1. The preparation method of the pharmaceutical grade zinc chloride bulk drug is characterized by comprising the following steps:

mixing zinc oxide with water to obtain a suspension;

dropwise adding hydrochloric acid into the suspension, and stirring and reacting until the system is clear and transparent to obtain a first reaction solution;

adding zinc powder into the first reaction solution, and then heating and reacting to obtain a second reaction solution;

filtering the second reaction solution to obtain a first filtrate;

and adjusting the pH value of the first filtrate, and then concentrating and drying to obtain the pharmaceutical grade zinc chloride bulk drug.

2. The preparation method according to claim 1, wherein the mass ratio of the zinc oxide to the water is 1 (2.8-3.2), preferably 1: 3.

3. The preparation method according to claim 1, wherein the molar ratio of the zinc oxide to the hydrochloric acid is 1 (1.9-2.2), preferably 1 (2.0-2.1), and more preferably 1: 2.1.

4. The preparation method according to claim 1, wherein the mass ratio of the zinc powder to the zinc oxide added to the first reaction solution is (19-21): 100, preferably 1: 5.

5. The preparation method according to claim 1, wherein the first reaction solution is heated to 70 to 100 ℃, preferably 80 to 100 ℃, and more preferably 80 to 90 ℃ after the zinc powder is added; the heating time is 3-5 h.

6. The method of claim 1, wherein the step of filtering comprises: filtering with filter paper, and filtering with filter membrane.

7. The production method according to claim 6, wherein the filtration membrane has a size of 0.45 um.

8. The method of claim 1, wherein the pH of the first filtrate is adjusted to 1.5 or less with hydrochloric acid;

preferably, the mass concentration of the hydrochloric acid is 36%.

9. The method according to claim 1, wherein the step of concentrating and drying the first filtrate comprises: and (3) adopting a rotary evaporator to evaporate and concentrate the first filtrate at 85 ℃ and under the pressure of-0.1 MPa until no liquid drips out of the system, wherein the material is oily, and then evaporating at 180 ℃ and under the pressure of-0.1 MPa until loose white powder is obtained.

10. Pharmaceutical grade zinc chloride bulk drug, characterized in that it is obtained by the preparation method according to any one of claims 1 to 9.

Background

Zinc is one of essential trace elements for human body, and plays an extremely important role in the growth and development process of human body. Zinc is present in a number of enzyme systems, such as respiratory enzymes, lactate dehydrogenase, superoxide dismutase, DNA and RNA polymerase, and is an essential substance for the synthesis of nucleic acids, proteins, carbohydrates and vitamin A utilization. Zinc deficiency not only affects the immune function of the human body and the normal metabolism of sugar, amino acid and vitamin A, but also affects the synthesis, degradation and energy metabolism of related proteins; in addition, zinc deficiency can affect the intelligence and growth of children, and affect reproductive function. Therefore, proper zinc supplementation is essential for the human body.

At present, the specifications of zinc chloride adopted in domestic trace element preparations are analytical pure reagents, but are not pharmaceutical grade, and the zinc chloride with pharmaceutical grade specifications is not produced and sold. Therefore, the development of a method for preparing the zinc chloride bulk drug is very important, the pharmaceutical grade zinc chloride bulk drug can provide a new raw material supply choice for a microelement preparation manufacturer, the production flow is simplified, the production efficiency is improved, and the method has wide market prospect.

Disclosure of Invention

In order to make up for the defect that the existing market lacks pharmaceutical grade zinc chloride raw material medicines, the invention provides the preparation method of the pharmaceutical grade zinc chloride raw material medicines, the method is simple to operate and low in cost, and the prepared product has high safety.

The basic concept of the technical scheme adopted by the invention is as follows:

a method for preparing a pharmaceutical grade zinc chloride bulk drug, the method comprising:

mixing zinc oxide with water to obtain a suspension;

dropwise adding hydrochloric acid into the suspension, and stirring and reacting until the system is clear and transparent to obtain a first reaction solution;

adding zinc powder into the first reaction solution, and then heating and reacting to obtain a second reaction solution;

filtering the second reaction solution to obtain a first filtrate;

and adjusting the pH value of the first filtrate, and then concentrating and drying to obtain the pharmaceutical grade zinc chloride bulk drug.

