US3253990A - N-methyl glucammonium salicylate and uses therefor - Google Patents

N-methyl glucammonium salicylate and uses therefor Download PDF

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US3253990A
US3253990A US247491A US24749162A US3253990A US 3253990 A US3253990 A US 3253990A US 247491 A US247491 A US 247491A US 24749162 A US24749162 A US 24749162A US 3253990 A US3253990 A US 3253990A
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salicylate
methyl
glucammonium
methyl glucammonium
solution
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US247491A
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Suter Hans
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Mundipharma AG
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Mundipharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S424/00—Drug, bio-affecting and body treating compositions
    • Y10S424/15—Suppositories

Definitions

  • the present invention concerns a new and novel salicylate compound, the process for its preparation and the method of use to achieve an elevated blood level of salicylate ion.
  • N-methyl glucammonium salicylate the process for its preparation and the use of the said compound to achieve an elevated blood level of salicylate ion.
  • a problem of the usage of the ammonium derivatives extends to the general class of amine salicylate compounds and, that is, its hydroscopic properties, which limit the formulation of these compounds into pharmaceutically acceptable dosage forms.
  • the hygroscopic properties of salts of salicylic acid in general, are such that special techniques must be employed in the preparation of solid dosage forms and, consequently, the free acid form is most often used. While free salicylic acid may not be readily administered because of its tissue corrosive properties, the acetylated form is utilized, but is unstable to aqueous media.
  • N-methyl glucammonium salicylate possesses such characteristics which make it especially suitable for therapy over prolonged periods. Its administration will result in the rapid elevation of the blood level of salicylate ion, causing a more 3,253,999 Patented May 31, 1966 rapid onset of analgetic action. N-methyl glucammonium salicylate has important advantages over the numerous known salicylates which have been recommended for clinical use. It is more stable in aqueous solution than the commonly used acetylated salicylic acid (aspirin), and it does not cause the gastrointestinal disturbances which have been reported after the administration of aspirin and other conventional salicylate drugs. N-methyl glucammonium salicylate is rapidly absorbed into the blood stream and does not interfere with the acid-base balance of the blood nor does it contribute large quantities of sodium ion to affect the water retention of the tissues.
  • N-methyl glucammonium salicylate is a white crystalline solid, melting at C. and is stable under the usual conditions of storage. It does not have the hygroscopic properties of other substituted salts of salicylic acid and, therefore, may be prepared in solid dosage forms, suitable for oral administration without special techniques or costly manufacturing handling procedures.
  • N-methyl glucammonium salicylate The tolerance to N-methyl glucammonium salicylate is excellent and the compound has a low order of acute toxicity.
  • the cation moiety is tolerated practically without limit and causes none of the physiologic side reactions common to the older salicylate drugs.
  • the pH of an aqueous solution of N-methyl glucammonium salicylate is approximately neutral and the pH of a 10 percent aqueous solution of the compound is pH 6.6, while that for the 1 percent aqueous solution is pH 6.47.
  • the general method of preparing N-methyl glucammonium salicylate is to react N-methyl glucamine or the carbonate or bicarbonate salts of N-methyl glucamine with salicylic acid, or an acid salt of N-methyl glucamine with a metallic salt of salicylic acid and isolating the. resultant N-methyl glucammonium salicylate.
  • the solvent for this reaction may be water or a liquid alkanol of from 1 thru 6 carbon atoms, or acetone-water mixtures, or mixtures of these.
  • a preferred method for obtaining N-methyl glucammoniurn salicylate in relatively pure state is to react stoichiometric equivalent quantities of N.-methyl glucamine and salicylic acid in the presence of water or a lower alkanol containing from 1 thru 4 carbon atoms and utilizing gentle heat to facilitate the rate of compound formation. After a half-hour of warming, at temperatures not exceeding 60 C., the n-methyl glucammonium salicylate may be obtained in a high degree of purity by precipitation with isopropyl alcohol and chilling. The solid crystalline compound is filtered, Washed with small portions of cold isopropyl alcohol and dried.
