United States Patent
`
`[191
`
`Sinkula
`
`[111
`
`3,888,916
`
`[451 June 10, 1975
`
`[54] AMANTADINE SALT OF
`16,16-DIMETHYL-PGE2
`
`[75]
`
`Inventor: Anthony A. Sinkula, Kalamazoo,
`Mich.
`
`[73] Assignee: The Upjohn Company, Kalamazoo,
`Mich.
`
`[22]
`
`Filed:
`
`Aug. 1, 1974
`
`[21] Appl. No.: 493,544
`
`[52] U.S. C1.
`
`260/501.1; 260/468 D; 260/514 D;
`424/316
`Int. Cl. .......................................... .. C07c 97/00
`[51]
`[58] Field of Search ................... .. 260/501.17, 501.1
`
`[56]
`
`References Cited
`UNITED STATES PATENTS
`
`3,657,327
`
`4/I972 Morozowich ...... .f. ....... .. 260/501.17
`
`3,703,544
`3,759,978
`
`ll/1972 Morozowich ................ .. 260/501.17
`9/1973
`Lincoln, Jr................. .. 260/501.1 X
`
`Primary Examiner—-Joseph E. Evans
`Assistant Examiner—G. Breitenstein
`Attorney, Agent, or Fz'rm—Bruce Stein
`
`[57 ]
`
`ABSTRACT
`
`The amantadine salt of 16,16-dimethyl-PGE2, free-
`flowing crystals of the same, and the process for pro-
`ducing the same are disclosed. The salt in crystalline
`and non—crystalline form is useful for the same phar-
`macological and medical purposes as l6,16-dimethyl-
`PGE2 and is useful as a means for purifying 16,16-
`dimethyl-PGE2.
`
`2 Claims, No Drawings
`
`.SteadyMed - Exhibit 1016 - Page 1
`
`SteadyMed - Exhibit 1016 - Page 1
`
`

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`1
`AMANTADINE SALT OF 16,16-DIMETHYL-PGE,
`
`.
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`3,888,916
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`DESCRIPTION OF THE INVENTION
`
`
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`I0"
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`15
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`for easier '-storagejconditions. "The -"amantadine salt of
`l6‘,l6_-dimethyl-PGE2 is useful for th’e'same pharmaco-
`logical ‘and medicalvpurposes as -16,16-dirnethyl-PGE2.
`I have also‘ made the surprising and unexpected dis-
`This invention relates to free-flowing crystals and 5 j
`covery that free-flowing ‘crystals of the amantadine salt
`-' ‘of 16,] 6-dimethyl-PGEQ are pro‘duced~by mixing a solu-
`novel methods for producing the same. In particular,
`this invention relates to free-flowing crystals of the
`tionof _l 6,16-dimethyl-PGE‘2' in acetonitrile "with aman-
`tadine in butyronitrile at room‘ temperature; The result-
`amantadine salt of 16,16-dimethyl-PGE2_ a compound
`of the formula
`ing solution is cooledto the range of about -‘20° to 20°-
`C. until crystals are formed." These lfree-flowing" salt
`' crystals are non-hydroscopic, easily, ‘dried, and freehof
`water and solvent molecules. They also dissolve rapidly
`and completely in water, in hydroalcoholic solutions,
`and in the usual isotonic solutions used for intravenous
`injection or infusion.
`.
`_
`The production of the amantadine salt of 16_,l6-
`dimethyl-PGE2 in free-flowing crystalline form is espe-
`cially surprising and unexpected since the product is an
`oil when prepared by conventional methods for making
`amine salts utilizing alternative solvent systems. The
`salt in oil form is difficult to handle and purify and slow
`to dissolve in water, hydroalcoholic, and isotonic solu-
`tions.
`
`Amantadine
`( l-adamantanamine,
`aminoadamantane) is a compound of the formula
`
`l-
`
`20
`
`NH2
`
`I
`
`I
`
`25
`
`see the Merck Index, Merck and Co. Rathway, New
`Jersey (1968) page 48.
`16,16-Dimethyl-PGE2 is known to be useful for a va-
`riety of pharmacological and medical purposes; for ex-
`ample, to control excessive gastric secretions, to con-
`trol platelet aggregation, to control the reproductive
`cycle of
`female mammals,
`including humans,
`for
`smooth muscle stimulation, and for nasal decongestion.
`For these purposes the usual route of administration is
`intravenous injection, or infusion or oral. See German
`Offenlegungsschrift
`2217044, Derwent
`Farmdoc
`71483T.
`
`16,16-Dimethyl-PGE2, a carboxylic acid, does not
`dissolve readily in water, hydroalcoholic (water-ethyl
`alcohol) solutions, or the isotonic solutions necessary
`for intravenous injection or infusion. Preliminary treat-
`ment of the prostaglandin with a water-miscible or-
`ganic solvent and/or an aqueous solution of a base, for
`example, sodium hydroxide or sodium carbonate is
`usually necessary before an isotonic aqueous solution
`of the proper concentration can be formed. Moreover,
`16,16-dimethyl-PGE2 is a viscous oil which is difficult
`to purify and which is slow in dissolving in aqueous
`basic solutions.
`There would be a substantial advantage to having
`available 16,16-dimethyl-PGE2 in the form of a stable
`crystalline high melting salt which is rapidly soluble in
`water, in hydroalcoholic solutions, or in the isotonic so-
`lutions necessary for intravenous administration. There
`would also be substantial advantage in being able to
`produce preparations of the desired degree of purity of
`16,16-dimethyl-PGE2.
