Note: Descriptions are shown in the official language in which they were submitted.
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PRODUCTION OF STABLE CRYSTALLINE
SODIUM ACETYLSALICYLAT~
TABLE OF CONTENTS
PAGE
l. Technical Field
2. Background of the Invention 2
3. Summary of the Invention 5
10 4 Description of the Drawings 5
5. Description of the Preferred Embodiments 6
5.1 Example I
Preparation of Seed Crystals 7
5.2 Example II
Preparation of Sodium Aspirin Dihydrate 8
5.3 Example III
Drying Operation l0
6. Claims ll
7. Abstract of the Disclosure 13
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l. TECHNICAL FIELD
The present invention relates to a process for
preparing sodium *Aspirin in a form that is
free-flowing and stable at ambient temperature for
extended periods of time. More particularly, the
invention relates to the preparation of an analgesic,
anti-arthritic, anti-inflammatory, and anti-pyretic
composition containing dry crystalline sodium *Aspirin
which can be formulated into convenient dosage forms.
2. BACKGROUND OF THE INVENTION
The most widely used analgesic and
anti-inflammatory drug is *Aspirin, which is the drug
of choice for the treatment of arthritis and common
aches and pains. Unfortunately, the use of *Aspirin,
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the chemical name of which is acetylsalicylic acid,
can be accompanied by undesirable side effects. These
include gastric mucosal irritation, gastric distress
and intolerance, which are due to the acidic nature of
*Aspirin and to its poor water solubility. Once
ingested, *Aspirin tablets disintegrate, often leaving
insoluble particles which can lodge in and irritate
the gastric mucosa. Because of the irritation caused
by such conventional *Aspirin many individuals taking
*Aspirin suffer gastric distress. Acetaminophen (as
present in *Tylenol, *Datril, etc.) is sometimes taken
instead of *Aspirin to avoid gastric distress, but is
ineffective in reducing inflammation. Arthritis
patients who suffer from inflammation but cannot
tolerate *Aspirin must thus turn to other, more potent
drugs which are generally less pharmacologically
established.
In efforts to overcome the drawbacks of ordinary
*Aspirin, a number of approaches have been explored.
There are available today a number of buffered
*Aspirin compositions sold under brand names such as
*Bufferin, *Excedrin and *Anacin. These compositions
neutralize some gastric acid but do not eliminate the
basic problem-insoluble *Aspirin particles which cause
gastric mucosal irritation.
*Aspirin can be formulated into enteric coated
tablets, but such formulations merely shift the locus
of irritation to the duodenal mucosa and other regions
of the gastrointestinal tract, where the tablets
disintegrate. Moreover, the enteric coating delays
the desired effPct of the *Aspirin's activity, and
there is always the risk of premature release of the
*Aspirin in the stomach resulting from perforations in
the enteric coating.
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More effective are compositions similar to *Alka-
Seltzer, which produce a soluble form of *Aspirin upon
contact with water that is readily assimilated by the
body and which therefore does not cause localized
irritation. But the way such compositions accomplish
this objective is not very efficient. For example,
large quantities of sodium bicarbonate and citric acid
axe employed which may exceed the weight of the
*Aspirin by a factor of ten or more. Such
preparations are also relatively costly for the
analgesic dose they provide, suffer the inconvenience
of waiting for the chemical reaction to end, result in
the ingestion of relatively large amounts of sodium
ion, and can produce distending quantities of gas. As
ts a result, they are practically never used by arthritic
patients or by individuals with chronic arthritic pain
or inflammation.
The sodium salt of *Aspirin formed when
Alka-Seltzer dissolves in water would be useful in and
f itself as an analgesic if such *Aspirin could be
isolated free of excess bicarbonate and formulated
into a convenient dosage form, e.g., tablets, but
severe problems of stability make the attainment of
both of these objectives difficult. Thus, the
preparation of sodium *Aspirin in aqueous solution is
relatively easy, but removal of the water to yield
sodium *Aspirin in solid form is difficult. This is
because the acetate group of sodium *Aspirin tends to
hydrolyze to produce undesirable quantities of sodium
salicylate and other non *Aspirin species during the
dehydration step. The inability to crystallize sodium
*Aspirin free of the aforementioned by-products
results in a pharmaceutically unacceptable product.
