A ganetespib-malonate salt and a method of making the same

Abstract

The application discloses a ganbaxin-malonate crystal and a preparation method thereof, and the method comprises the following steps: step 1, dissolving ganbaxin solid in solvent I; step 2, adding malonic 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 4, and obtaining the ganbaxin-malonate crystal after drying. The ganbaxin-malonate new salt type obtained in the application has higher water solubility and thermal stability compared with the original crystal form of ganbaxin.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical separation technology, and specifically relates to a new salt form 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 in the figure 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] 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.

[0004] Salting 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 conduct research on new salt forms of Ganbaosu. Malonic acid is commonly used as an intermediate in organic synthesis in pharmaceutical ligands for the synthesis of various drug molecules, such as antibiotics, anti-inflammatory drugs, and anticoagulants. Summary of the Invention

[0005] The purpose of this invention is to provide a new salt form of galbac-malonic acid, which has higher water solubility and thermal stability compared with the original galbac crystal form.

[0006] To achieve the above objectives, the present invention provides a novel salt-type crystal of gamboglin, wherein the X-ray powder diffraction pattern of the crystal is as follows: diffraction angles 2 = 8.539 ± 0.2°, 11.619 ± 0.2°, 12.260 ± 0.2°, 12.721 ± 0.2°, 13.400 ± 0.2°, 13.638 ± 0.2°, 15.760 ± 0.2°, 16.138 ± 0.2°, 17.159 ± 0.2°, 18.938 ± 0.2°, 19.357 ± 0.2°, and 19.801 ± 0.2°. The characteristic peaks are located at °, 20.943±0.2°, 21.597±0.2°, 21.999±0.2°, 22.398±0.2°, 23.798±0.2°, 24.719±0.2°, 25.802±0.2°, 26.543±0.2°, 27.461±0.2°, 28.660±0.2°, 29.558±0.2°, 31.458±0.2°, 33.002±0.2°, 33.558±0.2°, and 33.857±0.2°.

[0007] Preferably, the DSC-TG shows that the melting point of the new salt type is 114.79℃.

[0008] Preferably, the crystals are in the form of a white powder.

[0009] This invention also provides a method for preparing the above-mentioned glycyrrhizin-malonate crystals, comprising the following steps:

[0010] Step 1: Dissolve the solid glycyrrhizin in solvent I;

[0011] Step 2: Add solid malonic acid to the solution obtained in Step 1;

[0012] Step 3: Heat the solution obtained in Step 2 and maintain the temperature while continuously stirring;

[0013] Step 4: Filter the clear solution obtained in Step 3, and evaporate the filtrate;

[0014] Step 5: Dry the crystals obtained in Step 5 to obtain the ganbaosu-malonate crystals.

[0015] Preferably, the ratio of the solid gluconol to solvent I is 90 mg / ml to 100 mg / ml. The gluconol used in the initial reactant of this invention is a gluconol product existing in the prior art and commercially available. The solute-solvent ratio of the initial reactant 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, 0.10 g:1 mL, and ranges thereof.

[0016] 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.

[0017] In any of the above-mentioned preferred embodiments, in step 1, the temperature at which the galbacin solid dissolves in solvent I is 30–50°C. More preferably, it is 30, 35, 40, 45, 50°C or a range thereof.

[0018] Preferably, in step 2, the molar ratio of the malonic acid solid to the glycyrrhizin solid added in step 1 is 1:1 to 1.2:1. The malonic acid used in the initial reactants of this invention is a malonic acid product existing in the prior art and can be commercially available. More preferably, the molar ratio of the malonic acid solid to the glycyrrhizin solid is 1:1, 1.1:1, 1.2:1, or a range thereof.

[0019] Preferably, in step 3, the solution heating temperature is 30–50°C. More preferably, it is 30, 35, 40, 45, 50°C or a range thereof.

[0020] Preferably, in step 3, the stirring rate is 100–200 rpm. More preferably, it is 100, 150, 170, 200 rpm or a range thereof.

[0021] In any of the above-mentioned preferred embodiments, the constant temperature time in step 3 is 3 to 5 hours, and more preferably 3, 3.5, 4, 4.5, 5 hours or a range thereof.

