JP2002212140A - Injectable sodium acetylsalicylate and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an injectable sodium acetylsalicylate that has high purity and stability and is suitably useful as a subcutaneously injectable medicine and provide a method of producing anhydrous sodium acetylsalicylate, too. SOLUTION: This anhydrous sodium acetylsalicylate is formed by removing steam from the dihydrate form of sodium acetyl-salicylate at the same rate as that when the anhydrous form is formed. The resultant sodium actylsalicylate can be stored at least for 2 or 3 years and shows high purity as much as 97-100% even after 3-year storage at room temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates generally to aspirin compositions, and in particular, to new and useful aspirin compositions, which can be administered to mammals by subcutaneous injection, to produce such compositions. Methods and the use of such compositions.

Aspirin is the most widely used drug worldwide. It has many important uses in medicine, and is a valuable analgesic, antipyretic, and heart attack preventive.

[0003] Aspirin is also the most potent anti-inflammatory agent and a major drug for the treatment of arthritis. It stimulates the immune system, reduces opportunistic infections, and reduces cancer, A
It is very useful as an aid in the treatment of IDS and other immunodeficiencies. It is also promising in the treatment of Alzheimer's disease and is also used in the treatment of rheumatic fever, gout and cataract, and relieves pain from tendinitis, headache, back pain, muscle pain, and other disorders. In particular, acetaminophen and ibuprofen exert a special analgesic effect in migraine in a state where they show no activity at all. No other drug in the history of medicine has this set of multifaceted therapeutic properties.

[0004] Aspirin is widely used as an anti-inflammatory agent, despite the fact that it is in fact a major drug in arthritis-a disease directly caused by inflammation because of the large dose when administered orally. Not. In fact,
Its use in arthritis is almost always limited to pain relief, for which a dose of 325-500 mg is sufficient. To be an effective anti-inflammatory agent, doses of over 5,000 mg aspirin per day are required. When administered orally at such levels, large amounts of undissolved aspirin adhere to the gastrointestinal mucosa and greatly promote local irritation and side effects.

[0005] Anesthetics are often used to control the pain of arthritis. However, anesthetics are addictive, can suppress respiration, and can cause serious side effects such as osteoporosis, duodenal ulcer, convulsions, high blood pressure, and allergic reactions. However, steroids are also often used for treating arthritis and controlling pain. However, one or both of these can cause serious side effects such as anesthetic poisoning, duodenal ulcer, convulsions, high blood pressure, and allergic reactions.

[0006] Clearly, the advantages of injectable forms of aspirin have great pharmaceutical potential. For example, it has been shown that the efficacy of aspirin injected directly into the spinal column of a patient is 100-500 times greater than orally administered aspirin. Injectable forms of aspirin thus provide a non-toxic, safe alternative to steroids and anesthetics commonly used to treat arthritic or injured joints today I do. Injectable aspirin could also be used for post-surgical measures to control pain, fever, and inflammation. Aspirin is as effective as morphine without the side effects of anesthesia and is therefore promising in treating pain in cancer treatment. Injectable aspirin could be used in sports medicine and veterinary medicine. That is, the present invention can be widely applied to mammals.

[0007] The FDA imposes severe restrictions on the basic pharmaceutical purity for compositions suitable for use in subcutaneous injection administration. Thus, it can be expected that approval of such an acceptable subcutaneous injectable aspirin composition will require a high level of purity and considerable stability at ambient temperatures during prolonged storage.

Among the soluble compounds of aspirin that have potential use (eg, sodium and potassium), the most promising injectable salt is sodium acetylsalicylate. It is non-toxic, basically neutral, readily soluble in water, and can coexist with serum in the blood.

However, it has not been possible to prepare sodium acetylsalicylate having a purity and stability suitable for injection. Sodium acetylsalicylate prepared according to the prior art is unstable and degrades during storage.

For example, the sodium acetylsalicylate composition described in US Pat. No. 3,985,792, which is incorporated herein by reference in its entirety, reacts aspirin with sodium bicarbonate in water to form an organic polar compound. Isolate the crystalline dihydrate from the aqueous solution by adding a solution (typically a low alcohol), then filter the crystals, wash with cold isopropanol and then with benzene, dry the crystals, It is made by removing water from hydration from dihydrate to form anhydrous sodium acetylsalicylate. Thus, the prior art ignores the importance of the water removal rate, and no special consideration in this regard has been directed or taken during the dewatering step. The composition thus made is considered to have excellent stability, but in practice it has a compounding rate of about 3.5% per year or at least about 5% during a two year storage period. At a rate of -7%, there was a tendency to deteriorate through decomposition.

[0011] Such decomposition of sodium acetylsalicylate leads to the formation of by-products such as salicylic acid, sodium salicylate, acetic acid. Certain degradations may be tolerated for orally administered drugs, but are not acceptable for injected drugs. Injectable drugs have a much higher risk of toxic and allergic reactions and require higher standards of purity and stability.

