CA1280424C - Process for the preparation of the modification a of cimetidine - Google Patents
Process for the preparation of the modification a of cimetidineInfo
- Publication number
- CA1280424C CA1280424C CA000546508A CA546508A CA1280424C CA 1280424 C CA1280424 C CA 1280424C CA 000546508 A CA000546508 A CA 000546508A CA 546508 A CA546508 A CA 546508A CA 1280424 C CA1280424 C CA 1280424C
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- Prior art keywords
- cimetidine
- modification
- temperature
- preparation
- patent specification
- Prior art date
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A process for the preparation of modification A of cimetidine (N-cyano-N' -methyl- N" -(2-/(5-methylimidazole-4-yl)methylthio/ethyl]guanidine} from cimetidine H (or, with another name, cimetidine M-i) which comprises treating cimetidine H in a fluidized or mixed state with a gas flow of a temperature between 70°C and 110°C under continuous maintenance of the crystalline state.
The modification A of cimetidine is an excellent histamine H2 receptor blocking agent and can be used for treating ulcer.
A process for the preparation of modification A of cimetidine (N-cyano-N' -methyl- N" -(2-/(5-methylimidazole-4-yl)methylthio/ethyl]guanidine} from cimetidine H (or, with another name, cimetidine M-i) which comprises treating cimetidine H in a fluidized or mixed state with a gas flow of a temperature between 70°C and 110°C under continuous maintenance of the crystalline state.
The modification A of cimetidine is an excellent histamine H2 receptor blocking agent and can be used for treating ulcer.
Description
8o424 The present inven~ion relates to a process for the preparation of modification A of cimetidine tcimetidine = N-cyano-N -methyl-NN-~5-methylimidazole-4-yl)methylthio/ethyl]guanidine} from cimetidine H (or, with another name, cimetidine M-l).
It is known that cimetidine is an excellent histamine H2 receptor blocking agent and thus it is the active ingredient of a medicine being very effective against ulcer /J. Int. Med. Res. 3, 86 (1975)/.
The fact that cimetidine is polimorphous, i.e. it has several morphologically signiflcant modifications, is well known in the art. The characteristic features of the modification A have been described in the prior art the earliest ~e.g. in the British Patent Specification No. 1,543,238); however, 4 modifications (Gazz. Chim. Ita. 109, 535) were known in 1979, while 7 morphologically well distinguishable modifications containing no or certain amount of crystall water /J. Pharm. Biomed. Anal. 3, 303 (1985)/ were described in 1985.
,~ .
-` ~280424 The modification A of c;metidine as disclosed in the Br;tish Patent Specification No. 1,543,283 was introduced for human therapeutical use and this is mentioned also in the prescriptions of the up-to-date pharmacopoeias. Simultaneously, recent years the cimetidine molecule has been prepared through different chemical synthetic routes. These new procedures contributed to the technical development, the synthesis could be simplified, however, they frequently resulted in a modification of cimetidine having a different morphology than cimetidine A. Thus e.g. when cimetidine is prepared by a process elaborated by Hungarian researchers, ending with a step wherein aqueous methylamine is applied ~c.f.
the British Patent Specification No. 2,103,206), depending -15 on the conditions of crystallization cimetidine Z (British Patent Specification No. 2,108,117) or cimetidine H--monohydrate (British Patent Specification No. 2,101,991) is formed. Therefore there is a need for a process for the transformation of these modifications into cimetidine A being most suitable as the active ingredient of medicines.
According to the British Patent Specification No. 1,543,238 cimetidine A can be prepared by recrystalliza-tion from a water-free organic solvent, preferably from isopropanol or acetonitrile. Cimetidine A has already been prepared from the modification H of cimetidine (or, with an other name, cimetidine-M-1) by recrystallizat;on from isopropanol (c f. Examples 3/a and 3/b of the Hungarian ratent specification No. 185,636). However, ''-` 12804Z4 it is well known in the art that the recrystallization from an organic solvent has several disadvantages. Of these the drawbacks should be stressed that, on the one hand, this method always leads to a considerable loss and, on the other, the price of the organic solvents has highly increased in the last decade. From the technical disadvantages the poisonous and inflammable or combustible character of these solvents should also be regarded.
