CN118084990A - Sogliflozin-L-proline eutectic, and preparation method and application thereof - Google Patents

Abstract

The present invention discloses a soglide-L-proline cocrystal and a preparation method and application thereof. The soglide-L-proline cocrystal is prepared by using soglide and L-proline in a molar ratio of 1:1 to 1:2 as raw materials; using Cu-Kα ray measurement, the X-ray diffraction pattern represented by the diffraction angle 2θ has characteristic diffraction peaks at 5.6°±0.2°, 7.4°±0.2°, 9.7±0.2°, 14.8°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 20.2°±0.2°, and 22.0°±0.2°. The soglide-L-proline cocrystal of the present invention is a new type of cocrystal, which does not undergo crystal transformation under accelerated conditions for at least one month, has higher solubility than soglide, and has a simple preparation method and can be scaled up for industrial production.

Description

Sogliflozin-L-proline cocrystal and preparation method and application thereof

Technical Field

The present invention belongs to the technical field of pharmaceutical chemistry, and more specifically, to a sogliflozin-L-proline cocrystal and a preparation method and application thereof.

Background technique

Sotagliflozin is an experimental novel oral dual inhibitor of sodium-glucose co-transporters 1 and 2 (SGLT-1 and SGLT-2) developed by Lexicon Pharmaceuticals. In May 2023, the FDA approved the marketing application of Sotagliflozin for patients with heart failure and patients with certain cardiovascular risk factors to reduce the risk of death, heart failure hospitalization, and emergency heart failure visits.

The chemical name of Sogliflozin is: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol, and its structural formula is shown in formula (I):

The same drug molecule forms different solid forms due to different stacking or arrangement methods, which have different physical and chemical properties. For example, for poorly soluble drugs, the amorphous form of the drug has different water solubility and bioavailability compared to other crystalline forms. Different crystal forms may also affect their solubility, thermal stability, hygroscopicity, fluidity and other properties.

According to the Chinese Pharmacopoeia, a crystalline substance formed by two or more chemical substances is called a co-crystal, which belongs to the category of crystalline substances. Pharmaceutical co-crystal is a solid technology that improves the physicochemical properties of active ingredients of drugs, improves bioavailability and improves clinical treatment effects. Co-crystals have higher room for improvement in properties compared to different crystal forms. Different solid forms of drugs may have different operating properties (such as fluidity, compressibility), dissolution rate, solubility and stability, all of which can affect the production of dosage forms.

The original Lexicon disclosed the anhydrous crystalline forms 1 and 2 of sogliflozin in patent CN102112483A. However, the preparation method of crystal form 1 has poor repeatability, crystal form 2 is unstable in a high water activity environment, has poor grinding stability, and is prone to crystal transformation during the preparation of the preparation, which is not conducive to post-processing in the drug development process. Patent WO2017202351 discloses 8 crystal forms of sogliflozin, including crystal forms I to VIII, and their preparation methods. CN 112898255A discloses 3 crystal forms, including Form 3 to 5. WO2018067805A1 discloses 10 crystal forms, including crystal forms A to K, of sogliflozin.

Therefore, it is necessary to develop a solid form of sogliflozin with high stability, high solubility, and easy scale-up production.

Summary of the invention

Based on this, the object of the present invention is to provide a sogliflozin-L-proline cocrystal and a preparation method and application thereof. The sogliflozin-L-proline of the present invention has high stability and high solubility.

The technical solutions for achieving the above-mentioned invention objectives include the following.

In the first aspect of the present invention, a sogliatin-L-proline cocrystal is provided, which is prepared using sogliatin and L-proline as raw materials in a molar ratio of 1:1 to 1:2; and its X-ray diffraction pattern represented by a diffraction angle 2θ measured using Cu-Kα rays has characteristic diffraction peaks at 5.6°±0.2°, 7.4°±0.2°, 9.7±0.2°, 14.8°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 20.2°±0.2°, and 22.0°±0.2°.

