Purification method of methocarbamol

Abstract

The invention discloses a methocarbamol purification method which comprises the following steps: adding a methocarbamol crude product into an acidic system solution consisting of at least one solvent A selected from water, an alcohol solvent and an ester solvent and at least one solvent B selected from an acidic solvent, and uniformly mixing to obtain a mixed solution; and heating the mixed solution, stirring and dissolving, cooling, stirring and crystallizing, carrying out suction filtration, and drying to obtain purified methocarbamol. The method is used for solving the technical problem that a high-purity methocarbamol medicinal raw material meeting the medicinal standard cannot be obtained.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to a method for purifying methocarbamol. Background Art

[0002] Methocarbamol, chemically named (±)-3-[o-methoxyphenoxy]-1,2-propanediol-1-carbamate, has the following structural formula:

[0003] Methocarbamol is a central muscle relaxant developed by Roberts Murphey Company in the United States. It has a selective effect on the central nervous system, especially on neurons in the spinal cord. It inhibits the nerve synaptic reflex related to skeletal muscle spasm, has the effect of anti-strychnine and anti-convulsion caused by electrical stimulation, and has analgesic, pain-relieving and anti-inflammatory effects.

[0004] After being first launched in the United States in 1957, it has been produced and applied in many countries and regions on all continents of Europe, Asia and Africa, and has remained popular for more than seventy years. In the past two decades, many foreign scientists have carried out research on developing methocarbamol. On the basis of the research on the original products, we have conducted a comprehensive analysis of methocarbamol and found that the shortcoming of methocarbamol itself is that it is easily degraded into guaifenesin glycerol ether and methocarbamol carbamate isomer impurities in the preparation process, which affects the effectiveness and safety of the API prepared therefrom.

[0005] The preparation method of methocarbamol has been disclosed in the prior art, and methocarbamol is easily degraded during the preparation and purification processes, and the degradation products are guaifenesin glycerol ether and methocarbamol carbamate isomers, which brings high difficulty to the purification work of the final product. As shown in Table 2, according to the internal control standard of methocarbamol raw material in USP-NF2024, the content of guaifenesin glycerol ether shall not exceed 0.15%, and the content of methocarbamol carbamate isomer shall not exceed 0.05%. Therefore, it is still of great significance to find a new method for purifying methocarbamol.

[0006] Table 2 Quality Standard of Methocarbamol in USP-NF2024

[0007] Name Limit Guaifenesin ≤0.15％ Methocarbamol Carbamate Isomer ≤0.05％ Methocarbamol — Guaifenesin Cyclocarbonate ≤0.05％ Other Single Impurity ≤0.05％ Total Impurities ≤1.0％

[0008] Among them, the structural formulas of guaifenesin glycerol ether, guaiacylglycerol cyclic carbonate and methocarbamol carbamate isomer are as follows:

[0009] Summary of the Invention

[0010] The present invention provides a method for purifying methocarbamol, aiming to solve the technical problem that high-purity methocarbamol medicinal raw materials meeting the medicinal standards cannot be obtained currently.

[0011] In view of this, a method for purifying methocarbamol provided by the present invention includes the following steps:

[0012] S1: Add the crude methocarbamol to an acidic system solution composed of at least one A solvent selected from water, alcohol solvents, and ester solvents and at least one B solvent selected from acidic solvents, mix well to obtain a mixed solution;

[0013] S2: Heat up the mixed solution, stir to dissolve, then cool down, stir to crystallize, filter by suction, and dry to obtain purified methocarbamol.

[0014] Further, a method for purifying methocarbamol includes the following steps:

[0015] S1: Add the crude methocarbamol to an acidic system solution composed of at least one A solvent selected from water, alcohol solvents, and ester solvents and at least one B solvent selected from acidic solvents, mix well to obtain a mixed solution;

[0016] S2: Heat up the mixed solution, stir to dissolve, then cool down to below 15°C for low-temperature crystallization, stir to crystallize, filter by suction, and dry to obtain purified methocarbamol;

[0017] Wherein, the addition amount of water or alcohol solvent or ester solvent per 1 g of crude methocarbamol is 10 - 15 mL, the weight ratio of the crude methocarbamol to the acid component in the acidic solvent is 1:(0.05 - 0.1), and the dissolution temperature in step S2 is 30 - 80°C.