The aim of the invention was to work out a process for the preparation of the modification A of cimetidine without using any organic solvent.
Preliminary thermoanalytical examinations were made in connection with the cimetidine H monohydrate ~5 prepared according to the British Patent Specification No. 2,101,991. It was found that the compound melts in a temperature range of 70 to 80 C upon heating at a conventional rate and after the removal of the crystal water a mixture of different modifications of un-reproducible composition is obtained.
However, in the course of our experiments, itwas surprisingly found that if the heat treatment is carried out with a gas stream of suitable temperature, the H (M-1) modification of cimetidine can excellently be transformed into cimetidine A on large scale.
This recognition is surprising as the prior art does not comprise any teaching in connection with the conditions of the dehydration of cimetidine monohydrates.
1'~80424 Accordlng to the publication J. Pharm. slomed. Anal. 3, 303(1985) the modification H ( or M-l) may suffer changes due to light or during storage at room temperature for months that some llnes belng characteristic for modification A occur in the IR spectra.
It is also well known that the modlflcation A of cimetidine can be prepared by crystallization from a water-free organic solvent (British Patent Specification No. 1,543,238) or from an organic solvent comprising a small amount of water (~ritish Patent Specification No. 2,101,991~.
Thus, the basis of our invention is the recognition that cimetidine A can be prepared from cimetidine H (or, with an other name, cimetidine M-l) by dehydratlon whlch ls simple to carry out.
The present inventlon provldes a process for the preparation of the modification A of cimetidine from the modification H (or M-of cimetidine which comprises treating cimetidine H in a fluidized or mixed state with a gas flow of a temperature between 70C and 110C under continuous maintenance of the crystalline state.
Durlng the practical performance of the process of the invention air, inert gas or nltrogen is preferably used as one gas. The gas flow is maintained by overpressure or vacuum. It is practical to control the heating up by a time-pattern control.
The efficacy of the dehydration can be enhanced by ,, 804z'~
mechanical methods (stirring, agitation, etc.) or by fluidization technique.
Cimetidine H used as starting material can be prepared by a method disclosed in the British Patent Specification No. 2,101,991 (by excluding organic solvents) or it can be obtained by the crystallization of any modification of cimetidine from water using rapid cooling.
According to our experiments it is preferred to start from a homodisperse or almost homodisperse system in order to increase the efficacy of the dehydration. The particle size can be adjusted by sieving.
The process according to the invention can also be carried out by using wet cimetidine H (as wet as it is obtained on the filter in the form of a nutch or as it is obtained after centrifuging), which humidity content is derived from the aqueous medium where it was crystalliz-ed from. The cimetidine H is dried at a relatively low temperature range (40 to 50 C) by heating up under a time-pattern control, thereafter the process of the inven-tion can be carried out in a single step, by gradually increasing the temperature of the heating, resulting in the transformation of the modification.
The advantages of the process of the invention can be surrmarized as follows:
1. An end-product of excellent quality, meeting the requirements of the prescriptions of pharmacopoeia, can be obtained.
It is known that cimetidine is an excellent histamine H2 receptor blocking agent and thus it is the active ingredient of a medicine being very effective against ulcer /J. Int. Med. Res. 3, 86 (1975)/.
The fact that cimetidine is polimorphous, i.e. it has several morphologically signiflcant modifications, is well known in the art. The characteristic features of the modification A have been described in the prior art the earliest ~e.g. in the British Patent Specification No. 1,543,238); however, 4 modifications (Gazz. Chim. Ita. 109, 535) were known in 1979, while 7 morphologically well distinguishable modifications containing no or certain amount of crystall water /J. Pharm. Biomed. Anal. 3, 303 (1985)/ were described in 1985.
