CN108084031B - A kind of preparation method of nitroglycerin - Google Patents
A kind of preparation method of nitroglycerin Download PDFInfo
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- CN108084031B CN108084031B CN201711401087.3A CN201711401087A CN108084031B CN 108084031 B CN108084031 B CN 108084031B CN 201711401087 A CN201711401087 A CN 201711401087A CN 108084031 B CN108084031 B CN 108084031B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/02—Preparation of esters of nitric acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C203/00—Esters of nitric or nitrous acid
- C07C203/02—Esters of nitric acid
- C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
- C07C203/06—Glycerol trinitrate
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Abstract
The invention discloses a kind of preparation methods of nitroglycerin, comprising the following steps: (1) nitration reaction；(2) it refines: A, purifying water washing；B, desiccant removes water；C, activated carbon adsorption.The present invention also provides the nitroglycerins and its ethanol solution that are prepared according to the method.Preparation method yield provided by the invention is high, it is few to generate impurity, the decomposition of reaction temperature, residual moisture and acid to nitroglycerin can effectively be avoided, reduce the decomposition product of nitroglycerin, nitroglycerin and its ethanol solution are controlled in storing process in relation to the content of substance, keep nitroglycerin product more stable, it is ensured that quality meets relevant regulations before the deadline for it.
Description
Technical field
The invention belongs to chemical technology fields, and in particular to a kind of preparation method of nitroglycerin.
Background technique
Nitroglycerin, scientific name are glycerine trisnitrate (glycerol trintrate), and molecule skeleton symbol is C3H5(ONO2)3,
It is the product that esterification occurs for glycerol and nitric acid.In field of medicaments, nitroglycerin energy vasodilator follows to be conducive to blood
Ring significantly improves effect to cardiovascular system generation.
Nitroglycerin determines that it is a kind of than more sensitive drug based on itself structure and speciality, impurity,
Water, acid, temperature can all decompose it and have an impact.It is documented that nitroglycerin fusing point be 2.8 DEG C, be instability mode, 13.5
DEG C when be stable type, 50 DEG C or more start to decompose, and when temperature be lower than 13.2 DEG C, it can generate crystallization.Nitroglycerin is in water
Solubility in although less (1.4kg/t water, 12 DEG C；1.5kg/t water, 20 DEG C), but in the washing process of manufacture nitroglycerin
In need to use a large amount of water, the loss by solution of nitroglycerin or considerable in water in this way, and nitroglycerin is having
In the presence of water, it is easy to decompose.So in production washing times and water should be reduced to the greatest extent under the premise of guaranteeing quality
Amount, while should as far as possible eliminate the remaining water of nitroglycerin, in order to avoid reduce yield and generate impurity.In addition, used in reaction
Nitration mixture (fuming nitric aicd and the concentrated sulfuric acid) for nitroglycerin in addition to have dissolution ability other than, also have the function of decomposition,
Therefore deacidification step is particularly critical in system after the reaction.
Remaining water and acid can all cause nitroglycerin to decompose in temperature, reaction solution in above-mentioned production process, decompose
Product has 1,2- dinitro acid glycerol and 1,3- dinitro acid glycerol, " Chinese Pharmacopoeia " version in 2015 to this two kinds of related content of material into
Restriction is gone, further, this two kinds of impurity present in nitroglycerin will accelerate the decomposition of nitroglycerin, and it is sweet to eventually lead to nitric acid
Oil and its preparation related substance in storing process are exceeded, are unable to satisfy quality requirement.
Summary of the invention
Based on this, a kind of nitroglycerin is provided it is an object of the invention to overcome in place of above-mentioned the deficiencies in the prior art
Preparation method can effectively avoid the decomposition of reaction temperature, residual moisture and acid to nitroglycerin.