[0022] In any of the above-mentioned preferred embodiments, in step 4, the evaporation temperature of the solution is 0–15°C, and more preferably 4°C.

[0023] In any of the above-mentioned preferred embodiments, in step 4, the evaporation time of the solution is 3 to 7 days, and more preferably 3, 4, 5, 7 days or a range thereof.

[0024] In any of the above-mentioned preferred embodiments, in step 5, the crystal drying temperature is 40-50°C, and more preferably 40, 45, 50°C or a range thereof.

[0025] Preferably, in step 5, the drying time is 3 to 4 hours. More preferably, it is 3, 3.5, or 4 hours or a range thereof.

[0026] 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.

[0027] In the method described in this invention, the crystallization method is evaporation crystallization.

[0028] The chemical stability of the ganbaosu-malonate crystals prepared according to the preferred embodiment of the present 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 1.

[0029] Table 1. Chemical stability study of the galbac-malonate crystals described in this invention.

[0030] 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％

[0031] The solubility of the raw material and the new salt form of glycyrrhizin and glycyrrhizin-malonate crystals was investigated by placing them in water at 25°C. The results are as follows: Figure 3 As shown, the solubility of the raw material cyproterone in water is 0.04595 mg / mL, while the solubility of cyproterone malonate in water is 1.0144 mg / mL, which is 25 times that of the raw material. This shows that the water solubility of cyproterone malonate is much better than that of the original cyproterone form. Attached Figure Description

[0032] Figure 1 X-ray powder diffraction pattern of ganbaosu-malonate in preferred embodiment 1 of the present invention.

[0033] Figure 2 The DSC-TG analysis chromatogram of ganbaosu-malonate in preferred embodiment 1 of the present invention.

[0034] Figure 3 Dissolution curves of ganbaosu-malonate and the original crystal form in preferred embodiment 1 of the present invention. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0036] Example 1

[0037] 0.270 g of glycyrrhizin solid was dissolved in 3.0 ml of methanol at 35 °C, and 0.096 g of malonic acid was added. The mixture was magnetically stirred at 150 rpm and kept at 35 °C for 3.5 h. The solution was then filtered, and the filtrate was evaporated at atmospheric pressure at 4 °C for 4 days. The resulting crystals were then dried in a nitrogen drying oven at 50 °C for 3 h. The final glycyrrhizin-malonate crystal product was obtained after drying. The results are as follows: Figures 1-3 As shown.

[0038] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 8.539±0.2°, 11.619±0.2°, 12.260±0.2°, 12.721±0.2°, 13.400±0.2°, 13.638±0.2°, 15.760±0.2°, 16.138±0.2°, 17.159±0.2°, 18.938±0.2°, 19.357±0.2°, 19.801±0.2°, and 20.943±0.2°. Characteristic peaks were observed at 21.597±0.2°, 21.999±0.2°, 22.398±0.2°, 23.798±0.2°, 24.719±0.2°, 25.802±0.2°, 26.543±0.2°, 27.461±0.2°, 28.660±0.2°, 29.558±0.2°, 31.458±0.2°, 33.002±0.2°, 33.558±0.2°, and 33.857±0.2°. DSC-TG results showed a melting temperature of 114.79℃. The product was a white powder with a purity of 99.8% and a process yield of 86%.

[0039] Example 2

[0040] 0.276 g of ganbaosu solid was dissolved in 3.0 ml of ethanol at 35 °C, and 0.098 g of malonic 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 placed in a nitrogen drying oven at 50 °C and dried for 4 h. The final ganbaosu-malonate crystal product was obtained after drying.

[0041] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 8.539±0.2°, 11.619±0.2°, 12.260±0.2°, 12.721±0.2°, 13.400±0.2°, 13.638±0.2°, 15.760±0.2°, 16.138±0.2°, 17.159±0.2°, 18.938±0.2°, 19.357±0.2°, 19.801±0.2°, and 20.943±0.2°. Characteristic peaks were observed at 21.597±0.2°, 21.999±0.2°, 22.398±0.2°, 23.798±0.2°, 24.719±0.2°, 25.802±0.2°, 26.543±0.2°, 27.461±0.2°, 28.660±0.2°, 29.558±0.2°, 31.458±0.2°, 33.002±0.2°, 33.558±0.2°, and 33.857±0.2°. DSC-TG results showed a melting temperature of 114.79℃. The product appeared as a white powder with a purity of 99.7% and a process yield of 87%.

