Note: Descriptions are shown in the official language in which they were submitted.
15)687~)7
The present invention relates to certain heterocyclic organic com-
pounds which may be referred to as 4-(omega-substituted alkyl)-2-pyrrolidin-
ones and is more particularly concerned with l-R-4-(omega-substituted alkyl)-
3,3-diphenyl-2-pyrrolidinones, processes for the production thereof, composi-
tions containing the same as active ingredients, and the methods of making
and using them.
The invention is especially concerned with compounds of the for-
mula:
(~ (CH2)n~'~R
N Formula I
R
wherein
Ph is the phenyl radical,
R is hydrogen, lower alkyl or benzyl,
Rl is hydrogen, chloro, bromo or fluoro,
A is hydroxy, lower-alkylcarbonyloxy or lower-alkoxycarbonyl,
wherein the alkyl groups or moieties each contain from 1 to 4 carbon atoms, and
n is 1, 2 or 3, and their pharmaceutically acceptable acid addi-
tion salts.
The compounds of the invention having the foregoing Formula I
are generally characterized by important pharmacological activity indicative
of their use in counteracting certain physiological abnormalities in an
animal body. The compounds possess analgetic and antidiarrheal properties.
The l-R-4-[omega-(4-hydroxy-4-phenylpiperidinyl)alkyl]-3,3-di-
phenyl-2-pyrrolidinones of Formula I-A
C6HS ~( 2)n /~2
Formula I-A
* - 2 -
106870'7
are included as part of the present inYentiOn as well as the pharmaceuticallyacceptable acid-addition salts thereof. The values of R, Rl, R2 and n are
as set forth hereinabove. The compounds of Formula I-A have antidiarrheal
`:
`
~ `
~ ~ - 2~ -
1 ()68707
properties.
In accordance with the invention, compounds of formulà I and their
pharmaceutically acceptable acid-addition salts are prepared by
(a) reacting together corresponding compounds of the formulae II and
III
Rl R2
C6H5 ~ ( 2)n t ~
~ (O)-O-alkyl
II ~ III
H
wherein X is halogen and alkyl is lower alkyl; or
Cb) reacting together corresponding compounds of the formulae II and
IV
/~Rl
H0 ~ R2
~NJ
H IV
and, where a compound of formula I in which A is lower-alkylcarbonyloxy is
required, esterifying the resulting compound in which A is hydroxy to intro-
duce the required lower-alkylcarbonyl radical; wherein R is selected from
the group consisting of hydrogen and lower-alkyl, Rl is selected from the
group consisting of hydrogen, chloro, bromo, fluoro, trifluoromethyl and
lower-alkoxy, R2 is selected from the group consisting of hydrogen, chloro,
bromo and fluoro, A is selected from the group consisting of lower-alkyl-
carbonyloxy and lo~er-alkoxycarbonyl and n is 1, 2 or 3.
In the definitions of symbols in the foregoing Formula I and
where they appear elsewhere throughout this specification, the terms have the
following significance.
AHR-289-CIP
106870~
The term "lower-alkyl~ as used herein includes straight
and branched chain radicals oE up to eight carbon atoms
inclusive and is exemplified by such groups as methyl, ethyl,
propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl,
octyl, and the like. "Lower-alkoxy~' has the formula -0-lower-
alkyl.
The invention also contemplates as mentioned hereinabove
the pharmaceutically acceptable acid a~dition salts of the
compounds of Formula I and I-A formed with non-toxic organic
and inorganic acids. Such salts are easily prepared by methods
known in the art. The acids which can be used to prepare the
preferred non-toxic acia addition salts are those which produce,
when combined with the free bases, salts whose anions are
j relatively innocuous to the animal organism in therapeutic doses
f the salts, so that beneficial physiological properties
ir.herent in the free bases are not vitiated by side effects
ascribable to the anions.
