CN111517960A

CN111517960A - Continuous production nitroglycerin tablet

Info

Publication number: CN111517960A
Application number: CN202010423926.7A
Authority: CN
Inventors: 张志祥
Original assignee: Qidong Xinchen Enterprise Management Consulting Co ltd
Current assignee: Qidong Xinchen Enterprise Management Consulting Co.,Ltd.
Priority date: 2020-05-19
Filing date: 2020-05-19
Publication date: 2020-08-11

Abstract

According to the specific process for continuous production of raw materials and tablets of nitroglycerin, unexpected progress is made in the aspect of continuous production of green preparations of nitroglycerin through hard innovation, green, safe and risk-free synthesis is realized on key API preparation, and the combined API and nitroglycerin tablets are produced integrally.

Description

Continuous production nitroglycerin tablet

Technical Field

The invention belongs to the field of medicaments, and particularly relates to a nitroglycerin tablet produced continuously.

Background

Angina pectoris is a clinical syndrome with paroxysmal chest pain or chest discomfort caused by insufficient blood supply to coronary arteries, acute transient ischemia and hypoxia of cardiac muscle. Nitroglycerin can directly relax vascular smooth muscle, especially small vascular smooth muscle, to relax peripheral blood vessels, reduce peripheral resistance, reduce blood volume of return heart, reduce cardiac output, reduce cardiac load, and reduce myocardial oxygen consumption, thereby relieving angina pectoris. Nitroglycerin promotes the formation of collateral circulation. The medicine is taken by sublingual administration for 1 tablet, and the effect is achieved after 2-3 minutes, and the effect is maintained for about 30 minutes.

Nitroglycerin, also called glyceryl trinitrate, is formed by the nitration of glycerin. The reaction equation is as follows:

glyceryl trinitrate belongs to nitrate, nitrate is an important organic compound and plays a great role in the fields of war industry, medicine and energy, and polyol nitrate is used for preparing an explosive agent and a rocket propellant in the field of war industry; nitrate esters are used in the pharmaceutical field for the preparation of cardiotonic and vasodilators; alkyl nitrates are used in the petroleum processing field as promoters for the production of diesel cetane.

In the preparation of nitrate esters, the raw material nitric acid is a strong oxidizing agent which can continuously oxidize intermediates, namely partially nitrated mononitrate and dinitrate, and can also oxidize alkyl alcohol raw materials to form CO2, H2O and N2 in a positive feedback manner, so that potential explosion risks exist. Therefore, a key step in the production of nitrate esters is to improve the safety and controllability of the nitration step. Common nitration systems today include: concentrated nitric acid nitration, mixed acid nitration, N2O 5/organic solvent system. These nitration systems have their own advantages and disadvantages,

the yield of the concentrated nitric acid nitration is high, but the adaptability to the raw material is poor. The mixed acid nitration method has high yield, but has poor selectivity, difficult product separation and easy environmental pollution, and is not suitable for water-sensitive and acid-sensitive substances. The N2O 5/organic solvent system has mild conditions, can nitrify acid-sensitive substances or water-sensitive substances and can selectively nitrify multifunctional substances, and has the defect that the organic solvent is generally a toxic chlorinated hydrocarbon solvent. To solve these problems, the prior art discloses related art solutions.

The nobel explosive and system technology limited liability company discloses cn200580005057.x, disclosing a method for the preparation of liquid nitrates by mixing an alcohol solution with nitrating acid in a microreactor for the preparation of glycerol trinitrate or ethylene glycol dinitrate, using a microreactor or micromixer in the sub-millimeter range, which can achieve significantly higher reaction temperatures (30-50 ℃ c, rather than the usual 25-30 ℃) without increasing safety risks.

The key invention of the nobel explosive and system technology company, llc, includes microreactors. Microreactors are one of the important areas of development in chemical synthesis today.

The microreactor is described in detail in the point that the DPX Fine chemistry CN200880122237.X from Austria diplex is likewise inventive. The advantages of laminar flow are particularly emphasized in discussing microreactor publications. It is highly desirable in the prior art that the Reynolds number (Reynolds number) be significantly below 1000. Microreactors, micromixers and micro heat exchangers have been developed in germany (i.e. IMM, Mainz and forschunszentrumkarlsruhe) and in the us (i.e. MIT and DuPont).

