Preparation method of pharmaceutical-grade sodium calcium edetate

Abstract

The invention belongs to the technical field of preparation of organic compounds, and relates to a preparation method of pharmaceutical-grade sodium calcium edetate, which abandons the use of common calcium chloride, calcium oxide or calcium hydroxide as a main raw material, and uses self-synthesized calcium carbonate with high purity and extremely low content of harmful impurity metal arsenic as a raw material. Therefore, chloride ions brought in by the raw materials of calcium chloride, calcium oxide or calcium hydroxide in the process of producing sodium calcium edetate through reaction and sulfides brought in by the raw materials are avoided.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound preparation, in particular to a method for preparing pharmaceutical-grade calcium sodium edetate. Background Art

[0002] Medical grade calcium sodium edetate is a pharmaceutical antidote. This substance is used as a heavy metal complex detoxifier and is clinically used for the treatment of poisoning by lead, heavy metals and fission products of radioactive elements. Calcium sodium edetate can combine with a variety of metals to form a stable and soluble complex, which is excreted in the urine. Therefore, it is used for some metal poisoning, especially for inorganic lead poisoning (but ineffective for tetraethyl lead poisoning). It has a detoxifying effect on cobalt, copper, chromium, cadmium, manganese and radioactive elements (such as radium, uranium, thorium, etc.), but is ineffective for strontium. This product has a weak complexing force with mercury and is rarely used for the detoxification of mercury poisoning. The daily allowable intake is 2.5mg / kg. It is mainly used to treat lead poisoning, and can also treat cadmium, manganese, chromium, nickel, cobalt and copper poisoning, as well as for diagnostic lead movement tests.

[0003] In summary, medical grade calcium sodium edetate is a compound with broad application prospects. It has strong complexation with heavy metal ions in the blood and is a widely used heavy metal detoxifier. It has important application value in drug formulation, occupational disease prevention and treatment, and lead diagnosis. With the continuous development of the chemical field, researchers' in-depth research on this compound and the prospect of its application will further promote the application of this compound in various fields. Summary of the invention

[0004] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for preparing pharmaceutical grade calcium sodium edetate, which has simple steps and effectively improves production efficiency.

[0005] The present invention solves the technical problem by adopting the following technical solutions:

[0006] A method for preparing pharmaceutical grade calcium sodium edetate comprises the following steps:

[0007] S1. Add calcium chloride and purified water to a batching kettle respectively, stir and heat until completely dissolved; then add ammonium sulfide to the batching kettle, and after the reaction is complete, let the solution stand until it is completely clarified, filter, and obtain filtrate 1;

[0008] S2, add ammonium carbonate and purified water to another batching kettle, stir and heat until completely dissolved, then stand until the solution is completely clarified, filter, and obtain filtrate 2;

[0009] S3, placing filtrate 1 and filtrate 2 in a reaction kettle, maintaining the temperature at 40-80°C until no more precipitation is produced, filtering, and drying to obtain purified calcium carbonate;

[0010] S4, respectively adding disodium ethylenediaminetetraacetate and purified water to another reaction kettle, stirring and heating until completely dissolved, then sequentially adding purified calcium carbonate and ammonia water, then standing the solution until completely clarified, filtering, and obtaining filtrate 3;

[0011] S5, placing the filtrate 3 in a concentration kettle, heating and concentrating it until it is concentrated to two-thirds of the raw material, then cooling it to room temperature, adding ethanol, stirring, precipitating calcium sodium edetate crystals, filtering, and drying to obtain high-purity pharmaceutical grade calcium sodium edetate.

[0012] Moreover, the drying is vacuum drying, and the drying temperature is 80-90°C.

[0013] Moreover, the calcium chloride is of industrial grade, the ethanol is of food grade, and the ammonium carbonate, ammonia water, ammonium sulfide and disodium ethylenediaminetetraacetate are of reagent grade.

[0014] The advantages and positive effects of the present invention are:

[0015] 1. The method of the present invention does not need to use expensive special equipment during production, and can meet the preparation of pharmaceutical grade calcium edetate sodium. The prepared pharmaceutical grade calcium edetate sodium has a purity of more than 99.5%, and the content of chloride ions, sulfides and toxic heavy metal arsenic ions is extremely low, thereby improving the application of the product in high-precision fields, especially in the fields of medical quality and pharmaceutical testing.

