JP2003206229A - Method for producing mixture of famotidine polymorph a with famotidine b - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a mixture of famotidine polymorphs A with famotidine polymorphs B. <P>SOLUTION: This invention provides a method for producing a mixture of famotidine polymorphs A and B in which a weight ratio of the famotidine polymorph A to the famotidine polymorph B is (3:97) to (45:55) by using a crude famotidine obtained by organic synthesis as a raw material. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

The present invention relates to a mixture of famotidine polymorphs A and B from famotidine [chemical name: N-sulfamyl-3- (2-guanidinothiazol-4-yl-methylthio) -proionamidine]. The present invention relates to a manufacturing method.

[0002]

Famotidine is a competitive inhibitor of the histamine H ₂ receptor. The main clinical pharmacological activity of famotidine is suppression of gastric secretion. At the same time as suppressing pepsin secretion, famotidine suppresses both acidity and gastric juice volume of gastric acid secretion.

Two polymorphic forms of famotidine are polymorphic form A and polymorphic form B, and the production method thereof has been reported by Richter Gedeon of Hungary (Patent Documents 1 to 5). As a result, famotidine polymorph A and famotidine polymorph B It is known that there are differences in R spectrum, DSC measurement value, X-ray analysis value, and solubility.

In the above-mentioned prior art documents, the cooling rate is changed,
Various processes have been described for obtaining famotidine polymorph A or famotidine polymorph B by using the method of crystallization from water or a mixture of water and alcohol.

[0005]

[Patent Document 1] US Pat. No. 5,120,850

[Patent Document 2] US Pat. No. 5,128,477

[Patent Document 3] Canadian Patent No. 1265809

[Patent Document 4] European Patent No. EP 256 747

[Patent Document 5] Japanese Patent Laid-Open No. 7-316141

[0006]

[Problems to be Solved by the Invention] Famotidine polymorph A
Is more stable and has lower solubility properties, while polymorph B is metastable and has higher solubility properties. The properties of polymorph A are clearly advantageous from a handling and stability point of view, but in the case of chemicals the dissolution rate is very important, the latter being higher for polymorph B. Further, crude famotidine produced by organic synthesis contains impurities and is not suitable as a chemical.

The main object of the present invention is to provide a process for the preparation of a mixture of famotidine polymorph A and famotidine polymorph B which has a controlled dissolution rate and has the desired famotidine dissolution properties. Also, famotidine polymorphs A and B
Is a specific ratio (A: B 3:97 to 45:55 and 1
5: 85-40: 60).

[0008]

Means for Solving the Problems (1) Famotidine polymorphs'A 'and'B' having different melting points, bulk densities, solubilities, and thermodynamic stability can be produced by crystallization to obtain desirable dissolution characteristics and bulk densities. Famotidine characterized by being a mixture of polymorphs “A” and “B”
N-sulfamyl-3- (2-guanidinothiazole-
4-yl-methylthio) -proionamidine] polymorph A
And a method for producing a mixture of B.

(2) Crude famotidine is dissolved in an alcohol solvent and the solvent is removed under reduced pressure.
Famotidine [Chemical name: N-sulfamyl-3- (2-
Guanidinothiazol-4-yl-methylthio) -proionamidine] process for preparing a mixture of polymorphs A and B.

(3) Famotidine [Chemical name: N-sulfamyl-3-] characterized in that crude famotidine is dissolved in an alcohol solvent, the solution is cooled, and seed crystals are charged.
(2-guanidinothiazol-4-yl-methylthio)
-Proionamidine] A method for producing a mixture of polymorphs A and B.

(4) Crude famotidine is treated with hydrochloric acid in an alcohol solvent to obtain famotidine hydrochloride, the hydrochloride is filtered off, dissolved in the alcohol solvent, and the alcohol solvent is adjusted to be basic. , Famotidine [chemical name: N, characterized by removing alcohol solvent under reduced pressure]
-Sulfamyl-3- (2-guanidinothiazole-4
-Yl-methylthio) -proionamidine] A process for preparing a mixture of polymorphs A and B.