[0042] Example 3

[0043] 0.300 g of ganbaosu solid was dissolved in 3.0 ml of methanol at 40 °C, and 0.107 g of malonic 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 placed in a nitrogen drying oven at 50 °C and dried for 3.5 h. The final ganbaosu-malonic acid crystalline product was obtained after drying.

[0044] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 8.539±0.2°, 11.619±0.2°, 12.260±0.2°, 12.721±0.2°, 13.400±0.2°, 13.638±0.2°, 15.760±0.2°, 16.138±0.2°, 17.159±0.2°, 18.938±0.2°, 19.357±0.2°, 19.801±0.2°, and 20.943±0.2°. Characteristic peaks were observed at 21.597±0.2°, 21.999±0.2°, 22.398±0.2°, 23.798±0.2°, 24.719±0.2°, 25.802±0.2°, 26.543±0.2°, 27.461±0.2°, 28.660±0.2°, 29.558±0.2°, 31.458±0.2°, 33.002±0.2°, 33.558±0.2°, and 33.857±0.2°. DSC-TG results showed a melting temperature of 114.79℃. The product was a white powder with a purity of 99.6% and a process yield of 87%.

[0045] Example 4

[0046] 0.300 g of ganbaosu solid was dissolved in 3.0 ml of ethanol at 40 °C, and 0.117 g of malonic 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 placed in a nitrogen drying oven at 50 °C and dried for 4 h. The final ganbaosu-malonic acid crystalline product was obtained after drying.

[0047] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 8.539±0.2°, 11.619±0.2°, 12.260±0.2°, 12.721±0.2°, 13.400±0.2°, 13.638±0.2°, 15.760±0.2°, 16.138±0.2°, 17.159±0.2°, 18.938±0.2°, 19.357±0.2°, 19.801±0.2°, and 20.943±0.2°. Characteristic peaks were observed at 21.597±0.2°, 21.999±0.2°, 22.398±0.2°, 23.798±0.2°, 24.719±0.2°, 25.802±0.2°, 26.543±0.2°, 27.461±0.2°, 28.660±0.2°, 29.558±0.2°, 31.458±0.2°, 33.002±0.2°, 33.558±0.2°, and 33.857±0.2°. DSC-TG results showed a melting temperature of 114.79℃. The product appeared as a white powder with a purity of 99.5% and a process yield of 89%.

[0048] Example 5

[0049] 0.285 g of galangol solid was dissolved in 3.0 ml of methanol at 35 °C, and 0.114 g of malonic 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 placed in a nitrogen drying oven at 50 °C and dried for 3.5 h. The final galangol-malonic acid crystalline product was obtained after drying.

[0050] The X-ray powder diffraction pattern of the product is shown at diffraction angles 2θ = 8.539±0.2°, 11.619±0.2°, 12.260±0.2°, 12.721±0.2°, 13.400±0.2°, 13.638±0.2°, 15.760±0.2°, 16.138±0.2°, 17.159±0.2°, 18.938±0.2°, 19.357±0.2°, 19.801±0.2°, and 20.943±0.2°. Characteristic peaks were observed at 21.597±0.2°, 21.999±0.2°, 22.398±0.2°, 23.798±0.2°, 24.719±0.2°, 25.802±0.2°, 26.543±0.2°, 27.461±0.2°, 28.660±0.2°, 29.558±0.2°, 31.458±0.2°, 33.002±0.2°, 33.558±0.2°, and 33.857±0.2°. DSC-TG results showed a melting temperature of 114.79℃. The product appeared as a white powder with a purity of 99.7% and a process yield of 87%.

[0051] Example 6

[0052] The chemical properties of the glycyrrhizin-malonate products obtained in Examples 1-5, i.e., the glycyrrhizin-malonate crystals of the present invention, were tested.