More recently, other pharmaceutical preparations have been taught to provide comparable effects to aspirin. However, these new drugs cannot withstand long-term therapeutic tests and may not be safe or effective at this stage.

[0013] Accordingly, an injectable form having sufficient stability to maintain a high level of purity and at the same time be substantially free of toxic compounds causing side effects and suitable for storage under normal conditions for at least about 2 years There is a need for aspirin.

It is therefore an object of the present invention to provide an anhydrous sodium acetylsalicylate composition suitable for subcutaneous injection which has a very high purity and can be stored for 2-3 years with little or no deterioration. is there.

It is another object of the present invention to provide a method for making the above anhydrous sodium acetylsalicylate composition.

Accordingly, the present invention provides a composition of sodium acetylsalicylate having very high purity and which can be stored for a considerably long period. Anhydrous sodium acetylsalicylate having such high purity and stability suitable for injection is a dehydration method comprising removing water by hydration from dihydrate of sodium acetylsalicylate at a rate higher than the rate at which free water vapor is formed. It has been discovered that anhydrous sodium acetylsalicylate can be formed with such high purity and stability suitable for injection, formed by the procedure. The rate of free water vapor formation can be monitored by various known means, for example, using a calibrated gas flow meter. On a small scale, this weighs the flask containing sodium acetylsalicylate dihydrate and then subtracts it from the weight gain of the (tareed) connection vessel containing a moisture adsorbent such as calcium chloride or sulfuric acid. This can be done by determining the weight loss. In that case, conditions for the dehydration process, such as vacuum pump capacity and application temperature, are such that the rate of water removal from the dihydrate is equal to the rate of steam formation and the atmosphere from the atmosphere on the dihydrate salt itself. Need to be adjusted.

The effective storage period of such an anhydrous sodium acetylsalicylate according to the present invention thus produced is of the order of a few years, provided that it is stored in an almost anhydrous atmosphere at room temperature. It will continue to show a purity in the range of about 97% to 100% after storage for 3 years. Sodium acetylsalicylate has almost the same therapeutic value as aspirin itself.

One method for preparing sodium acetylsalicylate is to use a vacuum dehydration technique.
The sodium acetylsalicylate dihydrate in particulate form is placed in a suitable container or container connected to a vacuum pump. Then, at the same time as discharging the air using a large-capacity vacuum pump, the hydrated water is removed from the dihydrate sodium acetylsalicylate as water vapor at a speed equal to or higher than the water vapor formation speed. A tube or other conduit of sufficient diameter is placed between the vessel and the pump to allow the water vapor to be removed to flow freely and unimpeded.

The various features which characterize the invention are set forth with particularity pointed out in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operational advantages and the specific objects attained by its use, reference is made to the following description, in which preferred embodiments of the invention are shown.

The injectable aspirin composition according to the present invention is made from sodium acetylsalicylate dihydrate by removing the water formed during dehydration at the same rate as it is formed. This sodium acetylsalicylate dihydrate first reacts aspirin with sodium bicarbonate in water and then crystallizes, for example, sodium acetylsalicylate in dihydrate form using a suitable solvent / non-solvent medium. Can be prepared. Modifications and adaptations of the procedure described in U.S. Pat. No. 3,985,792 can be used to prepare dihydrate as a starting material for the present invention.

This step is followed by dehydration under carefully controlled conditions.

The anhydrous sodium acetylsalicylate obtained by the process of the present invention is very stable.
After storage at room temperature for 3 years, the injectable composition shows little degradation. The composition is 97% to 100%
Retains purity levels in the% range.

The following example is provided to illustrate the invention.

EXAMPLE 1 100 g of sodium acetylsalicylate dihydrate in fine particle form, prepared as described herein
Into a shallow dish placed in a vacuum desiccator at a depth of 3
Layered in the range of cm-4cm. A suitable dehydrating agent can be used in a separate or connected vessel downstream of the desiccator. Further, the desiccator is connected to a vacuum pump. The dehydrating agent for collecting water may be, for example, either calcium chloride or sulfuric acid, or any of phosphorus oxides. The vacuum in the desiccator was maintained at 3 to 15 mmHg for about 1 hour. At this point, the desiccator was opened and the platelet-like contents of the granular, partially dehydrated sodium acetylsalicylate dihydrate in the dish were briefly stirred.
Thereafter, the vacuum treatment was performed again for about 4-5 hours.

An essentially pure anhydrous sodium acetylsalicylate was obtained which was stable and pharmaceutically acceptable for subcutaneous injection into mammals.

Example 2 400 g of granular sodium acetylsalicylate dihydrate
Was prepared as described above, placed in a stainless steel drying pan in the form of a large crystal plate, and stoked at room temperature in air without heating under a vacuum of 1.5 mmHg without heating.
s Dry overnight in a vacuum oven. The product was then removed from the oven, stirred, and crushed. At this stage, a granular cake-like material was observed. Then, vacuum processing was performed again for 3 hours. In this case, too, high purity and granular dehydrated sodium acetylsalicylate suitable for injection were obtained.

