Note: Descriptions are shown in the official language in which they were submitted.
1~9G3~'7
This invention relates to a process for the production of a
polymorphic form of cimetidine which is substantially crystallographically
pure.(hereinafter referred to as cimetidine A). Such a process for the
production of cimetidine A is suitable for the commercial production thereof.
Cimetidine, the full chemical name of which is N-methyl-N -cyano-
N -[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-guanidine, is a potent
antagonist of histamine H2 receptors, a utility which is described in de-
tail in, for example, J. Int. Med. Research 1975, 3, No. 2, 86-92, by
Brimblecombe et al and in British Specifications No. 1338169 and 1397436.
It has been found that cimetidine can exist in a number of poly-
morphic forms and, particularly as it is known from studies on other drugs,
that polymorphism may influence bio-availability. It is consequently an
ob~ect of one aspect of the present invention to characterized one of these
forms and to provide a process for its production.
Accordingly by one broad aspect of this invention, a process is
provided for the production of cimetidine A, a substantially crystallo-
graphically pure polymorphic form of cimetidine which is characterized by
an infra red spectrum (1% KBr disc) having very strong, broad peaks at
1400 and 1385 cm 1, a strong, sharp peak at 1205 cm 1 and a medium-sharp
peak at 1155 cm 1 and having no peak at 1180 cm 1 which comprises: dissolv-
ing cimetidine in a hot, non-aqueous solvent; cooling the resultant solu-
tion with sufficient agitation to ensure efficient heat transfer to yield
a suspension of cimetidine A in such solvent, the suspension having good
handling properties; and separating off the cimetidine A.
By a variant thereof, the solvent is selected from the group con-
sisting of acetonitrile, acetone, methylisobutylketone and toluene.
By another variant thereof, the solvent is a lower alkanol, e.g.,
ethanol, isopropanol or n-butanol, preferably, isopropanol.
By a variation thereof, the cooling rate used is 10C. to 60C.
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i . ~
1~)963~'7
~..
per hour.
By another variation, the cimetidine A is separated from the sus-
; pension centrifugation.
By a further variant, the suspension of cimetidine A is such thatit acts as a Newtonian fluid in a continuous shear test, is not by reason
of its fluidity quantifiable on a cone penetration test and possesses a dy-
namic modulus as assessed on a rheogoniometer in the range of from 0.01 to
1.0 Hz of less than 0.001.
By "substantially crystallographically pure" we mean cimetidine
A which contains no more than 5%, preferably no more than 3% of any other
polymorphic form of cimetidine, and has the formula
~ CN
CH ~ CH2scH2cH2NHc \
NHCH3
~ _ _ N~
and is characterized by an infra red spectrum (1% KBr disc) having very
strong, broad peaks at 1400 and 1385 cm 1, a strong, sharp peak at 1205 cm
and a medium-sharp peak at 1155cm 1 and having no peak at 1180 cm 1.
In the accompanying drawings,
Figure 1 is a typical infra red spectrum of cimetidine A; and
Figure 2 is a portion of the infra red spectrum of cimetidine B.
The words "very strong" and "medium" used in relation to the peaks
of the infra red spectrum refer to the relative heights of the peaks. These
; terms are well known and understood to those accustomed to the interpre-
tation of such spectra.
As seen in Figure 1, which is the relevant portion of a typical
. infra red spectrum of cimetidine A, the four characteristic peaks are
marked.
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We have discovered that cimetidine may crystal]ise in at ]eastthree different forms, one of which is cimetidine A. The other forms re-
ferred to as cimetidine B and cimetidine C do not have an infra red spec-
trum containing the abovementio1led four character;stic peaks of cimetidine
but do have a very strong, sharp peak at 11~0 cm . Th;s can be seen from
Figuré 2 whicll is the relevant portion of the iuf1-a rcd spectl-um of c;meti-
dine B.
C;met;dine A ;s preferred to either of the other two {orms since
it is more easily obtai1)able in a crystallographically pure state. It is
also slightly more water so]uble than either of these forms preferably hav-
ing a rate of dissolution at 25C from the flat surface of a standard com-
pressed disc of at least 0.20 mg/1n;n/cm . A further advantage is that
cimetidine A is rather more easy to handle, particularly in large scale
operations such as centrifugation. The easier hand]ing of suspensions of
cimetidine A as compared with other forms of cimetidine is demonstrated by
the following comparative tests carried out on a 25% (w/v) suspension of
cimetidine A in isopropanol and a 25% (w/v) suspension of a cimetidine B/
cimetidine C mixture in isopropanol/water (3.l).
(a) Co ti_u us shear
A Rllec)1nat R~130 rheo1neter thennostatted at 25C was employed.
Cup and bob system A w.ls used for cimetidine A suspension to obtain rates
of sl1ear from 0 to approximately 700 sec l.
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The following data was obtained for cimetidine A suspension:-
Shear rate (sec ~ lean Shear stress (dyne cm 2)
O O
17.5 1.19
32.4 2.38
59.9 3.21
111.0 5.59
205.0 10.12
378.0 18.45
514.0 22.59
698.0 34-7
These data show that the suspension behaved as a Newtonian
Fluid with a viscosity of 0.0496 poise.
Because of the solid properties of cimetidine B/C suspension,
it was not possible to obtain continuous shear data.
(b) Cone penetration
To quantify the solid properties of cimetidine Form B/C
. suspension, a Seta Universal Penetrometer was employed
fitted with a 1806 cone and 150 g. loading weight.