The base is reacted with the calculated amount of organic
- or inorganic acid in a~ueous miscible solvent, such as ethanol
or isopropanol, with isolation of the salt by concentration and
cooling, or the base is reacted with an excess of the acid in
aqueous immiscible solvent, such as ethyl ether or isopropyl
ether, with the desired salt separating directly. Exemplary
of such organic salts are those formed with malaic, fumaric,
benzoic, ascorbic, pamoic, succinic, methan~ sulfonic, citric,
propionic, tartaric, citric, maleic acid, and the like.
Exemplary of such inorganic salts are those formed with
-` 106870~
hydrochloric, hydrobromic, sulfuric~ sulfamic, phosphoric and nitric
acids.
Generally speaking, the novel compounds of the present invention
can be prepared according to the following reaction schemes. Herein-
below R, Rl, R2 and n are as defined in the generic formula and X is ahalogen radical chlorine being preferred.
(1) Rl R2
C6H5 ~ (CH2)n + ~ C (O) -O-alkyl
II ~ III R
C6H5 ~ ~CH2)n - N~R2
N C (O) -O-alkyl
R
(2) C6H5 Rl
C6 ~ ~C~)X + H ~ R2 >
II R IV NH
C6H5 ~ (CH ) _ N ~ R2 C H ~ ~CH ) - N ~ R
R I-A Rl R
C ~6 ~ (CH ) ~ R2 Na
N
R 6 5 ~ 1
H
I
a) R is benzyl
, ., ~
1068707
The l-R-4-(omega-haloalkyl)-3,3-diphenyl-2-pyrrolidinones of
Formula II wherein n is 2 or 3 are known compounds which are either dis-
closed or can be readily prepared by the procedures disclosed in United
States Patent No. 3,192,230.
The l-R-4-~omega-haloalkyl)-3,3-diphenyl-2-pyrrolidinones of
Formula II wherein n is 1 are novel compounds which may be prepared by
reacting a 4,5-dihydro-3,3-diphenyl-4-(R-aminomethyl)-furan-2-(3H)-one
with a catalytic amount of a strong base such as an alkali metal hydride,
amide, t-butoxide or hydroxide to produce the corresponding l-R-4-hydroxy-
methyl-3,3-diphenyl-2-pyrrolidinone by intramolecular rearrangement, and
then halogenating the latter with a thionyl halide to form the corres-
ponding 4-halomethyl derivative.
The 4-phenyl-4-lower-alkoxycarbonylpiperidine reactants of
Formula III and the 4-hydroxy-4-phenylpiperidines reactants of Formula
IV and the substituted phenyl analogs thereof, e.g., 4-(p-fluorophenyl)-
4-lower-alkoxycarbonylpiperidine, 4-hydroxy-4-(p-fluorophenyl)piperidine,
4-hydroxy-4-(m-trifluoromethylphenyl)piperidine and 4-hydroxy-4-(p-
methoxyphenyl)piperidine are either known compounds or they can be read-
ily prepared by methods known to the art.
Thus, suitable piperidine compounds of Formula III and IV
which can be used in the present invention include:
4- ~-fluorophenyl)-4-ethoxycarbonylpiperidine,
4-~p-bromophenyl)-4-ethoxycarbonylpiperidine,
4-~p-methoxyphenyl)-4-propoxycarbonylpiperidine,
4-(p-chlorophenyl)-4-propoxycarbonylpiperidine,
4-(m-trifluoromethylphenyl)-4-methoxycarbonylpiperidine,
4-(m-trifluoromethyl-p-chloro)-4-ethoxycarbonylpiperidine,
4-(m-trifluoromethyl-p-bromo)-4-ethoxycarbonylpiperidine,
4-hydroxy-4-~m-trifluoromethylphenyl)piperidine,
4-hydroxy-4-(m-trifluoromethyl-p-chlorophenyl)piperidine,
-- 6 --
( ~- AHR~289-CIP
1068707
... . . .. .
4-hydroxy-4-(p-chlorophenyl)piperidine,
4-hydroxy-4-(p-fluorophenyl)piperidine, and
4-hydroxy-4-(m-trifluoromethyl-p-fluoro)piperidine.
