Glycyrrhizic acid derivative crystal form and preparation method thereof

Abstract

The invention provides a glycyrrhizic acid derivative crystal form and a preparation method thereof. The glycyrrhizic acid derivative crystal form is stable in physicochemical property and small in moisture content fluctuation, especially content difference of active substances caused by water loss in the storage process is avoided, a solid is not prone to moisture absorption and caking after being placed for a long time, and strict nitrogen protection is not needed for storage conditions. And the preparation method is simple and environment-friendly, has good reproducibility and high drying efficiency, and is more suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a crystalline form of a glycyrrhizic acid derivative and a preparation method thereof. Background Art

[0002] The natural plant Glycyrrhiza Uralensis is a commonly used medicinal plant, and its rhizome mainly contains glycyrrhizic acid with 18-β configuration and glycyrrhizic acid with 18-α configuration. With the continuous deepening of research, it is found that magnesium glycyrrhizinate with 18-α configuration has an anti-hepatic injury effect.

[0003] This article relates to a crystalline form of a glycyrrhizic acid derivative and a preparation method thereof, and its structural formula is as follows:

[0004]

[0005] For the same drug, due to different crystallization conditions and processes, crystalline forms with different spatial structures and molecular arrangements may be obtained, and this phenomenon is called the polymorphism of drugs. The change of the crystalline form of a medicinal compound usually results in the compound having different melting points, solubilities, stabilities and hygroscopicities, and these properties all affect the ease of drug preparation, storage stability, etc.

[0006] Patent CN1169826C reported magnesium isoglycyrrhizinate tetrahydrate, which is obtained by dissolving refined isoglycyrrhizic acid in 70% isopropanol, adding a calculated amount of basic magnesium carbonate, refluxing in a boiling water bath until no CO2 is generated, slightly cooling and then filtering off a small amount of insoluble substances, allowing the filtrate to stand overnight, washing the crystals with isopropanol, filtering and drying to obtain magnesium isoglycyrrhizinate tetrahydrate, and its [α]D20 is +18.0°. The inventor found in the study of the crystalline form of magnesium isoglycyrrhizinate that when using the method reported in Patent CN1169826C to prepare magnesium isoglycyrrhizinate tetrahydrate, the process repeatability is poor, the content of isopropanol in the isopropanol aqueous solution has a great influence on the crystalline form, and it is difficult to remove the residual isopropanol in the solid by baking, which affects the product quality.

[0007] Therefore, obtaining a superior crystalline form has high commercial value for product development and drug application.

[0008] The inventor found a new crystalline form of the glycyrrhizic acid derivative during the study of the glycyrrhizic acid derivative. Summary of the Invention

[0009] The purpose of the present invention is to provide a crystalline form of a glycyrrhizic acid derivative and a preparation method thereof.

[0010] In the first aspect of the present invention, there is provided a crystalline form of a glycyrrhizic acid derivative. Using Cu-Kα radiation, the X-ray powder diffraction spectrum of this crystalline form has diffraction peaks at 2θ values of approximately 3.80 ± 0.2°, 7.67 ± 0.2°, 10.86 ± 0.2°, and 12.73 ± 0.2°. The structural formula of the glycyrrhizic acid derivative is as follows:

[0011]

[0012] According to an embodiment of the present invention, using Cu-Kα radiation, the X-ray powder diffraction spectrum of this crystalline form has diffraction peaks at 2θ values of approximately 3.80 ± 0.2°, 7.67 ± 0.2°, 10.86 ± 0.2°, 12.46 ± 0.2°, 12.73 ± 0.2°, and 16.38 ± 0.2°.

[0013] According to an embodiment of the present invention, using Cu-Kα radiation, the X-ray powder diffraction spectrum of this crystalline form has diffraction peaks at 2θ values of approximately 3.80 ± 0.2°, 7.67 ± 0.2°, 10.86 ± 0.2°, 12.46 ± 0.2°, 12.73 ± 0.2°, 14.43 ± 0.2°, 16.38 ± 0.2°, 17.73 ± 0.2°, and 21.39 ± 0.2°.

[0014] According to an embodiment of the present invention, using Cu-Kα radiation, the X-ray powder diffraction in terms of 2θ angle is shown in Table 1:

[0015]

[0016] According to an embodiment of the present invention, this crystalline form has a substantially Figure 1 as shown X-ray powder diffraction pattern.

[0017] According to an embodiment of the present invention, in the differential scanning calorimetry thermogram of this crystalline form, there is an endothermic peak at the onset point of approximately 55.84 °C.

