Amorphous substance of magnesium glycerophosphate and preparation method thereof

Abstract

The invention relates to an amorphous substance of magnesium glycerophosphate and a preparation method thereof. The magnesium glycerophosphate amorphous substance prepared by the invention meets the standards of Korean Pharmacopoeia, British Pharmacopoeia and European Pharmacopoeia, is suitable for long-term storage and preparation production, is simple in production operation, and meets the requirements of industrial mass production.

Description

Technical Field

[0001] The invention belongs to the field of chemistry, and in particular relates to an amorphous magnesium glycerophosphate and a preparation method thereof. Background Art

[0002] Magnesium glycerophosphate is an effective magnesium supplement with a variety of health benefits, including supplementing magnesium, promoting energy metabolism, improving nerve function, supporting bone health, and maintaining cardiovascular health. Magnesium glycerophosphate is an amorphous form of magnesium salt with a high absorption rate. It is one of the most easily absorbed magnesium sources by the human body. Its bioavailability is significantly higher than that of magnesium oxide, and it is also the most cost-effective among chelated magnesium. In addition, the glycerophosphate ester released after magnesium glycerophosphate is absorbed into the blood can be used as a phosphorus supplement to meet the body's daily phosphorus needs. Phosphorus is involved in bone formation and in the composition of cell membranes in the form of phospholipids. At the same time, phosphorus is related to the activity of enzymes in many metabolisms and plays a vital role in energy metabolism.

[0003]

[0004] Magnesium glycerophosphate has been included in the Korean Pharmacopoeia, the British Pharmacopoeia, and the European Pharmacopoeia. The quality of magnesium glycerophosphate currently sold in the domestic market does not meet the requirements of the above pharmacopoeia standards, especially the solubility, clarity and magnesium content indicators. In view of the above facts, it is urgent to develop a solid form of magnesium glycerophosphate to fill this gap in China. Summary of the invention

[0005] The invention aims to provide an amorphous material of magnesium glycerophosphate, which has good chemical stability and quality indicators such as solubility, clarity and magnesium content that meet European Pharmacopoeia standards.

[0006] On one hand, the present invention provides an amorphous material of magnesium glycerophosphate, whose X-ray powder diffraction spectrum has two diffraction peaks in the range of 2θ of 0-40°.

[0007] As a preferred technical solution, the amorphous X-ray powder diffraction pattern of the magnesium glycerophosphate of the present invention has one diffraction peak in the range of 2θ of 0-10° and 10-40°, respectively, and the peak intensity in the range of 0-10° is greater than the peak intensity in the range of 10-40°.

[0008] As a more preferred technical solution, its X-ray powder diffraction pattern is basically as follows Figure 1 shown.

[0009] As a preferred technical solution, the infrared spectrum of the amorphous substance of the present invention is shown as follows: -1 、1001.27cm -1 、1081.60cm -1 、1457.44cm-1 、1652.53cm -1 、2062.79cm -1 、2359.73cm -1 、2952.18cm -1 、3350.96cm -1 There is an absorption peak at.

[0010] As a more preferred technical solution, the infrared absorption spectrum of the amorphous substance of the present invention is as follows Figure 2 shown.

[0011] As a more preferred technical solution, the infrared absorption spectrum of the amorphous substance of the present invention is as follows Figure 2 shown.

[0012] Another aspect of the present invention provides a method for preparing an amorphous magnesium glycerophosphate, characterized in that the method comprises the following steps: (1) adding glycerophosphate dropwise into a mixture of an inorganic base and water and stirring to react to prepare a suspension system; (2) filtering the suspension system to obtain a filtrate; (3) dropping the filtrate into alcohol to precipitate solid, which is then dried; As a preferred technical solution, the inorganic base includes magnesium carbonate and magnesium hydroxide.

[0013] As a preferred technical solution, the solvent is one or a mixed solvent of methanol, ethanol, and isopropanol.

[0014] The last aspect of the present invention also provides a pharmaceutical composition comprising any of the above-mentioned magnesium glycerophosphate amorphous substances and a pharmaceutically acceptable carrier or excipient.

[0015] The pharmaceutical composition is composed of the amorphous magnesium glycerophosphate of the present invention and a pharmaceutically acceptable carrier or excipient. Specifically, the pharmaceutically acceptable carrier or excipient includes but is not limited to a filler, a binder, a disintegrant, a lubricant, and the like.

[0016] The pharmaceutical composition can be prepared into preparations including but not limited to tablets, capsules, granules, powders, suppositories and the like. Preferably, the pharmaceutical composition can be prepared into tablets.

