A cabozantinib-hexanedioic acid co-crystal and a preparation method thereof

Abstract

The application discloses a ganbaxin-adipic 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 adipic 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 crystals obtained in step 5, and obtaining the ganbaxin-adipic acid co-crystal after drying. The ganbaxin-adipic acid co-crystal has good chemical stability; the water solubility of the ganbaxin-adipic acid co-crystal is much better than that of the original crystal, and the wet stability is better than that of ganbaxin raw material 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. Adipic acid is mainly used in the pharmaceutical industry as a key intermediate in the synthesis of various drugs, especially in the production of antibiotics (such as penicillin G), local anesthetics (such as procaine), and immunosuppressants (such as cyclosporine A). Summary of the Invention

[0006] The purpose of this invention is to provide a new eutectic of galbacic acid-adipic acid, which has higher water solubility and hygroscopic stability compared with the original galbacic acid crystal form.

[0007] To achieve the above objectives, the present invention provides a glycopyridine-adipic acid eutectic crystal, wherein the X-ray powder diffraction pattern of the crystal is as follows: at diffraction angles 2θ = 10.699 ± 0.2°, 12.638 ± 0.2°, 13.341 ± 0.2°, 13.738 ± 0.2°, 14.661 ± 0.2°, 16.460 ± 0.2°, 18.341 ± 0.2°, 18.581 ± 0.2°, 19.299 ± 0.2°, 19.780 ± 0.2°, 20... Characteristic peaks are observed at 0.701±0.2°, 21.480±0.2°, 22.999±0.2°, 23.481±0.2°, 23.958±0.2°, 24.401±0.2°, 25.240±0.2°, 25.420±0.2°, 25.980±0.2°, 27.700±0.2°, 28.918±0.2°, 31.581±0.2°, 32.460±0.2°, and 34.779±0.2°.

[0008] Preferably, DSC-TG shows the new salt form has a melting point of 76.64℃.

[0009] Preferably, the crystal decomposition temperature is 172.33°C.

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

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

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

[0013] Step 2: Add solid adipic 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-adipic acid eutectic.

[0017] Preferably, in the method described in this invention, the crystallization method is evaporation crystallization.

[0018] 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.

[0019] In any of the above-mentioned preferred embodiments, in step 1, the solvent I includes at least one of acetonitrile and ethanol, and is more preferably acetonitrile.

[0020] In any of the above-mentioned preferred embodiments, in step 1, the temperature at which the galangal solid dissolves in solvent I is 40–50°C. More preferably, it is 40, 45, or 50°C or a range thereof. More preferably, it is 45 or 50°C or a range thereof.

[0021] Preferably, in step 2, the molar ratio of the adipic acid solid to the galangal solid added in step 1 is 1:1.8 to 1:2.2. The adipic acid used in the initial reactants of this invention is an adipic acid product existing in the prior art and can be commercially available. More preferably, the molar ratio of the adipic acid solid to the galangal solid added in step 1 is 1:1.8, 1:2.0, or a range thereof.

[0022] In any of the above-mentioned embodiments, in step 3, the solution heating temperature is 40–50°C. More preferably, it is 40, 45, or 50°C or a range thereof. More preferably, it is 45 or 50°C or a range thereof.

[0023] 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.

[0024] In any of the above-mentioned embodiments, the constant temperature time in step 3 is preferably 3 to 5 hours, more preferably 3, 3.5, 4, 4.5, 5 hours or a range thereof. More preferably, it is 3.5 or 4 hours or a range thereof.

[0025] 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.

[0026] In any of the above-mentioned preferred embodiments, in step 4, the evaporation time of the solution is 4 to 7 days, preferably 4, 5, 6, or 7 days or a range thereof, and more preferably 5 or 6 days or a range thereof.

[0027] In any of the above-mentioned preferred embodiments, in step 5, the crystal drying temperature is 45-50°C, and more preferably 50°C.

[0028] In any of the above-mentioned options, the drying time in step 5 is preferably 3 to 4 hours. More preferably, it is 3.5 to 4 hours.

