CN102408398A - Preparation method of ranitidine bismuth citrate - Google Patents
Preparation method of ranitidine bismuth citrate Download PDFInfo
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- CN102408398A CN102408398A CN2011102774802A CN201110277480A CN102408398A CN 102408398 A CN102408398 A CN 102408398A CN 2011102774802 A CN2011102774802 A CN 2011102774802A CN 201110277480 A CN201110277480 A CN 201110277480A CN 102408398 A CN102408398 A CN 102408398A
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Abstract
The invention provides a preparation method of ranitidine bismuth citrate and belongs to the technical field of preparation of medicinal compounds. The preparation method comprises the following steps: preparing materials: firstly introducing water into a reaction vessel with a stirring device, sequentially introducing N-methyl-1-methylthio-2-nitroethylene amine and Thiobisethylamine into the reaction vessel under the condition that the stirring device is started, and controlling the weight ratio of the water, N-methyl-1-methylthio-2-nitroethylene amine and Thiobisethylamine, thus obtaining material for condensation reaction; carrying out condensation reaction; carrying out cooling crystallization; carrying out centrifugal separation; carrying out salifying reaction; decoloring;carrying out filter pressing;crystallizing;separating;and crushing and drying. The preparation method has the following advantages: catalysts are not used, so that the reaction time is obviously shortened, thus not only can energy sources be effectively saved, but also the industrial enlarged production requirements can be met.
Description
Technical field
The invention belongs to the medical compounds preparing technical field, be specifically related to a kind of preparation method of bismuth citrate ranitidine.
Background technology
Bismuth citrate ranitidine also is called as RBS, and its English name is: (english abbreviation is Renitidine BismuchCitrate: RBC); Chemical name is:
N-[2-[5-[(dimethylamino) methyl]-2-furyl methyl sulfo-] ethyl]-N-methyl-2-nitro-1,1-ethylene diamine 2-hydroxyl-1,2, the 3-third tri hydroxy acid bismuth salt (complex compound); Its structural formula is:
RBC is in the existing history of more than two decades nearly of the clinical use of medical treatment; It is to be used for the medicine such as stomach ulcer, duodenal ulcer, esophageal ulcer etc. by what Britain GLAXO (Glan is plain) company took the lead in succeeding in developing; Can suppress the Pepsin isozyme effectively; Have the dual function that Ranitidine HCL suppresses acid secretion and the anti-Hp of bismuth salt protection stomach mucous membrane concurrently, ranitidine hydrochloride and the various bismuth salt of being superior to evident in efficacy is added up according to related data; And at present, the whole world has reached 75 countries and has used.
Preparing method about RBC; Report is early arranged, typical " a kind of method for preparing bismuth citrate ranitidine " that provides like " preparation method of a kind of RBS or Ranitidine HCL Bismuth tartrate mixture " and the patent of invention CN100402514C of Chinese invention patent Granted publication CN1256332C recommendation in disclosed patent documentation.
The former (being CN1256332C) in above-mentioned two patents remedied prior art such as the existing shortcoming of CN1039419A, CN1156143A and CN1236779A (unexposed purified technical intelligence); Thereby proposed to utilize phase transfer catalysis process to react and reaction product isolated at 0-50 ℃; Specifically: in reaction solution, add the dewatering agent azeotropic and separate out; Perhaps with the reaction solution spraying drying, perhaps with the reaction solution lyophilize.
Latter's (being CN100402514C) in above-mentioned two patents is same in view of two kinds of existing drawbacks of method that aforementioned CN1039419A introduced (referring to the conclusion of specification sheets page 1 final stage to first section of the page 2 of CN100402514C); Thereby having proposed elder generation suspends in water bismuth citrate; Adding ammoniacal liquor and Ranitidine HCL react under pH6-12 and 4-64 ℃ of condition in water again; Reaction solution filters and spraying drying to neutral, gets product RBC.
Above-mentioned CN1256332C not only preparation cost height but also reaction times tediously long (not comprising the time for preparing ranitidine alkali), is unfavorable for save energy, thereby is difficult to adapt to industrial amplification production owing to need to use catalyzer.And aforementioned CN100402514C with ammoniacal liquor as catalyzer; Have the high shortcoming of preparation cost equally, and ammoniacal liquor has strong impulse property smell, exert an influence preparing on-the-spot operating environment; Especially the post-processed of ammoniacal liquor comparatively bothers, and can undermine environment if deal with improperly.