[0018] According to an embodiment of the present invention, this crystalline form has a substantially Figure 2 as shown differential scanning calorimetry / thermogravimetric analysis (TGA) thermogram.

[0019] According to an embodiment of the present invention, this crystalline form is a hydrate and has a water content of approximately 14 - 18% by weight (wt%).

[0020] In some embodiments, this crystalline form has a water content of 15 - 16.5% by weight (wt%).

[0021] In the second aspect of the present invention, a method for preparing a crystalline form of a glycyrrhizic acid derivative is provided, which includes adding a crude product of the glycyrrhizic acid derivative to water, heating to a certain temperature for pulping, filtering, and drying to obtain the crystalline form of the glycyrrhizic acid derivative.

[0022] According to an embodiment of the present invention, the mass-volume ratio of the crude product of the glycyrrhizic acid derivative to water is 1:2 to 20 g / ml.

[0023] According to an embodiment of the present invention, the heating to a certain temperature is 25 to 75 °C; when the temperature rises above 25 °C, it needs to be cooled to room temperature after pulping.

[0024] According to an embodiment of the present invention, the pulping time is 2 to 8 hours.

[0025] According to an embodiment of the present invention, the drying temperature is 50 to 60 °C.

[0026] According to an embodiment method of the present invention, the drying time is 15 to 24 hours.

[0027] In the third aspect of the present invention, a pharmaceutical composition is provided, which contains the crystalline form and may further contain one or more pharmaceutically acceptable excipients. The pharmaceutical composition suitable for parenteral administration includes injection forms, such as sterile solutions, suspensions or emulsions, preferably sterile solutions.

[0028] Compared with the prior art, the present invention obtains positive technical effects:

[0029] 1) The crystalline form of the glycyrrhizic acid derivative provided by the present invention has stable physicochemical properties and small fluctuations in moisture content. Especially during storage, it will not cause differences in the content of active substances due to water loss, and the solid is not easy to absorb moisture and cake after long-term placement, and strict nitrogen protection is not required for storage conditions.

[0030] 2) The method for preparing the crystalline form of the glycyrrhizic acid derivative provided by the present invention is simple, environmentally friendly, has good reproducibility, and high drying efficiency, and is more suitable for large-scale industrial production. Description of the Drawings

[0031] Figure 1 It is the X-ray powder diffraction pattern of the crystalline form of the glycyrrhizic acid derivative prepared in Example 1 of the present invention.

[0032] Figure 2 It is the combined differential scanning calorimetry / thermogravimetric analysis (TGA) spectrum of the crystalline form of the glycyrrhizic acid derivative prepared in Example 1 of the present invention.

[0033] Figure 3 It is the superimposed X-ray powder diffraction pattern of the crystalline form of the glycyrrhizic acid derivative prepared in Example 1 of the present invention when it is placed open for 7 days, 14 days, placed under light for 7 days, 14 days, and placed sealed for 7 days, 14 days.

[0034] Figure 4 This is the glycyrrhizic acid derivative crystal form A prepared in Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0035] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0036] Raw materials and general test methods:

[0037] X-ray powder diffraction detection method:

[0038] Instrument model: Bruker D8 ADVANCE

[0039] Testing basis: Chinese Pharmacopoeia 2020 Edition Part 4 General Rules 0451 Method 2

[0040] Test conditions:

[0041] Anode target: Cu; voltage and current: 40kv 40mA; divergence slit 0.6mm, Soller slit 2.5°;

[0042] Continuous scanning; scanning range: 3°-40°; step length: 0.02°; scanning speed: 0.2s / step; detector: LynxEye.

[0043] Sample preparation: Place 2-5 mg of sample in the middle of a background-free sample holder or a common sample holder and flatten it with a spatula.

[0044] Differential scanning calorimetry / thermogravimetric analysis (TGA) combined detection method:

[0045] Instrument model: Mettler TGA / DSC 2

[0046] Testing basis: General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia 0661

[0047] Crucible type: Al2O3 crucible (open)

[0048] Temperature conditions: 30oC-350oC, 10oC / min

[0049] Atmosphere conditions: Purge gas: N2 50ml / min; Protective gas: N2 20ml / min

[0050] Sample preparation: Place the sample in the center of the crucible and make full contact with the crucible.