In one embodiment, the mass ratio of the zinc oxide to the water is 1 (2.8 to 3.2), preferably 1: 3.

In one embodiment, the molar ratio of the zinc oxide to the hydrochloric acid is 1 (1.9 to 2.2), preferably 1 (2.0 to 2.1), and more preferably 1: 2.1.

In one embodiment, the mass ratio of the zinc powder to the zinc oxide added to the first reaction solution is (19-21): 100, preferably 1: 5.

As one mode, after adding zinc powder into the first reaction solution, heating to 70-100 ℃, preferably 80-100 ℃, and more preferably 80-90 ℃; the heating time is 3-5 h.

By one approach, the step of filtering comprises: filtering with filter paper, and filtering with filter membrane.

In one embodiment, the filtration membrane has a size of 0.45 um.

As one mode, hydrochloric acid is used for adjusting the pH of the first filtrate to be less than or equal to 1.5.

Preferably, the mass concentration of the hydrochloric acid is 36%.

In one mode, the step of concentrating and drying the first filtrate comprises: and (3) adopting a rotary evaporator to evaporate and concentrate the first filtrate at 85 ℃ and under the pressure of-0.1 MPa until no liquid drips out of the system, wherein the material is oily, and then evaporating at 180 ℃ and under the pressure of-0.1 MPa until loose white powder is obtained.

The invention also provides a pharmaceutical grade zinc chloride bulk drug, which is obtained by adopting the preparation method of any one of the above.

Compared with the prior art, the invention has the technical advantages that:

1. the preparation method adopts zinc powder to remove impurities, because the metal activity of zinc is greater than Cd, Co, Ni, Pb, Sb, Cu and Hg, the impurity elements are replaced by adding the zinc powder to reduce the level of heavy metal elements, and then the aim of removing the impurities is fulfilled by filtering.

2. The invention further controls the mass ratio of the zinc oxide to the water to be 1:3, so that the zinc oxide can be fully dispersed in the water under the condition of a small amount of water, and the full stirring is ensured.

3. According to the invention, by controlling the molar ratio of zinc oxide to hydrochloric acid to be 1 (1.9-2.2), on one hand, the content of alkali metal and alkaline earth metal in the final product can be ensured to be qualified; on the other hand, the levels of various metal elements (including Li, V, Co, Ni, Cu, Cd, Sb, Hg and Pb) and As elements in the final product can be ensured to be lower than 30 percent of PDE.

4. According to the invention, the mass ratio of the zinc powder to the zinc oxide added into the first reaction solution is controlled to be (19-21): 100, so that on one hand, metal impurities (Cd, Co, Ni, Pb, Sb, Cu and Hg) in the system can be fully replaced, and the levels of all metal elements (Cd, Co, Ni, Pb, Sb, Cu and Hg) in the prepared zinc chloride bulk drug are lower than 30% of PDE, thereby achieving the standard of the bulk drug. On the other hand, the content of alkali metal and alkaline earth metal in the final product can be ensured to be qualified.

5. According to the invention, after zinc powder is added into the first reaction solution, the reaction temperature of the system is controlled to be 70-100 ℃, so that the reaction can be fully carried out, and metal impurities (Cd, Co, Ni, Pb, Sb, Cu and Hg) in the system can be fully replaced; in addition, the operation at not higher than 100 ℃ also improves the safety of the reaction.

6. The pH value of the first filtrate is controlled to be less than or equal to 1.5, so that the content of alkali metal and alkaline earth metal in the final product is qualified.

7. The first filtrate after the pH is adjusted is concentrated and dried through rotary evaporation, so that the color, the solubility and the contents of alkali metal and alkaline earth metal of the obtained zinc chloride product are qualified.

Drawings

FIG. 1 is a process flow diagram of the preparation method of the present invention.