For years, attempts have been made to prepare a
stable, non-acidic analgesically effective
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water-soluble derivative of *Aspirin on a commercial
scale. Such a derivative affords important advantages
over *Aspirin itself. For example, it could be given
in aqueous solution to patients unable to swallow
tablets, would be more readily absorbed by the body,
and would be much less likely to cause
gastrointestinal disturbances that might otherwise
result from the acidic nature and low solubility of
regular *Aspirin.
Among the many possible derivatives of *Aspirin,
the sodium, calcium, potassium, lithium, ammonium,
magnesium and amino acid salts, calcium salt complexes
with urea and the like have been prepared. These
compounds normally lack sufficient stability for
prolonged storage, apparently because the carboxylate
moiety renders the acetyl group sensitive to
hydrolysis and decomposition. Consequently, such
compounds decompose rapidly on storage with the
formation of various undesirable by-products such as
salicylic and acetic acids.
on the other hand, the salts of *Aspirin,
particularly sodium *Aspirin, are much more soluble,
are more potent, and generally do not exhibit the
undesirable side effects of ordinary *Aspirin as
described hereinabove. Sodium *Aspirin can be
prepared by a variety of methods, e.g., reacting
*Aspirin with sodium carbonate in the presence of
small amounts of organic solvents such as methyl and
ethyl formate, methyl and ethyl acetate, and the like.
Unfortunately, the resulting product is impure and
unstable, probably because of the heterogeneous nature
of the reaction. The sodium *Aspirin prepared by this
method fuses after prolonged storage due to the
formation of acetic and salicylic acids and their
salts. Sodium *Aspirin can also be prepared by
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reacting *Aspirin with sodium bicarbonate in aqueous
solution. However, it is difficult to separate the
product from the solution because of its high
solubility, and distillation or crystallization must
be used to recover the sodium *Aspirin product.
Distillation has several obvious disadvantages, the
most apparent being the energy costs, failure to
remove impurities and the tendency of the sodium
*Aspirin to undergo hydrolysis during the
distillation, which results in low yields of an impure
product having poor stability.
Granular, plate-like, free-flowing crystals of
sodium *Aspirin have been produced by Galat (U.S.
Patent 3,985,792) in a process involving precipitation
of the compound from aqueous solution and removal of
the water of hydration. Although the process
disclosed in that patent, gives satisfactory results
on a laboratory scale, a need for improvement exists
in order to optimize the process for commercial
production.
SUMMARY OF THE INVENTION
The present invention overcomes the
aforementioned difficulties in a process involving the
preparation of a solution of sodium *Aspirin by
reacting USP *Aspirin with USP sodium bicarbonate in
water, preferably distilled or deionized water,
containing an aliphatic alcohol having 3 to 5 carbon
atoms in the molecule. Sodium *Aspirin in the form of
plate-like crystals of dehydrate is recovered by
crystallization from solution at a reduced temperature
while intermittently adding plate-like seed crystals
recovered from a previous batch or prepared
specifically for the purpose of facilitating the
crystallization of the dehydrate. When the
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crystallization is complete, the crystals are
separated from the mother liquor and are dried under
careful conditions in a fluidized bed granular dryer.
4. DES~ Q~ Q~ TH~ D~AWINGS
Fig. l is a schematic view of the type of
apparatu~ used for the preparation sodium *Aspirin.
Fig. 2 is a schematic view of a type of
commercially availablQ fluid bed dryer for drying the
sodium *Aspirin dehydratQ to form a stable, anhydrous
sodium *Aspirin.
5. THE DESC~IPTION OF THE
PREFER~ EMBODIME~TS
The ~irst step in the process of the present
invention i8 the preparation o~ sodium *Aspirin as the
dihydrate. In this step, a quantity o~ USP grade
*Aspirin powder, pre~erably having a particle SiZQ O~
about 400 to 500 microns (35 to 40 mesh) i~ reacted
with a 5 to 15% stoichiometric excess, preferably a 7
to 14% excess, o~ sodium bicarbonate in the pre~ence
of a quantity o~ water equal to about 0.4 to 8.45
liter per kilogr~m of *A~pirin. This water contains
from about 15 to 20 volum- percent, pre~erably about
17 to 20 volum- p-rcent, o~ an alcohol having 3 to 5
carbon atom~, preferably isopropyl alcohol. When the
reaction is complete, an additional quantity (1.7
liters per kilogram o~ *Aspirin) o~ alcohol is charged
to the reactor and the reaction mixture is agitated
for sevQral minutes. The unreacted bicarbonate is
~iltered off and the filtrate i8 charqed to a
crystallizer.