To achieve the above object, the technical scheme adopted by the invention is as follows: a kind of preparation method of nitroglycerin, including following
Step: (1) nitration reaction: weighing and be cooled to 10 DEG C 1~5 part of fuming nitric aicd below, and addition is placed in the reaction vessel of ice bath,
It is slowly added to be cooled to 10 DEG C 2~8 parts of the concentrated sulfuric acid below while stirring, is uniformly mixed, obtains mixed acid；Acid cooling to be mixed
When to 15 DEG C or less, 0.5~2 part of glycerine is slowly added dropwise while stirring, reacting liquid temperature control is 12~18 during dropwise addition
℃；Continue 0.5~1.0h of stirring after being added dropwise at 12~18 DEG C, after stratification, abandons lower layer's acid solution, it is thick to obtain nitroglycerin
Product；
(2) refine: A, purifying water washing: the nitroglycerin crude product that step (1) obtains is transferred to be placed in advance it is isometric pure
In the liquid separatnig container for changing water, washing is fullyd shake, after stratification, abandon supernatant liquid, wash 8~10 times repeatedly with method to wash-off
Liquid pH value is 5.5~7.0；
Or the nitroglycerin crude product that step (1) obtains is transferred in the liquid separatnig container for being placed with isometric buffer salt in advance, it fills
Divide concussion, stratification is collected lower liquid and is transferred in the liquid separatnig container for being placed with isometric purified water in advance, fullys shake and wash
It washs, stratification, abandons supernatant liquid, washed repeatedly with purified water 3~5 times with method, until eluate pH value 5.5~7.0.
B, desiccant removes water: the nitroglycerin crude product that step A is obtained being transferred in the container of drying, it is thick that nitroglycerin is added
The desiccant of product weight 0.5~1.0%, sealing are stood to complete clarification, and filtrate is collected in filtering；
C, activated carbon adsorption: being added the active carbon of filtrate weight 1.5~3.0% in the filtrate obtained to step B, sufficiently mixed
It is even, 24~72h is stood, filtering collects filtrate to get the nitroglycerin.
Preferably, the step (1), which weighs, is cooled to 10 DEG C 2.5 parts of fuming nitric aicd below, and addition is placed in the anti-of ice bath
It answers in container, is slowly added to be cooled to 10 DEG C 4 parts of the concentrated sulfuric acid below while stirring, be uniformly mixed, obtain mixed acid；It is to be mixed
When acid is cooled to 15 DEG C or less, 1 part of glycerine is slowly added dropwise while stirring.
Preferably, it should slowly, be at the uniform velocity added dropwise when glycerine is added dropwise into mixed acid for the step (1), and in 2 hours
It is added dropwise.
Preferably, buffer salt is ammonia-ammonium chloride, borax-calcium chloride, boric acid-potassium chloride in the step A of the step (2)
Or sodium tetraborate-sodium phosphate buffer salt；In the step B of the step (2) desiccant be selected from anhydrous calcium chloride, anhydrous sodium sulfate or
Anhydrous magnesium sulfate.
Preferably, active carbon is passing through pretreatment, the preprocess method using preceding in the step C of the step (2) are as follows:
Alkaline matter solid abrasive is at powder, by alkaline matter powder and active carbon by 1:(5~20) mass ratio mix well after,
Drying to get；Preferably, the alkaline matter is selected from KOH, NaOH or NaHCO3.
Anhydrous calcium chloride, anhydrous sodium sulfate and anhydrous magnesium sulfate is added in the present invention in purifying the nitroglycerin after water washing
A possibility that equal desiccant, the absorbable a small amount of water remained in nitroglycerin, reduction causes nitroglycerin to decompose due to water.Into
Active carbon after alkali process is added by standing in the nitroglycerin of aforementioned purifying water washing and desiccant water suction step one step
Absorption, on the one hand can be by the adsorption bleaching function of active carbon, by nitroglycerin in nitration reaction, purifying water washing and desiccant
Decomposed in water absorption course generation related substance (1,2- dinitro acid glycerol, 1,3- dinitro acid glycerol) and other impurity absorptions；Separately
On the one hand, through the processing of super-alkaline substance, active carbon is in that alkalescent further neutralizes remaining acid while absorption.Invention
People's discovery, the additional amount of active carbon treatment process neutral and alkali substance need strict control, can obtain most in the application use scope
Otherwise good effect will lead to nitroglycerin pH value greater than 7, meta-alkalescence can accelerate the decomposition of nitroglycerin.
