阅读说明：本技术 一种左磷右胺盐中二醇物的测定分析方法 (Method for determining and analyzing glycols in levophosphorus dextroamine salt ) 是由 祝宏 方世通 李雪 曾祥聪 陈家宝 于 2019-10-18 设计创作，主要内容包括：本发明属于化学分析检测技术领域,更具体的说是涉及一种左磷右胺盐中二醇物的测定分析方法。本发明所提供的左磷右胺盐中二醇物的测定分析方法可以准备、方便的测定左磷右胺盐中二醇物的含量。其所基于的碘量法简单、可靠,从而确保该测定分析方法简单、可靠、易于实现。(The invention belongs to the technical field of chemical analysis and detection, and particularly relates to a method for determining and analyzing a diol in levophosphorus dextroamine salt. The method for determining and analyzing the diol in the levophosphorus dextroamine salt can prepare and conveniently determine the content of the diol in the levophosphorus dextroamine salt. The iodometry method based on the method is simple and reliable, so that the method for determining and analyzing the iodometry is simple, reliable and easy to implement.)

1. A method for measuring and analyzing a diol in levofosfomycin dextroamine salt is characterized by comprising the following steps:

1) taking a standard sample of the levo-phosphorus dextro-amine salt, dissolving the standard sample of the levo-phosphorus dextro-amine salt in an acidic buffer solution, and adding an excessive potassium periodate solution for reaction;

2) adding excessive potassium iodide solution for reaction when the reaction in the step 1) is complete and the color is not changed any more;

3) after the reaction in the step 2) is complete and the color is not changed any more, titrating the generated iodine with sodium thiosulfate, and recording the using amount of the sodium thiosulfate;

4) performing blank control, taking the same amount of the acidic buffer solution in the step 1), and adding the same amount of the potassium periodate solution in the step 1);

5) adding the potassium iodide solution with the same amount as that in the step 2) for reaction;

6) after the reaction in the step 5) is complete and the color is not changed any more, titrating the generated iodine with the sodium thiosulfate, and recording the using amount of the sodium thiosulfate;

7) the weight percentage of the glycols in the levophosphorus dextroamine salt was calculated according to the following formula:

wherein C is the concentration of the sodium thiosulfate titration solution, and the unit is mol/L;

V₀the thiosulfuric acid consumed for step 6) of the blankThe volume of the sodium titration solution is mL;

V₁the volume of the sodium thiosulfate titration solution consumed in the step 3) is mL;

m is the molar mass of the levo-phosphamide salt, 176.12 g/mol;

w is the mass of the standard sample of the levo-phosphorus dextro-amine salt, and the unit is g;

z is the number of moles of periodic acid required to be consumed for one mole of sample and has a value of 1.

2. The method for assaying glycols in levofosfomycin dextroamine salt according to claim 1, characterized in that:

in the step 3), the judgment mode of the reaction end point is as follows: titrating the solution with the sodium thiosulfate until the solution is light yellow, adding 1-2 ml of starch indicator, shaking up, and continuously dropwise adding the sodium thiosulfate until the solution is colorless, thus obtaining a reaction end point;

in the step 6), the judgment mode of the reaction end point is as follows: and titrating with the sodium thiosulfate until the solution is light yellow, adding 1-2 ml of starch indicator, shaking up, and continuously dropwise adding the sodium thiosulfate until the solution is colorless, thus obtaining the reaction end point.

3. The method for assaying glycols in levofosfomycin dextroamine salt according to claim 1, characterized in that:

in the step 1), adding excessive potassium periodate solution, shaking and uniformly mixing, standing in a dark place for 1-2 hours, and waiting for complete reaction;

and 4) adding a corresponding amount of potassium periodate solution in the step 4), shaking and uniformly mixing, standing in a dark place for 1-2 hours, and waiting for complete reaction.

4. The method for assaying glycols in levophosphorus dextroamine salt according to any one of claims 1 to 3, characterized in that: the acidic buffer solution is a potassium hydrogen phthalate buffer solution, and the pH value of the acidic buffer solution is 6.3-6.5.

5. The method for assaying diol compounds in levofosetyl amine salt according to claim 4, wherein the potassium hydrogen phthalate buffer is prepared by: dissolving every 100g of potassium hydrogen phthalate in 600ml of water, heating to 75 ℃, cooling after the potassium hydrogen phthalate is dissolved, and adjusting the pH value to 6.3-6.5 by using a saturated sodium hydroxide solution to obtain the potassium hydrogen phthalate.

Technical Field

The invention belongs to the technical field of chemical analysis and detection, and particularly relates to a method for determining and analyzing a diol in levophosphorus dextroamine salt.

Background

Fosfomycin sodium is a novel broad-spectrum antibiotic, the sterilization mechanism of the fosfomycin sodium is to inhibit the early synthesis of bacterial cell walls, the probability of anaphylactic shock is very small, the fosfomycin sodium is mainly used for treating the infection of urinary tract, skin, soft tissue, intestinal tract and the like, the fosfomycin sodium has strong sterilization effect on most gram-positive bacteria and gram-negative bacteria, the clinical application is wide, and the market demand is large. Wherein, (1R,2S) - (-) -cis-1, 2-epoxypropylphosphonic acid (R) - (+) -alpha-phenylethylamine salt, called levofosfomycin dextroamine salt for short, is an important intermediate for synthesizing fosfomycin, and is usually prepared by an epoxidation process. The impurity content of the product directly influences the quality of downstream products. In order to ensure the quality and safety of the medicine, a detection method needs to be established to control and monitor the content of the diol in the intermediate. The fosfomycin sodium diol is an epoxy bond ring-opening product of fosfomycin sodium, is a main impurity of fosfomycin sodium for injection, and is controlled by Chinese pharmacopoeia, European pharmacopoeia and British pharmacopoeia. However, the prior art discloses few methods for measuring and analyzing the glycols in levofosfomycin dextroamine salt, and the methods are used as references.