(5) The crude famotidine polymorph is 50-70.
(2), which is soluble in (v / w) times as much alcohol solvent
The method according to any one of (3) and (4).

(6) The mass ratio of polymorphs A and B in the obtained mixture of famotidine polymorphs is 5: 95-4.
The method according to any of (3) and (5) above, which is 0:60.

(7) The mass ratio of polymorphs A and B in the obtained mixture of famotidine polymorphs is 3: 97-4.
The method according to any one of (2), (4), and (5) above, which is 5:55.

(8) Seed crystals are famotidine polymorphs A and B
The method according to any of (3), (5), and (6) above, wherein the mass ratio to

(9) The method according to any one of (3), (5), (6), and (8), in which a seed crystal is charged at 15 to 25 ° C.

(10) The above-mentioned (2), wherein the alcohol solvent is removed under reduced pressure of 45 to 58 ° C.
The method according to any one of (4), (5), and (7) (11) A method for producing a mixture of famotidine polymorphic forms A and B, which comprises the following steps: (a) Crude in an alcohol solvent such as methanol. Famotidine is added and dissolved by heating and stirring; (b) Activated carbon is added to the solution of step (a) at 45 ° C. for 30 minutes; (c) The solution of step (a) is filtered to give a colorless transparent liquid. (D) The solution is concentrated under reduced pressure at 45 to 58 ° C. to condense the solvent to obtain a crystal slurry; (e) Crystals of a mixture of famotidine polymorph A and B are collected by filtration; The crystals are dried in a dryer.

(12) The method according to (11) above, wherein the crude famotidine is produced by organic synthesis.

(13) 50 to 7 of crude famotidine polymorph
The method according to (11) above, wherein the method is dissolved in 0 (v / w) -fold alcohol solvent.

(14) The method according to (11) above, wherein the filtration is carried out using a Buchner funnel.

(15) Add about 4 parts of the solution of step (b)
The method according to (11) above, wherein the solvent is concentrated under reduced pressure of 5 to 55 ° C. to obtain a crystalline slurry.

(16) The drying in the step (f) is carried out at 50-
The method according to (11) above, which is performed at 60 ° C.

(17) The method according to (11) above, wherein the mass ratio of the famotidine polymorphs A and B in the obtained mixture of famotidine polymorphs is 3:97 to 45:55.

(18) A method for producing a mixture of famotidine polymorphs A and B comprising the following steps: (a) adding crude famotidine in an alcohol solvent and heating and stirring to dissolve; (b) step (a) To obtain a colorless transparent solution; (c) cooling the solution of step (b) with a mixture of ice and salt with stirring; (d) adding to the cooled solution of step (c), Seed crystals of a mixture of famotidine polymorphs A and B are added; (e) crystals of a mixture of famotidine polymorphs A and B are collected by filtration; (f) crystals of a mixture of famotidine polymorphs A and B are dried. Dry in a container.

(19) The method according to (18) above, wherein the crude famotidine is produced by organic synthesis.

(20) 50 to 7 of crude famotidine polymorph
The method according to (18) above, wherein the method is dissolved in 0 (v / w) -fold alcohol solvent.

(21) Step (a) The heating temperature is 6
The method according to (18) above, which is 0 to 75 ° C.

(22) The method according to (18) above, wherein the famotidine solution of step (a) is treated with activated carbon.

(23) The method according to (18) above, wherein the filtration in step (b) is performed with a Buchner funnel.

(24) The method according to (18) above, wherein the colorless and transparent solution of step (b) is cooled to 15 to 25 ° C. with a mixture of ice and salt.

(25) The method according to (18) above, wherein the proportion of famotidine polymorphs A and B in the seed crystal is 20:80 to 50:50.

(26) The drying in step (f) is carried out at 50-
The method according to (18) above, which is performed at 60 ° C.