Summary of the invention
Task of the present invention is to provide a kind of and need not to use catalyzer and use and shorten the preparation method of reaction times with the bismuth citrate ranitidine that satisfies industrial amplification production and require effectively.
Task of the present invention is accomplished like this, and a kind of preparation method of bismuth citrate ranitidine may further comprise the steps:
A) get the raw materials ready; Earlier water is introduced and had in the reaction vessel of whipping appts; Under the state of opening whipping appts, successively N-methyl isophthalic acid-methylthio group-2-nitroethylene amine and aminoethyl thioether are introduced in the reaction vessel again; The weight ratio of control water, N-methyl isophthalic acid-methylthio group-2-nitroethylene amine and aminoethyl thioether obtains condensation reaction and uses material;
B) heating unit of reaction vessel is opened in condensation reaction, and makes material be warming up to 40-60 ℃ under the whipping appts whipped state keeping, treat 3-6h after, obtain the ranitidine alkali reaction solution;
C) crystallisation by cooling; The ranitidine alkali reaction solution is changed in the crystallisation by cooling container; And under the state of the whisking appliance of opening the cooling crystallisation vessel, heat-eliminating medium is introduced in the crystallisation by cooling container, made the ranitidine alkali reaction solution be cooled to 0-5 ℃, obtain containing the ranitidine alkali crystallisate of mother liquor;
D) spinning, the ranitidine alkali crystallisate that will contain mother liquor is introduced the centrifugal mother liquor that removes of centrifugal device, obtains crystallisate, the mother liquor reuse, then with water at low temperature to crystallisate drip washing, and after drip washing, dewater, obtain ranitidine alkali;
E) salt-forming reaction; By weight earlier purified water and bismuth citrate being dropped in the salify container successively; Open the whisking appliance of salify container and make the temperature of salify container remain in 60-90 ℃, obtain the bismuth citrate saline solution, again by weight adding ranitidine alkali; Lower the temperature behind the stirring reaction 45-60min, obtain bismuth citrate ranitidine solution;
F) decolouring joins gac in the bismuth citrate ranitidine solution, and insulation decolouring under whipped state, the weight ratio of control gac and bismuth citrate ranitidine solution, the bismuth citrate ranitidine solution that obtains decolouring;
G) press filtration is pressed into crystallisation vessel through decarbonization filtering device and accurate filter with the bismuth citrate ranitidine solution of the decolouring in the salify container under control pressure and successively, the filtering gac, and the gac waste residue of filtering is collected, and obtains thing to be crystallized;
H) crystallization joins ethanol in the thing to be crystallized and to stir, and control churning time, and the weight ratio of control ethanol and thing to be crystallized obtain containing the material of ethanol mother liquor;
I) separate, the material that will contain the ethanol mother liquor is introduced whizzer and is got rid of filter from crystallisation vessel, remove ethanol mother liquor and recovery ethanol mother liquor; Obtain filter cake, then with washing medium to filter cake washing once or plural number, washing back dries; And the recovery washing medium obtains waiting to pulverize the exsiccant filter cake;
J) pulverize drying, will wait to pulverize the exsiccant filter cake and take out and be transferred to the kibbler pulverizing from whizzer, the pulverizing back packs and after pack, introduces drying under reduced pressure in the vacuum drying oven, obtains bismuth citrate ranitidine.
In a concrete embodiment of the present invention; Steps A) reaction vessel of stating in is a retort; The weight ratio of described control water, N-methyl isophthalic acid-methylthio group-2-nitroethylene amine and aminoethyl thioether is that weight ratio is controlled to be 1-2: 1: 1-2; Described water is the water through purifying treatment, and described water through purifying treatment is meant the water that meets CNS " drinking water sanitary standard ".
The heating unit of the unlatching reaction vessel in another concrete embodiment of the present invention, step B) is that to introduce temperature be 90-100 ℃ hot water for the chuck internal recycle that points to reaction vessel.
In another concrete embodiment of the present invention, step C) the crystallisation by cooling container described in is the crystallisation by cooling jar, and described heat-eliminating medium is a water.
The temperature of the water at low temperature in another concrete embodiment of the present invention, step D) is 0-5 ℃, and the water quality of said water at low temperature is for meeting the water of CNS " drinking water sanitary standard ".