The second aspect of the present invention provides a method for preparing the above-mentioned sogliflozin-L-proline cocrystal, comprising the following steps:

(1) adding sogliflozin and L-proline at a molar ratio of 1:1 to 1:2 to an alcohol solvent to form a suspension;

(2) Stir or grind the suspension, filter, and dry to obtain the product.

The third aspect of the present invention provides the use of the above-mentioned sogliflozin-L-proline cocrystal in the preparation of drugs for treating heart failure or diabetes.

The fourth aspect of the present invention provides a drug for treating heart failure or diabetes, comprising the above-mentioned sogliflozin-L-proline cocrystal and a pharmaceutically acceptable carrier.

The present invention has the following beneficial effects:

The inventors of the present invention have discovered that the co-crystal prepared by combining sogliflozin and L-proline at a molar ratio of 1:1 to 1:2 is a new type of crystal form, which has high thermal stability (no crystal transformation occurs for at least 31 days under accelerated conditions of 40°C and 75% RH) and high solubility (the apparent solubility in water is increased by 3.4 times relative to sogliflozin).

The preparation method of sogliflozin-L-proline of the present invention is simple and can be scaled up for industrial production.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a PXRD pattern of the sogliflozin-L-proline cocrystal prepared in Example 1 of the present invention.

FIG2 is a PXRD pattern of the sogliflozin-L-proline cocrystal prepared in Example 2 of the present invention.

FIG3 is a PXRD pattern of the sogliflozin-L-proline cocrystal prepared in Example 3 of the present invention.

FIG4 is a PXRD pattern of the sogliflozin-L-proline cocrystal prepared in Example 4 of the present invention.

FIG5 is a DSC graph of the sogliflozin-L-proline cocrystal in Example 5 of the present invention.

Figure 6 is a TGA chart of the sogliflozin-L-proline cocrystal in Example 5 of the present invention.

7 is a comparative PXRD spectrum of the sogliflozin-L-proline cocrystal prepared in Example 1 of the present invention placed under accelerated conditions (40° C., 75% RH) for 0 days, 5 days, 15 days and 31 days.

FIG8 is a comparison of Raman spectra of the sogliflozin-L-proline cocrystal, sogliflozin and L-proline and a physical mixture prepared in Example 1 of the present invention.

FIG. 9 is a ¹ H-NMR spectrum of the sogliflozin-L-proline cocrystal prepared in Example 1 of the present invention.

Detailed ways

In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and/or" used in the present invention includes any and all combinations of one or more of the related listed items.

The experimental methods in the following examples where specific conditions are not specified are generally carried out under conventional conditions, such as those described in Green and Sambrook et al., Molecular Cloning: A Laboratory Manual (2013), or under conditions recommended by the manufacturer. The various commonly used chemical reagents used in the examples are all commercially available products.

In some embodiments of the present invention, a sogliafloxacin-L-proline cocrystal is disclosed, which is prepared using sogliafloxacin and L-proline in a molar ratio of 1:1 to 1:2 as raw materials; its X-ray powder diffraction pattern represented by a diffraction angle 2θ measured using Cu-Kα rays has characteristic diffraction peaks at 5.6°±0.2°, 7.4°±0.2°, 9.7±0.2°, 14.8°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 20.2°±0.2°, and 22.0°±0.2°.

In some of the embodiments, the differential scanning calorimetry spectrum of the sogliflozin-L-proline cocrystal has an endothermic peak at 190-210°C, preferably at 202.7°C±5°C.

In other embodiments of the present invention, a method for preparing a sogliflozin-L-proline cocrystal is disclosed, comprising the following steps:

(1) adding sogliflozin and L-proline at a molar ratio of 1:1 to 1:2 to an alcohol solvent to form a suspension;

(2) Stir or grind the suspension, take out the suspension, filter, and dry to obtain the product.

In some embodiments, the molar ratio of sogliflozin to L-proline is 1:1 or 1:2.

In some embodiments, the mass volume ratio of sogliflozin to alcohol solvent is 1-500 mg:1 mL.

In some of the embodiments, the mass volume ratio of sogliflozin to alcohol solvent is 4-10 mg:1 mL.

