CA1083602A - Stable sodium acetylsalicylate and method for its manufacture. - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A novel crystalline form of sodium acetyl-salicylate (sodium aspirin) is obtained by first preci-pitating sodium aspirin dihydrate in crystalline form and thereafter dehydrating it to form anhydrous sodium aspirin. The process is carried out under controlled conditions and the product exhibits high storage stability and other desirable physical properties.

Description

SUM~ ~ Y OF THE INVENTION
In accordance with the invention a lhighly concentrated aqueous solution of sodium acetylsalicylate (sodium aspirin*~ is formed~ the concentrated solution is then contacted with water miscilbe organic solvent, preferably one selected from among the C3 and C4 aliphatic alcohols, added gradually at temperatuTes between ordinary room temperature and the freezing point of the solution at such a rate that the formation of needle-like crystals is avoided. The sodium aspirin dihydrate crystallizes out in the form of granular plate-like crystals which are then isolated and dehydrated to form pure anhydrous sodium aspirin in the form of stable granular free-flowing crystals also having a plate-like structure.

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DETAI~ED DESCRIPTION OF T~IE INVENTION

Ever since the discovery of the valuable analgesic and antipyretic properties of acetylsalicylic acid (aspirin) some 60 years ago, continuous attempts have been made to prepare a stable,neutral, water soluble derivative of this compound. Such a derivative would offer a number of im~
portant advantages over aspirin itself - it could be given in solution form to patients unable to swallow tablets~ it would be more readily absorbed, and, most important, it would reduce the incidence of gastrointestinal disorders resulting from the acidic nature and the low water 901u-bility (1 g./100 ml.) of aspirin.

In attempts to prepare a stableJ neutral, water soluble deriva~ive of aspirin, a very large number of salts and other derivatives of this compound have been synthesized:
lithium, ammonium, sodiumg potassium, calcium and magnesium salts, amine and amino acid salts, calcium salt complexes with urea, with amino acids and the like. Unfortunately, these compounds proved to be of unreliable stability on storage. Apparently, neutralization of the carboxyl group of acetylsalicylic acid makes the acetyl group extraordinarily sensitive to hydrolysis and other types of decomposition, and, as a result, many of these compounds rapidly decompose on storage with the formation of various breakdown products such as salicylic acid, acetic acid and others.

Especially troublesome is the fact that the storage behavior of these aspirin salts and other derivatives is extremely erratic and unpredictable. ~ifferent lots of such compounds, prepared by the same process, vary greatly in stability; some lots decomposing after several weeks storage, others after several months, while still o~hers ~83~

remain in apparently good condition for even longer periods only to begin to decompose sudd~nly and at a very rapid rate for no apparent reason. This unpredictable behavior undoubtedly explains in large measure the contradictory claims regarding the stability of salts and various other derivatives of aspirin made by various ingestigators in the past.

Simple salts of aspirin are much more soluble, are more potent ~nd longer lasting pharmacologically, less irritating to the stomach, and more palatable than aspirin itself. Of such salts sodium acetylsalicylate ~sodium aspirin) i5 the most advantageous with respect to solubilityJ
speed of action~ serum levels and palatability. Sodium aspirin is almost lO00 times as soluble in water as aspirin itself~ It is a neutral, well tolerated compound,readily absorbed ~rom the gastrointestinal tract. It is faster acting and more predictable in its action than aspirin it-self and its various formulations. Sodium aspirin is a com-pound with a salty, but acceptable taste, when taken in solid form, and is nearly tasteless when taken in solution.
Unfortunately, as is true with many other salts o aspirin ~potassium, ammonium, lithium, calcium, magnesium, etc.
salts), the sodium aspirin of the prior art is obtained as an unstable compound which decomposes appxeciably even after only several months storage at room temperature. The ; absence of a practical and commercially feasible process for the manufacture of a stable sodium aspirin has prevented the use of this valuable drug in medical practice.

Sodium aspirin has been prepared by a variety of methods. Thus~ aspirin has been reacted with sodium carbon-ate in the presence of small amounts of organic solvents, ~ such as methanol, methyl and ethyl formate, methyl and ethyl ; acetate, and the like. The resulting product is very ~83602 impure and unstable, probably due to the heterogeneousnature of the reaction in which insoluble reactants are converted into an insoluble reaction product. Sodium aspirin prepared by this method fuses after storage for several months with production of considerable amounts of acetic and salicylic acids.

