CN104876942A - Isosorbide mononitrate hemihydrate - Google Patents
Isosorbide mononitrate hemihydrate Download PDFInfo
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- CN104876942A CN104876942A CN201510232671.5A CN201510232671A CN104876942A CN 104876942 A CN104876942 A CN 104876942A CN 201510232671 A CN201510232671 A CN 201510232671A CN 104876942 A CN104876942 A CN 104876942A
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- isosorbide mononitrate
- hemihydrate
- isosorbide
- mononitrate
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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 the technical field and specifically relates to an isosorbide mononitrate hemihydrate. The isosorbide mononitrate hemihydrate is good in stability, and not obvious in moisture absorption weight increase under a high humidity condition, and relevant substances are not increased; compared with isosorbide mononitrates in other crystalline states, the solubility of the isosorbide mononitrate hemihydrate is high; the preparation method of the isosorbide mononitrate hemihydrate comprises weighing the isosorbide mononitrate and putting into a reaction container, adding a petroleum ether ethyl acetate solution by an appropriate volume, stirring, heating for reflux, stirring, naturally cooling to a room temperature, continuing stirring for crystallization for 1 hour, filtering, performing drip washing on the filter cake, and drying at 50 DEG C, thereby obtaining the isosorbide mononitrate hemihydrate; the chemical purity of the isosorbide mononitrate hemihydrate is 99.9%, and the maximum single impurity does not exceed 0.05%.
Description
Technical field
The present invention relates to the medicine in field of medicaments, especially relate to a kind of isosorbide mononitrate hemihydrate and preparation method thereof.
Background technology
At current clinical medicine domain, cardiovascular system diseases is one of disease kind of easily attractive human death always, and coronary heart disease and angina pectoris is modal frequently-occurring disease in cardiovascular system diseases.This disease is a kind of stenocardia is cardiac muscle temporary transient ischemic sharply and the clinical symptom caused by anoxic, patient is in the majority with the elderly, often betide certain inducement when existing, its feature is the squeezing of paroxysmal shirtfront or pain perception, mainly be positioned at breastbone rear portion, can emit to patient pareordia, left upper extremity, deirid portion or lower jaw part, severe patient is threat to life even, greatly affects the health quality of people.In the last few years, along with the day by day aging of social population's age structure, the sickness rate of coronary heart disease and angina pectoris rises year by year, and has the trend of morbidity rejuvenation, become the current principal disease threatening human health, therefore effectively tool has been prevented and treated to it and be of great significance.
5-isosorbide mononitrate, chemical name Isosorbide-5-Nitrae, 3,6-bis-dewaters-D-glucitol-5-Mononitrate, and have another name called isosorbide mononitrate, isosorbide mononitrate is that one treats coronary heart disease and anginal common drug.First to be developed by German BoehringerMannheim Gmb.H company, and in listing in 1981, through Clinical practice for many years, determined curative effect.Its Main Function mechanism is by release nitrogen oxide (NO), NO is identical with endothelium relaxation, activates guanylate cyclase, the cyclic guanosine monophosphate in smooth muscle cell (cGmp) is increased, thus lax vascular smooth muscle, reach the object of prevention and therapy.But, patient, in Long-term taking medicine, shows toxic side effects in various degree, as Pulsating quality severe headache, giddy, dizzy, even there is postural hypotension, meanwhile, ocular angiogenesis also can be made to expand and increase intraocular pressure, cause glaucomatous generation, have impact on result for the treatment of, and slowly effective, with regard to recent, the late result acquired by it, result is unsatisfactory.
The isosorbide mononitrate of bibliographical information has multiple preparation method, as process for purification in 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: elimination gac after gac thermosol, sterling is filtered to obtain in cold analysis, without purity explanation; US Patent No. 4431830 process for purification: this product crude product chloroform or toluene thermosol, cold analysis are refining once, without purity explanation; Process for purification in US Patent No. 4065488: this product crude product cold isopropanol, at-10 DEG C of continuously stirring 2h, filters, with cold isopropanol drip washing 2-3 time, purity >=99%; Academic dissertation, the synthesis of Ismo 20, (HUST), in the marine process for purification this product crude product chloroform thermosol of 2011, Xing Hui, cold analysis refining once, without purity explanation.
