Note: Descriptions are shown in the official language in which they were submitted.
;~L2~2~5~
The present invention relates to pharmaceutical
compositions for oral administration an din particular, to
tablets which contain as their active ingredient cimetidine.
The compound known by common name as cimetidine,
described as an amorphous off-white powder, has the chemical
formula N-cyano-N'-methyl-N"-(2-((4-methyl-5-imidazolyl)-
methylthio)ethyl)guanidine and the structural formula:
NON
H3C cH2scH2cH2NHcNHcH3
HO N
Cimetidine has been found to inhibit competitively
the action of histamine at the histamine Ho receptor and is
useful for mammalian treatment where the inhibition of gastric
acid secretion is desired such as duodenal and non-malignant
gastric ulcer and other conditions associated with gastric
acid secretion. The efficacy of cimetidine in the treatment of
duodenal ulcer has been confirmed by numerically well-docu-
minted studies.
Initially, a large variety of dally doses ranging from
800 my. to 2000 my. have been shown to be effective (see
Brogdenj R.N. et at., Doug 15: 93 (1978)). Although in all-
Nikolai studies, cimetidine has been used in dosages us to 2400
my. per diem in divided doses, the usual dosage of cimetidine
recommended for the treatment in human subjects of acute duo-
dental ulcer is 1200 my. per diem in four divided doses of 300
my. each given with meals and at bedtime. Following cimetidine-
induced ulcer healing, a daily maintenance regimen of 400 my.
at bedtime for 6 to 12 months is recommended.
~2Z9~Z
To these ends, cime-tidine is available from a
number of manufacturers in a variety of dosage forms and
strengths including tablets which contain 200, 300, 400 and
600 my. of cimetidine as active ingredient. These tablets
generally contain about 67 to 76 % w/w of cimetidine and
about 24 to 33 % w/w of pharmaceutically acceptable excip-
tents such as granulating agents and aids, disintegrants, lit-
tens and lubricants. Cimetidine tablets are generally film-
coated using conventional coating solutions and film-coating
methods for the purpose of masking the bitter taste of cimetidine
and attaining better elegance. A dye or dyes is usually added
to the tablet composition or, in the case of a film-coated
tablet, to the film-coating solution to provide for color in
the finished cimetidine tablet.
It is standard practice to manufacture cimetidine
tablets using a wet granulation process, as the physical net-
use of the material together with the high content of active
ingredient in the composition render tabulating by direct
compression undesirable. In a standard wet granulation pro-
cuss, the cimetidine is mixed with intra-granular excipients
such as fillers and disintegrants. The filler in this case
may act as an aid to granulation, controlling wet mass
consistency and doughtiness. The disintegrants act as
granule disintegrants. This mix is blended with one or
more binders in aqueous or non-aqueous solution until grant
elation is achieved; that is, wet massing to form partial
agglomeration. The binders may be added out of solution
to the dry mix of cimetidine and intragranular
-- 2 --
So
xcipients. Granulation is then achieved by wetting the dry
mass with a granulating solvent until granulation is achieved.
The granules thus formed are milled if required and then dried
to the desired moisture content. The granules are mixed with
extra-granular excipients such as fillers, disintegrants andlu-
bricants to give specified tablet weigh-t and size, disintegra-
lion properties and desired flow properties for tabulating.
The resulting material is then ready for compression into tablet
form. The compressed tablet core may then be fllm-coated by
conventional methods.
It has been known for some time that 800 my. of
cimetidine given twice daily in 400 my. doses is effective for
the treatment of duodenal ulcer (see Kerr et at. "Cimetidine:
twice daily administration in duodenal ulcer results of a
US and Ireland multicentre study": C~mQ~d~nQ on ho 80~;
1981: Long man Group Limited, at page 9 and Eckardt et at.
"Cimetidine: twice daily administrationiin duodenal ulcer--
results of a European multicentre study"; C~mQ~d~nQ on ho 80~;
1981: Long man Group Limited, at page 14).
