JP7005071B1 - How to prepare metformin salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a bioavailability of a metformin base, which is weaker in hygroscopicity, has better solubility in water, can delay the intrinsic dissolution rate of metformin, is more stable and easy to store, as compared with a conventional metformin base. Provided are a novel salt of metformin, which is expected to be improved, and a method for preparing the same. SOLUTION: The method for preparing a metformin salt includes a step of weighing a raw material drug of metformin and a pharmaceutical additive acid, mixing them uniformly, pulverizing them with a ball mill, passing them through a 154 μm stainless steel mesh, and obtaining a metformin salt. The pharmaceutical additive acids include 1-naphthalene acetic acid, 1-hydroxy-2-naphthoic acid, 2-hydroxy-3-naphthoic acid, 2-naphthoic acid, 1,5-dihydroxynaphthalene, and 3,7-dihydroxy-2-. It is one of naphthoic acid and 2,3-dihydroxynaphthalene. [Selection diagram] FIG. 38

Description

The present invention belongs to the field of pharmaceutical formulations and, in particular, relates to metformin salts and methods and applications thereof.

In the research process of pharmaceutical formulations, the solubility of the drug can be improved 100 to 1000 times by performing chloride through the salt screening step, and the chloride is hygroscopic and soluble by the researcher by the pharmaceutical method. And it is the first choice method to overcome problems such as bioavailability.

Commercially available metformin is mainly sold in the form of hydrochloride. Metformin free base, which is a raw material for chloride of metformin, has strong hygroscopicity. Commercially available metformin hydrochloride has certain side effects on the gastrointestinal tract because it is relatively easy to bind to water of crystallization and the intrinsic dissolution rate of metformin hydrochloride is too fast. This reduced the bioavailability of metformin.

It is also reported that metformin acetylsalicylate (aspirin) is present, and such salts have three crystalline forms, of which the I form is anhydrous, 0.5 at room temperature and air. Easy to convert to crystalline form with individual water. Therefore, it has a certain degree of hygroscopicity and is not stable enough. In recent years, pamoate has also been reported, but the structure of such an acid is complicated, expensive, and disadvantageous for sale as a salt form.

Therefore, it is necessary to study the synthesis of novel metformin salts in order to reduce the intrinsic dissolution rate of metformin, improve its stability and reduce its hygroscopicity.

In order to overcome the shortcomings and deficiencies of the prior art, a first object of the present invention is to provide a method for preparing a metformin salt.

Another object of the present invention is to provide a metformin salt prepared by the above method.

Yet another object of the present invention is to provide a single crystal structure of a metformin salt prepared by the above method.

Yet another object of the present invention is to provide the use of the above-mentioned metformin salt in the production of a hypoglycemic drug, an antitumor drug, an antiaging drug, an anti-Alzheimer's disease drug, an antipolycystic ovary syndrome drug and an obesity-suppressing drug. Is.

The object of the present invention is realized by the following technical proposals.

The method for preparing a metformin salt includes a step of weighing a raw material drug of metformin and a pharmaceutical additive acid, mixing them uniformly, pulverizing them with a ball mill, passing them through a 154 μm stainless steel mesh, and obtaining a metformin salt.

The raw material drug for metformin is a metformin free base.

The pharmaceutical additive acids include 1-naphthalene acetic acid, 1-hydroxy-2-naphthoic acid, 2-hydroxy-3-naphthoic acid, 2-naphthoic acid, 1,5-dihydroxynaphthalene, and 3,7-dihydroxy-2-. Nafoic acid, one of 2,3-dihydroxynaphthalene,
The molar ratio of the raw material drug of metformin to the drug additive acid is 1: 1 or 1: 2, preferably 1: 1.
The uniform mixing is preferably to uniformly mix the two by dropping ethanol into the raw material drug of metformin and the drug additive acid, pulverizing the ball mill, and immediately volatilizing the sample to dry the sample. More preferably, 1 to 2 drops of ethanol are added dropwise to the mixture of the raw material drug of metformin and the drug additive acid per 0.1 g.

In the ball mill crushing, preferably, the mixture is placed in a 100 mL ball mill crushing tank, two zirconium dioxide ball mill balls having a diameter of 22 mm are added, the mixture is sealed with a sealing lid, and then incorporated into the ball mill crusher to rotate the parameters of the equipment. The speed is set to 35s ^-1 and run for 5 minutes, passing through a 154 μm stainless steel mesh to obtain the metformin salt after ball mill milling.

The metformin salt prepared by the above method depends on the auxiliary acid required for use, such as metformin and 1-naphthalene acetate, metformin and 2-naphthoate, metformin and 1-hydroxy-2-naphthoate, and metformin and 2-. Hydroxy-3-naphthoate, metformin salt and 2,3-dihydroxynaphthalene, metformin and 1,5-dihydroxynaphthalene salt, metformin and 3,7-dihydroxy-2-naphthoate, metformin and 2-naphthalene acetate. There may be.