  • N-methyl glucammonium salicylate may also be prepared thru the inter-reaction of a salt of N-methyl glucamine as, for example, N-methyl glucamine carbonate, N-methyl glucamine bicarbonate, N-methyl glucamine hydrochloride, N-methyl glucamine hydrobromide, N- methyl glucamine hydroiodide, N-methyl glucamine sulfate and N-methyl glucamine nitrate, with a metallic salt of salicylic acid, as for example, sodium salicylate, potassium salicylate, calcium salicylate, magnesium salicylate, aluminum salicylate, lead salicylate, copper salicylate and silver salicylate.
  • a salt of N-methyl glucamine as, for example, N-methyl glucamine carbonate, N-methyl glucamine bicarbonate, N-methyl glucamine hydrochloride, N-methyl glucamine hydrobromide, N- methyl glucamine hydroiodide,
  • an insoluble salicylate salt as, for example, lead salicylate, copper salicylate, aluminum salicylate and silver salicylate
  • from 1 to 5 percent of sodium hydroxide, based upon the weight of metallic salicylate used, may be added to the reaction mixture.
  • the separation'of the inorganic salt formed as a consequence of the double decomposition reaction employed is achieved through the proper choice of eluting solvents.
  • hot ethanol will preferentially dissolve the N-methyl glucamine salicylate in preference to the inorganic metallic salt formed.
  • selective solubilization of the inorganic salt may also be utilized to achieve a separation of the products of the reaction.
  • calcium sulfate forms in addition to N-methyl glucammonium salicylate.
  • N-methyl glucammonium salicylate An alternate method for preparing N-methyl glucammonium salicylate is to react N-methyl glucamine carbonate or bicarbonate with salicylic acid in an aqueous media. The carbon dioxide formed volatilizes and the residue consist of pure N-methyl glucammonium salicylate.
  • N-methyl glucammonium salicylate When it is desired to utilize N-methyl glucammonium salicylate in therapy, then it may be administed in the form of tablets, capsules, granules or liquid preparations by the oral route or as suppositories by the rectal route, with a dosage range of from 0.2 gm. to 1.5 gm. per unit dosage form. Daily dos-age levels of from 0.2 gm. to 12 gm. of N-methyl glucammonium salicylate, per day, may be utilized in therapy through the administration of multiples of the unit dosage form. It is recognized that the individual daily dosage will depend upon the particular clinical indication being treated, as well as the individual patients needs.
  • Example 1 In a glass reaction vessel containing 60 ml. of ethanol is placed 27.6 gm. of salicylic acid and 39.05 gm. of N- methyl glucamine. The mixture is warmed slightly while stirring until complete solution'is achieved. The resulting solution is concentrated under vacuum and a viscous syrup is obtained, which is set aside to crystallize. Crystallization will be complete on standing for several days or may be accelerated by seeding with a crystal of N- methyl glucammonium salicylate and placing in an ice chest overnight. The resultant crystalline product is filtered and washed with a small quantity of cold ethanol and dried.
  • N-methyl glucammonium salicylate melts at 100 C. It is soluble in water, methanol, hot ethanol and hot isopropanol. It is insoluble in cold, absolute ethanol, cold isopropanol and acetone.
  • N-methyl glucammonium salicylate has the empirical formula, C H O N with 'a molecular weight of 333.33. 011 analysis for carbon, hydrogen and nitrogen, there was good agreement with the calculated theoretical values:
  • N-methyl glucammonium salicylate thus obtained is suitable for use in the preparation of tablets, granules, capsules, liquid and suppository preparations.
  • Example 2 To 55.2 gm. of salicylic acid, dissolved in 180 ml. of ethanol, is added 80.5 gm. of N-methyl glucamine bicarbonate, in small increments. The mixture is stirred throughout the entire period of the reaction and warmed to remove the formed carbon dioxide from the solvent. When complete solution has been achieved, and no further ebulition of gas occurs, the mixture is cooled in an ice chest and seeded with a crystal of N-methyl glucammonium salicylate and the whole set aside to crystallize for a period of 14 to 16 hours. The mixture is then filtered and the solid material washed with a small quantity of cold ethanol and the solid portion dried. The dried crystalline salt is N-methyl glucammonium salicylate, corresponding in every way to that obtained as a result of Example 1, above.