[0016] 2. All steps of the present invention are simple, easy to operate, easy to realize industrialized production, and the production and processing time is short, which greatly improves production efficiency and shortens working hours.

[0017] 3. The present invention further reasonably optimizes all raw material ratios and other reaction conditions. DETAILED DESCRIPTION

[0018] The present invention is further described in detail below through specific examples. The following examples are only illustrative and not restrictive, and the protection scope of the present invention cannot be limited thereto.

[0019] The invention abandons the use of common calcium chloride, calcium oxide or calcium hydroxide as the main raw material, and uses calcium carbonate synthesized by itself with high purity and extremely low content of harmful impurity metal arsenic as the raw material, thereby avoiding the introduction of chloride ions brought into the raw material calcium chloride, calcium oxide or calcium hydroxide during the reaction process of producing calcium sodium edetate, and the introduction of sulfides into the raw material.

[0020] At the same time, whether it is calcium chloride, calcium oxide or calcium hydroxide, it is a very common industrial product. Commercially available calcium chloride, calcium oxide or calcium hydroxide is mainly made from calcium in brine or stone as the starting material. Since industrial calcium is often rich in a series of metal ions, especially highly toxic arsenic ions, it will cause great side effects as a medicine. Therefore, the sodium calcium edetate used as an antidote cannot be toxic. In order to solve the problem of excessive toxic metal impurity ions including but not limited to arsenic ions in calcium chloride, calcium oxide or calcium hydroxide as raw materials, the present invention aims to purify the raw material calcium chloride into high-purity calcium carbonate. This avoids the influence of a series of anions including but not limited to chloride ions and sulfides in the product on the purity of sodium calcium edetate. At the same time, by purifying calcium carbonate, the toxic effects of heavy metal impurity cations including highly toxic arsenic ions on sodium calcium edetate are removed.

[0021] Example 1

[0022] A method for preparing pharmaceutical grade calcium sodium edetate comprises the following steps:

[0023] S1. Into a 3-ton batching kettle equipped with a heating device, an electric stirrer, a thermometer, and a titration feeder, 100 kg of industrial-grade calcium chloride and 2 tons of pure water as raw materials are respectively added, the electric stirrer is turned on and heated to 80°C to dissolve all the calcium chloride, and then 150 g of ammonium sulfide is added, and stirring is continued for 2 hours to allow the arsenic ions to fully react to form a precipitate, then the heating is stopped and the electric stirrer is turned off, the solution is allowed to stand until it is completely clarified, and mechanical impurities and precipitates containing arsenic ions are filtered out to obtain filtrate 1; and the filtered solution is added to a 5-ton reactor equipped with a heating device, an electric stirrer, a thermometer, and a titration feeder, and the electric stirrer of the reactor is turned on.

[0024] S2, in another 3-ton batching kettle equipped with a heating device, electric stirring, a thermometer, and a titration feeder, 50 kg of ammonium carbonate is dissolved in 2 tons of pure water, the electric stirring is turned on to heat and dissolve, then the heating is stopped and the electric stirring is turned off, the solution is allowed to stand until it is completely clarified, and filtered to obtain filtrate 2;

[0025] S3, placing filtrate 1 and filtrate 2 in a 5-ton reactor, maintaining the temperature at 60°C until no more precipitation is produced in the reactor, filtering the precipitate, and vacuum drying at 70°C to obtain purified calcium carbonate;

[0026] S4. Into a 5-ton reactor equipped with a heating device, electric stirring, thermometer, and titration feeder, add 1,350 kg of disodium ethylenediaminetetraacetate and 3 tons of pure water respectively, turn on the electric stirring and heat until they are completely dissolved, then add 400 kg of newly reacted and purified calcium carbonate, and control the pH value to 8.7 accurately by adding 25% ammonia water, and use this as the control point, then stop heating and turn off the electric stirring, let the solution stand until it is completely clarified, filter through a filter column containing activated carbon filler, and after obtaining a clarified solution, prepare filtrate 3, which is slowly added to the 5-ton concentration kettle.

