CN103330684A - Preparation method of diammonium glycyrrhizinate lipid compound effervescent granule - Google Patents

Abstract

The invention relates to a preparation method of diammonium glycyrrhizinate lipid complex effervescent granules. The purpose is that the method provided should be able to effectively improve the drug absorption effect and bioavailability, so as to achieve the effect of protecting liver cell membrane and improving liver function, and also has the characteristics of convenient administration. The technical solution is: the preparation method of diammonium glycyrrhizinate lipid complex effervescent granules is carried out according to the following steps: 1) preparing the diammonium glycyrrhizinate lipid complex mixture; 2) making diammonium glycyrrhizinate lipid Diammonium glycyrrhizinate lipoplex effervescent granules were made from the lipid complex mixture. The preparation method of the diammonium glycyrrhizinate lipid complex is as follows: 1) preparing soybean phospholipid tetrahydrofuran solution; 2) weighing the purified diammonium glycyrrhizinate, refluxing and dissolving it, and taking it out and standing when the solution is clear; 3) preparing Take diammonium glycyrrhizinate lipoplex. The preparation method of the sodium bicarbonate clathrate comprises: 1) carrying out clathrate, cooling to room temperature after clathrate is uniform; 2) obtaining the clathrate of sodium bicarbonate.

Description

Preparation method of diammonium glycyrrhizinate lipid complex effervescent granule

technical field

The invention relates to a preparation method of medicine, in particular to a preparation method of diammonium glycyrrhizinate lipid complex effervescent granules.

Background technique

Diammonium Glycyrrhizinate (DG) is an effective drug for the treatment of liver diseases. It can significantly reduce serum alanine aminotransferase and aspartate aminotransferase, protect liver cell membranes and improve liver function. It is suitable for chronic diseases with elevated alanine aminotransferase. Persistent hepatitis and chronic active hepatitis.

The DG preparations currently on the market mainly include enteric-coated tablets, enteric-coated capsules and capsules (there is no significant difference in bioavailability among the three and are bioequivalent). If the drug dissolves quickly and stays in the stomach for a long time, the better the absorption effect of the drug and the higher the bioavailability. However, DG is a weakly acidic drug, and its physical and chemical properties determine that it is easily soluble in water but not easily soluble in acidic solutions. Therefore, the capsule dissolves slowly and incompletely in the stomach, and enteric-coated tablets and enteric-coated capsules also have slow disintegration. The problem.

Therefore, in the current DG preparations, enteric-coated tablets, enteric-coated capsules and capsules have poor absorption in the human body, low bioavailability, and the effect of protecting the liver and reducing enzymes is not very satisfactory (compared with its injections), and at the same time People who have difficulty taking medicine such as children and the elderly are also more difficult to take, which is very inconvenient.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the above-mentioned background technology and provide a preparation method of diammonium glycyrrhizinate lipid complex effervescent granules, which should be able to effectively improve the drug absorption effect and bioavailability, so as to protect the liver cell membrane And the effect of improving liver function, and also has the characteristics of taking convenience.

Technical scheme of the present invention is: the preparation method of diammonium glycyrrhizinate lipoplex effervescent granule, carry out according to the following steps:

1) Take 30-35 parts of diammonium glycyrrhizinate lipid complex, 12-18 parts of ascorbic acid, 126-132 parts of filler, 30-35 parts of citric acid, 50-55 parts of sodium bicarbonate clathrate and chloride 28-32 parts of sodium, uniformly mixed to form diammonium glycyrrhizinate lipid complex mixture;

2) Diammonium glycyrrhizinate lipoplex mixture was made into effervescent granules of diammonium glycyrrhizinate lipoplex by wet granulation.

The preparation method of the diammonium glycyrrhizinate lipid complex is:

1) Put 8-12 parts of soybean lecithin and 500 parts of tetrahydrofuran into the container, and then reflux and dissolve in a water bath at 70±4°C by magnetic stirring to obtain soybean lecithin tetrahydrofuran solution;

2) Weigh 8-12 parts of purified diammonium glycyrrhizinate, then pour it into the cooled soybean lecithin tetrahydrofuran solution, shake it gently, and then reflux and dissolve it in a water bath at 70±4°C by magnetic stirring for more than 2-4h. When the solution is clear, take it out and let it stand;

3) Pour the above solution and pour the supernatant into another container, rotatory evaporate until there is no tetrahydrofuran smell, then grind and sieve to obtain diammonium glycyrrhizinate lipoplex with a content of 45-48%.