In a general method of preparation according to reaction
sequence (I) a l-R-4-(omega-haloalkyl)-3,3-diphenyl-2-
pyrrolidinone (II) wherein n is 2 or 3, e.g., a 1-R-4-(2-chloro-
ethyl)-3,3-diphenyl-2-pyrrolidinone or a 1-R-4-(3-chloropropyl)-
3,3-diphenyl-2-pyrrolidinone and a 4-phenyl-4-lower-alkoxy-
carbonylpiperidine (III) are reacted together in a lower alkanol
solvent as, for example, n-butanol containing an acid binding
agent such as a metal carbonate. The reaction is preferably
run at reflux for a period of from about 12 hours to about 24
hours. The cooled reaction mixture is filtered, concentrated at
reduced pressure, and the residual basic oil converted to a
suitable acid addition salt which can be further purified by
crystallization from a suitable solvent.
In reaction sequence (2) the reaction between a 1-R-4-
(omega-haloalkyl)-3,3-diphenyl-2-pyrrolidinone (II) wherein
n is 2 or 3, e.g., a 1-R-4-(2-chloroethyl)-3,3-diphenyl-2-
pyrrolidinone or a 1-R-4-(3-chloropropyl)-3,3-diphenyl-2-
pyrrolidinone and 4-hydroxy-4-phenylpiperidine (IV) is carried
out under the reaction conditions described hereinabove. The
l-R-4-~omega-(4-hydroxy-4-phenyl-1-piperidinyl)alkyl]-3,3-diphenyl-
2-pyrrolidinone (Ia) is reacted with a lower-alkylcarbonyl chloride
in a mixture of a chlorinated hydrocarbon, e.g., chloroform and
ice water together with an acid binding agent such as a metal
carbonate. The reaction is generally completed in a short time,
( ( AHR-289-CIP
1068707
the layers separated and the basic product isolated from the
dried organic layer by concentration at reduced pressure. The
basic material is converted to a suitable acid addition salt
which can be further purified by crystallization from a suitable
solvent.
When reaction sequence (I) or (II) is carried out using a
compound of Formula II wherein n is 1, e.g., a 1-R-4-chloro-
methyl-3,3-diphenyl-2-pyrrolidinone, it is necessary to heat the
reactants in a steel bomb at an elevated temperature of from
o o
about 180 C. to about 220 C. and for a period of from about
40 hours to about 60 hours to effect reaction between the
2-pyrrolidinone compound II and the piperidine reactants III and
IV.
In reaction sequence (3) a 1-benzyl-4-[omega-(4-phenyl-4-
A-piperidinyl)alkyl]--3,3-diphenyl-2-pyrrolidinone is debenzylated
in liquid ammonia using sodium metal to furnish a compound of
Formula I wherein R is hydrogen.
Another aspect of the present invention contemplates and
provides a pharmaceutical preparation in dosage unit form adapted
for administration to obtain an analgetic effect comprising per
dosage unit, an analgetic effective, non-toxic amount within the
range of from about 5 to about 100 milligrams of at least one
compound of Formula I as defined hereinabove, and a pharmaceutical
diluent.
A further aspect of the present invention contemplates and
provides a pharmaceutical preparation in dosage unit form as
described immediately hereinabove to obtain an antidiarrheal effect.
( ( AHR-289-CIP
1068707
The following examples illustrate methods which can be
employed in preparing compounds useful in the practice of this
invention.
, g _ .
( ( AHR-289-CIP
1~68707
Example 1
l-Isopropyl-3~3-diphenyl-~-[2-(4-hydroxy-4-phenylPiperidinyl)
ethyll-2-pyrrolidinone Hydrochloride.
A stirred mixture of 26.5 g. (0.078 mole) of 4-(2-chloro-
ethyl)-l-isopropyl-3,3-diphenyl-2-pyrrolidinone, 14 g. (0.078
mole) of 4-phenyl-4-piperidinol and 27 g. of potassium carbonate
was refluxed for 18 hrs. The mixture was cooled, filtered and
the filtrate was evaporated to an oil. The crude product was
dissolved in ether and treated with ethereal hydrogen chloride.
After recrystallization from isopropanol the product melted at
130-1~2 C. (31.5 g-; 77O .