The reaction can al~o be carried out directly in
a cry~tallizer of the type shown in Pig. l. The
crystallizer lO i9 equipped with an anchor or
paddl~-type agitator ll driven by a variable-~peed
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motor (not shown) atop drive shaft 12. Any baffling
13 should be such that the baffles do not contact the
liquid at this point to prevent splashing of the
liquid onto the walls of the crystallizer which would
otherwise result in the formation of undesirable
acicular or needle-like (non-hydrated) crystals. The
solution is stirred slowly and the cry~tallizer is
cooled to approximately 6C by means of cooling jacket
14. The temperature is monitored through thermocouple
well 15. When the solution reaches this temperature,
approximately 0.05 volume percent of a slurry of
platelet (dihydrate) seed crystals (recovered from a
previous run or prepared as a separate slurry) are
added. It is important that no needle-like crystals
are present in the seed crystals. Cooling is then
continued to O~C. ~imilar quantities of seed crystals
are added incrementally until crystallization occurs,
whereupon an additional quantity of isopropyl alcohol
is added to ensure that crystallization is complete.
In the second step of the process, the crystals
are separated from the mother liquor, preferably in a
basket centrifuge. The crystals are washed with a
solution of 5 volume percent of distilled or deionized
water in isopropyl alcohol.
In the next step of the process, the crystals of
sodium *Aspirin dihydrate recovered from the
centrifuge are transferred to a fluidized bed dryer of
1100-liter bowl size 20 modified for incremental
addition of the crystals as shown in Fig. 2. The
crystals are fed to the dryer 20 equipped with bowl 24
through funnel 21 at a rate of about 400 to 500 kg,
preferably 450-475 kg, over a period of approximately
one-half hour. Air, at a rate sufficient to fluidize
the bed of crystals in dryer 20, is passed through the
dryer beginning at inlet 22 at an inlet temperature as
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low as possible to maintain an air temperature at the
exit 23 such that the relative humidity at the outlet
is below 60% so as to avoid hydrolysis. This depends
on the relative humidity of the outside air, but
normally requires an initial temperature of about
35C. When the isopropyl alcohol has evaporated, the
temperature of the inlet air is increased to 60C and
the temperature of the outlet air approaches 60C.
The drying is continued until the product exhibits a
water content of less than 0.3% by weight as can be
determined by means known to those skilled in the art.
The invention is illustrated in the following
nonlimiting examples.
5.1 Exam~le I
This example illustrates a typical method of
preparing the seed crystals that are to be used for
addition to the crystallizer. A quantity (5 grams) of
USP sodium *Aspirin (anhydrous) is dissolved in a
mixture of 2.5 grams of water and 7.5 grams of
isopropyl alcohol and the solution is stored in a
refrigerator at a temperature of about 4C until
several crystals are formed. The well-formed, plate
like, needle-free crystals can then be used to seed a
laboratory scale glassware batch to make a sufficient
quantity for production scale runs.
5.2. Example II
A quantity of sodium *Aspirin dehydrate is
prepared by reacting 841 kg of USP grade *Aspirin
having a particle size of 420 microns (40 mesh) with
420 kg of USP grade sodium bicarbonate in the presence
of 377 liters of water containing 65 liters of
isopropyl alcohol. When the reaction is complete, a
quantity (1400 liters) of isopropyl alcohol is added
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to the reaction mixture and stirring was continued for
several minutes. The mixture is then filtered and the
filtrate is introduced into a crystalli~er of the type
shown in Fig. 1.
The crystallizer 10 is equipped with an agitator
blade 11 driven by a variable-speed motor (not shown).
