PRODUITS PHARMACEUTIQUES LYOPHILISES

FREEZE DRIED PHARMACEUTICALS

Abrégé anglais

Abstract of the Disclosure
Process for preparing Aspirin salts having improved
stability and compositions containing same.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process of preparing a water-soluble, substantially
anhydrous material stable to hydrolysis comprising subjecting
a freeze-dried, water-soluble material containing molecularly
bound water and which is susceptible to hydrolysis to a vacuum
of 10 microns or less Hg to remove said molecularly bound water
and condensing the removed water on a condenser below -50°C.
2. A process of preparing water-soluble, substantially
anhydrous salt of acetylsalicylic acid stable to hydrolysis
comprising subjecting a frozen aqueous solution of a salt of
acetylsalicylic acid to freeze drying at a temperature of about
- 20° to about - 40°C under a vacuum of about 1 to about 0.1
microns Hg to provide a freeze dried salt of acetylsalicylic
acid containing molecularly bound water which is susceptible
to hydrolysis, subjecting said freeze-dried salt to a second
freeze drying at a vacuum of 10 microns or less Hg to remove
molecularly bound water and condensing said water on a condenser
below - 50°C.
3. The process of claim 4 wherein the salt of acetyl-
salicylic acid is a calcium salt of acetylsalicylic acid.
4. A water-soluble, substantially anhydrous pharmaceuti-
cal salt of acetylsalicylic acid stable to hydrolysis, when
prepared by the process of any one of claims 1, 2 or 3 or by
their obvious chemical equivalents.
5. A water-soluble, substantially anhydrous calcium
salt of acetylsalicylic acid stable to hydrolysis, when
prepared by the process of any one of claims 1, 2 or 3 or by
their obvious chemical equivalents.

Description

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FREEZE-DRIED PHARMACEUTICALS
This invention pertains to improved pharmaceu-
tical preparations and processes for making same. In a
specific embodiment, this invention also pertains to
aspirin salts (salts of acetylsalicylic acid) and processes
for producing them.
Aspirin salts are known to produce reduced ir-
ritation of the stomach lining. Previous attempts to pro-
duce an aspirin salt with satisfactory stability have been
unsuccessful because of the tendency to form hydrates which
result in "built-in" instability.
I have discovered methods for producing anhydrous
aspirin salts, and in addition have been able to produce
these soluble salts in flavored, palatable form. ~y dis-
coveries are also applicable to other pharmaceutical pro-
ducts whose hydrates have limited shelf life. This in-
vention also relates to flavoring other pharmaceuticals.
I will describe my process for the production of
Calcium Aspirin, however, it is applicable to other salts
such as Magnesium Aspirin and also to other pharmace~tical hydrates.
At the heart o~ ,
my discovery is the determination that Calcium Aspirin in
water, after being frozen, is stable for a considerable
period in the frozen state. This permits freeze-drying
without substantial decomposition.
Essentially my process differs from ordinary
fr~eze drying in that the frozen solution of Calcium Aspirin
is freeze dried first to produce the freeze dried hydrate
followed by drying the hydrale i~self. The temperature is
gradually raised during the drying process to permit a
satisfactory rate of drying, however, the temperature can
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not be elevated substantially until the aspirin salt next to
the heating surfaces is dry. When the material is dry but
still in partial hydrate form, the temperature may be raised
to approximately 50-60C for a period to accomplish the re-
moval of much of the water of hydration.
The freeze dried Calcium Aspirin at this point is a
mixture of anhydrous salt mixed with some hydrate. To insure
complete dehydration, I prefer to introduce a second step
which utilizes much higher vacuums and cooler condenser
temperatures and re~uires little or no heating.
For this second step, I provide a vacuum lower
than 100 microns, preferably 10 microns or lower. This is
in contrast to commercial freeze-drying in which the vacuum
is 1-4 mm. Hg and is not sustained below 100 microns.
In order to achieve this high vacuum in the freeze
drying process, it is important to maintain the condenser
temperature lower than -50C and preferably lower than -75
or lower. Under some circumstances it ls possible to use
a fresh condenser without disturbing the contents in the
chamber used for the first'stage.
EXAMPL~ 1. ' Anhydrous Calcium Aspirin. The pro-
duct made by reaction of Aspirin and Calcium Carbonate in
water, filtering, freezing, grinding the material in a room
at approximately -40, placing on txays in the freeze drying
chamber, applying vacuum of at least 1 mm Hg. and condensing
the water on a condesner at about -40. The plates are
~arm~d raising the temperature gradually as freeze drying
continues, starting so that the temperature of the dried
granules do not exceed that of room temperature, and reaching
at the end not above 40-50C.
When the gr~nules are dry and contain at most

