CN104876942B - isosorbide mononitrate hemihydrate - Google Patents
isosorbide mononitrate hemihydrate Download PDFInfo
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- CN104876942B CN104876942B CN201510232671.5A CN201510232671A CN104876942B CN 104876942 B CN104876942 B CN 104876942B CN 201510232671 A CN201510232671 A CN 201510232671A CN 104876942 B CN104876942 B CN 104876942B
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- isosorbide mononitrate
- hemihydrate
- isosorbide
- mononitrate
- petroleum ether
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
The invention belongs to pharmaceutical technology field, and in particular to a kind of Isosorbide Mononitrate hemihydrate, and Isosorbide Mononitrate hemihydrate stability provided by the present invention is good, and also unobvious even if the weightening of moisture absorption under high humidity conditions, relevant material does not increase；The Isosorbide Mononitrate solubility of more other crystalline state is high, and its preparation method adds the petroleum ether ethyl acetate solution of proper volume to weigh Isosorbide Mononitrate into reaction vessel, stirring, temperature rising reflux, stirring, Temperature fall is to room temperature, continue stirring and crystallizing 1 hour, filtering, after filter cake elution, in 50 DEG C of dryings, Isosorbide Mononitrate hemihydrate is obtained, chemical purity is up to 99.9%, and single largest impurity is no more than 0.05%.
Description
Technical field
The present invention relates to the medicine in field of medicaments, more particularly, to a kind of Isosorbide Mononitrate hemihydrate and its
Preparation method.
Background technology
In current clinical medicine domain, disease of cardiovascular system is always one of disease of easily attractive human death, and
Coronary disease and angina pectoris is most common frequently-occurring disease in disease of cardiovascular system.The disease is that a kind of angina pectoris is cardiac muscle drastically temporary transient
Ischemic and anoxic caused by clinical symptoms, patient is in the majority with the elderly, in the presence of often betiding certain inducement, its feature
Shirtfront squeezing or sensation of pain for paroxysmal, are predominantly located at breastbone rear portion, can emit to patient's pareordia, left upper extremity, deirid
Portion or lower jaw part, severe patient even threat to life, greatly affect the health quality of people.In the last few years, with social man
The increasingly aging of mouth age composition, the incidence of disease of coronary disease and angina pectoris rises year by year, and has the trend of morbidity rejuvenation,
The principal disease of human health is threatened as current, therefore tool effectively is prevented and treated to it and is of great significance.
5- Isosorbide Mononitrates, chemical name Isosorbide-5-Nitrae, 3,6- bis- are dehydrated-D-glucitol -5- Mononitrates, also known as single nitric acid
Soquad, Isosorbide Mononitrate is that one kind treats coronary heart disease and anginal common drug.First by Germany
Boehringer Mannheim Gmb.H companies develop, and are listed in 1981, through Clinical practice for many years, determined curative effect.It is led
It is that NO is identical with endothelium relaxation by discharging nitrogen oxide (NO) to want the mechanism of action, activates guanylate cyclase, makes smooth muscle
Intracellular cyclic guanylic acid (cGmp) increases, so that relaxation vascular smooth muscle, reaches the purpose of prevention and treatment.However, patient
In Long-term taking medicine, different degrees of toxicity is shown, such as Pulsating quality severe headache, giddy, dizziness, or even position occur
Property low blood pressure, meanwhile, can also make ocular angiogenesis expand and increase intraocular pressure, cause the generation of glaucoma, have impact on therapeutic effect, and
It is effective slow, it is as a result unsatisfactory for the recent, late result acquired by it.
The Isosorbide Mononitrate of document report has process for purification in a variety of preparation methods, such as Chinese patent CN161879A：
This product crude product chloroform thermosol, cold analysis are refined once, purity >=99.5%；Process for purification in Chinese patent CN102526174：This
Product crude product ethanol：Activated carbon is filtered off after activated carbon thermosol, sterling is filtered to obtain in cold analysis, and no purity illustrates；United States Patent (USP)
US4431830 process for purification：This product crude product chloroform or toluene thermosol, cold analysis are refined once, and no purity illustrates；United States Patent (USP)
Process for purification in US4065488：This product crude product cold isopropanol continuously stirs 2h at -10 DEG C, filtering, and 2- is eluted with cold isopropanol
3 times, purity >=99%；Academic dissertation, the synthesis of Ismo 20, (HUST), 2011, Xing Hui is marine
Refined once in process for purification this product crude product chloroform thermosol, cold analysis, no purity illustrates.