In some embodiments, the mass volume ratio of sogliflozin to alcohol solvent is 5-7 mg:1 mL, more preferably 6 mg:1 mL.

In some embodiments, the alcohol solvent is one or more of isopropanol and/or ethanol.

In some embodiments, the mass volume ratio of sogliflozin to isopropanol is 5-7 mg:1 mL, more preferably 6 mg:1 mL.

In some embodiments, the stirring or grinding temperature in step (2) is 10°C to 50°C, more preferably, the stirring or grinding temperature is 15°C to 30°C.

In some embodiments, the stirring or grinding time in step (2) is 10 minutes to 8 days, and more preferably, the stirring time is 3 days to 4 days.

In other embodiments of the present invention, the use of the above-mentioned sogliflozin-L-proline cocrystal in the preparation of drugs for treating heart failure or diabetes is disclosed.

In other embodiments of the present invention, a drug for treating heart failure or diabetes is disclosed, comprising the above-mentioned sogliflozin-L-proline cocrystal and a pharmaceutically acceptable carrier.

In the following examples, sogliflozin was purchased from Jiangsu Aikon Biopharmaceutical Research and Development Co., Ltd., and L-proline was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

Example 1 Preparation method of sogliflozin-L-proline cocrystal

The following steps are involved:

1. Weigh 15 mg of sogliflozin and 8.13 mg of L-proline (molar ratio of 1:2), add 2.5 mL of isopropanol, stir magnetically at room temperature (25°C ± 5°C) for 7 days, and filter;

2. Dry the filter cake at 40°C for 2 hours to obtain a white solid powder, namely, sogliflozin-L-proline cocrystal.

The product was characterized using a powder X-ray diffractometer (PXRD), and the results are shown in Figure 1. As shown in Figure 1, the sogliflozin-L-proline cocrystal prepared in Example 1 of the present invention has characteristic diffraction peaks at about 5.6°, 7.4°, 9.7, 14.8°, 16.8°, 17.5°, 18.4°, 19.6°, 20.2°, and 22.0°.

Example 2 Preparation method of sogliflozin-L-proline cocrystal

The following steps are involved:

1. Weigh 150 mg of sogliflozin and 81.3 mg of L-proline (molar ratio of 1:2), add 15 mL of isopropanol, stir magnetically at room temperature (25°C ± 5°C) for 3 h, and filter;

2. Dry the filter cake at 40°C for 2 hours to obtain a white solid powder, namely, sogliflozin-L-proline cocrystal.

The product was characterized using a powder X-ray diffractometer (PXRD), and the results are shown in Figure 2. As can be seen from Figure 2, the characteristic diffraction peaks of the co-crystal prepared in this example are substantially consistent with the characteristic diffraction peaks of the co-crystal prepared in Example 1.

Example 3 Preparation method of sogliflozin-L-proline cocrystal

The following steps are involved:

1. Weigh 30 mg of sogliflozin and 8.1 mg of L-proline (molar ratio of 1:1), add 0.5 mL of ethanol, stir magnetically at room temperature (25°C ± 5°C) for 6 h, and filter;

2. Dry the filter cake at 50°C for 2 hours to obtain a white solid powder, namely, sogliflozin-L-proline cocrystal.

The product was characterized by powder X-ray diffractometer (PXRD), and the results are shown in Figure 3. As shown in Figure 3, the characteristic diffraction peaks of the co-crystal prepared in this example are basically consistent with the characteristic diffraction peaks of the co-crystal prepared in Example 1.

Example 4 Preparation method of sogliflozin-L-proline cocrystal

The following steps are involved:

1. Weigh 15 mg of sogliflozin and 8.1 mg of L-proline (molar ratio of 1:2), add 0.2 mL of isopropanol, and grind at room temperature (25°C ± 5°C) for 10 min;

2. Dry the powder at 50°C for 2 hours to obtain a white solid powder, namely, sogliflozin-L-proline cocrystal.

The product was characterized by powder X-ray diffractometer (PXRD), and the results are shown in Figure 4. As shown in Figure 4, the characteristic diffraction peaks of the co-crystal prepared in this example are basically consistent with the characteristic diffraction peaks of the co-crystal prepared in Example 1.

