DK149804B - PROCEDURE FOR PREPARING A STABLE CHOLINE-SALICYLATE-CARBOXY-C1-4 ALKYL CELLULOSE METAL COMPLEX - Google Patents

Description

in U9804

The present invention relates to a process for the preparation of a stable, novel choline salicylate-carboxy-C 1-4 alkylcellulose metal complex suitable for the preparation of solid pharmaceutical dosage forms.

Choline salicylate is a well-known analgesic compound having desirable pharmacological and therapeutic properties, as disclosed in U.S. Patent 3,069,321. However, the compound has a natural limitation, being highly hygroscopic, so that it is not possible to prepare pharmaceutically useful solid dosage forms suitable for oral administration in choline salicylate therapy in humans and animals. Although crystalline choline salicylate, which melts at approx. 50 ° C, is known, its hygroscopic properties are such that traces of moisture are sufficient to reduce the crystalline compound to the liquid state, and no matter how rigorous the effort to remove the absorbed moisture, the product remains in the liquid state so that it cannot be used to form solid dosage forms for pharmaceutical use.

Many efforts have been made to prepare solid pharmaceutical dosage forms of choline salicylate. Thus, U.S. Patent No. 3,297,529 prescribes mixtures of choline salicylate and magnesium sulfate to form a solid product. U.S. Patent No. 3,326,760 also discloses a mixture of choline salicylate and polygalacturonic acid. U.S. Patent No. 3,759,980 relates to the formation of a chemical compound of choline salicylate and magnesium salicylate, which is a solid. However, none of these known methods for solving the problem of obtaining choline salicylate in stable solid dosage unit forms, as described above, have been found to be useful in practice. A solid dosage unit form which provides a therapeutically sufficient amount of choline salicylate for the required therapeutic purposes, and which also remains stable for a sufficient period of time to permit marketing, is not commercially available.

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It has been found that free-flowing, physiologically acceptable choline salicylate-containing complex, which has the necessary long-lasting stability, can be prepared from choline salicylate, salicylic acid, carboxy-C1-4 alkyl cellulose and aluminum, bismuth, calcium or magnesium ions. . Accordingly, the process of the invention is characterized by forming an aqueous solution of a carboxy-C 1-4 alkyl cellulose, choline salicylate and salicylic acid, adding aluminum, bismuth, calcium or magnesium ions to the solution in an amount sufficient for complexing with the choline salicylate and carboxy-C 1-4 alkyl cellulose, the molar ratio of choline salicylations: metal must be 1: 3: 1 and the amount of carboxy-C 1-4 alkyl cellulose is 2.5-25 wt., leaving the resulting reaction mass , Until thickened, and drying the thus-thickened reaction mass.

Carboxy-C 1-4 alkyl cellulose is e.g. carboxymethyl, carboxyethyl and carboxypropyl cellulose. Carboxymethyl cellulose is preferred due to availability and low cost.

Although the complex may contain varying proportions of its component parts, choline salicylate, metal ion and carboxy-C 1-6 alkyl cellulose, its compositions are homogeneous, reproducible and constant and have been found to have a dry, solid form durability of above four years, which from a commercial point of view 25 can be considered practically unlimited. Thus, the complexation of choline salicylate, metal ion and carboxy-C1-6 alkyl cellulose results in the formation of a highly stable, solid complex compound suitable for the preparation of solid pharmaceutical dosage forms which remain stable for over 4 years.

Further, the choline salicylate-carboxy-C C ^ alkyl alkylcellulose metal complex prepared by the process of the invention is substantially different from the previously described solid compounds and also from the simple mixtures of its constituents due to its chemical composition as well as its chemical composition. physical and pharmaceutical properties.

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The difference between the individual compositions is evident by comparing the critical solubility in polar solvents of magnesium carboxymethylcellulose-choline salicylate with the simple mixture of choline salicylate and magnesium salicylate, with the simple mixture of choline salicylate, magnesium salicylate and carboxymethylcellate. the known chemical compound of U.S. Patent No. 3,759,950, choline magnesium salicylate.