Chinese patent application CN201310614502.9 provides a kind of synthesis of 5- Isosorbide Mononitrates and purifying side
Method.Methods described includes step：(1) nitrating agent is prepared using concentrated nitric acid, acetic acid and acetic anhydride, directly nitrification isobide is obtained
To Isosorbide ester admixture；(2) add water and reaction is quenched, 0 DEG C~5 DEG C precipitation 2,5- Dilatrate-SRs, and cross elimination
Remove；(3) filtrate prepares Isosorbide Mononitrate sodium-salt hydrate with sodium hydroxide reaction and must precipitated, filtering, hydrolyzes sodium salt；(4)
Through extract, concentrate, recrystallize high-purity 5- Isosorbide Mononitrates.
Chinese patent application CN201210067244.2 is related to a kind of compound Isosorbide Mononitrate and its preparation technology, its
It is prepared by following weight proportioning raw material, 0.3 part of Isosorbide Mononitrate, 25 parts of the Radix Astragali, 20 parts of Ligusticum wallichii, 15 parts of deer horn, melon
12 parts of beach wormwood, capsule, tablet, particle are made after adding such as starch or edible cellulose pharmaceutic adjuvant according to common pharmaceutical methods
Formulation.
Chinese patent application CN200410006318.7 is taken off using sorbierite as raw material by using p-methyl benzenesulfonic acid
Water obtains anhydro sorbitol, with N, and N- dimethylamino naphthyridines carry out single protection with aceticanhydride as catalyst, using nitric acid/aceticanhydride/
Acetate system is nitrified, and finally obtains Isosorbide Mononitrate using potassium carbonate/methanol system deprotection.
Chinese patent application CN200410070446.8 is related to antianginal drug Isosorbide Mononitrate (Isosorbide-5-Nitrae: 3,6- bis-
Dehydration-D-glucitol -5- nitrates) preparation method, comprise the following steps：I) using fuming nitric aicd and 0-0.5 times of dense sulphur
Sour directly nitrification isobide (3) obtains 2,5- Dilatrate-SRs (4)；Then, ii) use ruthenium (II) complex catalysis hydrogen
Change, 2- nitros of selective reduction.
In research process, the method for repeating the patent document of above-mentioned preparation, obtained Isosorbide Mononitrate has many
Crystal formation phenomenon, and it is different, i.e., crystal formation is different.Relevant material increase, influences the quality and safety of medicine during storage
Property.The hemihydrated process for purification of Isosorbide Mononitrate there is no in detail research and openly.
The Isosorbide Mononitrate hemihydrate that the present invention is obtained, purity is high, and single largest impurity is no more than 0.05%,
Total impurities is no more than 0.1%；Stability is good, is increased weight even if moisture absorption under high humidity conditions also unobvious；Relevant material does not increase；
Obtained injection stability is good.
The content of the invention
One object of the present invention, discloses a kind of Isosorbide Mononitrate hemihydrate.
Another object of the present invention, discloses the hemihydrated preparation method of Isosorbide Mononitrate.
The invention also discloses Isosorbide Mononitrate hemihydrate in manufacture treatment coronary heart diseases and angina pectoris, cardiac muscle stalk
After death continue the application in the medicine such as angina pectoris and digitalis or diuretics use in conjunction, treatment chronic congestive heart failure.
Present invention is specifically described in conjunction with the purpose of the present invention.
The Isosorbide Mononitrate hemihydrate
Karl_Fischer method (Karl Fischer methods) is a kind of determines in material in all kinds of chemical methodes of moisture, to water most
For single-minded, the most accurate method, the standard method of determination of moisture in many materials, especially organic compound have been listed in,
Reliable results.Determined through 6 batches, the moisture that described invention compound contains is at 4.87%-5.08% (percentage by weight)
Between.The theoretical content of Isosorbide Mononitrate hemihydrate reclaimed water is 4.98%, it can be assumed that invention compound contains half
The individual crystallization water.
| Batch | 1 | 2 | 3 | 4 | 5 | 6 |
| Moisture (%) | 4.89 | 4.93 | 5.02 | 5.03 | 4.92 | 4.97 |
Isosorbide Mononitrate hemihydrate, is determined using D/Max-2500.9161 types x-ray diffractometer, determines bar
Part：Cu Ka targets, tube voltage 40KV, tube current 100mA.With its powder x-x ray diffraction collection of illustrative plates of 2 θ ± 0.2 °, Fig. 2 is seen.
