Crystal form of ipragliflozin hydrochloride and preparation method thereof

Abstract

The invention discloses a crystal form of ipragliflozin hydrochloride and a preparation method thereof, and belongs to the technical field of medicine synthesis. An X-ray powder diffraction pattern of the ipragliflozin hydrochloride crystal form disclosed by the invention has corresponding characteristic diffraction peaks at positions of 2theta values of 11.7 degrees, 14.8 degrees, 16.8 degrees, 17.7 degrees, 18.8 degrees, 20.5 degrees, 23.1 degrees, 23.4 degrees, 24.9 degrees, 25.5 degrees, 26.5 degrees, 26.9 degrees, 29.4 degrees and 32.7 degrees + / -0.2 degrees. The preparation method is simple and has excellent chemical stability and industrial practicability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a crystal form of ipraglimine hydrochloride and a preparation method thereof. Background Art

[0002] The chemical name of Igligrimine hydrochloride is: (6R)-N 2 ,N 2 ,6-trimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine hydrochloride, the structural formula is The original manufacturer is Sumitomo Pharma Co., Ltd. of Japan. It was approved for marketing in Japan in June 2021 under the trade name: Twymeeg. This preparation targets mitochondrial dysfunction and is a new oral hypoglycemic drug with a dual mechanism of action. It lowers blood sugar through pancreatic and extra-pancreatic effects. It can be used as a monotherapy or as an add-on therapy to other hypoglycemic therapies for the treatment of type 2 diabetes.

[0003] Ipagliflozin hydrochloride tablets can simultaneously play a role in the three key organs that maintain glucose balance in the human body, including the liver, muscles, and pancreas. Its special mechanism of action makes it effective in preventing endothelial and diastolic dysfunction, and has some protective effects on microvascular and macrovascular defects that may be caused by diabetes. In addition, it also has potential protective capabilities for the survival and functional realization of β-cells.

[0004] To exert its efficacy, drugs need to go through a series of processes such as release, penetration and absorption, and each stage affects the optimal efficacy of the drug to varying degrees. Among them, the dissolution of oral tablets plays an important role in drug efficacy, and the physical and chemical properties of the API itself, such as crystal form, particle size, solubility, stability, etc., have a great contribution to dissolution. To improve the dissolution of preparations, solubility is an important link, which is further reflected in the fact that the crystal form of the API has a great influence on solubility. It is well known in the pharmaceutical field that the polymorphic form of the drug not only determines the dissolution of the drug, but also has a profound impact on the fluidity, stability, compressibility and ease of handling during the preparation process. Therefore, the API used in the preparation needs to select a crystal form with good solubility and excellent stability to prevent it from changing crystals during the preparation process, storage, and use, which affects the efficacy.

[0005] Prior art WO2010109015A1 discloses a method for preparing a single-configuration ipraglimine from an ipraglimine racemate by a dominant crystallization method, wherein the content of the single-configuration ipraglimine hydrochloride is the highest (95.46%) when the racemic hydrochloride is dissolved and crystallized for 30 minutes. As the crystallization time increases, the single-configuration product decreases. After crystallization for 120 minutes, the content of the single-configuration product is only 70.36%. The single-configuration ipraglimine hydrochloride product obtained by this method has a high content of isomeric impurities and poor stability, and is not suitable for development as a drug. Summary of the invention

[0006] Technical issues:

[0007] In order to solve the above problems, the present invention prepares and provides a new single-configuration crystal of ipraglimine hydrochloride with better crystal stability and better solubility.

[0008] Technical solution:

[0009] The object of the present invention is to provide a crystalline form of ipraglimine hydrochloride and a preparation method thereof.

[0010] On the one hand, the present invention provides a crystal form of ipraglimin hydrochloride, whose X-ray powder diffraction spectrum has characteristic diffraction peaks corresponding to positions of 2θ values ​​(±0.2o) of 11.7o, 14.8o, 16.8o, 17.7o, 18.8o, 20.5o, 23.1o, 23.4o, 24.9o, 25.5o, 26.5o, 26.9o, 29.4o and 32.7o.

[0011] In this embodiment of the present invention, the ipraglimin hydrochloride crystalline form has the following Figure 1 The X-ray powder diffraction pattern is shown.

