Crystal form of nicotinoyl metformin and preparation method thereof

Abstract

The invention discloses a nicotinoyl metformin crystal form and a preparation method thereof. According to the nicotinoyl metformin crystal form shown in the formula I provided by the invention, in an X-ray powder diffraction pattern, at least three characteristic peaks exist at the diffraction angles of 10.64 + / -0.2 degrees, 11.42 + / -0.2 degrees, 15.18 + / -0.2 degrees, 16.06 + / -0.2 degrees, 16.44 + / -0.2 degrees and 25.22 + / -0.2 degrees, which are represented by 2 theta. The invention also provides a preparation method, which comprises the following steps: 1) dissolving metformin hydrochloride and ethyl nicotinate in an organic solvent in an inert gas atmosphere to form a solution 1; dissolving an organic metal strong base catalyst in an organic solvent to form a solution 2; and 2) dropwise adding the solution 2 into the solution 1 while stirring, reacting, pouring the reacted solution into ice water after the reaction is finished, filtering, washing, and drying to obtain the nicotinoyl metformin crystal form. The crystal form parameters of the nicotinoyl metformin are obtained for the first time, and the nicotinoyl metformin has high purity, high stability and low hygroscopicity; the preparation method can directly obtain the nicotinoyl metformin crystal form, and is simple, high in yield, simple in post-treatment and efficient in preparation.

Description

Technical Field

[0001] This invention belongs to the field of drug crystal form technology, and relates to the crystal form of nicotinic acid metformin and its preparation method. Background Technology

[0002] Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia, caused by absolute or relative insulin deficiency and impaired insulin utilization. It is mainly classified into three types: type 1, type 2, and gestational diabetes. The etiology is primarily attributed to the combined effects of genetic and environmental factors, including decreased insulin secretion due to pancreatic islet cell dysfunction, or insensitivity to insulin, or both, resulting in the ineffective utilization and storage of glucose in the blood. Some diabetic patients and their families exhibit disease clustering. Furthermore, the incidence and prevalence of diabetes are on the rise globally.

[0003] In recent years, metformin, as a first-line drug for treating type 2 diabetes, has expanded its pharmacological effects from simply lowering blood sugar to multiple areas such as anti-aging, metabolic regulation, and anti-tumor activity. However, monotherapy has limitations in bioavailability and the accumulation of toxic side effects, prompting researchers to explore its binding structure with other active molecules to enhance synergistic effects. Niacin has effects such as regulating blood lipids and is also a precursor to nicotinamide adenine dinucleotide (NAD+). Its binding with metformin may enhance biological functions through multi-target and multi-pathway synergistic effects, showing potential clinical application prospects, especially in metabolic regulation, tumor suppression, and aging intervention.

[0004] Indian patent IN202241059024A discloses the synthesis of nicotinic acid metformin, but the synthesis yield is low at only 75%. At the same time, it does not disclose data on the crystal morphology of nicotinic acid metformin, nor does it provide key drug property parameters such as stability. In addition, there is a risk of residual organic solvents in the Indian patent. Summary of the Invention

[0005] The purpose of this invention is to provide the crystalline form of nicotinic acid metformin and its preparation method.

[0006] The nicotinamide biguanide crystal form of Formula I provided by this invention has at least three characteristic peaks in its X-ray powder diffraction pattern, with diffraction angles of 10.64±0.2°, 11.42±0.2°, 15.18±0.2°, 16.06±0.2°, 16.44±0.2°, and 25.22±0.2°, represented by 2θ.

[0007]

[0008] In the nicotinic acid metformin crystal form shown in Formula I above, the nicotinic acid metformin crystal form shown in Formula I has at least one characteristic peak at 11.939±0.2°, 12.878±0.2°, 17.381±0.2°, 19.4±0.2°, 21.583±0.2°, 23.158±0.2°, 23.701±0.2°, 24.22±0.2°, 26.401±0.2°, 27.682±0.2° and 28.518±0.2° in the X-ray powder diffraction pattern, with the diffraction angle represented by 2θ.

[0009] In the nicotinic acid methyl guanidine crystal form shown in Formula I above, the nicotinic acid methyl guanidine crystal form shown in Formula I has at least one characteristic peak at 10.901±0.2°, 14.663±0.2°, 18.121±0.2°, 22.242±0.2°, 24.46±0.2°, 24.898±0.2°, and 27.139±0.2° in the X-ray powder diffraction pattern, with the diffraction angle represented by 2θ.