The Isosorbide Mononitrate hemihydrate structural formula that the present invention is obtained is C6H9NO6·0.5H2O；Molecular weight is
201.156g/mol；This product chemical property is stable, is easily dissolved in methanol, ethanol and water.Characteristic is significantly better than prior art
The Isosorbide Mononitrate of preparation.
Another object of the present invention, discloses the hemihydrated preparation method of Isosorbide Mononitrate, its feature
It is to comprise the following steps：Prepare petroleum ether：Ethyl acetate=5:1 solution, it is standby；Weigh Isosorbide Mononitrate and 0.3-
0.8% dimethylformamide (DMF) is into reaction vessel, and the petroleum ether ethyl acetate for adding the above-mentioned preparation of 1-10 volumes is molten
Liquid, is heated to 80 DEG C of dissolved clarifications, backflow 0.5h or so, then stops heating, continues to stir, it is down to room temperature (20 DEG C of left sides naturally
It is right), solution gradually becomes cloudy in temperature-fall period, there is crystal precipitation, is down to after room temperature and continues to stir 1h or so, then filters,
Filter cake is eluted 2~3 times with petroleum ether, and solid is dried, and obtains Isosorbide Mononitrate hemihydrate, chemical purity is up to
99.9%, single largest impurity is no more than 0.05%, and total impurities is no more than 0.1%.
The pharmaceutical composition of the present invention prepares as follows：Using standard and conventional technique, make the compounds of this invention and preparation
Acceptable solid or liquid-carrier are combined on, and be allowed to arbitrarily with acceptable adjuvant and excipient on galenic pharmacy
With reference to being prepared into particulate or microballoon.Said composition is used to prepare oral formulations, injection.In pharmaceutical composition and unit dosage form
The amount of the active ingredient (the compounds of this invention) contained can specifically be answered according to the state of an illness, the situation of diagnosis of patient
With the amount or concentration of compound used are adjusted in a wider scope, and the amount scope of reactive compound is composition
1%-30% (percentage by weight).
Continue the heart after manufacture treatment coronary heart diseases and angina pectoris, myocardial infarction present invention also offers Isosorbide Mononitrate
Application in the medicine such as angina and digitalis or diuretics use in conjunction, treatment chronic congestive heart failure.
Compared with prior art, the invention has the advantages that：
1) Isosorbide Mononitrate hemihydrate provided by the present invention thoroughly solves the steady of Isosorbide Mononitrate
Qualitative poor the problem of.
2) Isosorbide Mononitrate hemihydrate purity provided by the present invention is high, and stability is good, even in high humility
Under the conditions of moisture absorption weightening also not substantially, relevant material does not increase；The Isosorbide Mononitrate solubility of more other crystalline state is high.
3) Isosorbide Mononitrate hemihydrate provided by the present invention is for improving the yield of the product, reducing product
The market risk, preferably be applied to clinical treatment have very big help.
4) Isosorbide Mononitrate hemihydrate provided by the present invention is through industrialized production and study on the stability, card
Bright product quality is stable, and through pharmacology, toxicological test, solution is non-stimulated to blood vessel, no allergic reaction, also without haemolysis, to people
Body fanout free region.
5) the hemihydrated preparation method of Isosorbide Mononitrate provided by the present invention, this method is simple and easy to apply, institute
The injection Isosorbide Mononitrate stability of preparation is good, reliable in quality.
Figure of description：
Fig. 1, the hemihydrated structure chart of Isosorbide Mononitrate；
Fig. 2, the hemihydrated X-ray diffractogram of Isosorbide Mononitrate；
Embodiment：
With reference to embodiment, the present invention is described further, professional and technical personnel in the field is better understood from this
Invention.Embodiment is only explanatory, is in no way intended to it and limits the scope of the present invention in any way.
Isosorbide Mononitrate used, chemical entitled Isosorbide-5-Nitrae in the present invention：3,6- bis- are dehydrated-D-glucitol -5- single nitric acids
Ester, the method provided according to document is synthesized, purity 98.1% (HPLC normalization methods), and 1- is refined by the method for being disclosed patent
3 times, purity about 98.8% (HPLC normalization methods).Its chemical constitution through proton nmr spectra (1H-NMR), elementary analysis is true
Card, elementary analysis result：Measured value (calculated value),
C:33.19(33.15),H:5.10(5.10),N:6.45(6.48),O:55.26 (55.24), prove chemical constitution
It is correct.