Among the cimetidine manufacturers in the Canadian
pharmaceutical industry, it was Frank W. Homer Inc. that first
marketed in Canada a 400 my. twice-a-day cimetidine regimen,
allowing for significantly lower cost but equally effective
cimetidine therapy with the considerable advantage flower
overall dosage. This regimen was marketed after Homer carried
out further clinical trials demonstrating that the rates of
healing and duration of treatment necessary to obtain endoscopic
healing of ulcers and complete disappearance of symptoms were
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~2~9552
comparable for a regimen of 400 my. twice per day and 300 my.
four times per day (see Levis, D. et at., Comparative
efficacy of two dosage regimens of cimetidine in the treatment
of symptomatic duodenal ulcer: Results of a multi center
5 clinical trial, CU~L~(en~ The~ap~u~c Roy, 33:70 (1983)).
Homer also clinically established the efficacy ox an
800 mar once-a-day cimetidine regimen (see Lacerate, M et at.
Single daily dose of cimetidine for the treatment of symptomatic
duodenal ulcer: Results of a comparative two-cen-tre clinical
lo trial, CULT ~hQ~apQ~t~c RQ~Qa~ch, 35:777 (1984)). It will
be appreciated that such a regimen would increase Patient
compliance, since the patient would need to take 800 my. of
cimetldine once-a-day only rather than 400 my. twice-a-day
or 300 my. four times a day as with other regimens. Patient
compliance could be even further enhanced if it were
possible to have a single tablet containing 800 my. of
cimetidine, if it were not for the offsetting increase in
patient reluctance due to the size of a tablet which has 67 to 76
. % w/w of cimetidine and 24 to 33 % w/w of pharmaceutically
acceptable excipient.
It will thus be seen that it would be a significant
advantage in obtaining patient compliance if a single 800 my.
strength tablet could be provided with a reduction in size so
that there would be no apprehension about being able to swallow
same.
In a medicinal tablet composition however, the
: nature and quantity of pharmaceutically acceptable excipiènts
are most important from many points of view, including Forum-
ecological, toxic and allergenic, manufacturing, and aesthetic.
-- 4
~2~5S~
the choice of excipients and limitations on the amounts thereof
involves a careful weighing of several factors, some of which
are competing. The active ingredient itself must be well
granulated and processed with intragranular excipients to
form granules of such a consistent size and density that con-
sistent biopharmaceutical and handling properties are achieved.
During tabulating, the flow properties of the granulated mat-
trial must be such as to ensure a smooth and consistent flow
of material into the tablet die. Good compressibility with
sufficient hardness and low friability is required where tablets
are to be film-coated as in the case of cimetidine tablets
because of the relatively rough treatment of the tablet cores
in film-coating apparatus. The surface properties of the tablet
cores must be such as to give proper adherence of the tablet
coating solution. The compressibility is also important to
minimize tablet lamination and capping. These very problems
were encountered by Leonard et at,. (The Pharmaceutical Develop-
mint and Bioavailability of Cimetidine Capsule and Tablet
Formulations, Dow ~evQ~pmQn~ and Hindu a Pharmacy, I
217-226 (1979) with a 77% cimetidine formulation but were
avoided upon reducing the percentage of cimetidine to 72%
and altering the granulating base.
Furthermore, the bioavailability of the tablet must
be such as to satisfy clinical and regulatory requirements.
It is known that different tablet compositions may
exhibit varying levels of bioavailability due to varying factors
affecting the formulation and processing of the dosage form;
for example, manufacturing procedures and excipients. It has
been suggested that, in the case of cimetidine, bioavailability
is partly dependent on the rate of dissolution or disintegration
(see Leonard et at., The Pharmaceutical Development and Bevel-
-- 5 --
~2;~3552
Ability of Cimetidine Capsule and Tablet Formulations, Dug
VQvcQ~pmQ~ and Lou a Pharmacy, I, 217-226 (1979)).