The electrical conductivity data determined for the compounds 10 are in good agreement with the critical solubility data and establish that the compound formed magnesium carb oxymethyl cellulose choline salicylate is substantially different from the known compound magnesium choline salicylate having a chelate intramolecular structure. whereas the known molecule has a hydrogen bonded structure. Furthermore, the specific electrical conductivity of the resulting magnesium carboxymethyl cellulose choline salicylate differs from that of the simple mixture of the moieties, which again differs from the known hydrogen bonded compound magnesium choline salicylate.

New solid dosage forms prepared with choline-salicylate-carboxy-C ^^ alkylc alkyl cellulose-metal ion complexes provide special advantages for convenient administration of choline salicylate, excellent physiological tolerance, virtually absence of side reactions, and superior therapeutic efficacy. which is shown by a rapid rise in the salicylation content of the blood in humans and animals following administration of tablets, capsules, granules or suppositories containing a therapeutically sufficient amount of an appropriate choline salicylate carboxy-C 1-6 alkylcellulose and aluminum , bismuth, calcium or magnesium ion formed complex.

In the process of the invention one can first form a solution of carboxy-C 1-4 alkyl cellulose and then add the choline component, salicylic acid and metal ion. The complex formed is allowed to settle, thereby thickening, and then the pulp is dried, preferably at a temperature of approx. 40 ° C. Analysis of the resulting dried powders of the resulting choline salicylate carboxy-C 1-4 alkyl cellulose metal complex compound gives choline salicylate, carboxy C 1-4 alkyl cellulose and the respective metal ion in amounts which are in good agreement with the theoretical amounts.

10 The new powders retain their rice-resistant, solid properties for long periods of time without evidence of decomposition. Solid dosage forms such as tablets, capsules, granules or suppositories made with said solid powders are stable and retain their strength over an extended period of time. Although 15 g of a formed choline salicylate-carboxy-C 1-4 alkyl cellulose metal complex is placed in an open petri dish and exposed to the air for a long time, the powders retain their original solid, rice-resistant form without decomposition. When formulated in solid pharmaceutically acceptable dosage forms which are packaged and stored at room temperature, these pharmaceutical preparations are stable for over four years.

The general process for forming the subject complexes is described in detail below.

It is well known that carboxy-C 1-4 alkyl cellulose is insoluble in dry acid water. It is necessary to convert the carboxy-C 1-4 alkylcellulose acid into an aqueous solution, and this can be achieved by dissolving in water the common metal salts of carboxy-C 1-4 alkylcellulose, such as sodium or potassium carboxy-C 1-4 alkylcellulose, at the desired concentration. and then removing the solubilized ion, namely the sodium or potassium ion, by means of an acidic ion exchange column in a manner known per se. The exact composition of the acid ion exchange column is neither essential nor critical, as any of the metal ion exchange resins used to remove sodium and potassium ions from a solution are useful for this purpose. The ion exchange resins known as sulfonated polystyrene polymers which are crosslinked polyamine resins are known commercially under the name "Amberlite" ® or more specifically as "Amberlite" ® IR or “Amberlite” ® IR-120 resins sold by Rohm. Haas, Philadelphia, Pennsylvania. Resins of the same type are also sold by other chemical companies under other known trade names, and some of these resins and methods of making them are disclosed in U.S. Patent No. 2,402,384. These resins are used in hydrogen form in a manner known per se to remove sodium and / or potassium ions.

A gram of choline hydrogen carbonate is added to a prepared aqueous solution of carboxy-C C alkyl alkyl alkylcellulose obtained as eluate from an acidic ion exchange column after removal of the sodium or potassium ions and the mixture is stirred under heating to ca. 70 ° C. Stirring is continued for approx. an hour, or until there is no shower. Then, the pH of the mixture is determined, which will be in the range of 7-7.8 with an average pH of 7.4.

Preferably, then, 3 grams of salicylic acid is added to the choline hydrogen carbonate-carboxy-C 1-4 alkyl cellulose solution with stirring, and the mixture is heated at ca. 55 ° C for one hour.