Chinese patent application CN201310614502.9 provides a kind of synthesis and purification process of 5-isosorbide mononitrate.Described method comprises step: (1) utilizes concentrated nitric acid, acetic acid and diacetyl oxide to prepare nitrating agent, and direct nitrated Isosorbide obtains Isosorbide ester mixture; (2) cancellation that adds water is reacted, and separates out 2,5-Dilatrate-SR for 0 DEG C ~ 5 DEG C, and filters removal; (3) filtrate and sodium hydroxide react and prepare isosorbide mononitrate sodium-salt hydrate and must precipitate, and filter, hydrolysis sodium salt; (4) highly purified 5-isosorbide mononitrate is obtained through extraction, concentrated, recrystallization.
Chinese patent application CN201210067244.2 relates to a kind of compound isosorbide mononitrate and preparation technology thereof, it is prepared by following weight proportioning raw material and obtains, isosorbide mononitrate 0.3 part, the Radix Astragali 25 parts, Ligusticum wallichii 20 parts, 15 parts, deer horn, Snakegourd Fruit 12 parts, add as made the formulations such as capsule, tablet, particle after starch or edible fibre pharmaceutical excipient according to common pharmaceutical methods.
Chinese patent application CN200410006318.7 take sorbyl alcohol as raw material; carry out dehydration by adopting p-methyl benzenesulfonic acid and obtain anhydro sorbitol; with N; N-Dimethylamino pyridine is as catalyzer; single protection is carried out with aceticanhydride; adopt nitric acid/aceticanhydride/acetate system to carry out nitrated, finally adopt salt of wormwood/methanol system deprotection to obtain isosorbide mononitrate.
Chinese patent application CN200410070446.8 relates to antianginal drug isosorbide mononitrate (1,4: 3,6-bis-dewaters-D-glucitol-5-nitric ether) preparation method, comprise the steps: i) to adopt nitrosonitric acid and the 0-0.5 direct nitrated Isosorbide (3) of the vitriol oil doubly to obtain 2,5-Dilatrate-SR (4); Then, ii) use the hydrogenation of ruthenium (II) complex catalysis, selective reduction 2-position nitro.
In research process, repeat the method for the patent documentation of above-mentioned preparation, the isosorbide mononitrate obtained has polymorphism, and different, and namely crystal formation is different.In storage process, related substance increases, and affects quality and the security of medicine.The hemihydrated process for purification of isosorbide mononitrate there is no and studies in great detail and disclose.
The isosorbide mononitrate hemihydrate that the present invention obtains, purity is high, and single largest impurity is no more than 0.05%, and total impurities is no more than 0.1%; Good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions; Related substance does not increase; Obtained injection good stability.
Summary 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 manufacture treatment coronary heart diseases and angina pectoris, continue after myocardial infarction stenocardia, with purple foxglove or diuretic(s) combined utilization, the application for the treatment of in the medicines such as chronic heart failure.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
This isosorbide mononitrate hemihydrate
Karl_Fischer method (Karl Fischer method) a kind ofly measures in all kinds of chemical processes of moisture in material,, the most accurately method the most single-minded to water, be listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.Through 6 batches of mensuration, the moisture that described invention compound contains is between 4.87%-5.08% (weight percent).In isosorbide mononitrate hemihydrate, the theoretical content of water is 4.98%, can assert that invention compound contains half crystal water.
| Batch | 1 | 2 | 3 | 4 | 5 | 6 |
| Moisture (%) | 4.89 | 4.93 | 5.02 | 5.03 | 4.92 | 4.97 |
Isosorbide mononitrate hemihydrate, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: CuKa target, tube voltage 40KV, tube current 100mA.With its powder x-ray diffraction collection of illustrative plates of 2 θ ± 0.2 °, see Fig. 2.
The isosorbide mononitrate hemihydrate structural formula that the present invention obtains is C
6h
9nO
60.5H
2o; Molecular weight is 201.156g/mol; This product stable chemical nature, very easily dissolves in methyl alcohol, ethanol and water.Characteristic is significantly better than isosorbide mononitrate prepared by prior art.
Another object of the present invention, discloses the hemihydrated preparation method of isosorbide mononitrate, it is characterized in that comprising the following steps: to prepare sherwood oil: the solution of ethyl acetate=5:1, for subsequent use, take the dimethyl formamide (DMF) of isosorbide mononitrate and 0.3-0.8% in reaction vessel, add the sherwood oil ethyl acetate solution of the above-mentioned preparation of 1-10 volume, be heated to 80 DEG C clearly molten, backflow about 0.5h, then heating is stopped, continue to stir, it is made naturally to be down to room temperature (about 20 DEG C), solution becomes muddy gradually in temperature-fall period, crystal is had to separate out, continue to stir about 1h after being down to room temperature, then filter, filter cake sherwood oil drip washing 2 ~ 3 times, solid drying, obtain isosorbide mononitrate hemihydrate, chemical purity is up to 99.9%, single largest impurity is no more than 0.05%, total impurities is no more than 0.1%.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is the 1%-30% (weight percent) of composition.
