Amorphous material of magnesium glycerophosphate and preparation method thereof

Abstract

The present invention relates to an amorphous magnesium glycerophosphate and a preparation method thereof. The amorphous magnesium glycerophosphate prepared by the present invention complies with the standards of the Korean Pharmacopoeia, the British Pharmacopoeia, and the European Pharmacopoeia, is suitable for long-term storage and preparation production, has simple production operations, and meets the requirements of industrialized large-scale production.

Description

Technical Field

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

[0002] Magnesium glycerophosphate is an effective magnesium supplement with numerous health benefits, including magnesium supplementation, energy metabolism, improved neurological function, bone health, and cardiovascular health. Magnesium glycerophosphate, in its amorphous form, has a high absorption rate and is one of the most readily absorbed magnesium sources in the human body. Its bioavailability is significantly higher than that of magnesium oxide, making it the most cost-effective magnesium chelate. Furthermore, the glycerophosphate ester released by magnesium glycerophosphate after absorption into the bloodstream can be used as a phosphorus supplement to meet the body's daily phosphorus needs. Phosphorus is involved in bone formation and, in the form of phospholipids, in the composition of cell membranes. It is also involved in the activity of many metabolic enzymes and plays a crucial role in energy metabolism.

[0003]

[0004] Magnesium glycerophosphate is included in the Korean Pharmacopoeia, the British Pharmacopoeia, and the European Pharmacopoeia. However, the quality of magnesium glycerophosphate currently available in the domestic market does not meet the standards of these pharmacopoeias, particularly in terms of solubility, clarity, and magnesium content. Given these facts, there is an urgent need 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 the standards of the European Pharmacopoeia.

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

[0007] As a preferred technical solution, the X-ray powder diffraction pattern of the amorphous 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 it comprises the following steps:

[0013] (1) Glycerol phosphate is added dropwise to a mixture of an inorganic base and water, and stirred to react to prepare a suspension system;

[0014] (2) filtering the suspension to obtain a filtrate;

[0015] (3) Add the above filtrate dropwise into alcohol to precipitate solid, which is then dried;

[0016] As a preferred technical solution, the inorganic base includes magnesium carbonate and magnesium hydroxide.

[0017] As a preferred technical solution, the solvent is one or a mixed solvent of methanol, ethanol, and isopropanol.

[0018] The last aspect of the present invention also provides a pharmaceutical composition comprising any of the aforementioned magnesium glycerophosphate amorphous substances and a pharmaceutically acceptable carrier or excipient.

[0019] 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.

[0020] 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.

[0021] 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. As needed, the pharmaceutical composition can also be further coated with commonly used coating materials.

[0022] The "X-ray powder diffraction pattern or XRPD" described in the present invention refers to the Bragg equation 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 at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) on an atomic plane with a lattice plane spacing of a crystal or a partial crystal sample, 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

[0024] In the specification and claims of the application, unless otherwise indicated, the scientific and technological terms used herein have the implication 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 term provided in the application are inconsistent with the implication commonly understood by those skilled in the art, the definition and explanation of the term provided in the application shall be as the criterion.

[0025] The "X-ray powder diffraction pattern or XRPD" mentioned in the present invention refers to the Bragg equation 2d sinθ=nλ (wherein λ is the wavelength of the X-rays, and the diffraction order n is any positive integer, generally the first-order diffraction peak is taken, n=1). When the X-rays are incident at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) on an atomic plane with a lattice plane spacing d in a crystal or a portion of a crystalline sample, the Bragg equation is satisfied, thereby obtaining this set of X-ray powder diffraction patterns.

[0026] 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.

[0027] Through the above technical solution, compared with the existing technology, the present invention has the following beneficial effects:

[0028] 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;

[0029] 2. The amorphous magnesium glycerophosphate preparation method provided by the present invention is simple and reproducible, the quality is controllable, the production operation is simple, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is the XRPD pattern of the amorphous magnesium glycerophosphate of Examples 1 to 6 of the present invention;

[0031] Figure 2 It is the infrared absorption spectrum of the magnesium glycerophosphate amorphous substance of Examples 1 to 6 of the present invention. DETAILED DESCRIPTION

[0032] The present invention will be explained in more detail below with reference to the 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.

[0033] In the following examples, the experimental methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer.

