JP2001507028A - Acetaminophen salt - Google Patents

Abstract

  (57) [Summary] An isolated salt of acetaminophen is disclosed. Alkali metal salts and alkaline earth metal salts of acetaminophen are produced by reacting the free acid of acetaminophen with the corresponding metal hydroxide and then isolating the resulting salt immediately. These salts are more water soluble and less bitter than the free acids of acetaminophen.

Description

DETAILED DESCRIPTION OF THE INVENTION                           Acetaminophen salt                                Field of the invention   The present invention relates to a salt of acetaminophen, and in particular to an alkali of acetaminophen. It relates to metal salts and alkaline earth metal salts.                                 Background art   Acetaminophen (APAP) is a treatment that has both analgesic and antipyretic activity Well established as a drug. However, the solubility of acetaminophen in water is Due to its low bitterness and bitterness, it can be formulated into oral dosage forms that are acceptable to patients. It has become difficult. Most commercial acetaminophen oral dosage forms are Minofen grains are coated with a good-tasting mask or to mask the bitter taste of drugs Uses flavorings and sweeteners.   Other methods of treating the solubility and taste of acetaminophen include acetaminophen. There is the formation of amino acid esters. I. M. Kovach, Diss. Abstr. Int. B 1 975, 36 (2), pp. 734-735, p-acetamidophenylglycine Sinate (APG), α-p-acetamidophenyl aspartate (AAPA) ) And β-p-acetamidophenyl aspartate (BAPA). ing. These esters are reported to be less bitter than acetaminophen I have. APG-HBr is 5 times more soluble in water than acetaminophen, but BAPA-H Cl is four times less soluble in water than APAP.   In addition, hydrophobic compounds such as lipophilic carboxylic acids usually form appropriate salts and It is known to improve the water solubility of the compound With sodium ibuprofen Sodium naproxen is a pharmaceutically active lipophile with improved water solubility in salt form It is an example of a compatible carboxylic acid. These salts generally convert carboxylic acid to sodium hydroxide Alternatively, it is produced by reacting with a strong base such as potassium hydroxide.   USSR Inventor's Certificate No. 629,209 issued on September 11, 1978 Cetylaminophenol is hydroxylated with a solution of an organic solvent such as dimethylformamide. Reaction with an alkali agent such as lithium and then the resulting potassium phenolate solution Chlorex is reacted at the boiling point of the reaction mixture to give bis- [β- (4-acetyla 1 shows a method for producing minophenyloxy) ethyl] ether. Got Ethers have been reported to be effective in treating animals with helminthic diseases.   USSR Inventor's Certificate No. 1,803,833 issued March 23, 1993 3 shows a method for producing acetaminophen for measuring light intensity. Acetaminofe The sample is first dissolved in isopropyl alcohol and then KOH: Potassium hydroxide solution with 3-4 volume ratio of chloroform and 8% solution of chloroform Process and manufacture. Then heat at 70-80 ° C for 15-20 minutes And measure the fluorescence intensity of the sample.   Both of the above USSR inventors certificates treat acetaminophen with potassium hydroxide. However, none of the documents reported that the potassium salt of acetaminophen was simple. No release was reported.   