DPX fine chemistry austria diploma clearly indicates: a problem associated with the use of multiphase systems in continuous reactors, in particular in microreactors, is the mixing of the two phases. The movement of fluids through the reactor typically occurs with Taylor flow or slug flow. This results in alternating discrete zones of each phase flowing through the reactor at the same rate, allowing some degree of mass transfer.

CN200610154338.8 was filed by the board of university of california, disclosing a method for forming a chemical microreactor for mixing liquid sources such as ammonia, methanol, and butane with an appropriate amount of water and producing hydrogen fuel by a steam reforming process.

FMC ltd filed cn200680039719.x, disclosing the preparation of hydrogen peroxide by an autoxidation process via hydrogenation in a microreactor. A working solution comprising a reactive carrier compound is hydrogenated with hydrogen in a microreactor and subsequently autooxidised to form hydrogen peroxide.

CN200980120326.5 filed by international company for microfluidics discloses an apparatus, system and method that provides the use of microreactor technology to achieve desired mixing and interaction at the micro and/or molecular level between feed stream components.

CN201380010683.2 filed by corning incorporated discloses a method for oxidizing at least one alcohol group of at least one chemical compound to the corresponding carbonyl group in the presence of a buffered oxidizing hypohalous acid solution and a nitrogen oxide oxidizing catalyst, wherein the method is carried out within a microreactor.

Under the usual experimental conditions, this reaction is very dangerous: the mechanical sensitivity of the frozen nitroglycerin is higher than that of the liquid, and the mechanical sensitivity is higher when the frozen nitroglycerin is in a semi-frozen state; the explosion danger is caused by sudden cold and heat, impact and friction and when the fire is exposed and the heat is high; contact with strong acids can cause a strong reaction, causing combustion or explosion. This hazardous characteristic is the most important obstacle to nitroglycerin production.

The invention obtains unexpected progress in the aspect of continuous production of the green preparation of the nitroglycerin through hard innovation, realizes green, safe and risk-free synthesis on key API preparation, and subsequently integrally produces the combined API and the nitroglycerin preparation to develop an End to End process capable of implementing continuous production.

Disclosure of Invention

The invention relates to a nitroglycerin tablet, which is characterized in that: mixing concentrated sulfuric acid with fuming nitric acid through a microreactor chip (1); glycerol and dichloromethane are input into a mixer (2), mixed acid liquor of a micro-reactor chip (1) and solution of the mixer (2) are input into one or more combinations of micro-reactor chips (3), (4) and (5), reaction liquid is reserved in a micro-reactor, the reaction liquid is input into a liquid-liquid separator (6) from the micro-reactor chip, the acid liquor is input into a waste liquid processor, organic phase and water are input into the mixer (7) to be mixed and then input into a liquid-liquid separator (8), the water phase is input into the waste liquid processor, the organic phase and saturated salt solution are input into a liquid-liquid separator (9), the water phase is input into the waste liquid processor, the organic phase is connected with a molecular sieve desiccant column (10), the nitroglycerin concentration is detected through an active carbon column (11) through an ultraviolet detector (12), the dichloromethane flow rate is adjusted according to the nitroglycerin concentration and then input into a, a nitroglycerin dichloromethane solution was obtained. Preparing particles and tablets by using nitroglycerin and dichloromethane solution.