  • Example 3 To 160.1 gm. of sodium salicylate, dissolved in 1 liter of water is added, in small quantities, a solution of 231.7 gm. of N-methyl glucamine hydrochloride, dissolved in 2 liters of water. When all of the N-methyl glucamine hydrochloride has been added, the mixture is stirred and then carefully evaporated to dryness under reduced pressure. The solid material consists of N-methyl glucammonium salicylate and sodium chloride. A separation of the N-methyl glucammonium salicylate is achieved by extracting the solid residue with hot anydrous isopropanol. On cooling of the isopropanol extract, a crystallization of N-methyl glucammonium salicylate occurs, which is substantially pure and conforms, in every way, to that obtained as a result of Example 1, above.
  • Example 4 In place of the ethanol or isopropanol or water used in Examples 1 thru 3 above, there may be substituted, in equivalent quantities, a member of the class of alkanols of from 1 thru 6 carbons, or water, or mixtures of these.
  • Example 5 In place of the sodium salicylate described in Example 3, above, there may be substituted, in stoichiometric equivalent quantities, a metal salt of salicylic acid selected from the groups consisting of potassium salicylate, calcium salicylate, magnesium salicylate, aluminum salicylate, lead salicylate, copper salicylate and silver salicylate. The remainder of the steps being the same and the product obtained is N-methyl glucammonium salicylate, conforming in every way to that obtained as a result of Example 1, above.
  • a metal salt of salicylic acid selected from the groups consisting of potassium salicylate, calcium salicylate, magnesium salicylate, aluminum salicylate, lead salicylate, copper salicylate and silver salicylate.
  • Example 6 When it is desired to achieve a therapeutic effect with N-methyl glucammonium salicylate, then either tablets, capsules, granules or a liquid preparation may be administered by the oral route. If oral administration is not available, because of individual patient requirements, then the compound may be administered by the rectal route.
  • Tablets, granules and capsules of N-methyl glucammonium salicylate are prepared by the appropriate treatment of a granulation mixture by compounding into the selected final dosage form.
  • the granulation mixture is prepared by mixing 1 part of N-methyl glucammonium salicylate with an equal part of a neutral inert diluent as, for example corn starch, sucrose or lactose, and 0.1 part of kaolin. granulated with the aid of a granulating solution as, for example, 1 percent acacia solution or 1 percent gum tragacanth solution and passed thru a N0. 20 mesh screen, and dried.
  • each tablet contains from 200 to 1500 mg. of N-methyl glucammonium salicylate, with a preferred unit dosage concentration of N- methyl glucammonium salicylate of 500 mg. per tablet.
  • the powder is I Should it be desired to administer the compound in the form of capsules, then the granulation mixture prepared above, is filled directly into gelatin capsules of suitable size and shape so that each capsule contains an amount of the compound ranging in unit dosage of N-methyl glucammonium salicylate of from 200 mg. to 1500 mg. per capsule.
  • the granulation mixture prepared above, is mixed with 1 part of sucrose and 0.05 part of saccharin and the whole wetted with a mixture of 50 percent ethanol-water solution and granulated by passing thru a No. 8 mesh sieve and air dried.
  • the resultant granules are administered in a unit dosage ranging from 1 gram to 5 grams of granules, with a concentration of N-methyl glucammonium salicylate of from 0.2 gm. to 1.5 gm.
  • N-methyl glucammonium salicylate in the form of a liquid preparation, then the range of concentration of N-methyl glucammonium salicylate is from 0.2 gm. to 1.5 gm. of the compound, :per 5 cc. of solution.
  • a solution may be prepared by dissolving the calculated quantity of N-methyl glucammonium salicylate in the appropriate quantity of the solvent or by forming the active compound directly in the vehicle. The latter method is carried out as follows:
  • the amount of saccharin and cyclamate mixture to be added will depend upon the degree of sweetening preferred and will be found to be within the optimal range of between 750 mg. and 1 gm. of the mixture described.
  • the entire mixture is now warmed to 60 C. and stirred for one-half hour, after which time it is cooled to room temperature, filtered and then brought up to a volume of 500 cc. with distilled water. Should it be desired to color the solution, then appropriate quantities of pharmaceutically acceptable inert coloring agents may be used.