[0010] In this invention, the value of the diffraction angle represented by 2θ in the X-ray powder diffraction pattern is the experimentally determined value of the product obtained after the nicotinic acid dimethyl guanidine crystal form shown in Formula I is prepared by the following preparation method of this invention.

[0011] In the nicotinic acid metformin crystal form shown in Formula I above, the differential scanning calorimetry (DSC) spectrum of the nicotinic acid metformin crystal form exhibits an endothermic peak at 203.61–215 °C; preferably, the maximum absorption peak is at 207.08 °C; more preferably, the DSC spectrum of this crystal form is substantially as follows: Figure 4 As shown.

[0012] In the nicotinic acid metformin crystal form shown in Formula I above, the nicotinic acid metformin crystal form exhibits a weight loss of 0.59% in the 100.97–200.08℃ range and a weight loss of 93.32% in the 200.08–450.08℃ range, as determined by thermogravimetric analysis. Preferably, the thermogravimetric analysis spectrum of this crystal form is substantially as follows: Figure 5 As shown.

[0013] The present invention also provides a method for preparing the nicotinic acid methyl guanidine crystal form shown in Formula I above, comprising the following steps:

[0014] 1) In an inert gas atmosphere, metformin hydrochloride and ethyl nicotinate are dissolved in an organic solvent to form solution 1; and an organometallic strong base catalyst is dissolved in the organic solvent to form solution 2;

[0015] 2) While stirring, add 2 drops of the solution to the solution 1 to carry out the reaction. After the reaction is complete, pour the solution into ice water, filter, wash and dry to obtain nicotinic acid metformin.

[0016] In this invention, the reaction described in step 2) is monitored by thin-layer chromatography (TLC).

[0017] In the above preparation method, in step 1), the molar ratio of metformin hydrochloride to ethyl nicotinic acid can be 1.0:1.5 to 3.0;

[0018] In solution 1, the mass-to-volume ratio of metformin hydrochloride to the organic solvent can be 1g:10-30mL;

[0019] The molar ratio of metformin hydrochloride to the organometallic strong base catalyst can be 1.0:2.0 to 4.0;

[0020] The organometallic strong base catalyst is selected from at least one of potassium tert-butoxide, lithium diisopropylamino, sodium methoxide, sodium ethoxide, and butyllithium.

[0021] The organic solvent is selected from at least one polar aprotic organic solvent selected from dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and tetrahydrofuran.

[0022] In the above preparation method, in step 2), the temperature at which solution 2 is added can be 0 to 10°C, specifically 0°C, 3°C, or 5°C.

[0023] The rate at which solution 2 is added can be 10 to 20 mL / min, specifically 10 mL / min, 15 mL / min, or 20 mL / min;

[0024] The reaction temperature can be 0 to 50°C, specifically 10°C or 50°C. The reaction is carried out under stirring conditions, and the stirring time can be 1 to 30 minutes, specifically 3 minutes or 5 minutes.

[0025] The volume of the ice water is 7 to 20 times the volume of the reaction system solution;

[0026] The solvent used for washing is water, and the drying method includes at least one of vacuum drying, freeze drying, and forced-air oven drying.

[0027] In the above preparation method, after step 2), the following steps are also included: mixing the nicotinic acid metformin obtained in step 2) with a solvent, stirring under temperature control until completely dissolved, and then stirring to allow the temperature to naturally return to room temperature to precipitate a solid, thereby obtaining the nicotinic acid metformin crystal form shown in Formula I;

[0028] The solvent is selected from at least one of tetrahydrofuran (THF), ethyl acetate (EA), dichloromethane (DCM), and acetonitrile (ACN).

[0029] In the above preparation method, the mass ratio of nicotinic acid metformin shown in Formula I to the volume ratio of the solvent can be 1g:20-100mL;

[0030] The temperature control conditions can be 30-60℃, specifically 40, 50, or 60℃, preferably 50℃; the stirring speed during temperature control can be 100-400 rpm, specifically 100 rpm, 200 rpm, 300 rpm, or 400 rpm, preferably 200 rpm.

[0031] The stirring time at room temperature can be 5 to 24 hours, specifically 5 hours, 12 hours, or 24 hours, preferably 12 hours; the stirring speed can be 100 to 400 rpm, specifically 100 rpm, 200 rpm, 300 rpm, or 400 rpm; the room temperature is common knowledge in the art, specifically 10 to 30°C.