Example 3 Granular sodium acetylsalicylate dihydrate was prepared as described above and suspended at 20 ° C in dry air particles. Gradually increase the temperature in the air atmosphere to 45 ° C over 1 hour,
The temperature was additionally raised to 65 ° C. for another hour. Anhydrous sodium acetylsalicylate of suitable purity and stability for injection was obtained.

Examples 1-3 above illustrate different methods for obtaining anhydrous sodium acetylsalicylate of appropriate purity and stability. The technique used in each case is to remove the water generated from the dihydrate at a rate not less than the rate of formation of water vapor by hydration. A further important factor in the dehydration of sodium acetylsalicylate dihydrate is the constant exposure of the granular surface of sodium acetylsalicylate dihydrate to a (relatively) dry atmosphere to drain water therefrom. It is. One way to achieve this is to use a thin layer of granular sodium acetylsalicylate dihydrate. Further, the product may be agitated intermittently or continuously by appropriate physical equipment.

When the dehydration treatment is performed in a vacuum, the diameter of the pipe connected from the drying vessel to the vacuum generator may be very important, and the atmosphere containing moisture on the particulate matter is not disturbed. Should be of sufficient diameter to be quickly removed. For example, if the diameter of the tube that removes moisture from the system is not sufficient, or if the vacuum pump used to remove moisture has insufficient capacity or is inefficient, the resulting anhydrous sodium acetylsalicylate may be used. Is actually unstable and may degrade very quickly and become unusable. On the other hand, the performance of the vacuum device is sufficiently high, and the capacity of the pump is sufficiently large.
If tubes with a diameter in the range of mm are used,
The product is unstable because the flow is obstructed. However, in such cases, the use of tubing, that is, a discharge conduit generally having a diameter of at least 10 mm or more, allows steam to be removed and flow without resistance,
A stable product suitable for injection can be produced.

If the conditions for removing water from hydration at the same rate as the rate of water formation are met, the resulting product is stable and anhydrous sodium acetylsalicylate of a purity suitable for the use of injectable aspirin is obtained. can get.

Stated another way, the technique of the present invention achieves dehydration if the partial pressure of water vapor in the atmosphere in sodium acetylsalicylate dihydrate is maintained at a minimum level throughout the process. It is thought that it is possible.

While not wishing to be bound by any particular theory, it is believed that this procedure essentially prevents rehydration of the anhydrous sodium acetylsalicylate crystals, which then form a stable anhydrous crystal lattice structure.

It is particularly important in the process of the present invention that the crystal lattice structures of both sodium acetylsalicylate dihydrate and anhydrous sodium acetylsalicylate need to be platelet shaped rather than needle shaped. In the process of forming sodium acetylsalicylate dihydrate, some or all of the crystal structure tends to have a needle-like shape. It is much more preferred to carry out this process in which the crystal structure is formed almost entirely of platelet-shaped crystals.

[0034] Other techniques for preparing anhydrous sodium acetylsalicylate can also be used. For example, various inert gases such as nitrogen or argon can be used instead of air. Batch mode or continuously operated fluidized bed technology can be used, the bed itself being formed from granular sodium acetylsalicylate dihydrate. In such a case, it is desirable that the apparatus be capable of recovering fines formed during the fluidization step, while at the same time having equipment for removal and recovery of anhydrous sodium acetylsalicylate. It also uses a microporous elastomer substrate for fine-particle aspirin to allow air or any inert dry gas to pass through it, optionally with a continuous belt.
A method of continuously stirring using a system can also be used. These variously shaped devices are used in sequential combination in the desired order.

In addition, the azeotropic distillation technique is preferably used in an organic liquid that forms a non-polar, azeotropic substance in order to properly remove water due to hydration. The azeotropic boiling point can be reduced to some extent by using a slightly reduced pressure while maintaining a somewhat lower temperature and preferably refluxing to facilitate the process. Such an operation is beneficial if a non-polar or weakly polar solvent that forms an azeotrope is used to avoid decomposition of the starting material, and is also effective in removing water by hydration.

The resulting product is stored in a moisture-proof sealed container under an atmosphere having a relative humidity of less than 50%. The following table shows the stability of the materials obtained by various techniques as described above.

