HU198440B - Process for producing stabil christalline sodium-acetyl-salicilate - Google Patents

Description

The present invention relates to a process for the preparation of crystalline sodium acetyl salicylate which is stable over time at room temperature.

The most widely used analgesic and anti-inflammatory drug is aspirin, which is used to treat arthritis and relieve pain. However, aspirin, also known as acetylsalicylic acid, also has unwanted side effects. These include irritation of the gastric mucosa, stomach ache and hypersensitivity, which are caused by the acidity and poor solubility of aspirin in water. After ingestion, aspirin tablets disintegrate, often leaving insoluble particles that can settle and irritate the stomach lining. Many people who take aspirin suffer from stomach pain due to the irritation caused by the usual form of aspirin. Acetamylnophen (currently called Tylenol or Datril) is sometimes used to prevent stomach pain instead of aspirin, but it has no anti-inflammatory effect. Patients with arthritis who have inflammation but who, because of their sensitivity, cannot take aspirin, must take other, more potent, drugs that are generally less accepted from a medical perspective.

Numerous attempts have been made to eliminate the side effects of aspirin. Many buffered aspirin formulations are available, such as those available under the names Bufferin, Excedrin and Anacin. While these formulations neutralize some of the stomach acid, they do not remotely dispel the insoluble aspirin particles that cause the underlying problem, which causes irritation of the gastric mucosa.

Aspirin can be processed into enteric coated tablets, but such formulations only displace the site of irritation, in which case there is irritation of the duodenum or the mucosa of the digestive tract where the tablets disintegrate. In addition, the enteric coating delays the desired effect of aspirin and there is always the risk that aspirin will be released in the stomach early due to the puncture of the enteric coating.

They are more effective like Alka-Seltzer, which, when in contact with water, produces a soluble form of aspirin that is easily processed by the body and consequently does not cause local irritation. The way in which such formulations achieve this goal is not very effective. For example, large amounts of sodium bicarbonate and citric acid are used, which can increase the weight of aspirin to ten times or more. The analgesic dose of such formulations is relatively expensive, inconvenient to wait for the chemical reaction to complete, to consume relatively large amounts of sodium ions, and to produce gas in an amount that causes bloating. Therefore, patients with arthritis or patients with chronic arthritic pain and inflammation will practically never take these products.

The aspirin sodium salt formed upon dissolution of Alka-Seltzer in water could be a suitable analgesic by itself, if such aspirin could be separated from excess hydrogen carbonate and converted into suitable dosage units such as tablets, but these goals are very difficult to achieve problems occur. Thus, it is relatively easy to prepare sodium aspirin in aqueous solution, but it is difficult to remove water to obtain solid sodium aspirin. This is because the acetate group of sodium aspirin tends to hydrolyze and thus, during the delutation, an undesirable amount of sodium salicylate and other non-aspirin compounds are formed. Since sodium aspirin, which is free of said by-products, cannot be reclassified, the product is not acceptable for medical purposes.

Over the years, attempts have been made to produce a stable, non-acidic analgesic, water-soluble aspirin derivative on an industrial scale. Such a derivative would have important advantages over aspirin itself. For example, it could also be administered in aqueous solution to patients who are unable to swallow tablets, are more readily absorbed by the body, and are less likely to cause gastrointestinal disturbances that would otherwise be due to the known acidity and poor solubility of aspirin,

Among the many possible aspirin derivatives, the sodium, calcium, potassium, lithium, ammonium, magnesium and amino acid salts, the urea calcium salt complex and the like have been prepared. These compounds are normally not sufficiently stable when stored for prolonged periods, it seems that because the carboxylate group renders the acetyl group sensitive to hydrolysis and decomposition. Thus, such compounds are rapidly degraded during storage and many undesirable by-products such as salicic acid and acetic acid are formed.