The above metformin salt (methformin and 2-hydroxy-3-naphthoate form1 (molar ratio of metformin to 2-hydroxy-3-naphthoic acid is 1: 1), metformin and 2-hydroxy-3-naphthoate). form2 (molar ratio of metformin to 2-hydroxy-3-naphthoic acid is 1: 2), metformin to 1-hydroxy-2-naphthoate, metformin to 1-naphthalene acetate, metformin to 2-naphthoic acid. The parameters of the single crystal structure of the salt) are as shown in Table 1, respectively.

Use of the above metformin salts in the manufacture of hypoglycemic drugs, antitumor drugs, antiaging drugs, anti-Alzheimer's disease drugs, antipolycystic ovary syndrome drugs and obesity-suppressing drugs.

The present invention has the following advantages and beneficial effects over the prior art.
The present invention obtains new salts of 9 kinds of metformin, is easy to prepare, is environmentally friendly, does not generate waste liquid in the preparation process, has a high conversion rate, and is advantageous for industrial mass production.
These novel salts of metformin of the present invention have weaker hygroscopicity, better solubility in water, can delay the intrinsic dissolution rate of metformin, are more stable and easier to store, than conventional metformin. It is expected that the bioavailability of metformin base will be improved. Such metformin salts have potential for application to metformin drugs.

It is a powder x-ray diffraction pattern of the product metformin and 1-naphthalene acetate, 1-naphthalene acetate and metformin free base obtained in Example 1. FIG. It is a single crystal structure diagram of metformin and 1-naphthalene acetate in Example 1. FIG. It is a comparison diagram between the actual measurement (XRD spectrum) of metformin and 1-naphthalene acetate in Example 1 and the single crystal simulated XRD spectrum. It is a thermogravimetric analysis figure of metformin and 1-naphthalene acetate. It is a differential scanning calorimetry chart of metformin and 1-naphthalene acetate. It is a powder x-ray diffraction pattern of metformin and 2-naphthoate, 2-naphthoic acid and metformin free base in Example 2. FIG. It is a single crystal structure diagram of metformin and 2-naphthoate in Example 2. It is a comparison diagram between the actual measurement (XRD spectrum) of metformin and 2-naphthoate in Example 2 and the single crystal simulated XRD spectrum. It is a thermogravimetric analysis figure of metformin and 2-naphthoate. It is a differential scanning calorimetry chart of metformin and 2-naphthoate. It is a powder x-ray diffraction pattern of metformin and 1-hydroxy-2-naphthoate, 1-hydroxy-2-naphthoic acid and metformin free base in Example 3. FIG. It is a single crystal structure diagram of metformin and 1-hydroxy-2-naphthoate in Example 3. It is a comparison diagram between the actual measurement (XRD spectrum) of metformin and 1-hydroxy-2-naphthoate in Example 3 and the single crystal simulated XRD spectrum. It is a thermogravimetric analysis figure of metformin and 1-hydroxy-2-naphthoate. It is a differential scanning calorimetry chart of metformin and 1-hydroxy-2-naphthoate. FIG. 3 is a powder x-ray diffraction pattern of metformin and 2-hydroxy-3-naphthoate form 1, 2-hydroxy-3-naphthoic acid and metformin free base in Example 4. It is a single crystal structure diagram of metformin and 2-hydroxy-3-naphthoate form1 in Example 4. It is a comparison diagram between the actual measurement (XRD spectrum) of metformin and 2-hydroxy-3-naphthoate form1 in Example 4 and the single crystal simulated XRD spectrum. It is a thermogravimetric analysis figure of metformin and 2-hydroxy-3-naphthoate form1. It is a differential scanning calorimetry chart of metformin and 2-hydroxy-3-naphthoate form1. 5 is a powder x-ray diffraction pattern of metformin and 2-hydroxy-3-naphthoate form2, 2-hydroxy-3-naphthoic acid and metformin free base in Example 5. FIG. It is a single crystal structure diagram of metformin and 2-hydroxy-3-naphthoate form2 in Example 5. It is a comparison diagram between the actual measurement (XRD spectrum) of metformin and 2-hydroxy-3-naphthoate form2 in Example 5 and the single crystal simulated XRD spectrum. It is a thermogravimetric analysis figure of metformin and 2-hydroxy-3-naphthoate form2. It is a differential scanning calorimetry chart of metformin and 2-hydroxy-3-naphthoate form2. It is a powder x-ray diffraction pattern of metformin and 2,3-dihydroxynaphthalene salt, 2,3-dihydroxynaphthalene and metformin free base in Example 6. It is a powder x-ray diffraction pattern of metformin and 1,5-dihydroxynaphthalene salt, 1,5-dihydroxynaphthalene and metformin free base in Example 7. FIG. FIG. 3 is a powder x-ray diffraction pattern of metformin and 3,7-dihydroxy-2-naphthoate, 3,7-dihydroxy-2-naphthoic acid and metformin free base in Example 8. 9 is a powder x-ray diffraction pattern of metformin and 2-naphthalene acetate, 2-naphthalene acetate and metformin free base in Example 9. It is a thermogravimetric analysis figure of metformin and 2-naphthalene acetate. It is a differential scanning calorimetry chart of metformin and 2-naphthalene acetate. FIG. 3 is a powder x-ray diffraction pattern of the prepared product, raw material anhydrous citric acid and metformin free base in Comparative Example 1. It is a powder x-ray diffraction pattern of the product prepared in Comparative Example 2, the raw material transsilicic acid and the metformin free base. It is a calibration curve graph when the metformin control product solvent is ultrapure water. Metformin hydrochloride, Metformin and 1-hydroxy-2-naphthoate, Metformin and 2-hydroxy-3-naphthoate form1, Metformin and 1-naphthalene acetate, Metformin and 2-naphthoate, Metformin and 2-naphthalene acetate It is an elution diagram by the method of measuring the elution of salt in water. It is a calibration curve graph when the metformin control product solvent is a 0.1 mol / l hydrochloric acid solution. Metformin hydrochloride, Metformin and 1-hydroxy-2-naphthoate, Metformin and 2-hydroxy-3-naphthoate form1, Metformin and 1-naphthalene acetate, Metformin and 2-naphthoate, Metformin and 2-naphthalene acetate It is an elution diagram by the elution measurement method with a 0.1 mol / l hydrochloric acid solution of a salt. Metformin, Metformin hydrochloride, Metformin and 1-hydroxy-2-naphthoate, Metformin and 2-hydroxy-3-naphthoate form1, Metformin and 1-naphthalene acetate, Metformin and 2-naphthoate, Metformin and 2- It is a hygroscopic diagram of hydroxy-3-naphthoate form2, metformin and 2-naphthalene acetate.