Embodiment 1
1) petroleum ether is prepared：Ethyl acetate=5:1 solution, it is standby；
2) 100g Isosorbide Mononitrates and 0.3g dimethylformamide (DMF) are weighed into reaction vessel, is added
The petroleum ether ethyl acetate solution of the above-mentioned preparation of 1000ml volumes, is heated to 80 DEG C of dissolved clarifications, backflow 0.5h or so；
3) stop heating, continue to stir, it is down to room temperature (20 DEG C or so) naturally, solution gradually becomes in temperature-fall period
Muddiness, there is crystal precipitation；
4) it is down to after room temperature and continues to stir 1h or so, then filter, filter cake elutes 2-3 all over solid is done with petroleum ether
It is dry, Isosorbide Mononitrate hemihydrate 90.1g is obtained, the moisture measured with Karl_Fischer method is 4.95%.
The X-ray diffractogram of the compound is shown in Fig. 2.INSTRUMENT MODEL and condition determination：The types of Rigaku D/max 2500 spread out
Penetrate instrument；CuKa 40Kv 100mA；2 θ scanning ranges：0-50°.
Embodiment 2
1) petroleum ether is prepared：Ethyl acetate=5:1 solution, it is standby；
2) 100g Isosorbide Mononitrates and 0.8g dimethylformamide (DMF) are weighed into reaction vessel, is added
The petroleum ether ethyl acetate solution of the above-mentioned preparation of 1000ml volumes, is heated to 80 DEG C of dissolved clarifications, backflow 0.5h or so；
3) stop heating, continue to stir, it is down to room temperature (20 DEG C or so) naturally, solution gradually becomes in temperature-fall period
Muddiness, there is crystal precipitation；
4) it is down to after room temperature and continues to stir 1h or so, then filter, filter cake elutes 2-3 all over solid is done with petroleum ether
It is dry, Isosorbide Mononitrate hemihydrate 90.5g is obtained, the moisture measured with Karl_Fischer method is 4.99%.
The X-ray diffractogram of the compound is shown in Fig. 2.INSTRUMENT MODEL and condition determination：The types of Rigaku D/max 2500 spread out
Penetrate instrument；CuKa 40Kv 100mA；2 θ scanning ranges：0-50°.
Embodiment 3
Contain the hemihydrated injection of the Isosorbide Mononitrate of embodiment 1
Prescription：
Technique：Recipe quantity water for injection 70% is taken, temperature adds the sodium citrate of recipe quantity, stirring and dissolving at 55-65 DEG C
Afterwards；The Isosorbide Mononitrate hemihydrate of recipe quantity is added, stirring adds the chlorine of recipe quantity into solution to after dissolving
Change sodium, stirring is complete to dissolving；Initial pH value is measured, according to initial pH value, pH value is adjusted with 10% CYSTEAMINE HCL acid solution
Scope is in 4.5-5.5；Medical charcoal 0.05% is added, stirring is placed 30 minutes；Suction filtration, adds water for injection to full dose, and mixing is equal
It is even；Refined filtration；It is filling；In 121 DEG C of pressure sterilizings 15 minutes；Lamp inspection；Storage；Produce isosorbide mononitrate injection.
Test example 1
Stability test
Inventor is ground to the chemical stability of the Isosorbide Mononitrate hemihydrate (embodiment 1) of the present invention
Study carefully, investigation condition is high temperature (60 DEG C ± 2 DEG C), illumination (4500Lx ± 500lx), and high humidity (92.5%, RH) inspection target is outer
See, content and relevant material.
As a result：From 0-10 days under illumination, high temperature, super-humid conditions, outward appearance, relevant material, content do not change, explanation
Chemical stability is good, is adapted to the manufacture and long term storage of pharmaceutical preparation.
Test example 2
At 40 DEG C, under different relative humidity (RH) conditions (75%), the survey of moisture in Isosorbide Mononitrate (embodiment 1)
It is fixed：
As a result：At 40 DEG C, under different relative humidity (RH) conditions (75%), moisture change is little, and explanation has good stability,
It is adapted to the manufacture and long term storage of pharmaceutical preparation.