Also have among the concrete embodiment of the present invention; Step e) the salify container described in is for becoming salt cellar; The weight ratio of described purified water and bismuth citrate is 1: 0.5-0.75, wherein, the water quality of purified water is for meeting the water of CNS " drinking water sanitary standard ".
more of the present invention and among concrete embodiment, step e) ranitidine alkali described in and the weight ratio of bismuth citrate saline solution are 1: 0.6-1.2.
In of the present invention and then concrete embodiment, step F) gac described in is a medicinal carbon, and the weight ratio of this medicinal carbon and described bismuth citrate ranitidine solution is 1: 135-240.
Of the present invention again more and among concrete embodiment, step G) be to be 0.1-0.15MPa under the control pressure described in pressure-controlling; Step H) the control churning time described in is that churning time is controlled to be 10-16h, and the weight ratio of described control ethanol and thing to be crystallized is that weight ratio is controlled to be 1: 0.08-0.11, described ethanol is absolute ethyl alcohol.
In again of the present invention and then concrete embodiment, step I) plural number described in is twice or 3 times, and described washing medium is an absolute ethyl alcohol; Step J) kibbler described in is a swing kibbler of being furnished with the 5-14 mesh sieve, and the pressure of described drying under reduced pressure is 0.06MPa-0.09MPa, and drying temperature is 50-70 ℃.
Compared with present technology technical scheme provided by the invention owing to abandoned catalyzer, therefore can significantly shorten the reaction times, thereby both save energy effectively can satisfy the industrial amplification production requirement again.
Embodiment
For the inspector that the makes Patent Office especially public can be expressly understood technical spirit of the present invention and beneficial effect more; The applicant general elaborates with the mode of embodiment below; But the description to embodiment all is not the restriction to the present invention program, any according to the present invention design done only for pro forma but not substantial equivalent transformation all should be regarded as technical scheme category of the present invention.
The aminoethyl thioether (that is: 2-[[[5-(dimethylamino) methyl-2-furans] methyl] sulfenyl] ethamine) that relates among the following embodiment is following with the reaction equation of N-methyl isophthalic acid-methylthio group-2-nitroethylene amine:
Bismuth citrate and Ranitidine HCL reacting by heating, the reaction equation that generates bismuth citrate ranitidine is following:
Embodiment 1:
A) get the raw materials ready; With vacuum mode the water suction that tap water promptly meets CNS " drinking water sanitary standard " is furnished with in the retort of whipping appts, emptying is then introduced retort with N-methyl isophthalic acid-methylthio group-2-nitroethylene amine under the state of opening whipping appts; Sealing (sealing charging opening); The suction aminoethyl thioether obtains condensation reaction and uses material, and wherein: the weight ratio of water, N-methyl isophthalic acid-methylthio group-2-nitroethylene amine and aminoethyl thioether is 1: 1: 1 in this step;
B) condensation reaction; Open the heating unit of retort and promptly in the chuck (also can claim interlayer) of retort, introduce 90 ℃ hot water with the mode of circulating; And make material (being that material is used in condensation reaction) temperature slowly rise to 40 ℃ under the whipping appts whipped state keeping; Behind the question response 3h, obtain the ranitidine alkali reaction solution;
C) crystallisation by cooling; Will be by step B) the ranitidine alkali reaction solution that obtains changes in the crystallisation by cooling jar as the crystallisation by cooling container; The water that under the state of the whisking appliance of opening the cooling crystallizer, will promptly meet CNS " drinking water sanitary standard " as heat-eliminating medium is introduced in the crystallisation by cooling jar; Make the ranitidine alkali reaction solution be cooled to 0 ℃, obtain containing the ranitidine alkali crystallisate of mother liquor;
D) filter bag is completed earlier in spinning in whizzer, will be by step C) the ranitidine alkali crystallisate that contains mother liquor that obtains introduces in the whizzer and carries out centrifuge dehydration; Use removing mother liquor, obtain crystallisate, mother liquor is collected reuse; Then using temperature is that 0 ℃ water at low temperature is to crystallisate drip washing; After drip washing, dewater, obtain ranitidine alkali, wherein: water at low temperature is for meeting the water of CNS " drinking water sanitary standard ";