  • the resultant solution contains 1.5 gm. of N-methyl glucammonium salicylate per unit does of 5 cc. (one teaspoonful).
  • Suppositories of N-methyl glucammonium salicylate may be prepared by mixing 500 mg. of N- methyl glucammonium salicylate with a suitable quantity of pharmaceutically acceptable suppository base as, for example, cocoa butter and the solid polyoxyethylene glycols which are known in the trade as Carbowaxes, or mixtures of these, so that from 10 to 50 percent concentration of active ingredient in the suppository base, results. After intimate mixing, the suppositories are formed through the use of appropriate suppository molds so that each suppository shall range in weight of from 2 to 3 gm. and contain from 200 mg. to 1500 mg. of N-rnethyl glucammonium salicylate per unit dose.
  • Example 8 Under certain conditions, it may be desirable to administer N-methyl glucammonium salicylate in liquid form by either intramuscular or intravenous injection. This may be accomplished by preparing the solution of N- methyl glucammonium salicylate by an aseptic technique and packaging in a special glass ampule container to insure sterility.
  • the solution is cooled to room temperature and filtered.
  • the volume is then adjusted to exactly 3333 ml. to result in a 10 percent solution of N-methyl glucammonium salicylate.
  • the formed by-product, sodium chloride remains in solution as an inert substance without physiologic etfect.
  • the resultant solution is then filtered through sterile, porcelain, bacterial filters and filled into 2 cc. ampules of type I glass.
  • the sealed ampules may be sterilized by any of the conventional means as, for example, Tyndalization or autoclaving at 15 pounds pressure for one hour.
  • An alternate method of preparation of the ampule solution is to dissolve sufficient N-methyl glucammonium salicylate in water-for-injection to form a 10 percent so lution utilizing an aseptic technique, The remainder of the steps of filtering, sterilizing and packaging remain the same.
  • the sterile solution for injection may then be utilized by parenteral administration of sufficient solution to achieve a total daily dosage of from 0.2 gm. to 12 gm. per day.
  • the range in concentration of N-methyl glucammonium salicylate, in the solution for injection, is from 0.2 gm. to 1.5 gm. of N-methyl glucammonium salicylate per 2 cc. of solution.
  • Example 9 When it is desired to elevate the blood level of salicylate ion, then either the tablet, capsule, granule or liquid dosage form of N-methyl glucammonium salicylate may be administered in a daily dosage of from 0.2 gm. to 12 gm. of the active compound, per day. This may be readily accomplished thru the administration of multiples of the unit dosage containing from 0.2 to 1.5 gm. of N-methyl glucammonium salicylate per unit dose, several times per day. The compound will be found to be readily absorbed from the gastrointestinal tract and will not cause local gastrointestinal distress. Therapy with this compound may be maintained over prolonged periods depending upon the individual patient needs without the tolerance to the compounds being effected.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically sufficient amount of N-methyl glucammonium salicylate.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and from 0.2 gm. to 1.5 gm. per unit does of N-methyl glucammonium salicylate.
  • a pharmaceutical preparation comprising a pharmaceutical carrier in the form of a tablet including a therapeutically sufficient amount of N-methyl glucammonium salicylate.
  • a granule comprising a pharmaceutically acceptable diluent, a pharmaceutical binder and a therapeutically suflicient amount of N-methyl glucammonium salicylate.
  • a granule comprising a pharmaceutically acceptable diluent, a pharmaceutical binder and from 0.2 gm. to 1.5 gm. of N-methyl glucammonium salicylate per unit dose.
  • a liquid preparation comprising a pharmaceutical liquid vehicle and N-methyl glucammonium salicylate in a concentration of from 0.2 gm. to 1.5 gm. per unit dose of 5 cc. of liquid preparation.
  • a suppository medication comprising a pharmaceutically acceptable suppository base and a dispersion therein of from 0.2 gm. to 1.5 gm. of N-methyl glucammonium salicylate per suppository.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US247491A 1962-01-17 1962-12-27 N-methyl glucammonium salicylate and uses therefor Expired - Lifetime US3253990A (en)