Leonard et at. also pointed out the significant effect
that the addition of even a single excipien-tto a cimetldine form-
elation may have on the undesirable phenomenon of rapidly increasing dissolution time over normal compression ratios.
It will thus be appreciated that many significant
problems are encountered in providing a tablet composition
with a higher percentage of cimetidine than that encountered
in known cimetidine tablet compositions.
Surprisingly, it has now been found that a cimetidine
tablet composition may be obtained with a higher percentage of
cimetidine than has heretofore been achieved, for example about
94 % w/w, while maintaining adequate hardness, disintegration,
friability and other required parameters. Such a higher
percentage will minimize or eliminate patient reluctance
- due to size in ingesting a cimetidine tablet containing
800 my. of cimetidine which would otherwise, if known percent-
ages were utilized, present considerable compliance problems.
The higher percentage has been achieved upon the
discovery that cimetidine has unsuspected granulating properties
which could be utilized to obtain a surprising and unexpected
reduction in the w/w percentage of pharmaceutically acceptable
...... ... __
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3~Z~55~
excipients heretofore thought necessary to enable processing
and maintain the tablet properties required, and an even more
surprising and unexpected reduction in the v/v percentage of
such excipients.
Size considerations apart, the lower percentage of
excipients also results in lower production costs for tablets
containing any quantity of cimetidine and results in less
excipient being introduced into the system of the patient.
According to the present invention, a cimetidine tab-
let composition, processed with facility and having the
requisite properties, but of significantly reduced size, contains
from about 84 to about 98.25% w/w of cimetidine, a binder in an
amount of about 1% w/w or greater, a disintegrant in an amount of
about 0.25% w/w or greater and a lubricant in an amount from
about 0.5 to 1.5% w/w.
; In a preferred embodiment, the present invention
provides a tablet composition containing about 94% w/w of
cimetidine, from 2 to 4.5% w/w of a binder, from l to 3.5%
w/w of a disintegrant and from 0.5 to 1.5% w/w of a lubricant,
which cimetidlne, in further preferred embodiments, is present
in quantities of about 200 to 800 my.
- According to another aspect of the present invention,
there is provided a process for preparing a tablet composition
which comprises mixing about 84 to about 98.25% w/w of cimetidine
with about 1% w/w or greater of a binder, about 0.25% w/w or greater
of a disintegrant and from about 0.5 to 1.5% w/w of a lubricant.
As used herein, "cimetidine" means that compound
having the chemical formula N-cyano-N'-methyl-N"-(2((4~methyl-
5-imidazolyl)methylthio)ethyl) guanidine as identified in
Thy MCKEE dQX, Thea eon., Merck & Co. Inc., Roy, New
-- 7
:~2Z9SS2
Jersey, U.S.A. (1983) at page 323 and includes any forum-
ceutically acceptable acid addition salt thereof.
As used herein, "pharmaceutically acceptable acid
addition salt" means an acid addition salt possessing the
properties of the free compound and being not biologically
or otherwise undesirable and includes the hydrochloric, hydra-
bromic, sulfuric and malefic addition salts and the like.
As used herein, "pharmaceutically acceptable excip-
tent" means an excipient which is not biologically, forum-
ecologically, or otherwise undesirable. It will be appreciated
by those skilled in the art that references herein to excipients
such as binders, lubricants and disintegrants are necessarily
restricted to those excipients which are pharmaceutically
acceptable.
Binders which may be used in the present invention
are those binders commonly used in the art and include starch,
gelatin, cellulose derivatives; for example methylcelluloses,
ethylcelluloses and propylcelluloses, and preferably polyvinyl-
pyrrolidone; for example Plasdone* K-39-22.
Disintegrants which may be used in the present invent
lion are those disintegrants commonly used in the art and include
starch, sodium starch glycolate; for example, Primojel*,
and preferably carboxymethyl starch; for example, Explotab*.