Present invention also offers isosorbide mononitrate manufacture treatment coronary heart diseases and angina pectoris, continue after myocardial infarction stenocardia, with purple foxglove or diuretic(s) combined utilization, the application for the treatment of in the medicines such as chronic heart failure.
Compared with prior art, tool of the present invention has the following advantages:
1) isosorbide mononitrate hemihydrate provided by the present invention thoroughly solves the problem of the poor stability of isosorbide mononitrate.
2) isosorbide mononitrate hemihydrate purity provided by the present invention is high, good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions, related substance does not increase; High compared with the isosorbide mononitrate solubleness of other crystalline state.
3) isosorbide mononitrate hemihydrate provided by the present invention is for improving the yield of this product, reducing the market risk of product, and being better applied to clinical treatment has very large help.
4) isosorbide mononitrate hemihydrate provided by the present invention is through industrialized production and study on the stability, proves constant product quality, through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body fanout free region.
5) the hemihydrated preparation method of isosorbide mononitrate provided by the present invention, the method is simple, prepared injection isosorbide mononitrate good stability, reliable in quality.
Figure of description:
Fig. 1, the hemihydrated structure iron of isosorbide mononitrate;
Fig. 2, the hemihydrated X-ray diffractogram of isosorbide mononitrate;
Embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Isosorbide mononitrate used in the present invention, chemistry by name 1,4:3,6-bis-dewaters-D-glucitol-5-Mononitrate, according to the method synthesis that document provides, purity 98.1% (HPLC normalization method), refines 1-3 time by the method for existing publication, purity about 98.8% (HPLC normalization method).Its chemical structure through proton nmr spectra (
1h-NMR), ultimate analysis confirmation, results of elemental analyses: 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 that chemical structure is correct.
Embodiment 1
1) sherwood oil is prepared: the solution of ethyl acetate=5:1, for subsequent use;
2) dimethyl formamide (DMF) taking 100g isosorbide mononitrate and 0.3g, in reaction vessel, adds the sherwood oil ethyl acetate solution of the above-mentioned preparation of 1000ml volume, be heated to 80 DEG C clearly molten, backflow about 0.5h;
3) stop heating, continue to stir, make it naturally be down to room temperature (about 20 DEG C), solution becomes muddy gradually in temperature-fall period, has crystal to separate out;
4) continue to stir about 1h after being down to room temperature, then filter, filter cake is with sherwood oil drip washing 2-3 time, and solid drying, obtains isosorbide mononitrate hemihydrate 90.1g, and the moisture recorded with Karl_Fischer method is 4.95%.
The X-ray diffractogram of this compound is shown in Fig. 2.INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffractometer; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50 °.
Embodiment 2
1) sherwood oil is prepared: the solution of ethyl acetate=5:1, for subsequent use;
2) dimethyl formamide (DMF) taking 100g isosorbide mononitrate and 0.8g, in reaction vessel, adds the sherwood oil ethyl acetate solution of the above-mentioned preparation of 1000ml volume, be heated to 80 DEG C clearly molten, backflow about 0.5h;
3) stop heating, continue to stir, make it naturally be down to room temperature (about 20 DEG C), solution becomes muddy gradually in temperature-fall period, has crystal to separate out;
4) continue to stir about 1h after being down to room temperature, then filter, filter cake is with sherwood oil drip washing 2-3 time, and solid drying, obtains isosorbide mononitrate hemihydrate 90.5g, and the moisture recorded with Karl_Fischer method is 4.99%.
The X-ray diffractogram of this compound is shown in Fig. 2.INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffractometer; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50 °.
Embodiment 3
Containing the hemihydrated injection of embodiment 1 isosorbide mononitrate
Prescription:
Technique: get recipe quantity water for injection 70%, temperature, at 55-65 DEG C, adds the Sodium Citrate of recipe quantity, after stirring and dissolving; Add the isosorbide mononitrate hemihydrate of recipe quantity, after being stirred to dissolving, in solution, add the sodium-chlor of recipe quantity again, be stirred to and dissolve completely; Record initial pH value, according to initial pH value, by 10% CYSTEAMINE HCL acid solution adjust ph scope at 4.5-5.5; Add Medicinal Charcoal 0.05%, stir, place 30 minutes; Suction filtration, adds water for injection to full dose, mixes; Essence filter; Filling; 121 DEG C of pressure sterilizings 15 minutes; Lamp is examined; Warehouse-in; Obtain isosorbide mononitrate injection.