Detailed Description

The invention is further described below with reference to specific embodiments. So that the technical scheme of the invention can be more easily understood and mastered, but the invention is not limited to the technical scheme. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified. The specific reaction apparatus used in the examples is merely an example, and other apparatuses capable of achieving the reaction purpose may be used.

Example 1

Adding 300.00g of purified water and 100.00g of zinc oxide into a 1L four-neck flask (kettle) provided with a mechanical stirring device, and opening the mechanical stirring device to mix the zinc oxide and the water to obtain a suspension;

then 261.24g of hydrochloric acid with the mass fraction of 36% is added into a constant-pressure dropping funnel, the molar ratio of zinc oxide to hydrochloric acid is controlled to be 1:2.1, a valve of the constant-pressure dropping funnel is slowly opened, hydrochloric acid is slowly dropped into a four-neck flask (kettle) at room temperature, and the temperature in the four-neck flask (kettle) needs to be controlled below 80 ℃ due to obvious reaction heat release, the temperature in the four-neck flask (kettle) is recorded after the hydrochloric acid is completely dropped, and a first reaction solution is obtained after a stirring reaction is carried out until a system is clear and transparent;

adding 20g of zinc powder into a four-neck flask (kettle) containing a first reaction solution, then placing the four-neck flask (kettle) into a preheated water bath, wherein the temperature of the water bath is 90 ℃, starting timing when the temperature in the four-neck flask (kettle) reaches 80 ℃, and reacting for 4 hours to obtain a second reaction solution, wherein the temperature in the four-neck flask (kettle) is controlled to be 85 +/-5 ℃ during the water bath;

after the reaction is finished, the second reaction solution is filtered by common filter paper and then is filtered by a filter membrane with the specification of 0.45um to obtain a first filtrate;

adjusting the pH value of the first filtrate to be less than or equal to 1.5 (specifically to be 0.78) by using hydrochloric acid, carrying out rotary evaporation and concentration on the first filtrate with the adjusted pH value at 85 ℃ and-0.1 MPa until no liquid drips out of the system and the material is oily, and then carrying out rotary evaporation at 180 ℃ and-0.1 MPa until the material is loose white powder to obtain the final product, namely the zinc chloride bulk drug, wherein the yield is 90%.

Example 2

Adding 300.00g of purified water and 100.00g of zinc oxide into a 1L four-neck flask (kettle) provided with a mechanical stirring device, and opening the mechanical stirring device to mix the zinc oxide and the water to obtain a suspension;

then 236.36g of hydrochloric acid with the mass fraction of 36% is added into a constant pressure dropping funnel, the molar ratio of zinc oxide to hydrochloric acid is controlled to be 1:1.9, a valve of the constant pressure dropping funnel is slowly opened, hydrochloric acid is slowly dropped into a four-neck flask (kettle) at room temperature, the temperature in the four-neck flask (kettle) needs to be controlled below 70 ℃ due to obvious reaction heat release, the temperature in the four-neck flask (kettle) is recorded after the hydrochloric acid is completely dropped, and a stirring reaction is carried out until a system is clear and transparent to obtain a first reaction solution;

adding 19g of zinc powder into a four-neck flask (kettle) containing the first reaction solution, then placing the four-neck flask (kettle) into a preheated water bath, wherein the temperature of the water bath is 80 ℃, starting timing when the temperature in the four-neck flask (kettle) reaches 70 ℃, and reacting for 5 hours to obtain a second reaction solution, wherein the temperature in the four-neck flask (kettle) is controlled to be 75 +/-5 ℃ during the water bath;

after the reaction is finished, the second reaction solution is filtered by common filter paper and then is filtered by a filter membrane with the specification of 0.45um to obtain a first filtrate;

adjusting the pH value of the first filtrate to be less than or equal to 1.5 (specifically to be 1.46) by using hydrochloric acid, carrying out rotary evaporation and concentration on the first filtrate with the adjusted pH value under the conditions of 85 ℃ and-0.1 MPa until no liquid drips out of the system and the material is oily, and then carrying out rotary evaporation under the conditions of 180 ℃ and-0.1 MPa to obtain loose white powder, thus obtaining the final product zinc chloride bulk drug with the yield of 81%.