[0012] In this embodiment of the present invention, the melting point of the ipraglimin hydrochloride crystal form is 253.0-255.0°C.

[0013] On the other hand, the present invention also provides a method for preparing a crystalline form of ipraglimin hydrochloride, comprising the following steps:

[0014] 1) dissolving ipraglimine hydrochloride in a solvent, raising the temperature to 20-80°C to make it dissolve clearly;

[0015] 2) lowering the temperature of the solution to 0-40°C for crystallization, with a cooling rate of 4-30°C / hour during crystallization;

[0016] 3) Filter or centrifuge the precipitated solid, and dry the separated solid at 25 to 75°C.

[0017] In this embodiment of the present invention, in step 1), ipraglimine hydrochloride is a white solid with a melting point of 235.0-245.0° C. and a HPLC chiral purity of ≥98%.

[0018] In this embodiment of the present invention, the solvent in step 1) is selected from one or a mixture of methanol, ethanol, isopropanol, acetone, propanol, tetrahydrofuran, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide and water.

[0019] In this embodiment of the present invention, in step 1), the amount of the solvent relative to ipraglimin hydrochloride is 3-6 mL / g.

[0020] In this embodiment of the present invention, the solvent in step 1) can be selected from the following situations:

[0021] Ethanol, isopropanol, a mixture of ethanol and water, a mixture of acetonitrile and water, and a mixture of dimethyl sulfoxide and water.

[0022] In this embodiment of the present invention, in step 1), if the solvent is ethanol, the amount of solvent used is 3 mL / g; and the temperature is raised to 70-80°C.

[0023] In this embodiment of the present invention, in step 1), if the solvent is isopropanol, the amount of solvent used is 3 mL / g; and the temperature is raised to 50-80°C.

[0024] In this embodiment of the present invention, in step 1), if the solvent is a mixed system of dimethyl sulfoxide and water, the volume ratio of the two is 5:1, and the amount of solvent is 4 mL / g; the temperature is raised to 50-80°C.

[0025] In this embodiment of the present invention, in step 1), if the solvent is a mixed system of ethanol and water, the volume ratio of the two is 3:1, and the amount of solvent is 4 mL / g; the temperature is raised to 20-50°C.

[0026] In this embodiment of the present invention, in step 1), if the solvent is a mixed system of acetonitrile and water, the volume ratio of the two is 5:1, and the amount of solvent is 6 mL / g; the temperature is raised to 50-80°C.

[0027] In this embodiment of the present invention, the temperature in step 2) is reduced to 10-30°C.

[0028] In this embodiment of the present invention, the drying temperature in step 3) is 30-45°C.

[0029] In another aspect, the present invention also provides use of the above-mentioned iplagetamine hydrochloride crystal form in the preparation of hypoglycemic drugs.

[0030] Furthermore, a pharmaceutical composition is specifically provided, comprising the above-mentioned iplagetamine hydrochloride crystal form and pharmaceutical excipients.

[0031] In this embodiment of the present invention, the pharmaceutical excipients include any one or more of the following: solvents, propellants, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrities, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, flocculants and deflocculating agents, filter aids, and release retardants.

[0032] In this embodiment of the present invention, the pharmaceutical excipient further comprises a drug carrier, and the drug carrier is selected from microcapsules, microspheres, nanoparticles, and liposomes.

[0033] Beneficial effects:

[0034] The new crystal form of the present invention has an X-ray powder diffraction pattern at 2 θ Characteristic peaks appear at positions of 11.7o, 14.8o, 16.8o, 17.7o, 18.8o, 20.5o, 23.1o, 23.4o, 24.9o, 25.5o, 26.5o, 26.9o, 29.4 and 32.7o±0.2o. The preparation method is simple, the chemical stability is excellent, and it has industrial practicability. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The X-ray powder diffraction pattern of the ipraglimine hydrochloride crystal obtained in Example 1.

[0036] Figure 2 This is the DSC graph of the ipraglimin hydrochloride crystal obtained in Example 1.

[0037] Figure 3 This is the TGA diagram of the ipraglimin hydrochloride crystal obtained in Example 1.

[0038] Figure 4 This is the X-ray powder diffraction pattern of the ipraglimine hydrochloride crystal obtained in Example 2.

[0039] Figure 5 This is the X-ray powder diffraction pattern of the ipraglimin hydrochloride crystal obtained in Example 3.