E) salt-forming reaction; By weight elder generation the water that purified water promptly meets CNS " drinking water sanitary standard " is dropped into in the salt cellar with bismuth citrate successively, the temperature maintenance of opening into the whisking appliance of salt cellar and making into salt cellar obtains the bismuth citrate saline solution at 60 ℃; Again ranitidine alkali is joined the bismuth citrate saline solution that is arranged in in the salt cellar; Reduce to normal temperature behind the stirring reaction 45min, obtain bismuth citrate ranitidine solution, in this step; The weight ratio of purified water and bismuth citrate is 1: 0.5, and the weight ratio of ranitidine alkali and bismuth citrate is 1: 0.6;
F) decolouring; By weight; Medicinal carbon is joined by step e) in the bismuth citrate ranitidine solution that obtains; And insulation decolouring under whipped state, the bismuth citrate ranitidine solution that obtains decolouring, wherein: the weight ratio of medicinal carbon and bismuth citrate ranitidine solution is 1: 135;
G) press filtration at first regulates into the valve of salt cellar, the valve of decarbonization filtering device and the valve of crystallizer, will be by step F) that obtain and bismuth citrate ranitidine solution that be positioned at into the decolouring in the salt cellar is pressed in the crystallizer through decarbonization filtering device and accurate filter with the pressure of 0.10MPa successively; Use filtering gac waste residue; After press filtration finishes, emptying, and collect the useless pool of gac; So that focus on; And to decarbonization filtering device, accurate filter and one-tenth salt cellar cleaning, subsequent use, obtain thing to be crystallized;
H) crystallization by weight, joins absolute ethyl alcohol by step G) obtain and thing stirring 10h to be crystallized that be positioned at crystallizer, the weight ratio of absolute ethyl alcohol and thing to be crystallized is controlled to be 1: 0.08, obtains containing the material of ethanol mother liquor;
I) separate, will be by step H) material that contains the ethanol mother liquor that obtains introduces whizzer from crystallization kettle (also being crystallizer) and gets rid of filter, remove the ethanol mother liquor and reclaim the ethanol mother liquor; Obtain filter cake; The absolute ethyl alcohol that then is used as washing medium is to filter cake washing twice, and the washing back dries, and reclaims washing medium; Promptly reclaim absolute ethyl alcohol, obtain the filter cake of pulverizing to be dried;
J) pulverize and dry, will be by step F) filter cake that obtains takes out from whizzer, is transferred to the swing kibbler of being furnished with 5 mesh sieves and pulverizes; Pack into after the pulverizing in the dry bag, and place on the drip pan, take it by drip pan and send into drying under reduced pressure in the vacuum drying oven; Pressure is-0.06MPa that drying temperature is 50 ℃, until being dried to water ratio less than 2.0% back discharging; Pulverize the 30-60 order through kibbler, obtain bismuth citrate ranitidine.
Embodiment 2:
Only with steps A) in the weight ratio of water, N-methyl isophthalic acid-methylthio group-2-nitroethylene amine and aminoethyl thioether change 1.5: 1: 1.5 into; With step B) in the temperature of in the chuck of retort, introducing hot water change 95 ℃ into, the material ascending temperature changes 50 ℃ into, will the reaction times change 4.5h into; With step C) in the cooling temperature of ranitidine alkali reaction solution change 2.5 ℃ into; With step D) in the temperature of water at low temperature change 2.5 ℃ into; With step e) in the holding temperature of one-tenth salt cellar change 75 ℃ into, change the stirring reaction time into 50min; Change the weight ratio of purified water and bismuth citrate into 1: 0.6, change the weight ratio of ranitidine alkali and bismuth citrate into 1: 1.0; With step F) in gac and the weight ratio of bismuth citrate ranitidine alkali change 1: 180 into; With step G) in pressure change 0.12MPa into; With step H) in absolute ethyl alcohol and the weight ratio of crystallisate change 1: 0.09 into, change churning time into 12h; With step I) in washing times change into 1 time, change the order number of the sieve of swing kibbler into 10 orders; With step J) in the pressure of drying under reduced pressure change into-0.07MPa, drying temperature changes 60 ℃ into.All the other are all with the description to embodiment 1.