[0018] The crude methocarbamol in the present invention refers to the methocarbamol raw material whose purity does not meet the quality standard. For example, the purity of the crude methocarbamol is less than 96%, less than 94%, less than 93%, less than 90%, less than 85%, less than 80%. There is no specific limitation on the lower purity limit of the crude methocarbamol because the impurity removal effect of the method for purifying methocarbamol provided by the present invention is remarkable, and it can further purify both low-purity and high-purity crude methocarbamol.

[0019] There is no specific limitation on the charging sequence for the step of purifying the crude methocarbamol with the acidic system solution in the present invention, that is, dissolving the crude methocarbamol in the A solvent and / or the B solvent is included within the scope of the present invention.

[0020] Optionally, the alcohol solvent in step S1 is any one of methanol, ethanol, and isopropanol, and the ester solvent is ethyl acetate.

[0021] Optionally, the acidic solvent described in step S1 is any one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, and acetic acid.

[0022] Optionally, the content of related substances or impurities in the purified methocarbamol is determined by HPLC detection.

[0023] Optionally, the method for detecting the content of related substances or impurities in the purified methocarbamol by HPLC includes the following steps:

[0024] Use a chromatographic column packed with octadecylsilyl-bonded silica gel for gradient elution;

[0025] Preparation of blank solution: Use an aqueous solution of potassium dihydrogen phosphate - methanol as the blank solution;

[0026] Preparation of system suitability solution: Take the test sample, place it in a volumetric flask, dissolve it with the blank solution, add sodium hydroxide solution, let it stand, then add hydrochloric acid solution to neutralize, and dilute to the mark with the blank solution, shake well to obtain the system suitability solution;

[0027] Preparation of test sample solution: Take this product, place it in a volumetric flask, dilute to the mark with the blank solution, shake well to obtain the test sample solution;

[0028] Control solution: Take the test sample solution, place it in a volumetric flask, dilute to the mark with the blank solution, shake well, then take this solution, place it in a volumetric flask, dilute to the mark with the blank solution, shake well to obtain the control solution;

[0029] Determination method: Measure the blank solution and the system suitability solution, inject them into the high-performance liquid chromatograph respectively, record the chromatogram, and the resolution between the methocarbamol carbamate isomer peak and the methocarbamol peak in the system suitability solution chromatogram should be not less than 1.5; then measure the test sample solution and the control solution, inject them into the high-performance liquid chromatograph respectively, and record the chromatogram;

[0030] Calculation: Calculate the content of related substances or impurities in the purified methocarbamol according to the chromatogram.

[0031] Furthermore, the method for detecting the content of related substances or impurities in the purified methocarbamol by HPLC includes the following steps:

[0032] Use a chromatographic column packed with octadecylsilyl-bonded silica gel (Megassil XB-L C18 column, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency), for gradient elution;

[0033] Preparation of blank solution: Use an aqueous solution of potassium dihydrogen phosphate at 6.8 g / L (adjust the pH value to 4.5 with phosphoric acid) - methanol (the volume ratio of the two is 70:30) as the blank solution;

[0034] Preparation of system suitability solution: Take 20 mg of the test substance, place it in a 10 mL volumetric flask, dissolve it with 2 mL of blank solution, add 1 mL of 0.2 mol / L sodium hydroxide solution, let it stand for 3 min, then add 1 mL of 0.2 mol / L hydrochloric acid solution for neutralization, and dilute to the mark with blank solution, shake well to obtain the system suitability solution;

[0035] Preparation of test solution: Take 20 mg of this product, place it in a 10 mL volumetric flask, dilute to the mark with blank solution, shake well to obtain the test solution;

[0036] Control solution: Take 1 mL of the test solution, place it in a 100 mL volumetric flask, dilute to the mark with blank solution, shake well, then take 1 mL of this solution, place it in a 10 mL volumetric flask, dilute to the mark with blank solution, shake well to obtain the control solution;

[0037] Assay method: Measure the blank solution and the system suitability solution, inject them into the high performance liquid chromatograph respectively, record the chromatogram. The resolution between the carbamate isomer peak of methocarbamol and the methocarbamol peak in the chromatogram of the system suitability solution should be not less than 1.5; then measure 20 μL of the test solution and the control solution respectively, inject them into the high performance liquid chromatograph, record the chromatogram;

[0038] Calculation: Calculate the content of related substances or impurities in the purified methocarbamol according to the chromatogram.