[0032] The method further includes the steps of filtering and drying the solid; the drying temperature is 50-120℃, specifically 50℃, 60℃, 100℃, 120℃, preferably 60℃; the drying time is 1-5 hours, specifically 1 hour, 2 hours, 3 hours, 5 hours, preferably 2 hours.

[0033] The present invention has the following beneficial effects:

[0034] 1. The crystal form parameters of nicotinic acid metformin were disclosed for the first time, and it has high purity (HPLC≥99%), high stability and low hygroscopicity, showing excellent performance;

[0035] 2. The method for preparing nicotinic acid metformin of the present invention can directly obtain the crystalline form of nicotinic acid metformin. The preparation method is simple, has a high yield, and is very convenient for post-processing, making the preparation highly efficient. Attached Figure Description

[0036] Figure 1 For nicotinic acid metformin 1 H NMR spectrum.

[0037] Figure 2 For nicotinic acid metformin 13 C NMR spectrum.

[0038] Figure 3 The XRPD spectra of nicotinamide metformin crystals in different solvents are shown. Figure 3 In the diagram, 3a, 3b, 3c, and 3d are XRPD spectra of nicotinic acid metformin crystallized in DCM, THF, ACN, and EA solvents, respectively, and 3e is the XRPD spectra of nicotinic acid metformin prepared in Examples 1-3.

[0039] Figure 4 The image shows the DSC pattern of the nicotinamide metformin crystal form.

[0040] Figure 5 The TGA spectrum is for the nicotinamide metformin crystal form.

[0041] Figure 6 The HPLC purity chromatogram is for the nicotinamide metformin crystal form. Detailed Implementation

[0042] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0043] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0044] The detection instrument model, settings, and descriptions are as follows in the following embodiments:

[0045] 1. MRI: Magnetic Resonance Imaging System Model: AVANCE III 400;

[0046] 2. X-ray powder diffraction (XRPD): Rigaku Miniflex 600 X-ray powder diffractometer; radiation source Cu Generator kV: 30kV; Generator mA: 10mA; Initial 2θ: 5.000°; Scan range: 5.0000~80.000°, scan step size: 0.02°, scan speed: 10° / min;

[0047] Measurement discrepancies associated with these X-ray powder diffraction (XPD) analysis results are caused by a variety of factors, including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration discrepancies, (d) operator errors (including errors occurring when determining peak positions), and (e) the properties of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in shifts in the same direction for all peaks. When using a flat support, small differences in sample height can lead to large shifts in XRPD peak positions. Systematic studies have shown that a 1 mm sample height difference can result in peak shifts as high as 1° 2θ. These shifts can be identified from the XRPD spectra and can be eliminated by compensating for the shifts (applying a systematic calibration factor to all peak position values) or by recalibrating the instrument. As mentioned above, measurement errors from different instruments can be corrected by applying a systematic calibration factor to ensure consistent peak positions.

[0048] 3. Thermogravimetric analysis (TGA): SDT Q600 instrument from TA Instruments, USA; temperature range: 25–500℃; heating rate: 10℃ / min; air flow rate: 100 mL / min. It should be understood that, similar to the potential for deviations in X-ray powder diffraction values, the values ​​cited in thermogravimetric analysis should not be interpreted as absolute values.

[0049] 4. Differential Scanning Calorimetry (DSC): DSC Q20 instrument from TA Instruments, USA; temperature range: -60~220℃, heating rate: 10℃ / min, nitrogen flow rate: 50mL / min. It should be understood that, similar to the potential deviations in X-ray powder diffraction values, the values ​​cited in differential scanning calorimetry cannot be interpreted as absolute values.

[0050] The nicotinamide biguanide crystal form of Formula I provided by this invention has at least three characteristic peaks (specifically, three, four, five, or six) at diffraction angles of 10.64±0.2°, 11.42±0.2°, 15.18±0.2°, 16.06±0.2°, 16.44±0.2°, and 25.22±0.2°, as indicated by 2θ, in its X-ray powder diffraction pattern.

[0051]

[0052] Furthermore, the nicotinic acid dimethyl guanidine crystal form shown in Formula I, in its X-ray powder diffraction pattern, exhibits at least one characteristic peak (specifically, one, two, or more) at diffraction angles (denoted by 2θ) of 11.939±0.2°, 12.878±0.2°, 17.381±0.2°, 19.4±0.2°, 21.583±0.2°, 23.158±0.2°, 23.701±0.2°, 24.22±0.2°, 26.401±0.2°, 27.682±0.2°, and 28.518±0.2°.