Test example 1
Stability test
The chemical stability of contriver to isosorbide mononitrate hemihydrate of the present invention (embodiment 1) is studied, investigation condition is high temperature (60 DEG C ± 2 DEG C), illumination (4500Lx ± 500lx), high humidity (92.5%, RH) inspection target is outward appearance, content and related substance.
Result: from 0-10 days under illumination, high temperature, super-humid conditions, outward appearance, related substance, content do not change, and illustrate that chemical stability is good, are applicable to manufacture and the standing storage of pharmaceutical preparation.
Test example 2
At 40 DEG C, under different relative humidity (RH) condition (75%), the mensuration of moisture in isosorbide mononitrate (embodiment 1):
Result: at 40 DEG C, under different relative humidity (RH) condition (75%), change of soil water content is little, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
Test example 3
Solubility test
Solubleness is a kind of physical properties of medicine.The selection of solvent, should adopt with this medicine dissolution characteristics closely related as far as possible, formulated, prepare solution or purification operations the common solvent commonly used; Kind should simplify, and does not enumerate too much, and avoids using solvent that is expensive or that be of little use.Can not adopt and first add lower limit amount, then add to the method for upper limit amount, should again sample the solvent adding upper limit amount.Be arranged in order by solubleness size, " very easily dissolving " front, is " Yi Rong ", " dissolving ", " slightly molten ", " slightly soluble ", " soluble,very slightly " and " almost insoluble or insoluble " thereafter; The solvent that wherein solubleness is similar, be then arranged in order (water, methyl alcohol, ethanol, the third heir, acetic acid second vinegar, chloroform, ether or hexanaphthene etc.) by its polarity size; Before hot water or hot ethanol (hot solvents without other) are placed on each solvent of same solubleness; Solubleness in acid or basic solution is placed on finally, and acid used or basic solution will indicate title (not using the nouns such as " ore deposit acid " or " alkali hydroxide ") preferably can write concentration exactly.
The approximate solubility of medicine is shown with following noun list:
Very easily dissolve and mean that solute 1g (ml) can dissolve in solvent is less than 1ml;
Yi Rong means that solute 1g (ml) can dissolve in solvent 1 ~ less than 10ml;
Dissolving means that solute 1g (ml) can dissolve in solvent 10 ~ less than 30ml;
Slightly moltenly mean that solute 1g (ml) can 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;
Almost insolublely or insoluble mean that solute 1g (ml) can not dissolve completely in solvent 10000ml.
Test method(s): unless otherwise specified, takes the trial-product (embodiment 1) being ground into fine powder, is placed in the solvent of 25 DEG C ± 2 DEG C of certain capacities, powerful jolting 30 second every 5 minutes; Observing the dissolving situation in 30 minutes, during as cannot see particles of solute or drop, being namely considered as dissolving completely.
Solubility test result
| Solvent | Sample size (mg) | Quantity of solvent (ml) | Result | Conclusion |
| Water | 500.12 | 0.5 | Dissolve completely | Very easily molten |
| Methyl alcohol | 500.13 | 0.5 | Dissolve completely | Very easily molten |
| Dehydrated alcohol | 500.11 | 0.5 | Dissolve completely | Very easily molten |
Conclusion: be very easily dissolved in water, methyl alcohol, ethanol.
Comparison test example 1
This test example compares with the isosorbide mononitrate solubleness of prior art for comparing isosorbide mononitrate hemihydrate of the present invention
Test 1: isosorbide mononitrate hemihydrate prepared by the embodiment of the present invention 1;
Test 2: isosorbide mononitrate hemihydrate prepared by the embodiment of the present invention 2;
Contrast 1: the traditional Chinese medicines accurate word H20113276 isosorbide mononitrate bulk drug that Shandong Fangming Pharmaceutical Group Co., Ltd. produces
Contrast 2: the traditional Chinese medicines accurate word H20103517 isosorbide mononitrate bulk drug that Shandong Xinshidai Pharmaceutical Industry Co., Ltd. produces
Contrast 3: the traditional Chinese medicines accurate word H20074192 isosorbide mononitrate bulk drug that Beijing Yimin Pharmaceutical Co., Ltd. produces
Contrast 4: Chinese patent application CN201310614502.9 embodiment 1
Contrast 5: Chinese patent application CN200410070446.8 embodiment 1
| Solvent | Test 1 | Test 2 | Contrast 1 | Contrast 2 | Contrast 3 | Contrast 4 | Contrast 5 |
| Water | Very easily dissolve | Very easily dissolve | Dissolve | Dissolve | Dissolve | Dissolve | Dissolve |
| Methyl alcohol | Very easily dissolve | Very easily dissolve | Yi Rong | Yi Rong | Yi Rong | Yi Rong | Yi Rong |
| Ethanol | Very easily dissolve | Very easily dissolve | Yi Rong | Yi Rong | Yi Rong | Yi Rong | Yi Rong |
Above test-results shows: the isosorbide mononitrate hemihydrate in the present invention has good solubility, and its solubleness is better than the solubleness of the isosorbide mononitrate that prior art is produced.