The preparation method of described sodium bicarbonate clathrate is:

1) Heat and melt a certain amount of polyethylene glycol, then take an equal amount of sodium bicarbonate for stirring, and slowly add molten polyethylene glycol to the sodium bicarbonate for clathrate, clathrate evenly and cool to room temperature;

2) Grinding and sieving the above clathrate to obtain the clathrate of sodium bicarbonate.

The filler is xylitol or sucrose or glucose or fructose or mannitol.

The filling agent is added with orange flavor essence or orange flavor essence or strawberry flavor essence or peach flavor essence.

The method of adding essence in the described filler is:

1) Take a certain amount of filler, sieve it, and mix it with an appropriate amount of essence to make granules;

2) Sieve the above granules, and then dry them in an environment above 40±3°C for more than 2 hours;

3) Grind the above granules finely and sieve.

Described wet granulation is:

1) Add the diammonium glycyrrhizinate lipid complex mixture into absolute ethanol to make a soft material, then sieve it to make wet granules, and dry it in an environment above 40±3°C for more than 2 hours;

2) Sieve the above granules, then add 6 parts of microcrystalline cellulose and 0.15 parts of magnesium stearate, mix well, and dry in a vacuum environment at 40±3°C for 2-3 hours;

3) Sieve the above granules to obtain diammonium glycyrrhizinate lipid complex effervescent granules.

The preparation method of described diammonium glycyrrhizinate extract is:

1) Add 100 parts of diammonium glycyrrhizinate and 700-900 parts of ethanol aqueous solution into the container, and heat in a water bath at 100±5°C until dissolved;

2) Let the above solution stand for a while, then pour the supernatant into another container to cool and stand for 10-14h, and obtain crystals by suction filtration;

3) Add the above crystals and 500-700 parts of ethanol aqueous solution into the container, and heat in a water bath at 100±5°C until dissolved;

4) Repeat step 2), and then dry the crystals to a state without ethanol smell;

5) Dry the above-mentioned crystals in an environment above 55°C for more than 24 hours to obtain a purified product of diammonium glycyrrhizinate with a content of 97.3%.

The beneficial effects of the present invention are:

In the present invention, diammonium glycyrrhizinate is made into effervescent granules, and the effervescent granules will be dissolved in vitro in the form of a solution (there is no dissolution process in the body), which can not only significantly improve the drug absorption effect and bioavailability (blood drug concentration) and liver tissue concentrations are about 2 times and 26 times that of diammonium glycyrrhizinate capsules respectively), which can protect the liver cell membrane and improve liver function, which is of positive significance for the recovery of the liver; at the same time, the effervescent granules are very convenient to take, It is more suitable for children and the elderly who have difficulties in taking medicine.

Detailed ways

The preparation method of diammonium glycyrrhizinate lipid complex effervescent granules will be further described below, but the present invention is not limited to the following examples.

Embodiment one:

The first step, pretreatment of raw materials:

1, diammonium glycyrrhizinate is made into diammonium glycyrrhizinate lipid complex;

1) Diammonium glycyrrhizinate is made into diammonium glycyrrhizinate extract:

①Add 100 parts of diammonium glycyrrhizinate and 700 parts of ethanol aqueous solution (80-85% purity) into the container, and heat it in a water bath at 95°C until it dissolves;

②Let the above solution stand for a while, then pour the supernatant into another container to cool and let it stand for 10 hours, and obtain crystals by suction filtration;

③Add the above crystals and 500 parts of ethanol aqueous solution (80-85% purity) into the container, and heat in a water bath at 95°C until dissolved;

④Repeat step ②, and then dry the crystals to a state without ethanol smell;

⑤ Dry the above-mentioned crystals in an environment above 55°C for more than 24 hours to obtain a purified diammonium glycyrrhizinate with a content of 97.3%.