On the other hand, the aspirin salts, especially the aspirin sodium salt, are much more soluble and more effective and generally do not exhibit the aforementioned undesirable side effects. Aspirin sodium can be prepared in many ways, such as by reacting aspirin with sodium carbonate in the presence of a small amount of an organic solvent, such as methyl or ethyl formate, methyl or ethyl acetate or the like. However, the resulting product is contaminated and unstable, probably due to the heterogeneous reaction. The sodium aspirin thus produced is fused to form acetic acid, salicylic acid and their salts for extended storage. Aspirin sodium can also be prepared by reacting aspirin with sodium bicarbonate in aqueous solution. However, due to its high solubility, the product is difficult to separate from solution and must be recovered by distillation or crystallization. Distillation has a number of obvious disadvantages, most obviously the cost of energy, impurities cannot be removed and aspirin sodium tends to undergo hydrolysis during the distillation process, resulting in a low yield of contaminated, poorly soluble product.

Granular, sheet-like, crystalline aspirin sodium crystals have been prepared according to U.S. Patent 3,985,792 by precipitation of the compound from an aqueous solution and removal of the hydration water. Although the process provides good laboratory scale, industrial scale production requires is to improve the procedure.

According to the present invention, the above difficulties are solved by preparing an aspirin sodium solution by reacting aspirin and sodium bicarbonate in water containing from 3 to 5 carbon atoms aliphatic alcohol, preferably distilled or deionized water. Aspirin sodium is obtained from the solution by crystallization at a reduced temperature in the form of sheet-like di-hydrate crystals, while sheet-seeded crystals obtained from one of the previous batches or prepared separately are occasionally added to the solution to facilitate crystallization of the dihydrate. When crystallization is complete, the crystals are separated from the mother liquor and carefully dried in a fluid bed granulator.

Figure 1 is a schematic view of an apparatus for the preparation of aspirin sodium.

Figure 2 is a schematic diagram of a commercially available fluid bed dryer for aspirin sodium dihydrate, which provides a stable, anhydrous aspirin sodium dihydrate.

A preferred embodiment of the process of the invention is as follows:

The first step in the process is the preparation of aspirin sodium dihydrate. In this step, pharmacopoeial aspirin of about 400 to 500 μm particle size is reacted with 515%, preferably 7-14% excess sodium bicarbonate relative to the stoichiometric amount in the presence of about 0.4 0.45 liter of water per kg of aspirin. It contains from 15 to 20% by volume, preferably from 17 to 20% by volume, of a C3 to C5 alcohol, preferably isopropyl alcohol. After completion of the reaction, additional alcohol (1.7 L / kg aspirin) was added to the reactor and the reaction mixture was stirred for several minutes. Unreacted hydrogen carbonate is filtered off and the filtrate is transferred to the crystallizer.

The reaction can also be carried out directly in the crystallizer of the type shown in Figure 1. The crystallizer 10 is provided with an anchor or paddle mixer 11 driven by a variable speed motor (not shown) mounted on the drive shaft 12. The baffles 13 must be such as to prevent the liquid from being injected onto the crystallization wall, which would otherwise produce undesired needle-shaped (non-hydrated) crystals. The solution is stirred slowly and the crystallizer is cooled to about 6 ° C using the cooling jacket 14. The temperature is controlled by the thermocouple 15. When the solution reaches this temperature, about 0.05% (v / v) of a slab (dihydrate) seed crystal suspension (obtained from a previous preparation or prepared as a separate suspension) is added. It is important that there is no needle-like crystal between the seed crystals. The cooler was maintained at 0 ° C. A similar amount of seed crystal is added periodically while the crystallization is proceeding, and additional isopropyl alcohol is added to complete the crystallization.

In the second step of the process, the crystals are separated from the mother liquor, preferably in a basket centrifuge. The crystals were washed with 5% (v / v) distilled or deionized water in isopropyl alcohol.

In the next step, the asplrin sodium dihydrate crystals taken from the centrifuge are transferred to a fluid bed dryer (1100 liters), shown in Figure 2, which has been converted to add the crystals. The crystals are introduced through the funnel 21 into the dryer 20 with the container 24 in a quantity of about 400-500 kg, preferably 450-475 kg, in about half an hour. Air is introduced into the inlet 22 at such a rate as to maintain the crystals in a fluid state, the air temperature at the inlet being preferably as low as possible to maintain the outlet temperature at outlet 23 such that the relative humidity at exit is 60%. below. This depends on the relative humidity of the outside air, but generally the initial temperature should be around 35 ° C. When the isopropanol is evaporated, the inlet air temperature is raised to 60 ° C, and the outlet air temperature is close to 60 volts. Drying is continued until the water content of the product is below 0.3% by weight.