Lubricants which may be used in the present invent
lion are those lubricants commonly used in the art and in-
elude Starkey acid and its salts e.g. magnesium, calcium or
sodium Stewart.
*trade mark
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~ZZ955Z
A further understanding of the invention and its
further advantages can be had from the following non-limiting
examples.
Example I
35.5 g. of Plasdone* K-29-32 (polyvinylpyrrolidone)
was mixed with 176 ml. of purified water until dissolution
WAS complete. 500 g. of cimetidine was mixed with 23.7 g. of
Explotab* (carboxymethyl starch) for 5 minutes and then grant
slated wit the prepared Plasdone*/water solution. The grant
slated material was then tray-dried overnight in a convection
oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were passed
through a No. 12 screen and then mixed for a further 3 minutes.
Approximately 8 g. of screened and mixed granules were with-
drawn and mixed with 8.9 g. of magnesium Stewart, passed through a No. 12 screen and returned to the previously screened
and mixed granules. This mixture was mixed for 10 minutes with
23.7 g. of Explotab* (carboxymethyl starch). The resulting
mixture was compressed on a Majesty* F-3 single press compress
soon machine to provide tablets having a hardness range of 9.0
to 11.0 kg. (Stokes scale) and a moisture content of 0.4% at
compression. Average tablet weight was 946 my., containing
800 my. of cimetidine.
EXAMPLE II
10.4 g. of Plasdone* K-29-32 (polyvinylpyrrolidone)
was mixed with 51.6 ml. of purified water until dissolution
was complete. 500 g. of cimetidine was mixed with 2.6 g. of
Explotab* (carboxymethyl starch) for 5 minutes and then grant--
fated with the prepared Plasdone*/water solution. The
*trade mark
I
translated material was then tray-~lried overnight in a convect
lion oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were
passed through a No. 12 screen and then mixed for a further 3
minutes. Approximately 8 g. of screened and mixed granules
were withdrawn and mixed with 2.6 g. of magnesium Stewart,
passed through a No. 12 screen and returned to the previously
screened and mixed granules. This mixture was mixed for 10
minutes with 2.6 g. of Explotab* (carboxymethyl starch). The
resulting mixture was compressed on a Majesty* F-3 single press
compression machine to provide tablets having a hardness range
of 9.0 to 11.0 kg. (Stokes scale) and a moisture content of
0.4% at compression. Average tablet weight was 829 my., con-
twining 800 my. of cimetidine.
EXAMPLE III
18.6 g. of Plasdone* K-29-32 (polyvinylpyrrolidone)
was mixed with 92.2 ml. of purified water until dissolution
was complete. 500 g. of cimetidine was mixed with 5.3 I. of
Explotab* (carboxymethyl starch) for 5 minutes and then grant-
fated with the prepared Plasdone*/water solution. The grant-
fated material was then tray-dried overnight in a convection
oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were
passed through a No. 12 screen and then mixed for a further
3 minutes. Approximately 8 g. of screened and mixed granules
were withdrawn and mixed with 2.7 g. of magnesium Stewart,
passed through a No. 12 screen and returned to the previously
screened and mixed granules. This mixture was mixed for 10
minutes with 5.3 g. of Explotab* (carboxymethyl starch). The
* trade mark
-- 10 --
ssz~:
exulting mixture was compressed on a Majesty* F-3 single
press compression machine to provide concave, beveled,
ellipsoid tablets of dimensions 11/32" x 23/32" having a
hardness range of 9.0 to 11.0 kg. (Stokes scale) and a moist
lure content off% at compression. Average tablet wits 851 my., containing 800 my. of cimetidine.