Example 4 Preparation of Sodium Aspirin A laboratory batch of 0.55 mole sodium acetylsalicylate was prepared using the following procedure. Drug: aspirin 100 gm sodium bicarbonate 50 gm toluene 8 ml water 45 ml isopropanol 1 liter First mix aspirin, sodium bicarbonate, toluene and water in a 400 ml beaker. 2. The beaker was placed in a water bath at 40-45 ° C. and the mixture was stirred until bubbling stopped (about 60 minutes). Foaming was controlled by adding as much additional toluene (8 ml) as needed. 3. Isopropanol (300 ml) was added, the mixture was stirred, and unreacted sodium hydrogen carbonate was filtered (the filter paper was not washed). Then the solution is 5-6 ° C
And seeded with sodium acetylsalicylate dihydrate platelet crystals (see below for adjustment of seeding). Isopropanol (525 ml, T =
5-6 [deg.] C). The mixture is then
2 corresponding to the period during which crystallization of aspirin dihydrate occurs
The mixture was stirred in a water bath (ice + water) for a time. Next, it was kept in a refrigerator all day and night. The resulting product was platelet-shaped crystals. 4. The mixture was stirred and filtered, isopropanol (150 ml, T = 5-6 ° C.) and benzene (100
ml) and dried at room temperature or with a lamp in a large shallow dish. During drying, the mixture was agitated well and the agglomerates were broken with a spatula (these agglomerates become very hard without continuous grinding). Weight = about 55 gm, almost 50% of theory. 5. The dried product was placed in a vacuum desiccator and placed in a vacuum using calcium chloride as a desiccant in a chamber separated from the sodium acetylsalicylate dihydrate product. The next day, the product was stirred and placed under vacuum for an additional 24 hours. All of these operations were performed in an atmosphere of air having a relative humidity of about 40% or less. Next, the obtained anhydrous product in the form of crystals on platelets was placed in an airtight bottle. Preparation of seed crystal When the sodium acetylsalicylate (5 gm) obtained in the previous operation and 1.5 ml of water were stirred with a glass rod for a few minutes in a wide-mouth test tube, the granular mixture was purified. Isopropanol (5 ml) was added and stirred in a warm water bath until almost all was dissolved. It was then cooled in ice-water, stirred until crystallization started, and ground.
The crystallized material was kept in an ice bath with occasional stirring until used in (# 3) above. The dihydrate platelet seeds are freshly formed and must be kept in a refrigerator or freezer until used. However, if left in that state for a long time, they hydrolyze.

If seed crystals are not available in the first operation, a portion of the solution (# 3 above) is placed in a test tube and the wall is scratched with a glass rod in a water (ice + water) bath. The mixture was further crystallized by inducing onset of crystallization and then stirring occasionally for 2-3 hours or more to further crystallize.

Example 5 An 8.9 mole experimental batch was made using the following procedure. 1. Aspirin and sodium bicarbonate were mixed in a 5-liter beaker, and 120 ml of toluene was added with stirring, followed by 720 ml of water. 2. The beaker was placed in a 40 ° C. ± 2 ° C. water bath and physical stirring was started and continued until bubbling was complete (about 75 minutes). Note: During the reaction, this compound became a pale pink syrupy fluid. Some sodium bicarbonate remained unreacted. 3. Isopropanol (4,800 ml) was added to the above beaker and stirred. The suspension was then filtered through Watman # 2 paper using a water absorption tube to remove any unreacted sodium bicarbonate and the filtrate was divided into two equal portions. 4. Each part was placed in an ice-salt bath and placed in a 12 liter round bottom flask equipped with a paddle stirrer, additional funnel, and thermometer. 5. The solution was stirred for half an hour or until the temperature reached 2-5 ° C. Crystallization was induced by placing sodium acetylsalicylate dihydrate platelets. Note: The crystallization does not actually occur immediately, but requires stirring the solution until crystals form. The sodium acetylsalicylate dihydrate platelet crystal seed is described elsewhere herein. 6. About 15 minutes after crystallization occurred, 5-6 liters of isopropanol were added dropwise to each flask over 3 hours with stirring. 7. The crystal concentration of both flasks was suction filtered through the same Buckner funnel using Watman # 2 filter paper, followed by washing with about 300 ml of benzene. 8. Combine the two lots of crystals and then
Subdivide into four stainless steel drying pans and 1.5 m without heating in a Stokes vacuum oven
and dried overnight under vacuum. 9. Remove the product from this oven, stir,
The cake was then crushed and placed under vacuum for another 3 hours. 10. The platelet crystals dried at this stage were removed from the oven, passed through a screen (mesh # 20), placed in a bottle containing a silica gel drying bag, and sealed with plastic tape.

Anhydrous sodium acetylsalicylate was packaged using a wide-mouthed amber bottle filled with plastic-coated cardboard. The bottle was flushed with dry air and allowed to equilibrate to low temperature overnight.