[0039] Optionally, the mobile phase gradient elution program is shown in Table 1:

[0040] Time / min Mobile Phase A % Mobile Phase B % 0 73 27 25 73 27 55 30 70 65 30 70 65.1 73 27 80 73 27

[0041] Optionally, in the liquid chromatography detection, mobile phase A is an aqueous solution of potassium dihydrogen phosphate, and mobile phase B is methanol - acetonitrile.

[0042] Furthermore, in the liquid chromatography detection, mobile phase A is an aqueous solution of potassium dihydrogen phosphate, and mobile phase B is methanol - acetonitrile;

[0043] Among them, the concentration of the aqueous solution of potassium dihydrogen phosphate is 6.8 g / L, and the pH value is adjusted to 4.5 with phosphoric acid. The volume ratio of methanol to acetonitrile is 90:10.

[0044] Optionally, in the liquid chromatography detection, the detection wavelength is 274 nm, the flow rate is 0.8 mL per minute, the column temperature is 25 °C, and the injection volume is 20 μL.

[0045] Optionally, the calculation formula is as follows:

[0046]

[0047] Total impurities % = Known impurities % + Total other impurities %

[0048] In the formula:

[0049] f is the correction factor of the known impurity;

[0050] A known impurity is the peak area of each known impurity in the test solution;

[0051] A other single impurity is the peak area of the largest single impurity other than the known impurities in the test solution;

[0052] A reference is the peak area of the main peak in the reference solution;

[0053] A sum of other impurities is the total peak area of all impurities other than the known impurities in the test solution.

[0054] Note: For known impurities whose correction factors are not specified in the standard, the correction factor is calculated as 1.0.

[0055] In addition, the standard stipulates that in the chromatogram of the test solution, the peak of the blank solvent is ignored. If there are impurity peaks, the peak areas of methocarbamol carbamate isomers (chromatographic peaks with the same retention time as the methocarbamol carbamate isomer peak in the chromatogram of the system suitability solution) and guaifenesin cyclic carbonate (relative retention time is about 1.15) shall not be greater than 0.5 times (0.05%) of the peak area of the main peak in the reference solution; the peak areas of guaifenesin (relative retention time is about 0.8, correction factor 0.8) after correction shall not be greater than 1.5 times (0.15%) of the peak area of the main peak in the reference solution; the peak areas of other single impurities shall not be greater than 0.5 times (0.05%) of the peak area of the main peak in the reference solution, and the total impurities shall not exceed 0.5%. Chromatographic peaks in the test solution that are less than 0.05 times (0.005%) of the peak area of the main peak in the reference solution are ignored.

[0056] The synthetic route used in the present invention is as follows:

[0057]

[0058] As can be seen from the above technical solutions, the embodiments of the present invention have the following advantages:

[0059] 1. Through the purification method provided by the present invention, the purity of methocarbamol can be significantly improved, and pure methocarbamol meeting the standards can be obtained. Through the purification method provided by the present invention, it has good scavenging ability for guaifenesin and methocarbamol carbamate isomers in methocarbamol, can significantly improve the purity of methocarbamol, and obtain pure methocarbamol meeting the USP-NF2024 standard. It shows that the present invention has significant superiority compared with the existing processes.

[0060] 2. The method for purifying methocarbamol of the present invention is simple, the preparation conditions are mild, the ability to remove impurities is strong, the solvents used are environmentally friendly and have extremely low toxicity, making it suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] The present invention will be further described in detail below in conjunction with the drawings and specific embodiments.

[0062] Figure 1 HPLC chromatogram of the crude methocarbamol (CP-1) used in the present invention.

[0063] Figure 2 HPLC chromatogram of the crude methocarbamol (CP-2) used in the present invention.

[0064] Figure 3 HPLC chromatogram of methocarbamol (SS-1) in Example 1.

[0065] Figure 4 HPLC chromatogram of methocarbamol (SS-2) in Example 1.