; 2~
.~lean depth of penetration of cone 5.5 mm at 20 C.
Because of the fluid properties of Cimetidine Form A, it
~- was not possible to obtain penetrometer results with this
suspension.
(c) Oscillatory testing
A modified R16 Weissenberg Rheogoniometer equipped with
3.75 cm radius parellel plates was used in the oscillatory
3~ mode at 25C. Using oscillation frequencies ranging from
0.01 to 1~.5 Hz, data were obtained for both cimetidine
suspensions with the aid of a Solartron Transfer Function
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L Analyser (J~11600/JX1606). Computer analysis of the data
produced the following values for dynamic modulus:-
Oscillation frequency (Hz) Dynamic modulus (G')
Cimetidine Form A Cimetidine Form B/C
O . 01 0 . 0007 4 0.06646
0.1 0.00063 0.06402
0.5 0.00080 0.06206
1.0 0.00082 0.06574
2 . 5 0 . 0007 9 0 . 05977
5 . O O . 0007 4 0.0~400
10.0 0.00039 0.02463
12.6 O. 00007 ~ O . 00462
From a plot of log dynamic modulus vs log oscillation it is
evident that for both suspensions the dynamic modulus is
independent of frequency within the range of 0.01 to 1.0 Hz.
~he solid nature of cimetidine B/C suspension is evident from
the fact that its dynamic modulus in this frequency range is
greater than 0.06 whereas that of cimetidine A is less than
0 .001 .
Samples of cimetidine A which we have obtained are also
characterised by a density of less than 1.30 g/cc. We have
found that cimetidine A may be reproduceably formed by
selecting the correct solvent for crystallisation, by
carefully controlling the rate of cooling of the solvent
just prior to and during crystallisation and by also
carefully controlling the agitation of the solvent just prior
. to and during crystallisation.
Suitable solvents for crystallisation include non-aqueous
solvents, e.~., acetonitrile, acetone, methylisobutylketone,
3~ toluene and lower alkanols e.g., ethanol, isopropanol and
n-butanol. Isopropanol is particularly suitable in
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L practice because of its rela~ive cheapness, ready
availability and lack of effluent disposal problems.
Agitation during cooling should be sufficient to ensure
efficient heat transfer throughout the liquid phase. On
a commercial scale, efficient heat transfer through the
cooling surfaces of the vessel used is also desirable.
A cooling rate of from 10C to 60C per hour has been
found to be effective. A commercial scale process for
the production of cimetidine A is illustrated by the
following example: .
Cimetidine (245 Kg) was dissolved in hot (80 C) isopropanol
(850 l) and the resultant solution clarified by filtration.
The filtrate was placed in a 300 gallon glass-lined vessel
la having a heat transfer surface of 4.8M2 and a U-value of
- 200 Kcal/M .h.C. and fitted with a standard impellor/
agitator. With the agitator rotating at 90 r.p.m. the
solution was cooled from 80C to 15C over a period of
2 hours.
The precipitated produced was in the form of well developed
prisms which were readily separated by-centrifugation, and
then dried on a fluid bed drier.
The product obtained had an infra red spectrum between 1600
and 200 cm l as shown in Figure l, a density of 1.28 g/cc and
a rate of dissolution in water at 25C (from the flat surface
of a 9.6 mm diameter compressed disc) of 0.21 mg/min/cm2.
Pharmaceutical compositions comprising cimetidine A and a
solid pharmaceutical carrier
also provided herein. Exemplary of solid carriers
are lactose! microcrystalline cellulose, terra alba, sucrose,
talc, starch, gelatin, agar pectin, polyvinylpyrrolidone,
3~ acacia, magnesium stearate, stearic acid and the like.
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A wide variety of pharmhceutical forms can be employed, and these
will normally be ~appropriate to the desired mDde of administration. Thus
the preparation can be tableted or placed in a hard gelatin capsule in p~w-
der or pellet form. In these cases the amount of solid carrier will vary
widely but preferably will be from 25 mg to 1 g. Alternatively an injecta-
ble solution or a cream or ointment for topical administration may be
used.
me pharmaceutical ocmpositions are prepared by conventional tech-
niques involving procedures e.g. mixing, granulating and compressing. An
initial milling process is preferably carried out. It is found that this
improves the uniformity of the product without affecting its excellent
handling characteristics. Milled cimetidine A preferably that which has
been passed through a 60 mesh screen on the mill outlet ~e.g., a Fitz-
patrick hammer mill) is also therefore a subject of the present invention.
Cohesion tests carried out using a sh OE cell apparatus as described by
Kocova and Pilpel, Powder Technology 5 329 ~197V72) showed that samples
; of this milled cimetidine A had an angle of internal friction of from 34
to 38.
Cimetidine A will be present in the ccmpositions in an effective
amount to block histamine H2-receptors.
Preferably, each dosage unit will contain the active ingredient
in an amount of from 50 mg to 750 mg, preferably 200 mg to 600 mg.
me active ingredient will preferably be administered one to six
times per day. mis daily dosage regimen will preferably be from 500 mg
to 1500 mg.
Combination preparations ccmprising cimetidine A and another ac-
tive ingredient may also be used. Examples of such active ingredients in-
clude histamine Hl-receptor antagonists e.g. meypramine or anti-inflammatory
compounds e.g. acetylsalicyclic acid, naproxen, ibuprofen or ketoprofen.
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