2) Make diammonium glycyrrhizinate lipid complex from diammonium glycyrrhizinate extract:

①Put 8 parts of soybean lecithin and 500 parts of tetrahydrofuran into the container, and then reflux and dissolve in a water bath at 66°C by magnetic stirring to obtain a solution of soybean lecithin in tetrahydrofuran;

② Weigh 8 parts of the purified diammonium glycyrrhizinate, then pour it into the cooled soybean phospholipid tetrahydrofuran solution, shake it gently, and then reflux and dissolve it in a water bath at 66°C by magnetic stirring for more than 2 hours. When the solution is clear, take it out and let it stand ;

③Pour the above solution into another container and pour the supernatant into another container, and evaporate until there is no tetrahydrofuran smell, then grind it finely and pass it through an 80-mesh sieve to obtain diammonium glycyrrhizinate lipid complex with a content of 45-48%.

2. Inclusion of sodium bicarbonate with polyethylene glycol:

1) Heat and melt a certain amount of polyethylene glycol, then take an equal amount of sodium bicarbonate for stirring, and slowly add molten polyethylene glycol to the sodium bicarbonate for clathrate, clathrate evenly and cool to room temperature;

2) Grind the above clathrate and pass through an 80-mesh sieve to obtain the clathrate of sodium bicarbonate.

3. Add flavor to filler:

1) Take a certain amount of xylitol and pass it through an 80-mesh sieve, and mix it with an appropriate amount of orange flavor essence to make granules;

2) Pass the above granules through an 80-mesh sieve, and then dry them in an environment above 37°C for more than 2 hours;

3) Grind the above particles finely and pass through an 80-mesh sieve.

4. Pass microcrystalline cellulose, magnesium stearate, ascorbic acid, citric acid and sodium chloride through an 80-mesh sieve.

The second step, take 30 parts of diammonium glycyrrhizinate lipid complex, 12 parts of ascorbic acid, 126 parts of flavoring agent, 30 parts of citric acid, 50 parts of sodium bicarbonate clathrate and 28 parts of sodium chloride, and mix evenly to form Diammonium Glycyrrhizinate Lipid Complex Mixture;

In the third step, the diammonium glycyrrhizinate lipid complex mixture is made into diammonium glycyrrhizinate lipid complex effervescent granules by wet granulation; the wet granulation is divided into the following steps:

1. Add diammonium glycyrrhizinate lipid complex mixture into absolute ethanol to make a soft material, then pass through a 16-mesh sieve to make wet granules, and dry in an environment above 37°C for more than 2 hours;

2. Pass the above granules through a 16-mesh sieve, then add 6 parts of microcrystalline cellulose and 0.15 parts of magnesium stearate, mix well, and dry at 37°C for 2 hours in a vacuum environment;

3. Pass the above granules through a 16-mesh sieve to obtain diammonium glycyrrhizinate lipid complex effervescent granules.

Embodiment two:

The first step, pretreatment of raw materials:

1, diammonium glycyrrhizinate is made into diammonium glycyrrhizinate lipid complex;

1) Diammonium glycyrrhizinate is made into diammonium glycyrrhizinate extract:

① Add 100 parts of diammonium glycyrrhizinate and 800 parts of ethanol aqueous solution (purity 80-85%) into the container, and heat it in a water bath at 100°C until it dissolves;

②Let the above solution stand for a while, then pour the supernatant into another container to cool and stand for 12 hours, and obtain crystals by suction filtration;

③ Add the above crystals and 600 parts of ethanol aqueous solution (80-85% purity) into the container, and heat in a water bath at 100°C until dissolved;

④Repeat step ②, and then dry the crystals to a state without ethanol smell;

⑤ Dry the above-mentioned crystals in an environment above 55°C for more than 24 hours to obtain a purified diammonium glycyrrhizinate with a content of 97.3%.

2) Make diammonium glycyrrhizinate lipid complex from diammonium glycyrrhizinate extract:

① Put 10 parts of soybean lecithin and 500 parts of tetrahydrofuran in a container, and then reflux and dissolve in a water bath at 70°C by magnetic stirring to obtain a solution of soybean lecithin in tetrahydrofuran;

② Weigh 10 parts of the purified diammonium glycyrrhizinate, then pour it into the cooled soybean phospholipid tetrahydrofuran solution, shake it gently, and then reflux and dissolve it in a water bath at 70°C by magnetic stirring for more than 3 hours. When the solution is clear, take it out and let it stand ;

③Pour the above solution into another container and pour the supernatant into another container, and evaporate until there is no tetrahydrofuran smell, then grind it finely and pass it through an 80-mesh sieve to obtain diammonium glycyrrhizinate lipid complex with a content of 45-48%.