It is another object of the present invention to provide the nitroglycerins that above-mentioned preparation method is prepared.
The present invention also provides a kind of nitroglycerin solutions, and it includes the nitroglycerins.
The present invention also provides the preparation methods of the nitroglycerin solution, comprising the following steps: (1) according to claim
Nitroglycerin is prepared in any one of 1~3 the method；It (2) is by weight that 1g:10 mL takes above-mentioned nitroglycerin with volume ratio
And dehydrated alcohol, it is uniformly mixed to get the nitroglycerin solution.
Preferably, the nitroglycerin solution obtained in the step (2) can further pass through alkalescent packed column；It is preferred that
Ground, the alkalescent packed column is in alumina filled column, magnesia packed column, calcium carbonate-filled column and unmodified packed column
It is at least one.
The present invention also provides a kind of nitroglycerin injections, and it includes the nitroglycerins.
The present invention also provides the preparation methods of the nitroglycerin injection, comprising the following steps: (1) is wanted according to right
Ask 6 the methods that nitroglycerin solution is prepared；(2) nitroglycerin solution and dehydrated alcohol that step (1) obtains are pressed into body
Product is than being uniformly mixed for 1:10 to get the nitroglycerin injection.
Preferably, the nitroglycerin injection obtained in the step (2) can further pass through alkalescent packed column；It is preferred that
Ground, the alkalescent packed column is in alumina filled column, magnesia packed column, calcium carbonate-filled column and unmodified packed column
It is at least one.
Compared with the existing technology, the invention has the benefit that the throwing of (1) each raw material of preparation method strict control of the present invention
Material proportion, while temperature control is produced at 12~18 DEG C, the decomposition of nitroglycerin caused by reaction temperature can be effectively avoided, simultaneously
Avoid local impact, friction etc. that it is made to generate hot localised points and lead to accident；(2) preparation method of the present invention can effectively remove nitre
Remaining water and acid in acid glycerol avoid residual moisture from causing to reduce yield and generate impurity, while avoiding acid to nitroglycerin
Dissolution and decomposition；(3) preparation method of the present invention can effectively remove the decomposition product 1,2- dinitro of nitroglycerin in production process
Acid glycerol, 1,3- dinitro acid glycerol and other impurities, control nitroglycerin and its ethanol solution is being stored and transported
In relation to the content of substance in journey, keep nitroglycerin product more stable, it is ensured that quality meets relevant regulations before the deadline for it；(4)
Preparation method yield of the present invention is high, is more advantageous to energy-saving and emission-reduction, reduces loss.
Specific embodiment
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiment to the present invention
It is described further.
Embodiment 1
A kind of embodiment of nitroglycerin preparation method of the present invention, comprising the following steps: (1) nitration reaction: weigh cooling
To 3 parts of fuming nitric aicd of 10 DEG C, addition is placed in the reaction vessel of ice bath, is slowly added to be cooled to 10 DEG C of dense sulphur while stirring
6 parts of acid is uniformly mixed, obtains mixed acid；When acid to be mixed is cooled to 10 DEG C, 1 part of glycerine is slowly added dropwise while stirring, is added dropwise
Reacting liquid temperature control is at 12 DEG C in the process；Continue to stir 0.8h at 12 DEG C after being added dropwise, after stratification, abandons lower layer's acid
Liquid obtains nitroglycerin crude product；
(2) refine: A, purifying water washing: the nitroglycerin crude product that step (1) obtains is transferred to be placed in advance it is isometric pure
In the liquid separatnig container for changing water, washing is fullyd shake, after stratification, abandoning supernatant liquid washs 8 times repeatedly with method, measures wash-off
Liquid pH value is 7.0；B, desiccant removes water: the nitroglycerin crude product that step A is obtained being transferred in the container of drying, it is sweet that nitric acid is added
The anhydrous magnesium sulfate of oily crude product weight 0.7%, sealing are stood to complete clarification, and filtrate is collected in filtering；C, activated carbon adsorption: to
The active carbon of filtrate weight 2.5% is added in the filtrate that step B is obtained, mixes well, stands 60h, filtering collects filtrate, i.e.,
Obtain the nitroglycerin.
