FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)

A PROCESS FOR THE PREPARATION OF A COMPOSITION OF FAMOTIDINE
POLYMORPHS A and B
M/S. TONIRA PHARMA LIMITED, 301, Yogi Complex, 44, Sampatrao Colony, Alkapuri, Vadodara - 390 005, an Indian Company incorporated under the Companies
Act, 1956.
The following specification particularly describes and the nature of this invention, and the manner in which it is to be performed.

The present invention relates to " A process for the preparation of a combination of Famotidine Polymorphs A and B". Famotidine chemical name is N-Sulfamyl - 3-(2-guanidinothiazole-4-yl-methylthio) proionamidine].
Famotidine is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacological activity of Famotidine is inhibition of gastric secretion. Famotidine suppresses both the acid concentration and volume of gastric secretion, while changes in pepsin secretion are proportional to volume output.
There are two polymorphs of Famotidine reported as Polymorph "A" and Polymorph "B" and their manufacturing process has been reported by M/s. Richter Gedeon, Hungary in the US Patents 4,894,459 (Jan.16, 1990), 5,120,850 (Jun.9 1992), 5,128,477 (Jul.7 1992), Canadian Patent 1265809 (Feb 13, 1990), European Patent EP 256747 ( Nov, 11, 1992) and Japanese Patent 7316141 (Feb 24 , 1988). The Famotidine Polymorph "A" and Famotidine Polymorph "B" differ in their I.R Spectra, Differential Scanning Calorimetry (DSC) Measurement Data, X-Ray Diffraction Data and Solubility data.
The process for the preparation of the individual Famotidine Polymorph "A" and Polymorph "B", use a crystallization method from water or water-alcohol mixtures, with a varying rate of cooling as described in the above referred prior art Patents.
Polymorph A of Famotidine is more stable and is having low dissolution properties, while Famotidine Polymorph B is metastable and is having higher dissolution properties.
The co-pending Patent Application No. 1156/MUM/2001 Dated 6th December, 2001 Describes "A process for the preparation of a combination of Famotidine Folymorphs A and B" The Process described in the said Patent Application No. 1156/MUM/2001), Famotidine (Crude) is dissolved in the solvent / Methanol and the solution is colled in ice and salt mixture with seeding to give a mixture of Famotidine Polymorph "A" and Famotidine Polymorph "B" wherein the ratio of Polymorph "A" to Polymorph "B" in the combination of Famotidine Polymorph varies from 15:85 to 35:65.
The main object of this invention is to provide "A process for the preparation of a combination of Famotidine Polymorphs A and B" whereby the dissolving rates can be controlled and the desired solubility properties of the Famotidine can be achieved.
Another object of this invention is to provide "A process for the preparation of a combination of Famotidine Polymorphs A and B" wherein Polymorph A and Polymorph B are specific ratio as desired (A.B 5:95 to 40:60 combinations).
Accordingly this invention provides a process based on evaporative crystallisation for the preparation of a combination of Famotidine [Chemical Name (N-Sulfamyl - 3-(2-guanidinothiazole-4-yl-methylthio) proionamidine] Polymorphs A and B comprising the following steps:-
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(a) dissolving Famotidine(crude) in solvent such as methanol under heating and stirring to form a solution;
(b) adding Activated Carbon to the solution of step (a);
(c) maintaining the above solution of step (b) at 45°C to 58°C for 30 minutes;
(d) filtering the solution of step (c) to give a clear and colourless solution;
(e) transferring the solution obtained under step (d) to another container and distilling out the solvent such as methanol under vacuum at a temperature of 45°C to 58°C under vacuum;
(f) distilling out 33 % to 90 % of the solvent such as methanol under the conditions of Step (e) to get a crystalline slurry, which is a combination of Famotidine Polymorph "A" and Famotidine Polymorph "B";
(g) filtering the crystalline slurry of step(f) to give the wet crystalline product, which is dried at 60°C to give a combination of Famotidine Polymorphs "A" and Famotidine Polymorph "B"
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wherein the crude Famotidine is prepared by an organic synthetic process;
wherein Famotidine (crude) to solvent such as methanol ratio is 1:50 to 1:70;
wherein the Famotidine methanol solution of the above step (a) is treated with activated carbon;
wherein the Famotidine- methanol solution with Activated Carbon is filtered in Buchner funnel for obtaining clear colourless solution;
wherein clear colourless solution of the above step (d) is concentrated under vacuum to effect an evaporative crystallization at a temperature Qf 45°C to 58°C and a vacuum^""
wherein the quantity of distilled solvent ranging from 33% to 90% by volume, a. crystalline slurry of the combination of Famotidine Polymorph "A" and Famotidine Polymorph "B" is obtained which is filtered in a Buchner Funnel
wherein the crystals of Famotidine Polymorphs A and B combination in the above step (e) are dried in an oven at a temperature of 50 to 60 degrees centigrade(°C)
wherein the ratio of Polymorph A to Polymorph B in the combination of Famotidine Polymorphs is specific and varies from 05:95 to 40:60 as desired;
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In the process for the preparation of a combination of Famotidine Polymorphs A and B, according to this invention the starting material is Famotidine (crude), which is manufactured by a synthetic process, having different impurities and hence not suited for the use as a Pharmaceutical product. The crude Famotidine is dissolved in pure Methanol in the ratio of 50 to 70 times by volume to Famotidine (crude) and concentrated by evaporative crystallization (Distilation of solvent such as methanol by heating under vacuum) at a temperature ranging from 45°C to 58°C under vacuum to give a combination of Famotidine Polymorph "A" and Famotidine Polymorph "B".