Disclosure of Invention

In order to solve the defects of the prior art, the invention provides a method for determining and analyzing the diol in the levophosphorus dextroamine salt.

The technical scheme provided by the invention is as follows:

a method for determining and analyzing a diol in levofosfomycin dextroamine salt comprises the following steps:

1) taking a standard sample of the levo-phosphorus dextro-amine salt, dissolving the standard sample of the levo-phosphorus dextro-amine salt in an acidic buffer solution, and adding an excessive potassium periodate solution for reaction;

2) adding excessive potassium iodide solution for reaction when the reaction in the step 1) is complete and the yellow color is not changed any more;

3) after the reaction in the step 2) is complete and the yellow color is not changed any more, titrating the generated iodine with sodium thiosulfate, and recording the using amount of the sodium thiosulfate;

4) performing blank control, taking the same amount of the acidic buffer solution in the step 1), and adding the same amount of the potassium periodate solution in the step 1);

5) adding the potassium iodide solution with the same amount as that in the step 2) for reaction;

6) after the reaction in the step 5) is complete and the yellow color is not changed any more, titrating the generated iodine with the sodium thiosulfate, and recording the using amount of the sodium thiosulfate;

7) the weight percentage of the glycols in the levophosphorus dextroamine salt was calculated according to the following formula:

wherein C is the concentration of the sodium thiosulfate titration solution, and the unit is mol/L;

V₀the volume of the sodium thiosulfate titration solution consumed in step 6) in the blank control is mL;

V₁the volume of the sodium thiosulfate titration solution consumed in the step 3) is mL;

m is the molar mass of the levo-phosphamide salt, 176.12 g/mol;

w is the mass of the standard sample of the levo-phosphorus dextro-amine salt, and the unit is g;

z is the number of moles of periodic acid required to be consumed for one mole of sample and has a value of 1.

In the above technical scheme:

potassium periodate can oxidize compounds with 2 or more adjacent alcoholic hydroxyl groups, but is unreactive with compounds with a single alcoholic hydroxyl group or compounds with nonadjacent alcoholic hydroxyl groups. The reaction formula of the o-alcoholic hydroxyl compound oxidized by periodate can be represented as follows:

the commonly used measurement method is iodometry. From the above results, it can be seen that each molecule of periodate reacts to produce a molecule of iodic acid, both of which are capable of oxidizing potassium iodide in an acidic medium, but the amount of iodine evolved by the reaction is different:

2HIO₄+14KI+14H⁺＝14K⁺+8H₂O+8I₂

2HIO₃+10KI+10H⁺＝10K⁺+6H₂O+6I₂

one molecule of periodic acid is consumed and one molecule of iodic acid is produced per molecule of ortho-dihydroxy compound oxidized, while one molecule of iodine is produced. The following relationship can be derived:

1 molecule of o-dihydroxy compound ═ 1 molecule of HIO₄1-molecule less produced I₂

The difference between the blank titration and the sample titration performed in parallel can be used to calculate the amount of ortho-dihydroxy contained in the sample.

The technical scheme is based on an iodometry method, is simple and reliable, and is easier to realize than the method for directly measuring the generated carbonyl compound or iodate under the condition of excess periodate.

Specifically, in the step 3), the judgment mode of the reaction end point is as follows: and titrating with the sodium thiosulfate until the solution is light yellow, adding 1-2 ml of starch indicator, shaking up, and continuously dropwise adding the sodium thiosulfate until the solution is colorless, thus obtaining the reaction end point.

Based on the technical scheme, the reaction endpoint can be accurately judged.

Specifically, in step 6), the reaction end point is determined by the following method: and titrating with the sodium thiosulfate until the solution is light yellow, adding 1-2 ml of starch indicator, shaking up, and continuously dropwise adding the sodium thiosulfate until the solution is colorless, thus obtaining the reaction end point.

Based on the technical scheme, the reaction endpoint can be accurately judged.

Specifically, in the step 1), after adding excessive potassium periodate solution, shaking and uniformly mixing, standing in a dark place for 1-2 hours, and waiting for complete reaction.

Based on the technical scheme, the complete reaction can be ensured.

Specifically, in the step 4), after the potassium periodate solution is added, the mixture is shaken and uniformly mixed, and is placed in a dark place for standing for 1-2 hours until the reaction is complete.

Based on the technical scheme, the complete reaction can be ensured.

Specifically, the acidic buffer solution is a potassium hydrogen phthalate buffer solution, and the pH value of the acidic buffer solution is 6.3-6.5.

Based on the technical scheme, the reaction of oxidizing the o-alcoholic hydroxyl compound by periodate can be completely carried out.

Specifically, the preparation method of the potassium hydrogen phthalate buffer solution comprises the following steps: dissolving every 100g of potassium hydrogen phthalate in 600ml of water, heating to 75 ℃, cooling after the potassium hydrogen phthalate is dissolved, and adjusting the pH value to 6.3-6.5 by using a saturated sodium hydroxide solution to obtain the potassium hydrogen phthalate.

Based on the technical scheme, the potassium hydrogen phthalate buffer solution can be conveniently and conveniently prepared.

In general, the method for determining and analyzing the diol in the levophosphorus dextroamine salt provided by the invention can prepare and conveniently determine the content of the diol in the levophosphorus dextroamine salt. The iodometry method based on the method is simple and reliable, so that the method for determining and analyzing the iodometry is simple, reliable and easy to implement.

Detailed Description

The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.