Embodiment 2
A kind of embodiment of nitroglycerin preparation method of the present invention, comprising the following steps: (1) nitration reaction: weigh cooling
To 1 part of fuming nitric aicd of 6 DEG C, addition is placed in the reaction vessel of ice bath, is slowly added to be cooled to 6 DEG C of the concentrated sulfuric acid while stirring
It 2 parts, is uniformly mixed, obtains mixed acid；When acid to be mixed is cooled to 15 DEG C, 0.5 part of glycerine is slowly added dropwise while stirring, is added dropwise
Reacting liquid temperature control is at 18 DEG C in the process；Continue to stir 0.5h at 18 DEG C after being added dropwise, after stratification, abandons lower layer's acid
Liquid obtains nitroglycerin crude product；
(2) refine: A, purifying water washing: the nitroglycerin crude product that step (1) obtains is transferred to be placed in advance it is isometric pure
In the liquid separatnig container for changing water, washing is fullyd shake, after stratification, abandoning supernatant liquid washs 10 times repeatedly with method, measures wash-off
Liquid pH value is 5.5；B, desiccant removes water: the nitroglycerin crude product that step A is obtained being transferred in the container of drying, it is sweet that nitric acid is added
The anhydrous calcium chloride of oily crude product weight 0.5%, sealing are stood to complete clarification, and filtrate is collected in filtering；C, activated carbon adsorption: to
The active carbon through alkali process of filtrate weight 1.5% is added in the filtrate that step B is obtained, mixes well, stands for 24 hours, filters, receive
Collect filtrate to get the nitroglycerin.
The active carbon alkali treatment method are as follows: powder and active carbon are pressed the matter of 1:5 at powder by NaHCO3 solid abrasive
Amount than after mixing well, drying to get.
Embodiment 3
A kind of embodiment of nitroglycerin preparation method of the present invention, comprising the following steps: (1) nitration reaction: weigh cooling
To 3.5 parts of fuming nitric aicd of 9 DEG C, addition is placed in the reaction vessel of ice bath, is slowly added to be cooled to 9 DEG C of dense sulphur while stirring
5.5 parts of acid is uniformly mixed, obtains mixed acid；When acid to be mixed is cooled to 15 DEG C, 1 part of glycerine is slowly added dropwise while stirring, drips
Reacting liquid temperature control is at 12 DEG C during adding；Continue to stir 0.7h at 12 DEG C after being added dropwise, after stratification, abandons lower layer
Acid solution obtains nitroglycerin crude product；
(2) refine: A, purifying water washing: the nitroglycerin crude product that step (1) obtains is transferred to be placed in advance it is isometric pure
In the liquid separatnig container for changing water, washing is fullyd shake, after stratification, abandoning supernatant liquid washs 9 times repeatedly with method, measures wash-off
Liquid pH value is 6.32；B, desiccant removes water: the nitroglycerin crude product that step A is obtained being transferred in the container of drying, nitric acid is added
The anhydrous calcium chloride of glycerol crude product weight 0.5%, sealing are stood to complete clarification, and filtrate is collected in filtering；C, activated carbon adsorption:
The active carbon through alkali process of filtrate weight 1.5% is added in the filtrate obtained to step B, mixes well, stands 50h, filters,
Filtrate is collected to get the nitroglycerin.
The active carbon alkali treatment method are as follows: powder and active carbon are pressed the matter of 1:20 at powder by NaHCO3 solid abrasive
Amount than after mixing well, drying to get.