[0066] Figure 5 HPLC chromatogram of methocarbamol (SS-3) in Example 2.

[0067] Figure 6 HPLC chromatogram of methocarbamol (SS-4) in Example 2.

[0068] Figure 7 HPLC chromatogram of methocarbamol (SS-5) in Example 3.

[0069] Figure 8 HPLC chromatogram of methocarbamol (SS-6) in Example 3.

[0070] Figure 9 HPLC chromatogram of methocarbamol (SS-7) in Example 4.

[0071] Figure 10 HPLC chromatogram of methocarbamol (SS-8) in Example 4.

[0072] Figure 11 HPLC chromatogram of methocarbamol (DZ-1) in Comparative Example 1.

[0073] Figure 12 HPLC chromatogram of methocarbamol (DZ-2) in Comparative Example 1.

[0074] Figure 13 HPLC chromatogram of methocarbamol (DZ-3) in Comparative Example 2.

[0075] Figure 14It is the HPLC chromatogram of methocarbamol (DZ-4) for Comparative Example 2. Detailed implementation mode

[0076] In order to enable those skilled in the art to better understand the solution of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention. Unless otherwise specifically stated, all kinds of raw materials, reagents, instruments and equipment used in the present invention can be obtained through the market or can be prepared by existing methods.

[0077] Two batches of crude methocarbamol, with numbers and purities as shown in Table 3, and the peak tables are shown in Tables 4 and 5 respectively.

[0078] Table 3 Quality of crude methocarbamol

[0079] Batch Number of Crude Methocarbamol CP-1 CP-2 Guaifenesin (%) 1.659 0.355 Guaifenesin Cyclocarbonate (%) 0.361 0.040 Methocarbamol Carbamate Isomer (%) 0.768 0.220 Other Single Impurity (%) 0.022 0.028 Total Impurities (%) 2.844 0.665

[0080] Note: The data of guaifenesin in the table have been multiplied by the correction factor.

[0081] Table 4 Peak table of CP-1

[0082] Peak Number Retention Time Area Height Area % Height % 1 14.666 1950 92 0.007 0.012 2 15.646 594904 20377 2.074 2.655 3 17.588 220304 6589 0.768 0.859 4 19.939 27746299 736979 96.741 96.039 5 22.865 103438 2853 0.361 0.372 6 25.226 6223 141 0.022 0.018 7 46.352 6423 278 0.022 0.036 8 54.449 1550 70 0.005 0.009 Total 28681090 767379 100.000 100.000

[0083] Table 5 Peak table of CP-2

[0084]

[0085]

[0086] Embodiment

[0087] Embodiment 1

[0088] Take 10 g of CP-1 and CP-2 respectively, and perform parallel operations in two batches in the following manner, denoted as SS-1 and SS-2. Add 150 ml of purified water to a 250 ml three-necked flask, add 0.50 g of concentrated sulfuric acid, stir, add the crude methocarbamol, heat to 65 °C and stir to dissolve, cool to 5 °C and stir to crystallize, filter by suction, and dry to obtain a white solid, that is, purified methocarbamol. The specific yield and purity are shown in Table 6, the peak table of SS-1 is shown in Table 7, and the peak table of SS-2 is shown in Table 8.

[0089] Table 6 Quality of methocarbamol in Embodiment 1

[0090] Batch Number of Crude Methocarbamol SS-1 SS-2 Input Quantity of Crude Methocarbamol (g) 10 10 Methocarbamol (g) 8.81 8.94 Yield (%) 88.1 89.4 Guaifenesin (%) 0.037 0.012 Guaifenesin Cyclocarbonate (%) Not Detected Not Detected Methocarbamol Carbamate Isomer (%) 0.042 0.006 Other Single Impurity (%) Not Detected 0.004 Total Impurities (%) 0.079 0.022

[0091] Table 7 Peak table of SS-1

[0092] Peak Number Retention Time Area Height Area % Height % 1 15.653 12259 466 0.046 0.060 2 17.596 11205 368 0.042 0.047 3 19.928 26630830 775834 99.912 99.893 Total 26654295 776668 100.000 100.000

