Empagliflozin crystal form III and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a novel crystal form of empagliflozin and a preparation method thereof. The X-ray powder diffraction pattern of the novel crystal form of empagliflozin is as shown in Figure 1. The novel empagliflozin crystal form III provided by the invention is superior to other crystal forms in stability and solubility, and has an excellent prospect in the pharmaceutical industry. The invention further provides corresponding preparation methods of the five new crystal forms, the preparation methods are simple and convenient and easy for industrial application, and the yield of the new crystal forms obtained by adopting the corresponding preparation method embodiment 1 can reach 90% or above.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry crystallization, and in particular to a new crystal form III of empagliflozin and a preparation method of the crystal form. Background Art

[0002] Empagliflozin, also known as Empagliflozin, English name: Empagliflozin, chemical name: (1S)-1,5-dehydro-1-(4-chloro-3-{4-[(3S)-tetrahydrofuran-3-oxy]benzyl}phenyl)-D-glucitol, chemical formula is as follows:

[0003] It is clinically used to treat type 2 diabetes. Empagliflozin is a SGLT2 inhibitor in the treatment of type 2 diabetes. It is a new type 2 diabetes drug jointly developed by Eli Lilly and Company and Boehringer Ingelheim. On August 1, 2014, Empagliflozin was approved by the US FDA for marketing. It is the third oral SGLT-2 inhibitor approved for marketing in the United States after canagliflozin and dapagliflozin. Empagliflozin is an oral tablet of sodium-glucose co-transporter 2 (SGLT-2) inhibitor. The drug is distributed in the small intestinal mucosa and renal tubular sodium-glucose co-transporter. It reduces the glucose reabsorption of the kidneys by inhibiting SGLT-2 expressed in the kidneys, thereby reducing the plasma glucose level. It is used to control blood sugar in adult patients with type 2 diabetes.

[0004] The main problems with the known crystal forms of empagliflozin include crystal form diversity and insufficient research. There are 6 crystal forms of empagliflozin that have been disclosed. However, currently only one crystal form, a hydrate and an amorphous form of empagliflozin are available, and there is a lack of systematic research. The empagliflozin A crystal form in patent WO2006 / 117359A1 has disadvantages such as small particles, easy agglomeration, poor fluidity, low solubility in water, and low dissolution rate. Although the amorphous drug of empagliflozin in patent CN117402152A has better solubility to a certain extent, it has poor stability and a short storage time at room temperature. This shows that in the crystal form research of empagliflozin, there are challenges in accurately identifying and classifying the crystal forms. For drugs such as empagliflozin, although multiple crystal forms have been disclosed, there is still a need for in-depth research and development to more fully understand its crystal form characteristics, optimize drug performance, and reduce potential risks and uncertainties. Summary of the invention

[0005] The present invention provides a new crystal form of empagliflozin to solve the problems existing in the known crystal forms, and provides a preparation method thereof.

[0006] The present invention provides a crystalline form III of empagliflozin, which is prepared by using an X-ray powder diffractometer (PXRD). The measured PXRD pattern includes diffraction peaks at diffraction angles of 2θ=3.8, 6.9, 7.5, 9.8, 11.3, 15.1, and 17.3 degrees, and the 2θ error is 0.2.

[0007] In an embodiment of the present invention, the characteristic peaks and their relative intensities of the XRPD pattern of the Form III expressed in 2θ angles are as follows.

[0008]

[0009] The crystalline form of empagliflozin has the following Figure 1 The X-ray powder diffraction pattern is shown.

[0010] The DSC thermal analysis diagram of Empagliflozin Form III is shown in the attached figure. Figure 2 As shown, under the condition of heating rate of 10℃ / min, there are two endothermic peaks at 97℃ and 139℃.

[0011] The present invention provides a method for preparing the crystal form III, comprising the following steps: Step 1: Add empagliflozin to esters, alcohols or their mixed solvents, place the solution in an ultrasonic generator, turn on the ultrasonic temperature control at 50°C~80°C, stir for 1~2 hours, and the solution reaches equilibrium.

[0012] Step 2: Filter, place the filtrate in an ultrasonic generator, cool it down to -20℃~10℃ at a uniform rate over 0.5~3h, turn on the ultrasound, stir to precipitate crystals, and the crystal growth time is 4~12h.

[0013] Step 3: Filter and wash the filter cake with an alcohol or ester solvent, and after drying, the new crystal form III of empagliflozin is obtained.

[0014] More specific In the first step, the solvent is preferably methyl acetate, ethyl acetate, methanol, ethanol, isopropanol. The empagliflozin is in crystalline form A.