Embodiment 4
A kind of embodiment of nitroglycerin preparation method of the present invention, comprising the following steps: (1) nitration reaction: weigh cooling
To 5 parts of fuming nitric aicd of 8 DEG C, addition is placed in the reaction vessel of ice bath, is slowly added to be cooled to 8 DEG C of the concentrated sulfuric acid while stirring
It 8 parts, is uniformly mixed, obtains mixed acid；When acid to be mixed is cooled to 12 DEG C, 2 parts of glycerine are slowly added dropwise while stirring, were added dropwise
Reacting liquid temperature control is at 16 DEG C in journey；Continue to stir 1.0h at 16 DEG C after being added dropwise, after stratification, abandons lower layer's acid
Liquid obtains nitroglycerin crude product；
(2) it refines: A, purifying water washing: the nitroglycerin crude product that step (1) obtains being transferred to and is placed with isometric boron in advance
It in sand-calcium chloride buffer salt liquid separatnig container, fullys shake, stratification, collects lower liquid and be transferred to preparatory be placed in equal volume
In the liquid separatnig container of purified water, washing fullys shake, stratification is abandoned supernatant liquid, is washed repeatedly with purified water 3 times with method,
Measure eluate pH value 7.0；B, desiccant removes water: the nitroglycerin crude product that step A is obtained being transferred in the container of drying, is added
The anhydrous sodium sulfate of nitroglycerin crude product weight 1.0%, sealing are stood to complete clarification, and filtrate is collected in filtering；C, active carbon
Absorption: the active carbon through alkali process of filtrate weight 3.0% is added in the filtrate obtained to step B, mixes well, stands
72h, filtering collect filtrate to get the nitroglycerin.
The active carbon alkali treatment method are as follows: powder and active carbon are pressed the quality of 1:10 at powder by KOH solid abrasive
After mixing well, drying to get.
Embodiment 5
A kind of embodiment of nitroglycerin preparation method of the present invention, comprising the following steps: (1) nitration reaction: weigh cooling
To 2.5 parts of fuming nitric aicd of 5 DEG C, addition is placed in the reaction vessel of ice bath, is slowly added to be cooled to 5 DEG C of dense sulphur while stirring
4 parts of acid is uniformly mixed, obtains mixed acid；When acid to be mixed is cooled to 10 DEG C, 1 part of glycerine is slowly added dropwise while stirring, is added dropwise
Reacting liquid temperature control is at 13 DEG C in the process；Continue to stir 0.8h at 13 DEG C after being added dropwise, after stratification, abandons lower layer's acid
Liquid obtains nitroglycerin crude product；
(2) it refines: A, purifying water washing: A, purifying water washing: the nitroglycerin crude product that step (1) obtains is transferred in advance
It is placed in isometric sodium tetraborate-sodium phosphate buffer salt liquid separatnig container, fullys shake, stratification, collect lower liquid and turn
Enter and be placed in the liquid separatnig container of isometric purified water in advance, fully shake washing, stratification abandons supernatant liquid, with method with pure
Change water to wash repeatedly 5 times, measures eluate pH value 5.5；B, desiccant removes water: the nitroglycerin crude product that step A is obtained is transferred to
In the container of drying, the anhydrous magnesium sulfate of nitroglycerin crude product weight 0.7% is added, sealing is stood to complete clarification, filtering,
Collect filtrate；C, activated carbon adsorption: being added the active carbon through alkali process of filtrate weight 2.5% in the filtrate obtained to step B,
It mixes well, stands 60h, filtering collects filtrate to get the nitroglycerin.
The active carbon alkali treatment method are as follows: powder and active carbon are pressed the quality of 1:15 at powder by NaOH solid abrasive
After mixing well, drying to get.
Embodiment 6
A kind of embodiment of nitroglycerin solution preparation method of the present invention, comprising the following steps: (1) according to 1 institute of embodiment
Nitroglycerin is prepared in the method stated；(2) the nitroglycerin 10g in step (1) is taken, 100mL dehydrated alcohol is added, mixing is equal
It is even, then by alumina filled column, obtain nitroglycerin solution.
Embodiment 7
A kind of embodiment of nitroglycerin solution preparation method of the present invention, comprising the following steps: (1) according to 5 institute of embodiment
Nitroglycerin is prepared in the method stated；(2) the nitroglycerin 20g in step (1) is taken, 200mL dehydrated alcohol is added, mixing is equal
It is even, then by magnesia packed column, obtain nitroglycerin solution.