[0093] Table 8 SS-2 Peak Table

[0094] Peak Number Retention Time Area Height Area % Height % 1 15.694 4092 152 0.015 0.019 2 17.648 1727 58 0.006 0.007 3 19.967 27558229 797666 99.975 99.969 4 50.765 1111 39 0.004 0.005 Total 27565159 797915 100.000 100.000

[0095] Example 2

[0096] Take 10 g each of CP-1 and CP-2, and perform two batches in parallel in the following manner, denoted as SS-3 and SS-4. Add 150 ml of purified water to a 250 ml three-necked flask, add 1.0 g of acetic acid, stir, add the crude methocarbamol, heat to 65 °C and stir until dissolved, cool to 5 °C and stir for crystallization, filter by suction, and dry to obtain a white solid, which is the purified methocarbamol. The specific yield and purity are shown in Table 9, the SS-3 peak table is shown in Table 10, and the SS-4 peak table is shown in Table 11.

[0097] Table 9 Methocarbamol Quality in Example 2

[0098] Batch Number of Crude Methocarbamol SS-3 SS-4 Input Quantity of Crude Methocarbamol (g) 10 10 Methocarbamol (g) 8.52 8.47 Yield (%) 85.2 84.7 Guaifenesin (%) 0.069 0.057 Guaifenesin Cyclocarbonate (%) Not Detected Not Detected Methocarbamol Carbamate Isomer (%) 0.026 Not Detected Other Single Impurity (%) 0.004 0.005 Total Impurities (%) 0.099 0.061

[0099] Table 10 SS-3 Peak Table

[0100] Peak Number Retention Time Area Height Area % Height % 1 16.331 24551 912 0.086 0.114 2 18.367 7281 243 0.026 0.030 3 20.835 28452763 801118 99.884 99.845 4 42.272 1225 86 0.004 0.011 Total 28485820 802359 100.000 100.000

[0101] Table 11 SS-4 Peak Table

[0102] Peak Number Retention Time Area Height Area % Height % 1 16.322 19893 732 0.071 0.093 2 20.818 28085820 789992 99.925 99.896 3 42.248 1276 90 0.005 0.011 Total 28106989 790814 100.000 100.000

[0103] Example 3

[0104] Take 10 g each of CP-1 and CP-2, and perform two batches in parallel in the following manner, denoted as SS-5 and SS-6. Add 150 ml of purified water to a 250 ml three-necked flask, add 1.0 g of phosphoric acid, stir, add the crude methocarbamol, heat to 65 °C and stir until dissolved, cool to 5 °C and stir for crystallization, filter by suction, and dry to obtain a white solid, which is the purified methocarbamol. The specific yield and purity are shown in Table 12, the SS-5 peak table is shown in Table 13, and the SS-6 peak table is shown in Table 14.

[0105] Table 12 Methocarbamol Quality in Example 3

[0106]

[0107]

[0108] Table 13 SS-5 Peak Table

[0109] Peak Number Retention Time Area Height Area % Height % 1 16.316 26085 890 0.093 0.121 2 18.380 2854 88 0.010 0.012 3 20.827 28023653 733878 99.892 99.857 4 44.311 1459 75 0.005 0.010 Total 28054050 734931 100.000 100.000

[0110] Table 14 SS-6 Peak Table

[0111] Peak Number Retention Time Area Height Area % Height % 1 16.331 21227 767 0.075 0.097 2 18.377 2132 78 0.008 0.010 3 20.839 28145910 787430 99.902 99.868 4 23.882 1637 51 0.006 0.006 5 42.220 1045 65 0.004 0.008 6 44.329 1553 84 0.006 0.011 Total 28173504 788474 100.000 100.000

[0112] Example 4

[0113] Take 10 g each of CP-1 and CP-2, and perform two batches in parallel in the following manner, denoted as SS-5 and SS-6. Add 100 ml of ethanol to a 250 ml three-necked flask, add 1.0 g of acetic acid, stir, add the crude methocarbamol, heat to 65 °C and stir until dissolved, cool to 5 °C and stir for crystallization, filter by suction, and dry to obtain a white solid, which is the purified methocarbamol. The specific yields and purities are shown in Table 15, the peak table of SS-7 is shown in Table 16, and the peak table of SS-8 is shown in Table 17.