[0017] The excipients are commonly used auxiliary materials in the field. Specifically, the fillers include but are not limited to starch, lactose, mannitol, sucrose, microcrystalline cellulose, etc.; the binders include but are not limited to hydroxymethyl cellulose, sodium carboxymethyl cellulose, starch slurry, gelatin, etc.; the disintegrants include but are not limited to sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, dry starch, cross-linked sodium carboxymethyl cellulose, etc.; the lubricants include but are not limited to micro-powdered silica gel, talc, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., and the pharmaceutical composition can be further coated with commonly used coating materials as needed.

[0018] The "X-ray powder diffraction pattern or XRPD" described in the present invention refers to the Bragg formula 2d sinθ=nλ (wherein λ is the wavelength of the X-ray, λ=1.54056Å, the diffraction order n is any positive integer, generally the first-order diffraction peak is taken, n=1). When the X-ray is incident on a certain atomic plane with d lattice plane spacing of a crystal or a partial crystal sample at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle), the Bragg equation is satisfied, thereby measuring this set of X-ray powder diffraction patterns. The XRD spectrum of the amorphous magnesium glycerophosphate described in the present invention does not show obvious and sharp diffraction peaks, which is consistent with the characteristics of amorphous. Figure 1 The magnesium glycerophosphate shown is amorphous, and its X-ray powder diffraction (XRD) spectrum has two broad and weak non-sharp diffraction peaks, which are two diffraction peaks with 2θ between 0 and 40°. DETAILED DESCRIPTION OF THE INVENTION In the specification and claims of the application, unless otherwise stated, the scientific and technological terms used herein have the meanings commonly understood by those skilled in the art. However, in order to better understand the present invention, the definition and explanation of some related terms are provided below. In addition, when the definition and explanation of the terms provided in the application are inconsistent with the meanings commonly understood by those skilled in the art, the definition and explanation of the terms provided in the application shall prevail.

[0020] The "X-ray powder diffraction pattern or XRPD" mentioned in the present invention refers to the Bragg formula 2d sinθ=nλ (wherein λ is the wavelength of the X-ray, the diffraction order n is any positive integer, generally the first-order diffraction peak is taken, n=1). When the X-ray is incident on an atomic plane with a lattice plane spacing d of a crystal or a partial crystal sample at a grazing angle θ (the complementary angle of the incident angle, also called the Bragg angle), the Bragg equation is satisfied, thereby measuring this set of X-ray powder diffraction patterns.

[0021] The "2θ or 2θ angle" mentioned in the present invention refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ is ±0.1 to ±0.5, preferably ±0.1 to ±0.3, and more preferably ±0.2.

[0022] Through the above technical solution, compared with the prior art, the present invention has the following beneficial effects: 1. The amorphous form of magnesium glycerophosphate provided by the present invention has good chemical stability, and its quality indicators such as solubility, clarity and magnesium content meet the standards of the European Pharmacopoeia; 2. The amorphous magnesium glycerophosphate preparation method provided by the present invention is simple and has good repeatability, controllable quality, simple production operation, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is the XRPD pattern of the amorphous magnesium glycerophosphate of Examples 1 to 6 of the present invention; Figure 2 It is the infrared absorption spectra of the amorphous magnesium glycerophosphate of Examples 1 to 6 of the present invention. DETAILED DESCRIPTION

[0024] The present invention will be explained in more detail below in conjunction with embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and are not intended to limit the essence and scope of the present invention.

[0025] In the following examples, the experimental methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer.

[0026] Test instruments used in the experiment: 1. Fourier Transform Infrared Spectrometer Instrument model: Shimadzu IRSpirit-T Reagent solution: Potassium bromide Standard substance: magnesium glycerophosphate reference substance Operation method: Take 1~1.5mg of the test sample and about 200~300mg of potassium bromide, put them in an agate mortar, grind them evenly, put them in a die, spread them evenly, pressurize them to 1.5~2.0T, keep them for more than 15 seconds, remove the pressure, take out the prepared tablets, and visually check that they should be uniform without obvious particles. Prepare the reference substance at the same time. Determine according to infrared spectrophotometry (General Rules 0402 of Part IV of the 2020 Edition of the Chinese Pharmacopoeia).