The invention relates to a nitroglycerin tablet, which is characterized in that: concentrated sulfuric acid and fuming nitric acid are mixed by a microreactor chip (1) in a ratio of 1: 1, mixing at a speed ratio; glycerol and dichloromethane were mixed at a ratio of (0.2-2): (2-10) inputting the speed ratio into the mixer (2), and mixing the acid solution of the microreactor chip (1) with the solution of the mixer (2) in the ratio of (0.2-10): the speed ratio of (1-5) is input into one or more combinations of the micro-reactor chips (3), (4) and (5), the retention time of the reaction liquid in the micro-reactor is 10min to 30min, the reaction liquid is input into a liquid-liquid separator (6) from the micro-reactor chip, acid liquid is input into a waste liquid processor, organic phase and water are mixed in an input mixer (7), inputting into a liquid-liquid separator (8), inputting the water phase into a waste liquid processor, inputting the organic phase and the saturated salt solution into a liquid-liquid separator (9), inputting the water phase into the waste liquid processor, inputting the organic phase into a molecular sieve desiccant column (10), the concentration of the nitroglycerin is detected by an active carbon column (11) and an ultraviolet detector (12), the flow rate of dichloromethane was adjusted in accordance with the nitroglycerin concentration and fed to a mixer (13) to obtain a nitroglycerin dichloromethane solution of 10% concentration. . Preparing particles and tablets by using nitroglycerin and dichloromethane solution.

Pumping the 10% nitroglycerin dichloromethane solution into a hot melt extruder, and adding lactose particles, wherein the ratio of the 10% nitroglycerin dichloromethane solution to the lactose particles is (2-20 ml): (1-20 g), granulating by adopting a wet granulation mode, and drying in vacuum to obtain green particles of nitroglycerin.

2-5 ml of 10% nitroglycerin dichloromethane solution, 20-15 g of beta-cyclodextrin and 0.1-1.0 g of polyvinylpyrrolidone; taking beta-cyclodextrin, adding a proper amount of water for injection, and stirring to completely dissolve the raw materials; slowly adding nitroglycerin solution and polyvinylpyrrolidone, stirring while adding until completely mixing, and stirring for inclusion for 2-4 h; vacuum drying to obtain green preparation of nitroglycerin;

2-20 ml of 10% nitroglycerin dichloromethane solution, 1-10 g of polyvinylpyrrolidone and 2-40 g of lactose; adding appropriate amount of water for injection, slowly adding nitroglycerin solution, polyvinylpyrrolidone and lactose, stirring while adding until completely mixing, and stirring for about 2-4 hr; vacuum freeze-drying to obtain green freeze-dried particles of nitroglycerin.

Microreactor chip (1): the microreactor consists of a set of chips, and the single chip can play a role in mixing and preheating or precooling.

The microreactor chips (3), (4) and (5) are the same chip, and the reaction time is increased by increasing the number of chips.

The temperature of the microreactor is controlled by the high-low temperature all-in-one machine, the insulating sleeve is arranged on the outer layer of the microreactor, and the reaction problem of the microreactor can be controlled when the cooling liquid in the high-low temperature all-in-one machine flows through the insulating sleeve

The micro-reactor is provided with a pressure sensor, and the pressure is controlled by controlling the flow rate.

The green granular preparation of the nitroglycerin and the green freeze-dried preparation of the nitroglycerin are prepared into the following specific green preparations of the nitroglycerin according to a conventional method: tablet, sublingual tablet, buccal tablet, and oral administration.

The green granular preparation of the nitroglycerin and the green freeze-dried preparation of the nitroglycerin are prepared into the following specific green preparations of the nitroglycerin according to a conventional method: can be used for preparing medicines for treating or preventing coronary heart disease, angina pectoris, and myocardial infarction.

The invention relates to an analysis method of nitroglycerin and related substances, which comprises the following steps:

chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile-water (40: 60) as mobile phase; the detection wavelength was 215 nm. And taking a proper amount of nitroglycerin reference substance and isosorbide dinitrate, adding a mobile phase for dissolving, preparing a solution containing 20 mu g of nitroglycerin and isosorbide dinitrate in each 1ml, taking 20 mu l of the solution to inject into a liquid chromatograph, recording a chromatogram, wherein the number of theoretical plates is not less than 2000 calculated according to the nitroglycerin peak, and the separation degree of the nitroglycerin peak and the isosorbide dinitrate peak is in accordance with the requirement.

The determination method comprises the following steps: taking a sample to be detected, placing the sample into a 250ml quantitative bottle, precisely adding 50ml of mobile phase, fully shaking to dissolve nitroglycerin, filtering, precisely taking 2ml of subsequent filtrate, placing the subsequent filtrate into a 50ml quantitative bottle, adding the mobile phase to dilute to a scale, shaking uniformly, precisely measuring 20 mu l, injecting into a liquid chromatograph, and recording a chromatogram; taking a proper amount of nitroglycerin as a reference substance, adding a mobile phase to prepare a solution containing 20 mu g of nitroglycerin in each 1ml, and determining by the same method: the amount of nitroglycerin contained in each tablet is calculated by the peak according to an external standard method.