[0114] Table 15 Quality of Methocarbamol in Example 4

[0115] Batch Number of Crude Methocarbamol SS-7 SS-8 Input Quantity of Crude Methocarbamol (g) 10 10 Methocarbamol (g) 7.95 8.11 Yield (%) 79.5 81.1 Guaifenesin (%) 0.106 0.072 Guaifenesin Cyclocarbonate (%) 0.022 0.006 Methocarbamol Carbamate Isomer (%) 0.033 0.006 Other Single Impurity (%) N / A N / A Total Impurities (%) 0.159 0.084

[0116] Table 16 Peak Table of SS-7

[0117]

[0118]

[0119] Table 17 Peak Table of SS-8

[0120] Peak Number Retention Time Area Height Area % Height % 1 16.328 24992 914 0.090 0.117 2 18.354 1613 63 0.006 0.008 3 20.843 27790558 777628 99.898 99.867 4 23.930 1720 56 0.006 0.007 Total 27818882 778661 100.000 100.000

[0121] Comparative Example

[0122] Comparative Example 1

[0123] Take 10 g each of CP-1 and CP-2, and perform two batches in parallel in the following manner, denoted as DZ-1 and DZ-2. Add 150 ml of purified water to a 250 ml three-necked flask, stir, add the crude methocarbamol, heat to 65 °C and stir until dissolved, cool to 5 °C and stir for crystallization, filter by suction, and dry to obtain a white solid, which is the purified methocarbamol. The specific yields and purities are shown in Table 18, the peak table of DZ-1 is shown in Table 19, and the peak table of DZ-2 is shown in Table 20.

[0124] Table 18 Quality of Methocarbamol in Comparative Example 1

[0125] Batch Number of Crude Methocarbamol DZ-1 DZ-2 Input Quantity of Crude Methocarbamol (g) 10 10 Methocarbamol (g) 8.81 8.94 Yield (%) 88.1 89.4 Guaifenesin (%) 0.460 0.374 Guaifenesin Cyclocarbonate (%) 0.048 0.023 Methocarbamol Carbamate Isomer (%) 0.785 0.437 Other Single Impurity (%) 0.005 0.016 Total Impurities (%) 1.316 0.838

[0126] Table 19 Peak Table of DZ-1

[0127] Peak Number Retention Time Area Height Area % Height % 1 15.701 159943 5872 0.575 0.742 2 17.659 218611 7079 0.785 0.894 3 20.019 27439848 778053 98.569 98.278 4 22.918 13260 392 0.048 0.050 5 46.358 4414 202 0.016 0.026 6 54.392 2143 88 0.008 0.011 Total 27838219 791688 100.000 100.000

[0128] Table 20 Peak Table of DZ-2

[0129]

[0130]

[0131] Comparative Example 2

[0132] Take 10 g each of CP-1 and CP-2, and perform two batches of parallel operations in the following manner, denoted as DZ-3 and DZ-4. Add 100 ml of ethanol to a 250 ml three-necked flask, stir, add the crude methocarbamol, heat to 65 °C and stir until dissolved, cool to 5 °C and stir for crystallization, filter by suction, and dry to obtain a white solid, namely purified methocarbamol. The specific yield and purity are shown in Table 21, the peak table of DZ-3 is shown in Table 22, and the peak table of DZ-4 is shown in Table 23.

[0133] Table 21 Quality of Methocarbamol in Comparative Example 2

[0134] Batch Number of Crude Methocarbamol DZ-3 DZ-4 Input Quantity of Crude Methocarbamol (g) 10 10 Methocarbamol (g) 7.81 8.02 Yield (%) 78.1 80.2 Guaifenesin (%) 0.349 0.227 Guaifenesin Cyclocarbonate (%) 0.138 0.068 Methocarbamol Carbamate Isomer (%) 0.454 0.296 Other Single Impurity (%) 0.161 0.090 Total Impurities (%) 1.341 0.824