[0053] Furthermore, the nicotinic acid dimethyl guanidine crystal form shown in Formula I has at least one characteristic peak (specifically, one, two, or more) at diffraction angles of 10.901±0.2°, 14.663±0.2°, 18.121±0.2°, 22.242±0.2°, 24.46±0.2°, 24.898±0.2°, and 27.139±0.2°, as indicated by 2θ, in its X-ray powder diffraction pattern.

[0054] The method for preparing the nicotinic acid methyl guanidine crystal form shown in Formula I provided by the present invention includes the following steps:

[0055] 1) In an inert gas atmosphere, metformin hydrochloride and ethyl nicotinate are dissolved in an organic solvent to form solution 1; and an organometallic strong base catalyst is dissolved in the organic solvent to form solution 2;

[0056] 2) While stirring, add 2 drops of the solution to the solution 1 to carry out the reaction. After the reaction is complete, pour the solution into ice water, filter, wash with water, and dry to obtain the nicotinic acid metformin crystal form.

[0057] Example 1: Preparation of Nicotinyl Metformin

[0058] Under nitrogen protection, metformin hydrochloride (20.00 g, 120.75 mmol, 1.0 eq) and ethyl nicotinic acid (36.51 g, 241.51 mmol, 2.0 eq) were first added to a 1000 mL round-bottom flask. After drying under reduced pressure for 30 min using an oil pump, metformin hydrochloride and ethyl nicotinic acid were dissolved in 300 mL of dry DMSO. Then, potassium tert-butoxide (33.38 g, 301.89 mmol, 2.5 eq) was dissolved in 100 mL of dry DMSO. The round-bottom flask was then placed in an ice bath, and the potassium tert-butoxide DMSO solution was added dropwise at a rate of 15 mL / min. After the addition was complete, the ice bath was removed, and the mixture was allowed to rise naturally to room temperature (25°C). Stirring continued for 5 minutes, and the reaction progress was monitored by TLC (the reaction solution was spotted onto a silica gel plate, with dichloromethane:methanol = 20:1 (v / v) as the developing solvent; after development, the sample was observed under a UV lamp (254 nm). The product, nicotinamide metformin R… f =0.24). After the reaction was completed, the solution was slowly poured into 4000 mL of ice water, then filtered under reduced pressure. The filter cake was washed with 200 mL of water and finally dried under vacuum to obtain 24.35 g of nicotinic acid metformin white solid, with a yield of 84.5%.

[0059] Example 2: Preparation of Nicotinyl Metformin

[0060] Under nitrogen protection, metformin hydrochloride (10.00 g, 60.38 mmol, 1.0 eq) and ethyl nicotinic acid (18.25 g, 120.75 mmol, 2.0 eq) were first added to a 500 mL round-bottom flask. After drying under reduced pressure for 20 min using an oil pump, metformin hydrochloride and ethyl nicotinic acid were dissolved in 150 mL of dry DMF. Then, sodium methoxide (8.15 g, 150.94 mmol, 2.5 eq) was dissolved in 100 mL of dry DMF. The round-bottom flask was kept at 5 °C, and the sodium methoxide DMF solution was added dropwise at a rate of 10 mL / min. After the addition was complete, the temperature was maintained at 10℃, and stirring was continued for 5 minutes. The reaction progress was monitored by TLC (the reaction solution was spotted onto a silica gel plate, and dichloromethane:methanol = 20:1 (v / v) was used as the developing solvent. After development, the mixture was observed under a UV lamp (254 nm). The product nicotinamide metformin Rf = 0.24). After the reaction was completed, the solution was slowly poured into 1750 mL of ice water, then filtered under reduced pressure. The filter cake was washed with 100 mL of water, and finally freeze-dried to obtain 11.54 g of nicotinamide metformin as a white solid, with a yield of 81.59%.