[0015] In the second step, the cooling time is 0.5 to 3 h.

[0016] In the second step, the output power of the ultrasonic generator is between 180W and 240W.

[0017] Compared with other inventions, this invention has the following advantages: Compared with the existing crystal form, the new crystal form has improved solubility in water relative to the known crystal form A, which is conducive to the rapid absorption of the drug, can exist stably for a long time, and can extend the shelf life of the drug. The preparation process of the present invention is easy to operate, cost-controllable, and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the XRPD spectrum of the empagliflozin crystal form III of the present invention.

[0019] Figure 2 This is the DSC spectrum of the empagliflozin crystal form III of the present invention.

[0020] Figure 3 This is the XPRD spectrum of the known empagliflozin crystalline form A. DETAILED DESCRIPTION

[0021] The present invention will be further described below in conjunction with the examples so that professionals in the field can better understand the present invention. The examples are only illustrative and are not intended to limit the scope of the present invention in any way.

[0022] Preparation Example 1 Preparation of Crystalline Form A of Empagliflozin 2 g of empagliflozin was dissolved in 60 ml of methanol solution heated at 60°C, the solution was slowly cooled to 20°C, and crystals were precipitated by stirring. The obtained white solid was filtered. Its spectrum is as follows Figure 3 The results are shown in Table 1. The results are consistent with the crystal form A disclosed in patent document WO2006 / 117359A1. Example 1

[0023] Take 5g of empagliflozin crystal form A and add it to methyl acetate solvent. Place the solution in an ultrasonic generator, turn on the ultrasonic wave, heat the solution system to a controlled temperature of 50°C, and continue stirring for 2 hours until the solution reaches equilibrium. Filter, collect the filtrate and put it back into the ultrasonic generator, cool it down to 10°C at a uniform speed over 0.5 hours, turn on the ultrasonic wave after reaching the target temperature, with an ultrasonic power of 180w, stir and crystallize, and keep the crystal at a constant temperature for 4 hours. Filter, wash the filter cake with ethanol solution, dry it, and determine it as new crystal form III by X-ray powder diffraction.

[0024] like Figure 1 Shown is the X-ray powder diffraction (XRD) pattern of Form III of this example; Figure 2 It is the differential scanning calorimetry (DSC) diagram of Form III. Example 2

[0025] Take 5g of empagliflozin crystal form A and add it to a mixed solution of anhydrous ethanol and methyl acetate (volume ratio 2:3), place the solution in an ultrasonic generator, turn on the ultrasonic wave, heat the solution system to a controlled temperature of 70°C, and continue stirring for 1 hour until the solution reaches equilibrium. Filter, collect the filtrate and put it back into the ultrasonic generator, cool it down to -10°C at a uniform speed for 2 hours, turn on the ultrasonic wave after reaching the target temperature, the ultrasonic power is 240w, stir and crystallize, and keep the crystal at a constant temperature for 8 hours. Filter, wash the filter cake with ethanol solution, dry it, and determine it as new crystal form III of empagliflozin by X-ray powder diffraction. Example 3

[0026] Take 5g of empagliflozin crystal form A and add it to ethyl acetate solvent, place the solution in an ultrasonic generator, turn on the ultrasonic wave, heat the solution system to 60°C, and continue stirring for 1h until the solution reaches equilibrium. Filter, collect the filtrate and put it back in the ultrasonic generator, cool it down to 0°C at a uniform speed for 3h, turn on the ultrasonic wave after reaching the target temperature, with an ultrasonic power of 200w, stir and crystallize, and keep the crystal at a constant temperature for 12h. Filter, wash the filter cake with ethanol solution, dry it, and determine it as new crystal form III by X-ray powder diffraction. Example 4

[0027] Take 5g of empagliflozin crystal form A and add it to isopropanol solvent. Place the solution in an ultrasonic generator, turn on the ultrasonic wave, heat the solution system to 80°C, and continue stirring for 1h until the solution reaches equilibrium. Filter, collect the filtrate and put it back in the ultrasonic generator, cool it down to -10°C at a uniform speed for 1h, turn on the ultrasonic wave after reaching the target temperature, with an ultrasonic power of 180w, stir and crystallize, and keep the crystal at a constant temperature for 4h. Filter, wash the filter cake with ethanol solution, dry it, and determine it as new crystal form III by X-ray powder diffraction. Example 5

[0028] Take 5g of empagliflozin crystal form A and add it to a mixed solution of ethyl acetate and methyl acetate (volume ratio 1:9), place the solution in an ultrasonic generator, turn on the ultrasonic wave, heat the solution system to a controlled temperature of 80°C, and continue stirring for 2 hours until the solution reaches equilibrium. Filter, collect the filtrate and put it back into the ultrasonic generator, cool it down to -20°C at a uniform rate for 1.5 hours, turn on the ultrasonic wave after reaching the target temperature, with an ultrasonic power of 220w, stir and crystallize, and keep the crystal at a constant temperature for 10 hours. Filter, wash the filter cake with ethanol solution, dry it, and determine it as new crystal form III of empagliflozin by X-ray powder diffraction.