Sodium aspirin has also been prepared by reacting aspirin with compounds such as sodium bicarbonate, sodium ; silicate, etc. in aqueous solution. Whila the reaction is homogeneous, the product cannot be directly isolated from the reaction mixture because of its great solubility in water. Consequently, removal of water by distillation is required. However, not only are such distillations expen-sive and time consuming on a commercial scale, but the sodium aspirin undergoes hydrolysis during the distillation resulting in low yields of an impure product or of poor stability. In order to minimize hydrolytic decomposition during the distillation operation, it has been proposed that the removal of water be conducted at very low temperatures and pressures while maintaining the reaction mixture in the frozen state. This is obviously an expensive~ tedious and impractical process, unsuitable for the production of a low cost product such as an aspirin derivative. Moreover, this process also produces a product of unsatisfactory stability.
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In order to avoid the distillation operation, it has been proposed to react aspirin with sodium bicarbonate in the presence of an extremely small amount of water, just - sufficient to wet the mixture. However, again~ probably because of the heterogeneous nature of the reaction the product obtained is unstable and impure, being contaminated with unreacted aspirin and sodium bicarbonate.

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_5_ 1~8~ 2 In the present invention, a highly concentrated aqueous solution of sodium aspirin is prepared and then treated under such conditions as to cause the sodium aspirin to crystallize in the form of a hydrate. The hydrate is isolated then dehydrated to produce anhydrous sodium aspirin in the form of a stable, free flowing and non-caking particulate solid. Unexpectedly, this pro-duct is obtained in the form of plate-like granular crystals rather than the elongated needle-like crystals of the prior art.
According to the present invention, there is provided a process for the production of anhydrous sodium acetylsalicylate which comprises forming a concentrated aqueous solution of sodium ace~ylsalicylate, precipitating sodium acetylsalicylate dihydrate therefrom in the form of granular plate-like crystals while avoiding the formation of needle-like crystals, separating the dihydrate and removing the water o hydration from the dihydTate to obtain pure anhydrous sodium acetylsalicylate.
Preferably, the process comprises a concentrated aqueous solution of sodium acetylsalicylate containing about 1 to 2.5 parts by weight of sodium acetylsalicylate for each part by weight of water, gradually and thoroughly admixing with said solution a water miscible organic solvent selected form the 3 and 4-carbon saturated aliphatic alcohols and mixtures thereof in the proportion of about 5 to 10 parts by weight of solvent for each part by weight of sodium acetylsalicylate as the sole precipitating agent to precipiate while maintaining the temperature during precipitation between -lOCC and ~10C, separating siid dihydrate, and removing the water of hydration to obtain sub-stantially pure anhydrous sodium acetylsalicylate.
When a water miscible organic solvent such as a lower aliphatic alcohol, is added to an aqueous solution of sodi~ aspirin in accordance with the usual and conventional procedures of organic chemistry, a precipitate of ; sodium aspirin in the form of needle-like crystals is obtained. A typical procedure of this kind is described in Example I.

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. -6-: ;-~31l336~2 EXAMPLE I

A solution of sodium aspirin obtained by reacting 100 g. of aspirin with sodium bicarbonate in the presence of 50 ml. water was mixed with 1,000 ml. of iso-propanol at 5C~ The resulting mixture was refrigerated for 5 hours, the crystalline product filtered, washed with cold isopropanol, then washed with benzene and dried at room temperature.
The yield was 40 g. (35.7% theory~.

The product was in the form of voluminous white needles melting at about 220C. The purity of the product was 99.5% + 0.2%. The analysis as well as the melting point correspond to the anhydrous sodium salt of acetylsalicylic acid. The anhydrous sodium aspirin obtained exhibits all the characteristics of sodium aspirins produced by various methods of the prior art, including instability~
~, , I have discovered that sodium aspirin possessing high storage stability as well as other desirable characteristics ~such as free-flow and non-caking characteristics and ready compressibility) is obtained when this salt is crystallized first in hydrated form and then dehydrated. This is all the more surprising since the intermediate hydrate is an unstable compound which readily breaks down into acetic acid, salic~lic acid and other decomposition products,exhibiting substantial decomposition with 24 hours at room temperature (several per cent).

