CN106432149B - A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble - Google Patents
A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble Download PDFInfo
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- CN106432149B CN106432149B CN201610823327.8A CN201610823327A CN106432149B CN 106432149 B CN106432149 B CN 106432149B CN 201610823327 A CN201610823327 A CN 201610823327A CN 106432149 B CN106432149 B CN 106432149B
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- 229960001520 ranitidine hydrochloride Drugs 0.000 title claims abstract description 66
- -1 ranitidine hydrochloride compound Chemical class 0.000 title claims abstract description 32
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims abstract description 10
- 210000002784 stomach Anatomy 0.000 title claims abstract description 9
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 8
- 230000005260 alpha ray Effects 0.000 claims abstract description 5
- 238000005259 measurement Methods 0.000 claims abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 16
- 239000012046 mixed solvent Substances 0.000 claims description 12
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical class CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 229910017488 Cu K Inorganic materials 0.000 claims description 4
- 229910017541 Cu-K Inorganic materials 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 abstract description 15
- 238000010521 absorption reaction Methods 0.000 abstract description 10
- 239000013078 crystal Substances 0.000 abstract description 7
- 238000002845 discoloration Methods 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000012795 verification Methods 0.000 abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 229960000620 ranitidine Drugs 0.000 description 7
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 238000004088 simulation Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960001380 cimetidine Drugs 0.000 description 3
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 150000003839 salts Chemical group 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 108010079943 Pentagastrin Proteins 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960000444 pentagastrin Drugs 0.000 description 2
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010583 slow cooling Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100021022 Gastrin Human genes 0.000 description 1
- 108010052343 Gastrins Proteins 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229950002342 bisfentidine Drugs 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- FXJAOWANXXJWGJ-UHFFFAOYSA-N n-[4-(2-methyl-1h-imidazol-5-yl)phenyl]-n'-propan-2-ylmethanimidamide Chemical compound C1=CC(NC=NC(C)C)=CC=C1C1=CN=C(C)N1 FXJAOWANXXJWGJ-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
Abstract
The invention discloses a kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble, belong to pharmaceutical technology field.Compound produced by the present invention is as shown in Figure 1 using the X ray powder diffraction patterns that Cu K alpha ray measurements obtain, the novel crystal forms of the compound are different from the crystalline structure of the prior art, pass through verification experimental verification, surprisingly find using the novel crystal forms structure compound it is not easy to moisture absorption, stability is good, fundamentally solve ranitidine hydrochloride meet it is wet, hot, air is unstable, product is easily aoxidized, the problems such as easy moisture absorption discoloration, stability is poor, provided a convenient for the preparation of preparation.
Description
The application is the joyful Pharmaceutical Technology Co., Ltd of applicant Yantai City Chinese, the invention of Wang Yufeng, Li Xianmeng proposition
Patent application（It is entitled：A kind of medicine ranitidine hydrochloride compound for treating stomach trouble and preparation method thereof, application number
For：201510273209X, the applying date be：On May 26th, 2015）Divisional application.
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of preparation for the medicine ranitidine hydrochloride compound for treating stomach trouble
Method.
Background technology
Ranitidine is the medicine of most widely used treatment canker at present as Cimetidine.By Britain Ge Lan elements
（glaxo）Company develops.1976 by Britain's Price（price）Deng synthesis, Bradshaw in 1979（bradshaw）Illustrate
Its pharmacology, bass tower in 1980（berstad）Report is effective for duodenal ulcer, lists within 1981, in the world more or less a hundred
Countries use.China was produced in 1985 by Shanghai No.6 Pharmaceutical Factory.
Ranitidine is the bisfentidine of a selectivity, can effectively inhibit histamine, pentagastrin and food thorn
Gastric acid secretion caused by after swashing, reduces the activity of hydrochloric acid in gastric juice and gastric enzyme, but the secretion on gastrin and sex hormone is without influence.Effect ratio
Cimetidine is 5~8 times strong, high the effect of to gastric and duodenal ulcer, have the characteristics that it is quick-acting and long-acting, Small side effects and
Safety.30~90 minutes after single oral 80mg, average Cmax is 165ng/ml, when effect lasts 12 are small.