Steps # 9 and # 10 were performed in a low humidity environment with a relative humidity of 15%. Results: Theory 1,782 grams Actual yield 1,344 grams Notes: a: The method described here is described in US Pat.
5,782 basic content. However, this method has been further improved in order to make products suitable for injection-quality preparations according to the invention. b: For successful preparation, it is important to avoid the formation of acicular crystalline forms of sodium acetylsalicylate. When a concentrated aqueous solution of sodium acetylsalicylate is treated with a solvent such as isopropanol without paying special attention, a needle-like shape tends to be preferentially formed. This shape is in many ways inferior to the plate-like shape. The needle shape is difficult to handle, stir, filter, wash and dry. Also, the yield is considerably lower than in the case of a plate. Needle-shaped crystals are also difficult to fill in small injection containers.
The formation of needle-shaped crystals is strictly controlled by the conditions such as the proportion of reactants, the amount of water and isopropanol, the temperature, the stirring speed, and the availability of carefully prepared plate-shaped crystal seeds. Can be prevented by doing so. c: It is important to control the rate at which hydrated water is removed from sodium acetylsalicylate dihydrate, that is, the rate at which hydrated water is formed is equal to or greater than that at which it is formed. The conditions for making a stable product have been found based on the observation that it has to be removed at the same time. This can be achieved by using good vacuum and large diameter conduits. Dewatering needs to be achieved very efficiently using fluidized beds. d: For storage of anhydrous sodium acetylsalicylate, the product was placed in a waterproof, airtight glass container.
The product was not hygroscopic at RH <50% and was therefore packed under these conditions. e: In terms of stability and degradation, the following table shows the stability of this product made under various conditions. The column "% free salicylic acid" shows the non-aspirin salicylate content in the various preparation lots. As shown here, the stability after storage at room temperature for one year was very high with an average purity of 99%. The results of the accelerated aging test (30 days at 50 ° C.) showed similar stability (see Table A, lots A, B, C and D below). f: For dehydration, water content can be measured by Karl Fischer or IR assay and is about 0.1
% (See table below). g: In the examples, the atmospheric temperature was used unless otherwise specified. h: With respect to the desiccant, if the dihydrate starting material easily loses water due to its hydration, CaSO ₄ , P
₂ O ₅ , MgSO ₄ , and molecular sieves can be used. In such cases, the most effective and commercially used method is a fluidized bed or other at least semi-continuous method. i: For Example 2, the product tends to be caked as the product is dehydrated. Again, this phenomenon can be prevented by using fluidized bed technology. In other ways,
By using various stirring methods, it is possible to prevent cake formation during dehydration. For example, one method is to rotate the flask in a vacuum. Since the particles are constantly moving, cake formation can be avoided.

Analysis Procedure for Anhydrous Sodium Aspirin The procedure described here is a manual procedure. Most assays can be performed with this procedure automated. All solutions are stored on ice. 1. Reagents (a) Buffer: Equal volumes of 2-propanol and pH
2.2 Mix the HCl / KCL solution. The latter is 3.72
gm of KCl in distilled water and dissolve in 39 ml or 0.1 ml.
Prepared by adding 2 molar HCL. Dilute the mixture to 1 liter. (B) Iron nitrate: 5 g of iron nitrate and 2.5 ml of concentrated nitric acid were dissolved in water and diluted to 500 ml. 2. Preparation of Comparative Sample About 40 mg of accurately weighed sodium salicylate was dissolved in buffer and diluted to 25.0 ml with buffer. 3. Assay This section describes the first assay. Samples for stability require different dilutions.

About 60 mg of accurately weighed sample is
Place in 0 ml volumetric flask. Dissolve the sample,
Dilute and mark with cold buffer. Store the solution on ice. In a spectrometry curette, mix 4.0 ml sample solution and 2.0 ml cold iron nitrate solution. Using a mixture of 4.0 ml of buffer and 2.0 ml of iron nitrate solution as a blank, the absorption values of these solutions are read at 520 μm. * Concentration for comparison in 10 ml of final dilution

Analysis of Salicylate Content Reagent a) Ferric solution : 1 ml of Fe Alum (1 g)
Dissolved in 200 ml containing concentrated hydrochloric acid. b) Comparative salicylic acid solution : 1 gm dissolved in 1 liter of water (0.1 wt. 2. Color comparison test tube (Nessler) Length: 154 mm; ID: 19 MM; od: 22 mm 3. Procedure (a) 50 mg of the compound was dissolved in 20 ml of water and placed in a first Nessler tube, 4 drops of glacial acetic acid were added, followed by 8 drops of ferric solution (b) 20 ml of water was added to the second Nessler tube. And 4 drops of glacial acetic acid were added thereto.
Add drops. Next, while applying vibration, (Nessle
r 0.1% salicylic acid solution was added until the color matched the solution in the first Nessler tube (not in the depth direction of the tube, but in the width direction and under a white background). One drop of a 0.1% salicylic acid solution corresponds to 0.05 mg salicylic acid. The concentration of the solution to be tested must be adjusted so that the salicylic acid solution does not exceed 6-7 drops. Otherwise, the colors would be too strong to make comparisons. 4. NOTE This test requires 5 minutes to run. As aspirin salts hydrolyze in water, the test must be completed as quickly as possible.