When a lower aliphatic alcohol such as isopropanol is adcled to a concentrated solution of sodium aspirin with-- out any special precautions, there is produced,as clescribed in Example I above, a voluminous precipitate of anhydrous sodium aspirin in the form of needle-like crystals. ~ow~ver when the same operation is performed in accordance with the special conditions and procedures described by way of illus-tration in detail in Example II, post, there i5 formed a hydrated sodium aspirin which in contrast to the needle-like crystals of Example I, is obtained in the form of granular, free-flowing crystals I have further discovered that the latter product, upon dehydration, produces an anhydrous sodium aspirin differing in its crystalline form and other properties from the anhydrous form obtained directly. This new anhydrous form of sodium aspirin of my invention is a free-flowing solid, in the form of granular plate-like crystals or platelets, exhibiting good stability on storage and is readily compressible into tablets and other dosage forms.

In the operation of my process, I prefer to use as a solvent~ a C3 or C4 aliphatic alcohol such as propanol, isopropanol, butyl alcohol, isobutyl alcohol, or tertiary butyl alcohol, or mixtures of any of these. Generally, isopropanol is a useful, inexpensive and preferred solvent.
The solvent may readily be recovered for re-use by distilla-tion.

I have further discovered that the yield of sodium aspirin is very substantially increased when the process of my invention is used over that obtained when the anhydrous form is produced directly as described in Example I.
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The method used for the preparation of the con-centrated aqueous solution of sodium aspirin employed as a starting material in the practice of my invention is im-material. Aqueous solutions of sodium aspirin may be pre-pared by ~reating aspirin with neutralizing agents such as sodium hydroxide, sodium carbonate and sodium bicarbonate.
Due to the high alkalinity of the first two agents and re-sulting extensive hydrolysis, sodium bicarbonate is the preferred neutralizing agent.

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EXAMPLE II

A solution of sodium aspirin obtained by reacting 100 g. aspirin with sodium bicarbonate in the presence of So ml. water was cooled to 5C and 1,000 ml. of isopropanol added slowly with stirring and cooling. The rate of addi-tion of the alcohol was about 300 ml. per hour, the rate of stirring about 60 RPM, and the temperature was maintained at 5C. The resulting crystalline precipitate was separated by filtration~ washed with cold isopropanol followed by benzene, and then dried at room temperature.
Yield: 103 g. (7~/0 theory).

The purity of the product was 99.5% ~ 0.2% and it was obtained in the form of heavy granular, free-flowing crystals. Analysis showed that the product contained 15%
water of crystallization, corresponding to sodium aspirin dihydrate.

EXAMPLE III

The procedure of Example II was carried out except that 1,000 ml. o tertiary butyl alcohol was added slowly with stirring and cooling to maintain a temperature of about 5C. The resulting granular, plate-like dihydrate crystalline precipitate was separated, washed with cold tertiary butyl alcohol, followed by benzene and dxied at room temperature. The yield was 99 gms. (75% theory).
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The melting of the dihydrate was characterized by the followi~g behavior. As the temperature of the di-hydrate was raised rapidly, the compound shrank over the temperature range 20C, to about 105C~, and gradually became wet. It melted at about 125C then resolidified in the range of 140-150C, there being no furthel~ apparent change from 150 to 250C.

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The dihydrate is somewhat unstable and undergoes substantial decomposition into salicy:Lic acid, acetic acid and other compounds on standing for more than a few hours at room temperature, and decomposes even more r~pidly at higher temperatures. For this reason, it is advisable to promptly separate the hydrate and carry out the dehydration to the anhydrous form.

The above examples show that the anhydrous acicular form and hydrated sodium aspirin are formed under closely similar conditions; only a slight variation in the operating conditions will produce either the anhydrous compound or the dihydrate. It is helpful although not absolutely necessary, to seed the reaction mixture with a crystal of the hydrated salt when the latter form is desired.

To produce the hydrated form of sodium aspirin, particularly to secure this product in high yield, careful control must be exercised over operating variables. In the first place, the aqueous solution of sodium aspirin employed as the starting material must be highly concentrated so the ~0 liquid portion of the reaction mixture obtained at the con-; clusion of the operations described in Examples II and III
has a very low content of free water. If this precaution is not observed, the recovery of hydrated sodium aspirin is very materially reduced due to the solubility thereof in solvent containing appreciable amounts of water. On the other hand, the initial aqueous sodium aspirin solution abviously must provide sufficient water to form the di-hydrate of the sodium aspirin it contains during the cour~e of the subsequent operations. As will be seenV thle aqueous sodium aspirin solution of Examples II and III contains about 2.5 times the stoichiometric requirement of water for ~08~60;Z
the dihydrate forming reaction, thus, providing more than sufficient water for completion of thls r~acti~n, but at the same time resulting in a final reaction mixture contain-ing appreciably less than 5% free water.

