EP0297107A4

EP0297107A4 - Production of stable crystalline sodium acetylsalicylate.

Info

Publication number: EP0297107A4
Application number: EP19870901924
Authority: EP
Inventors: Fred P Ducatman
Original assignee: Pharmacontrol Corp
Current assignee: Pharmacontrol Corp
Priority date: 1986-02-20
Filing date: 1987-02-20
Publication date: 1989-06-14
Also published as: AU7122187A; HUT46883A; CA1293738C; EP0297107A1; ZA871148B; HU198440B; WO1987005010A1; CN86102837A; CN1020895C

Abstract

A process for preparing sodium acetylsalicylate (sodium aspirin) in the form of plate-like crystals by preparing a solution of sodium aspirin, transferring the solution to a crystallizer, agitating the solution while cooling the crystallizer, intermittently adding seed crystals as crystallization progresses, separating the crystals from the mother liquor, and drying in a fluid bed dryer.

Description

PRODUCTION OF STABLE CRYSTALLINE SODIUM ACETYLSALICYLATE

1. 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, 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 effect 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. More effective are compositions similiar 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 are 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 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 of 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 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 gastro-intestinal 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 oridnary 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 salicyclic acids and their salts. Sodium aspirin can also be prepared by 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, the disclosure of which is incorporated herein by reference, 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 dihydrate 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 dihydrate. When the crystallizaion is complete, the cystals are separated from the mother liquor and are dried under careful conditions in a fluidized bed granular dryer.

4. DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic view of the type of apparatus used for the preparation sodium aspirin. Fig. 2 is a schematic view of a type of commercially available fluid bed dryer for drying the sodium aspirin dihydrate to form a stable, anhydrous sodium aspirin.

5. THE DESCRIPTION OF THE PREFERRED EMBODIMENTS

5 The first step in the process of the present invention is the preparation of sodium aspirin as the dihydrate. In this step, a quantity of USP grade aspirin powder, preferably having a particle size of about 400 to 500 microns (35 to 40 mesh) is reacted with a 5 to 15% 0 stoichiometric excess, preferably a 7 to 14% excess, of sodium bicarbonate in the presence of a quantity of water equal to about 0.4 to 0.45 liter per kilogram of aspirin. This water contains from about 15 to 20 volume percent, preferably about 17 to 20 volume percent, of an alcohol 5 having 3 to 5 carbon atoms, preferably isopropyl alcohol. When the reaction is complete, an additional quantity (1.7 liters per kilogram of aspirin) of alcohol is charged to the reactor and the reaction mixture is agitated for several minutes. The unreacted bicarbonate is filtered off and the o filtrate is charged to a crystallizer.

The reaction can also be carried out directly in a crystallizer of the type shown in Fig. 1. The crystallizer 10 is equipped with an anchor or paddle-type agitator 11 driven by a variable-speed motor (not shown) atop drive ₅ 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 0 stirred slowly and the crystallizer is cooled to approximately 6^*C 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 5 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 0^βC. Similar 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 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 35*C. When the isopropyl alcohol has evaporated, the temperature of the inlet air is increased to 60^#C and the temperature of the outlet air approaches 60*C. 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 nonli iting examples.

5.1 Example 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 4^βC 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 dihydrate 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 to the reaction mixture and stirring was continued for several minutes. The mixture is then filtered and the filtrate is introduced into a crystallizer 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 crystallizer, the 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 -20*C is fed to the jacket of the crystallizer and the solution is cooled to 6'C. When this temperature is reached, 0.67 liter of a slurry of seed crystals from a previous batch is added and slow agitation is continued for approximately one-half hour. When the temperature reaches 3*C, an additional 0.67 liter of seed slurry is added if crystalization has not already begun. After one half hour, or when the temperature reaches O'C, an additional 0.67 liter of seed slurry is added if necessary and agitation is continued at 0^βC to 2"C until crystallization is apparent, whereupon an additional quantity (47501) isopropyl alchol is added and the temperature lowered to between -10* to -15*C to optimize the crystallization.

When the crystallization is complete, the slurry is centrifuged in a basket-type centrifuge to separate the crystals from the supernatent liquor. The crystals are washed in the centrifuge with 50-liter quantities of a mixture of isopropyl alcohol 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: 19mm, 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 HC1. In another, identical Nessler tube are placed 20 ml water followed by 4 drops of glacial acetic acid and then 8 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 is 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. 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 1100-liter bowl capacity. The dryer was modified in the manner shown in Fig. 2. The dryer 20 is 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 5 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.

Claims

6. CLAIMS I claim:

1. A process for producing stable crystalline sodium acetylsalicylate in the form of platelet crystals, comprising the steps of: a) forming sodium acetylsalicylate in aqueous solution by reacting USP aspirin with USP sodium bicarbonate in water containing an alcohol having 3 to 5 carbon atoms in the molecule; b) cooling the solution to O'C in the presence of sodium acetylsalicylate platelet seed crystals to precipitate the sodium acetylsalicylate formed in step (a) in the form of platelet crystals of dihydrate; c) adding isopropyl alcohol to the solution in step (b) to optimize the crystallization; d) separating the crystals obtained in step (b) from the supernatent liquid; and e) drying the sodium aspirin dihydrate platelet crystals obtained in step (c) in a fluidized bed dryer to remove the water of hydration. 2. The process according to claim 1 wherein the sodium aspirin is prepared by reacting USP aspirin with a slight stoichiometric excess of USP grade sodium bicarbonate in the presence of distilled water containing about 10 to 20 volume percent of an alcohol having 3 to 5 carbon atoms in the molecule.

3. The process according to claim 2 wherein the USP aspirin has a particle size of 400 to 500 microns and is reacted with a stoichiometric excess of 5 to 15 percent USP sodium bicarbonate in the presence of a quantity of distilled water containing from about 15 to 20 percent of isopropyl alcohol, in an amount equal to 0.4 to 0.45 liter per kilograms of aspirin.

4. The process according to claim 1 wherein the crystals are separated from the mother liquor in^'step (c) by centrifugation. 5. The process according to claim 1 wherein the crystals separated from the mother liquor are dried in step (e) by being fed intermittently into a fluid bed dryer while passing air at a temperature approximately 35*C through the dryer until the evaporation of the isopropyl alcohol is completed and then increasing the air temperature to about 55'C to 60*C until the drying is completed.