(27) The method according to (18) above, wherein the ratio of the obtained famotidine polymorphs A and B is 15:85 to 40:60.

(28) A method for producing a mixture of famotidine polymorphs A and B comprising the following steps: (a) treating crude famotidine with hydrochloric acid in an alcohol solvent to give famotidine hydrochloride; (b) the famotidine hydrochloride Dissolve the salt in an alcohol solvent; (c) add activated carbon to the solution of step (b) at 45 ° C. for 30 minutes; (d) filter the solution of step (c) to obtain a clear solution; e) adding trimethylamine to the solution of step (d) to make it basic; (f) concentrating the solution of step (e) under reduced pressure at 45-58 ° C .; (g) famotidine polymorph A and B (H) Dry the crystals in a drier.

(29) The method according to (28) above, wherein the crude famotidine is produced by organic synthesis.

(30) 50 to 7 of crude famotidine hydrochloride
The method according to (28) above, wherein the method is dissolved in 0 (v / w) -fold alcohol solvent.

(31) The method according to (28) above, wherein the filtration in step (d) is carried out with a Buchner funnel.

(32) The drying in the step (h) is 50 to
The method according to (28) above, which is performed at 60 ° C.

(33) The method according to (28) above, wherein the ratio of the obtained famotidine polymorphs A and B is in a mass ratio of 3:97 to 45:55.

[0040]

BEST MODE FOR CARRYING OUT THE INVENTION The first aspect of the present invention is to obtain a melting point, a bulk density,
The famotidine polymorphs'A 'and'B' differing in solubility and thermodynamic stability are made into a mixture of polymorphs'A 'and'B' having desirable solubility characteristics and bulk densities by crystallization methods. A method for producing a mixture of famotidine [chemical name: N-sulfamyl-3- (2-guanidinothiazol-4-yl-methylthio) -proionamidine] polymorph A and B characterized.

The second aspect of the present invention is to dissolve crude famotidine in an alcohol solvent and remove the solvent under reduced pressure. Famotidine (chemical name: N-sulfamyl-
3- (2-guanidinothiazol-4-yl-methylthio) -proionamidine] polymorphs A and B.

Crude famotidine containing impurities produced by organic synthesis is added to an alcohol solvent, heated and stirred. To obtain a colorless transparent liquid, an adsorbent is added to the solution and the solution is filtered.

As the alcohol solvent, methanol,
Examples include ethanol, preferably methanol,
The crude famotidine polymorph is dissolved in 50 to 70 (v / w) times the alcohol solvent. The solution may be heated to a boiling point of 60-75 ° C. The famotidine solution obtained is treated with activated carbon and then filtered. The filtration is preferably performed with a Buchner funnel. The adsorbent is preferably activated carbon.

Next, the filtrate obtained is removed of the alcohol solvent under reduced pressure at 45 to 58 ° C., and the resulting crystalline slurry is filtered and dried to obtain a mixture of famotidine polymorphs A and B.

The alcohol solvent is preferably concentrated in the range of 33 to 90% by volume, and the filtration is preferably carried out with a Buchner funnel. When the drying is performed in a drier at 50 to 60 ° C., famotidine polymorph A and famotidine polymorph B are 3:97 to 4:
A mixture is obtained in a ratio of 5:55, preferably 5:95 to 40:60.

A third aspect of the present invention is characterized in that crude famotidine is dissolved in an alcohol solvent, the solution is cooled, and seed crystals are charged, and famotidine [chemical name: N-sulfamyl-3- (2-guanidino) is used. Thiazol-4-yl-methylthio) -proionamidine] polymorphs A and B.

Crude famotidine containing impurities produced by organic synthesis is added to an alcohol solvent, heated and stirred. An adsorbent is added to the solution to obtain a colorless and transparent liquid, and the solution is filtered.