[0061] Example 3: Preparation of Nicotinyl Metformin

[0062] Under nitrogen protection, metformin hydrochloride (10.00 g, 60.38 mmol, 1.0 eq) and ethyl nicotinic acid (18.25 g, 120.75 mmol, 2.0 eq) were first added to a 500 mL round-bottom flask. After drying under reduced pressure for 10 min using an oil pump, metformin hydrochloride and ethyl nicotinic acid were dissolved in 150 mL of dry THF. Then, butyllithium (9.67 g, 150.94 mmol, 2.5 eq) was dissolved in 100 mL of dry THF. The round-bottom flask was kept at 3 °C, and the butyllithium THF solution was added dropwise at a rate of 20 mL / min. After the addition was complete, the temperature was maintained at 50°C, and stirring was continued for 3 minutes. The reaction progress was monitored by TLC (the reaction solution was spotted onto a silica gel plate, and dichloromethane:methanol = 20:1 (v / v) was used as the developing solvent. After development, the mixture was observed under a UV lamp (254 nm). The Rf of the product nicotinamide metformin was 0.24). After the reaction was completed, the solution was slowly poured into 5000 mL of ice water, then filtered under reduced pressure. The filter cake was washed with 100 mL of water, and finally freeze-dried to obtain 10.98 g of the product nicotinamide metformin, with a yield of 77.63%.

[0063] The structures of nicotinic acid metformin prepared in Examples 1-3 above were confirmed as follows:

[0064] 1¹H NMR (400MHz, DMSO-d⁶) δ 9.40 (d, J = 1.4Hz, 1H), 8.70 (dd, J = 4.8, 1.6Hz, 1H), 8.55 (dt, J = 7.9, 1.9Hz, 1H), 7.51 (dd, J = 7.9, 4.8Hz, 1H), 6.96 (s, 2H), 3.15 (d, J = 42.8Hz, 6H), spectrum as shown in the figure. Figure 1 As shown.

[0065] 13 C NMR (101MHz, DMSO-d6) δ 168.4, 167.4, 165.7, 152.2, 149.6, 135.6, 133.0, 123.9, 36.2, spectrum as shown in the figure. Figure 2 As shown.

[0066] The XRPD data of the white solid nicotinic acid metformin prepared in Examples 1-3 are shown in Table 1, and the XRPD spectra are shown in Table 2. Figure 3 As shown in Figure 3e, the error range of the 2θ value is ±0.2°.

[0067] Table 1. XRPD data for nicotinamide metformin crystals

[0068]

[0069] Table 1 (continued) XRPD data for nicotinic acid metformin crystals

[0070]

[0071] The yields of nicotinic acid metformin obtained by the preparation methods in Examples 1-3 above were 84.5%, 81.59%, and 77.63%, respectively. Compared with the 75% yield of nicotinic acid metformin described in Indian Patent IN202241059024 A in the background art, the yields obtained by the preparation method of the present invention are all improved; moreover, through Figure 1-2 middle 1 H NMR, 13 The C NMR spectrum is clean and free of disordered peaks, indicating that the nicotinic acid methyl guanidine prepared according to this invention has high purity while improving yield. At the same time, this invention uses conventional reaction conditions, which makes the synthesis rapid and the post-processing simple and environmentally friendly. The product directly yields the nicotinic acid methyl guanidine crystal form, which greatly reduces the synthesis cost and is more suitable for large-scale production.

[0072] Example 4: Crystallization of nicotinic acid metformin in DCM (dichloromethane)

[0073] Weigh 500.0 mg of nicotinic acid metformin obtained from the preparation methods in Examples 1-3 into a round-bottom flask, add 40 mL of DCM, place the round-bottom flask in a 30°C oil bath and heat under reflux. Stir at 400 rpm until the solid is completely dissolved, then stop heating and maintain stirring at 400 rpm to allow it to return to room temperature (25°C, the same below) and stir for 5 hours. Filter to precipitate the solid, dry at 50°C for 5 hours to obtain nicotinic acid metformin crystals. The XRPD data of the obtained crystal form are shown in Table 2, and the XRPD spectrum is shown in... Figure 3 As shown in Figure 3a, the error range of the 2θ value is ±0.2°.

[0074] Table 2 XRPD data for nicotinamide metformin crystallization in DCM

[0075]

[0076] Example 5: Crystallization of nicotinic acid metformin in THF (tetrahydrofuran)

[0077] Weigh 500.0 mg of nicotinic acid metformin obtained from the preparation methods in Examples 1-3 into a round-bottom flask, add 15 mL of THF, place the round-bottom flask in a 40°C oil bath and heat under reflux. Stir at 100 rpm until the solid is completely dissolved, then stop heating, maintain stirring at 100 rpm to allow it to return to room temperature and stir for 12 hours. Filter to precipitate the solid, dry at 60°C for 2 hours to obtain nicotinic acid metformin crystals. The XRPD data of the crystals are shown in Table 3, and the XRPD spectrum is shown in... Figure 3 As shown in Figure 3b, the error range of the 2θ value is ±0.2°.