Embodiment 3:
Only with steps A) in the weight ratio of water, N-methyl isophthalic acid-methylthio group-2-nitroethylene amine and aminoethyl thioether change 2: 1: 1 into; With step B) in the temperature of in the chuck of retort, introducing hot water change 100 ℃ into, the material ascending temperature changes 60 ℃ into, will the reaction times change 6h into; With step C) in the cooling temperature of ranitidine alkali reaction solution change 5 ℃ into; With step D) in the temperature of water at low temperature change 5 ℃ into; With step e) in the holding temperature of one-tenth salt cellar change 90 ℃ into, change the stirring reaction time into 60min; Change the weight ratio of purified water and bismuth citrate into 1: 0.75, change the weight ratio of ranitidine alkali and bismuth citrate into 1: 1.2; With step F) in gac and the weight ratio of bismuth citrate ranitidine alkali change 1: 240 into; With step G) in pressure change 0.15MPa into; With step H) in absolute ethyl alcohol and the weight ratio of crystallisate change 1: 0.11 into, change churning time into 16h; With step I) in washing times change into 3 times, change the order number of the sieve of swing kibbler into 14 orders; With step J) in the pressure of drying under reduced pressure change into-0.09MPa, drying temperature changes 70 ℃ into.All the other are all with the description to embodiment 1.
Claims (10)
1.
A kind of preparation method of bismuth citrate ranitidine is characterized in that may further comprise the steps:
A) get the raw materials ready; Earlier water is introduced and had in the reaction vessel of whipping appts; Under the state of opening whipping appts, successively N-methyl isophthalic acid-methylthio group-2-nitroethylene amine and aminoethyl thioether are introduced in the reaction vessel again; The weight ratio of control water, N-methyl isophthalic acid-methylthio group-2-nitroethylene amine and aminoethyl thioether obtains condensation reaction and uses material;
B) heating unit of reaction vessel is opened in condensation reaction, and makes material be warming up to 40-60 ℃ under the whipping appts whipped state keeping, treat 3-6h after, obtain the ranitidine alkali reaction solution;
C) crystallisation by cooling; The ranitidine alkali reaction solution is changed in the crystallisation by cooling container; And under the state of the whisking appliance of opening the cooling crystallisation vessel, heat-eliminating medium is introduced in the crystallisation by cooling container, made the ranitidine alkali reaction solution be cooled to 0-5 ℃, obtain containing the ranitidine alkali crystallisate of mother liquor;
D) spinning, the ranitidine alkali crystallisate that will contain mother liquor is introduced the centrifugal mother liquor that removes of centrifugal device, obtains crystallisate, the mother liquor reuse, then with water at low temperature to crystallisate drip washing, and after drip washing, dewater, obtain ranitidine alkali;
E) salt-forming reaction; By weight earlier purified water and bismuth citrate being dropped in the salify container successively; Open the whisking appliance of salify container and make the temperature of salify container remain in 60-90 ℃, obtain the bismuth citrate saline solution, again by weight adding ranitidine alkali; Lower the temperature behind the stirring reaction 45-60min, obtain bismuth citrate ranitidine solution;
F) decolouring joins gac in the bismuth citrate ranitidine solution, and insulation decolouring under whipped state, the weight ratio of control gac and bismuth citrate ranitidine solution, the bismuth citrate ranitidine solution that obtains decolouring;
G) press filtration is pressed into crystallisation vessel through decarbonization filtering device and accurate filter with the bismuth citrate ranitidine solution of the decolouring in the salify container under control pressure and successively, the filtering gac, and the gac waste residue of filtering is collected, and obtains thing to be crystallized;
H) crystallization joins ethanol in the thing to be crystallized and to stir, and control churning time, and the weight ratio of control ethanol and thing to be crystallized obtain containing the material of ethanol mother liquor;
I) separate; The material that will contain the ethanol mother liquor is introduced whizzer and is got rid of filter from crystallisation vessel, remove the ethanol mother liquor and reclaim the ethanol mother liquor, obtains filter cake; Then with washing medium to filter cake washing once or the plural number time; The washing back dries, and reclaims washing medium, obtains waiting to pulverize the exsiccant filter cake;
J) pulverize drying, will wait to pulverize the exsiccant filter cake and take out and be transferred to the kibbler pulverizing from whizzer, the pulverizing back packs and after pack, introduces drying under reduced pressure in the vacuum drying oven, obtains bismuth citrate ranitidine.
2. the preparation method of
bismuth citrate ranitidine according to claim 1; It is characterized in that steps A) in the reaction vessel of stating be retort; The weight ratio of described control water, N-methyl isophthalic acid-methylthio group-2-nitroethylene amine and aminoethyl thioether is that weight ratio is controlled to be 1-2: 1: 1-2; Described water is the water through purifying treatment, and described water through purifying treatment is meant the water that meets CNS " drinking water sanitary standard ".