Example 5 Thermal Behavior of Sogliflozin-L-Proline Cocrystal

The thermal behavior of the sogliflozin-L-proline co-crystal obtained in Example 1 was analyzed using a differential scanning calorimeter Q2000 (TA Instruments, USA). The sample chamber was set to have a nitrogen purge flow of 50 mL/min, balanced at 25°C, and a heating rate of 10°C/min from 25°C to 250°C, and the data analysis software was TA Universal Analysis (TA Instruments, USA). The results are shown in Figure 5. The sogliflozin-L-proline co-crystal has an endothermic peak at 202.7°C (peak), which is the melting peak of the co-crystal, and also indicates that the co-crystal has high thermal stability.

Thermogravimeter Q500 (TA Instruments, USA) was used to analyze the weight change of the sample with temperature. The nitrogen purge gas flow in the sample chamber was set to 60 mL/min, the heating rate was heated from 25°C to 250°C at a rate of 10°C/min, and the data analysis software TAUniversal Analysis (TA Instruments, USA) was used. As shown in Figure 6, the sogliflozin-L-proline cocrystal had no obvious weight loss before 150°C. Therefore, the sogliflozin-L-proline cocrystal is an anhydrous substance.

Example 6 Stability Study of Sogliflozin-L-Proline Cocrystal

The sogliflozin-L-proline co-crystal obtained in Example 1 was placed in an artificial climate chamber under accelerated conditions (40°C, 75% RH), and samples were taken on the 5th, 15th and 31st days and characterized using a powder X-ray diffractometer (PXRD), and the results are shown in Figure 7. As can be seen from Figure 7, the sogliflozin-L-proline co-crystal did not undergo a crystal transformation under accelerated conditions for at least 31 days.

Example 7 Raman spectrum of Sogliflozin-L-proline cocrystal

Raman spectra were collected using a Renishaw inVia Raman microspectrometer equipped with a near-infrared diode laser source and a Rencam charge coupled device (CCD) silicon detector. The sogliatin-L-proline cocrystal, sogliatin, L-proline and a physical mixture of sogliatin and L-proline in a molar ratio of 1:2 prepared in Example 1 were placed on a microscope slide, focused and observed under a 20x objective lens and Raman imaging was performed. The detection conditions were as follows: detection wavelength 785nm, detection range 200cm ^- 1-1800cm ^-1 , laser intensity 100%, exposure time 3s, 2 accumulations, data acquisition and analysis software wire 4.3.

The results of the Raman detection spectrum are shown in Figure 8. At Raman shifts of approximately 1448 cm ^-1 , 1366 cm ^-1 , 1162 cm ^-1 , 1044 cm ^-1 , and 850 cm ^-1 , there are obvious differences between the soggliflozin-L-proline co-crystal and the physical mixture of soggliflozin-L-proline (1:2). 1448 cm ^-1 and 1366 cm ^-1 belong to the out-of-plane bending region of the OH of the carboxyl group on L-proline and the in-plane bending vibration region of the OH on the hydroxyl group of soggliflozin, 1162 cm ^-1 and 1044 cm ^-1 belong to the CO stretching vibration region on the hydroxyl group of soggliflozin, and 850 cm ^-1 belongs to the out-of-plane bending vibration region of the NH of L-proline. Therefore, in the soggliflozin-L-proline co-crystal, hydrogen bonds exist between soggliflozin and the carboxyl and hydroxyl groups, and between the hydroxyl and amine groups of L-proline.

Example 8 Characterization of the Apparent Solubility of Sogliflozin-L-Proline Cocrystals

5 mg of the soggliflozin-L-proline cocrystal prepared in Example 1 and 3.2 mg of soggliflozin (equimolar ratio to soggliflozin in the cocrystal) were added to 50 mL of deionized water, respectively, and stirred at 20°C ± 3°C at a stirring speed of 100 rpm for 2 h. The sample was filtered and tested with a UV-visible spectrophotometer, and the absorption wavelength was 225 nm.