Embodiment 8
A kind of embodiment of nitroglycerin injection preparation method of the present invention, comprising the following steps: (1) according to embodiment 4
Nitroglycerin is prepared in the method；(2) the nitroglycerin 30g in step (1) is taken, 300mL dehydrated alcohol, mixing is added
Uniformly, nitroglycerin solution is obtained；(3) the nitroglycerin solution 10mL in step (2) is taken, 100mL dehydrated alcohol, mixing is added
Uniformly, then by calcium carbonate-filled column to get the nitroglycerin injection.
Embodiment 9
A kind of embodiment of nitroglycerin injection preparation method of the present invention, comprising the following steps: (1) according to embodiment 3
Nitroglycerin is prepared in the method；(2) the nitroglycerin 50g in step (1) is taken, 500mL dehydrated alcohol, mixing is added
Uniformly, nitroglycerin solution is obtained；(3) the nitroglycerin solution 40mL in step (2) is taken, 400mL dehydrated alcohol, mixing is added
Uniformly, then by calcium carbonate-filled column to get the nitroglycerin injection.
Embodiment 10
The present embodiment detection produces the yield of nitroglycerin using preparation method of the present invention.
One, experimental design
Nitroglycerin is prepared by Examples 1 to 5 the method, while control group 1~5 is set, 1~5 benefit of control group
Nitroglycerin is prepared with conventional method, each group purified water washing times are different, and the yield for preparing nitroglycerin to each group carries out
Research.
Two, experimental method
1, nitroglycerin preparation method of the present invention: same to Examples 1 to 5.
2, it traditional preparation methods: (1) nitration reaction: weighs and is cooled to 10 DEG C 2.5 parts of fuming nitric aicd below, addition is placed in
It in the reaction vessel of ice bath, is slowly added to be cooled to 10 DEG C 4 parts of the concentrated sulfuric acid below while stirring, is uniformly mixed, is mixed
Acid；When acid to be mixed is cooled to 10 DEG C, 1 part of glycerine is slowly added dropwise while stirring, reacting liquid temperature control exists during dropwise addition
12℃；Continue to stir 0.8h at 12 DEG C after being added dropwise, after stratification, abandons lower layer's acid solution, obtain nitroglycerin crude product；
(2) it refines: purifying water washing: the nitroglycerin crude product that step (1) obtains being transferred to and is placed with isometric purifying in advance
In the liquid separatnig container of water, washing is fullyd shake, after stratification, discard supernatant liquid, wash 15~20 times repeatedly with method to washing
Liquid pH value is 5.5~7.0 out, collects filtrate to get the nitroglycerin.
3, calculated yield (yield) as follows:
Three, experimental result
The testing result of each group preparation method nitroglycerin yield (yield) is as shown in table 1, the testing result of intermediate products
It is as shown in table 2:
Influence of the different preparation methods of table 1 to nitroglycerin yield
2 intermediate products testing result of table
Remarks: herein described nitroglycerin intermediate products refer to that reaction gained refines nitroglycerin, according to " middle traditional Chinese medicines
Allusion quotation " 2015 years version and applicant's internal control quality standard, intermediate products quality control index and standards are as follows: 1. character: it should be colourless
Clear liquid；2. nitrate: the regulation according to " Chinese Pharmacopoeia " version in 2015 about " nitrate " check item；3. pH value: according to
" Chinese Pharmacopoeia " version in 2015 is in relation to nitroglycerin pH value measuring method, and pH value should be 6.3~7.0 in enterprise's internal control quality standard；
4. in relation to substance: according to the regulation in " Chinese Pharmacopoeia " version in 2015 about Related substances separation item.