2. Inclusion of sodium bicarbonate with polyethylene glycol:

1) Heat and melt a certain amount of polyethylene glycol, then take an equal amount of sodium bicarbonate for stirring, and slowly add molten polyethylene glycol to the sodium bicarbonate for clathrate, clathrate evenly and cool to room temperature;

2) Grind the above clathrate and pass through an 80-mesh sieve to obtain the clathrate of sodium bicarbonate.

3. Add flavor to filler:

1) Take a certain amount of glucose and pass it through an 80-mesh sieve, and mix it with an appropriate amount of orange flavor essence to make granules;

2) Pass the above granules through an 80-mesh sieve, and then dry them in an environment above 40°C for more than 2 hours;

3) Grind the above particles finely and pass through an 80-mesh sieve.

4. Pass microcrystalline cellulose, magnesium stearate, ascorbic acid, citric acid and sodium chloride through an 80-mesh sieve.

The second step, take 33.6 parts of diammonium glycyrrhizinate lipid complex, 15 parts of ascorbic acid, 129 parts of flavoring agent, 33.75 parts of citric acid, 52.5 parts of sodium bicarbonate clathrate and 30 parts of sodium chloride, and mix evenly to form Diammonium Glycyrrhizinate Lipid Complex Mixture;

In the third step, the diammonium glycyrrhizinate lipid complex mixture is made into diammonium glycyrrhizinate lipid complex effervescent granules by wet granulation; the wet granulation is divided into the following steps:

1. Add diammonium glycyrrhizinate lipid complex mixture into absolute ethanol to make soft material, then pass through a 16-mesh sieve to make wet granules, and dry in an environment above 40°C for more than 2 hours;

2. Pass the above granules through a 16-mesh sieve, then add 6 parts of microcrystalline cellulose and 0.15 parts of magnesium stearate, mix well, and dry at 40°C for 2.5 hours in a vacuum environment;

3. Pass the above granules through a 16-mesh sieve to obtain diammonium glycyrrhizinate lipid complex effervescent granules.

Embodiment three:

The first step, pretreatment of raw materials:

1, diammonium glycyrrhizinate is made into diammonium glycyrrhizinate lipid complex;

1) Diammonium glycyrrhizinate is made into diammonium glycyrrhizinate extract:

①Add 100 parts of diammonium glycyrrhizinate and 900 parts of ethanol aqueous solution (80-85% purity) into the container, and heat it in a water bath at 105°C until it dissolves;

②Let the above solution stand for a while, then pour the supernatant into another container to cool and stand for 14 hours, and obtain crystals by suction filtration;

③Add the above crystals and 700 parts of ethanol aqueous solution (80-85% purity) into the container, and heat in a water bath at 105°C until dissolved;

④Repeat step ②, and then dry the crystals to a state without ethanol smell;

⑤ Dry the above-mentioned crystals in an environment above 55°C for more than 24 hours to obtain a purified diammonium glycyrrhizinate with a content of 97.3%.

2) Make diammonium glycyrrhizinate lipid complex from diammonium glycyrrhizinate extract:

①Put 12 parts of soybean lecithin and 500 parts of tetrahydrofuran in a container, and then reflux and dissolve in a water bath at 74°C by magnetic stirring to obtain a solution of soybean lecithin in tetrahydrofuran;

② Weigh 12 parts of the purified diammonium glycyrrhizinate, then pour it into the cooled soybean lecithin tetrahydrofuran solution, shake it gently, and then reflux and dissolve it in a water bath at 74°C by magnetic stirring for more than 4 hours. When the solution is clear, take it out and let it stand ;

③Pour the above solution into another container and pour the supernatant into another container, and evaporate until there is no tetrahydrofuran smell, then grind it finely and pass it through an 80-mesh sieve to obtain diammonium glycyrrhizinate lipid complex with a content of 45-48%.

2. Inclusion of sodium bicarbonate with polyethylene glycol:

1) Heat and melt a certain amount of polyethylene glycol, then take an equal amount of sodium bicarbonate for stirring, and slowly add molten polyethylene glycol to the sodium bicarbonate for clathrate, clathrate evenly and cool to room temperature;

2) Grind the above clathrate and pass through an 80-mesh sieve to obtain the clathrate of sodium bicarbonate.