Comparison test example 2
This test example compares with the isosorbide mononitrate related substance of prior art for comparing isosorbide mononitrate hemihydrate of the present invention
Test 1: isosorbide mononitrate hemihydrate prepared by the embodiment of the present invention 1;
Test 2: isosorbide mononitrate hemihydrate prepared by the embodiment of the present invention 2;
Contrast 1: the traditional Chinese medicines accurate word H20113276 isosorbide mononitrate bulk drug that Shandong Fangming Pharmaceutical Group Co., Ltd. produces
Contrast 2: the traditional Chinese medicines accurate word H20103517 isosorbide mononitrate bulk drug that Shandong Xinshidai Pharmaceutical Industry Co., Ltd. produces
Contrast 3: the traditional Chinese medicines accurate word H20074192 isosorbide mononitrate bulk drug that Beijing Yimin Pharmaceutical Co., Ltd. produces
Contrast 4: Chinese patent application CN201310614502.9 embodiment 1
Contrast 5: Chinese patent application CN200410070446.8 embodiment 1
Above test-results shows: the hemihydrated related substance of isosorbide mononitrate that the embodiment of the present invention is produced is less, is better than isosorbide mononitrate prepared by prior art, and steady quality is reliable, and impurity is controlled, is beneficial to and is prepared into injection.
Claims (5)
1. the isosorbide mononitrate hemihydrate shown in formula I,
Measure with Karl_Fischer method, described isosorbide mononitrate hemihydrate contains the moisture of 4.87%-5.08% (weight percent); Described isosorbide mononitrate hemihydrate, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle and D value,
The error of 2 θ diffraction angle is ± 0.2.
2. the hemihydrated feature of isosorbide mononitrate according to claim 1, its preparation method is to comprise the following steps: to prepare sherwood oil: the solution of ethyl acetate=5:1, for subsequent use, take the dimethyl formamide (DMF) of isosorbide mononitrate and 0.3-0.8% in reaction vessel, add the sherwood oil ethyl acetate solution of the above-mentioned preparation of 1-10 volume, be heated to 80 DEG C clearly molten, backflow about 0.5h, then heating is stopped, continue to stir, it is made naturally to be down to room temperature (about 20 DEG C), solution becomes muddy gradually in temperature-fall period, crystal is had to separate out, continue to stir about 1h after being down to room temperature, then filter, filter cake is with sherwood oil drip washing 2-3 time, solid drying, obtain isosorbide mononitrate hemihydrate, chemical purity is up to 99.9%, single largest impurity is no more than 0.05%, total impurities is no more than 0.1%.
3. the hemihydrated composition of isosorbide mononitrate that forms of the hemihydrate of isosorbide mononitrate and one or more pharmaceutically acceptable carriers according to claim 1.
4. the composition required by right described in 3, is characterized in that said composition is for the preparation of solid preparation or injection.
5. according to claim 1 isosorbide mononitrate hemihydrate manufacture treatment coronary heart diseases and angina pectoris, continue after myocardial infarction stenocardia, with purple foxglove or diuretic(s) combined utilization, the application for the treatment of in the medicines such as chronic heart failure.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112174975A (en) * | 2020-11-09 | 2021-01-05 | 鲁南贝特制药有限公司 | Green refining method of isosorbide mononitrate |
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2015
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| EP0201067A2 (en) * | 1985-05-10 | 1986-11-12 | Consiglio Nazionale Delle Ricerche | Process for the preparation of isosorbide-5-mononitrate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112174975A (en) * | 2020-11-09 | 2021-01-05 | 鲁南贝特制药有限公司 | Green refining method of isosorbide mononitrate |
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