As the alcohol solvent, methanol,
Examples thereof include ethanol, and preferably methanol. The crude famotidine polymorph is dissolved in 50 to 70 (v / w) times the alcohol solvent and heated to the boiling point of 60 to 75 ° C. In addition, it is preferable to add activated carbon as the adsorbent.
Mix for 0 minutes and then filter. More preferably, the filtration is performed with a Buchner funnel.

The filtrate obtained is then cooled with stirring with a mixture of ice and salt for about 1 hour at 15 to 25 ° C. and seed crystals of a mixture of famotidine polymorphs A and B are charged. The resulting crystals are filtered and dried in a drier at 50-60 ° C to give a mixture of famotidine polymorphs A and B.

If the ratio of famotidine polymorph A to famotidine polymorph B is 20:80 to 50:50 in the seed crystal, the mass ratio of famotidine polymorphs A and B is 15:50.
85-40: 60, preferably 15: 85-35: 65
It is possible to obtain a mixture of famotidine polymorphs A and B in the following proportions:

In a fourth aspect of the present invention, crude famotidine is treated with hydrochloric acid in an alcohol solvent to obtain famotidine hydrochloride, the hydrochloride is filtered off, dissolved in an alcohol solvent, and the alcohol solution is diluted with a basic solution. And then the alcohol solvent is removed under reduced pressure. Famotidine [Chemical name: N-sulfamyl-3- (2-guanidinothiazol-4-yl-methylthio) -proionamidine] polymorph A And a method for producing a mixture of B and B.

Crude famotidine produced by organic synthesis is converted to famotidine hydrochloride with hydrochloric acid in an alcohol solvent. Examples of the alcohol solvent include methanol and ethanol, and more preferably methanol. Crude famotidine is added to the alcohol solution, and hydrochloric acid is further added to the solution to obtain famotidine hydrochloride. Famotidine hydrochloride is dissolved in an alcohol solvent of 50 to 70 (v / w) times to make a colorless and transparent solution, to which activated carbon is added, and the solution is kept at 45 to 58 ° C. for 30 minutes and then filtered.
The filtration is preferably carried out in a Buchner funnel.

Then, for example, triethylamine is added to the famotidine hydrochloride solution to make it basic, and the alcohol solvent is removed under reduced pressure at 45 to 58 ° C. The resulting crystalline slurry is filtered and dried to give a mixture of famotidine polymorphs A and B.

The alcohol solvent is distilled off at 33 to 90% by volume, and the drying is carried out at 50 to 60 ° C. The mixture comprises famotidine polymorphs A and B in a ratio of 3:97 to 45:55, preferably 5:95 to 40:60.

[0055]

EXAMPLES The present invention will be specifically described below with reference to examples.

Comparative Example 1 A 3000 ml three-necked round bottom flask equipped with a stirrer, a thermometer and a reflux condenser was placed in a water bath, and methanol 2 was added.
750 ml was charged and 50 g of crude famotidine was added.
The mixture was heated to a boiling point of 75 ° C to dissolve all famotidine. To this, 20 g of activated carbon was added, mixed well for 30 minutes, and filtered with a Buchner funnel to give a colorless transparent liquid.
Immediately add the solution to another 30 with a stirrer and thermometer.
Transferred to a 00 ml 3-neck round bottom flask. While stirring and cooling with cooling water, the temperature was lowered to 25 ° C over about 2 hours, and the mixture was cooled to 0 ° C with a mixture of ice and salt. The famotidine crystals thus obtained were filtered and dried in an oven at 60 ° C.

DSC analysis showed that the crystals were pure polymorphic Form A of famotidine (FIG. 1).