`16,16-Dimethyl-PGE2 and the process for making the
`same is known in the art. See German Offenlegungss-
`chrift 2217044, Derwent Farmdoc 7 l483T.
`I have made the surprising and unexpected discovery
`that the amantadine salt of 16,16-dimethyl-PGE2 is
`more stable to thermal decomposition than the free
`acid. It therefore has a greater shelf life which provides
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`30
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`50
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`55
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`60
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`65
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`In carrying out the novel process of this invention, it
`is desirable to use equivalent molar amounts of the
`prostaglandin and amantadine. Using less than an
`equivalent amount of the amine will result in part of the
`prostaglandin remaining in solution.
`It is preferred that proportions of acetonitrile and bu-
`tyronitrile be such that the maximum amount o.f salt
`crystallizes from the solvent mixture, as will be readily
`determined by one skilled in the art.
`It is advantageous to add the amantadine to the buty-
`ronitrile and heat to about 40° to 80° C. to effectuate
`solution. The solution should then be cooled to about
`room temperature. The 16,16-dimethyl-PGE2 is advan-
`tageously dissolved in acetonitrile without heating. The
`16,16-dimethyl-PGE2 solution is then added dropwise
`with vigorous stirring to the butyronitrile solution of
`amantadine. The resulting mixture is cooled to about
`—20° to 20° C. to promote crystallization.
`I have also made the surprising and unexpected dis-
`covery of a manufacture or a process for preparing
`free-flowing crystals of the amantadine salt of 16,16-
`dimethyl-PGE2 which comprises the steps of:
`I
`1. dissolving amantadine in a -liquid organic solvent
`forming a solution;
`2. dissolving 16,16-dimethyl-PGE2 in a second liquid
`organic solvent forming a second solution;
`3. adding the product of step 2 to the product of step
`1 to form a solution of the amantadine salt of 16,16-
`dimethyl-PGE2;
`4. cooling the product of step 3 to about —20° to 20°
`C. until crystals have formed; and
`5. collecting the crystals.
`In this process, it is preferred that the liquid organic
`solvent is butyronitrile. It is also preferred that the sec-
`ond Iiquid organic solvent is acetonitrile.
`When the process is first carried out it is advanta-
`geous to do it in a glass vessel, the inner walls of the
`vessel being scratched vigorously with a glass rod when
`the mixture just starts to become cloudy. Doing so will
`hasten crystal formation. In subsequent preparations, a
`few crystals from this first crystallization can be added
`as seeds at the same point of initial clouding to hasten
`crystal formation, and a glass vessel need not be used.
`
`SteadyMed - Exhibit 1016 - Page 2
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`SteadyMed - Exhibit 1016 - Page 2
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`

`
`Q
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`443,888,916
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`3
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`following example.
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`4
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`‘EXAMPLE 1
`
`VA
`
`After this initial cooling andcrystallization, the,mix~-
`ture is maintained at thesame temperature until no fur-
`ther crystallization occurs. The crystals are then col-
`lected by conventional
`techniques, e.g. filtration or
`centrifugation and washed with a small amount of the
`solvent‘ mixture. Most of the solvent mixture is re-
`moved eitherunder reduced pressure or in a current of
`warm nitrogen or argon. The crystals are then ground
`to a finer particle size if desired, and dried. Drying is
`completed by heating in the range about 50° to about
`‘ 70° C.
`When the amantadine salt of 16,16-dimethyl-PGE, is
`prepared by the above procedure, the purity is such
`that recrystallization is unnecessary.
`When recovery of 16,16-dimethyl-PGE2 from the
`amantadine salt is desired, it is accomplished by dis-
`solving the salt in water, adjusting the pH of that solu-
`tion to the range 6 to 7, and extracting the solution re-
`peatedly with ethyl acetate. The ethyl acetate extracts
`are combined, washed successively with water, and sat-
`urated aqueous sodium chloride solution, dried and
`evaporated to give 16,16-dimethyl-PGE2.
`The invention can be more fully understood by the
`
`Free-flowing crystals of the amantadine salt of 16,16-
`dimethyl—PGE2
`‘
`-
`A solutionof’16,16-dimethyl-PGE2 (589.82 mg.),
`dissolved in 15 ml. of acetonitrile, is added dropwise
`_ with vigorous stirring to a solution of amantadine
`(226.0 mg.) dissolvedin 50 ml. of butyronitrile. The
`solution is stirred for about 1 hour. The solution is then
`cooled to 4° C. with crystallization resulting. The re-
`sulting crystals are collected by filtration, washed on
`the filter with butyronitrile/acetonitrile. The product is
`dried at room temperature under vacuum. The yield is
`594.5 mg. The melting point is 86°—87.7° C. Infrared
`spectral peaks are at 3,400, 2,600, 1,625, 1,550, 1,400,
`1,080, 1,000, and 980 cm.“. The ultraviolet spectrum
`in basic ethanol is }t,,,,,_, = 280nm (E = 25,900).
`I claim:
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`10
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`15
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`1. The amantadine salt of 16,16-dimegthyl-PGE2.
`2. Free-flowing crystals of the amantadine salt of
`16,16-dimethyl-PGE2.>l<
`*
`*
`*
`*
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`40
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`45
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`50
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`55
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`60
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`65
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`SteadyMed - Exhibit 1016 - Page 3
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`SteadyMed - Exhibit 1016 - Page 3