Ranitidine is absorbed soon, from the influence of food and antiacid.Oral administration biaavailability is about that 50%, t1/2 is about
2~2.7 it is small when, it is slightly long compared with Cimetidine.After oral 12 it is small when interior energy gastric acid secretion caused by pentagastrin is reduced 30%.
Intravenous 1mg/kg, instantaneous blood concentration are 3000ng/ml, maintain more than 100ng/ml up to 4 it is small when；With 0.5ng/ per hour
30~60 minutes blood concentration peakings, are proportionate between Cmax and dosage after kg speed intravenous infusions.It is most of to be arranged with original shape from kidney
Let out, renal clearance is every point of 7.2ml/kg.
Ranitidine hydrochloride heat, wet, air is extremely unstable, and product is easily by easy decomposed metamorphic when oxidation and high fever.Due to
Bulk pharmaceutical chemicals are easy to the moisture absorption, cause to change colour, and the reason such as stability difference, has seriously affected formulation products quality, the preparation to preparation
Bring difficulty.
Therefore, it is necessary to develop a kind of ranitidine hydrochloride noval chemical compound, fundamentally solve ranitidine hydrochloride meet it is wet,
The problems such as heat, air are unstable, and product is easily aoxidized, easy moisture absorption discoloration, stability is poor, provides conveniently for the preparation of preparation.
The content of the invention
The goal of the invention of the present invention is to provide a kind of medicine ranitidine hydrochloride compound for treating stomach trouble and its preparation
Method.
In order to achieve the object of the present invention, the technical solution used for：
A kind of medicine ranitidine hydrochloride compound for treating stomach trouble, it is characterised in that the ranitidine hydrochloride
Compound is as shown in Figure 1 using the X-ray powder diffraction figure that Cu-K alpha ray measurements obtain.
A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble of the present invention, includes the following steps：Will
Ranitidine hydrochloride solid is dissolved in methanol solution；Ethanol, the mixed solvent of acetone are first added, stirring while adding, control temperature
20-25 DEG C of degree, when growing the grain 0.5-1 is small；Then acetone, the mixed solvent of 2,4- lutidines are added, when growing the grain 1-2 is small
Afterwards, cool down, be then kept stirring 120-150 revs/min of stirring and crystallizing of speed, growing the grain 2-3 it is small when；Filtering, is dried to obtain hydrochloric acid
Ranitidine crystalline compounds.
Preferably, the volume of the methanol solution is 8-10 times of ranitidine hydrochloride weight.
Preferably, the temperature of the methanol solution is 20-25 DEG C.
Preferably, first add ethanol, acetone mixed solvent volume total amount be ranitidine hydrochloride weight 10-12
Times, the volume ratio of ethanol and acetone is 1.5:1.
Preferably, add acetone, the volume total amount of mixed solvent of 2,4- lutidines is ranitidine hydrochloride
The volume ratio of 12-25 times of weight, acetone and 2,4- lutidines is 3:2.
Preferably, the cooling is to be cooled to -5 DEG C with 10-15 DEG C/h of speed.
Preferably, the drying condition is 40-50 DEG C, is dried under reduced pressure.
Technical scheme is made further explanation below：
The present invention prepares a kind of new ranitidine hydrochloride chemical combination by varying the crystallization condition of ranitidine hydrochloride
Thing, the X-ray powder diffraction figure obtained by using Cu-K alpha ray measurements are as shown in Figure 1.
The preparation method of the present invention, finely controls crystallization condition, has obtained a kind of new crystalline compounds.The present invention is logical
The control to temperature, mixing speed etc. is crossed, so that the crystallization process of stringenter control solution.