,~ .
-` ~280424 The modification A of c;metidine as disclosed in the Br;tish Patent Specification No. 1,543,283 was introduced for human therapeutical use and this is mentioned also in the prescriptions of the up-to-date pharmacopoeias. Simultaneously, recent years the cimetidine molecule has been prepared through different chemical synthetic routes. These new procedures contributed to the technical development, the synthesis could be simplified, however, they frequently resulted in a modification of cimetidine having a different morphology than cimetidine A. Thus e.g. when cimetidine is prepared by a process elaborated by Hungarian researchers, ending with a step wherein aqueous methylamine is applied ~c.f.
the British Patent Specification No. 2,103,206), depending -15 on the conditions of crystallization cimetidine Z (British Patent Specification No. 2,108,117) or cimetidine H--monohydrate (British Patent Specification No. 2,101,991) is formed. Therefore there is a need for a process for the transformation of these modifications into cimetidine A being most suitable as the active ingredient of medicines.
According to the British Patent Specification No. 1,543,238 cimetidine A can be prepared by recrystalliza-tion from a water-free organic solvent, preferably from isopropanol or acetonitrile. Cimetidine A has already been prepared from the modification H of cimetidine (or, with an other name, cimetidine-M-1) by recrystallizat;on from isopropanol (c f. Examples 3/a and 3/b of the Hungarian ratent specification No. 185,636). However, ''-` 12804Z4 it is well known in the art that the recrystallization from an organic solvent has several disadvantages. Of these the drawbacks should be stressed that, on the one hand, this method always leads to a considerable loss and, on the other, the price of the organic solvents has highly increased in the last decade. From the technical disadvantages the poisonous and inflammable or combustible character of these solvents should also be regarded.
The aim of the invention was to work out a process for the preparation of the modification A of cimetidine without using any organic solvent.
Preliminary thermoanalytical examinations were made in connection with the cimetidine H monohydrate ~5 prepared according to the British Patent Specification No. 2,101,991. It was found that the compound melts in a temperature range of 70 to 80 C upon heating at a conventional rate and after the removal of the crystal water a mixture of different modifications of un-reproducible composition is obtained.
However, in the course of our experiments, itwas surprisingly found that if the heat treatment is carried out with a gas stream of suitable temperature, the H (M-1) modification of cimetidine can excellently be transformed into cimetidine A on large scale.
This recognition is surprising as the prior art does not comprise any teaching in connection with the conditions of the dehydration of cimetidine monohydrates.
1'~80424 Accordlng to the publication J. Pharm. slomed. Anal. 3, 303(1985) the modification H ( or M-l) may suffer changes due to light or during storage at room temperature for months that some llnes belng characteristic for modification A occur in the IR spectra.
It is also well known that the modlflcation A of cimetidine can be prepared by crystallization from a water-free organic solvent (British Patent Specification No. 1,543,238) or from an organic solvent comprising a small amount of water (~ritish Patent Specification No. 2,101,991~.
Thus, the basis of our invention is the recognition that cimetidine A can be prepared from cimetidine H (or, with an other name, cimetidine M-l) by dehydratlon whlch ls simple to carry out.
The present inventlon provldes a process for the preparation of the modification A of cimetidine from the modification H (or M-of cimetidine which comprises treating cimetidine H in a fluidized or mixed state with a gas flow of a temperature between 70C and 110C under continuous maintenance of the crystalline state.
Durlng the practical performance of the process of the invention air, inert gas or nltrogen is preferably used as one gas. The gas flow is maintained by overpressure or vacuum. It is practical to control the heating up by a time-pattern control.
The efficacy of the dehydration can be enhanced by ,, 804z'~
mechanical methods (stirring, agitation, etc.) or by fluidization technique.
Cimetidine H used as starting material can be prepared by a method disclosed in the British Patent Specification No. 2,101,991 (by excluding organic solvents) or it can be obtained by the crystallization of any modification of cimetidine from water using rapid cooling.