EXAMPLE IV
20.0 g. of Plasdone* K-29-32 (polyvinylpyrrolidone)
was mixed with 100 ml. of purified water until dissolution
was complete. 500 g. of cimetidine was mixed with 5.3 g. of
Explotab* (carboxymethyl starch) for 5 minutes and then grant-
fated with the prepared Plasdone*/water solution. The grant-
fated material was then tray-dried overnight in a convection
oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo scale) was obtained. The granules thus dried were
passed through a No. 12 screen and then mixed for a further
3 minutes. Approximately 8 g. of screened and mixed granules
were withdrawn and mixed with 2.7 g. of magnesium Stewart,
passed through a No. 12 screen and returned to the previously
screened and mixed granules. This mixture was mixed for lo
minutes with 5.3 g. of Explotab* (carboxymethyl starch). The
resulting mixture was compressed on a rqaneSty* F-3 single press
compression machine to provide concave, beveled, ellipsoid
tablets of dimensions 11/32" x 23/32" having a hardness range
of 9.0 to 11.0 kg. (Stokes scale) and a moisture content of
0.4% at compression. Average tablet weight was 853 my., con-
twining 800 my. of cimetidine.
EXAMPLE V
Granules ready for tabulating were prepared as in
* trade mark
-- 11 --
issue
example IV. Concave, beveled, round tablets of 5/16" diameter
were compressed on a Majesty* F-3 single press compression ma-
chine having a hardness range of 5.0 to 7.0 kg. (Stokes scale)
and a moisture content of 0~4% at compression. Average tablet
weight was 213 my., containing 200 my. of cimetidine.
EXAMPLE VI
Granules ready for tabulating were prepared as in
Example IV. Concave, beveled, round tablets of 3/8" die-
meter were compressed on a Majesty* F-3 single press compress
soon machine having a hardness range of 5.0 to 7.0 kg. (Stokes
scale) and a moisture content of 0.4% at compression. Average
tablet weight was 319 my., containing 300 my. of cime-tidine.
EXAMPLE VII
Granules ready for tabulating were prepared as in
Example IV. Concave, beveled, round tablets of 7/16" die-
meter were compressed on a Majesty* F-3 single press compress
soon machine having a hardness value of 5.0 to 8.0 kg. (Stokes
scale) and a moisture content of 0.4% at compression. Average
tablet weight was 426 my., containing 400 my. of cimetidine.
SAMPLE VIII
Granules ready for tabulating were prepared as in
Example IV. Concave, beveled, round tablets of 15/32" die-
meter were compressed on a Majesty* F-3 single press compress
soon machine having a hardness value of 6.0 to 8.0 kg. (Stokes
25` scale) and a moisture content of 0.4% at compression. Average
tablet weight was 639 my., containing 600 my. of cimetidine.
EXAMPLE IX
17.5 g. of Plasdone* K-29-32 (polyvinylpyrrolidone~
was mixed with 80 ml. of purified water until dissolution was
* trade mark
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:~L22~SS2
complete. 470.05 g. of cimetidine was mixed with 5.0 g. of
Explotab* (carboxymethyl starch) for 2 minutes and transferred
to a mortar. The cimetidine/Explotab* mixture was granulated
with the prepared Plasdone*/water solution, an additional 59
ml. of purified water being added. The granulated material
was then tray-dried for 1 3/4 hours in a convection oven to a
moisture content of 1.2% (Congo scale). The granules thus
dried were passed through a No. 15 screen and transferred to
a plastic bag. 2.45 g. of magnesium Stewart was mixed with
an equal weight of screened granules withdrawn from the pies-
tic bag. This mixture was passed through a No. 15 screen and
returned to the plastic bag containing the remaining granules.
This mixture was mixed with 5.0 g. of Explotab* (carboxymethyl
starch) for 2 minutes and compressed on a Majesty* E-3 single press
compression machine using a 5/8" concave, round, plain punch to
provide tablets of thickness 5.56 mm. having a hardness range of
9-10 kg. (Stokes scale) and a moisture content of 0.9% at compress
soon. Average tablet weight was 851 my., containing 800 my. of
cimetidine. The tablets had a friability value of 0.31% and a
disintegration time of 5 minutes in HO at 37C.