U.S. Pat. S. Yu and others are partially ionized and acidic Improves the solubility of basic or amphoteric drugs, filled with soft gel, two-piece capsule Pharmaceutical carrier cis to produce high concentration predominantly water-insoluble solutions suitable for the manufacture of tablets or tablets Discussing Tem. Acetaminophen solution is added to polyethylene glycol, 25 % (Wt.) To 40% (wt.) Acetaminophen, acetaminophen 0.4 mol to 1.0 mol of hydroxide ion and 1% (wt.) To 1 mol It contained 20% (wt.) Water. Suitable for use as soft gel filling One example of a concentrated solution of acetaminophen is 1 equivalent APAP (35% by weight), 1 equivalent The amount contained potassium hydroxide and the balance polyethylene glycol 600.   D. L. Simmons US Pat. No. 5,273,759 discloses solid Mg (OH)_TwoTo , APAP-containing tablets.   However, both Yu et al. And Simmons reported isolation of individual salts of acetaminophen. I haven't.   Acetoa with improved water solubility and taste compared to conventional forms of acetaminophen There is a need for an isolated salt of minofen.                                Disclosure of the invention   The present invention provides an isolated acetaminophen salt. Preferably, an isolated salt Are alkali metal and alkaline earth metal salts of acetaminophen.   In another aspect of the invention, the isolated salt has the formula: Here, n is 1 or 2, and when n is 1, M is an alkali metal and n is 2 Where M is an alkaline earth metal and X is 0 to about 10. These salts are Water solubility was improved and bitterness was reduced compared to the free acid form of toaminophen. Also book The invention also includes methods for making these salts.   Another aspect of the invention relates to the use of these salts in mammals in need of an analgesic and / or antipyretic therapeutic. And a method of administering. Further, the present invention relates to an oral administration comprising an acetaminophen salt. Related to the form of administration.                             BRIEF DESCRIPTION OF THE FIGURES   FIG. 1 shows a tablet containing the free acid acetaminophen and each isolated acetaminophen. It is a graph which shows the dissolution test result about the tablet containing a fen salt.   FIG. 2 shows the bioequivelency test in dogs of Example VII. FIG. 1 is a graph showing the relationship between acetaminophen plasma concentration and time.                      BEST MODE FOR CARRYING OUT THE INVENTION   Prior to the present invention, the isolation of any individual salt (phenolate) of APAP was reported Had not been. In addition, any deprotonated APAP species No in-situ solution properties of AP species) species were reported . As used herein, the "free acid" of acetaminophen is defined as AP Means the protonated phenol form of AP.   One reason that the scientific literature does not consider APAP salts is the anionic form of APAP. Is stable in aqueous solution (pH> 11) only for a short period (<24 hours) is there. If the salt is not isolated immediately after formation, p-aminophenolate (PAP ) May form and the product may discolor.   The isolated salt of acetaminophen used in the present invention is acetaminophen. -Hydroxyacetate formed by deprotonation of phenolic protons 2 shows a salt of toanilide. Preferably, the isolated salt is an acetaminophen alcohol Li metal salts and alkaline earth metal salts. In another aspect of the invention, the isolated salt is It has the following formula: Here, n is 1 or 2, and when n is 1, M is an alkali metal and n is 2 Where M is an alkaline earth metal and X is 0 to about 10.   The APAP salt is prepared by one step of APAP and the desired monovalent or divalent metal hydroxide. Produced by aqueous reaction. Examples of suitable monovalent or divalent metal hydroxides include hydroxyl. Sodium hydroxide, calcium hydroxide, lithium hydroxide, potassium hydroxide, There are gnesium and cesium hydroxide. Hydroxide to acetaminophen The molar ratio is from about 1: 2 to about 10: 1, preferably from about 1: 2 to about 1: 1. A PAP and metal hydroxide in water, or water and acetonitrile, methanol, isop Mixing with water-miscible organic solvents such as lopanol, ethanol or tetrahydrofuran Dissolve in the material. The less polar water-miscible reaction mixture is then added to precipitate. Thus, the crude reaction product is recovered or isolated. In general, the formation of PAP results in a product To reduce the likelihood of discoloration, recover or recover the reaction product as soon as Should be isolated. Thereafter, the final product may be vacuum dried.   