Table 1 illustrates the nature of polymorph obtained by different crystallization process. In order to determine the ratio of Polymorph "A" and Polymorph "B", the Differential Scanning Calorimetry technique (DSC analysis) was found to be the best method in our opinion and this data is taken in our all experiments. It is clarified that the other techniques like solubility determination, I R Spectra and X-ray diffraction will not be able to determine the ratio of the individual polymorphs.
Table 1

No Famotidine (Crude) Solvent Ratio (Wt:Volume) Crystallisation Method Polymorph Ratio
1. 50 g Methano 1 1:55 Cooling water Polymorph "A"
2. 50 g Methano 1 1:55 Ice + Salt mixture Polymorph "B"
3. 50 g Methano 1 1:55 Evaporative crystallization 333 /% solvent distilled out PolymorprTA 05% Polymorph "B" 95%
4. 50 g Methano 1 1:60 EvaporativeCrystallisationmethod90% solventdistilled out Polymorph "A" 27% Polymorph "B" 73%
In the accompanying drawings Fig.l illustrates the DSC analysis indicating Famotidine
pure polymorph A.
In the accompanying drawings Fig.2 illustrates the DSC analysis indicating Famotidine
pure polymorph B.
In the accompanying drawings Fig.3 illustrates the DSC analysis indicating a
combination of Famotidine polymorph A and polymorph B in a specific ratio of 05:95
In the accompanying drawings Fig.4 illustrates the DSC analysis indicating a
combination of Famotidine polymorph A and polymorph B in a specific ratio of 27:73.
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The following examples are illustrated of the process of preparation of Famotidine pure polymorph A (of Fig. 1), Famotidine pure polymorph B (of Fig.2) and a combination of Famotidine polymorph A and B (according to this invention) in a specific ratio of 13:87 of Fig.3, a combination of Famotidine polymorph A and B (according to this invention) in a specific ratio of 27:73 of Fig.4.