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CH48162A CH407159A (de) 1962-01-17 1962-01-17 Verfahren zur Herstellung von neuem N-Methylglucaminsalicylat

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DK (1) DK109148C (en))
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GB (1) GB1028201A (en))
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3427300A (en) * 1965-11-12 1969-02-11 Merck & Co Inc Anti-inflammatory steroid 2'-acetamido-2'-deoxy-glucoside compounds
CN107072192A (zh) * 2014-08-13 2017-08-18 科莱恩国际有限公司 阴离子农药的有机铵盐

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3583131A (en) * 1969-03-27 1971-06-08 Paul Gaudlitz Apparatus for tying sausage casings or the like

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2427887A (en) * 1943-10-23 1947-09-23 Smith Kline French Lab Analgesic composition
US2471394A (en) * 1946-09-30 1949-05-24 Gubner Richard Salicylate and succinate therapeutic preparations
US2654774A (en) * 1950-05-15 1953-10-06 Dow Chemical Co Method of making 4-tertiary-butylphenyl salicylate
US2686199A (en) * 1949-07-19 1954-08-10 Firestone Tire & Rubber Co Reaction product of bisphenol-a and salicylic acid
US2903444A (en) * 1956-04-27 1959-09-08 Schenley Ind Inc Acyl derivatives of 4,6-dihydroxy-isophthalic acid
US3008874A (en) * 1958-05-15 1961-11-14 Pfizer & Co C Pharmaceutical compositions
US3118875A (en) * 1959-03-02 1964-01-21 Miles Lab Glucosamine acetylsalicylate and process for preparing same

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2427887A (en) * 1943-10-23 1947-09-23 Smith Kline French Lab Analgesic composition
US2471394A (en) * 1946-09-30 1949-05-24 Gubner Richard Salicylate and succinate therapeutic preparations
US2686199A (en) * 1949-07-19 1954-08-10 Firestone Tire & Rubber Co Reaction product of bisphenol-a and salicylic acid
US2654774A (en) * 1950-05-15 1953-10-06 Dow Chemical Co Method of making 4-tertiary-butylphenyl salicylate
US2903444A (en) * 1956-04-27 1959-09-08 Schenley Ind Inc Acyl derivatives of 4,6-dihydroxy-isophthalic acid
US3008874A (en) * 1958-05-15 1961-11-14 Pfizer & Co C Pharmaceutical compositions
US3118875A (en) * 1959-03-02 1964-01-21 Miles Lab Glucosamine acetylsalicylate and process for preparing same

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3427300A (en) * 1965-11-12 1969-02-11 Merck & Co Inc Anti-inflammatory steroid 2'-acetamido-2'-deoxy-glucoside compounds
CN107072192A (zh) * 2014-08-13 2017-08-18 科莱恩国际有限公司 阴离子农药的有机铵盐
CN107072192B (zh) * 2014-08-13 2021-08-06 科莱恩国际有限公司 阴离子农药的有机铵盐

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GB1028201A (en) 1966-05-04
FI40721B (en)) 1969-01-31
SE302771B (en)) 1968-08-05
DE1493954B1 (de) 1972-06-08
DK109148C (da) 1968-03-25
CH407159A (de) 1966-02-15
NL287824A (en))
BE626944A (en))

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