[0029] Experimental Example 1: Preparation of Form A: A certain amount of empagliflozin was dissolved in an ethanol solution at 60°C, the solution was slowly cooled to 20°C, stirred to precipitate crystals, and the obtained white solid was filtered, which was consistent with Form A disclosed in patent WO2006 / 117359A1.

[0030] Experimental Example 2: Preparation of amorphous: A certain amount of empagliflozin was fully dissolved in a methanol solution at 60°C, and the solution was subjected to rotary evaporation at 60°C to rapidly evaporate the solvent to obtain the target crystal, which was consistent with the amorphous crystal disclosed in patent CN117402152A.

[0031] Test Example 3: Stability Study Referring to the 9001 API Stability Test Guidelines of the Chinese Pharmacopoeia 2020 Edition, the most intense influencing factor experimental method was used to evaluate the stability of the new crystal form of Empagliflozin obtained in the embodiment of the present invention, and compared with the above-prepared crystal form A and amorphous samples, where serial numbers 1 and 2 are parallel experiments to ensure the accuracy of the results. The results are as follows:

[0032] The test results show that the crystal form III of the present invention has high stability and will not undergo crystal transformation under normal storage conditions. Crystal form III, crystal form A and amorphous form will not undergo single crystal transformation or inter-transformation under normal storage conditions.

[0033] Test Example 4: Solubility Test

[0034] The test results show that the solubility of the crystal form III of the present invention is relatively high, much higher than that of the currently used pharmaceutical crystal form A.

[0035] In summary, the empagliflozin crystal form III described in the present invention has the characteristics of good stability and high solubility, which can make up for the shortcomings of the existing empagliflozin and is of great practical significance.

[0036] The above specific description of the present invention is only used to illustrate the present invention and is not limited to the technical solutions described in the embodiments of the present invention. Those skilled in the art should understand that the present invention can still be partially modified or replaced by equivalents to achieve the same technical effects; as long as the use requirements are met, they are within the protection scope of the present invention.

Claims

1. A crystalline form III of empagliflozin, characterized in that The powder X-ray diffraction pattern of empagliflozin crystal form III has characteristic diffraction peaks at diffraction angles of 2θ=3.8, 6.9, 7.5, 9.8, 11.3, 15.1, and 17.3 degrees, and the 2θ error is 0.

2.

2. The new crystalline form III of empagliflozin according to claim 1, characterized in that: Its differential scanning calorimetry diagram is shown in Figure 2. There are two endothermic peaks between 90°C and 50°C, and the endothermic peak values ​​are 97°C and 139°C respectively.

3. A method for preparing the new crystalline form I of empagliflozin according to any one of claims 1 and 2, characterized in that: Empagliflozin solid is used as a raw material, and after dissolution, ultrasonication, filtration and crystallization, the empagliflozin crystal form III is obtained.

4. The method for preparing the empagliflozin crystal form III according to claim 1, characterized in that The steps include: Step 1: Add empagliflozin to esters or alcohols or their mixed solvents, place the solution in an ultrasonic generator, turn on the ultrasonic temperature control at 50°C~80°C, stir for 1~2 hours, and the solution reaches equilibrium. Step 2: Filter, place the filtrate in an ultrasonic generator, cool it to -20°C~10°C at a uniform rate over 0.5~3 hours, turn on the ultrasound, stir to precipitate crystals, and the crystal growth time is 4~12 hours. Step 3: Filter, wash the filter cake with an alcohol or ester solvent, and after drying, it is the new crystalline form III of empagliflozin.

5. The method for preparing the new crystalline form III of Empagliflozin according to claim 4, characterized in that The solvent in the first step is preferably methyl acetate, ethyl acetate, methanol, ethanol, isopropanol or a mixed solution thereof.

6. The method for preparing the crystal form III of Empagliflozin according to claim 4, characterized in that The output power of the ultrasonic generator in the second step is between 180W and 240W.

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