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Example 1
In a 3000 ml, three necked round bottomed flask, equipped with a stirrer, thermometer and a reflux condenser, placed on a water bath, Methanol (2750 ml) is taken and Famotidine (crude) (50 g) is added into it. The mixture is heated to boiling point (75°C) and all the Famotidine is dissolved to give a solution. Activated carbon (20 g) is added into it and mixed well for 30 minutes. It is then filtered in a Buchner funnel to give a clear colorless solution. The solution is immediately transferred to another 3000 ml, three necked round bottomed flask, equipped with a stirrer, thermometer and cooled under agitation with cooling water. The temperature dropped to 25°C in about 2 hours time and it was cooled in ice + salt mixture to 0°C. The crystals of Famotidine thus obtained was filtered and dried in oven at 60° C. The DSC analysis indicate it to be Famotidine Polymorph "A" Pure (Fig 1)
Example 2
In a 3000 ml, three necked round bottomed flask, equipped with a stirrer, thermometer and a reflux condenser, placed on a water bath. Methanol (2750 ml) is taken and Famotidine (crude) (50 g) is added into it. The mixture is heated to boiling point (75°C) and all the Famotidine is dissolved to give a solution. Activated carbon (20 g) is added into it and mixed well for 30 minutes. It is then filtered in a Buchner funnel to give a clear colorless solution. The solution is immediately transferred to another 3000 ml, three necked round bottomed flask, equipped with a stirrer, thermometer and cooled under agitation with Ice + Salt mixture. The temperature dropped to 0°C in about 1 hour. The crystals of Famotidine thus obtained was filtered and dried in oven at 60°C. The DSC analysis indicate it to be Famotidine Polymorph "B"Pure (Fig.2)
Example 3
In a 3000 ml, three necked bottomed flask, equipped with a stirrer, thermometer and a reflux condenser, placed on a water bath, Methanol (2750 ml) is taken and Famotidine (crude) (50 g) is added into it. The mixture is heated to dissolve and all the Famotidine is dissolved to give a solution. Activated carbon (20 g) is added into it and mixed well for 30 minutes at 45°C . It is then filtered in a Buchner funnel to give a clear colorless solution. The solution is immediately transferred to another 3000 ml, three necked round
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bottomed flask, equipped with a stirrer, thermometer and concentrated under vacuum at 45-58°C to effect Evaporative crystallization. After distilling about 33% of the solvent, a crystalline slurry was obtained, which was filtered at 45°C .The crystals of combination of Famotidine polymorph" A" and Famotidine Polymorph "B". Famotidine, thus obtained was dried in oven at 60° C. (DSC analysis : Fig -3)
The DSC analysis indicate it to be a mixture of "P Famotidine Polymorph "A" and Famotidine Polymorph "B" (05:95) (Fig.3)
Example 4
In a 3000 ml, three necked bottomed flask, equipped with a stirrer, thermometer and a reflux condenser, placed on a water bath, Methanol (2750 ml) is taken and Famotidine (crude) (50 g) is added into it. The mixture is heated to dissolve and all the Famotidine is dissolved to give a solution. Activated carbon (20 g) is added into it and mixed well for 30 minutes at 45°C. It is then filtered in a Buchner funnel to give a clear colorless solution. The solution is immediately transferred to another 3000 ml, three necked round bottomed flask, equipped with a stirrer, thermometer and concentrated under vacuum at 45-58°C to effect Evaporative crystallization. After distilling about 90% of the solvent, a crystalline slurry was obtained, which was filtered at 45°C The crystals of combination of Famotidine polymorphs"A" and "B" Famotidine thus obtained was dried in oven at 60° C.
The DSC analysis indicate it to be a mixture of Famotidine Famotidine Polymorph "A" and Famotidine Polymorph "B" (27:73) (Fig.4)
The above description with reference to examples has been given just to understand the invention rather than to limit its scope.
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We claim:
(1) A process for the preparation of a combination of Famotidine [(N-Sulfamyl - 3-(2-
guanidinothiazole-4-yl-methylthio) proionamidine] Polymorphs A and B comprising the
following steps :-
(a) dissolving Famotidine crude in methanol at a ratio 1:50 to 1:70 under heating and stirring to form a solution;
(b) adding 20 g activated carbon to the solution of step (a) at 45°C for 30 minutes;
(c) filtering the solution of step (b) in Buchner funnel to obtain a clear colourless solution;
(d) concentrating the solution under vacuum at a temperature of 45°C to 55°C to get a crystalline slurry;
(e) filtering out the crystals of Famotidine Polymorphs A and B combination; and
(f) drying the said crystals of Famotidine Polymorphs A and B combination in an oven at 50°C to 60°C.
(2) A process for the preparation of a combination of Famotidine Polymorphs A and B
substantially as herein described and illustrated in the examples 3 and 4 and Figures 3 and 4.
Dated this 22nd day of April 2002.

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ABSTRACT
A process for the preparation of a combination of Famotidine [(N-Sulfamyl - 3-(2-guanidinothiazole-4-yl-methylthio) proionamidine] Polymorphs A and B comprising the following steps:-
(a) dissolving Famotidine crude in methanol at a ratio 1:50 to 1:70 under heating and stirring to form a solution;
(b) adding 20 g activated carbon to the solution of step (a) at 45°C for 30 minutes;
(c) filtering the solution of step (b) in Buchner funnel to obtain a clear colourless solution;
(d) concentrating the solution under vacuum at a temperature of 45°C to 55°C to get a crystalline slurry;
(e) filtering out the crystals of Famotidine Polymorphs A and B combination; and
(a) drying the said crystals of Famotidine Polymorphs A and B combination in an oven at 50°C to 60°C.
Dated this day of 22nd April 2002