Hereinafter, the present invention will be described in more detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto. In the embodiment, if the specific conditions are not specified, the conventional conditions or the conditions submitted by the manufacturer are followed. The reagents or equipment used are all general commercial products unless the manufacturer is specified.

The metformin free base in the examples is prepared by the following method.

(1) Crude Metoformin Free Base: 16.5 g of metformin hydrochloride and 4.0 g of sodium hydroxide are weighed in an Erlenmeyer flask, 250 mL of absolute ethanol is added, and the mixture is stirred and reacted at room temperature for 12 hours, then filtered under reduced pressure and filtered. A crude product of metformin free base can be obtained by concentrating the liquid on a rotary evaporator to dryness.

(2) Purification of free base of metformin: At room temperature, 13.2 g of the crude product of the free base of metformin was collected, 100 mL of anhydrous acetone was added, magnetically stirred at room temperature for 40 minutes, filtered under reduced pressure, and the filtrate was filtered. It was crystallized for 48 hours under the condition of −8 ° C. and filtered to obtain 5.9302 g yellow granular crystals.

Example 1: Preparation of Metformin and 1-Naphthalene Acetate After collecting 0.0430 g of commercially available free base of metformin and 0.0621 g of 1-phthalene acetic acid, 1 to 2 drops of absolute ethanol are added dropwise and mixed uniformly. , Put in a 100 mL ball mill crusher tank, add two zirconium dioxide ball mill balls with a diameter of 22 mm, seal with a sealing lid, incorporate into the ball mill crusher, set the equipment parameters to rotation speed 35s ^-1 and 5 It was run for 1 minute and passed through a 154 μm stainless steel mesh to give 0.58 g of product metformin naphthalene acetate powder, with a yield of 98%.

Powder X-ray diffraction analysis was performed on the products metformin and 1-naphthalene acetate yellow powder, raw materials 1-naphthalene acetate and metformin free base obtained in Example 1, respectively, and the analysis results are as shown in FIG. be. As can be seen from FIG. 1, the prepared metformin and 1-naphthalene acetate yellow powder differs from the characteristic diffraction peaks of the metformin free base and 1-naphthalene acetate, and the prepared yellow powder is a novel salt form. I can judge.

The prepared metformin and 1-naphthalene acetate were sufficiently dissolved in ethanol to obtain a saturated solution, filtered to obtain a saturated solution, the solution was yellow, and the mixture was allowed to stand at room temperature for 48 hours to precipitate pale yellow crystals from the solution. The obtained pale yellow crystals are single crystals of metformin and 1-naphthalene acetate, and the single crystal structure diagram and the single crystal structure parameters are as shown in FIGS. 2 and 1, respectively.

The comparison diagram between the measured measurement of metformin and 1-naphthalene acetate (XRD spectrum) and the single crystal simulated XRD spectrum is as shown in FIG. 3, and as can be seen from FIG. 3, the obtained compound is surely in a novel salt form. Formed.

As can be seen from FIG. 4, metformin and 1-naphthalene acetate have a remarkable weight loss step before decomposition, and at about 120 ° C., there is a 2.78% weight loss step, and the sample becomes 0.5 equivalent. It was estimated that the corresponding water molecule (the theoretically calculated value was 2.77%) was lost, suggesting that it was a hemihydrate. As can be seen from FIG. 5, the melting point of metformin and 1-naphthalene acetate was 187.2 ° C.