[0029] 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.

[0030] The chemical stability of the ganbaosu-adipic 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 glycoside-adipic acid eutectic crystal described in this 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 API cocrystal was investigated by placing ganbaosu and ganbaosu-adipic 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-adipic acid cocrystal in water is 0.2889 mg / mL, which is 6 times that of the raw material. This shows that the water solubility of the ganbaosu-adipic acid cocrystal is much better than that of the original crystalline form.

[0034] The hygroscopicity of different crystal forms of ganbaosu raw material and ganbaosu-adipic acid eutectic were investigated at 25℃ and 0-95% RH. The results are as follows: Figure 4 As shown, up to 95% RH, the mass change of the crystalline form of Ganbaosu API was 0.55%, while the mass change of the new eutectic of Ganbaosu-adipic acid was only 0.41%. This indicates that the hygroscopic stability of the new eutectic of Ganbaosu-adipic acid is better than that of the crystalline form of Ganbaosu API. Attached Figure Description

[0035] Figure 1 X-ray powder diffraction pattern of the glycoside-adipic acid eutectic in preferred embodiment 1 of the present invention.

[0036] Figure 2 DSC-TG analysis chromatogram of the glycoside-adipic acid eutectic in preferred embodiment 1 of the present invention.

[0037] Figure 3 Dissolution curves of the glycoside-adipic acid eutectic and the original crystal form in preferred embodiment 1 of the present invention.

[0038] Figure 4 DVS curves of the glycoside-adipic acid eutectic and glycoside raw material crystal forms in preferred embodiment 1 of the present invention. Detailed Implementation

[0039] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0040] Example 1

[0041] 0.270 g of ganbaosu solid was dissolved in 3.0 ml of acetonitrile at 50 °C, and 0.067 g of adipic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 50 °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-adipic acid eutectic crystal product was obtained after drying.

[0042] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 10.699 ± 0.2°, 12.638 ± 0.2°, 13.341 ± 0.2°, 13.738 ± 0.2°, 14.661 ± 0.2°, 16.460 ± 0.2°, 18.341 ± 0.2°, 18.581 ± 0.2°, 19.299 ± 0.2°, 19.780 ± 0.2°, 20.701 ± 0.2°, and 21.48. Characteristic peaks were observed at 0±0.2°, 22.999±0.2°, 23.481±0.2°, 23.958±0.2°, 24.401±0.2°, 25.240±0.2°, 25.420±0.2°, 25.980±0.2°, 27.700±0.2°, 28.918±0.2°, 31.581±0.2°, 32.460±0.2°, and 34.779±0.2°. DSC-TG results showed a melting temperature of 76.64℃ and a decomposition temperature of 172.33℃. The product was a white powder with a purity of 99.8% and a process yield of 90%.

[0043] Example 2

[0044] 0.276 g of ganbaosu solid was dissolved in 3.0 ml of ethanol at 45 °C, and 0.069 g of adipic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 45 °C for 3.5 h. The mixture was then filtered, and the filtrate was evaporated at normal pressure in an environment of 4 °C. After evaporation for 5 days, the resulting crystals were dried in a nitrogen drying oven at 50 °C. The final ganbaosu-adipic acid eutectic crystal product was obtained after drying.

[0045] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 10.699 ± 0.2°, 12.638 ± 0.2°, 13.341 ± 0.2°, 13.738 ± 0.2°, 14.661 ± 0.2°, 16.460 ± 0.2°, 18.341 ± 0.2°, 18.581 ± 0.2°, 19.299 ± 0.2°, 19.780 ± 0.2°, 20.701 ± 0.2°, and 21.48. Characteristic peaks were observed at 0±0.2°, 22.999±0.2°, 23.481±0.2°, 23.958±0.2°, 24.401±0.2°, 25.240±0.2°, 25.420±0.2°, 25.980±0.2°, 27.700±0.2°, 28.918±0.2°, 31.581±0.2°, 32.460±0.2°, and 34.779±0.2°. DSC-TG results showed a melting temperature of 76.64℃ and a decomposition temperature of 172.33℃. The product was a white powder with a purity of 99.7% and a process yield of 89%.