When the salicylic acid is added and a solution is obtained, the mixture is allowed to cool to room temperature and 25 grams of the metal ion donor is added. The addition of the metal ion donor compound is carried out with vigorous stirring, while the temperature is again increased to approx. 70 ° C. When the metal-donor compound has been added to the mixture and the solution is ready, stirring is stopped and the batch is allowed to settle for 16 hours.

After standing, the pulp becomes thick and is then dried for approx. 24 hours in an oven at 80 ° C. The resulting, substantially dry material is pulverized and then further dried in a vacuum oven at a temperature of ca. 40 ° C and a pressure of 2 mm Hg to constant weight. The dry powder thus obtained is the metal choline salicylate carboxy-C 1-6 alkyl cellulose compound which is stable, possesses unique and reproducible properties and is useful in the preparation of solid dosage forms such as capsules, tablets, granules. and suppositories containing a therapeutically sufficient amount of the active ingredient described above.

The following metal compounds are preferred: a) as aluminum ion donor: aluminum isopropoxide and aluminum hydroxide; b) as magnesium ion donor: magnesium hydroxide and magnesium ethoxide; c) as bismuth ion donor: bismuth citrate, bismuth phosphate or bismuth hydroxide, d) as calcium ion oxide,

When choline salicylate is prepared in situ, choline chloride, choline arbonate or any other soluble salt of choline in an equivalent amount can be used instead of choline hydrogen carborate in the above described.

The dry powders of the complex obtained by the present process are white, rice-resistant and stable with reproducible physical and chemical properties. The respective compounds (molar ratio of choline: salicylate: metal is 1: 3: 1) have the following assay values: aluminum choline salicylate carboxymethyl cellulose compound contains substantially 5.1% aluminum ion, 91.65% choline salicylate and 3.25% carboxymethyl cellulose, magnesium choline salicylate carboxymethyl cellulose compound contains essentially 3.0% magnesium ion, 92.3% choline salicylate, 5.16% carboxymethyl cellulose, calcium choline salicylate carboxymethyl cellulose compound contains calcium 4.35%, calcium 4.35%, contains calcium 4.35% , 65%, and the bismuth choline salicylate carboxymethyl cellulose compound contains bismuth 27.28%, choline salicylate 49.5% and carboxymethyl cellulose 21.2%.

When it is desired to use the novel complex compounds in the treatment of humans and animals to obtain an analgesic, antipyretic or anti-inflammatory effect and to raise the salicylate content of the blood, a therapeutically sufficient amount of the appropriate new compound may be administered to humans and animals in the dosage forms tablet, granule, capsule or suppository. Thus, the dosage unit concentration of the respective new dry choline salicylate-carboxymethyl cellulose metal ion complexes in the tablet, capsule, granule or suppository dosage form is preferably sufficient to provide an amount of the respective compound corresponding to ca. 250 mg of the salicylate part per dose unit or approx. 339 mg of the aluminum choline salicylate carboxymethyl cellulose compound ice cream, 370 mg of the magnesium choline salicylate carboxymethyl cellulose compound, 395 mg of the calcium choline salicylate carboxymethyl cellulose compound ice cream and 693 mg of the bismuth choline salicyl acetate compound. The concentration range per dosage unit is from 0.1 g of the respective active compound mentioned above. dosage unit to 1.0 g of the selected active compound per 20 g. dosage unit. The exact dosage concentration required depends on the therapeutic target to be achieved and the individual patient's needs.

The method according to the invention is further illustrated by the following examples.

Example 1.

Ca. 4.5 liters of a 4% solution of sodium carboxymethyl cellulose is circulated through a column containing an acidic ion exchange resin, such as e.g. "Amberlite" ® IR-120H to remove the sodium ions. The eluate solution of carboxymethyl cellulose in 30 water contains approx. 0.75 weight percent solids. A sufficient amount of this eluate to give 32.7 g of carboxymethyl cellulose is put into a glass flask fitted with a stirrer and heating sheath. The carboxymethyl cellulose solution is heated to ca. 30 ° C and 22.47 g of choline hydrogen carbonate are added in small portions.