3. Add flavor to filler:

1) Take a certain amount of mannitol and pass it through an 80-mesh sieve, and mix it with an appropriate amount of strawberry flavor essence to make granules;

2) Pass the above granules through an 80-mesh sieve, and then dry them in an environment above 43°C for more than 2 hours;

3) Grind the above particles finely and pass through an 80-mesh sieve.

4. Pass microcrystalline cellulose, magnesium stearate, ascorbic acid, citric acid and sodium chloride through an 80-mesh sieve.

The second step, take 35 parts of diammonium glycyrrhizinate lipid complex, 18 parts of ascorbic acid, 132 parts of flavoring agent, 35 parts of citric acid, 55 parts of sodium bicarbonate clathrate and 32 parts of sodium chloride, and mix evenly to form Diammonium Glycyrrhizinate Lipid Complex Mixture;

In the third step, the diammonium glycyrrhizinate mixture is made into diammonium glycyrrhizinate lipid complex effervescent granules by wet granulation; the wet granulation is divided into the following steps:

1. Add diammonium glycyrrhizinate lipid complex mixture into absolute ethanol to make a soft material, then pass through a 16-mesh sieve to make wet granules, and dry in an environment above 43°C for more than 2 hours;

2. Pass the above granules through a 16-mesh sieve, then add 6 parts of microcrystalline cellulose and 0.15 parts of magnesium stearate, mix well, and dry at 43°C for 3 hours in a vacuum environment;

3. Pass the above granules through a 16-mesh sieve to obtain diammonium glycyrrhizinate lipid complex effervescent granules.

The difference between effervescent agents (including effervescent granules) and ordinary tablets (enteric-coated tablets, enteric-coated capsules, and capsules) is that effervescent agents contain effervescent disintegrants; , under the action of the effervescent disintegrating agent, a large number of bubbles (carbon dioxide) will be generated immediately, which can promote the effervescent agent to roll up and down in the water to achieve the effect of rapid disintegration and melting, and after the carbon dioxide is partially dissolved in the water, it can also make the water It has a mouthfeel similar to that of soda; therefore, the diammonium glycyrrhizinate lipid complex is made into effervescent granules for taking, which has the advantages of rapid disintegration, good taste, and convenient administration (suitable for children, the elderly and other people who have difficulty taking medicine), It has the characteristics of rapid onset and remarkable curative effect.

The experimental data of the present invention are as follows:

In the comparative experiment of diammonium glycyrrhizinate lipoplex effervescent granules and diammonium glycyrrhizinate capsules on acute liver damage, mice were injected intraperitoneally with carbon tetrachloride to reproduce the acute liver damage model and used to measure serum ALT , AST and pathological observation of the liver.

The results showed that compared with Diammonium Glycyrrhizinate Capsules, Diammonium Glycyrrhizinate Lipid Complex Effervescent Granules could better reduce the ALT level in mice with acute liver injury (P<0.01). The effervescent granule of substance complex can significantly reduce the pathological score of carbon tetrachloride-infected liver tissue (P<0.01).

The blood drug concentration and liver tissue concentration of the diammonium glycyrrhizinate lipoplex effervescent granule group were about 2 times and 26 times that of the diammonium glycyrrhizinate capsule group; The liver tissue concentration of the effervescent granule group is about 13-14 times of the blood concentration, and the blood concentration of the diammonium glycyrrhizinate capsule group is basically the same as the liver tissue concentration.

Therefore, diammonium glycyrrhizinate lipid complex effervescent granules can significantly increase the drug concentration in mice, and can effectively enrich the drug into the liver tissue, playing a targeting role, and has a certain effect on acute chemical liver injury in mice. Better protective effect; thus, diammonium glycyrrhizinate lipid complex effervescent granules can effectively improve drug absorption and bioavailability, so as to achieve the effect of protecting liver cell membrane and improving liver function, and the curative effect is remarkable.

The "parts" described herein are all parts by weight.

Claims (8)

1. the preparation method of diammonium glycyrrhizinate lipid complex effervescent granule, carry out according to following steps:

1) extracting liquorice acid diammonium lipid complex 30-35 part, ascorbic acid 12-18 part, filler 126-132 part, citric acid 30-35 part, sodium bicarbonate clathrate 50-55 part and sodium chloride 28-32 part are evenly mixed the back and are formed diammonium glycyrrhizinate lipid complex mixture;

2) by wet granulation diammonium glycyrrhizinate lipid complex mixture is made diammonium glycyrrhizinate lipid complex effervescent granule.