The nitroglycerin has absorption to ultraviolet light and strong hydrophobicity, the main impurities of the nitroglycerin are GMN and GDN, the GMN and the GDN respectively have 1 hydroxyl and 2 hydroxyl, the hydrophobicity is weaker than that of GTN, and the GMN and the GDN have absorption to the ultraviolet light. The invention adopts High Performance Liquid Chromatography (HPLC) to analyze the related substances of nitroglycerin, and the detector is an ultraviolet detector

The invention relates to an infrared spectrum of nitroglycerin, which comprises the following components in percentage by weight:

vacuumizing the glycerol dichloromethane solution synthesized by the microreactor and the nitroglycerin ethanol solution synthesized by the flask, removing dichloromethane and ethanol, and performing infrared spectrogram test.

Test example 1:

optimization process of nitroglycerin synthesis process of microreactor

Glycerol produces Glycerol Mononitrate (GMN), glycerol dinitrate (GDN: 1,2-GDN, 1,3-GDN) and Glycerol Trinitrate (GTN) during nitroesterification.

When nitroglycerin is prepared according to the present invention, the molar ratio of nitric acid to glycerin is preferably 3: 1-10: 1.

the reaction temperature for preparing the nitroglycerin is 5-15 ℃, and the reaction temperature is particularly preferably 10 ℃.

The reaction time for preparing nitroglycerin is 1-15 minutes, and the preferable time is 5 minutes.

According to different conditions, nitroglycerin is prepared, and a final product is analyzed by High Performance Liquid Chromatography (HPLC), wherein a detector is an ultraviolet detector.

The results of the nitroglycerin reaction in the microreactor are listed in the following table:

comparative test example 1:

the method for synthesizing nitroglycerin in the flask is as follows: adding 5mL of concentrated sulfuric acid into a 20mL flask, cooling to below 5 ℃ in an ice-water bath, adding 5mL of fuming nitric acid, keeping the temperature below 5 ℃, dropwise adding 1.5mL of glycerol within 2 minutes, keeping the temperature at 5 ℃, stirring for 30min, pouring into an aqueous solution, mixing, separating liquid, discarding an aqueous phase, adding 5mL of saturated sodium carbonate solution into an organic phase, immediately separating liquid, discarding the aqueous phase, adding 5mL of saturated sodium chloride solution into the organic phase, immediately separating liquid, discarding the aqueous phase, adding 5mL of anhydrous sodium sulfate into the organic phase, drying, adding 5mL of ethanol, and placing in a refrigerator for analysis.

The results of the reaction for synthesizing nitroglycerin from the flask are listed in the following table:

test example 2

HPLC integration of nitroglycerin in microreactors

Advantageous technical Advances in the invention

The new process solves the explosive problem in the reaction process by means of a microreactor, changing the reaction mode, adding a solvent and the like: (1) the nitroglycerin is diluted by the inert solvent, so that the probability of mutual collision among nitroglycerin molecules is reduced; (2) the problem of easy explosion of nitroglycerin pipeline transportation and storage is solved. The new process adopts a micro-reactor technology, overcomes the difficulty of mixing and layering of the glycerol and the inert solvent, and solves the problem of large-scale heat release which is difficult to control in the reaction process. HPLC detection shows that the purity is over 99%.

Advantageous technical Advances in the invention

The composition of the invention can be applied to a subject and can be used for treating or preventing coronary heart disease and angina pectoris.

The compositions of the present invention may be applied to the skin of a subject for promoting wound healing, including cuts, abrasions, wounds, burns, lacerations or other accidental wounds. The wound site includes an anal fissure, a surgical site, a trauma site, or any other damaged area of the skin.

The composition of the invention can be applied to the skin of a subject for promoting the healing of bone fractures, fractures.

The compositions of the present invention may be administered to a subject, including the skin of a subject, for the treatment or prevention of sexual dysfunction, including erectile dysfunction.