[0078] Table 3. XRPD data for nicotinamide metformin crystallization in THF

[0079]

[0080] Table 3 (continued) XRPD data for nicotinamide metformin crystallization in THF

[0081]

[0082] Example 6: Crystallization of nicotinic acid metformin in ACN (acetonitrile)

[0083] Weigh 500.0 mg of nicotinic acid metformin obtained from the preparation methods in Examples 1-3 into a round-bottom flask, add 50 mL of LACN, place the round-bottom flask in a 60°C oil bath and heat under reflux. Stir at 300 rpm until the solid is completely dissolved, then stop heating and continue stirring at 300 rpm until the mixture returns to room temperature and is stirred for 24 hours. Filter to precipitate the solid, dry at 100°C for 3 hours to obtain nicotinic acid metformin crystals. The XRPD data of the obtained crystal form are shown in Table 4, and the XRPD spectrum is shown in... Figure 3As shown in 3c, the error range of the 2θ value is ±0.2°.

[0084] Table 4. XRPD data for nicotinamide metformin crystallization in ACN

[0085]

[0086] Table 4 (continued) XRPD data for nicotinamide metformin crystallization in ACN

[0087]

[0088] Example 7: Crystallization of nicotinic acid metformin in EA (ethyl acetate)

[0089] Weigh 500.0 mg of nicotinic acid metformin obtained from the preparation methods in Examples 1-3 into a round-bottom flask, add 10 mL of EA, place the round-bottom flask in a 50°C oil bath and heat under reflux. Stir at 200 rpm until the solid is completely dissolved, then stop heating, maintain stirring at 200 rpm to allow it to return to room temperature and stir for 17 hours. Filter to precipitate the solid, dry at 120°C for 1 hour to obtain nicotinic acid metformin crystals. The XRPD data of the obtained crystal form are shown in Table 5, and the XRPD spectrum is shown in... Figure 3 As shown in 3d, the error range of the 2θ value is ±0.2°.

[0090] Table 5 XRPD data for nicotinamide metformin crystallization in EA

[0091]

[0092] By comparing the data in Tables 1-5 above and Figure 3 The crystalline spectrum of the prepared nicotinamide metformin (e.g.) Figure 3 (as shown in e) and its crystal structure obtained by crystallization in different solvents, as shown in... Figure 3 As shown in Figures a to d, the spectra were compared using the XRPD analysis software JADE. The results showed that the crystal form obtained by crystallizing nicotinic acid metformin in the above-mentioned different solvents was consistent with the crystal form obtained by the preparation method of this invention, indicating that the crystal form has high stability.

[0093] Example 8: Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) for the determination of nicotinamide metformin crystal forms.

[0094] DSC analysis was performed on the nicotinamide metformin crystal forms prepared in Examples 1-3 of this invention. The DSC spectra are shown below. Figure 4 As shown, there is an endothermic peak in the range of 203.61 to 215 °C, with the maximum absorption peak at 207.08 °C, which is caused by the melting of the nicotinic acid metformin crystal form. This indicates that the melting point of the nicotinic acid metformin crystal form prepared by the present invention is about 207.08 °C.

[0095] TGA analysis was performed on the nicotinamide biguanide crystal forms obtained in Examples 1-3 of this invention. The TGA spectra are shown below. Figure 5 As shown, the weight loss was 0.59% in the range of 100.97–200.08℃ and 93.32% in the range of 200.08–450.08℃.

[0096] Comprehensive analysis by DSC and TGA showed that the nicotinic acid metformin crystal form is a single crystal and contains no solvent. At the same time, this crystal form has an improved melting point of 183-186℃ compared with that of nicotinic acid metformin described in Indian patent IN202241059024 A, which further indicates that the thermal stability of the nicotinic acid metformin crystal form obtained by the present invention has been improved.