2. the preparation method of diammonium glycyrrhizinate lipid complex effervescent granule according to claim 1, it is characterized in that: the preparation method of described diammonium glycyrrhizinate lipid complex is:

1) in container, put into 8-12 part soybean phospholipid and 500 parts of oxolanes, then in 70 ± 4 ℃ water-bath by the magnetic agitation dissolving that refluxes, obtain the soybean phospholipid tetrahydrofuran solution;

2) take by weighing 8-12 part diammonium glycyrrhizinate purification thing, pour into then in the cooled soybean phospholipid tetrahydrofuran solution, shake gently the back in 70 ± 4 ℃ water-bath by the dissolving that refluxes more than the magnetic agitation 2-4h, after solution is clear and bright, take out and leave standstill;

3) above-mentioned solution is inclined supernatant to another container, rotary evaporation is distinguished the flavor of until no oxolane, porphyrize and sieving then, and obtaining content is the diammonium glycyrrhizinate lipid complex of 45-48%.

3. the preparation method of diammonium glycyrrhizinate lipid complex effervescent granule according to claim 2, it is characterized in that: the preparation method of described sodium bicarbonate clathrate is:

1) a certain amount of Polyethylene Glycol of heating and melting, the sodium bicarbonate of getting equivalent then stirs, and the Polyethylene Glycol that slowly adds fusion in the sodium bicarbonate carries out enclose, and enclose is cooled to room temperature after evenly;

2) with behind the above-mentioned clathrate porphyrize and sieve, obtain the sodium bicarbonate clathrate.

4. the preparation method of diammonium glycyrrhizinate lipid complex effervescent granule according to claim 3, it is characterized in that: described filler is xylitol or sucrose or glucose sugar or fructose or mannitol.

5. the preparation method of diammonium glycyrrhizinate lipid complex effervescent granule according to claim 4 is characterized in that: be added with fragrant citrus flavor essence or Fructus Citri tangerinae flavor essence or Fructus Fragariae Ananssae flavor essence or honey peach flavor essence in the described filler.

6. the preparation method of diammonium glycyrrhizinate lipid complex effervescent granule according to claim 5 is characterized in that: the method method of adding essence in the described filler is:

1) get a certain amount of filler and sieve, and with make granule after an amount of essence mixes;

2) above-mentioned granule is sieved, then in the environment more than 40 ± 3 ℃ more than the dry 2h;

3) will sieve behind the above-mentioned granule porphyrize.

7. the preparation method of diammonium glycyrrhizinate lipid complex effervescent granule according to claim 6, it is characterized in that: described wet granulation is:

1) diammonium glycyrrhizinate lipid complex mixture is added in the dehydrated alcohol make soft material, sieve then and make wet granular, and in the environment more than 40 ± 3 ℃ more than the dry 2h;

2) above-mentioned granule is sieved, adds mix homogeneously after 6 parts of microcrystalline Cellulose and the 0.15 part of magnesium stearate then, and under 40 ± 3 ℃ vacuum environment dry 2-3h;

3) above-mentioned granule is sieved, obtain diammonium glycyrrhizinate lipid complex effervescent granule.

8. the preparation method of diammonium glycyrrhizinate lipid complex effervescent granule according to claim 7, it is characterized in that: the preparation method of described diammonium glycyrrhizinate purification thing is:

1) in container, adds 100 parts of diammonium glycyrrhizinates and 700-900 part ethanol water, and in 100 ± 5 ℃ water-bath, be heated to dissolved state;

2) with above-mentioned solution left standstill a moment, incline then and get supernatant cooling to another container and leave standstill 10-14h, obtain crystalline solid by sucking filtration;

3) add above-mentioned crystalline solid and 500-700 part ethanol water in the container, at 100 ± 5 ℃ heating in water bath to dissolved state;

4) repeating step 2), then crystalline solid is dried in the air to no ethanol flavor state;

5) with above-mentioned crystalline solid in the environment more than 55 ℃ more than the dry 24h, obtain content and be 97.3% diammonium glycyrrhizinate purification thing.