The invention is illustrated by the following examples.

Example 1

This example illustrates the preparation of seed crystals to be added to the crystallizer.

Anhydrous aspirin sodium (LSO) grade g is dissolved in a mixture of 2.5 g water and 7.5 g isopropyl alcohol and stored in a refrigerator at about 4 ° C until crystals form. Λ Sheet crystals without needle crystals can be used to inoculate a laboratory-sized batch to produce an appropriate amount for industrial-scale production.

Example 2

841 kg of Pharmacopoeia (USP) grade aspirin in 420 µl of water containing 377 liters of 65 liters of isopropylalkiolol were reacted with 420 kg of Pharmacopoeia (USP) grade sodium bicarbonate. After completion of the reaction, 1400 L of isopropylalkobol are added and stirring is continued for several minutes. The mixture was then filtered and the filtrate transferred to a crystallizer of the type shown in Figure 1.

The crystallizer 10 is equipped with a variable speed motor-driven agitator blade 11 and is provided with a liquid cooling jacket 14 to facilitate crystallization. The baffle plate 13 is located on the side of the crystallizer. A thermocouple is attached to the crystallizer in the case 15 to record the temperature as the crystallization proceeds. After the solution is added to the crystallizer, the agitator is moved at about 15 rpm to prevent the liquid from sticking to the walls. Coolant at about -20 ° C was introduced into the crystallization jacket and the solution was cooled to 6 ° C. When this value is reached, 0.67 liters of seed crystal suspension from the previous production is added to the crystallizer and slow stirring is continued for about half an hour. When the temperature reaches 3 ° C, an additional 0.67 L of seed crystal suspension is added, if crystallization has not yet begun. After half an hour or when the temperature reaches 0 ° C, an additional 0.67 liter of seed crystal suspension is added, if necessary, and stirring is continued at 0-2 ° C until crystallization is apparent, at which time an additional (4750 liters) is obtained. isopropyl alcohol is added and the temperature is lowered to -10 to 15 ° C to optimize crystallization.

After the crystallization is complete, the suspension is centrifuged in a basket centrifuge to separate the crystals from the supernatant liquid. The crystals are washed with 50 L portions of isopropyl alcohol containing about 5 volumes of distilled water in the centrifuge. Wash is continued until the centrifuge cake contains less than 0.1% by weight of salicylate as determined below. Transfer 50 mg of the cake to be examined into a Nessler color comparison test tube (manufactured by Scientific Glass CO, C-6535, length: 154 mm, internal diameter: 19 mm, external diameter: 22 mm), followed by 20 ml of water and 4 drops of glacial acetic acid. and then 8 drops of an iron (III) solution prepared by dissolving 1 g of iron salt in 200 ml of water containing 1 ml of concentrated hydrochloric acid. Another Nessler test tube was charged with 20 ml of water, 4 drops of glacial acetic acid and 8 drops of ferric salt solution. The latter test tube is shaken by adding dropwise a quantity of 0,1% standard salicylate solution (prepared by dissolving 1 g of salicylic acid in 1000 ml of water) so that, when viewed from the side, it does not have the same color as the white background. first solution in a Nessler test tube. (One drop of the 0,1% solution corresponds to 0,05 mg of salicylic acid.) The concentration of the test solution should be adjusted to a maximum of

6-7 drops of salicylic acid solution should be used, otherwise the color is too deep for comparison. The test takes up to 5 minutes. As aspirin sodium is hydrolysed in water, the test should be performed as quickly as possible.

Example 3

This example shows drying.

Drying is carried out in a commercial Glatt WDG-UD 300 with a 1100 liter tank capacity. The dryer is modified as shown in Figure 2. The dryer 20 is fitted with a funnel 21 so that the material can be continuously fed into the drying chamber. The product container 24 is placed in the chamber and the material is fed from the centrifuge into the dryer. In about half an hour, a total of 465 kg of crude centrifuge cake is introduced into the dryer. The material is metered through the addition funnel so that the nozzle is open and the damper is positioned so that the material can be drawn into the chamber and fluidized. The dryer is operated in this way because besides the 15.1% hydration water in the molecule, the crystalline material is wetted by about 5-6% isopropyl alcohol and 0.5% water. By adding the crystals in half an hour, it is avoided that the concentration of isopropyl alcohol in the dryer may reach the explosion limit.