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some water of hydration, the condenser is removed and a
new condenser assembly is attached capable of lower tempera-
tures. ~nother vacuum pump is used which produces a vacuum
o~ less than 100 microns and preferably about 1 micron. The
condenser temperature should be maintained at -50 to -100C.
or lower. The granules may be warmed to keep them at room
temperature or above and may be warmed to 40-50C. toward
t he end of the cycle.
Calcium Aspirin made using the above procedure is
shown to contain less than 0.1 mol of water of hydration and
usually contains less than 0.02 mols. This is confirmed
when the material is heated under vacuum in the oven at
120-130C. the weight loss resulting ~rom the formation of
acetic acid (from the reaction of the aspirin with the water
of hydration) is insignificant. Material made by ordinary
freeze drying shows a significant weight loss under these
conditions showing the presence of significant hydrate.
In performin~ the above process, I have discovered
that I can use microwave heatin~ to reduce the overheating
resulting from the normal heating method. This permits
localizing the heating to the granules with the most water
and reduces the heating of granules which are already dry.
The granules made using the above process are some-
what soft. They may be used in forming tablets and can also
be dissolved in water for easy swallowing. Although the
taste of aspirin salts is not bad, this can be improved by
flavoring. The granules may be made harder and flavor can
be added prior to the freeze-drying by the addition of a
soluble starch hydrolysate to the mixture prior to freezing.
Sugar or lactose may also be used in the formation. This
discovery tha~ the addition of starch hydrolysate causes a
harder and more stable granule and i~ addition permits the

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addition of flavor prior to freeze drying is an important
finding. It is applicable to t~e freeze drying of other
soluble pharmaceuticals, but it will be described in con-
nection with the preparation of the Calcium Aspirin.
Many people, including children, have difficulty
swallowing tablets, and some people prefer to take their
medication in liquid form. In order to prepare aspirin with
a flavor that is readily soluble in water, it is important to
have a product with substantial bulk so that it can be
measured accurately and with a tasteful flavor.
I have shown that the addition of Maltodextrin to
Methyl Salicylate solutions which are frozen and freeze
dried reduces the flavor loss tremendously. I use Malto-
dextrins with a dextrose equivalent (DE) of from 5 to 30
with 10 being the preferred DE. This type has a maximum
stability with a minimum of lowering of freezing point.
I generally prefér a mixture prior to freeze
drying which contains about 60% water and 40% solids. The
solids would genexally consist of about forty to eighty
percent carbohydrate, some flavor and color, and the re-
mainder could be active ingredient, which in this case
is Calcium Aspirin.
EXAMPLE 2. Anhydrous Magnesium Aspirin. This
product is prepared following the procedure of Example 1
and substituting Magnesium Carbonate for Calcium ~arbonate.
EXAMPLE 3 . Calcium Aspirin with Maltodextrins.
Six grams of Aspirin were stirred with 3 grams of calcium
carbonate added in portions to 300 ccs of water (at 10C~.
~hree grams of spray dried 20% USP Lemon Flavor, 30 grams
of sugar and 44 grams of DE10 Maltodextrin are added. The
mixture is filtered, frozen, and freeze dried as in the
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example 1 given above. The resulting product are hard
granules, readily water soluble, with a good flavor.
When Calcium Aspirin is administered orally to
rats in large doses, gastrointestinal bleeding may be
observed upon disection. Despite the fact that the aspirin
is already neutral, I have discovered that the addition of an
excess of bicarbonate salt reduces this bleeding considerably
and often prevents it. I use at least one part bicarbonate
however greater excesses are ~ery desirable. The amoun~ of
bicarbonate is even greater when acid aspirin is used. In-
stead of bicarbonate, a carbonate such as calcium carbonate
may also be used since it is the bicarbonate ion which ap-
pears to reduce the to~icity of the salicylate ion. I have
also established that other aromatic carboxylic acids show
similar detoxification with bicarbonate ion. This refers
to benzoate, salicylate and their deriva~ives.
A~pirin salt prepared according to this invention
may be used for achieving this saer form of aspirin. The
Calcium saltj as an example, can he enteric coated so that
it utilizes the bicarbonate in the duodenum and bipasses
the stomach. -It may also be combined ~ith calcium carbonate
in a similar dosage form with or without enteric coating.
The aspirin salt ma~ be freeze dried using the
above technology with bicarbonate or carbonate since I have
discovered that bicarbonates such as sodium bicarbonate
may be freeze dried. Calcium carbonate has the advantage
that it does not lower the freezing point as does the
sodium bicarbonate.
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