[0097] Example 9: Purity test of nicotinic acid metformin crystal form

[0098] 20.0 mg of the nicotinic acid metformin crystal form obtained in Examples 1-3 of this invention was dissolved in 20 mL of methanol. The purity of the nicotinic acid metformin crystal form was determined by high-performance liquid chromatography (HPLC) area method. The HPLC conditions are as follows, and the obtained HPLC purity chromatogram is shown below. Figure 6 As shown, the purity of the nicotinic acid metformin crystal form is 99.89%.

[0099] Instrument model: HPLC-1260II, which features a quaternary pump and a variable wavelength detector (VWD).

[0100] Separation column: Alphasil VC-C18AQ 4.6 x 250 mm 5 μm

[0101] Column constant temperature: 25℃

[0102] Mobile phase: 0.1% (wt) aqueous solution of NH4HCO3, chromatographic grade acetonitrile; gradient elution conditions are shown in Table 6; flow rate: 1.0 mL / min

[0103] Detection: VWD: 254nm

[0104] Retention time: 13.7 min

[0105] Table 6. Elution gradients (volume ratios) for high performance liquid chromatography

[0106] Time / min Acetonitrile <![CDATA[Aqueous solution of 0.1% (wt) NH4HCO3]]> 0 5 95 3 5 95 20 80 20 24 80 20 25 5 95 30 5 95

[0107] Example 10: Accelerated stability test of nicotinamide metformin crystal form

[0108] The nicotinic acid metformin (3 portions, 50.0 mg each) prepared in Examples 1-3 of this invention were placed in black sealed bags and placed in an accelerating chamber at 37°C and 75% humidity, respectively, and labeled as Sample 1, Sample 2, and Sample 3. Accelerated stability tests were conducted on the three samples for 1 month, 2 months, and 3 months, respectively. After the expiration period, 20.0 mg of each sample was weighed, and the content of nicotinic acid metformin was detected using the same HPLC method as in Example 9. The retention rate of nicotinic acid metformin = the content of nicotinic acid metformin detected by HPLC in the sample at each time period / the amount of nicotinic acid metformin detected in the sample at 0 months. The retention rate of nicotinic acid metformin at 0 months was considered as 100%, and the retention rates of the corresponding samples are shown in Table 7. After three months of accelerated testing, although the retention rate of nicotinic acid metformin decreased slightly, it remained above 90%, meeting the general product qualification standards for accelerated testing, indicating that the nicotinic acid metformin prepared by this invention has good stability.

[0109] Table 7 Retention rates of nicotinic acid metformin samples at different retention times

[0110] Sample Name Retention time Retention rate Sample 1 1 month 99.17％ Sample 2 2 months 99.80％ Sample 3 3 months 98.75％

[0111] Example 11: Hygroscopicity test of nicotinic acid metformin crystal form

[0112] The hygroscopicity test was performed according to the steps described in the Chinese Pharmacopoeia (2020 edition), specifically as follows:

[0113] (1) Take a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm), place it in a suitable constant temperature desiccator at 25℃±1℃ (relative humidity 80%±2%) one day before the test, and take it out and accurately weigh it as M1.

[0114] (2) Take three portions of nicotinic acid metformin prepared in Examples 1-3 of the present invention as appropriate amounts of test samples, spread them evenly in the weighing bottle above, the thickness of the test sample is generally about 1 mm, and the weight is accurately measured as M2.

[0115] (3) Leave the weighing bottle open and place it together with the bottle cap under the above-mentioned constant temperature and humidity (set temperature is 25℃, relative humidity is 80%) conditions for 24 hours.

[0116] (4) After 24 hours, cover the weighing bottle and take it out. Accurately weigh it as M3.

[0117] Table 8. Weights of nicotinic acid metformin crystal form test samples at specific times.

[0118] Sample Name M1 (mg) M2 (mg) M3 (mg) Percentage of weight gain Sample 1 13584.07 14182.05 14181.64 -0.068％ Sample 2 13475.18 14298.57 14299.15 0.070％ Sample 3 13878.58 14751.05 14751.78 0.083％

[0119] The weight gain percentage was calculated as (M3-M2)×100% / (M2-M1), and the results are shown in Table 8. Since the weight gain percentage of all three groups of samples was less than 0.2%, according to the classification in the Chinese Pharmacopoeia, this indicates that the nicotinic acid metformin crystal form of the present invention has no or almost no hygroscopicity.