The temperature of the air entering the dryer is maintained at the above-mentioned value to prevent hydrolysis of the product. When the isopropyl alcohol is completely evaporated, increase the inlet air temperature to 60 ° C. When the outlet air temperature reaches 60 ° C, a material sample is taken and the vf content is determined. The dryer is operated at 60 ° C until the water content of the sample taken from the container is less than 0.3%. The dryer is then turned off and the material is removed. '

The stability of the sodium acetyl salicylate prepared by the process of the present invention is illustrated by the following assays.

Tablets are prepared from the product of the present invention having the following composition: A: 80.0% sodium acetylsalicylate;

10.01% poly (ethylene glycol) 8000,

8.5% by weight of calcium hydrogen phosphate,

1.5% hydrogenated vegetable oil (Sterotex, manufactured by Capitol City Products, Columbus, Ohio),

B: 80.0% sodium acetylsalicylate, 0% polyethylene glycol) 8000,

8.5% by weight of anhydrous lactose,

2.5% hydrogenated vegetable oil. For comparison, tablets were prepared according to the method described in U.S. Pat

U.S. Patent No. 792, prepared by the procedure described in U.S. Patent No. 792. Tablets that have the following composition need to be given a disintegrant (cellulose) to disintegrate the tablet within a reasonable time:

C: 82.3% sodium acetylsalicylate,

8.0% microcrystalline cellulose (PVP XL),

7.01% crystalline cellulose (Avicel ph 101),

1.0% stearic acid,

1.0% silicon dioxide (Syloid 72),

D: 80.0% sodium acetylsalicylate,

19.7% crystalline cellulose,

0.3% by weight magnesium stearate. '

The tablets were stored at 25, 37 and 40 ° C and then determined by liquid chromatography (HPLC) to determine the salicylic acid content of the tablets (running time: acetonitrile-water-formic acid = 36-65-02, flow rate 1.5 ml / min, spectrophotometric evaluation). 280 nm (cn). The results are shown in the table below.

test (month) storage (° C) Salicylic acid content (Wt%) THE, 1 40 1.4 2 40 1.7 3 40 2.5 B 1 40 2.0 2 40 2.3 3 40 3.3 C. 1 40 8.2 1 37 8.1 2 25 6.6 D. 1 40 19.9 1 37 27.4

The results illustrate that the tablets containing the active ingredient according to the invention have a significantly higher stability than the tablets containing the active ingredient in the known manner, but also that they are rapidly disintegrated without the addition of a disintegrant.

Claims (5)

Claims A process for the preparation of stable, crystalline sodium acetyl salicylate in the form of sheet crystals by reacting acetyl salicylic acid and sodium bicarbonate in water containing aliphatic alcohol, precipitating sodium acetyl salicylate from the aqueous reaction mixture and removing the vfe. e) by reacting the acetyl salicylate and sodium bicarbonate in water containing 3 to 5 carbon atoms with a solution of aqueous sodium acetyl salicylate4 A solution of 198.440 was prepared, the solution was cooled to 0 ° C in the presence of plate-seeded sodium acetylsalicylate seed crystals, the solution was added to the solution, the crystals were separated from the supernatant and the resulting plate-dried water is removed. 2. A process according to claim 1, wherein the preparation of sodium acetylsalicylate is carried out by stoichiometric amounts of sodium hydrogen hydrogen in the presence of 10 to 20 volumes of distilled water containing 3 to 5 carbon atoms of alcohol. with carbonate. 3. The process according to claim 2, wherein the acetylsalicylic acid has a particle size of 400-500 μg and is reacted with a stoichiometric amount of 5 to 15% more sodium bicarbonate per kg of acetylsalicylic acid. , 4 in the presence of 0.45 liters of distilled water containing 15 20% isopropyl alcohol. 4. The process of claim 1, wherein the crystals are separated from the mother dilution by centrifugation. 5. The process of claim 1, wherein the crystals separated from the mother liquor are dried by intermittently feeding them in a fluid bed dryer, passing air at 35 ° C until the isopropyl alcohol is completely evaporated, and then drying the air at drying temperature. until completion 55 to 60 ° C.