Analysis: Calculated for C32H39Cl~2O2: C,74.03; H,7-57; N,5.40
Found : C,7~.71; H,7.61; N,5.14
Example 2
l-Isopropyl-3,3-diphenyl-4-[2-(4-phenyl-4-propionoxY-
piperidinyl)ethyl]-2-pyrrolidinone Oxalate.
A stirred mixture of 0.04 mole of 4-~2-(4-hydroxy-4-phenyl-
l-piperidinyl)ethyl]-l-isopropyl-3,3-diphenyl-2-pyrrolidinone
and 60 g. of potassium carbonate in 50 ml. of chloroform was
treated with 4.5 g. (0.05 mole) of propionyl chloride in 25 ml.
of chloroform. After stirring for one hour the mixture was
cooled to 0 in ice and treated with 100 ml. of crushed ice.
The mixture was stirred until the ice melted, the chloroform
layer was separated, dried over magnesium sulfate and evaporated
to an oil. The oxalate salt was prepared in isopropanol and
precipitated with isopropyl ether. Recrystallization from the
same solvent system gave 14.5 g. (58~), m.p. 178-180 C.
-- 10 --
< (~ AHR-289-CIP
~)68707
Analysis: calc~lated for C37H44N2O7: c,~o.68; H~7.05; ~,4.45
Found : C,70.47; H,6.82; N,4.66
Example
l-Isopropyl-3~3-diphenyl-4-t2-phenyl-4-ethoxycarbon
piperidinyl~ vl ~2 l~yrrolidinone Oxalate.
A stirred mixture of 15 g. (0.044 mole) of 4-(2-chloro-
ethyl)-l-isopropyl-3,3-diphenyl-2-pyrrolidinone, 0.044 mole
of 4-ethoxycarbonyl-4-phenylpiperidine and 15 g. of potassium
carbonate in 50 ml. of n-butanol was refluxed for 24 hours.
The mixture was cooled, filtered and evaporated to an oil.
An oxalate salt was prepared in isopropanol and precipitated
with isopropyl ether. The white salt was amorphous and
solvated but gave a good analysis after drying at 110C. under
vacuum. The compound melted over a wide range below 100 C.
The dried salt weighed 22.5 g. (80O .
Analysis: Calculated for C37H44~207: C,70.68; H,7.05; ~,4.45
Found : C,70.45; H,6.94; N,4~34
Examples 4-19
By following the manipulative procedures disclosed herein-
above and in the preceding examples and using the appropriately
substituted l-R-4-(omega-haloalkyl)-3,3-diphenyl-2-pyrrolidinone
and 4-hydroxy-4-phenylpiperidines and 4-phenyl-4-lower-alkoxy-
carbonylpiperidines, the following compounds are prepared:
l-methyl-4-{2-[4-(p-fluorophenyl~-4-ethoxycarbonylpiperidinyl]
ethyl}-3,3-diphenyl-2-pyrrolidinone,
l-methyl-4-{2-C4-(p-bromophenyl)-4-ethoxycarbonylpiperidinyl]
ethyl}-3,3-diphenyl-2-pyrrolidinone,
-- 11 --
(- ( AHR-289-CIP
1068707
l-ethyl-4-{2-[4-(p-methoxyphenyl)-4-propoxycarbonyl
piperidinyl]ethyl}-3,3-diphenyl-2-pyrrolidinone,
l-isopropyl-4-{2-~4-(p-chlorophenyl)-4-propoxycarbonyl
piperidinyl]ethyl}-3,3-diphenyl-2~pyrrolidinone,
51-isopropyl-4-{2-[4-(m-trifluoromethylphenyl)-4-methoxy
carbonylpiperidinyl]ethyl}-3,3-diphenyl-2-pyrrolidinone,