Claims

1. The nicotinamide dimethyl guanidine crystal form shown in Formula I, characterized in that, In the X-ray powder diffraction pattern, 2θ indicates that the diffraction angles have at least three characteristic peaks at 10.64±0.2°, 11.42±0.2°, 15.18±0.2°, 16.06±0.2°, 16.44±0.2° and 25.22±0.2°; 2. The nicotinic acid methyl guanidine crystal form according to formula I of claim 1, characterized in that, The nicotinic acid dimethyl guanidine crystal form shown in Formula I exhibits at least one characteristic peak at diffraction angles (denoted by 2θ) at 11.939±0.2°, 12.878±0.2°, 17.381±0.2°, 19.4±0.2°, 21.583±0.2°, 23.158±0.2°, 23.701±0.2°, 24.22±0.2°, 26.401±0.2°, 27.682±0.2°, and 28.518±0.2° in its X-ray powder diffraction pattern.

3. The nicotinic acid methyl guanidine crystal form of Formula I according to claim 1 or 2, characterized in that, The nicotinamide biguanide crystal form shown in Formula I has at least one characteristic peak at 10.901±0.2°, 14.663±0.2°, 18.121±0.2°, 22.242±0.2°, 24.46±0.2°, 24.898±0.2°, and 27.139±0.2° in its X-ray powder diffraction pattern, with 2θ representing the diffraction angle.

4. The nicotinic acid methyl guanidine crystal form of Formula I according to claim 1 or 2, characterized in that, The nicotinamide metformin crystal form exhibited an endothermic peak in the range of 203.61–215 °C when analyzed by differential scanning calorimetry.

5. The nicotinic acid methyl guanidine crystal form of Formula I according to claim 1 or 2, characterized in that, The nicotinamide metformin crystal form showed a weight loss of 0.59% in the 100.97–200.08℃ range and a weight loss of 93.32% in the 200.08–450.08℃ range, as determined by thermogravimetric analysis.

6. A method for preparing the nicotinic acid dimethyl guanidine crystal form of Formula I as described in any one of claims 1-5, comprising the following steps: 1) In an inert gas atmosphere, metformin hydrochloride and ethyl nicotinate are dissolved in an organic solvent to form solution 1; and an organometallic strong base catalyst is dissolved in the organic solvent to form solution 2; 2) While stirring, add 2 drops of the solution to the solution 1 to carry out the reaction. After the reaction is complete, pour the solution into ice water, filter, wash and dry to obtain nicotinic acid metformin.

7. The preparation method according to claim 6, characterized in that, In step 1), the molar ratio of metformin hydrochloride to ethyl nicotinic acid is 1.0:1.5 to 3.0; In solution 1, the mass-to-volume ratio of metformin hydrochloride to the organic solvent is 1g:10-30mL; The molar ratio of metformin hydrochloride to the organometallic strong base catalyst is 1.0:2.0 to 4.0; The organometallic strong base catalyst is selected from at least one of potassium tert-butoxide, lithium diisopropylamino, sodium methoxide, sodium ethoxide, and butyllithium. The organic solvent is selected from at least one polar aprotic organic solvent selected from dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and tetrahydrofuran.

8. The preparation method according to claim 6 or 7, characterized in that, In step 2), the temperature at which solution 2 is added is 0–10°C; The rate at which solution 2 is added is 10–20 mL / min; The reaction temperature is 0–50°C, the reaction is carried out under stirring conditions, and the stirring time is 1–30 min; The volume of the ice water is 7 to 20 times the volume of the reaction system solution; The solvent used for washing is water, and the drying method includes at least one of vacuum drying, freeze drying, and forced-air oven drying.

9. The preparation method according to claim 6, characterized in that, The process also includes the following steps: mixing the nicotinic acid metformin obtained in step 2) with a solvent, stirring under controlled temperature until completely dissolved, and then allowing the temperature to naturally return to room temperature while stirring to precipitate a solid, thus obtaining the nicotinic acid metformin crystal form; The solvent is selected from at least one of tetrahydrofuran, ethyl acetate, dichloromethane, and acetonitrile.

10. The preparation method according to claim 9, characterized in that, The mass ratio of the nicotinic acid metformin to the volume ratio of the solvent is 1g:20-100mL; The temperature control conditions are 30–60°C; the stirring speed during temperature control is 100–400 rpm. The stirring time at room temperature is 5 to 24 hours, and the stirring speed is 100 to 400 rpm. The method further includes the steps of filtering and drying the solid; the drying temperature is 50-120°C; and the drying time is 1-5 hours.

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