The APAP salt of the present invention is also susceptible to a cation exchange reaction. For example, acetamino When the aqueous slurry or solution of the monovalent metal salt of fen contacts the divalent metal cation, An anhydrous divalent metal salt of acetaminophen is formed by the cation exchange reaction. So Afterwards, the salt is quickly recovered. In particular, C₁₆H₁₆N_TwoO_FourCa is C₈H₈NO_TwoN a) with 0.5 equivalent of calcium chloride (CaCl 2)_Two) To react with Wear. After vacuum drying above room temperature, the resulting C₁₆H₁₆N_TwoO_FourCa is anhydrous It was a thing.   In addition to the anhydrous form, various hydrated forms of the APAP salt can be prepared depending on the reaction conditions . Preferably, these hydrated salts contain less than 10 moles of water per mole of APAP salt. For example, acetaminophen sodium pentahydrate, acetaminophen nato Lium hexahydrate, acetaminophen sodium heptahydrate, acetaminophen There are calcium dihydrate and lithium acetaminophen hexahydrate.   The water solubility of the APAP salt of the present invention at 22 ° C. is such that the sodium salt is 490 mg / mL. ~ 540mg / mL, lithium salt is 450mg / mL ~ 470mg / mL , Calcium salt is 13 mg / mL. Therefore, sodium salt, lithium salt and And calcium salts are about 260 mg / mL to 280 m2 of APAP free acid, respectively. g / mL, equivalent to 250 mg / mL to 270 mg / mL and 10 mg / mL It has solubility.   The APAP salt has a higher dissolution rate compared to the traditional free acid form of acetaminophen. Has risen considerably. USP melting device 2 (paddle speed: 50rpm) In 0.1N hydrochloric acid at 37 ° C., the concentration of acetaminophen after 30 seconds is It was as follows.               APAP form (powder) APAPmg / mL                 Sodium salt 0.30                 Lithium salt 0.32                 Calcium salt 0.20                 Free acid (control) 0.02   FIG. 1 is a diagram showing the tablet dissolution rate of the salt of the present invention. APAP Nutrition Tablets, each of which is a salt of a sodium salt, a lithium salt and a calcium salt, and a conventional form of APAP. The solution was compressed and the dissolution rate was measured under the above conditions. The dissolution medium is in free acid form. Acetaminophen was assayed. In FIG. 1, the salt of the present invention is free This indicates that the dissolution rate of acetaminophen is considerably higher than that of acid.   The calcium and sodium salts of acetaminophen are available in the form of conventional free acid forms. The absence of the bitter taste of cetaminophen was observed. Most calcium salts It was tasteless and the sodium salt was a bit salty. Improved taste of the salt of the present invention Therefore, it is possible to formulate an acetaminophen oral dosage form having an improved taste. Become.   In contrast to the free acid form, the isolated salt of the invention opens up the action of acetaminophen. It is thought that the beginning is early. Due to the high solubility of the salt of the present invention, Fen plasma concentration peaks faster. Due to this property, acetaminophen The onset of analgesic and / or antipyretic activity is potentially accelerated.   