[0040] Figure 6 This is the X-ray powder diffraction pattern of the ipraglimin hydrochloride crystal obtained in Example 4.

[0041] Figure 7 This is the X-ray powder diffraction pattern of the ipraglimine hydrochloride crystal obtained in Example 5.

[0042] Figure 8 This is the X-ray powder diffraction pattern of the ipraglimine hydrochloride product obtained in Comparative Example 2. DETAILED DESCRIPTION

[0043] In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments, but the present invention is not limited thereto.

[0044] The ipraglimine hydrochloride raw material involved in the present invention can be purchased from Hubei Wei's Chemical Reagent Co., Ltd., and is a white solid with a melting point of 235.0-245.0° C. and a HPLC chiral purity of ≥98%.

[0045] Example 1

[0046] In a 25mL three-necked flask, add ipraglimine hydrochloride (3.0g) and ethanol (9.0mL), heat to 79℃ to dissolve, turn off the heat, cool to 20-30℃ for crystallization, filter, rinse, and dry the filter cake at 40℃ to obtain 2.85g of white crystals, with a yield of 95.0% and a chiral purity of 99.95%. The X-ray powder diffraction (XRD) results are as follows: Figure 1 , Differential Scanning Calorimetry (DSC) Figure 2 , thermogravimetric analysis (TGA) Figure 3 .

[0047] Example 2

[0048] In a 25mL three-necked flask, add ipraglimine hydrochloride (3.0g) and isopropanol (9.0mL), heat to 65℃ to dissolve, turn off the heat, cool to 20-30℃ for crystallization, filter, rinse, and dry the filter cake at 40℃ to obtain 2.88g of white crystals, with a yield of 96.0% and a chiral purity of 99.97%. The X-ray powder diffraction (XRD) results are as follows: Figure 4 .

[0049] Example 3

[0050] In a 25mL three-necked flask, add ipraglimine hydrochloride (3.0g), dimethyl sulfoxide (10.0mL) and water (2.0mL), heat to 60℃ to dissolve, turn off the heating, cool to 20-30℃ for crystallization, filter, rinse, and dry the filter cake at 40℃ to obtain 1.86g of white crystals, with a yield of 62.0% and a chiral purity of 99.99%. The X-ray powder diffraction (XRD) results are as follows: Figure 5 .

[0051] Example 4

[0052] In a 25mL three-necked flask, add ipraglimine hydrochloride (3.0g), ethanol (9.0mL) and water (3.0mL), heat to 30℃ to dissolve, turn off the heating, cool to 20-25℃ for crystallization, filter, rinse, and dry the filter cake at 40℃ to obtain 2.76g of white crystals, with a yield of 92.0% and a chiral purity of 99.98%. The X-ray powder diffraction (XRD) results are as follows: Figure 6 .

[0053] Example 5

[0054] In a 20L reactor, add ipraglimine hydrochloride (1.0kg), acetonitrile (5.0L) and purified water (1.0L), heat to 60°C, turn off the heating, cool to 20-30°C for crystallization, filter, rinse, and dry the filter cake at 40°C to obtain 972.1g of white crystals with a yield of 97.2% and a chiral purity of 99.98%. The X-ray powder diffraction (XRD) results are as follows: Figure 7 .

[0055] Comparative Example 1

[0056] The reference substance 1 was prepared with reference to the prior art WO2010109015A1, and the specific process was as follows:

[0057] Add racemic hydrochloride (50g) and ethanol (350.0mL) to a 500mL three-necked flask, heat to reflux to dissolve, cool to 40°C and inoculate with racemic slurry to promote crystallization, keep equilibrium overnight after crystals precipitate. Filter the reaction solution into a reaction bottle (the reaction bottle is preheated to about 40°C in advance), heat to 60°C after filtration to dissolve it completely, cool to 40°C and detect the sample concentration by HPLC, and precipitate a small amount of solid when cooled to 13°C. Heat to 60°C again to dissolve it completely, cool to 40°C and keep for 30min, add R-ibriglimine hydrochloride with a chiral purity of 94.5%, and keep the cooling rate at 1°C / 5min. Filter and rinse when crystallization is 30min, and dry the filter cake at 40°C to obtain 23.7g of reference substance with a chiral purity of 95.57%.