In ranitidine hydrochloride crystallization process, formed in methanol solution two kinds of solvents of addition of ranitidine hydrochloride mixed
Bonding solvent, then by the means such as gradient crystallization, growing the grain, slow cooling, stirring, so as to control the crystallization of ranitidine hydrochloride
Journey.At the same time using gradient crystallization by the way of, organic solvent carries out slow cooling after adding, the speed of cooling for 10-15 DEG C/
The speed of hour is cooled to -5 DEG C.Stringent control by multiple crystallization and to Crystallization Process, has obtained a kind of new hydrochloric acid
Ranitidine compound.
By it is experimentally confirmed that the ranitidine hydrochloride compound for preparing of the present invention is not easy to moisture absorption, stability is good, from basic
On solve ranitidine hydrochloride and meet that wet, hot, air is unstable, product is easily aoxidized, the discoloration of the easy moisture absorption, and stability difference etc. is asked
Topic, provides a convenient for the preparation of preparation.
It is well known to those skilled in the art：Volume and weight is g/ml, kg/L so matched, and the volume of above-mentioned solvent is salt
The statement of the multiple of sour ranitidine weight may be interpreted as every ml solvents and correspond to ranitidine hydrochloride how many g or per L solvents pair
Ranitidine hydrochloride how many kg answered.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction collection of ranitidine hydrochloride compound prepared by the embodiment of the present invention 1.
Embodiment
The content of the invention of the present invention is described in further detail below by specific embodiment, but is not therefore limited
Determine present disclosure.
Embodiment 1：The preparation method of ranitidine hydrochloride compound, step are as follows：
Ranitidine hydrochloride solid is dissolved in 8 times of methanol solutions that 20 DEG C of volumes are ranitidine hydrochloride weight；First
Add the volume ratio of 10 times of ethanol, the mixed solvent of acetone that volume total amount is ranitidine hydrochloride weight, ethanol and acetone
For 1.5:1, it is stirring while adding, 20 DEG C of temperature is controlled, when growing the grain 0.5 is small；Then it is ranitidine hydrochloride to add volume total amount
The volume ratio of 12 times of acetone, the mixed solvent of 2,4- lutidines of weight, acetone and 2,4- lutidines is 3:2,
After when growing the grain 1 is small, -5 DEG C are cooled to 10 DEG C/h of speed, 120 revs/min of stirring and crystallizings of speed is then kept stirring, supports
When crystalline substance 2 is small；Filtering, 40 DEG C, be dried under reduced pressure to obtain ranitidine hydrochloride crystalline compounds.
The X-ray powder diffraction that the ranitidine hydrochloride compound crystal being prepared is obtained using Cu-K alpha ray measurements
Figure is as shown in Figure 1.
Embodiment 2：The preparation method of ranitidine hydrochloride compound, step are as follows：
Ranitidine hydrochloride solid is dissolved in 9 times of methanol solutions that 22.5 DEG C of volumes are ranitidine hydrochloride weight；
First add the volume of 11 times of ethanol, the mixed solvent of acetone that volume total amount is ranitidine hydrochloride weight, ethanol and acetone
Than for 1.5:1, it is stirring while adding, 22.5 DEG C of temperature is controlled, when growing the grain 0.75 is small；Then it is hydrochloric acid thunder Buddhist nun to add volume total amount
The volume ratio of the mixed solvent of 18.5 times of acetone, 2,4- lutidines for fourth weight, acetone and 2,4- lutidines
For 3:2, when growing the grain 1.5 is small after, be cooled to -5 DEG C with 12.5 DEG C/h of speed, be then kept stirring 135 revs/min of speed
When stirring and crystallizing, growing the grain 2.5 are small；Filtering, 45 DEG C, be dried under reduced pressure to obtain ranitidine hydrochloride crystalline compounds.
The X-ray powder diffraction figure for the crystal that the ranitidine hydrochloride compound crystal being prepared is prepared with embodiment 1
The characteristic peak of spectrum is identical.