Example 2: Preparation of metformin and 2-naphthoate 0.0430 g of free base of metformin and 0.0574 g of 2-naphthoic acid were collected, 1 to 2 drops of anhydrous ethanol were added dropwise, and the mixture was uniformly mixed, and then 100 mL. Put it in a ball mill crushing tank, add two zirconium dioxide ball mill balls with a diameter of 22 mm, seal it with a sealing lid, incorporate it into the ball mill crusher, set the equipment parameters to a rotation speed of 35s ^-1 , and operate for 5 minutes. Then, it passed through a 154 μm stainless steel mesh to obtain a powder of the product metformin and 2-naphthoate.

Powder X-ray diffraction analysis was performed on each of the powders prepared from metformin, 2-naphthoate, 2-naphthoic acid, and metformin free base, and the analysis results are as shown in FIG. As can be seen from FIG. 6, metformin and 2-naphthoate differ from the characteristic diffraction peaks of metformin free base and 1-naphthalene acetic acid, and the prepared metformin and 2-naphthoate are novel solid forms. Was suggested.

The prepared metformin and 2-naphthoate were sufficiently dissolved in ethanol to obtain a saturated solution, filtered, and allowed to stand at room temperature for 48 hours to precipitate crystals from the solution. The obtained crystals are single crystals of metformin and 2-naphthoate, and the single crystal structure diagram and the single crystal structure parameters are as shown in FIGS. 7 and 1, respectively.

The comparison diagram between the measured measurement of metformin and 2-naphthoate (XRD spectrum) and the single crystal simulated XRD spectrum is as shown in FIG. 8, and as can be seen from FIG. 8, the obtained compound is surely in a novel salt form. Formed.

As can be seen from FIG. 9, metformin and 2-naphthoate do not have a significant weight loss step, suggesting that they are water- or solvent-free anhydrates. As can be seen from FIG. 10, the melting point of metformin and 2-naphthoate was 199.8 ° C.

Example 3: Preparation of Metformin and 1-Hydroxy-2-naphthoate Collect 0.0430 g of Metformin free base and 0.0627 g of Metformin and 1-hydroxy-2-naphthoic acid, and add 1 to 2 drops of absolute ethanol. After dropping and mixing uniformly, put it in a 100 mL ball mill crushing tank, add two zirconium dioxide ball mill balls having a diameter of 22 mm, seal it with a sealing lid, incorporate it into the ball mill crusher, and set the parameters of the equipment to the rotation speed. It was set to 35s ^-1 and operated for 5 minutes and passed through a 154 μm stainless steel mesh to obtain a powder of the product metformin salt.

Powder X-ray diffraction analysis was performed on powders prepared from metformin, 1-hydroxy-2-naphthoate, 1-hydroxy-2-naphthoic acid, and metformin free base, respectively, and the analysis results are as shown in FIG. Is. As can be seen from FIG. 11, metformin and 1-hydroxy-2-naphthoate differ from the characteristic diffraction peaks of the free base metformin and 1-hydroxy-2-naphthoic acid, and the prepared metformin and 1-hydroxy-2. -It was suggested that naphthoate is a novel solid form.

The prepared metformin and 1-hydroxy-2-naphthoate were sufficiently dissolved in ethanol to obtain a saturated solution, filtered, and allowed to stand at room temperature for 48 hours to precipitate crystals from the solution. The obtained crystals are single crystals of metformin and 1-hydroxy-2-naphthoate, and the single crystal structure diagram and the single crystal structure parameters are as shown in FIGS. 12 and 1, respectively.

The measured (XRD spectrum) and single crystal simulated XRD spectra of metformin and 1-hydroxy-2-naphthoate are as shown in FIG. 13, and as can be seen from FIG. 13, the obtained compound is surely in a novel salt form. Formed.

As can be seen from FIG. 14, metformin and 1-hydroxy-2-naphthoate have a remarkable weight loss step before decomposition, and at about 138 ° C., there is a 4.47% weight loss step, and the sample is one. It was estimated that the molecule of water of crystallization (the theoretically calculated value was 5.37%) was lost, suggesting that it was a hydrate. As can be seen from FIG. 15, the melting point of metformin and 1-hydroxy-2-naphthoate was 177.8 ° C.

Example 4: Preparation of Metformin and 2-Hydroxy-3-naphthoate form1 0.0430 g of Metformin free base and 0.0627 g of 2-hydroxy-3-naphthoic acid (molar ratio 1: 1) were collected from 1 to 1. After dropping 2 drops of absolute ethanol and mixing them uniformly, put them in a 100 mL ball mill crushing tank, add two zirconium dioxide ball mill balls having a diameter of 22 mm, seal them with a sealing lid, and then incorporate them into a ball mill crusher. The instrument parameters were set to a rotation speed of 35 s ^-1 and operated for 5 minutes, passing through a 154 μm stainless steel mesh to give the product metformin salt powder.

Powder X-ray diffraction analysis was performed on the powder prepared from metformin and 2-hydroxy-3-naphthoate form1, 2-hydroxy-3-naphthoic acid, and metformin free base, respectively, and the analysis results are shown in FIG. That's right. As can be seen from FIG. 16, metformin and 2-hydroxy-3-naphthoate form1 differ from the characteristic diffraction peaks of the free base metformin and 2-hydroxy-3-naphthoic acid, and the prepared metformin and 2-hydroxy-. It was suggested that 3-naphthoate form1 is a novel solid form.