Also, to secure sodium aspirin in hydrated form, it is advantageous to maintain other operating variables essentially as described in Example II when operating on a similar scale.

r~he concentration of the aqueous sodium aspirin -starting solution employedJ the amount of isopropanol em-ployed, the rate of addition of this alcohol, the temperature maintained during the addition of isopropanol or other sol-vent, and the rate of stirring, all as set forth in Example II, have been found by experiment to be an advantageous combination of operating variables from a practical stand-point.

These amounts and conditions while preferred how-ever, are not critical for the successful practice of my invention. Thus, lowering the temperature of isopropanol or other solvent, addition to -15C., does not substantially increase the yield of hydrated sodium aspirin. It has also been found that increasing the amount of isopropanol to more than 10 parts per part of aspirin also does not sub stantially affect the yield, whereas a significant drop in :~.
- yield is observed when this ratio is lowered materially i~
~ below 5 parts by weight for each part by weight of aspirin.
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In general however, the best results obtained is by utilizing a concentrated sodium aspirin solution con-taining about 1 to 2.5 parts of sodium aspirin by weight for each part by weight of water, with a preferred concen~ra--tion of 0.4 to 0.6 parts of water for each part of sodlum aspirin~recipitation of sodium aspirin dihydrate is generally ~336~Z

obtained using at least several parts of solvent by weight for each part by weight of sodium aspirin within the range of about 5-10 parts of solvent for each part of sodium aspirin, with greater excess not contributing greatly to the process~ but undesirable only from the standpoint of economics of recovery. The temperature at which precipi-tation may be carried out will range from the freezing point of the solution to room temperature, and preferably, between about -10C and +10C.

Within certain limits~ the rate of addition o solvent as well as the rate of stirring shown in Example II are also not critical. It is to be noted however, that rate of addition of isopropanol and rate of agitation are closely inter-related. Thus, at a given rate of agitation the addition of isopropanol must be so adjusted as to pre-vent formation of the acicular anhydrous salt. Formation of this anhydrous salt is readily detected by direct visual examination of a sample of the mixture., The presence of needle-like crystals indicates production of anhydrous salt, thus re~uiring for the selected rate of agitation a slower rate of addition of the alcohol. As will be obvious to those skilled in the art, the relative rates of addi-tion and stirring will vary, depending upon the size of the batch, type of equipment used, and mechanical factors in-volved. Thus, these factors can be predetermined or con- ~ r trolled during production so as to avoid formation of the needle-like crystals.
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Additionally, rate of stirring exhibits another quite independent effect. Rate of stirring has a direct ~ 30 effect on the si2e of the crystals formed; the slower the - rate of stirring, the larger the crystals, and vice-versa.
It is often desirable that crystals of a certain size be ~8;~60Z

prepared since this factor affects flow characteristics of the dehydrated product as well as its suitability and convenience in the preparation of dosage forms such as tablets.

The previous ~xamples show that although the quantities of the reactants are identical in both, the yield is more than twice as high when the product is precipitated in the form of the hydrate followed by dehydration9 than when the anhydrous form is produced directlyg undoubtedly `~
due to the lesser solubility of the hydrate in the final reaction medium.

The sodium aspirin dihydrate of this invention may be readily converted to anhydrous sodium aspixln by removing the water of hydration by heating in vacuum at moderate temperatures, such as in the range o 20-50C.
There is thus obtained from 100 g. of the hydrate, about 85 g. of pure anhydrous salt, melting at about 220C.

It is possible to convert needle-like anhydrous crystals of sodium aspirin of the prior art to the new granular form of anhydrous sodium aspirin of this invention by first hydrating the needle-like anhydrous crystals fol~
lowed by dehydration. This procedure is illustrated in the following Example.
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~ . _ 100 g. of anhydrous sodium aspirin o the needle-like crystalline orm were dissolved in 50 ml. water~ cooled to 5C, and then treated with isopropanol exactly as des-cribed in Example II. After filtratior o the crystalline 3L~836~2 precipitate which was the dihydrate, washing, and dehy-dration to remove water of hydration, there was obtained about 75 g. of a product possessing the granular anhydrous crystalline form of the sodium aspirin of this invention.
The purity of the product was 99.5% + 0.2%.