3. the preparation method of
bismuth citrate ranitidine according to claim 1 is characterized in that step B) described in the heating unit of unlatching reaction vessel be that to introduce temperature be 90-100 ℃ hot water for the chuck internal recycle that points to reaction vessel.
4. the preparation method of
bismuth citrate ranitidine according to claim 1 is characterized in that step C) described in the crystallisation by cooling container be the crystallisation by cooling jar, described heat-eliminating medium is a water.
5. the preparation method of
bismuth citrate ranitidine according to claim 1; It is characterized in that step D) described in the temperature of water at low temperature be 0-5 ℃, the water quality of said water at low temperature is for meeting the water of CNS " drinking water sanitary standard ".
6. the preparation method of
bismuth citrate ranitidine according to claim 1; It is characterized in that step e) described in the salify container for becoming salt cellar; The weight ratio of described purified water and bismuth citrate is 1: 0.5-0.75; Wherein, the water quality of purified water is for meeting the water of CNS " drinking water sanitary standard ".
7. the preparation method of
bismuth citrate ranitidine according to claim 1 is characterized in that step e) described in ranitidine alkali and the weight ratio of bismuth citrate saline solution be 1: 0.6-1.2.
8. the preparation method of
bismuth citrate ranitidine according to claim 1; It is characterized in that step F) described in gac be medicinal carbon, the weight ratio of this medicinal carbon and described bismuth citrate ranitidine solution is 1: 135-240.
9. the preparation method of
bismuth citrate ranitidine according to claim 1 is characterized in that step G) described in control pressure under be to be 0.1-0.15MPa with pressure-controlling; Step H) the control churning time described in is that churning time is controlled to be 10-16h, and the weight ratio of described control ethanol and thing to be crystallized is that weight ratio is controlled to be 1: 0.08-0.11, described ethanol is absolute ethyl alcohol.
10.
The preparation method of bismuth citrate ranitidine according to claim 1 is characterized in that step I) described in plural number time be twice or 3 times, described washing medium is an absolute ethyl alcohol; Step J) kibbler described in is a swing kibbler of being furnished with the 5-14 mesh sieve, and the pressure of described drying under reduced pressure is 0.06MPa-0.09MPa, and drying temperature is 50-70 ℃
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896888A (en) * | 2014-03-28 | 2014-07-02 | 常州兰陵制药有限公司 | Preparation method of ranitidine bismuth citrate |
| CN107382921A (en) * | 2017-07-28 | 2017-11-24 | 常州兰陵制药有限公司 | The method for preparing bismuth citrate ranitidine |
| CN107501216A (en) * | 2017-08-03 | 2017-12-22 | 江苏汉斯通药业有限公司 | The new synthetic method of high stability Chinese holly edge acid ranitidine bismuth |
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| WO1999065890A1 (en) * | 1998-06-17 | 1999-12-23 | Russinsky Limited | Ranitidine adduct |
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| CN1039419A (en) * | 1988-07-18 | 1990-02-07 | 格拉克索公司 | Process for preparation of furan derivatives |
| WO1999065890A1 (en) * | 1998-06-17 | 1999-12-23 | Russinsky Limited | Ranitidine adduct |
| CN1236779A (en) * | 1999-04-28 | 1999-12-01 | 常州市第二制药厂 | Process for preparing bismuth ranitidine-citrate |
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| 王浦海 等: "雷尼替丁枸橼酸铋的合成及其表征", 《中国药物化学杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896888A (en) * | 2014-03-28 | 2014-07-02 | 常州兰陵制药有限公司 | Preparation method of ranitidine bismuth citrate |
| CN103896888B (en) * | 2014-03-28 | 2015-11-18 | 常州兰陵制药有限公司 | The preparation method of bismuth citrate ranitidine |
| CN107382921A (en) * | 2017-07-28 | 2017-11-24 | 常州兰陵制药有限公司 | The method for preparing bismuth citrate ranitidine |
| CN107501216A (en) * | 2017-08-03 | 2017-12-22 | 江苏汉斯通药业有限公司 | The new synthetic method of high stability Chinese holly edge acid ranitidine bismuth |
| CN107501216B (en) * | 2017-08-03 | 2021-01-19 | 江苏汉斯通药业有限公司 | Novel synthesis method of high-stability bismuth citrate ranitidine |
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| Publication number | Publication date |
|---|---|
| CN102408398B (en) | 2012-12-05 |
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