[0046] Example 3

[0047] 0.300 g of ganbaosu solid was dissolved in 3.0 ml of acetonitrile at 40 °C, and 0.075 g of adipic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 50 °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 6 days, the resulting crystals were dried in a nitrogen drying oven at 50 °C. The final ganbaosu-adipic acid eutectic crystal product was obtained after drying.

[0048] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 10.699 ± 0.2°, 12.638 ± 0.2°, 13.341 ± 0.2°, 13.738 ± 0.2°, 14.661 ± 0.2°, 16.460 ± 0.2°, 18.341 ± 0.2°, 18.581 ± 0.2°, 19.299 ± 0.2°, 19.780 ± 0.2°, 20.701 ± 0.2°, and 21.48. Characteristic peaks were observed at 0±0.2°, 22.999±0.2°, 23.481±0.2°, 23.958±0.2°, 24.401±0.2°, 25.240±0.2°, 25.420±0.2°, 25.980±0.2°, 27.700±0.2°, 28.918±0.2°, 31.581±0.2°, 32.460±0.2°, and 34.779±0.2°. DSC-TG results showed a melting temperature of 76.64℃ and a decomposition temperature of 172.33℃. The product was a white powder with a purity of 99.6% and a process yield of 91%.

[0049] Example 4

[0050] 0.300 g of ganbaosu solid was dissolved in 3.0 ml of ethanol at 50 °C, and 0.075 g of adipic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 50 °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-adipic acid eutectic crystal product was obtained after drying.

[0051] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 10.699 ± 0.2°, 12.638 ± 0.2°, 13.341 ± 0.2°, 13.738 ± 0.2°, 14.661 ± 0.2°, 16.460 ± 0.2°, 18.341 ± 0.2°, 18.581 ± 0.2°, 19.299 ± 0.2°, 19.780 ± 0.2°, 20.701 ± 0.2°, and 21.48. Characteristic peaks were observed at 0±0.2°, 22.999±0.2°, 23.481±0.2°, 23.958±0.2°, 24.401±0.2°, 25.240±0.2°, 25.420±0.2°, 25.980±0.2°, 27.700±0.2°, 28.918±0.2°, 31.581±0.2°, 32.460±0.2°, and 34.779±0.2°. DSC-TG results showed a melting temperature of 76.64℃ and a decomposition temperature of 172.33℃. The product was a white powder with a purity of 99.7% and a process yield of 91%.

[0052] Example 5

[0053] 0.285 g of ganbaosu solid was dissolved in 3.0 ml of acetonitrile at 45 °C, and 0.079 g of adipic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 45 °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 6 days, the resulting crystals were dried in a nitrogen drying oven at 50 °C. The final ganbaosu-adipic acid eutectic crystal product was obtained after drying.

[0054] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 10.699 ± 0.2°, 12.638 ± 0.2°, 13.341 ± 0.2°, 13.738 ± 0.2°, 14.661 ± 0.2°, 16.460 ± 0.2°, 18.341 ± 0.2°, 18.581 ± 0.2°, 19.299 ± 0.2°, 19.780 ± 0.2°, 20.701 ± 0.2°, and 21.48. Characteristic peaks were observed at 0±0.2°, 22.999±0.2°, 23.481±0.2°, 23.958±0.2°, 24.401±0.2°, 25.240±0.2°, 25.420±0.2°, 25.980±0.2°, 27.700±0.2°, 28.918±0.2°, 31.581±0.2°, 32.460±0.2°, and 34.779±0.2°. DSC-TG results showed a melting temperature of 76.64℃ and a decomposition temperature of 172.33℃. The product was a white powder with a purity of 99.7% and a process yield of 90%.

[0055] Example 6

[0056] The chemical properties of the ganbaosu-adipic acid eutectic products obtained in Examples 1-5, namely the ganbaosu-adipic acid eutectic crystals of the present invention, were tested.

[0057] 1) The chemical stability of the galbac-adipic 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 good chemical stability of the crystal form. The results are shown in Table 2.