The acetaminophen salt of the present invention can be administered to a mammal in a therapeutically effective amount. With treatment An effective dose is one that will cause the desired therapeutic response when orally administered, and will be readily determined by those skilled in the art. Can be determined. In determining such amounts, the particular compound to be administered, the bioavailability of the compound Consideration should be given to irability, mode of administration, age and weight of the patient and other factors Absent. A typical human oral dosage unit is between about 80 mg and 1000 mg (A PAP free acid base).   Generally, the acetaminophen salts of the invention are administered orally in solid form. Suitable solid Examples of body preparations are swallowable, chewable or fast-dissolving Tablets, pills, capsules, caplets, powders, wafers, sachets hets), gelatin-coated tablets and granules. Acetoa when manufacturing solid form Minofen salt is corn starch, talc, calcium phosphate, calcium sulfate , Calcium stearate, magnesium stearate, stearic acid, sorby Tall, microcrystalline cellulose, mannitol, gelatin, natural or synthetic rubber, etc. (Carboxymethylcellulose, methylcellulose, alginate, dextra , Acacia gum, karaya gum, carob gum, etc.) It can be mixed with the body and other conventional carriers. In addition, diluents, binders Other components such as lubricants, disintegrants, colorants and flavors can also be used. Dosage form It may be film-coated.   Conventional methods can be used for preparing the solid dosage forms of the present invention. Appropriate technology, Remi ngton's Pharmaceutical Sciences, 18th edition, Chapter 89 (1990). This document is incorporated herein by reference.   The following examples illustrate certain embodiments of the present invention. However, the present invention The present invention is not limited to the specific items described above, but is limited to the claims. Unless otherwise indicated Ratios and ratios are by weight.Example I   In this example, sodium acetaminophen (C₈H₈NO_TwoNa 6H_TwoO) The production method is shown.   3. Add 30 mL of 1N NaOH solution (0.030 mol) to 25 mL of water. 53 g (0.033 mol) of acetaminophen was added to the stirred suspension. All solid After dissolving the form, add 200 mL of acetonitrile while rapidly stirring the solution. I got it. The obtained white precipitate (9.15 g, yield 99% as hexahydrate) was fritted. And washed with tetrahydrofuran (THF) and dried at room temperature.¹1 H NMR (DMF d₇) Δ 9.4 (s, 1H, NH), 7.1 (m, 2H, Ar-H) , 6.3 (m, 2H, Ar-H), 1.96 (s, 3H, CO-CH_Three); IR (Cm^-1, KBr) 3421 (broad, OH), 1635 (sharp, CO) , 1594 (sharp), 1534 (sharp), 1500 (sharp), 12 79 (Sharp); Combustion analysis C₈H₈NO_TwoNa 6H_TwoCalculated value of O: C34.16 , H7.12, N4.98; measured values: C34.05, H6.96, N5.00; Water content C₈H₈NO_TwoNa 6H_TwoCalculated O: 38%; Measured: 38% (curl Fisher); FAB mass spectrum analysis m / e C₈H₈NO_TwoNa 6H_TwoO's Calculated value: 173; measured value: 174 (M + 1). Water solubility at 22 ° C is 49 It was 3 mg / mL.                                Example II   In this example, sodium acetaminophen (C₈H₈NO_TwoNa ・ 7H_TwoO) The production method is shown.   80 g (2.00 mol) of NaOH was dissolved in 400 mL of water, and 302 g (2 . (00 mol) of APAP dissolved in 2100 mL of isopropanol The mixture was added dropwise to the flask with stirring at 50 ° C. Allow the solution to cool to room temperature, (Yellowish white) precipitate formed. The solid was filtered off and 200 mL of isopropano And dried in vacuo (500 g, 84% as heptahydrate).¹H N MR and IR spectra are C₈H₈NO_TwoNa 6H_TwoSame as O. Combustion analysis C₈ H₈NO_TwoNa ・ 7H_TwoCalculated value of O: C32.11, H7.41, N4.68; Fixed value: C31.99, H7.38, N4.31; Water content C₈H₈NO_TwoNa ・ 7 H_TwoCalculated O: 42.1%; found: 42.7% (Karl Fischer). 