According to our experiments it is preferred to start from a homodisperse or almost homodisperse system in order to increase the efficacy of the dehydration. The particle size can be adjusted by sieving.
The process according to the invention can also be carried out by using wet cimetidine H (as wet as it is obtained on the filter in the form of a nutch or as it is obtained after centrifuging), which humidity content is derived from the aqueous medium where it was crystalliz-ed from. The cimetidine H is dried at a relatively low temperature range (40 to 50 C) by heating up under a time-pattern control, thereafter the process of the inven-tion can be carried out in a single step, by gradually increasing the temperature of the heating, resulting in the transformation of the modification.
The advantages of the process of the invention can be surrmarized as follows:
1. An end-product of excellent quality, meeting the requirements of the prescriptions of pharmacopoeia, can be obtained.
2. There is no need for the application of expensive, -~ 1280424 inflammable or combustible organic solvents, thus the recirculation and regeneration of the solvents can be eliminated.
3. The process does not require any special equipment. Moreover, the process can be carried out on large scale by direct drying and dehydrating of the starting material (cimetidine H) prepared or crystalliz-ed according to the British Patent Specification No.
2,101,991 after filtration or centrifugation, by time--pattern controlled heating.
The invention is illustrated by the following, non-limiting examples.
Example 1 Modification H of cimetidine (its preparation is described in the British Patent Specification No.
2,101,991) is fractionated by sieving, thereafter 50 9.
of cimetidine H of a particle size of 0.25 to 0.125 mm.
are charged into a tube of a diameter of 50 mm. and of a length of 400 mm., which is closed by a dense sieve cloth at the bottom and supplied with a suction connection at the top. A thermometer is fitted to the tube under the sieve cloth and the heating equipment used for the introduction of air of suitable temperature is also connected there.
The suction connection being at the top of the tube is connected to the network vacuum conduit through a laboratory dust cyclone seParator. The middle part of the tube is covered by aluminium foil in order to ~ ~8042A
decrease the heat losses.
Then the dehydration under fluidization of 50 9.
of cimetidine H (M-1) is started in the equipment thus assembled and closed, by adjusting the air flow appropriate-Iy in order to avoid a too high or too low value. After the fluid state is stabilized, the temperature of the entering air is set to 70 C and maintained at this temperature for an hour with an accuracy of + 3 C. After one hour the temperature of the entering air is set to 80 C according to the above method, then after a further hour the temperature is set to 90 C. The temperature of the air flowing into the tube is gradually increased to 110 C with isothermic stages of one hour duration.
After a further hour the system is cooled below 70 C
by introduction of an air flow of room temperature. The substance is removed from the fluidization tube. The characteristic data of the IR spectra of the product are as follows:
(cm 1) 3401, 3226s, 3142s, 3098, 3051, 3038, 2995, 2943, 2898, 2621, 2298, 2237, 2178s, 1662, 1623s, 1588, 1502, 1466, 1454s, 1443, 1422, 1403, 1388s, 1347s, 1308, 1283, 1243, 1228, 1204s, 1156s, 1124, 999, 954s, 864, 842, 832, 800, 764, 755, 743, 716, 688s, 667s, 635s, 603, 560, 534, 428, 418. (s means a significant peak).
The product modification A weights 32.7 9. 11.8 9.
of product are recovered from the dust separator. This material is not morphologically uniform, therefore it can be used up as starting material in a next cycle of the process.
Example 2 3.4 9. of cimetidine H (or M-1) comprising 1.6 % of water in addition to the crystal water in a crystallizing dish are placed into a space where air of a temperature of 62 to 64 C is flowed through. After 3 hour flowing in of air, the substance is removed and measured.
The product is 3.12 9. of cimetidine A of a melting point of 140 - 141 C, the IR spectra of which is the same as that of the product prepared according to Example 1.
2,101,991 after filtration or centrifugation, by time--pattern controlled heating.