Comparative Example 2 3000 ml equipped with a stirrer, thermometer and reflux condenser
Place the 3-neck round bottom flask in a water bath and
50 ml was charged and 50 g of crude famotidine was added. The mixture was heated to a boiling point of 75 ° C to dissolve all famotidine. To this, 20 g of activated carbon was added, mixed well for 30 minutes, and filtered with a Buchner funnel to give a colorless transparent liquid. The solution was immediately added to another 300 with stirrer and thermometer.
Transfer to a 0 ml 3-neck round bottom flask and cool to 0 ° C. over about 1 hour with stirring and cooling with a mixture of ice and salt. The famotidine crystals thus obtained were filtered and dried in a dryer at 60 ° C.

DSC analysis showed that the crystals were famotidine polymorph B (FIG. 2).

Example 1 3000 m equipped with a stirrer, thermometer and reflux condenser
A 3-necked round bottom flask was placed in a water bath. 2750 ml of methanol was charged, and 50 g of crude famotidine was added. The mixture was heated to a boiling point of 75 ° C. to dissolve all famotidine into a solution. Add 20g of activated carbon to it,
Mix well for 30 minutes and filter through a Buchner funnel to give a clear colorless liquid. The solution was immediately transferred to another 3000 ml three neck round bottom flask equipped with stirrer, thermometer and cooled with stirring with a mixture of ice and salt to a temperature of 20 ° C over about 1 hour. After lowering, seed crystals of a mixture of famotidine polymorph A: B (20:80) were added. The famotidine crystals thus obtained were filtered and dried in a drier at 55 ° C.

DSC analysis shown in FIG. 3 showed that the crystals were a 21:79 mixture of famotidine polymorphs A and B.

Example 2 3000 ml equipped with a stirrer, thermometer and reflux condenser
A 3-necked round bottom flask was placed in a water bath. 2750 ml of methanol was charged, and 50 g of crude famotidine was added. The mixture was heated to a boiling point of 75 ° C. to dissolve all famotidine into a solution. Add 20g of activated carbon to it,
Mix well for 30 minutes and filter through a Buchner funnel to give a clear colorless liquid. The solution was immediately transferred to another 3000 ml three neck round bottom flask equipped with stirrer, thermometer and cooled with ice and salt under stirring. The temperature is lowered to 25 ° C over about 1 hour, and famotidine polymorph A: B (2
Seed crystals of the mixture of 0:80) were added. The famotidine crystals thus obtained were filtered and dried in a drier at 55 ° C.

DSC analysis shown in FIG. 4 showed that the crystals were a 39:61 mixture of famotidine polymorphs A and B.

Example 3 A 3000 ml three-neck round bottom flask equipped with a stirrer, thermometer and reflux condenser was placed in a water bath. Methanol 2
750 ml was charged and 50 g of crude famotidine was added.
The mixture was heated to a boiling point of 75 ° C. with stirring to dissolve all famotidine. Add 20g of activated carbon to it,
Mix well for 30 minutes and filter through a Buchner funnel to give a clear colorless liquid. The solution was immediately transferred to another 3000 ml three-necked round bottom flask equipped with a stirrer and a thermometer, cooled with cooling water while stirring, and the temperature was lowered to 25 ° C over about 1 hour. Form A: B (5
Seed crystals of the mixture of 0:50) were added. The famotidine crystals thus obtained were filtered and dried in a drier at 55 ° C.

DSC analysis shown in FIG. 5 showed that the crystals were a 16:84 mixture of famotidine polymorphs A and B.

Example 4 A 3000 ml three-necked round-bottomed flask equipped with a stirrer, a thermometer, and a reflux condenser was placed in a water bath, and methanol 275 was added.
0 ml was charged and 50 g of crude famotidine was added. The mixture was heated to dissolve all famotidine. 20g of activated carbon was added to this and mixed well at 45 ° C for 30 minutes,
It was filtered with a Buchner funnel to give a colorless transparent liquid. The solution was immediately added to another 3000 m equipped with a stirrer and thermometer.
After transferring to a 3-l round-bottomed three-neck flask and distilling off about 33% of the alcohol solvent under a reduced pressure of 45 to 58 ° C, a crystalline slurry was obtained, which was filtered at 45 ° C. The famotidine thus obtained was dried in a dryer at 60 ° C.