22 The water solubility at ℃ was 541 mg / mL.                               Example III   This example demonstrates acetaminophen calcium (C₁₆H₁₆N_TwoO_FourCa ・ 2H_TwoO ) Is shown.   5 g (0.033 mol) of APAP and 1.22 g (0.016 mol) of Ca (O H)_TwoIs suspended in 200 mL of water, and the mixture is stirred for 4 hours. Dissolved in the liquid. The solution is frozen in a liquid nitrogen bath and freeze-dried to give Wight solids (5.44 g, 100% crude yield based on dihydrate) remained.¹HN MR (DMF d₇) Δ 9.39 (s, 1H, NH), 7.15 (m, 4H, A r), 6.80 (m, 4H, Ar), 2.10 (s, 6H, CO-CH_Three); I R 3287 (broad, OH), 1648 (sharp, NH), 1594,1 541, 1500, 1279 (sharp); Combustion analysis C₁₆H₁₆N_TwoO_FourCa ・ 2H_Two Calculated value of O: C51.05, H5.36, N7.45; 9.6; measured value: C5 1.21, H5.21, N7.63; water content (Karl Fischer) C₁₆H₁₆N_Two O_FourCa ・ 2H_TwoCalculated O: 9.6%; found: 9.8%. At 22 ° C Had a water solubility of 13 mg / mL.                                Example IV   In this example, lithium acetaminophen (C₈H₈NO_TwoLi ・ 6H_TwoO) made Show the law.   5 g (0.033 mol) of APAP was added to 30 mL of isopropanol / THF ( 1: 3, degassed with argon). This solution is added to 20 mL of water (argon degassing). Flask containing 1.38 g (0.033 mol) of LiOH dissolved in Quickly added. The colorless solution was stored at 0 ° C. for 16 hours, forming white crystals . The crystals were filtered under argon, washed with THF and dried in vacuo for 16 hours (4. 25 g, hexahydrate).¹1 H NMR (DMF-d⁷) Δ¹1 H NMR (DMF d₇ ) D 9.39 (s, 1H, NH), 7.15 (m, 4H, Ar), 6.80 (m , 4H, Ar), 2.10 (s, 6H, CO-CH_Three); IR 3568 (sha ), 3402, 3243 (broad), 1672, 1618 (sharp, N H), 1533, 1501, 1407, 1267, 1174 (sharp); combustion Analysis C₈H₈NO_TwoLi ・ 6H_TwoCalculated value of O: C36.23, H7.60, N5.2 8; measured values: C36.67, H7.68, N5.23; water content (curl fitting) Sha) C₈H₈NO_TwoLi ・ 6H_TwoCalculated O: 40.1%; found: 38.4% there were. The water solubility at 22 ° C. was 455 mg / mL.                                 Example V   In this example, lithium acetaminophen (C₈H₈NO_TwoLi ・ 6H_TwoO) other The following shows the production method.   Acetaminophen (15.1 g; 0.1 mol), 90 mL of water and lithium hydroxide Um 1N (100 mL, 0.1 mol) was placed in a 2 L beaker. The solution is clear Once, acetonitrile (1500 mL) was rejected. The resulting white solid is filtered , Washed with THF (about 500 mL) and dried in air to obtain a dry white solid (2 3.0 g, C₈H₈NO_TwoLi ・ 6H_Two87% based on O).¹1 H NMR (DMF -D⁷) Δ 2.0 (s, 3H, CO-CH_Three), 6.5 (m, 2H, Ar-H), 7.2 (m, 2H, Ar-H), 9.3 (s, 1H, AC-NH-Ar), 2. 0 (s, 3H, CO-CH_Three) 6.5 (m, 2H, Ar-H), 7.2 (m, 2 H, Ar-H), 9.3 (s, 1H, AC-NH-Ar); IR 3568 (cy Sharp), 3402, 3243 (broad), 1672, 1618 (sharp, NH), 1533, 1501, 1407, 1267, 1174 (Sharp) ; Combustion analysis C₈H₈NO_TwoLi ・ 6H_TwoCalculated value of O: C36.23, H7.60, N 5.28; measurements: C 36.56, H 7.56, N 5.05; water content (curl Fisher) C₈H₈NO_TwoLi ・ 6H_TwoCalculated value for O: 40.1%; It was 0%. The water solubility at 22 ° C. was 472 mg / mL.                                Example VI   This example demonstrates anhydrous acetaminophen calcium (C₁₆H₁₆N_TwoO_FourMade of Ca) Show the law.   Acetaminophen (90.6 g, 0.60 mol) was suspended in 135 mL of water. A solution containing sodium hydroxide (24.0 g, 0.6 mol) and 36 mL of water. It was added at 8 ° C. to 26 ° C. over 30 minutes. To the obtained NaAPAP-slurry, add salt Calcium iodide (CaCl_Two) (44.1 g, 0.3 mol) and 54 mL of water The solution was added at room temperature between 20 ° C and 25 ° C over 30 minutes. Then the reaction mixture is Heat to 60 ° C. within 60 minutes. As soon as the temperature reaches 60 ° C., the slurry is Cool to 20 ° C. within minutes and stir at 20 ° C. for 30 minutes. Obtained C₁₆H₁₆N_Two O_FourFilter Ca (79 g, 78%) with isopropyl alcohol (75 mL) Washed and dried under vacuum at 80 ° C. overnight.