_ AMPLE X
The procedure of Example IX was followed substituting
the following quantities of materials:
Cimetidine 200 g.
Explotab* (intragranular) 2.1 g
Plasdone* 4.19 g.
Purified water 36.5 ml.
Extra water added 33 ml.
Explotab* (extra granular) 2.1 g.
Magnesium Stewart 1.05 g.
* trade mark - 13 -
~.~7Z~3/SS;~
Llabletting was carried out on a Majesty* F-3 single press
compression machine using a 5/8" concave, round, plain punch
to provide tablets having hardness values of 6 1/2 kg. and
8 kg. (Stokes scale) and a moisture content of 1.1% at come
press ion. Average tablet weight was 838 my., containing
800 my. of cimetidine. The tablets having a hardness value
of 6 1/2 kg. had a friability value of 0.36% and a disinter-
ration time of 2 minutes in HO at 37C, and those having
a hardness value of 8 kg. had a friability value of 0.36%
and a disintegration time of 5 minutes in HO at 37C.
EXAMPLE XI
The procedure of Example IX was followed substitute
in the following quantities of materials:
; Cimetidine 200 g.
; 15 Explotab* (intragranular) 2.14 g.
Plasdone* 8.56 g.
Purified Water 36.5 ml.
Extra water added 23 ml.
Explotab* (extra granular) 2.14 g.
Magnesium Stewart 1.07 g.
Tabulating was carried out on a Majesty* F-3 single press
compression machine using a 5/8" concave, round, plain punch
to provide tablets having hardness values of 7 to 8 kg. and
10 kg. (Stokes scale) and a moisture content owe 0.5% at come
press ion. Average tablet weight was 856 my., containing 800
my. of cimetidine. The tablets having a hardness value of
7 to 8 kg. had a friability value of 0.35% and a disintegration
time of 5 minutes in HO at SUE and those having a hardness
value of 10 kg. had a friability value of 0.26% and a disk
integration time of 9 minutes in HO at 37C.
* trade mark
- 14 -
;~LZZ9S52
EXAMPLE XII
The procedure of Example IX was followed substitute
in the following quantities of materials:
Cimetidine 200 g.
Explotab* (intragranular) 4.42 g.
Plasdone* 11.05 g.
Purified Water 36.5 ml.
Extra water added 18.5 ml.
- Explotab* (extra granular) 4.42 g.
magnesium Stewart 1.105 g.
Tabulating was carried out on a Majesty* F-3 single press
compression machine using a 5/8" concave, round, plain punch
to provide tablets having a hardness value of 8 to 9 kg.
(Stokes scale) and a moisture con-tent of 0.8% at compression.
Average tablet weight was 884 my., containing 800 my. of
cimetidi,ne. The tablets had a friability value of 0.39% and
a disintegration time of 12 minutes in HO at 37C.
E SAMPLE XI I I
10.8 kg. of Plasdone* K-29-32 (polyvinylpyrrolidone)
was mixed with 53.0 1. of purified water until dissolution was
complete. 290.0 kg. of cimetidine was mixed with 3080 g. of
Explotab* (carboxymethyl starch) for 5 minutes and then
granulated with the prepared Plasdone*/water solution. The
granulated material was then tray-dried overnight in a convection
25' oven set at 45C until a moisture content of 0.4% to 1.2%
(Congo Schulz obtained. The granules thus dried were passed
through a No. 12 screen and then mixed for a further 3
minutes. Approximately 5 kg. of screened and mixed granules
were withdrawn and mixed with 1817 q. of magnesium Stewart,
passed through a No. 12 screen and returned to the previously
* trade mark - 15 -
955~
screened and mixed granules. This mixture was rnlxéd for 10
minutes with 3080 g. of Explotab* (carboxymethyl starch.