[0051] Balance model: The instrument comes with a balance

[0052] It should be noted that in the X-ray powder diffraction pattern, the diffraction pattern obtained from a crystalline compound is often characteristic of a specific crystal form. The relative intensity of the spectral bands (especially at low angles) may vary due to the preferred orientation effect caused by differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensity of the diffraction peaks is not characteristic of the targeted crystal form. When determining whether it is the same as a known crystal form, more attention should be paid to the relative positions of the peaks rather than their relative intensities. In the XRD pattern, the peak position is usually represented by the 2θ angle or the interplanar spacing d. Since the 2θ angle is related to the wavelength of the incident X-ray, it is more representative to use the interplanar spacing d. There is a simple conversion relationship between the two: d = λ / 2sinθ, where d represents the interplanar spacing, λ represents the wavelength of the incident X-ray (for Cu-Kα), and θ is the diffraction angle. For the same crystal form of the same compound, its XRD pattern is generally similar as a whole. The error of the d value representing the peak position is generally within ±2%, and most errors do not exceed ±1%; the measurement error unit of the 2θ value is about ±0.2 degrees; the relative intensity error can be relatively large. It should also be pointed out that in the identification of mixtures, due to factors such as a decrease in content, some diffraction lines may be missing. At this time, it is not necessary to rely on all the spectral bands observed in a high-purity sample, and even a few spectral bands may be characteristic of a given crystallization.

[0053] Differential scanning calorimetry measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting. For the same crystal form of the same compound, in consecutive analyses, the thermal transition temperature and melting point error are within about 5°C, usually within about 3°C. When we say that a compound has a given DSC peak or melting point, this refers to the DSC peak or melting point ±5°C. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary within a larger range. In addition, since decomposition occurs during the melting process of a substance, the melting temperature is related to the heating rate.

[0054] Example 1: Preparation method of crude glycyrrhizic acid derivative

[0055] Add 7.0 g of 18-β-configured glycyrrhizic acid to 28 g of isopropanol to form a solution containing 18-β-configured glycyrrhizic acid. Add an aqueous solution of magnesium acetate (1.21 g of magnesium acetate and 0.6 ml of water), stir for 0.5 h, heat up to 65°C - 70°C, keep stirring for 2 h, cool down to 20 - 25°C, filter, and place the filter cake in an oven at 45 ± 3°C to dry to obtain the crude glycyrrhizic acid derivative.

[0056] Example 2:

[0057] 0.5 g of the crude glycyrrhizic acid derivative was added to 7.5 ml of water, and the mixture was slurried at 45 - 50 °C for 2 h, then slowly cooled to room temperature and filtered to collect the filter cake; the filter cake was dried at 50 °C for 15 - 24 h to obtain the crystalline form of the glycyrrhizic acid derivative, with a yield of 93% and a purity of 99.5%.

[0058] Results:

[0059] The obtained crystalline form of the glycyrrhizic acid derivative was subjected to X - RPD testing, DSC / TGA testing, and moisture content testing.

[0060] Figure 1 is the X - ray powder diffraction pattern of the crystalline form of the glycyrrhizic acid derivative prepared in Example 2. As can be seen from Figure 1 it, diffraction peaks are present at 2θ values of approximately 3.80°, 7.67°, 10.86°, 12.46°, 12.73°, 14.43°, 16.38°, 17.73°, and 21.39°.

[0061] Figure 2 is the DSC / TGA spectrum of the crystalline form of the glycyrrhizic acid derivative prepared in Example 2. As can be seen from Figure 2 it, there is an endothermic peak at the onset point of approximately 55.84 °C, and as can be seen from Figure 2 it, a weight loss of approximately 15.1% occurs at 29 - 178 °C. Additionally, the moisture content was determined to be 15.9% by the Karl Fischer titration method, and it contains approximately 9 moles of water of crystallization.

[0062] Example 3:

[0063] 0.5 g of the crude glycyrrhizic acid derivative was added to 2.5 ml of water, and the mixture was slurried at 25 - 30 °C for 8 h, then slowly cooled to room temperature and filtered to collect the filter cake; the filter cake was dried at 50 °C for 15 - 24 h to obtain the crystalline form of the glycyrrhizic acid derivative, with a yield of 95% and a purity of 99.5%. The obtained crystalline form is basically the same as that obtained in Example 1.

[0064] Example 4:

[0065] 0.5 g of the crude glycyrrhizic acid derivative was added to 5.0 ml of water, and the mixture was slurried at 45 - 50 °C for 4 h, then slowly cooled to room temperature and filtered to collect the filter cake; the filter cake was dried at 60 °C for 15 - 24 h to obtain the crystalline form of the glycyrrhizic acid derivative, with a yield of 94% and a purity of 99.5%. The obtained crystalline form is basically the same as that obtained in Example 1.