[0027] 2. X-ray Powder Diffraction (XRPD) Instrument model: Bruker D8 Discover A25 X-ray powder diffractometer Ray: Monochromatic Cu-Kα ray (λ=1.5406) Scanning mode: θ / 2θ, scanning range: 10~48° Voltage: 40KV, Current: 40mA Implementation Case 1 At room temperature, 794 g Mg(OH) 2 , 6.25 L purified water, stirred and dispersed, a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, heat was obviously released, and the temperature was controlled at 25~45℃; after the addition was completed, it was stirred at room temperature for 30 minutes; the reaction liquid was filtered, the filter cake was discarded, and the filtrate was set aside; 33.75 L methanol was added to a 50 L reactor, and the filtrate from the previous step was dropped therein, and solid precipitated; after the addition was completed, it was stirred at room temperature for 5~10 minutes, the suspension system was filtered, and the filter cake was rinsed with 5L methanol; the filter cake was collected and dried in a 60℃ forced air oven for 15 hours to obtain 1.16 kg of white solid, with a yield of 57.1%.

[0028] Implementation Case 2 At room temperature, 794 g Mg(OH) 2 , 6.25 L purified water, stirred and dispersed, a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, heat was obviously released, and the temperature was controlled at 25~45℃; after the addition was completed, it was stirred at room temperature for 1h; the reaction liquid was filtered, the filter cake was discarded, and the filtrate was set aside; 33.75 L ethanol was added to a 50 L reactor, and the filtrate from the previous step was dropped therein, and solids precipitated; after the addition was completed, it was stirred at room temperature for 5~10min, the suspension system was filtered, and the filter cake was rinsed with 5L ethanol; the filter cake was collected and dried in a 60℃ forced air oven overnight to obtain 1.27 kg of white solid, with a yield of 62.7%.

[0029] Implementation Case 3 At room temperature, 794 g Mg(OH) 2 , 6.25 L purified water, stirred and dispersed, a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, heat was obviously released, the temperature was controlled at 35~45℃, and after the addition was completed, it was stirred at room temperature for 30 minutes; the reaction liquid was filtered, the filter cake was discarded, and the filtrate was set aside; 33.75 L of isopropanol was added to a 50 L reactor, and the filtrate from the previous step was dropped therein, and solids precipitated; after the addition was completed, it was stirred at room temperature for 5~10 minutes, the suspension system was filtered, and the filter cake was rinsed with 5L of isopropanol; the filter cake was collected and dried in a 60℃ forced air oven overnight to obtain 1.24 kg of white solid, with a yield of 61.0%.

[0030] Implementation Case 4 At room temperature, 1.146 kg MgCO was added to a 30 L reactor. 3, 6.25 L purified water, stirred and dispersed, a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, heat was obviously released, the temperature was controlled at 35~45℃, and after the addition was completed, it was stirred at room temperature for 1h; the reaction liquid was filtered, the filter cake was discarded, and the filtrate was set aside; 33.75 L methanol was added to a 50 L reactor, and the filtrate from the previous step was dropped therein, and solid precipitated; after the addition was completed, it was stirred at room temperature for 5~10min, the suspension system was filtered, and the filter cake was rinsed with 5L methanol; the filter cake was collected and dried in a 60℃ forced air oven overnight to obtain 1.38 kg of white solid, with a yield of 68.1%.

[0031] Implementation Case 5 At room temperature, 1.146 kg MgCO was added to a 30 L reactor. 3 , 6.25 L purified water, stirred and dispersed, a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, heat was obviously released, and the temperature was controlled at 35~45℃; after the addition was completed, it was stirred at room temperature for 30 minutes; the reaction liquid was filtered, the filter cake was discarded, and the filtrate was set aside; 33.75 L ethanol was added to a 50 L reactor, and the filtrate from the previous step was dripped into it, and solid precipitated; after the addition was completed, it was stirred at room temperature for 5~10 minutes, the suspension system was filtered, and the filter cake was rinsed with 5L ethanol; the filter cake was collected and dried in a 60℃ forced air oven overnight to obtain 1.31 kg of white solid, with a yield of 64.5%.

[0032] Implementation Case 6 At room temperature, 1.146 kg MgCO was added to a 30 L reactor. 3 , 6.25 L purified water, stirred and dispersed, a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, heat was obviously released, and the temperature was controlled at 35~45℃; after the addition was completed, it was stirred at room temperature for 1h; the reaction liquid was filtered, the filter cake was discarded, and the filtrate was set aside; 33.75 L isopropanol was added to a 50 L reactor, and the filtrate from the previous step was dripped into it, and solid precipitated; after the addition was completed, it was stirred at room temperature for 5~10min, the suspension system was filtered, and the filter cake was rinsed with 5L isopropanol; the filter cake was collected and dried in a 60℃ forced air oven overnight to obtain 1.37 kg of white solid, with a yield of 67.4%.

[0033] The magnesium glycerophosphate obtained in the above example was tested according to the standards and methods of the European Pharmacopoeia, with emphasis on solution clarity, drying loss, and magnesium content. The test results are as follows: Experimental Example 1: Solution Clarity Detection

[0034] Instruments and equipment: electronic analytical balance, volumetric flask. Reagents: turbidity standard solution III.