[0058] Comparative Example 2

[0059] Reference substance 2 was prepared with reference to the prior art CN118955413A, and the specific process was as follows:

[0060] Weigh 13.90g of N,N-dimethyl-2,4-diamino-1,3,5-triazine, 3.30g of formaldehyde, catalyst (0.34g of p-toluenesulfonic acid and 0.98g of dodecylbenzenesulfonic acid), and 4.01g of hydrochloric acid, put into a beaker containing 34.75g of isobutanol, heat to 100℃±1℃, reflux reaction for 11h, the material gradually clarifies from a suspended state, the end point is a clear state, the reaction is completed, and a clear solution is obtained; then the clear solution is distilled to distill out 0.5 times of isobutanol, cool to 15℃±1℃ for solid-liquid separation, then rinse with 0.5 times of isobutanol, and dry to obtain crude imeglimine hydrochloride. Finally, the crude imeglimine hydrochloride is dissolved in an ethanol solution 6 times its mass, heated to 57℃±1℃, stirred, cooled to room temperature, the solid is filtered, and washed with an ethanol solution, and the solid is dried to obtain a reference substance. X-ray powder diffraction (XRD) results are shown in Figure 8 .

[0061] Characterization:

[0062] The X-ray powder diffraction patterns of the products of Examples 1-5 are as follows: Figure 1 , 4 -7. Among them, characteristic peaks appear at 2θ values ​​of 11.7o, 14.8o, 16.8o, 17.7o, 18.8o, 20.5o, 23.1o, 23.4o, 24.9o, 25.5o, 26.5o, 26.9o, 29.4 and 32.7o±0.2o.

[0063] Combining the X-ray powder diffraction pattern of the reference substance in Comparative Example 1 (the single-configuration product in figure 2 of WO2010109015A1), it can be seen that the X-ray powder diffraction of the reference substance obtained by the prior method has no characteristic peaks at 2θ values ​​of 18.8°, 23.1°, and 23.4°. It can be seen that the crystalline product obtained in the embodiment of the present invention is obviously different from the product obtained by the prior method.

[0064] Combined with the X-ray powder diffraction pattern of the reference substance in Comparative Example 2 ( Figure 8 ) It can be seen that the reference product 2 has only very weak signal peaks at 2θ values ​​of 17.7o and 20.5o, which are even negligible, and the peak intensity value at 2θ value of 25.5o is significantly different from that of the embodiment of the present invention. It can be seen that the crystals obtained in the embodiment of the present invention are significantly different from the reference product 2.

[0065] The DSC diagram of the iplagetamine hydrochloride crystal obtained in Example 1 is as follows: Figure 2 Differential thermal analysis shows an endothermic peak at 253.13-255.26°C, that is, the melting point of the crystal form is 253-255°C.

[0066] The TGA diagram of the iplagetamine hydrochloride crystal obtained in Example 1 is as follows: Figure 3 Thermogravimetric analysis shows that the weight loss is only 0.2858% when heated to 105°C.

[0067] Example 7 Stability Determination

[0068] In order to investigate the stability of the samples of the present invention and the control samples, the API products obtained in Example 5 and Comparative Example 1 were selected for accelerated test research to obtain stability data. The storage conditions were a temperature of 40°C ± 2°C and a relative humidity of 75% RH ± 5% RH. The key quality attributes were tested at 0, 3, and 6 months, respectively. The specific experimental results are shown in Tables 1 and 2:

[0069] Table 1 Stability data of products prepared in Example 5

[0070]

[0071] It can be seen from Table 1 that the main component proportion of the untreated ipraglimin hydrochloride related substances is less than 99.5%, the impurity content is high, and the chiral purity is poor. Due to the high impurity content, the content is low and it cannot be developed into a marketed drug; while the product of the embodiment of the present invention has excellent stability, the product properties and impurity levels have not changed, the main component proportion is always greater than 99.5%, and the chiral purity has not changed, indicating that racemization has not occurred during the storage process, the main component content is in the ideal numerical range, and the water content is consistent with the TGA test of 0.2858%, indicating that the product is not hygroscopic under the experimental conditions and meets the requirements for development into a drug.