From the above results, compared with traditional handicraft, preparation method of the present invention can significantly improve the purification of nitroglycerin
Yield and total recovery (Examples 1 to 5), and intermediate products comply fully with regulation.Wherein, 5 preparation method yield of embodiment is most
Height, when the mass ratio for illustrating raw material fuming nitric aicd of the present invention, the concentrated sulfuric acid and glycerine is 2.5:4:1, yield highest；In addition, this
The yield that 1 preparation method of inventive embodiments produces nitroglycerin is lower than embodiment 2~5, illustrates that use is through alkali in purification step
The activated carbon adsorption of processing uses adsorption effect of activated carbon in water more preferable than directly.In traditional handicraft, only it is arranged after nitration reaction
Water wash step is purified, does not purify subtractive process further, is remained in nitroglycerin to eliminate nitration reaction as far as possible
Thus acid can only can lead to two negative effects: in nitroglycerin by increasing purifying water and/or purified water washing times
Introducing more water and purifying water washing dissolution nitroglycerin causes yield to reduce.For example, purifying water washing in traditional handicraft
Number is up to 15 to 20 times, according to nitroglycerin in water meltage (1.4kg/t, 12 DEG C；1.5kg/t water, 20 DEG C) meter
It calculates, generally because purified water loss by solution is still considerable.Preparation method of the present invention increases essence after purified water washing process
Step processed is capable of the reduction purified water washing times of high degree, is more advantageous to energy-saving and emission-reduction, reduces loss.
Embodiment 11
The present embodiment detects the stability of nitroglycerin injection of the present invention during storage.
One, experimental method
1, shady place stores
The nitroglycerin being prepared in 10 control group 1~3 of Example 3~5 and embodiment, by side described in embodiment 9
Nitroglycerin injection is prepared in method.By the In Shade preservation of each group nitroglycerin injection, detect the 0th respectively, 3,6,
9,12,18,24 and at 36 months each group nitroglycerin injection quality index, respectively refer to object detection method referring to " middle traditional Chinese medicines
Allusion quotation " 2015 years versions regulation.
2,30 DEG C of storages
The nitroglycerin being prepared in 10 control group 1~5 of Example 1~5 and embodiment, by side described in embodiment 9
Nitroglycerin injection is prepared in method.Each group nitroglycerin injection is placed under 30 DEG C of constant temperatures and is saved, is detected respectively
The quality index of each group nitroglycerin injection when the 0th, 1,2,3 and 6 months respectively refers to object detection method referring to " Chinese Pharmacopoeia "
The regulation of version in 2015.
Two, experimental result
According to the regulation of " Chinese Pharmacopoeia " version in 2015, the requirement of each index is as follows: (1) nitroglycerin content: this product is
The sterilizing ethanol solution of the nitroglycerin, (C containing nitroglycerin3H5(ONO2)3) it should be the 90.0%~110.0% of labelled amount；
(2) pH value: taking this product 5ml, adds water 5ml and saturated potassium chloride solution 1 to drip, mixes, measures (general rule 0631) in accordance with the law, pH value is answered
It is 3.0~6.5.(3) in relation to substance: if any impurity peaks in the chromatogram of test solution, single impurity peak area is not greater than
Contrast solution main peak area
(1%), the sum of each impurity peak area is not greater than 3 times (3.0%) of contrast solution main peak area.To each group nitric acid
The testing result of quality index is as shown in table 3~5 in glycerol injections liquid storing process:
The experimental result that 3 conventional preparation techniques of table influence nitroglycerin injection long-time stability
The experimental result that the preparation process of the present invention of table 4 influences nitroglycerin injection long-time stability
Influence of the 5 30 DEG C of accelerated tests of table to Different Preparation nitroglycerin injection quality
According to the result of table 3 and table 4 it is found that under customary storage conditions, the nitroglycerin of present invention process preparation is more steady
It is fixed, it is less susceptible to decompose generation impurity, related substances is just detected after storage 18 months, and the nitric acid of traditional handicraft preparation is sweet
Oil can detect related substances when storing 9 months, and total peak area and single impurity peak area are obviously higher than the present invention
Technique.As shown in Table 5, in 30 DEG C of accelerated tests, the content of the nitroglycerin related substances of traditional handicraft preparation is in storage 2
Present invention process has been apparently higher than when the moon；The nitroglycerin storage 6 of present invention process preparation is almost had reached when storing 3 months
Content at a month, the nitroglycerin for further demonstrating present invention process preparation have better stability, in storage process
In be not easily decomposed.