[0027] S5. Heat the 5-ton concentration kettle, keep the electric stirring on and the solution in the concentration kettle boiling, and heat and concentrate the liquid to about 2 / 3 of the raw material; stop heating, and naturally cool to room temperature under stirring. No crystals will be precipitated at this time; add 1250 kg of food-grade ethanol at room temperature, stir for 1 hour, and sodium calcium edetate crystals will precipitate. Turn off the electric stirring, filter the crystal precipitate, and vacuum dry at 70°C to obtain high-purity pharmaceutical grade sodium calcium edetate.

[0028] Example 2

[0029] A method for preparing pharmaceutical grade calcium sodium edetate comprises the following steps:

[0030] S1. Into a 3-ton batching kettle equipped with a heating device, an electric stirrer, a thermometer, and a titration feeder, 100 kg of industrial-grade calcium chloride and 2 tons of pure water as raw materials are respectively added, the electric stirrer is turned on and heated to 80°C to dissolve all the calcium chloride, and then 175 g of ammonium sulfide is added, and stirring is continued for 2 hours to allow the arsenic ions to fully react to form a precipitate, then the heating is stopped and the electric stirrer is turned off, the solution is allowed to stand until it is completely clarified, and mechanical impurities and precipitates containing arsenic ions are filtered to obtain filtrate 1; and the filtered solution is added to a 5-ton reactor equipped with a heating device, an electric stirrer, a thermometer, and a titration feeder, and the electric stirrer of the reactor is turned on.

[0031] S2, in another 3-ton batching kettle equipped with a heating device, electric stirring, a thermometer, and a titration feeder, 50 kg of ammonium carbonate is dissolved in 2 tons of pure water, the electric stirring is turned on to heat and dissolve, then the heating is stopped and the electric stirring is turned off, the solution is allowed to stand until it is completely clarified, and filtered to obtain filtrate 2;

[0032] S3, placing filtrate 1 and filtrate 2 in a 5-ton reactor, maintaining the temperature at 60°C until no more precipitation is produced in the reactor, filtering the precipitate, and vacuum drying at 70°C to obtain purified calcium carbonate;

[0033] S4. Into a 5-ton reactor equipped with a heating device, electric stirring, thermometer, and titration feeder, add 1,350 kg of disodium ethylenediaminetetraacetate and 3 tons of pure water respectively, turn on the electric stirring and heat until they are completely dissolved, then add 410 kg of newly reacted and purified calcium carbonate, and control the pH value to 8.7 accurately by adding 25% ammonia water, and use this as the control point, then stop heating and turn off the electric stirring, let the solution stand until it is completely clarified, filter through a filter column containing activated carbon filler, and after obtaining a clarified solution, prepare filtrate 3, which is slowly added to the 5-ton concentration kettle.

[0034] S5. Heat the 5-ton concentration kettle, keep the electric stirring on and the solution in the concentration kettle boiling, and heat and concentrate the liquid to about 2 / 3 of the raw material; stop heating, and naturally cool to room temperature under stirring. No crystals will be precipitated at this time; add 1300 kg of food-grade ethanol at room temperature, stir for 1 hour, and calcium sodium edetate will crystallize. Turn off the electric stirring, filter the crystal precipitate, and vacuum dry at 70°C to obtain high-purity pharmaceutical-grade calcium sodium edetate.

[0035] Example 3

[0036] A method for preparing pharmaceutical grade calcium sodium edetate comprises the following steps:

[0037] S1. Into a 3-ton batching kettle equipped with a heating device, an electric stirrer, a thermometer, and a titration feeder, 100 kg of industrial-grade calcium chloride and 2 tons of pure water as raw materials are respectively added, the electric stirrer is turned on and heated to 80°C to dissolve all the calcium chloride, and then 200 g of ammonium sulfide is added, and stirring is continued for 2 hours to allow the arsenic ions to fully react to form a precipitate, then the heating is stopped and the electric stirrer is turned off, the solution is allowed to stand until it is completely clarified, and mechanical impurities and precipitates containing arsenic ions are filtered to obtain filtrate 1; and the filtered solution is added to a 5-ton reactor equipped with a heating device, an electric stirrer, a thermometer, and a titration feeder, and the electric stirrer of the reactor is turned on.