DSC analysis shown in FIG. 6 showed that the crystals were a mixture of famotidine polymorphs A and B 3:97.

Example 5 A 3000 ml three-necked round bottom flask equipped with a stirrer, a thermometer and a reflux condenser was placed in a water bath, and methanol 27
50 ml was charged, and 50 g of crude famotidine was added to methanol. The mixture was heated to dissolve all famotidine. Activated carbon (20 g) was added thereto, and the mixture was thoroughly mixed at 45 ° C. for 30 minutes and then filtered with a Buchner funnel to give a colorless transparent liquid. The solution was immediately transferred to another 3000 ml three necked round bottom flask equipped with a stirrer and thermometer.
After distilling off about 90% of the alcohol solvent under reduced pressure of ˜58 ° C., a crystalline slurry was obtained, which was filtered at 60 ° C. The famotidine thus obtained was dried in a dryer at 60 ° C.

The DSC analysis shown in FIG. 7 showed that the crystals were a mixture of famotidine polymorphs A and B at 27:73.

Example 6 A 3000 ml three-necked round bottom flask equipped with a stirrer, a thermometer and a reflux condenser was placed in a water bath, and methanol 50
0 ml was charged and 50 g of crude famotidine was added. Hydrochloric acid was added to dissolve and the solution was heated to 40 ° C. to precipitate famotidine hydrochloride. The precipitated famotidine hydrochloride was filtered on a Buchner funnel and the filtered famotidine hydrochloride was added to 2750 ml of methanol and heated to dissolve famotidine hydrochloride. Activated carbon 20
g was added, well mixed at 45 ° C. for 30 minutes, and filtered with a Buchner funnel to obtain a colorless transparent liquid. The solution was immediately transferred to another 3000 ml three-necked round bottom flask equipped with a stirrer and a thermometer, made basic with 60 ml of triethylamine, and distilled under reduced pressure of 45 to 58 ° C to distill about 70% of an alcohol solvent. After leaving, a crystalline slurry was obtained which was filtered on a Buchner funnel. The famotidine crystals thus obtained by filtration were dried in a drier at 60 ° C.

The DSC analysis shown in FIG. 8 showed that the crystals were a 42:58 mixture of famotidine polymorphs A and B.

The embodiments described above are merely illustrative of the present invention, and the present invention is not limited to these embodiments.

Tables 1 and 2 show the properties of polymorphs obtained by different production methods. Differential scanning calorimetry (DSC analysis) proved to be the best method in our view for determining the proportions of polymorph A and polymorph B, and this data was used from the examples. Solubility measurement, IR spectrum,
And other methods such as X-ray diffraction have made it clear that the proportion of each polymorph cannot be determined.

[0074]

[Table 1]

[0075]

[Table 2]

[0076]

As described above, according to the present invention, famotidine polymorphs A and B have a mass ratio of 3:97 to 45: 5.
A mixture of 5 can be produced.

[Brief description of drawings]

FIG. 1 is a DSC analysis of famotidine polymorph A.

FIG. 2: DSC analysis of famotidine polymorphic Form B.

FIG. 3 shows that famotidine polymorphs A and B are 21: 7.
9 is a DSC analysis of 9 mixture.

FIG. 4 shows that famotidine polymorphs A and B are 39: 6.
1 is a DSC analysis of the mixture of 1.

FIG. 5 shows that famotidine polymorphs A and B are 16: 8.
4 is a DSC analysis of the mixture of 4.

Figure 6: Famotidine polymorphic forms A and B are 3:97.
3 is a DSC analysis of the mixture of.

FIG. 7 shows that famotidine polymorphs A and B are 27: 7.
3 is a DSC analysis of the mixture of 3.

FIG. 8 shows that famotidine polymorphs A and B are 42: 5.
9 is a DSC analysis of the mixture of 8.