Embodiment 3：The preparation method of ranitidine hydrochloride compound, step are as follows：
Ranitidine hydrochloride solid is dissolved in 10 times of methanol solutions that 25 DEG C of volumes are ranitidine hydrochloride weight；First
Add the volume ratio of 12 times of ethanol, the mixed solvent of acetone that volume total amount is ranitidine hydrochloride weight, ethanol and acetone
For 1.5:1, it is stirring while adding, 25 DEG C of temperature is controlled, when growing the grain 1 is small；Then it is ranitidine hydrochloride weight to add volume total amount
The volume ratio of 25 times of acetone, the mixed solvent of 2,4- lutidines of amount, acetone and 2,4- lutidines is 3:2, support
After when crystalline substance 2 is small, -5 DEG C are cooled to 15 DEG C/h of speed, is then kept stirring speed 150 revs/min of stirring and crystallizings, growing the grains
3 it is small when；Filtering, 50 DEG C, be dried under reduced pressure to obtain ranitidine hydrochloride crystalline compounds.
The X-ray powder diffraction figure for the crystal that the ranitidine hydrochloride compound crystal being prepared is prepared with embodiment 1
The characteristic peak of spectrum is identical.
Experimental example 1
1. hot test
Three batches of ranitidine hydrochloride compound 101,102,103 that Example 1 is prepared, simulation listing bag
Dress, puts in sealing clean container, is placed 10 days at a temperature of 40 ± 2 DEG C, is sampled in the 5th day and the 10th day, by stability emphasis
Investigation project is detected, and result of the test is compared with 0 day.
2. high humility is tested
Three batches of ranitidine hydrochloride compound 101,102,103 that Example 1 is prepared, simulation listing bag
Dress, puts in sealing clean container, is placed 10 days under conditions of 25 ± 2 DEG C of relative humidity 90% ± 5%, in the 5th day and the 10th day
Sampling, is detected by stability high spot reviews project, and result of the test was tested with 0 day than 3. strong illuminations
Three batches of ranitidine hydrochloride compound 101,102,103 that Example 1 is prepared, simulation listing bag
Dress, puts in sealing clean container, is placed in illumination to be placed 10 days under conditions of 4500lx, was sampled in the 5th day and the 10th day, by steady
Qualitative high spot reviews project is detected, and as a result compared with 0 day, the results are shown in Table 1.
The influence result of the test of 1 high temperature of table, high humidity, illumination to ranitidine hydrochloride compound
The result shows that：The ranitidine hydrochloride compound that the present invention is prepared, its stability is good, in high temperature, height
Under wet, high light conditions, equal retention property is stablized.Ranitidine hydrochloride compound prepared by other embodiments of the present invention is carried out
Influence factor is tested, and has obtained identical experimental result.
Experimental example 2：Acceleration study
Three batches 201,202,203 of the ranitidine hydrochloride compound of the gained of Example 2, simulation listing packaging,
Put in sealing clean container, placed 6 months under the conditions of 42 DEG C, 80%RH, taken during experiment respectively at 1,2,3,6 the end of month
Sample once, tests each stability high spot reviews project.Result of the test is as shown in table 2：
Each stability high spot reviews item-test result of the ranitidine hydrochloride compound of the present invention of table 2
The result shows that：The ranitidine hydrochloride compound that the present invention is prepared, its stabilization of accelerated results showed that
It is functional.Acceleration study is carried out to ranitidine hydrochloride compound prepared by other embodiments, has obtained identical experiment knot
Fruit.