Drawings

FIG. 1: scheme 1

FIG. 2: HPLC FIG. 1

FIG. 3: HPLC FIG. 2

FIG. 4: infrared atlas

FIG. 1 is a schematic illustration of

1. A microreactor chip; 2. a mixer;

3. a micro reactor chip, 4, 5, a micro reactor chip;

6. zaiput liquid-liquid separator; 7. a mixer, a water-gas separator and a water-gas separator,

8. zaiput liquid-liquid separator; 9. a liquid-liquid separator of Zaiput,

10. a molecular sieve desiccant column; 11. an activated carbon column;

12. an ultraviolet detector; 13. a mixer.

The present invention is not limited to the above-described embodiments, and the present invention is not limited to the above-described examples, and those skilled in the art may make variations, modifications, additions and substitutions within the spirit and scope of the present invention. And shall also fall within the scope of the present invention.

The specific implementation mode is as follows:

example 1:

a tablet of nitroglycerin characterized by: mixing concentrated sulfuric acid with fuming nitric acid through a microreactor chip (1); glycerol and dichloromethane are input into a mixer (2), mixed acid liquid of a microreactor chip (1) and solution of the mixer (2) are input into microreactor chips (3), (4) and (5), reaction liquid is reserved in a microreactor, the reaction liquid is input into a Zaiput liquid-liquid separator (6) from the microreactor chip (5), acid liquid is input into a waste liquid processor, organic phase and water are input into the mixer (7) to be mixed and then input into the Zaiput liquid-liquid separator (8), aqueous phase is input into the waste liquid processor, organic phase and saturated salt solution are input into the Zaiput liquid-liquid separator (9), aqueous phase is input into the waste liquid processor, organic phase is input into a molecular sieve desiccant column (10), nitroglycerin concentration is detected through an active carbon column (11) through an ultraviolet detector (12), dichloromethane flow rate is adjusted according to the nitroglycerin concentration and then input into a mixer (13), a nitroglycerin dichloromethane solution was obtained. Preparing particles and tablets by using nitroglycerin and dichloromethane solution.

Example 2:

a tablet of nitroglycerin characterized by: concentrated sulfuric acid and fuming nitric acid are mixed by a microreactor chip (1) in a ratio of 1: 1, mixing at a speed ratio; glycerol was mixed with dichloromethane at a ratio of 0.2: 2 speed ratio is input into the mixer (2), and the mixed acid liquid of the micro-reactor chip (1) and the solution of the mixer (2) are mixed in a ratio of 2: 2.75 of the speed ratio is input into the micro-reactor chips (3), (4) and (5), the retention time of the reaction liquid in the micro-reactor is 10min to 30min, the reaction liquid is input into the Zaiput liquid-liquid separator (6) from the micro-reactor (5), the acid liquid is input into the waste liquid processor, the organic phase and the water are mixed in the input mixer (7), inputting into a Zaiput liquid-liquid separator (8), inputting the water phase into a waste liquid processor, inputting the organic phase and the saturated salt solution into a Zaiput liquid-liquid separator (9), inputting the water phase into the waste liquid processor, passing the organic phase through a molecular sieve desiccant column (10), the concentration of the nitroglycerin is detected by an active carbon column (11) and an ultraviolet detector (12), the flow rate of dichloromethane was adjusted according to the concentration of nitroglycerin and the mixture was fed into a mixer (13) to obtain a nitroglycerin dichloromethane solution of 10% concentration, to prepare granules, and to prepare tablets.

Nitroglycerin green particle (1)

A 10% nitroglycerin dichloromethane solution (10 ml) was pumped into a hot melt extruder, 9 g of lactose particles were added, granulated using a wet granulation mode, and dried under vacuum to give green nitroglycerin particles (1).

Green freeze-dried granule of nitroglycerin (1)

20ml of 10% nitroglycerin dichloromethane solution, 5 g of polyvinylpyrrolidone and 18 g of lactose; adding appropriate amount of water for injection, slowly adding 0% nitroglycerin dichloromethane solution, polyvinylpyrrolidone and lactose, stirring while adding until completely mixing, and stirring for about 2-4 hr; vacuum freeze-drying yielded green freeze-dried particles of nitroglycerin (1).