[0035] Operation method: Weigh 2.5 g of the test sample and place it in a 50 ml volumetric flask.2 The purified water was dissolved and the volume was fixed. The test results are shown in Table 1.

[0036]

[0037] The experimental results show that the solution clarity of the amorphous magnesium glycerophosphate prepared by the present invention in water is qualified and meets the European Pharmacopoeia standard.

[0038] Experimental Example 2: Drying loss analysis method

[0039] Instruments and equipment: electronic analytical balance, electric blast drying oven.

[0040] Reagent: Phosphorus pentoxide.

[0041] Operation method: Take the sample, mix it evenly (if it is a large crystal, it should be quickly crushed into small particles less than 2 mm), take about 1g or the weight specified under each variety, put it in a flat weighing bottle that has been dried to constant weight under the same conditions as the sample, weigh it accurately, and dry it at 150℃ and normal pressure for 4 hours (add desiccant: phosphorus pentoxide at the same time). Calculate the drying loss of the sample from the lost weight and the sample amount. The test results are shown in Table 2.

[0042] Table 2 Drying loss test results

[0043] The experimental results show that the drying loss of the magnesium glycerophosphate amorphous material prepared by the present invention is ≤12%, which meets the European Pharmacopoeia standard.

[0044] Experimental Example 3: Magnesium content analysis method

[0045] Instruments and equipment: electronic analytical balance, conical flask, burette, water bath.

[0046] Reagents: pH 10 ammonium chloride buffer, chrome black T indicator, 0.1 M sodium ethylenediaminetetraacetic acid titration solution.

[0047] Operation method: Weigh 0.2 g sample and dissolve it in 40 mL water, add it to a 500 mL conical flask, dilute it to 300 mL with water, add 10 mL pH 10 ammonium chloride buffer (5.4 g ammonium chloride, dissolve it in 20 mL water, add 35 mL ammonia water, and dilute it to 100 mL with water), add 50 mg chrome black T indicator (1 g chrome black T powder is mixed evenly with 100 g sodium chloride), heat to 40 degrees, and titrate with 0.1M sodium ethylenediaminetetraacetic acid titrant at this temperature. The test results are shown in Table 3.

[0048] Table 3 Magnesium content test results

[0049] The experimental results show that the magnesium content of the amorphous magnesium glycerophosphate prepared by the present invention is 11.0% to 12.5% ​​(based on the dry product), which meets the European Pharmacopoeia standard.

[0050] It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as those generally understood by those skilled in the art to which this application belongs. It should also be understood that terms such as those defined in common dictionaries should be understood to have meanings consistent with the meanings in the context of the prior art, and will not be interpreted with idealized or overly formal meanings unless defined as herein.

Claims

1. An amorphous substance of magnesium glycerophosphate, characterized in that: Its X-ray powder diffraction spectrum has two diffraction peaks in the range of 2θ 0-40°.

2. The magnesium glycerophosphate amorphous substance according to claim 1, wherein Its X-ray powder diffraction spectrum has one diffraction peak in the range of 2θ of 0-10° and 10-40°, respectively, and the peak intensity in the range of 0-10° is greater than the peak intensity in the range of 10-40°.

3. The magnesium glycerophosphate amorphous substance according to claim 1, wherein The amorphous magnesium glycerophosphate has an X-ray powder diffraction pattern as shown in FIG1 .

4. The magnesium glycerophosphate amorphous substance according to claim 1, wherein The infrared spectrum of the amorphous substance is shown at 810.49 cm -1 、1001.27cm -1 、1081.60cm -1 、1457.44cm -1 、1652.53cm -1 、2062.79cm -1 、2359.73cm -1 、2952.18cm -1 、3350.96cm -1 There is an absorption peak at.

5. The magnesium glycerophosphate amorphous substance according to claim 1, wherein The infrared absorption spectrum of the amorphous material is shown in FIG2 .

6. The method for preparing the amorphous magnesium glycerophosphate according to any one of claims 1 to 5, comprising the following steps: (1) adding glycerophosphate dropwise into a mixture of an inorganic base and water and stirring to react to prepare a suspension system; (2) filtering the suspension system to obtain a filtrate; (3) The filtrate is dropped into an alcohol solvent to precipitate a solid which is then dried.

7. The preparation method according to claim 6, wherein the inorganic base is selected from magnesium carbonate and magnesium hydroxide.

8. The preparation method according to claim 6, wherein the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol.

9. A pharmaceutical composition comprising the amorphous magnesium glycerophosphate according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or excipient.

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