The solubility of the solafloxacin-L-proline cocrystal in water was found to be about 50 μg/mL (equivalent to a solafloxacin solubility of 32.5 μg/mL), and the solubility of solafloxacin was 9.6 μg/mL. Therefore, the solubility of the solafloxacin-L-proline cocrystal in water was increased by about 3.4 times compared to that of solafloxacin.

Example 9 H-NMR Spectrum Characterization of Sogliflozin-L-Proline Cocrystal

The sogliflozin-L-proline cocrystal obtained in Example 1 was characterized by ¹ H-NMR, and the obtained spectrum is shown in FIG9 .

¹ H NMR (600 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.20 (dd, J = 8.2 ,2.2Hz,1H),7.11–7.08(m,2H),6.84–6.81(m,2H),5.13(d,J＝148.7Hz,2H),4.33(d,J＝9.5Hz,1H),4.08 (d, J = 9.5 Hz, 1H), 3.9 7 (t, J = 6.8 Hz, 4H), 3.62 (dd, J = 8.7, 5.6 Hz, 2H), 3.26 (t, J = 8.7 Hz, 3H), 3.22–3.12 (m, 6H), 2.99 (dt ,J＝11.2,7.6Hz,2H),2.02(s,5H),1.94–1.89(m,2H),1.80–1.73(m,2H),1.67(dp,J＝12.6,7.6Hz,2H), 1.29 (t, J = 7.0 Hz, 3H). Combining the molecular structures of sogliflozin and L-proline, it can be seen that sogliflozin and L-proline exist in the co-crystal at a molar ratio of 1:2.

The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, 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 attached claims.

Claims (10)

1. A sogliptin-L-proline cocrystal, characterized in that it is prepared from sogliptin and L-proline in a molar ratio of 1:1 to 1:2 as raw materials; and measured using Cu-Kα rays, its X-ray diffraction pattern represented by a diffraction angle 2θ has characteristic diffraction peaks at 5.6°±0.2°, 7.4°±0.2°, 9.7±0.2°, 14.8°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 20.2°±0.2°, and 22.0°±0.2°. 2. The method for preparing the sogliflozin-L-proline cocrystal according to claim 1, characterized in that it comprises the following steps: (1) adding sogliflozin and L-proline at a molar ratio of 1:1 to 1:2 to an alcohol solvent to form a suspension; (2) Stir or grind the suspension, filter, and dry to obtain the product. 3. The method for preparing the sogliacin-L-proline cocrystal according to claim 2, characterized in that the molar ratio of sogliacin to L-proline is 1:1 or 1:2. 4. The method for preparing the sogliflozin-L-proline cocrystal according to claim 2, characterized in that the mass volume ratio of sogliflozin to the alcohol solvent is 1 to 500 mg: 1 mL. 5. The method for preparing the sogliflozin-L-proline cocrystal according to claim 3, characterized in that the mass volume ratio of sogliflozin to the alcohol solvent is 4-10 mg:1 mL; preferably 5-7 mg:1 mL, and more preferably 6 mg:1 mL. 6. The method for preparing sogliflozin-L-proline cocrystal according to any one of claims 2 to 5, characterized in that the alcohol solvent is isopropanol and/or ethanol. 7. The method for preparing the sogliacin-L-proline cocrystal according to claim 6, characterized in that the mass volume ratio of sogliacin to isopropanol is 5-7 mg:1 mL, more preferably 6 mg:1 mL. 8. The method for preparing the sogliflozin-L-proline cocrystal according to any one of claims 2 to 5, characterized in that the stirring or grinding temperature in step (2) is 10°C to 50°C, preferably, the stirring or grinding temperature is 15°C to 30°C; and/or the stirring or grinding time is 10 min to 8 d, preferably, the stirring or grinding time is 3 d to 4 d. 9. Use of the sogliflozin-L-proline cocrystal according to claim 1 in the preparation of drugs for treating heart failure or diabetes. 10. A drug for treating heart failure or diabetes, comprising the sogliflozin-L-proline cocrystal according to claim 1, and a pharmaceutically acceptable carrier.