Anhydrous sodium aspirin (physical properties) a) Appearance: free-flowing white granular powder; monoclinic plate b) Properties: melting point / decomposition point: 210-213 ° C (document: 217.5 ° C) c A) Purity (measured): 97-103% (aspirin content) d) Water content: up to 0.1% by Karl Fischer or IR assay e) Solubility: very high solubility in water as follows . Methanol: 3.50% w / v ethanol: 0.30% w / v isopropanol: 0.05% w / v f) free salicylate: salicylate 1% or less g) mol. Wt = 202 Sodium = 12.8% by weight h) Hygroscopicity with RH> 50% The following table shows the stability data.

[0046]

[Table 1] Note: RT = room temperature RV = rotary flask, vacuum, water bath 20 ° C-50 ° C-85
° C FB = fluidized bed Initial free salicylic acid in all experiments <0.05%.

Examples of the improved preparation are shown below.

EXAMPLE 6 A mixture of aspirin (25.0 g, 0.139 mol), sodium bicarbonate (12.5 g, 0.147 mol) and toluene (2.0 ml) was placed in a 250 ml Erlenmeyer flask and mixed with water ( 12.2 ml) was added. The reaction mixture was physically stirred in a water bath at a temperature of 40-45 ° C. Foaming was observed. Toluene (3m
l) was added to reduce foaming. After the bubbling had ended after 45 minutes, isopropanol (75 ml) was dispersed and added. The reaction mixture was filtered, the clean filtrate was cooled in an ice bath and isopropanol (130 m
l) was further processed. The clear solution was stirred with a stirring rod to cause crystallization, and stored in the refrigerator overnight. The resulting crystalline product was filtered, washed with isopropanol (37 ml) and dried at room temperature. A total of 8.73 g (26.4% yield) of the dihydrate product was obtained. Material properties: softens at 143 ° C. Resolidifies at 165 ° C and melts at 238 ° C to decompose.

A portion (5.50 g) of this product was dissolved in water (2.0 ml) and heated at 45 ° C. in a water bath to recrystallize, whereby a clear solution was obtained. . Isopropanol (7 ml) was added and the clear solution was placed in an ice bath for 3 hours.
Cool for 0 minutes. During this time, recrystallization of the dihydrate in the form of beautiful white platelets occurred, which was filtered and dried at room temperature. A total of 2.54 grams of product was obtained. Material properties: Softening started at 74 ° C and completely softened at 90 ° C. Further, it was melted at 237 ° C. and decomposed. Analysis: _{H 2} O content (14.51%) [Karl Fischer Analysis].

The dihydrate sodium acetylsalicylate product obtained in this preparation was then kinetic investigated under various drying conditions to form the desired anhydrous sodium acetylsalicylate as described below.

Example 7 Sodium acetylsalicylate dihydrate was placed in a tared vial and introduced into an Abder-Holden drying chamber filled with dried calcium chloride. Fig. 1
Shown in This Abder-Holden drying chamber was connected to a vacuum pump at a reduced pressure of 45 mm. At various times, the vials containing the sodium acetylsalicylate dihydrate were weighed and the weight loss (water equivalent) was plotted as a function of time (minutes). In the case of sodium acetylsalicylate dihydrate, the theoretical water equivalent is 2.00. The following table summarizes the drying curves at each temperature studied.

As generally shown in FIG. 1, the Abder-Holden apparatus 10 has a flask 12 for containing a dilutable fluid in communication with an outer chamber 14 through a connecting tube 16. Outer chamber 1
4 has an inner chamber 18 mounted in a generally connected state for containing a sample 20 to be processed and to be isolated from all communication with its outer chamber 14. The outer chamber 14 is rotated and fixed by a reflux concentrator 22 in order to reflux the concentrated reflux liquid to the flask 12. The inner chamber 18 is, in this case, attached to a second flask 24 for containing a desiccant. A stopcock 28 is further provided in the flask 24.
Alternatively, means are provided for allowing connection to a vacuum pump (not shown) via a line to which another valve device 28 is attached. The connections between the flask 12, the outer chamber 14, the concentration column 22, and the inner chamber 18 and the flask 24 are each conveniently made by a ground glass joint 30. When a liquid having an appropriate boiling point is placed in the flask 12, the outer chamber 1
A sample (here, sodium acetylsalicylate dihydrate) contained in an inner chamber (e.g., by a ring seal 32) that is isolated from 4 can be maintained at an appropriate predetermined temperature through the action of concentrator 22. .
The desiccant in flask 24 is selected to be heated in a vacuum at the temperature of the refluxing medium so as to effectively absorb hydration moisture as it is removed from the initial dehydration starting material.

[0053]

[Table 2] FIG. 2 is a diagram of the resulting drying process, which shows the asymptotic curve when this procedure forms anhydrous sodium acetylsalicylate according to the present invention.