[0058] Table 2. Chemical stability study of the ganbaosu-adipic acid eutectic described in this invention.

[0059]

[0060]

[0061] 2) such as Figure 1 The image shows the X-ray powder diffraction pattern of the galbac-adipic acid eutectic obtained in Example 1, and the X-ray powder diffraction patterns of the galbac-adipic acid eutectic obtained in Examples 1-5. Figure 1 Therefore, it will not be provided again here.

[0062] 3) The galbac-adipic 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-adipic acid eutectic crystal obtained in Example 1 is shown below. Figure 2As shown, the DSC analysis chromatogram indicates a melting temperature of 76.64℃ and a decomposition temperature of 172.33℃. The information in the figure confirms that the ganbaosu-adipic acid eutectic obtained in the examples is stable. The results of Examples 1-5 are consistent, and images are not repeated here.

[0063] 4) Figure 3 The figures show the dissolution curves of the ganbaosu-adipic 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-adipic acid cocrystal is 0.2889 mg / mL, which is 6 times that of the API. This demonstrates that the water solubility of the ganbaosu-adipic 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-adipic acid cocrystal is significantly better than that of the original crystal form.

[0064] 4) Figure 4 This is a comparison chart of the hygroscopic curves of the hydrochloric acid-adipic acid eutectic obtained in Example 1 and the hygroscopic curves of the hydrochloric acid active pharmaceutical ingredient crystal form, as shown below. Figure 4 As shown, up to 95% RH, the mass change of the crystalline form of ganbaosu active pharmaceutical ingredient (API) was 0.55%, while the mass change of the new ganbaosu-adipic acid eutectic was only 0.41%. This indicates that the hygroscopic stability of the new ganbaosu-adipic acid eutectic is better than that of the crystalline form of API. The results of Examples 1-5 are consistent, and images are not repeated here. It is evident that the hygroscopic stability of the new ganbaosu-adipic acid eutectic is better than that of the crystalline form of API.

[0065] 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.

[0066] The crystal form of the glycopyridine-adipic 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 glycoside-adipic acid eutectic crystal, characterized in that, The X-ray powder diffraction pattern of the crystal is observed at diffraction angles 2θ = 10.699 ± 0.2°, 12.638 ± 0.2°, 13.341 ± 0.2°, 13.738 ± 0.2°, 14.661 ± 0.2°, 16.460 ± 0.2°, 18.341 ± 0.2°, 18.581 ± 0.2°, 19.299 ± 0.2°, 19.780 ± 0.2°, 20.701 ± 0.2°, and 21.4°. Characteristic peaks are observed at 80±0.2°, 22.999±0.2°, 23.481±0.2°, 23.958±0.2°, 24.401±0.2°, 25.240±0.2°, 25.420±0.2°, 25.980±0.2°, 27.700±0.2°, 28.918±0.2°, 31.581±0.2°, 32.460±0.2°, and 34.779±0.2°.

2. The crystal as described in claim 1, characterized in that, The melting point of the crystal is 76.64℃.

3. The crystal as described in claim 1, characterized in that, The crystal decomposition temperature is 172.33℃.

4. A method for preparing the eutectic crystal according to any one of claims 1-3, comprising the following steps: Step 1: Dissolve the solid glyphosate in solvent I; solvent I is acetonitrile and / or ethanol; Step 2: Add solid adipic acid to the solution obtained in Step 1; Step 3: Heat the solution obtained in Step 2 to 40-50°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℃; Step 5: Dry the crystals obtained in Step 5 to obtain the ganbaosu-adipic acid eutectic.

5. The method as described in claim 4, characterized in that, In step 1, the ratio of the solid glycyrrhizin to solvent I is 90 mg / ml to 100 mg / ml.

6. The method as described in claim 4, characterized in that, In step 2, the molar ratio of the adipic acid solid to the ganbaosu solid in step 1 is 1:1.8 to 1:2.

2.

7. The method as described in claim 4, characterized in that, In step 3, the stirring speed is 100-200 rpm.

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