¹H NMR (D_TwoO) δ 7.01 (d, 8 , 4H), 6.57 (d, 8, 4H), 2.06 (s, 6H, CO-CH_Three); IR (cm^-1): 1651 (Sharp, NH), 1506, 1276, 854 ( Sharp); Combustion analysis C₁₆H₁₆N_TwoO_FourCalculated value of Ca: C55.65, H4.7, N8.23; measured values: C55.80, H4.53, N8.13.                               Example VII   Dogs to Measure Bioavailability of Acetaminophen Sodium Experimented with As a control, the free acid form of acetaminophen was used. The following set Compressed cylindrical pellets were prepared.   Acetaminophen sodium-compressed as is (no excipient)   Controls-150 mg APAP, 30 mg microcrystalline cellulose and                     30mg dextrate   Eight pure male beagle dogs weighing approximately 9-14 kg at the first dose Used for the experiment. Give dogs both PMI®-certified Canine Diet Meal No. 5007 and water Both were allowed to take freely. Dogs fast for about 12 hours overnight before dosing and 4 hours after dosing I put things back.   The dogs were divided into two groups, each group containing sodium acetaminophen or One of the control (free acid APAP) pellets was administered. 300 mg of acetoate A single dose equivalent to minofen free acid is used in oral gavage using a gastric tube. Administration. 20 mL of water was given after each dose. One week later, each group Another form of toaminophen (APAP sodium) was administered again. 12 blood Samples were collected from each dog on each day of administration (1 day before administration to 11 days thereafter). blood The serum was separated and tested for acetaminophen. The results of the pharmacokinetic measurement of acetaminophen are summarized below.Parameter APAP Sodium Control   AUC (ug-hr / mL) 31.4 ± 5.7 27.4 ± 6.1   C_max(Ug / mL) 23.6 ± 4.2 19.4 ± 6.9   T_max(Hour) 0.27 ± 0.1 0.60 ± 0.3   AUC: area under the plasma concentration-time curve up to the last measurable concentration   C_max: Peak plasma concentration   T_max: Peak time   FIG. 2 is a diagram in which an acetaminophen plasma concentration-time curve is plotted. This In the figure, the acetaminophen salt of the present invention shows that the free acid acetaminophen control Shows rapid absorption. T of acetaminophen salt_maxIs faster Indicates that the onset of analgesic and antipyretic activity is faster compared to the free acid control. Is shown.   From the above experiment, various modifications can be made without departing from the spirit and scope of the invention. It is.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, M W, SD, SZ, UG, ZW), EA (AM, AZ, BY) , KG, KZ, MD, RU, TJ, TM), AL, AM , AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, E S, FI, GB, GE, GH, HU, IL, IS, JP , KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, M W, MX, NO, NZ, PL, PT, RO, RU, SD , SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Nadigu, David             United States, 19446 Pennsylvania             Waikel Road, Lansdale, Oregon             591 (72) Inventor Higgins, John, Dee, The Third             United States, 19380 Pennsylvania             State, West Chester, North New             ー Street 10 (72) Inventor Ray, Max             CH, Switzerland-8304 Wallisset             -Ren, Rieden Elstrasse 69

Claims (1)