The anhydrous salt of this invention differs in several important respects from the anhydrous salts pre-pared by prior art procedures or the product described in Example I. ~he great difference in gross physical appearance between the anhydrous sodium aspirin of this invention and the sodium aspirin prepared in accordance with Example I
is apparent on visual examination due to the difference in appearance between plate-like and needle-like crystals.

Of greatest practical importance is the fact that the stability of the product of this invention is sufficient-ly high for all practical purposes. Kept at room temperature, in a closed vial for one year, the extent of the decomposition r is uniformly less than 3.5~u r The anhydrous sodium aspirin of this invention is a free-flowing, non-caking, granular mass of plate-like crystalline habit. These free-flowing, non-caking granular platelets are directly and Pasily compressible into pharma-ceu'tical tablets and similar unitary dosage forms exhibiting good stability on storage. This had not been found to be true in the case of the needle-like crystals of the prior art, which require preliminary grinding and compacting ~e-fore compression which leads to contamination and loss of stability.

1~836(~2 As is customary in the preparation, handling and storage of hygroscopic products, prevention of accumulation of moisture during these aspects is desirable. -In the compounding and formulation of the anhydrous plate-like crystals of sodium aspirin, conventional proce-dures and ingredients may be used. The crystals may be compressed into tablets along with binders, carriers, exci-pients and buffering agents such as calcium carbonate, magne-sium carbonate, magnesium stearate, aluminum hyclroxide, a-luminum glycerate and the like. The high stability and solubility of the crystals permits the formation of almost tasteless solutions so that in use the crystals or efferves- ~ ;
cent tablets formulated therefrom can be dissolved in water and administered in liquid form rather than as tablets.
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Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the production of anhydrous sodium acetylsalicylate which comprises forming a concentrated aqueous solution of sodium acetylsalicy-late, precipitating sodium acetylsalicylate dihydrate therefrom in the form of granular plate-like crystals while avoiding the formation of needle-like crystals, separating the dihydrate and removing the water of hydration from the dihydrate to obtain pure anhydrous sodium acetylsalicylate.

2. A process for the production of pure stable anhydrous sodium acetyl-calicylate in the form of plate-like crystals, which comprises forming a con-centrated aqueous solution of sodium acetylsalicylate, gradually adding an excess of a water miscible organic solvent at a rate such as to avoid the formation of needle-like anhydrous crystals of sodium acetylsalicylate to precipitate plate-like crystals of sodium acetylsalicylate dihydrate, dehydrating the dihydrate to obtain the sodium acetylsalicylate crystals in the anhydrous state.

3. A process of production of anhydrous sodium acetylsalicylate in the form of plate-like crystals which comprise forming a concentrated aqueous solution of sodium acetylsalicylate containing about 1 to 2.5 parts by weight of sodium acetylsalicylate for each part by weight of water, gradually and thoroughly admixing with said solution a water miscible organic solvent selected from the 3 and 4-carbon saturated aliphatic alcohols and mixtures thereof in the proportion of about 5 to 10 parts by weight of solvent for each part by weight of sodium acetylsalicylate as the sole precipitating agent to precipitate while maintaining the temperature during precipitation between about -10°C and +10°C, separating said dihydrate, and removing the water of hydration to obtain substantially pure anhydrous sodium acetylsalicylate.

4. A process according to claim 3 wherein the solvent is isopropyl alcohol.

5. A process according to claim 3 wherein the sodium acetylsalicylate is dissolved in 0.4 to 0.6 parts by weight of water, wherein the solvent is isopropanol and wherein said solvent is added in the proportion of at least 5 parts by weight for each part by weight of sodium acetylsalicylate.

6. Anhydrous sodium acetylsalicylate in the form of granular plate-like crystals exhibiting high storage stability, superior dry flow characteristics and ready direct compressibility, whenever prepared by the process according to claim 1, or an obvious chemical equivalent thereof.

7. Pure stable anhydrous sodium acetylsalicylate in the form of plate-like crystals produced by precipitation of plate-like crystals of sodium acetylsalicylate dihydrate from a concentrated aqueous solution of sodium acetylsalicylate by the gradual addition of an excess of a water miscible organic solvent at a rate such as to avoid the formation of needle-like an-hydrous crystals thereof, followed by dehydration of the dihydrate to obtain the sodium acetylsalicylate crystals in the anhydrous state, whenever prepared by the process according to claim 2, or an obvious chemical equivalent thereof.

8. Pure stable anhydrous sodium acetylsalicylate in the form of plate-like crystals whenever prepared by the process according to claim 3, or an obvious chemical equivalent thereof.