[0054]

[Table 3] FIG. 3 is also a diagram of the obtained drying curve similar to FIG. 2 and shows an asymptotic curve.

[0055]

[Table 4] FIG. 4 is also a diagram of the obtained drying curve similar to FIGS. 2 and 3, showing an asymptotic curve.

FIG. 5 is a comparison of FIGS. 2, 3 and 4, wherein the rate of conversion of the process of the present invention and sodium acetylsalicylate dihydrate to the anhydrous form is temperature dependent (as discussed above). The same vacuum of 45 mm Hg was used in this series of plots). At 22 ° C., conversion to the anhydrous state was 50% complete after about 10 hours. At 40 ° C., conversion to the anhydrous state was 50% complete after 4 hours. At the highest temperature employed in this study, 56.5%, 50% conversion of the dihydrate to the anhydrous form is completed within 40 minutes.

The dihydrate samples (Tables 3 and 4) used in the drying experiments at 40 ° C. and 56.5 ° C. showed sub-theoretical final hydrate removal, which is probably due to The samples were stored overnight in a refrigerator over calcium chloride before use in the above experiments, and some of the water due to hydration had been removed. The effectiveness of this experiment is not affected by these circumstances.

At the temperatures investigated in these series of kinetic studies, no signs of decomposition of sodium acetylsalicylate dihydrate were shown. However, drying should not be carried out at temperatures much higher than about 60 ° C., as at higher temperatures the sodium acetylsalicylate dihydrate may begin to soften and decompose (see below for physical properties).

When obtained by the above procedure, after drying, anhydrous sodium acetylsalicylate was recovered as a white powder. Material properties: onset softening at 107 ° C., complete softening at 121 ° C., and starting decomposition at 174 ° C. and 205 ° C.
Completely disassembled. Analysis: H ₂ O content (0.85%)
[Karl Fischer method].

The Karl Fischer analysis is very useful in measuring the process of conversion of sodium acetylsalicylate from dihydrate to anhydride. For example, a sample of partially dehydrated sodium acetylsalicylate dihydrate (taken at 1300 minutes during drying at 22.0 ° C.) (see Table 2), as expected, had a Karl Fisher analysis. Had a moisture content of 6.11% as determined by the method of Example 1.

It can be concluded that azeotropic removal of water from sodium acetylsalicylate dihydrate is also possible. However, in practice, especially on a large scale, such azeotropic mixtures will lead to decomposition of the product if not carried out under reduced pressure. Drying at temperatures below about 60 ° C. (ie, about 56 ° C., which is the boiling point of acetone for reflux as used in the Abder-Holden apparatus described above), is such that the process proceeds quickly (about 2 ° C.). Time), a preferred method for addition to the anhydride. Of course, large-scale drying processes require periodic mixing or spinning of the sample, and may require longer times and / or lower temperatures.

The above examples demonstrate that drying to a fixed volume is a sufficient measure of the complete addition of anhydrous sodium acetylsalicylate.

Thus, the present invention provides a method for dehydrating sodium acetylsalicylate dihydrate, wherein the predominant presence of platelet crystal form and the high purity maintained over a storage period of at least 2-3 years. Also provide a new preferred process for making anhydrous sodium acetylsalicylate which is partially characterized. This product has sufficient purity and stability to be used for subcutaneous injection for therapeutic purposes. This dehydration process is particularly characterized by the rapid removal of water vapor from the system as it is formed to prevent rehydration of the sodium acetylsalicylate and to prevent eventual degradation of its desirable properties. I have. Such a process should be performed at such a high temperature that it does not induce degradation of the basic sodium acetylsalicylate molecular structure to achieve high purity. Various approaches for achieving these goals have been described above in accordance with the application of the principles of the present invention. For example, instead of isopropanol, another C ₃ or C ₄ alcohol is used in the precipitation and crystallization of this dihydrate, as described in the process of US Pat. No. 3,985,792 referred to above. It is also possible. Accordingly, it will be appreciated that implementations may be made without departing from such principles and are limited only by the spirit and scope of the following claims.

[Brief description of the drawings]

FIG. 1 is a schematic diagram of the apparatus used in some of the experiments disclosed herein.

FIG. 2 is a kinetic diagram for dihydrate drying at 22 ° C.

FIG. 3 is a kinetic diagram for the drying of the dihydrate at 40 ° C.

FIG. 4 is a kinetic diagram for the dihydrate drying at 56.5 ° C.