   ─────────────────────────────────────────────────── ─── Continued front page    (71) Applicant 502440447             301, YOGI COMPLEX, 44, S             AMPATRAO COLONY, 44, S             AMPATRAO COLONY, VAD             ODARA-390 003, GUJARAT,             India (72) Inventor Mandayum Chakra Bercy Sri Lama             The             India, Gujarat, Bado Dollar-             390 003, Alkapri, San Patraco             Ronnie, 44, Yogi Complex,             301, inside Tonilla Pharma Limited (72) Inventor Jagnesh Harikesh Villaz             India, Gujarat, Bado Dollar-             390 003, Alkapri, San Patraco             Ronnie, 44, Yogi Complex,             301, inside Tonilla Pharma Limited (72) Inventor Janade Han Prasad Sayar             India, Gujarat, Bado Dollar-             390 003, Alkapri, San Patraco             Ronnie, 44, Yogi Complex,             301, inside Tonilla Pharma Limited (72) Inventor Mahesh Natwarar Shah             India, Gujarat, Bado Dollar-             390 003, Alkapri, San Patraco             Ronnie, 44, Yogi Complex,             301, inside Tonilla Pharma Limited (72) Inventor Jogestalia             India, Gujarat, Bado Dollar-             390 003, Alkapri, San Patraco             Ronnie, 44, Yogi Complex,             301, inside Tonilla Pharma Limited F-term (reference) 4C033 AD04 AD06 AD18                 4C086 AA04 BC82 GA15 MA34 NA02                       ZA68 ZC02

Claims (10)

[Claims] 1. Famotidine polymorphs'A 'and'B' that differ in melting point, bulk density, solubility, and thermodynamic stability.
Is a mixture of polymorphs'A 'and'B' having desirable solubility properties and bulk densities depending on the crystallization method. [Chemical name: N-sulfamyl-3
-(2-guanidinothiazol-4-yl-methylthio) -proionamidine] A process for preparing a mixture of polymorphs A and B. 2. Famotidine (chemical name: N-sulfamyl-3-) characterized in that crude famotidine is dissolved in an alcohol solvent and the alcohol solvent is removed under reduced pressure.
(2-guanidinothiazol-4-yl-methylthio)
-Proionamidine] A method for producing a mixture of polymorphs A and B. 3. Famotidine (chemical name: N-sulfamyl-3-) characterized in that crude famotidine is dissolved in an alcohol solvent, the solution is cooled, and seed crystals are charged.
(2-guanidinothiazol-4-yl-methylthio)
-Proionamidine] A method for producing a mixture of polymorphs A and B. 4. The crude famotidine is treated with hydrochloric acid in an alcohol solvent to obtain famotidine hydrochloride, the hydrochloride is filtered off, dissolved in the alcohol solvent, and the alcohol solvent is adjusted to be basic, A mixture of famotidine [Chemical name: N-sulfamyl-3- (2-guanidinothiazol-4-yl-methylthio) -proionamidine] polymorphs A and B, characterized in that the alcohol solvent is removed under reduced pressure. Manufacturing method. 5. The crude famotidine polymorph is 50-70 (v
/ W) times the amount of the alcoholic solvent is dissolved in the solvent, The method in any one of Claims 2, 3, and 4. 6. A mass ratio of polymorphs A and B in the obtained mixture of famotidine polymorphs of 15: 85-40:
60. The method according to any of claims 3 and 5, which is 60. 7. The mass ratio of polymorphs A and B in the obtained mixture of famotidine polymorphs is from 3:97 to 45: 5.
6. The method according to any of claims 2, 4 and 5, which is 5. 8. The seed crystal, wherein the mass ratio of famotidine polymorphs A and B is 20:80 to 50:50.
7. The method according to any one of 6 and 6. 9. The method according to claim 3, wherein the seed crystal is charged at 15 to 25 ° C. 10. The method according to claim 2, wherein the alcohol solvent is removed under reduced pressure of 45 to 58 ° C.