Green freeze-dried granule of nitroglycerin (2)

2ml of 10% nitroglycerin dichloromethane solution, 15 g of beta-cyclodextrin and 0.5 g of polyvinylpyrrolidone; taking beta-cyclodextrin, adding a proper amount of water for injection, and stirring to completely dissolve the raw materials; slowly adding nitroglycerin solution and polyvinylpyrrolidone, stirring while adding until completely mixing, and stirring for inclusion; vacuum drying gave green lyophilized particles of nitroglycerin (2).

Example 3:

nitroglycerin green tablet (1)

The weight ratio of each component

The preparation method comprises the following steps:

(1) dry-mixing nitroglycerin green particles with microcrystalline cellulose sieved by a 200-mesh sieve for 1 hour, uniformly stirring, and mixing for 3 hours to prepare a soft material; preparing wet granules; drying at 40 deg.C for 4 hr; sieving the dried granules with a 80-mesh sieve; finishing granules to obtain medicine-containing granules;

(2) mixing the medicinal granules, crospovidone and magnesium stearate, and tabletting.

Nitroglycerin tablet (2)

The weight ratio of each component

The method comprises the following steps:

Example 4:

green sublingual tablet of nitroglycerin (1)

The weight ratio of each component

The preparation method comprises the following steps:

(1) weighing microcrystalline cellulose according to a prescription, wetting by using a low-substituted hydroxypropyl cellulose and an ethanol solution (40%) of polyvinylpyrrolidone, preparing a soft material, passing the soft material through a 16-mesh sieve, and drying the obtained particles at 50 ℃ to prepare blank particles;

(2) weighing green particles of nitroglycerin and sorbitol according to a prescription, passing the soft material through a 80-mesh sieve by an extrusion method, and drying the obtained particles at 30 ℃ under reduced pressure to obtain medicine-containing particles;

(3) mixing the blank granules and the medicine-containing granules, adding crospovidone and magnesium stearate, and mixing; and (6) tabletting.

Green sublingual tablet of nitroglycerin (2)

The weight ratio of each component

The method comprises the following steps:

(2) weighing green lyophilized granule (1) of nitroglycerin and sorbitol according to a prescription, passing the soft material through 80 mesh sieve by extrusion method, and drying the obtained granule under reduced pressure at 30 deg.C to obtain granule containing medicine;

Example 5:

4 rats are randomly divided into two groups, a reperfusion model of isolated rat cardiac myocardial ischemia is established, in a low-flow ischemia period, a nitroglycerin group (2 using groups) and a nitroglycerin group (2 control groups) are applied, and the reperfusion injury of the isolated rat cardiac myocardial ischemia is examined by using green particles of the nitroglycerin (1 multiplied by 10(-3) mmol/L nitroglycerin, the perfusion of a bicarbonate buffer solution) and the perfusion of the control group only giving the bicarbonate buffer solution. The control group of cardiomyocytes showed severe mitochondrial vacuolar degeneration and rupture of the myocardial fibers. The myocardial cells of the drug group have no mitochondrial vacuole degeneration and no rupture of myocardial fibers. The conclusion of the above experimental data is that: the green nitroglycerin particles can obviously improve the bad reconstruction of the heart of the rat with heart failure after myocardial infarction, effectively protect the heart function, and can prevent or treat myocardial infarction, coronary heart disease and angina.

Example 6:

Peak Number，X(cm-1)，Y(％T)

1，3437.02，64.96

2，2918.54，69.