l-propyl-4-{2-[4-(m-trifluoromethyl-p-chlorophenyl)-4-
ethoxycarbonylpiperidinyl]ethyl~-3,3-diphenyl-2-pyrrolidinone,
l-methyl-4-{2-~4-(m-trifluoromethyl-p-bromophenyl)-4-
10ethoxycarbonylpiperidinyl]ethyl~-3,3-diphenyl-2-pyrrolidinone,
l-methyl-4-t2-[4-hydroxy-4-(m-trifluoromethylphenyl)
piperidinyl~ethyl}-3,3-diphenyl-2-pyrrolidinone,
l-methyl-4-{3-[4-hydroxy-4-(m-trifluoromethylphenyl)
piperidinyl]propyl}-3j3-diphenyl-2-pyrrolidinone,
151-ethyl-4-{2-[4-hydroxy-4-(m-trifluoromethyl-p-chlorophenyl)
piperidinyl]ethyl}-3,3-diphenyl-2-pyrrolidinone,
l-ethyl-4-{2-[4-hydroxy-4-(p-chlorophenyl)piperidinyl]
ethyl}-3,3-diphenyl-2-pyrrolidinone,
l-isopropyl-4-{3-~4-hydroxy-4-(p-fluorophenyl)piperidinyl]
20ethyl}-3 J 3-diphenyl-2-pyrrolidinone,
~-isopropyl-4-{3-[4-hydroxy-4-(m-trifluoromethyl-p-
fluorophenyl)piperidinyl]propyl}-3,3-diphenyl-2-pyrrolidinone,
l-ethyl-4-{2-~4-propionoxy-4-(m-trifluoromethyl-p-chloro
phenyl)piperidinyl]ethyl}-3,3-diphenyl-2-pyrrolidinone,
251-ethyl-4-{2-[4-propionoxy-4-(p-chlorophenyl)piperidinyl]
ethyl}-3,3-diphenyl-2-pyrrolidinone,
l-isopropyl-4-{3-[4-propionoxy-4-(m-trifluoromethyl-p-
chlorophenyl)piperidinyl]propyl}-3,3-diphenyl-2-pyrrolidinone.
- 12 _
( - ( AHR-289-CIP
106~370~
l-benzyl-4-{2-[4-hydroxy-4-(m-trifluoromethylphenyl)
piperidinyl~ethyl}-3,3-diphenyl-2-pyrrolidinone,
l-benzyl-4-{3-[4-hydroxy-4-(p-fluorophenyl)piperidinyl]
propyl}-3~3-diphenyl-2-pyrrolidinone,
1-benzyl-4-{2-~4-propionoxy-4-(m-trifluoromethylphenyl)
piperidinyl]ethyl}-3,3-diphenyl-2-pyrrolidinone,
l-benzyl-4-{3-~4-propionoxy-4-(p-fluorophenyl)piperidinyl]
propyl}-3,3-diphenyl-2-pyrrolidinone,
l-benzyl-4-{2-~4-(p-chlorophenyl)-4-propoxycarbonyl
~piperidinyl]ethyl}-3,3-diphenyl-2-pyrrolidinone,
4-{2-[4-propionoxy-4-(m-trifluoromethylphenyl)piperidinyl]
ethyl}-3,3-diphenyl-2-pyrrolidinone,
4-{3-[4-propionoxy-4-(p-fluorophenyl)piperidinyl]propyl]-
3~3-diphenyl-2-pyrrolidinone,
4-{2-[4-(p-chlorophenyl)-4-propoxycarbonylpiperidinyl]-
ethyl}-3,3-diphenyl-2-pyrrolidinone.
Example 20
3,3-Diphenyl-l-isopropyl-4-(4-phenyl-4-hydroxypiperidinyl-
methyl)-2-pyrrolidinone Maleate.
A mixture of 15 g. (o.o46 mole) of 4-chloromethyl-3,3-
diphenyl-l-isopropyl-2-pyrrolidinone, 8.1 g. (o.o46 mole) of
4-hydroxy-4-phenylpiperidine, 8.2 g. (0.05 mole) of potassium
carbonate and 200 ml. of ethanol was heated in a steel bomb at
200 C. for 48 hours. The cooled mixture was partitioned between
water and isopropyl ether. The dried isopropyl ether layer
(sodium sulfate) was concentrated. The residual material (19 g.)
was dissolved in 150 ml. of isopropyl alcohol to which solution
- 13 -
~ ( AHR-289-CIP
106~7()7
was added 7.0 g of maleic acid and 50 ml. of isopropyl ether.