35 with rapid stirring. Violent showering occurs when the choline hydrogen carbonate aliquots are added and the temperature slowly increases to 70 ° C during the addition process. When all choline hydrogen carbonate has been added, the mixture is stirred for approx. one hour under heating, after which it is allowed to cool to room temperature. The pH of the solution is approx. 7.4 and within the range 7.0-7.8. To this solution, 48 g of salicylic acid is added portionwise at constant temperature with constant stirring. The mixture is heated for one hour, then the temperature is raised to 70 ° C, after which a further 10 is added a sufficient amount of aluminum isopropoxide to give 2.9 g of aluminum ion. Stirring and heating are continued for one hour, after which the batch is left for 16 hours.

The next day, the thickened mass is spread into a thin layer for drying in a hot oven at 80 ° C. When the material is dry, it is pulverized and then placed in a vacuum oven to continue the drying process at a temperature of 40 ° C and a pressure of 23 mm Hg until two successive samples show no further weight loss. The dried powder is then ground again, packaged and filled into glass bottles. The compound formed is aluminum choline salicylate carboxymethyl cellulose, a white powder containing 5.1% aluminum, 91.65% choline salicylate and 3.25% carboxymethyl cellulose. The powder is insoluble in water and stable when exposed to air at room temperature.

Instead of aluminum isopropoxide described as an aluminum ion donor, aluminum hydroxide dry gel or aluminum wet gel may be used in an amount sufficient to yield an amount of aluminum ion equivalent to the above.

Example 2,

To an aqueous solution of carboxymethyl cellulose containing 16.3 g of carboxymethyl cellulose is added 166 g of choline hydrogen carbonate. The mixture is stirred and heated until the gas burst stops and then 414.4 g of salicylic acid are added. The mixture is heated and stirred until all the solid has dissolved. Stirring is continued while heating to 70 ° C for approx. for one hour, and then 114.3 g of magnesium ethoxide are added. The mixture is stirred until all the solid has dissolved. The heating is continued for one hour and the mixture is then left for 16 hours.

The next day, the solution is dried to constant weight and the dry powder pulverized. The compound formed is magnesium choline salicylate carboxymethyl cellulose which contains 2.5% magnesium, 92.3% choline salicylate and 5.16% carboxymethyl cellulose. The dry white powder is insoluble in water and non-hygroscopic, it is stable for a long time when exposed to atmospheric air.

Instead of magnesium ethoxide, as a magnesium ion donor 151.78% magnesium hydroxide can be used.

Example 3

For an aqueous solution of carboxymethyl cellulose containing ca. Anhydrous 17 g of carboxymethyl cellulose are added to 1 gram of choline hydrocarbonate and 3 grams of salicylic acid.

The mixture is stirred until the substances are completely dissolved and heated with stirring to 70 ° C, then 398 g of bismuth citrate is added, sufficient to provide approx.

1 grammo1 bismuthion.

Instead of bismuth citrate, any soluble bismuth salt, such as bismuth chloride or bismuth phosphate, can be used as a bismuthion donor. When all bismuth compound has been added, the mixture is stirred under heating until a clear solution is formed, and then left for 16 hours at room temperature. The material is then dried in vacuo to constant weight.

The dry white powder is bismuth choline salicylate carboxymethyl cellulose which is stable at room temperature and non-hygroscopic.

Example 4

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To a solution of 4.6 g of carboxymethyl cellulose in 100 ml of water is added 91 g of choline salicylate and 96.7 g of salicylic acid dissolved in 100 ml of solution. The mixture is heated to 70 ° C for 3 hours and then 4.35 g of calcium ion in the form of calcium hydroxide or calcium hydrogen carbonate is added. When all the calcium salt has dissolved, the mixture is left for at least 10 hours and the product is then dried in vacuo to constant weight.

The resulting white powder is calcium choline salicylate-carboxymethyl cellulose, a stable, non-hygroscopic powder.