Test example 3
Solubility test
Solubility is a kind of physical property of medicine.The selection of solvent, should try one's best using close with the medicine dissolution characteristics
Correlation, formulated, prepares the common solvent that solution or purification operations are commonly used；Kind should simplify, and should not enumerate excessively, and keep away
Exempt from using solvent that is expensive or being of little use.Again sample can not should be claimed to add using lower limit amount, then the method for adding to upper limit amount is first added
The solvent of upper limit amount.Be arranged in order by solubility size, " easily dissolve " preceding, be thereafter " readily soluble ", " dissolving ", " slightly molten ",
" slightly soluble ", " soluble,very slightly " and " almost insoluble or insoluble "；Wherein the similar solvent of solubility, then arranged successively by its polarity size
Arrange (water, methanol, ethanol, the third heir, acetic acid second vinegar, chloroform, ether or hexamethylene etc.)；Hot water or hot ethanol are (without other warm
Solvent) it is placed on before each solvent of same solubility；Solubility in acid or alkaline solution is placed on finally, acid used or alkalescence
Solution will indicate title (should not use the nouns such as " ore deposit acid " or " alkali hydroxide ") and preferably write concentration exactly.
The approximate solubility of medicine is shown with following noun list：
Easily dissolving means that solute 1g (ml) can dissolve in solvent is less than 1ml；
It is readily soluble to mean that solute 1g (ml) dissolve in solvent 1~less than 10ml；
Dissolving means that solute 1g (ml) can dissolve in solvent 10~less than 30ml；
It is slightly molten to mean that solute 1g (ml) dissolve in solvent 30~less than 100ml；
Slightly soluble means that solute 1g (ml) can dissolve in solvent 100~less than 1000ml；
Soluble,very slightly means that solute 1g (ml) can dissolve in solvent 1000~less than 10000ml；
It is almost insoluble or insoluble mean that solute 1g (ml) can not be completely dissolved in solvent 10000ml.
Test method(s)：Unless otherwise specified, the test sample (embodiment 1) for being ground into fine powder is weighed, 25 DEG C of ± 2 DEG C of constant volumes are placed in
In the solvent of amount, every strength shaking in 5 minutes 30 seconds；Dissolving situation in observation 30 minutes, such as invisible particles of solute or
During drop, that is, it is considered as and is completely dissolved.
Solubility test result
| Solvent | Sample size (mg) | Quantity of solvent (ml) | As a result | Conclusion |
| Water | 500.12 | 0.5 | It is completely dissolved | It is easily molten |
| Methanol | 500.13 | 0.5 | It is completely dissolved | It is easily molten |
| Absolute ethyl alcohol | 500.11 | 0.5 | It is completely dissolved | It is easily molten |
Conclusion：Very soluble in water, methanol, ethanol.
Comparative test example 1
This test example is used for the different mountain of single nitric acid for comparing Isosorbide Mononitrate hemihydrate of the present invention and prior art
Pear ester solubility compares
Experiment 1：Isosorbide Mononitrate hemihydrate prepared by the embodiment of the present invention 1；
Experiment 2：Isosorbide Mononitrate hemihydrate prepared by the embodiment of the present invention 2；
Control 1：The different sorb of Chinese medicines quasi-word H20113276 single nitric acids of Shandong Fangming Pharmaceutical Group Co., Ltd.'s production
Ester bulk drug
Control 2：The Chinese medicines quasi-word H20103517 Isosorbide Mononitrate raw materials of Shandong Xinshidai Pharmaceutical Industry Co., Ltd.'s production
Medicine
Control 3：The Chinese medicines quasi-word H20074192 Isosorbide Mononitrate bulk drugs of Beijing Yimin Pharmaceutical Co., Ltd.'s production
Control 4：Chinese patent application CN201310614502.9 embodiments 1
Control 5：Chinese patent application CN200410070446.8 embodiments 1
| Solvent | Experiment 1 | Experiment 2 | Control 1 | Control 2 | Control 3 | Control 4 | Control 5 |
| Water | Easily dissolve | Easily dissolve | Dissolving | Dissolving | Dissolving | Dissolving | Dissolving |
| Methanol | Easily dissolve | Easily dissolve | It is readily soluble | It is readily soluble | It is readily soluble | It is readily soluble | It is readily soluble |
| Ethanol | Easily dissolve | Easily dissolve | It is readily soluble | It is readily soluble | It is readily soluble | It is readily soluble | It is readily soluble |
Above result of the test shows：Isosorbide Mononitrate hemihydrate in the present invention has good dissolubility,
Solubility of its solubility better than the Isosorbide Mononitrate that prior art is produced.