The maleate salt was collected and recrystallized from isopropyl
alcohol-water. The dried salt weighed 8.o g and melted at
207-208 C.
Analysis: Calcd. for C35H40N20~: C,71.90; H,6.90; ~,4.79
Found : C,72.19; H,6.95; N,4.72
Example 21
3,3-Diphenyl-l-isopropyl-4-(4-phenyl-4-propionoxypiperidinyl-
methyl)-2-py-rrolidinone~
Eight grams of 3,3-diphenyl-1-isopropyl-4-(4-phenyl-4-
hydroxypiperidinylmethyl)-2-pyrrolidinone was dissolved in
benzene, 0.58 g. of 57~ sodium hydride was added and after two
hours stirring at room temperature 1.56 g. of propionic anhydride
was added. Partial reaction occurred after two hours reaction
time. An additional 1.0 g. of 57~ sodium hydride and 3.0 g. of
propionic anhydride was added and the mixture stirred overnight
at room temperature and then refluxed for 48 hours. The cooled
mixture was washed with water, the benzene layer dried over
sodium sulfate and concentrated. The residue was chromatographed
on a magnesium silicate column and the product eluted from the
column using benzene and increasing amounts of acetone. The
product was isolated and confirmed by its nuclear magnetic
resonance spectra.
- 14 -
I ( ~ AHR-289-CIP
i068707
The compounds of this invention of Formula I-A produce
inhibition of diarrhea. The activity is demonstrated by
, administration to mice at doses of about 30 mg ~g. to about
100 mg ~g. orally compounds of Formula I-A. One hour post drug
administration the mice are given 50 mg~kg. of 5-hydroxytryptophane
intraperitoneally. Control animals are only given 5-hydroxy-
tryptophane. Compounds which inhibit the peristalsis effect of
5-hydroxytryptophane are considered active anti-diarrheals.
The compounds of this invention of Formula I wherein A is
lower-alkyl carbonyloxy or lower-alkoxy carbonyl produce analgesia
in animals. The analgetic activity is demonstrated by adminis-
tering the compounds to mice at 20 mg ~g. intraperitoneally.
¦ Effective quantities of any of the foregoing pharmacologi-
¦ cally active compounds of Formula I may be administered to a
! 15 living animal body for therapeutic purposes according to usual
t modes of administration and in usual forms, such as orally, in
solutions, emulsions, suspensions, pills, tablets and capsules,
or intramuscularly or parenterally in the form of sterile
solutions or suspensions, and intravenously, in some cases, also
in sterile solutions.
Although very small quan~ities of the active materials of
~ the present invention are effective when minor therapy is involved
¦ or in cases of administration to subjects having a relatively
- 15 -
( ( AHR-289-CIP
1068~07
low body weight, unit dosages are usually from 5 milligrams
or above and preferably 25, 50, or 100 milligrams or even
higher, depending of course upon the emergency of the situation
and the particular result desired. Five to 50 milligrams appears
optimum per unit dose, or usual broader ranges appear to be
1 to 100 milligrams per unit dose. Daily dosages should prefer-
ably range from 10 mg. to 100 mg. It is only necessary that
the active ingredient constitute an effective amount~ i.e.,
such that a suitable effective dosage will be obtained consistent
with the dosage form employed. Obviously, several unit dosage
forms may be administered at about the same time.
The following formulations are representative for all of
the pharmacologically active compounds of this invention.
; Formulations
(1) Capsules
Capsules of 10 mg., 25 mg., and 50 mg. of active ingredient
per capsule are prepared. With the higher amounts of active
ingredients, reduction may be made in the amount of lactose.
Typical blend for encapsulation Per capsule, mq.
Active ingredient, as salt 10
Lactose 259
Starch 126
Magnesium stearate
Total 399
Additional capsule formulations preferably contain a
higher dosage of active ingredient and are as follows:
- 16 -
~ AHR-289-CIP
1068707
100 mg. per250 mg. per500 mg. per
Ingredients~sule Capsule capsule
Active ingredient 100 250 5
Lactose 214 163 95
Starch 87 81 47
Magnesium stearate 4 6 8
Total 405 5 650
____ ,
- In each case, uniformly blend the selected active ingredient
with lactose, starch, and magnesium stearate and encapsulate
the blend.