Example 3

Adding 300.00g of purified water and 100.00g of zinc oxide into a 1L four-neck flask (kettle) provided with a mechanical stirring device, and opening the mechanical stirring device to mix the zinc oxide and the water to obtain a suspension;

then 248.80g of hydrochloric acid with the mass fraction of 36% is added into a constant-pressure dropping funnel, the molar ratio of zinc oxide to hydrochloric acid is controlled to be 1:2.0, a valve of the constant-pressure dropping funnel is slowly opened, hydrochloric acid is slowly dropped into a four-neck flask (kettle) at room temperature, and the temperature in the four-neck flask (kettle) needs to be controlled below 80 ℃ due to obvious reaction heat release, the temperature in the four-neck flask (kettle) is recorded after the hydrochloric acid is completely dropped, and a first reaction solution is obtained after a stirring reaction is carried out until a system is clear and transparent;

adding 20g of zinc powder into a four-neck flask (kettle) containing a first reaction solution, then placing the four-neck flask (kettle) into a preheated water bath, wherein the temperature of the water bath is 90 ℃, starting timing when the temperature in the four-neck flask (kettle) reaches 80 ℃, and reacting for 3.5 hours to obtain a second reaction solution, wherein the temperature in the four-neck flask (kettle) is controlled to be 85 +/-5 ℃ during the water bath;

after the reaction is finished, the second reaction solution is filtered by common filter paper and then is filtered by a filter membrane with the specification of 0.45um to obtain a first filtrate;

adjusting the pH value of the first filtrate to be less than or equal to 1.5 (specifically to be 0.65) by hydrochloric acid, carrying out rotary evaporation and concentration on the first filtrate with the adjusted pH value at 85 ℃ and-0.1 MPa until no liquid drips out of the system and the material is oily, and then carrying out rotary evaporation at 180 ℃ and-0.1 MPa until the material is loose white powder to obtain the final product, namely the zinc chloride bulk drug, wherein the yield is 86%.

Example 4

Adding 300.00g of purified water and 100.00g of zinc oxide into a 1L four-neck flask (kettle) provided with a mechanical stirring device, and opening the mechanical stirring device to mix the zinc oxide and the water to obtain a suspension;

adding 273.68g of hydrochloric acid with the mass fraction of 36% into a constant-pressure dropping funnel, controlling the molar ratio of zinc oxide to hydrochloric acid to be 1:2.2, slowly opening a valve of the constant-pressure dropping funnel, and slowly dropping the hydrochloric acid into a four-neck flask (kettle) at room temperature, wherein the reaction heat release is obvious, so that the temperature in the four-neck flask (kettle) needs to be controlled below 90 ℃, recording the temperature in the four-neck flask (kettle) after the hydrochloric acid is completely dropped, and stirring the reaction until a system is clear and transparent to obtain a first reaction solution;

adding 21g of zinc powder into a four-neck flask (kettle) containing a first reaction solution, then placing the four-neck flask (kettle) into a preheated water bath, wherein the temperature of the water bath is 100 ℃, starting timing when the temperature in the four-neck flask (kettle) reaches 90 ℃, and reacting for 3 hours to obtain a second reaction solution, wherein the temperature in the four-neck flask (kettle) is controlled to be 95 +/-5 ℃ during the water bath;

after the reaction is finished, the second reaction solution is filtered by common filter paper and then is filtered by a filter membrane with the specification of 0.45um to obtain a first filtrate;

adjusting the pH value of the first filtrate to be less than or equal to 1.5 (actually 0.53) by hydrochloric acid, carrying out rotary evaporation and concentration on the first filtrate with the adjusted pH value under the conditions of 85 ℃ and-0.1 MPa until no liquid drips out of the system and the material is oily, and then carrying out rotary evaporation under the conditions of 180 ℃ and-0.1 MPa until the material is loose white powder to obtain the final product zinc chloride bulk drug, wherein the yield is 91%.