The prepared metformin and 2-hydroxy-3-naphthoate are sufficiently dissolved in ethanol to obtain a saturated solution, filtered into vials, placed in a wide-mouthed bottle containing petroleum ester, sealed, and allowed to stand at room temperature for 48 hours. Then, crystals were precipitated from the solution. The obtained crystals are single crystals of metformin and 2-hydroxy-3-naphthoate form1, and the single crystal structure diagram and the single crystal structure parameters are as shown in FIGS. 17 and 1, respectively.

The actual measurement (XRD spectrum) of metformin and 2-hydroxy-3-naphthoate form1 and the single crystal simulated XRD spectrum are as shown in FIG. 18, and as can be seen from FIG. 18, the obtained compound is surely a novel salt. Formed a shape.

As can be seen from FIG. 19, metformin and 2-hydroxy-3-naphthoate form1 do not have a significant weight loss step, suggesting that they are water- or solvent-free anhydrates. As can be seen from FIG. 20, the melting point of metformin and 2-hydroxy-3-naphthoate form1 was 131.2 ° C.

Example 5: Preparation of Metformin and 2-Hydroxy-3-naphthoate form2 0.0430 g of Metformin free base and 0.1254 g of 2-hydroxy-3-naphthoic acid (molar ratio 1: 2) were collected and 1 to 1 to After dropping 2 drops of absolute ethanol and mixing them uniformly, put them in a 100 mL ball mill crushing tank, add two zirconium dioxide ball mill balls having a diameter of 22 mm, seal them with a sealing lid, and then incorporate them into a ball mill crusher. The instrument parameters were set to a rotation speed of 35 s ^-1 and operated for 5 minutes, passing through a 154 μm stainless steel mesh to give the product metformin salt powder.

Powder X-ray diffraction analysis was performed on the powder prepared from metformin, 2-hydroxy-3-naphthoate form2, 2-hydroxy-3-naphthoic acid, and metformin free base, respectively, and the analysis results are shown in FIG. 21. That's right. As can be seen from FIG. 21, metformin and 2-hydroxy-3-naphthoate form2 differ from the characteristic diffraction peaks of the free base metformin and 2-hydroxy-3-naphthoic acid, and the prepared metformin and 2-hydroxy-. It was suggested that 3-naphthoate form2 is a novel solid form.

The prepared metformin and 2-hydroxy-3-naphthoate form2 are sufficiently dissolved in water and acetonitrile to obtain a saturated solution, which is filtered into a vial, pierced and sealed, allowed to stand at room temperature for 48 hours, and then from the solution. Crystals were precipitated. The obtained crystals are single crystals of metformin and 2-hydroxy-3-naphthoate form2, and the single crystal structure diagram and the single crystal structure parameters are as shown in FIGS. 22 and 1, respectively.

The actual measurement (XRD spectrum) of metformin and 2-hydroxy-3-naphthoate form2 and the single crystal simulated XRD spectrum are as shown in FIG. 23, and as can be seen from FIG. 23, the obtained compound is surely a novel salt. Formed a shape.

As can be seen from FIG. 24, metformin and 2-hydroxy-3-naphthoate form2 do not have a significant weight loss step, suggesting that they are water- or solvent-free anhydrates. As can be seen from FIG. 25, the melting point of metformin and 2-hydroxy-3-naphthoate form2 was 152.7 ° C.

Example 6: Preparation of metformin salt and 2,3-dihydroxynaphthalene To collect 0.0430 g of free base of metformin and 0.0534 g of 2,3-dihydroxynaphthalene (molar ratio 1: 1), 1 to 2 drops of absolute ethanol are collected. After dropping and mixing uniformly, put it in a 100 mL ball mill crushing tank, add two zirconium dioxide ball mill balls having a diameter of 22 mm, seal it with a sealing lid, incorporate it into the ball mill crusher, and rotate the parameters of the equipment. The speed was set to 35s ^-1 and operated for 5 minutes, passing through a 154 μm stainless steel mesh to obtain a powder of the product metformin salt.

Powder X-ray diffraction analysis was performed on powders prepared from metformin, 2,3-dihydroxynaphthalene salt, 2,3-dihydroxynaphthalene, and metformin free base, respectively, and the analysis results are as shown in FIG. 26. As can be seen from FIG. 26, the prepared solid metformin and 2,3-dihydroxynaphthalene salts differed from the characteristic diffraction peaks of the metformin free base and 2,3-dihydroxynaphthalene, and the prepared solid metformin and 2,3- It was suggested that the dihydroxynaphthalene salt is a novel solid form.