Comparative test example 2
This test example is used for the different mountain of single nitric acid for comparing Isosorbide Mononitrate hemihydrate of the present invention and prior art
The relevant material of pear ester compares
Experiment 1：Isosorbide Mononitrate hemihydrate prepared by the embodiment of the present invention 1；
Experiment 2：Isosorbide Mononitrate hemihydrate prepared by the embodiment of the present invention 2；
Control 1：The different sorb of Chinese medicines quasi-word H20113276 single nitric acids of Shandong Fangming Pharmaceutical Group Co., Ltd.'s production
Ester bulk drug
Control 2：The Chinese medicines quasi-word H20103517 Isosorbide Mononitrate raw materials of Shandong Xinshidai Pharmaceutical Industry Co., Ltd.'s production
Medicine
Control 3：The Chinese medicines quasi-word H20074192 Isosorbide Mononitrate bulk drugs of Beijing Yimin Pharmaceutical Co., Ltd.'s production
Control 4：Chinese patent application CN201310614502.9 embodiments 1
Control 5：Chinese patent application CN200410070446.8 embodiments 1
Above result of the test shows：The Isosorbide Mononitrate that the embodiment of the present invention is produced is hemihydrated relevant
Material is smaller, and the Isosorbide Mononitrate prepared better than prior art, steady quality is reliable, and impurity is controllable, beneficial to being prepared into note
Penetrate agent.
Claims (5)
1. the Isosorbide Mononitrate hemihydrate shown in formula I,
Determined with Karl_Fischer method, the Isosorbide Mononitrate hemihydrate contains 4.87%-5.08% percentage by weights
Moisture；The Isosorbide Mononitrate hemihydrate, in being determined with CuKa rays as characteristic X-ray powder, its collection of illustrative plates
With the following 2 θ angles of diffraction and D values,
The error of the 2 θ angles of diffraction is ± 0.2.
2. the hemihydrated preparation method of Isosorbide Mononitrate according to claim 1, it is characterised in that including under
Row step：Prepare petroleum ether：Ethyl acetate=5:1 solution, it is standby；Weigh the two of Isosorbide Mononitrate and 0.3-0.8%
NMF (DMF) adds the petroleum ether ethyl acetate solution of the above-mentioned preparation of 1-10 volumes, is heated into reaction vessel
80 DEG C of dissolved clarifications, flow back 0.5h, then stops heating, continues to stir, it is down to room temperature naturally, solution in temperature-fall period gradually
Become cloudy, there is crystal precipitation, be down to after room temperature and continue to stir 1h, then filter, filter cake is eluted 2-3 times with petroleum ether, Gu
Soma is dry, obtains Isosorbide Mononitrate hemihydrate, and chemical purity is up to 99.9%, and single largest impurity is no more than
0.05%, total impurities is no more than 0.1%.
3. the hemihydrate of Isosorbide Mononitrate pharmaceutically acceptable is carried with one or more according to claim 1
The hemihydrated composition of Isosorbide Mononitrate of body composition.
4. composition according to claim 3, it is characterised in that said composition is used to prepare solid pharmaceutical preparation or injection.
5. according to claim 1 Isosorbide Mononitrate hemihydrate in manufacture treatment coronary heart diseases and angina pectoris, chronic fill
Application in the medicine of courageous and upright heart failure.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3479800D1 (en) * | 1983-11-25 | 1989-10-26 | Toshin Chemical Co | A method for the preparation of isosorbide-5-nitrate and sodium isosorbide-5-nitrate hydrate as a precursor thereof |
| EP0201067B1 (en) * | 1985-05-10 | 1991-08-07 | Consiglio Nazionale Delle Ricerche | Process for the preparation of isosorbide-5-mononitrate |
| CN1618798A (en) * | 2004-02-25 | 2005-05-25 | 鲁南制药股份有限公司 | Preparation process of isosorbide mononitrate |
| CN1257906C (en) * | 2004-03-05 | 2006-05-31 | 鲁南制药集团股份有限公司 | Prepn process of isosorbide mononitrate |
| CN103641840B (en) * | 2013-11-28 | 2016-03-16 | 青岛黄海制药有限责任公司 | A kind of synthesis of 5-isosorbide mononitrate and purification process |
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