Present inventor is effectively removed remaining water and acid in nitroglycerin, is avoided by the improvement to production technology
Residual moisture causes to reduce yield and generates impurity, while avoiding dissolution and decomposition of the acid to nitroglycerin, controls nitroglycerin
And its ethanol solution content in relation to substance in storage and transportational process, keep nitroglycerin product more stable, can cope with
Harsher external environment variation, it is ensured that quality meets relevant regulations before the deadline for it.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range is protected, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should
Understand, it can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the essence of technical solution of the present invention
And range.
Claims (4)
1. a kind of preparation method of nitroglycerin, which comprises the following steps: (1) nitration reaction: weigh and be cooled to 10
DEG C 1~5 part of fuming nitric aicd below, addition is placed in the reaction vessel of ice bath, be slowly added to be cooled to while stirring 10 DEG C with
Under 2~8 parts of the concentrated sulfuric acid, be uniformly mixed, obtain mixed acid；When acid to be mixed is cooled to 15 DEG C or less, slowly drip while stirring
Add 0.5~2 part of glycerine, reacting liquid temperature control is at 12~18 DEG C during dropwise addition；After being added dropwise at 12~18 DEG C after
Continue and stir 0.5~1.0h, after stratification, abandons lower layer's acid solution, obtain nitroglycerin crude product；
(2) it refines: A, purifying water washing: the nitroglycerin crude product that step (1) obtains being transferred to and is placed with isometric purified water in advance
Liquid separatnig container in, fully shake washing, after stratification, abandon supernatant liquid, wash 8~10 times repeatedly with method to eluate pH
Value is 5.5~7.0；
Or the nitroglycerin crude product that step (1) obtains is transferred in the liquid separatnig container for being placed with isometric buffer salt in advance, sufficiently shake
It swings, stratification, collects lower liquid and be transferred in the liquid separatnig container for being placed with isometric purified water in advance, washing fullys shake, it is quiet
Layering is set, supernatant liquid is abandoned, is washed repeatedly with purified water 3~5 times with method, until eluate pH value 5.5~7.0.
B, desiccant removes water: the nitroglycerin crude product that step A is obtained being transferred in the container of drying, nitroglycerin crude product weight is added
The desiccant of amount 0.5~1.0%, sealing are stood to complete clarification, and filtrate is collected in filtering；
C, activated carbon adsorption: being added the active carbon of filtrate weight 1.5~3.0%, mix well in the filtrate obtained to step B,
24~72h is stood, filtering collects filtrate to get the nitroglycerin.
2. the preparation method of nitroglycerin according to claim 1, which is characterized in that delay in the step A of the step (2)
Rushing salt is ammonia-ammonium chloride, borax-calcium chloride, boric acid-potassium chloride or sodium tetraborate-sodium phosphate buffer salt；The step (2)
Desiccant is selected from anhydrous calcium chloride, anhydrous sodium sulfate or anhydrous magnesium sulfate in step B.
3. the preparation method of nitroglycerin according to claim 1, which is characterized in that living in the step C of the step (2)
Property charcoal using it is preceding by pretreatment, the preprocess method are as follows: alkaline matter solid abrasive is at powder, by alkaline matter powder
With active carbon by 1:(5~20) mass ratio mix well after, drying to get.
4. the preparation method of nitroglycerin according to claim 3, which is characterized in that the alkaline matter be selected from KOH,
NaOH or NaHCO3.
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| CN103675152A (en) * | 2011-12-22 | 2014-03-26 | 张剑宇 | Nitroglycerin micro-emulsion spray content assaying method and application |
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| CN102590189A (en) * | 2012-02-01 | 2012-07-18 | 广州白云山明兴制药有限公司 | Method for detecting and pretreating nitroglycerin solution nitrate |
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