[Claims] 1. Isolated salt of acetaminophen. 2. The salt according to claim 1, wherein the salt is an alkali metal salt or an alkaline earth metal salt. 3. 3. The salt according to claim 2, wherein said alkali metal is selected from lithium, sodium, potassium and cesium. 4. 3. The salt according to claim 2, wherein said alkaline earth metal is selected from calcium and magnesium. 5. 3. The salt according to claim 2, which is in a hydrated form. 6. 3. The salt according to claim 2, which is in an anhydrous form. 7. 7. The salt according to claim 6, wherein said alkaline earth metal is calcium. 8. A solid in an orally administrable form comprising the salt according to claim 2. 9. A method of treating a mammal in need of an analgesic or antipyretic agent, comprising orally administering a therapeutically effective amount of an isolated salt of acetaminophen. 10. The method according to claim 9, wherein the salt is an alkali metal salt or an alkaline earth metal salt. 11. The method according to claim 10, wherein the alkali metal is selected from lithium, sodium, potassium and cesium. 12. The method according to claim 10, wherein the alkaline earth metal is selected from calcium and magnesium. 13. 11. The method of claim 10, wherein said salt is in a hydrated form. 14． 11. The method of claim 10, wherein said salt is in an anhydrous form. 15. 15. The method according to claim 14, wherein said alkaline earth metal is calcium. 16. A method of prematurely eliciting an analgesic or antipyretic response in a mammal, comprising orally administering an isolated salt of acetaminophen. 17． The method according to claim 16, wherein the salt is an alkali metal salt or an alkaline earth metal salt. 18. 18. The method according to claim 17, wherein said alkali metal is selected from lithium, sodium, potassium and cesium. 19. 18. The method according to claim 17, wherein said alkaline earth metal is selected from calcium and magnesium. 20. 18. The method according to claim 17, wherein said salt is in a hydrated form. 21. 18. The method of claim 17, wherein said salt is in an anhydrous form. 22. 22. The method according to claim 21, wherein said alkaline earth metal is calcium. 23. An isolated compound of the formula: Here, n is 1 or 2, when n is 1, M is an alkali metal, when n is 2, M is an alkaline earth metal, and X is 0 to about 10. 24. 24. The compound according to claim 23, wherein said alkali metal is selected from lithium, sodium, potassium and cesium. 25. 24. The compound according to claim 23, wherein said alkaline earth metal is selected from calcium and magnesium. 26. 24. The compound according to claim 23, which is in a hydrated form. 27. 24. The compound according to claim 23, which is in an anhydrous form. 28. 28. The compound according to claim 27, wherein said alkaline earth metal is calcium. 29. Acetaminophen comprising reacting acetaminophen with a monovalent or divalent metal hydroxide in the presence of a solvent to form a reaction mixture, and promptly recovering a salt obtained from the reaction mixture. A method for producing an isolated salt of 30. The method according to claim 29, wherein the solvent is water or a water-miscible organic liquid. 31. 30. The method of claim 29, wherein said salt is recovered by crystallization in a water-miscible solvent. 32. 30. The method of claim 29, wherein said salt is recovered by lyophilization. 33. A monovalent metal salt of acetaminophen is brought into contact with a divalent metal cation to form a divalent metal salt of acetaminophen by a cation exchange reaction, and the obtained anhydrous divalent metal salt of acetaminophen is promptly recovered. A method for producing an isolated anhydrous salt of acetaminophen, comprising: 34. The method according to claim 33, wherein the aqueous solution or slurry of the monovalent metal salt of acetaminophen is brought into contact with the divalent metal cation, and the obtained anhydrous salt is recovered by vacuum drying. 35. Method in the range 33 according claims the anhydrous salt is a _{C 16 H 16 N 2 O 4} Ca. 36. The method of claim 35, wherein the anhydrous salt is formed by a cation exchange reaction between sodium acetaminophen and calcium chloride.