The crystallizer is equipped with a jacket 14 for
cooling the liquid to facilitate crystallization. A
baffle 13 is positioned at the side of the
crystallizer. The crystallizer is equipped with a
thermocouple in a well 15 to record the temperature as
crystallization progresses After the solution was
added to the cry~tallizer, th~ agitator blade is
rotated at approximately 15 rpm to assure that no
splashing of the liquid onto the walls occurs. A
cooling medium at approximately -20C is fed to the
jacket of the crystallizer and the solution is cooled
to 6C. When this temperatur~ is reached, 0.67 liter
of a slurry of seed crystals from a previous batch is
added and slow agitation is continued for
approximately ona-half hour. When the temperaturQ
reachas 3C, an additional 0.67 liter of seed slurry
is added ir crystallization ha~ not already begun.
After one half hour, or when the temperature reaches
0C, an additional 0.67 liter of sQed slurry i8 added
if necessary and agitation i9 continued at 0C to 2C
until crystalllzation i~ apparent, whereupon an
additional quantity (4750 1) isopropyl alcohol i~
added and tho temperatur~ lowered to betwean -10 to
-15C to optimiz- the crystallization.
When the crystallization is completQ, the ~lurry
is centrifuged in ~ ba~ket-typo centrifuge to separate
the crystal~ from the supernat~nt liquor. The
crystals ar~ wa3h~d in tho centrifuge with 50-liter
quantities of a mixtur~ of isopropyl alcohol
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containing approximately 5 percent by volume distilled
water. Washing is continued in this way until the
centrifuge cake contains less than about 0.1% by
weight salicylate as determined according to the
following procedure: A quantity (50 mg) of the cake to
be tested is placed into a Nessler color comparison
test tube (Scientific Glass Co., C-6535; length: 154
mm, ID: l9mm, OD: 22mm), to which are then added 20 ml
of water and 4 drops of glacial acetic acid followed
by 8 drops of a ferric solution prepared by dissolving
1 g Fe alum in 200 ml water containing 1 ml
concentrated HCL. In another, identical Nessler tube
are placed 20 ml water followed by 4 drops of glacial
acetic acid and then a drops of the,ferric solution.
The latter tube is then shaken while adding to it
dropwise a 0.1% standard salicylate solution (prepared
by dissolving 1 gm salicylic acid in 1000 ml water)
until the color matches that of the solution in the
first Nessler tube (looking through the width) against
a white background. (Each drop of the 0.1% solution
corresponds to 0.05 mg of salicylic acid). The
concentration of the solution being tested must be
adjusted so that not more than 6-7 drops of salicylic
solution is required, otherwise the color in too deep
for comparison. The test requires less than 5 minutes
to perform, since sodium *Aspirin hydrolyzes in water
the test must be done as quickly as possible.
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Example III
This example illustrates a typical drying operation.
The drying is carried out in a commercially available Glatt
WDG-UD 300 dryer with a llO0-liter bowl capacity. The dryer
was modified in the manner shown in Fig. 2. The dryer ~0 is
5 equipped with a funnel element 21 so that the material can
be continuously sucked into the drying chamber. The product
bowl 24 is inserted into the chamber and the material from
the centrifuge is fed into the dryer. A total 465 kg of wet
cake was fed to the dryer over a period of approximately
one-half hour. The material was fed through the feed funnel
with the fan open and the flap set so that the material can
be sucked into the chamber and fluidized. The dryer is
operated in this manner because, in addition to 15.1 percent
water of hydration contained within the molecule, the
crystal is wet with approximately S to 6 percent of
isopropyl alcohol and 0.5 percent water. Adding the
crystals over a period of one-half hour avoids the
possibility of the concentration of isopropyl alcohol in
dryer reaching explosive limits.
The temperature of the air entering the dryer is
maintained as indicated hereinabove to prevent hydrolysis of
the product. When the isopropyl alcohol is completely
evaporated, the temperature of the inlet air is increased to
60-C. As the temperature of the outlet air approaches 60-C,
samples of the material are taken for determination of the
water content. The dryer is operated at a temperature of
60-C until it was found that the material taken from the
bowl-has a water content of 0.3 percent or less. The dryer
was then shut down and the product recovered.
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