The resulting mixture was compressed on a Stokes D-3 machine
to provide concave, beveled, ellipsoid tablets of dimensions
11/32" x 23/32" having a hardness range of 9.0 to 11.0 kg.
(Stokes scale). Average tablet weight was 852 my., containing
800 my. of cimetidine.
EXAMPLE XIV
18.52 g. of -Plasdone* X 29-32 (polyvinylpyrrolidone)
was mixed with 40 ml. of purified water until dissolution was
complete.- 500 g. of cimetidine was mixed with 2.63 g. of
Explotab* (carboxymethyl starch) for 2 minutes and transferred
to a mortar. The cimetidine/Explotab* mixture was granulated
with the prepared Plasdone*/water solution, an additional 80
ml. of purified water being added. The granulated material
was then tray dried in a convection oven to a moisture content
of 0.6% (Congo scale). The granules thus dried were passed
through a No. 15 screen and transferred to a plastic bag. 2.7 g.
of magnesium Stewart was mixed with an equal weight of screened
granules withdrawn from the plastic bag. This mixture was
passed through a No. 15 screen and returned to the plastic
bag containing the remaining granules. This mixture was mixed
for 2 minutes and compressed on a Majesty* F-3 single press
compression machine using an ellipsoid, biconcave, beveled
punch to give tablets of dimensions 11/32" x 23/32" having a
hardness of 8.5 kg. (Stokes scale). Average tablet weight
was 838 my., containing 800 my. of cimetidine. The tablets
had a disintegration time of 2 minutes in HO at 37C and 2
minutes CUSP method).
* trade mark
~Z~5~5S~
APPLE XV
18.52 g. of Plasdone* I~-29-32 (polyvinylpyrrolidone)
was mixed with 40 ml. of purified water until dissolution
was complete. 500 g. of cimetidine was placed in a mortar
and granulated with the prepared Plasdone*/water solution,
an additional 80 ml., approximately of water being added.
The granulated material was then tray-dried in a convection
oven to a moisture content of 0.6% (Congo scale). The grant
vies thus dried were passed through a No. 15 screen and
transferred to a plastic bag. 2.7 g. of magnesium Stewart
was mixed with an equal weight of screened granules with-
drawn from the plastic bag. This mixture was Dossed through
a No. 15 screen and returned to the plastic bag containing
the remaining granules. This mixture was mixed for 2 mint
vies with 2.63 g. of Explotab* (carboxymethyl starch) and compressed on a Majesty* F-3 single press compression machine
using an ellipsoid, biconcave, beveled punch to give tablets
of dimensions 11/32" x 23/3Z" having a hardness value of 10 kg.
(Stokes scale). Average tablet weight was 838 my., containing
800 my. of cimetidine. The tablets had a disintegration
time of 5 minutes in HO at 37C and 4 minutes CUSP method).
EXAMPLE XVI
The procedure of Example XV was followed but substitu-
tying 1.30 g. of ASSIDUOUSLY* (microcrystalline cellulose derivative)
for the 2.63 g. of Explotab* used in Example XV. Tablets were
compressed on a Majesty* F-3 single press compression machine
using an ellipsoid, biconcave, beveled punch to give tablets
of dimensions 11/32" x 23/32" having a hardness value of 10 kg.
(Stokes scale). Average tablet weight was 836 my., containing 800 my.
* trade mark - 17 -
so
of cimetidine. The tablets had a disintegration time of 5
minutes in HO at 37C and 2 minutes CUSP method).
Although the foregoing examples have been directed
to the preparation of high percentage cimetidine tablets for
human consumption, the present invention would extend, for
example, to cimetidine tablets for veterinary use as well.
Nor is the practice of the present invention restricted, for
example, to particular excipients or brands thereof or to a
specify lo process for the preparation of the tablets of the
present invention. Therefore, although various preferred
embodiments have been described herein in detail, it will be
appreciated by those skilled in the art that variations may
be made without departing from the spirit of the invention
or the scope of the appended claims.
.
- 18 -