[0135] Table 22 Peak Table of DZ-3

[0136] Peak Number Retention Time Area Height Area % Height % 1 16.264 120439 4426 0.436 0.569 2 18.298 125418 4065 0.454 0.522 3 20.734 27203997 766042 98.572 98.423 4 23.854 38211 1073 0.138 0.138 5 55.276 3061 127 0.011 0.016 6 58.662 2277 93 0.008 0.012 7 64.292 3905 115 0.014 0.015 8 66.782 44468 1066 0.161 0.137 9 67.800 3696 142 0.013 0.018 10 68.724 52555 1169 0.190 0.150 Total 27598026 778319 100.000 100.000

[0137] Table 23 Peak Table of DZ-4

[0138]

[0139]

[0140] Through the purification method provided by the present invention, it has a good scavenging ability for guaifenesin glycerol ether and methocarbamol carbamate isomers in methocarbamol, can significantly improve the purity of methocarbamol, and obtain a pure product of methocarbamol that meets the USP-NF2024 standard. It shows that the present invention has significant superiority compared with the existing process.

[0141] As mentioned above, the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for purifying methocarbamol, characterized in that: The steps include: S1: adding the crude methocarbamol to an acidic system solution consisting of at least one solvent A selected from water, alcohol solvents, and ester solvents and at least one solvent B selected from acidic solvents, and mixing to obtain a mixed solution; S2: heating the mixed solution to raise its temperature, stirring to dissolve, cooling it, stirring to crystallize, filtering with suction, and drying to obtain purified methocarbamol.

2. The method for purifying methocarbamol according to claim 1, wherein: In step S1, the alcohol solvent is any one of methanol, ethanol and isopropanol, and the ester solvent is ethyl acetate.

3. The method for purifying methocarbamol according to claim 1, wherein: The acidic solvent in step S1 is any one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid and acetic acid.

4. The method for purifying methocarbamol according to claim 1, wherein: The content of related substances or impurities in the purified methocarbamol is determined by HPLC detection.

5. The method for purifying methocarbamol according to claim 4, characterized in that: The method for detecting the content of related substances or impurities in purified methocarbamol by HPLC comprises the following steps: A chromatographic column with octadecylsilane bonded silica filler was used for gradient elution; Preparation of blank solution: Use potassium dihydrogen phosphate aqueous solution-methanol as blank solution; Preparation of system suitability solution: Take the test sample, place it in a volumetric flask, add blank solution to dissolve, add sodium hydroxide solution, let it stand, then add hydrochloric acid solution to neutralize, dilute to the scale with blank solution, shake well, and obtain system suitability solution; Preparation of test solution: Take the product, place it in a volumetric bottle, dilute it to the mark with blank solution, shake well, and obtain the test solution; Control solution: Take the test solution, put it in a volumetric bottle, dilute it to the mark with the blank solution, shake well, then take the solution, put it in a volumetric bottle, dilute it to the mark with the blank solution, shake well to obtain the control solution; Determination method: Measure the blank solution and system suitability solution, inject them into the HPLC, record the chromatogram, the separation degree between the methocarbamol carbamate isomer peak and the methocarbamol peak in the chromatogram of the system suitability solution should be no less than 1.5; then measure the test solution and the control solution, inject them into the HPLC, record the chromatogram; Calculation: Calculate the content of related substances or impurities in the purified methocarbamol based on the chromatogram.

6. The method for purifying methocarbamol according to claim 5, characterized in that: The mobile phase gradient elution program is shown in Table 1:

7. The method for purifying methocarbamol according to claim 5, characterized in that: In the liquid chromatography detection, mobile phase A is potassium dihydrogen phosphate aqueous solution, and mobile phase B is methanol-acetonitrile.

8. The method for purifying methocarbamol according to claim 5, wherein: In the liquid chromatography detection, the detection wavelength is 274 nm, the flow rate is 0.8 mL per minute, the column temperature is 25° C., and the injection volume is 20 μL.

9. The method for purifying methocarbamol according to claim 5, characterized in that: The calculation formula is as follows: Total impurities % = each known impurity % + total other impurities % Where: f - correction factor for known impurities; A Known impurities - the peak area of ​​each known impurity in the test solution; A Other single impurities - the peak area of ​​the largest single impurity in the test solution other than the known impurities; A: main peak area of ​​control solution; A Total of other impurities - the sum of the peak areas of all impurities in the test solution except the known impurities. Note: For known impurities whose correction factors are not specified in the standard, the correction factor is calculated as 1.0.

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