Example 5

When 19 g of aluminum choline salicylate carboxymethyl cellulose, magnesium choline salicylate carboxymethyl cellulose, bismuth choline salicylate carboxymethyl cellulose or calcium choline salicylate carboxymethyl cellulose are extracted with chloroform and the solvent is no longer evaporated, the solvent is not evaporated. This test establishes that there is no separation of salicylic acid from the compounds obtained as a result of Examples 1-4 described above.

20 g of the choline salicylate carboxymethyl cellulose metal complex prepared according to Examples 1-4 above are placed in a tared petri dish which is then exposed to atmospheric air on an open shelf. The same amount of crystalline choline salicylate, which melts at approx. 50 ° C, prepared according to the method 25 described in US Patent 3,069,321, is then placed in another petri dish which is placed next to the petri dish containing the choline salicylate carboxymethyl cellulose metal complex formed as described. in Examples 1-4 above. Both petri dishes are examined every hour on the first day, then every eight hours. At each observation, each petri dish is weighed to determine the weight gain due to water absorption, and the physical state of the solid is evaluated to determine if any changes have occurred.

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compounds. After being exposed to atmospheric air for one hour, the crystalline choline salicylate compound prepared according to U.S. Patent No. 3,069,321, liquid while forming new complexes prepared according to the procedure described in Examples 1-4, remained in their original solid state. The liquid choline salicylate showed a weight increase of 1.963 mg, showing an absorption of water of almost 20%, whereas the new complexes formed showed a weight gain of only 67 mg, showing that there was actually no hygroscopic activity.

After being exposed to atmospheric air for three days on the open shelf, the liquid choline salicylate compound had absorbed approx. 40% by weight (4.136 g) of water, whereas the new complexes formed showed a weight gain of less than 1% 15 or 331 mg. The rice viability of the powders of the new complexes formed remained unchanged throughout the trial period.

This test establishes that there is a complex formation between the components, which changes the ability of the choline salicylate to absorb water from the air. It is known that hydrogen bonding occurs between choline salicylate and water, and that the complex formation preferably blocks the formation of hydrogen bond, thereby preventing the absorption of water molecules.

Example 6

The ability of solid 25 complexes to retain their solid character as a result of the above Examples 1-4 was assessed by placing a 2 g sample of each complex in a tared glass dish stored under various humidity conditions up to 97% relative humidity at the elevated controlled temperature of 37 ° C. At predetermined intervals, the samples were examined and the physical state of the exposed powder was noted. In comparison, known choline salicylate products are tested similarly.

Claims (5)

149804 Choline salicylate, melting at 49.3 ° C, prepared according to U.S. Patent No. 3,069,321, became liquid within 2 minutes of exposure to all the relative humidity investigated. Magnesium choline salicylate, prepared according to U.S. Patent No. 5,759,980, was liquefied after 32 hours of exposure to an atmosphere of 60% relative humidity at 37 ° C, 20 hours of exposure to an atmosphere of 80% relative humidity at 37 ° C and 18 hours exposure to an atmosphere of 90% relative humidity at 37 ° C. Magnesium carboxymethyl cellulose choline salicylate, obtained as a result of Example 2, remained solid when exposed to an atmosphere of 90% relative humidity at 37 ° C for 7 days, but was liquid after being exposed for 7 days. for an atmosphere of 97% relative humidity at 37 ° C. Aluminum carboxymethyl cellulose choline salicylate, obtained as a result of Example 1, was partially solid after 7 days exposure to 80% relative humidity at 37 ° C and also after 7 days exposure to 90% relative humidity atmosphere at 37 ° C. Calcium carboxymethyl cellulose choline salicylate, obtained as a result of Example 4, was liquefied after 7 days exposure to an atmosphere of 60% relative humidity and greater relative humidity at 37 ° C. A process for preparing a stable choline salicylate-carboxy-C ^^ alkyl alkylcellulose metal complex, characterized in that an aqueous solution of a carboxy-C ^ alkyl alkyl alkylcellulose, choline salicylate and salicylic acid is added, adding aluminum, bismuth calcium or magnesium ions 30 to the solution in an amount sufficient for complexation with the choline salicylate and carboxy-C 1-6 alkyl cellulose,