[0072] Table 2 Comparative Example 1 Preparation of Reference Stability Data

[0073]

[0074] As shown in Table 2, during the stability study, the properties of the reference product did not change, but the related substances and their contents decreased to varying degrees, and the chiral purity changed greatly, which may be due to the racemization caused by the sample's moisture absorption and weight gain. The reference product was no longer suitable for drug development during the stability study.

[0075] Example 8 Solubility Determination

[0076] Prepare several round-bottom flasks, each equipped with a magnetic stirrer. At room temperature, take 1 g of ipraglimine hydrochloride from Example 5, add the solvent dropwise with a graduated constant dropper under stirring until the solid is completely dissolved by visual observation. The solubility is calculated according to the total amount of solvent added. The solubility data are shown in Table 3:

[0077] Table 3

[0078] Solvents Solubility (mg / mL) water 223 Methanol 222 Anhydrous ethanol 133 96% ethanol 185 Acetonitrile 9

[0079] As can be seen from Table 3, the solubility of ipraglitamine hydrochloride of the present invention is good, and meets the requirements for development into corresponding preparations.

[0080] Application Examples

[0081] A blood pressure lowering pharmaceutical composition comprises the ipraglimin hydrochloride crystal form obtained in Example 5 and pharmaceutical excipients. The pharmaceutical excipients include any one or more of the following: solvents, propellants, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesive agents, integrins, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, flocculants and deflocculating agents, filter aids, and release retardants.

[0082] A blood pressure lowering tablet, comprising 84-95% by weight of the ipraglimin hydrochloride crystal form obtained in Example 5, 4.5-7.0% by weight of a binder (hydroxypropyl cellulose, polyvinyl alcohol or hydroxypropyl methyl cellulose), and 0.2-7.5% by weight of a disintegrant (starch, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone or cross-linked carboxymethyl cellulose sodium and carboxymethyl starch sodium). The content of the ipraglimin hydrochloride crystal form in one tablet is 500 mg or 1000 mg.

[0083] The embodiments provided above are not intended to limit the scope of the present invention, and the steps described are not intended to limit the execution order thereof. Those skilled in the art may make obvious improvements to the present invention in combination with existing common knowledge, which also fall within the scope of protection defined by the claims of the present invention.

Claims

1. A crystalline form of ipraglimin hydrochloride, characterized in that: Its X-ray powder diffraction spectrum is 11.7o, 14.8o, 16.8o, 17.7o, 18.8o, 20.5 at 2θ values ​​(±0.2o). o There are characteristic diffraction peaks corresponding to the positions of 23.1o, 23.4o, 24.9o, 25.5o, 26.5o, 26.9o, 29.4o and 32.7o.

2. The ipraglimin hydrochloride crystal form according to claim 1, characterized in that: The ipaglimine hydrochloride crystal form has an X-ray powder diffraction pattern as shown in FIG1 .

3. The ipraglimin hydrochloride crystal form according to claim 1, characterized in that: Its melting point is 253-255°C.

4. A method for preparing the ipraglimin hydrochloride crystal form according to any one of claims 1 to 3, characterized in that: The following steps are involved: 1) dissolving ipraglimine hydrochloride in a solvent, raising the temperature to 20-80°C to make it dissolve clearly; 2) lowering the temperature of the solution to 0-40°C for crystallization, with a cooling rate of 4-30°C / hour during crystallization; 3) Filter or centrifuge the precipitated solid and dry it.

5. The preparation method according to claim 4, characterized in that: In step 1), the solvent is selected from one or a mixture of methanol, ethanol, isopropanol, acetone, propanol, tetrahydrofuran, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide and water.

6. The preparation method according to claim 4, characterized in that: The solvent in step 1) is specifically selected from: ethanol, isopropanol, a mixture of ethanol and water, a mixture of acetonitrile and water, or a mixture of dimethyl sulfoxide and water.

7. The preparation method according to any one of claims 4 to 6, characterized in that: The drying temperature in step 3) is 25-75°C.

8. Use of the iplagetamine hydrochloride crystal form according to any one of claims 1 to 3 in the preparation of hypoglycemic drugs.

9. A pharmaceutical composition, characterized in that The invention comprises the ipraglimin hydrochloride crystal form according to any one of claims 1 to 3, and pharmaceutical excipients.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical excipients include any one or more of the following: solvents, propellants, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrities, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, flocculants and deflocculating agents, filter aids, and release retardants.

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