Example 7: Preparation of metformin and 1,5-dihydroxynaphthalene salt 0.0430 g of free base of metformin and 0.0534 g of 1,5-dihydroxynaphthalene (molar ratio 1: 1) were collected, and 1 to 2 drops of absolute ethanol were collected. After dropping and mixing uniformly, put it in a 100 mL ball mill crushing tank, add two zirconium dioxide ball mill balls having a diameter of 22 mm, seal it with a sealing lid, incorporate it into the ball mill crusher, and rotate the parameters of the equipment. The speed was set to 35s ^-1 and operated for 5 minutes, passing through a 154 μm stainless steel mesh to obtain a powder of the product metformin salt.

Powder X-ray diffraction analysis was performed on powders prepared from metformin, 1,5-dihydroxynaphthalene salt, 1,5-dihydroxynaphthalene, and metformin free base, respectively, and the analysis results are as shown in FIG. 27. As can be seen from FIG. 27, the prepared solid metformin and 1,5-dihydroxynaphthalene salt differ from the characteristic diffraction peaks of metformin free base and 1,5-dihydroxynaphthalene, and the prepared solid metformin and 1,5-dihydroxynaphthalene are different. It was suggested that the dihydroxynaphthalene salt is a novel solid form.

Example 8: Preparation of 3,7-dihydroxy-2-naphthoate with metformin Collecting 0.0430 g of free base of metformin and 0.0681 g of 3,7-dihydroxy-2-naphthoic acid (molar ratio 1: 1). After dropping 1 to 2 drops of absolute ethanol and mixing them uniformly, put them in a 100 mL ball mill crushing tank, add two zirconium dioxide ball mill balls having a diameter of 22 mm, seal them with a sealing lid, and then use a ball mill crusher. The equipment was set to a rotation speed of 35 s ^-1 and operated for 5 minutes, passed through a 154 μm stainless steel mesh, and a powder of the product metformin salt was obtained.

Powder X-ray diffraction analysis was performed on the powder prepared from metformin, 3,7-dihydroxy-2-naphthoate, 3,7-dihydroxy-2-naphthoic acid, and metformin free base, and the analysis results are shown in the figure. As shown in 28. As can be seen from FIG. 28, the prepared solid metformin and 3,7-dihydroxy-2-naphthoate were prepared differently from the characteristic diffraction peaks of the metformin free base and 3,7-dihydroxy-2-naphthoic acid. Solid metformin and 3,7-dihydroxy-2-naphthoate were suggested to be novel solid forms.

Example 9: Preparation of Metformin and 2-Naphthalene Acetate 0.0430 g of free base of metformin and 0.0621 g of 2-naphthalene acetic acid (molar ratio 1: 1) were collected, and 1 to 2 drops of absolute ethanol were added dropwise. After mixing uniformly, put it in a 100 mL ball mill crushing tank, add two zirconium dioxide ball mill balls having a diameter of 22 mm, seal it with a sealing lid, incorporate it into the ball mill crusher, and set the parameters of the equipment to the rotation speed 35s ^-1 . The product was run for 5 minutes and passed through a 154 μm stainless steel mesh to obtain a powder of the product metformin salt.

Powder X-ray diffraction analysis was performed on powders prepared from metformin, 2-naphthalene acetate, 2-naphthalene acetate, and metformin free base, respectively, and the analysis results are as shown in FIG. 29. As can be seen from FIG. 29, the prepared solid metformin and 2-naphthalene acetate differ from the characteristic diffraction peaks of the metformin free base and 2-naphthalene acetate, and the prepared solid metformin and 2-naphthalene acetate are novel. It was suggested that it was in the salt form.

As can be seen from FIG. 30, metformin and 2-naphthalene acetate do not have a significant weight loss step, suggesting that they are water- or solvent-free anhydrates. As can be seen from FIG. 31, the melting point of metformin and 2-naphthalene acetate was 152.7 ° C.

Comparative Example 1:
0.0430 g of free base of metformin and 0.0607 g of anhydrous citric acid (molar ratio 1: 1) were collected, 1 to 2 drops of anhydrous ethanol were added dropwise and mixed uniformly, and then placed in a 100 mL ball mill crushing tank to obtain a diameter. Two zirconium dioxide ball mill balls with a diameter of 22 mm are added, sealed with a sealing lid, then incorporated into a ball mill crusher, the equipment parameters are set to a rotation speed of 35s ^-1 , and the operation is performed for 5 minutes, passing through a 154 μm stainless steel mesh. And the product metformin salt powder was obtained.

A powder X-ray diffraction analysis was performed on a solid prepared from the obtained product, anhydrous citric acid, and metformin free base, and the analysis results are as shown in FIG. 32. As can be seen from FIG. 32, the characteristic peaks of the products obtained in Comparative Example 1 were all observed in the raw material metformin or citric acid, and no new characteristic peaks were observed, so that no new salt was formed. ..

Comparative Example 2:
0.0430 g of free base of metformin and 0.0494 g of transsilicic acid (molar ratio 1: 1) were collected, 1 to 2 drops of anhydrous ethanol were added dropwise and mixed uniformly, and then placed in a 100 mL ball mill crushing tank to obtain a diameter. Add two zirconium dioxide ball mill balls with a diameter of 22 mm, seal them with a sealing lid, incorporate them into a ball mill crusher, set the equipment parameters to a rotation speed of 35s ^-1 , operate for 5 minutes, and pass through a 154 μm stainless steel mesh. And the powder of the product metformin salt was obtained.