3，1645.46，58.06

4，1428.09，72.64

5，1275.55，55.65

6，1009.74，71.00

7，838.78，65.70

8，764.16，56.08

9.750.04，51.02。

Claims

1. a tablet of nitroglycerin characterized by: mixing concentrated sulfuric acid with fuming nitric acid through a microreactor chip (1); glycerol and dichloromethane are input into a mixer (2), mixed acid liquid of a micro-reactor chip (1) and solution of the mixer (2) are input into one or more combinations of micro-reactor chips (3), (4) and (5), reaction liquid is reserved in a micro-reactor, the reaction liquid is input into a liquid-liquid separator (6) from the micro-reactor chip, acid liquid is input into a waste liquid processor, organic phase and water are input into the mixer (7) to be mixed and then input into a liquid-liquid separator (8), the water phase is input into the waste liquid processor, the organic phase and saturated salt solution are input into a liquid-liquid separator (9), the water phase is input into the waste liquid processor, the organic phase is connected with a molecular sieve desiccant column (10), the nitroglycerin concentration is detected through an active carbon column (11) through an ultraviolet detector (12), the dichloromethane flow rate is adjusted according to the nitroglycerin concentration and then input into a mixer (, obtaining nitroglycerin dichloromethane solution, preparing the nitroglycerin dichloromethane solution into particles, and then preparing the tablets.

2. A tablet of nitroglycerin according to claim 1, characterized in that: concentrated sulfuric acid and fuming nitric acid are mixed by a microreactor chip (1) in a ratio of 1: 1, mixing at a speed ratio; glycerol and dichloromethane were mixed at a ratio of (0.2-2): (2-10) inputting the speed ratio into the mixer (2), and mixing the acid solution of the microreactor chip (1) with the solution of the mixer (2) in the ratio of (0.2-10): the speed ratio of (1-5) is input into one or more combinations of micro-reactor chips (3), (4) and (5), the retention time of the reaction liquid in the micro-reactor is 10min to 30min, the reaction liquid is input into a liquid-liquid separator (6) from the micro-reactor chip, the acid liquid is input into a waste liquid processor, the organic phase and the water are input into a mixer (7) to be mixed and then input into a liquid-liquid separator (8), the water phase is input into the waste liquid processor, the organic phase and the saturated salt solution are input into a liquid-liquid separator (9), the water phase is input into the waste liquid processor, the organic phase is passed through a molecular sieve desiccant column (10), the nitroglycerin concentration is detected through an ultraviolet detector (12) through an activated carbon column (11), the flow rate of the dichloromethane is adjusted according to the nitroglycerin concentration and then input into a mixer (13) to, the nitroglycerin and dichloromethane solution is prepared into particles and then is prepared into a tablet.

3. A tablet of nitroglycerin according to claim 1, characterized in that:

the ratio of 10% nitroglycerin dichloromethane solution to lactose was (2-20 ml): (1-20 grams);

pumping the nitroglycerin dichloromethane solution with the concentration of 10% into a hot melt extruder, adding lactose, granulating by adopting a wet granulation mode, and drying in vacuum to obtain green nitroglycerin granules;

the method for preparing a nitroglycerin solution according to claim 1.

4. A tablet of nitroglycerin according to claim 1, characterized in that:

2-5 ml of 10% nitroglycerin dichloromethane solution, 20-15 g of beta-cyclodextrin and 0.1-1.0 g of polyvinylpyrrolidone;

taking beta-cyclodextrin, adding a proper amount of water for injection, and stirring to completely dissolve the raw materials; slowly adding 10% nitroglycerin dichloromethane solution and polyvinylpyrrolidone, stirring while adding until completely mixing, and stirring for inclusion for 2-4 h; vacuum drying to obtain green particles of nitroglycerin;

the method for preparing a nitroglycerin solution according to claim 1.

5. A tablet of nitroglycerin according to claim 1, characterized in that:

2-20 ml of 10% nitroglycerin dichloromethane solution, 1-10 g of polyvinylpyrrolidone and 2-40 g of lactose;

adding appropriate amount of water for injection, slowly adding 10% nitroglycerin dichloromethane solution, polyvinylpyrrolidone and lactose, stirring while adding until completely mixing, and stirring for about 2-4 hr; vacuum freeze-drying to obtain green freeze-dried particles of nitroglycerin.

The method for preparing a nitroglycerin solution according to claim 1.

6. A nitroglycerin tablet according to claims 1-4, for use in the preparation of tablets, sublingual tablets, buccal tablets.

7. A nitroglycerin tablet according to claims 1-4, for use in the preparation of: a medicament for treating or preventing coronary heart disease, a medicament for treating or preventing angina pectoris, and a medicament for treating or preventing myocardial infarction.