Note: Descriptions are shown in the official language in which they were submitted.
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
-- 2
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
- 4 -
,,
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
1280424
-- 8
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.