[0066] Comparative Example 1: (Reference CN1169826C)

[0067] Take 1.5 g of glycyrrhizic acid in 18-β configuration, dissolve it in 70% isopropanol, add a calculated amount of magnesium carbonate basic, reflux in a boiling water bath until carbon dioxide is produced. After cooling slightly, filter off a small amount of insoluble matter. Leave the filtrate to stand overnight, filter, wash the crystals with isopropanol, drain, and dry in air to obtain a glycyrrhizic acid derivative, which is named glycyrrhizic acid derivative A crystal form in this application. The water content is measured to be 7.8%. Using Cu-Kα radiation, the X-ray powder diffraction pattern is obtained as shown in the appendix Figure 4 as shown

[0068] Example 5:

[0069] The glycyrrhizic acid derivative crystal form obtained in Example 2 and the glycyrrhizic acid derivative A crystal form obtained in Comparative Example 1 are respectively placed open to the air under the conditions of 60 °C / 75% RH for 2 weeks, irradiated with light for 2 weeks, and placed open to the air under the conditions of 25 °C / 60% for 2 weeks to determine the content, water content, appearance change and crystal form change

[0070] Table 1 Stability study of glycyrrhizic acid derivative crystal form:

[0071]

[0072]

[0073] Note: * a The content determination is carried out by liquid chromatography, and the content is calculated as anhydrous magnesium isoglycyrrhizinate

[0074] * b The water content is determined by the Karl Fischer titration method

[0075] The above embodiments only represent several implementation modes of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims

Claims

1. A crystalline form of a glycyrrhizic acid derivative, characterized in that, The crystal form uses Cu-Kα radiation, and its X-ray powder diffraction spectrum has diffraction peaks at 2θ values of approximately 3.80 ± 0.2°, 7.67 ± 0.2°, 10.86 ± 0.2°, and 12.73 ± 0.2°. The structural formula of the glycyrrhizic acid derivative is as follows:

2. The crystalline form according to claim 1, wherein The crystal form uses Cu-Kα radiation, and its X-ray powder diffraction spectrum has diffraction peaks at 2θ values of approximately 3.80 ± 0.2°, 7.67 ± 0.2°, 10.86 ± 0.2°, 12.46 ± 0.2°, 12.73 ± 0.2°, and 16.38 ± 0.2°.

3. The crystalline form according to claim 1, characterized in that, The crystal form uses Cu-Kα radiation, and its X-ray powder diffraction spectrum has diffraction peaks at 2θ values of approximately 3.80 ± 0.2°, 7.67 ± 0.2°, 10.86 ± 0.2°, 12.46 ± 0.2°, 12.73 ± 0.2°, 14.43 ± 0.2°, 16.38 ± 0.2°, 17.73 ± 0.2°, and 21.39 ± 0.2°.

4. The crystalline form according to claim 1, characterized in that, The crystal form has an X-ray powder diffraction pattern as shown in Figure 1.

5. The crystalline form according to claim 1, characterized in that, In the differential scanning calorimetry thermogram, the crystal form has an endothermic peak at an onset of approximately 55.84°C.

6. The crystalline form according to claim 1, wherein, The crystal form is a hydrate and has a water content of approximately 14 to 18% by weight (wt%).

7. The crystalline form according to claim 1, wherein The crystal form has a water content of 15 to 16.5% by weight (wt%).

8. The crystalline form according to claim 1, characterized in that, The crystal form has a differential scanning calorimetry / thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 2.

9. A method for preparing the crystalline form of the glycyrrhizic acid derivative according to any one of claims 1 to 8, characterized in that, The method includes adding the crude glycyrrhizic acid derivative to water, heating to a certain temperature for pulping, filtering, and drying to obtain the glycyrrhizic acid derivative crystal form.

10. The preparation method according to claim 9, wherein, The mass-volume ratio of the crude glycyrrhizic acid derivative to water is 1:2 to 20 g / ml.

11. The preparation method according to claim 9, wherein The heating to a certain temperature is 25 to 75°C; when the temperature rises above 25°C, it needs to be cooled to room temperature after pulping; the drying temperature is 50 to 60°C.

12. The preparation method according to claim 9, characterized in that, The pulping time is 2 to 8 hours; the drying time is 15 to 24 hours.

13. A pharmaceutical composition comprising the glycyrrhizic acid derivative crystal form according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients.

Images