[0053] 1) The chemical stability of the ganbaosu-malonate 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 2.

[0054] Table 2. Chemical stability study of the ganbaosu-malonate described in this invention.

[0055]

[0056] 2) such as Figure 1 The image shows the X-ray powder diffraction pattern of ganbaosu-malonate obtained in Example 1, and the X-ray powder diffraction patterns of ganbaosu-malonate obtained in Examples 1-5. Figure 1 Therefore, it will not be provided again here.

[0057] 3) The ganbaosu-malonate crystals obtained in this invention were 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 ganbaosu-malonate obtained from the crystals obtained in Example 1 is shown below. Figure 2As shown, the DSC analysis chromatogram indicates a melting temperature of 114.79°C. The information in the chromatogram confirms that the glycyrrhizin-malonate obtained in Example 1 is stable. The results for Examples 1-5 are consistent, and images are not repeated here.

[0058] 4) Figure 3 The dissolution curves of the ganbaosu-malonate and the original crystal form obtained in Example 1 are shown below. Figure 3 As shown, the solubility of the active pharmaceutical ingredient (API) in water is 0.04595 mg / mL, while that of API-malonate is 1.0144 mg / mL, which is 25 times that of the API. This demonstrates that the water solubility of API-malonate is significantly better than that of the original API. The results of Examples 1-5 are consistent, and images are not repeated here. It is evident that the water solubility of API-malonate is significantly better than that of the original API.

[0059] This invention is described more clearly and completely through the following embodiments, but the described examples are only a part of the embodiments of this invention, not all of them. These embodiments are for the purpose of helping to understand this invention and should not be construed as limiting the scope of protection of this invention. The crystal form of ganbaosu-malonate 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, etc., 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 in the spirit, scope, and content of this invention.

Claims

1. A ganetespib-malonate crystal, the crystal having an X-ray powder diffraction pattern characterized by peaks at diffraction angles 2Θ = 8.539 ± 0.2°, 11.619 ± 0.2°, 12.260 ± 0.2°, 12.721 ± 0.2°, 13.400 ± 0.2°, 13.638 ± 0.2°, 15.760 ± 0.2°, 16.138 ± 0.2°, 17.159 ± 0.2°, 18.938 ± 0.2°, 19.357 ± 0.2°, 19.801 ± 0.2°, 20.943 ± 0.2°, 21.597 ± 0.2°, 21.999 ± 0.2°, 22.398 ± 0.2°, 23.798 ± 0.2°, 24.719 ± 0.2°, 25.802 ± 0.2°, 26.543 ± 0.2°, 27.461 ± 0.2°, 28.660 ± 0.2°, 29.558 ± 0.2°, 31.458 ± 0.2°, 33.002 ± 0.2°, 33.558 ± 0.2°, 33.857 ± 0.2°.

2. The crystal of claim 1, wherein The crystal has a melting point of 114.79 °C.

3. A method for preparing the ganetespib-malonate crystal according to claim 1 or 2, comprising the following steps: Step 1: dissolving ganetespib solid in solvent I; the solvent I is ethanol and / or methanol; Step 2: adding malonic acid solid to the solution obtained in step 1; Step 3: heating the solution obtained in step 2 to 30-50 °C and keeping the temperature for 3-5 h, continuously stirring; Step 4: filtering the clear solution obtained in step 3, and evaporating the filtrate; the evaporation temperature of the solution is 0-15 °C; Step 5: drying the crystal obtained in step 4, and obtaining the ganetespib-malonate crystal after drying.

4. The production method according to claim 3, wherein In step 1, the mass-volume ratio of ganetespib to solvent in the ganetespib solution obtained in step 1 is 0.09 g: 1 ml-0.10 g: 1 ml.

5. The production method according to claim 3, wherein In step 2, the molar ratio of malonic acid solid to ganetespib solid in step 1 is 1:1-1.2:

1.

6. The production method according to claim 3, wherein In step 5, the drying temperature of the crystal is 40-50 °C.

7. The production method according to claim 3, wherein In step 5, the drying condition is vacuum or nitrogen environment, and the drying time is 3-4 h.

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