A powder X-ray diffraction analysis was performed on a solid prepared from the obtained product, transsilicic acid, and metformin free base, and the analysis results are as shown in FIG. 33. As can be seen from FIG. 33, the characteristic peaks of the products obtained in Comparative Example 2 were all observed in the raw material metformin or transsilicic acid, and no new characteristic peaks were observed, so that no new salt was formed. rice field.

Comparative Example 3:
Succinic acid, DL-apple acid, tartaric acid, ascorbic acid, L-arginic acid, terephthalic acid, isophthalic acid, orthophthalic acid, 3-hydroxybenzoic acid, paraoxybenzoic acid, gallic acid, 5-hydroxyisophthalic acid, 1,4- Naphthalic acid, L-phenylalanine amino acid, L-theanine, ferulic acid, 3-hydroxy, and 2,6-naphthalenedicarboxylic acid were each replaced with anhydrous citric acid in Comparative Example 1, and the molar ratio of metformin to acid was 1: 1. After dropping 1 to 2 drops of absolute ethanol and mixing them uniformly, put them in a 100 mL ball mill crushing tank, add two zirconium dioxide ball mill balls having a diameter of 22 mm, seal with a sealing lid, and then crush the ball mill. No new characteristic peaks were observed in the XRD line diffraction pattern of the obtained powder, which was incorporated into the machine, the parameters of the equipment were set to the rotation speed of 35s ^-1 , the operation was performed for 5 minutes, and the powder passed through a 154 μm stainless steel mesh. Therefore, no new salt was formed.

As can be seen from Comparative Examples 1 to 3, not all acids can obtain the corresponding metformin salt by the preparation method of the present invention.

The elution measurement of the metformin salt in the examples is mainly carried out according to the following operation.

1. Solvent: Ultrapure water, 0.1 mol / l hydrochloric acid aqueous solution

2. Tableting and elution: First, add an appropriate amount (3 to 50 mg) of sample to the tableting machine, leave it for 30 seconds under a pressure of 5 bar to press it into a tablet, and then add 1000 mL of each solvent to the beaker. , 50 rpm elution test, aspirate 1 mL solvent every 2.5, 5, 15, 30, 45, 60 minutes and use high performance liquid chromatography to determine the content of metformin salt. It was measured.

3. Test equipment: Ultrapure water device (ultrapure water prepared using Mill-Q ultrapure water preparation system of Milli-pore, USA), ultra-high performance liquid chromatography-flight time mass analyzer (Agilent 1290-6545) Type)

4. Chemicals and reagents: Metformin control product (Metformin free base), Metformin and 1-naphthalene acetate, Metformin and 2-naphthoate, Metformin and 1-hydroxy-2-naphthoate, Metformin and 2-hydroxy-3 -Naftate form1, metformin and 2-hydroxy-3-naphthoate form2, metformin salt and 2,3-dihydroxynaphthalene, metformin and 1,5-dihydroxynaphthalene salt, metformin and 3,7-dihydroxy-2-naphthoe Acid salt, metformin and 2-naphthalene acetate.

5. Chromatographic mass analysis conditions Column: Octadecyl-bonded silica column C18 column, mobile phase: 0.1% formic acid aqueous solution: acetonitrile = 80:20, flow velocity: 1.0 ml / min, column temperature 30 ° C., sample injection amount: 5 μl / min.

Quantitative analysis was performed using an electrospray ion source (ESI), positive ion scanning, and multiple reaction monitoring method (MRM). Both the dry gas and the atomized gas are nitrogen gas, and the dry gas temperature: 300 ° C., dry gas flow rate: 20 L / min, sheath gas flow rate: 10 L / min, capillary voltage: 4 500 v, nozzle voltage: 2000 v, scan. Time: 0.2s, Metformin parent ion mass-to-charge ratio (m / z): 130, Child ion (m / z): 71.2, 60.3, 88.2, 46.3, Quantitative ion (m / z) ): 60.3, the collision energy was 9, and the abundance was 58482.

6. Construction of calibration curve for metformin control product (1) Weigh accurately 10 mg of metformin control product in a 100 ml volumetric flask, dissolve in ultrapure water, dilute to the scale, shake, and shake to a refrigerator at 4 ° C as a stock solution. Saved in.

Precisely weigh an appropriate amount of stock solution, dilute it with ultrapure water to a solution of 50.0, 25.0, 10.0, 5.0, 2.5, 0.5 μg · ml ^-1 series concentration, and filter. Then, 5 μl sample injection and measurement with a chromatograph-mass analyzer were performed. Linear regression of the peak area (A) of metformin chromatography with respect to the concentration (C) gives the regression equations when the solvent is ultrapure water: A1 = 166000c + 377250, r = 0.9977, and the solvent is 0.1 mol. Regression equations for a / l hydrochloric acid solution: A2 = 80931c + 75030, r = 0.9978, and as can be seen from the results, the concentration of metformin is 0.5-50.0 μg, as shown in FIGS. 34 and 36. A good linear relationship was shown within the range of ml ^-1 .