[0034] Test instruments used in the experiment:

[0035] 1. Fourier Transform Infrared Spectrometer

[0036] Instrument model: Shimadzu IRSpirit-T

[0037] Reagent solution: potassium bromide

[0038] Standard substance: magnesium glycerophosphate reference substance

[0039] Procedure: Take 1-1.5 mg of the test sample and approximately 200-300 mg of potassium bromide in an agate mortar and grind evenly. Place the mixture in a press mold and spread it evenly. Apply pressure to 1.5-2.0 T and hold for at least 15 seconds. Remove the pressure and remove the prepared tablet. Visually inspect the tablet for uniformity and absence of obvious particles. Simultaneously prepare a reference substance. Determine the content by infrared spectrophotometry (Chinese Pharmacopoeia 2020, Part IV, General Chapter 0402).

[0040] 2. X-ray Powder Diffraction (XRPD)

[0041] Instrument model: Bruker D8 Discover A25 X-ray powder diffractometer

[0042] Radiation: Monochromatic Cu-Kα radiation (λ=1.5406)

[0043] Scanning mode: θ / 2θ, scanning range: 10~48°

[0044] Voltage: 40KV, Current: 40mA

[0045] Implementation Case 1

[0046] At room temperature, 794 g Mg(OH)2 and 6.25 L purified water were added to a 30 L reactor, stirred and dispersed, and a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, and heat was significantly released. The temperature was controlled at 25-45°C; after the addition was complete, the mixture was stirred at room temperature for 30 min; the reaction liquid was filtered, the filter cake was discarded, and the filtrate was set aside; 33.75 L of methanol was added to a 50 L reactor, and the filtrate from the previous step was added dropwise thereto, and a solid precipitated; after the addition was complete, the mixture was stirred at room temperature for 5-10 min, the suspension system was filtered, and the filter cake was rinsed with 5 L of methanol; the filter cake was collected and dried in a forced air oven at 60°C for 15 h to obtain 1.16 kg of a white solid with a yield of 57.1%.

[0047] Implementation Case 2

[0048] At room temperature, 794 g Mg(OH)2 and 6.25 L purified water were added to a 30 L reactor, stirred and dispersed, and a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, and heat was significantly released. The temperature was controlled at 25-45°C; after the addition was complete, the mixture was stirred at room temperature for 1 hour; the reaction liquid was filtered, the filter cake was discarded, and the filtrate was set aside; 33.75 L of ethanol was added to a 50 L reactor, and the filtrate from the previous step was added dropwise thereto, and a solid precipitated; after the addition was complete, the mixture was stirred at room temperature for 5-10 minutes, the suspension system was filtered, and the filter cake was rinsed with 5 L of ethanol; the filter cake was collected and dried in a forced air oven at 60°C overnight to obtain 1.27 kg of a white solid with a yield of 62.7%.

[0049] Implementation Case 3

[0050] At room temperature, 794 g Mg(OH)2 and 6.25 L purified water were added to a 30 L reactor, stirred and dispersed, and a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, and heat was significantly released. The temperature was controlled at 35-45°C. After the addition was complete, the mixture 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 added dropwise thereto, and a solid precipitated; after the addition was complete, the mixture was stirred at room temperature for 5-10 minutes, the suspension system was filtered, and the filter cake was rinsed with 5 L of isopropanol; the filter cake was collected and dried in a 60°C forced air oven overnight to obtain 1.24 kg of a white solid with a yield of 61.0%.

[0051] Implementation Case 4

[0052] At room temperature, 1.146 kg MgCO3 and 6.25 L purified water were added to a 30 L reactor, stirred and dispersed, and a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, and heat was significantly released. The temperature was controlled at 35-45°C. After the addition was complete, the mixture was stirred at room temperature for 1 hour; the reaction liquid was filtered, the filter cake was discarded, and the filtrate was set aside; 33.75 L of methanol was added to a 50 L reactor, and the filtrate from the previous step was added dropwise thereto, and solid precipitated; after the addition was complete, the mixture was stirred at room temperature for 5-10 minutes, the suspension system was filtered, and the filter cake was rinsed with 5 L of methanol; the filter cake was collected and dried in a 60°C forced air oven overnight to obtain 1.38 kg of white solid, with a yield of 68.1%.

[0053] Implementation Case 5

[0054] At room temperature, 1.146 kg MgCO3 and 6.25 L purified water were added to a 30 L reactor, stirred and dispersed, and a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, and heat was significantly released. The temperature was controlled at 35-45°C; after the addition was complete, the mixture 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 added dropwise thereto, and a solid precipitated; after the addition was complete, the mixture was stirred at room temperature for 5-10 minutes, the suspension system was filtered, and the filter cake was rinsed with 5 L ethanol; the filter cake was collected and dried in a 60°C forced air oven overnight to obtain 1.31 kg of a white solid with a yield of 64.5%.