[0038] S2, in another 3-ton batching kettle equipped with a heating device, electric stirring, a thermometer, and a titration feeder, 50 kg of ammonium carbonate is dissolved in 2 tons of pure water, the electric stirring is turned on to heat and dissolve, then the heating is stopped and the electric stirring is turned off, the solution is allowed to stand until it is completely clarified, and filtered to obtain filtrate 2;

[0039] S3, placing filtrate 1 and filtrate 2 in a 5-ton reactor, maintaining the temperature at 60°C until no more precipitation is produced in the reactor, filtering the precipitate, and vacuum drying at 70°C to obtain purified calcium carbonate;

[0040] S4. Into a 5-ton reactor equipped with a heating device, electric stirring, thermometer, and titration feeder, add 1,350 kg of disodium ethylenediaminetetraacetate and 3 tons of pure water respectively, turn on the electric stirring and heat until they are completely dissolved, then add 420 kg of newly reacted and purified calcium carbonate, and control the pH value to 8.7 accurately by adding 25% ammonia water, and use this as the control point, then stop heating and turn off the electric stirring, let the solution stand until it is completely clarified, filter through a filter column containing activated carbon filler, and after obtaining a clarified solution, prepare filtrate 3, which is slowly added to the 5-ton concentration kettle.

[0041] S5. Heat the 5-ton concentration kettle, keep the electric stirring on and the solution in the concentration kettle boiling, and heat and concentrate the liquid to about 2 / 3 of the raw material; stop heating, and naturally cool to room temperature under stirring. No crystals will be precipitated at this time; add 1500 kg of food-grade ethanol at room temperature, stir for 1 hour, and sodium calcium edetate crystals will precipitate. Turn off the electric stirring, filter the crystal precipitate, and vacuum dry at 70°C to obtain high-purity pharmaceutical grade sodium calcium edetate.

[0042] Although the embodiments of the present invention are disclosed for illustrative purposes, those skilled in the art will appreciate that various substitutions, changes and modifications are possible without departing from the spirit and scope of the present invention and the appended claims. Therefore, the scope of the present invention is not limited to the contents disclosed in the embodiments.

Claims

1. A method for preparing pharmaceutical grade calcium sodium edetate, characterized in that: The steps include: S1. Add calcium chloride and purified water to a batching kettle respectively, stir and heat until completely dissolved; then add ammonium sulfide to the batching kettle, and after the reaction is complete, let the solution stand until it is completely clarified, filter, and obtain filtrate 1; S2, add ammonium carbonate and purified water to another batching kettle, stir and heat until completely dissolved, then stand until the solution is completely clarified, filter, and obtain filtrate 2; S3, placing filtrate 1 and filtrate 2 in a reaction kettle, maintaining the temperature at 40-80°C until no more precipitation is produced, filtering, and drying to obtain purified calcium carbonate; S4, respectively adding disodium ethylenediaminetetraacetate and purified water to another reaction kettle, stirring and heating until completely dissolved, then sequentially adding purified calcium carbonate and ammonia water, then standing the solution until completely clarified, filtering, and obtaining filtrate 3; S5, placing the filtrate 3 in a concentration kettle, heating and concentrating it until it is concentrated to two-thirds of the raw material, then cooling it to room temperature, adding ethanol, stirring, precipitating calcium sodium edetate crystals, filtering, and drying to obtain high-purity pharmaceutical grade calcium sodium edetate.

2. The method for preparing pharmaceutical grade calcium sodium edetate according to claim 1, wherein: The drying is vacuum drying at a temperature of 80-90°C.

3. The method for preparing pharmaceutical grade calcium sodium edetate according to claim 1, characterized in that: The calcium chloride is of industrial grade, the ethanol is of food grade, and the ammonium carbonate, ammonia water, ammonium sulfide and disodium ethylenediaminetetraacetate are of reagent grade.