Table 2 shows the chromatographic data of the metformin control product.

Dissolution data test of metformin salt in ultrapure water and 0.1 mol / l hydrochloric acid solution:

(1) Dissolution data test of metformin salt in ultrapure water: Cellulose (mass ratio 1: 5) is added to metformin salt and tableted to facilitate the formation of the pharmaceutical form, and the number of revolutions is 50 r / min. Was prepared and stabilized. Place the sample in a 1000 ml beaker whose elution medium is ultrapure water at a constant temperature (37.0 ° C), immediately start the device, and 1 ml (1 ml) at the timing of 2.5, 5, 15, 30, 45, and 60 minutes, respectively. (Replenish 1 ml of the same temperature medium at the same time) is sampled at a fixed point, immediately filtered using a micropore filtration membrane, directly injected with 5 μl of the sample for measurement, a calibration curve is substituted, and the drug concentration is calculated. An dissolution degree curve as shown in is created.

Table 3 shows the elution data of metformin salt in water.

(2) Dissolution data test of metformin salt in 0.1 mol / l hydrochloric acid solution: Cellulose (mass ratio 1: 5) is added to the sample and tableted to facilitate the formation of the pharmaceutical form, and the rotation speed is 50 r / min. The number of revolutions was adjusted and stabilized. Place the sample in a 1000 ml beaker with a constant temperature (37.0 ° C.) elution medium of 0.1 mol / l hydrochloric acid solution and immediately start the instrument for 2.5, 5, 15, 30, 45 and 60 minutes, respectively. At the timing of, 1 ml (supplement 1 ml of the same temperature medium at the same time) is sampled at a fixed point, immediately filtered with a micropore filtration membrane, 5 μl of the sample is directly injected and measured, a calibration curve is substituted, and the drug concentration is calculated. , A dissolution degree curve as shown in FIG. 37 was created.

Table 4 shows the elution data of metformin salt in 0.1 mol / l hydrochloric acid solution.

Measurement of hygroscopicity of metformin salt

The main operations are as follows.
EUT (methformin and 1-hydroxy-2-naphthoate, metformin and 2-hydroxy-3-naphthoate form1, metformin and 2-hydroxy-3-naphthoate form2, metformin and 1-naphthalene acetate, Metformin and 2-naphthalene acetate, metformin and 2-naphthoate, metformin and 1,5-dihydroxynaphthalene) were left open in a constant humidity airtight dry container, and at 25 ° C, at the bottom of the two airtight dry containers. A saturated solution of sodium chloride (relative humidity 75%) and a saturated solution of potassium nitrate (relative humidity 93%) were left, and the specimen was left on the upper layer for 10 days, respectively, at the timing of the 5th and 10th days. Sampling was performed, measurements were made according to the requirements of the stability priority consideration items, and at the same time, the weight of the EUT before and after the test was accurately weighed, and the moisture absorption and deliquescent performance of the EUT was considered. As can be seen from the test results, the hygroscopic weight increase of the specimen was less than 5%, and the hygroscopicity was significantly reduced as compared with metformin. The test data are as shown in Table 5.

As described above, the present invention can obtain nine novel salts of metformin and prepare them in large quantities using the methods described herein. Compared to traditional metformin, these new salts are less hygroscopic, better soluble in water, can slow down the intrinsic dissolution rate of metformin, are more stable, easier to store and easier to prepare. It is environmentally friendly, and the potential application of such metformin salts to metformin drugs is expected.

The above embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited to the above embodiment, and any other embodiment of the present invention may be performed within the technical idea and under the principle of the present invention. Modifications, modifications, substitutions, combinations, and simplifications are all equivalent substitution methods and are all within the scope of the protection of this application.

Claims (5)

Metformin raw material drug and pharmaceutical additive acid are weighed, mixed uniformly, then ball milled and passed through a 154 μm stainless steel mesh to obtain metformin salt .
A method for preparing a metformin salt, wherein the pharmaceutical additive acid is 1-hydroxy-2-naphthoic acid . The method for preparing a metformin salt according to claim 1, wherein the raw material drug for metformin is a free base of metformin. The method for preparing a metformin salt according to claim 1, wherein the molar ratio of the raw material drug of metformin to the acid of the pharmaceutical additive is 1: 1 or 1: 2. The metformin salt according to claim 1, wherein the uniform mixing is to add ethanol to the raw material drug of metformin and the pharmaceutical additive acid to uniformly mix the two. Preparation method. In the ball mill crushing, the mixture is placed in a ball mill crushing tank, two zirconium dioxide ball mill balls having a diameter of 22 mm are added, sealed with a sealing lid, and then incorporated into a ball mill crusher, and the parameters of the equipment are set to a rotation speed of 35 s ^-1 . The method for preparing a metformin salt according to claim 1, wherein the method is to operate for 5 minutes, pass through a 154 μm stainless steel mesh, and obtain a metformin salt after crushing by a ball mill.

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