(2) Tablets
A typical formulation for a tablet containing 10.0 mg. of
active ingredient per tablet follows. The formulation may be
usea for other strengths of active ingredient by adjustment of
weight of dicalcium phosphate.
Per tablet~ mg.
1. Active ingredient 10.0
2. Corn starch 15-0
3. Corn starch (paste) 12.0
1~. Lactose ~5 o
5. Dicalcium phosphate 1~2.0
6. Calcium stearate 2.0
Total206.0
Uniformly blend the active ingredient~ lactose, and
dicalcium phosphate. Granulate the blend with starch paste
and pass the wet mass through an eight mesh screen. The wet
granulation is dried and sized through a twelve mesh screen.
( (~ AHR-289-CIP
106~1707
The dried granules are blended with the calcium stearate and
compressed.
Additional tablet formulations preferably contain a higher
dosage of the active ingredients and are as follows:
A. 50 mg. tablet
Ingredients: Per tablet, mg.
Active ingredient 50.0
Lactose 100.0
Milo starch 50.0
Corn starch 50.0
Calcium stearate 2.0
Total252.0
Uniformly blend the active ingredient, lactose, milo starch,
and corn starch. This blend is granulated using water as a
granulating medium. The wet granules are passed through an eight
mesh screen and dried at 140 to 150 degrees Fahrenheit overnight.
The dried granules are passed through a number ten mesh screen
and blended with the proper amount of calcium stearate and this
blend is then converted into tablets on a suitable tablet press.
B. 100 mg. tablet
Ingredients: Per tablet, mg.
Active ingredient 100.0
Lactose go o
Dicalcium phosphate 90.0
Starch 33 0
Milo starch 17.0
Calcium stearate 2.0
Total332.0
- 18 -
( ( AHR-289-CIP
1068707
Uniformly blend the active ingredient, lactose, dicalcium
phosphate, starch and milo starch. This blend is granulated
with water and the wet mass is passed through a number eight
mesh screen. The wet granules are dried at 140-160 degrees
Fahrenheit overnight. The dried granules are passed through a
number ten mesh screen. These dried granules are blended with
the proper weight of calcium stearate and the lubricated granules
are then converted into tablets on a suitable tablet press.
C. 250 mg. tablet
Ingredients:Per tablet, mg
Active ingredient 250.0
corn starch 20.0
Carbowax 6000 (polyethylene
glycol of M.W. approx. 6000) 10.0
Lactose 20.0
Magnesium stearate ?
Total 302.0
Uniformly blend the active ingredient, Carbowa~ 6000,
lactose, and one-half the weight of magnesium stearate required.
This blend is then "slugged" on a suitable tablet press. These
"slugs" are granulated through a ten mesh screen on an oscillating
granulator. These granules are then blended with the remainder
of the magnesium stearate and the lubricated granules are then
converted into tablets on a suitable tablet press.
- 19 -
~ AHR-285-CIP
1068707
D. 500 mg. tablet
Ingredients: Per tablet, mg.
Active ingredient 500.0
Corn starch (wet) 50.0
Milo starch 20.0
calcium stearate 6.0
Corn starch (dry) 20.0
Total596.0
Uniformly blend the active ingredient, corn starch and
milo starch. This blend is wet granulated using water and the
wet mass is passed through a number eight mesh screen. These
wet granules are dried overnight at 140-160 degrees ~ahrenheit.
The dried granules are passed through a number ten mesh screen.
The dried granules and calcium stearate are uniformly blended
and these lubricated granules are compressed on a suitable tablet
press.
(~) Injectable - 2% sterile solution
Per cc.
Active ingredient mg. 5.0
PreservativeJ e.g., chlorobutanol,
percent wt./vol. 0.5
Water for injection q.s.
Prepare solution, clarify by filtration, fill into vials,
seal, and autoclave.
_ 20 -