[0055] Implementation Case 6

[0056] At room temperature, 1.146 kg MgCO3 and 6.25 L purified water were added to a 30 L reactor, stirred and dispersed, and a small amount of heat was released; 5.0 kg of glycerophosphate aqueous solution was added dropwise to the above suspension system, and heat was significantly released. The temperature was controlled at 35-45°C; after the addition was complete, the mixture was stirred at room temperature for 1 hour; 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 added dropwise thereto, and a solid precipitated; after the addition was complete, the mixture was stirred at room temperature for 5-10 minutes, the suspension system was filtered, and the filter cake was rinsed with 5 L of isopropanol; the filter cake was collected and dried in a 60°C forced air oven overnight to obtain 1.37 kg of a white solid with a yield of 67.4%.

[0057] The magnesium glycerophosphate prepared in the above embodiment was tested according to the standards and methods of the European Pharmacopoeia, with emphasis on solution clarity, loss on drying, and magnesium content. The test results are as follows:

[0058] Experimental Example 1: Solution Clarity Test

[0059] Instruments: Electronic analytical balance, volumetric flask. Reagents: Turbidity standard solution III.

[0060] Operation method: Weigh 2.5 g of the test sample and place it in a 50 ml volumetric flask. Dissolve it with CO2-free purified water and make up to volume. The test results are shown in Table 1.

[0061]

[0062] Experimental results show that the solution clarity of the amorphous magnesium glycerophosphate prepared in the present invention in water is qualified and meets the European Pharmacopoeia standards.

[0063] Experimental Example 2: Drying loss analysis method

[0064] Instruments and equipment: electronic analytical balance, electric blast drying oven.

[0065] Reagent: Phosphorus pentoxide.

[0066] Procedure: Take the test sample and mix it evenly (if it is large crystals, quickly crush it into small particles smaller than 2 mm). Take approximately 1g or the weight specified for each variety and place it in a flat weighing bottle dried to a constant weight under the same conditions as the test sample. Weigh it accurately and dry it at 150°C under normal pressure for 4 hours (add desiccant: phosphorus pentoxide). Calculate the loss on drying of the test sample based on the lost weight and the sample size. The test results are shown in Table 2.

[0067] Table 2 Drying loss test results

[0068]

[0069] 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.

[0070] Experimental Example 3: Magnesium content analysis method

[0071] Instruments and equipment: electronic analytical balance, conical flask, burette, water bath.

[0072] Reagents: pH 10 ammonium chloride buffer, Eriochrome Black T indicator, 0.1 M sodium EDTA titrant.

[0073] Operation method: Weigh 0.2 g of sample and dissolve it in 40 mL of water. Add it to a 500 mL conical flask, dilute it to 300 mL with water, add 10 mL of pH 10 ammonium chloride buffer (5.4 g of ammonium chloride, dissolve it in 20 mL of water, add 35 mL of ammonia water, and dilute it to 100 mL with water), add 50 mg of chrome black T indicator (1 g of chrome black T powder and 100 g of sodium chloride are mixed evenly), heat it to 40 degrees, and titrate it with 0.1 M sodium ethylenediaminetetraacetic acid solution at this temperature. The test results are shown in Table 3.

[0074] Table 3 Magnesium content test results

[0075]

[0076] Experimental results show that the magnesium content of the amorphous magnesium glycerophosphate prepared by the present invention is 11.0% to 12.5% ​​(calculated on a dry basis), which meets the standards of the European Pharmacopoeia.

[0077] 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 commonly 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 their meanings in the context of the prior art and, unless defined as such herein, will not be interpreted in an idealized or overly formal sense.

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 of 0 to 40 degrees, one diffraction peak in the range of 2θ of 0 to 10 degrees and one diffraction peak in the range of 2θ of 10 to 40 degrees, and the peak intensity in the range of 0 to 10 degrees is greater than the peak intensity in the range of 10 to 40 degrees.

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

3. The magnesium glycerophosphate amorphous material 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.

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

5. The method for preparing the amorphous magnesium glycerophosphate according to any one of claims 1 to 4, comprising the following steps: (1) adding glycerophosphate dropwise to a mixture of an inorganic base and water and stirring to react to prepare a suspension system; (2) filtering the suspension to obtain a filtrate; (3) dropping the filtrate into an alcohol solvent to precipitate a solid, which is then dried. The alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol.

6. The preparation method according to claim 5, wherein the inorganic base is selected from magnesium carbonate and magnesium hydroxide.

7. A pharmaceutical composition comprising the amorphous magnesium glycerophosphate according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

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