The invention is illustrated by the following, non-limiting examples.
Example 1 Modification H of cimetidine (its preparation is described in the British Patent Specification No.
2,101,991) is fractionated by sieving, thereafter 50 9.
of cimetidine H of a particle size of 0.25 to 0.125 mm.
are charged into a tube of a diameter of 50 mm. and of a length of 400 mm., which is closed by a dense sieve cloth at the bottom and supplied with a suction connection at the top. A thermometer is fitted to the tube under the sieve cloth and the heating equipment used for the introduction of air of suitable temperature is also connected there.
The suction connection being at the top of the tube is connected to the network vacuum conduit through a laboratory dust cyclone seParator. The middle part of the tube is covered by aluminium foil in order to ~ ~8042A
decrease the heat losses.
Then the dehydration under fluidization of 50 9.
of cimetidine H (M-1) is started in the equipment thus assembled and closed, by adjusting the air flow appropriate-Iy in order to avoid a too high or too low value. After the fluid state is stabilized, the temperature of the entering air is set to 70 C and maintained at this temperature for an hour with an accuracy of + 3 C. After one hour the temperature of the entering air is set to 80 C according to the above method, then after a further hour the temperature is set to 90 C. The temperature of the air flowing into the tube is gradually increased to 110 C with isothermic stages of one hour duration.
After a further hour the system is cooled below 70 C
by introduction of an air flow of room temperature. The substance is removed from the fluidization tube. The characteristic data of the IR spectra of the product are as follows:
(cm 1) 3401, 3226s, 3142s, 3098, 3051, 3038, 2995, 2943, 2898, 2621, 2298, 2237, 2178s, 1662, 1623s, 1588, 1502, 1466, 1454s, 1443, 1422, 1403, 1388s, 1347s, 1308, 1283, 1243, 1228, 1204s, 1156s, 1124, 999, 954s, 864, 842, 832, 800, 764, 755, 743, 716, 688s, 667s, 635s, 603, 560, 534, 428, 418. (s means a significant peak).
The product modification A weights 32.7 9. 11.8 9.
of product are recovered from the dust separator. This material is not morphologically uniform, therefore it can be used up as starting material in a next cycle of the process.
Example 2 3.4 9. of cimetidine H (or M-1) comprising 1.6 % of water in addition to the crystal water in a crystallizing dish are placed into a space where air of a temperature of 62 to 64 C is flowed through. After 3 hour flowing in of air, the substance is removed and measured.
The product is 3.12 9. of cimetidine A of a melting point of 140 - 141 C, the IR spectra of which is the same as that of the product prepared according to Example 1.
Claims (3)
1. A process for the preparation of modification A of cimetidine (N-cyano-N' -methyl-N"-[2-/(5-methylimidazole-4-yl)methylthio/ethyl]guanidine) from cimetidine H (or, with another name, cimetidine M-1) which comprises treating cimetidine H in a fluidized or mixed state with a gas flow of a temperature between 70°C and 110°C under continuous maintenance of the crystalline state.
2. The process as claimed in Claim 1 which comprises using air, inert gas or nitrogen as the gas flow.
3. The process as claimed in Claim 1 which comprises assuring the flow of gas by overpressure or vacuum.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000546508A CA1280424C (en) | 1986-09-11 | 1987-09-10 | Process for the preparation of the modification a of cimetidine |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU3912/86 | 1986-09-11 | ||
| CA000546508A CA1280424C (en) | 1986-09-11 | 1987-09-10 | Process for the preparation of the modification a of cimetidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1280424C true CA1280424C (en) | 1991-02-19 |
Family
ID=4136411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000546508A Expired - Fee Related CA1280424C (en) | 1986-09-11 | 1987-09-10 | Process for the preparation of the modification a of cimetidine |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1280424C (en) |
-
1987
- 1987-09-10 CA CA000546508A patent/CA1280424C/en not_active Expired - Fee Related
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