Experimental example 3：Moisture absorption comparative test
1 instrument and reagent
1.1 instrument
PL203 electronic balances, LRH-250-S constant temperature and humidities incubator, HH-400SD testing chamber for medicine stabilities；
1.2 reagent
Investigational agent：The ranitidine hydrochloride compound that embodiment 1 is prepared；Comparative example 1：Singapore's imported raw material hydrochloric acid
Ranitidine（Manufacturer：GlaxoWellcome Manufacturing Pte Ltd）；Comparative example 2：Domestic raw material hydrochloric acid thunder
Buddhist nun replaces fourth（Manufacturer：Changzhou Kangpu Pharmaceutical Co., Ltd.）
2 methods：Bottom is taken to fill the glass desicator of salt supersaturated solution（To ensure salting liquid saturation, drier bottom
Should be with the presence of excessive salt）, measuring cup built in drier, places 48h to constant humidity in insulating box.Sample about 2g is taken, puts weighing
Bottle in, it is accurately weighed, bottle cap is opened, is put into drier top, by different temperatures requirement put 25 DEG C of constant temperature and humidity incubators or
Preserved in 20 DEG C of stability test casees, 3 parts of operation repetitive, weighs, calculate the hydroscopicity of different time respectively in different time.
Calculation formula：Hydroscopicity=（Medicinal powder weight before medicinal powder weight-moisture absorption after moisture absorption）Medicinal powder weight × 100% before/moisture absorption.
The results are shown in Table 3：
The present invention of table 3 is compared with 1,2 hydroscopicity in different time of comparative example
According to above-mentioned experiment, the hygroscopicity of ranitidine hydrochloride compound prepared by the present invention is less than the prior art,
I.e. the stability of the compound is higher than the prior art.
Claims (1)
- A kind of 1. method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble, it is characterised in that include the following steps： Ranitidine hydrochloride solid is dissolved in 10 times of methanol solutions that 25 DEG C of volumes are ranitidine hydrochloride weight；First add volume Total amount is 12 times of ethanol, the mixed solvent of acetone of ranitidine hydrochloride weight, and the volume ratio of ethanol and acetone is 1.5:1, It is stirring while adding, 25 DEG C of temperature is controlled, when growing the grain 1 is small；Then 25 times that volume total amount is ranitidine hydrochloride weight are added Acetone, the mixed solvent of 2,4- lutidines, the volume ratio of acetone and 2,4- lutidines is 3:2, when growing the grain 2 is small Afterwards, -5 DEG C are cooled to 15 DEG C/h of speed, be then kept stirring 150 revs/min of stirring and crystallizings of speed, growing the grain 3 it is small when； Filtering, 50 DEG C, be dried under reduced pressure to obtain ranitidine hydrochloride crystalline compounds；X-ray powder diffraction figure such as Fig. 1 institutes that obtained ranitidine hydrochloride compound is obtained using Cu-K alpha ray measurements Show.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610823327.8A CN106432149B (en) | 2015-05-26 | 2015-05-26 | A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble |
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| CN201610823327.8A CN106432149B (en) | 2015-05-26 | 2015-05-26 | A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble |
| CN201510273209.XA CN104817523B (en) | 2015-05-26 | 2015-05-26 | A kind of medicine ranitidine hydrochloride compound treating gastropathy and preparation method thereof |
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| CN106432149A CN106432149A (en) | 2017-02-22 |
| CN106432149B true CN106432149B (en) | 2018-04-17 |
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| CN201610823211.4A Active CN106432148B (en) | 2015-05-26 | 2015-05-26 | A kind of preparation method for the medicine ranitidine hydrochloride compound for treating stomach trouble |
| CN201610823158.8A Active CN106432147B (en) | 2015-05-26 | 2015-05-26 | A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble |
| CN201610823327.8A Active CN106432149B (en) | 2015-05-26 | 2015-05-26 | A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble |
| CN201610807242.0A Withdrawn CN106397374A (en) | 2015-05-26 | 2015-05-26 | Method for preparing ranitidine hydrochloride compound as drug for treating stomach diseases |
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| CN201610823211.4A Active CN106432148B (en) | 2015-05-26 | 2015-05-26 | A kind of preparation method for the medicine ranitidine hydrochloride compound for treating stomach trouble |
| CN201610823158.8A Active CN106432147B (en) | 2015-05-26 | 2015-05-26 | A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble |
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| CN105055396A (en) * | 2015-09-17 | 2015-11-18 | 青岛华之草医药科技有限公司 | Ranitidine hydrochloride composition freeze-dried powder injection for treating stomach illness |
| CN107382922A (en) * | 2017-08-03 | 2017-11-24 | 江苏汉斯通药业有限公司 | The preparation method of high-transmittance ranitidine hydrochloride |
Citations (4)
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| US4521431A (en) * | 1980-10-01 | 1985-06-04 | Glaxo Group Limited | Aminoalkyl furan derivative |
| CN1098720A (en) * | 1991-12-20 | 1995-02-15 | 多坎化学有限公司 | The preparation of form 1 ranitidine hydrochloride |
| US5523423A (en) * | 1994-04-08 | 1996-06-04 | Acic (Canada) Inc. | Form of form 1 Ranitidine |
| US5621120A (en) * | 1994-05-13 | 1997-04-15 | Ranbaxy Laboratories Limited | Process for the manufacture of form 1 ranitidine hydrochloride |
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|---|---|---|---|---|
| GR852557B (en) * | 1985-10-23 | 1985-11-27 | Chemica Farmakeutiki Viomihani | |
| KR0152469B1 (en) * | 1995-07-13 | 1998-10-15 | 이승웅 | Process for manufacturing form -ñ‹ ranitidine hydrochloride |
| WO1997035853A1 (en) * | 1996-03-25 | 1997-10-02 | Hoechst Marion Roussel, Inc. | Process for the preparation of form 1 ranitidine hydrochloride |
| US20020151729A1 (en) * | 1997-02-26 | 2002-10-17 | Cheng Wen J. | Novel process for the preparation of form 1 ranitidine hydrochloride |
| AU4055699A (en) * | 1998-06-17 | 2000-01-05 | Russinsky Limited | Ranitidine adduct |
| CN1315818C (en) * | 2005-07-11 | 2007-05-16 | 石药集团中诺药业（石家庄）有限公司 | Synthesis method of ranitidine alkali and its hydrochloride |
| CN102010389B (en) * | 2009-09-04 | 2012-11-14 | 江苏汉斯通药业有限公司 | Method for preparing ranitidine hydrochloride |
| MX345168B (en) * | 2010-06-02 | 2017-01-19 | Laboratorios Senosiain S A De C V * | Process for preparing ranitidine hydrochloride form 2. |
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2015
- 2015-05-26 CN CN201510273209.XA patent/CN104817523B/en active Active
- 2015-05-26 CN CN201610823211.4A patent/CN106432148B/en active Active
- 2015-05-26 CN CN201610823158.8A patent/CN106432147B/en active Active
- 2015-05-26 CN CN201610823327.8A patent/CN106432149B/en active Active
- 2015-05-26 CN CN201610807242.0A patent/CN106397374A/en not_active Withdrawn
Patent Citations (4)
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| US4521431A (en) * | 1980-10-01 | 1985-06-04 | Glaxo Group Limited | Aminoalkyl furan derivative |
| CN1098720A (en) * | 1991-12-20 | 1995-02-15 | 多坎化学有限公司 | The preparation of form 1 ranitidine hydrochloride |
| US5523423A (en) * | 1994-04-08 | 1996-06-04 | Acic (Canada) Inc. | Form of form 1 Ranitidine |
| US5621120A (en) * | 1994-05-13 | 1997-04-15 | Ranbaxy Laboratories Limited | Process for the manufacture of form 1 ranitidine hydrochloride |
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| 盐酸雷尼替丁精制方法的改进;黄龙祥 等;《中国医药工业杂志》;20031231;第34卷(第5期);215 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106432148A (en) | 2017-02-22 |
| CN106397374A (en) | 2017-02-15 |
| CN104817523B (en) | 2016-11-09 |
| CN106432149A (en) | 2017-02-22 |
| CN106432147A (en) | 2017-02-22 |
| CN106432148B (en) | 2018-04-17 |
| CN104817523A (en) | 2015-08-05 |
| CN106432147B (en) | 2018-04-17 |
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