinic acid solid to the ganbaosu solid in step 1 is 1:1.8 to 1:2.

2.

7. The preparation method according to claim 3, characterized in that, In step 5, the crystal drying temperature is 40-50℃.

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