The quality of the zinc chloride bulk drug prepared in the embodiments 1 to 4 of the invention is detected, the detection results are shown in table 1, and table 1 compares the detection results of the zinc chloride quality standard and the products obtained in the embodiments 1 to 4.

Comparative example 1

The only difference from example 1 is that the molar ratio of the zinc oxide to the hydrochloric acid is 1:1.8, otherwise the same as example 1 holds.

Comparative example 2

The only difference from example 1 is that the molar ratio of the zinc oxide to the hydrochloric acid is 1:2.3, otherwise it is identical to example 1.

Comparative example 3

The only difference from example 1 is that the mass ratio of the zinc powder to the zinc oxide is 18:100, and the others are the same as example 1.

Comparative example 4

The difference from example 1 is only that the mass ratio of the zinc powder to the zinc oxide is 22:100, and the others are consistent with example 1.

Comparative example 5

The only difference from example 1 is that zinc powder was added to the first reaction solution and heated to 65 + -5 deg.C to obtain a second reaction solution, and the other steps were identical to example 1.

Comparative example 6

The only difference from example 1 is that the pH of the first filtrate was adjusted to 1.6, and the rest was identical to example 1.

Comparative example 7

The difference from the example 1 is that the first filtrate with the adjusted pH value is evaporated and concentrated under the conditions of 85 ℃ and-0.1 MPa until no liquid drips out of the system, the material is oily, and then the material is dried in a forced air drying oven (250 ℃) to obtain the zinc chloride product, and the others are consistent with the example 1.

Comparative example 8

The difference from the example 1 is that the first filtrate with the adjusted pH value is evaporated and concentrated under the conditions of 85 ℃ and-0.1 MPa until no liquid drips out of the system, the material is oily, and then the material is dried in a muffle furnace (200 ℃) to obtain a zinc chloride product, and the others are consistent with the example 1.

Comparative example 9

The difference from the example 1 is that the first filtrate with the adjusted pH value is evaporated and concentrated under the conditions of 85 ℃ and-0.1 MPa until no liquid drips out of the system, the material is oily, and then the material is dried in a vacuum drying oven (180 ℃ and-0.1 MPa) to obtain the zinc chloride product, and the others are consistent with the example 1.

TABLE 1

TABLE 2

The quality standards in tables 1 and 2 are established by combining "Chinese pharmacopoeia" 2020 edition and "United states pharmacopoeia". As can be seen from table 1, the bulk zinc chloride prepared in examples 1 to 4 of the present invention all meet the quality standards of the product. As can be seen from Table 2, the alkali metal and alkaline earth metal contents of comparative example 1, comparative example 4 and comparative example 6 were not qualified as compared with example 1.

Table 3 shows the limits of the levels of the respective metal elements, As elements, and the results of the tests of examples 1 to 4 and comparative examples 2, 3 and 5.

TABLE 3

As can be seen from table 3, the levels of various metal elements (including Li, V, Co, Ni, Cu, Cd, Sb, Hg, Pb) and the water average of As elements in the zinc chloride bulk drug prepared in examples 1 to 4 of the present invention are lower than 30% of PDE (Permitted yield Exposure, residual reference value), which meets the standards of bulk drug, so that the prepared product has high safety without establishing quality standards related to the levels of heavy metal elements.

In comparative example 2, the Co and Pb element levels were not satisfied, and the Ni element level exceeded 30% PDE; in comparative example 3, the levels of Co, Ni and Pb elements were not acceptable; in comparative example 5, the levels of Co, Ni and Pb all exceed 30% of the PDE value although the levels are acceptable, and the safety of the product is relatively lowered, so that the quality standards of the Co, Ni and Pb elements need to be established.

Table 4 shows the results of the zinc chloride product obtained by different drying methods in the later stage. As can be seen from Table 4, the zinc chloride product obtained by the rotary evaporation process of the present invention meets the quality requirements of the product.

TABLE 4

It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design alternative embodiments without departing from the scope of the appended claims. In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim. The word "comprising" does not exclude the presence of elements or steps not listed in a claim. The usage of the words first, second and third, etcetera do not indicate any ordering and these words may be interpreted as names.