FIG. 5 is a comparative kinetic diagram for the dihydrate drying at the above three temperatures.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 29/00 A61P 29/00 C07C 69/017 C07C 69/017 69/157 69/157 F-term (reference) 4C086 AA01 DA17 GA13 MA01 MA04 MA66 NA03 ZA08 ZA36 ZA96 ZB11 4H006 AA01 AA02 AB21 AB22 AD15 AD33 BJ50 BS30

Claims (17)

[Claims] 1. A monoclinic platelet formed by removing hydration moisture from sodium acetylsalicylate dihydrate at a rate corresponding to the rate at which water vapor is formed from the hydration moisture. Composed of sodium acetylsalicylate in a completely dehydrated form obtained in a form,
A therapeutic sodium acetylsalicylate having a long shelf life and pharmaceutically acceptable for subcutaneous injection into mammals. 2. The composition of claim 1 wherein said product is essentially completely anhydrous sodium acetylsalicylate having a melting point of about 210-213 ° C. 3. The method of claim 2, wherein the anhydrous sodium acetylsalicylate is sufficiently stable to have a purity of at least about 97% to 100% after storage at room temperature under air at about 50% relative humidity for at least 3 years. The composition according to claim 2, characterized in that: 4. White monoclinic platelets having a melting point of about 210 ° C. to 213 ° C., an H ₂ O content of about 1% by weight, and a free salicylic acid content of 1% by weight or less. A therapeutic acetylsalicylate composition consisting essentially of completely anhydrous sodium acetylsalicylate. 5. The method of claim 1 wherein the anhydrous sodium acetylsalicylate is sufficiently stable to have a purity of at least about 97% to 100% after storage at room temperature under air at about 50% relative humidity for at least 3 years. The composition according to claim 4, characterized in that: 6. A method of preparing a therapeutic composition of acetylsalicylate having a long shelf life and pharmaceutically acceptable for subcutaneous injection into a mammal, comprising at least essentially reducing the shape of platelet crystals. Initially providing a fixed amount of solid particulate sodium acetylsalicylate dihydrate, forming water from hydration from the acetylsalicylate dihydrate, and forming water vapor from the dihydrate At a speed higher than the speed, the residual water content level was removed so as to be about 2% by weight or less, and the shape of the white monoclinic platelet crystal was reduced to about 210%.
-Creating an anhydrous sodium acetylsalicylate having a melting point of -213 ° C. 7. The method of claim 6, wherein removing the hydration vapor further comprises placing the acetylsalicylate dihydrate under vacuum. 8. The method according to claim 1, wherein the vacuum is about 1 mmHg to 50 mmHg.
7. The method of claim 6, wherein the range is g. 9. The method according to claim 6, wherein the water from the hydration is removed using a vacuum oven. 10. The step of removing water by hydration further comprises the step of drying the inert gas stream for a necessary time sufficient to substantially completely remove the water by hydration of the dihydrate. 7. The method of claim 6, including exposing said solid sodium acetylsalicylate dihydrate. 11. The method of claim 11, wherein removing the water by hydration further comprises placing the solid sodium acetylsalicylate in an inert gas that is substantially dry at room temperature in the range of 50-60 ° C. 7. The method of claim 6, wherein: 12. The method according to claim 1, wherein the step of removing water due to hydration further comprises a step of stirring or stirring the solid sodium acetylsalicylate dehydrated crystal to prevent the formation of a cake. Item 7. The method according to Item 6. 13. A method for producing dehydrated crystalline sodium acetylsalicylate, comprising first preparing an aqueous suspension of acetylsalicylic acid, treating it with sodium bicarbonate, and then adding it to the resulting aqueous solution. Adding a C3-C4 alcohol while cooling to initiate precipitation of the sodium acetylsalicylate dehydration, and introducing preformed monoclinic platelet crystals of sodium acetylsalicylate dehydration to induce crystal formation And causing further crystallization of the sodium acetylsalicylate dehydration to form monohydrated platelet crystalline sodium acetylsalicylate dehydrated crystals. 14. The method according to claim 13, wherein said alcohol is isopropanol. 15. A therapeutic acetylsalicylate composition having a long shelf-life and suitable for subcutaneous injection into mammals, wherein said sodium acetylsalicylate dehydration at a rate greater than or equal to the rate of water vapor formation by hydration. A therapeutic acetylsalicylate composition obtained by removal of water by summing and obtained in monoclinic platelets having a melting point / decomposition point in the range of about 210 ° C to 213 ° C. 16. A therapeutic acetylsalicylate composition having a long shelf life and being pharmaceutically stable and suitable for subcutaneous injection into mammals, wherein at least the dehydration of said dihydrate comprises Acetylsalicylate composition comprising sodium acetylsalicylate in anhydrous form characterized by its formulation process by removing water vapor formed from water by hydration at a rate equal to the rate at which is formed. 17. A process for making anhydrous sodium acetylsalicylate pharmaceutically suitable for subcutaneous injection into a mammal, comprising first forming platelet-shaped isolated crystalline dihydrate of sodium acetylsalicylate; It is characterized by dehydrating the sodium acetylsalicylate by subsequently removing water by hydration in the form of steam generated, wherein the water vapor is at least as fast as it separates water from the dihydrate. A process wherein water is removed from said sodium acetylsalicylate crystals.