USOO8415337B1
`
`(12) United States Patent
`Krishna
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,415,337 B1
`Apr. 9, 2013
`
`(54) IBUPROFEN COMPOSITIONS AND
`METHODS OF MAKING SAME
`
`(75) Inventor: Aravind Krishna, Skillman, NJ (US)
`(73) Assignee: Recordati Rare Diseases Inc., Lebanon,
`NJ (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`(21) Appl. No.: 13/410,989
`
`(*) Notice:
`
`(22) Filed:
`
`Mar. 2, 2012
`
`Related U.S. Application Data
`(60) Provisional application No. 61/449,692, filed on Mar.
`6, 2011.
`
`(51) Int. Cl.
`AOIN 43/00
`(52) U.S. Cl.
`USPC .......................................................... S14f183
`(58) Field of Classification Search ................... 514f183
`See application file for complete search history.
`
`(2006.01)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,145,440 A
`3, 1979 Fitch et al.
`4.279,926 A
`7, 1981 Bruzzese et al.
`5,895,789 A
`4/1999 Gentile et al.
`6,342,530 B1
`1/2002 Darko
`FOREIGN PATENT DOCUMENTS
`102180785. A
`9, 2011
`
`CN
`
`OTHER PUBLICATIONS
`Zadora G. 2009, Classification of Glass Fragments Based on Elemen
`tal Composition and Refractive Index, J. Forensic Sci., 54(1):49-59.
`Press Release, Jul. 30, 2010, Lundbeck Inc. Announces the voluntary
`Nationwide Recall of Two Lots of NeoProfen (ibuprofen lysine)
`injection. http://www.lundbeck.com/us/media press-releases/2010/
`lundbeck-inc-announces-the-voluntary-nationwide-recall-of-two
`lots-of-neoprofen-ibuprofen-lysine-injection.
`Aug. 8, 2010, NeoProfen (ibprofen lysine) Injection: Recall and
`Shortage—Risk of Particulate Matter, http://wwwfda.gov/Safety/
`Medwatch/SafetyInformation?
`safetyalertsforhumanmedicalproducts/ucm220798.htm.
`Oct. 2009, “Special Solutions”, SHOTT forma vitrum.
`May 2009, "Daikyo Technical Report Characteristics of Daikyo
`Resin CZ.” Daikyo Seiko, DS-CZ-E012.
`Baydoun Let al., 2004, "Comparison of different ibuprofen-amino
`acid compounds with respect to emulsifying and cytotoxic proper
`ties'. International Journal of Pharmaceutics, 274: 157-165.
`Libiao, L. et al., 1994, "Preparation of Ibuprofen Lysine and Its
`injection”, Journal of China Pharmaceutical University, 25(2):80-82.
`Woertz, K. et al., 2011, "A Comparative study on two electronic
`tongues for pharmaceutical formulation development”. Journal of
`Pharmaceutical and Biomedical Analysis. 55:272-281.
`Zgoda, M. et al., 2007. “Viscosity of hydrogel pharmaceutical prod
`ucts and the rate of diffusion of ibuprofen hydrotropic binding
`through model phase boundary in vitro', Polymers in Medicine,
`TXXXVII.(1): 1-11.
`Primary Examiner — Brandon Fetterolf
`Assistant Examiner — Jean Cornet
`(74) Attorney, Agent, or Firm — Stephen G. Kalinchak:
`Margaret M. Buck
`
`ABSTRACT
`(57)
`The present invention provides an improved ibuprofen lysine
`pharmaceutical composition and a process for preparing the
`SaC.
`
`10 Claims, 5 Drawing Sheets
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`Apr. 9, 2013
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`U.S. Patent
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`Apr. 9, 2013
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`US 8,415,337 B1
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`U.S. Patent
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`Apr. 9, 2013
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`Sheet 5 of 5
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`US 8,415,337 B1
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`US 8,415,337 B1
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`1.
`BUPROFEN COMPOSITIONS AND
`METHODS OF MAKING SAME
`
`2
`FIG. 4: SEM monograph of the interior surface of a repre
`sentative vial having an inert interior coating.
`FIG. 5: SEM monograph of the interior surface of a repre
`sentative vial lacking an inert interior coating.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides a pharmaceutical compo
`sition comprising:
`a) an alkylammonium salt of R-ibuprofen, S-ibuprofen or
`R.S.-ibuprofen that is capable of complexing with alu
`minum; and
`b) an aqueous or a non-aqueous solvent; wherein:
`the composition is:
`c) in unit dosage form in an environment for keeping;
`d) preservative-free or in a presence of an excipient; and
`e) substantially-free of ibuprofen aluminum salt precipi
`tate.
`The present invention also provides a pharmaceutical com
`position comprising:
`a) an an alkylammonium salt of ibuprofen selected from
`the group consisting of R-ibuprofen, S-Ibuprofen and
`R.S.-ibuprofen that is capable of complexing with alu
`minum; and
`b) an aqueous or a non-aqueous solvent; wherein:
`the composition is in a unit dosage forminan environment for
`keeping comprising:
`c) optionally an absence of preservative;
`d) optionally a presence of an excipient; and
`e) a Substantial absence of ibuprofen aluminum salt pre
`cipitate.
`The present invention also provides a pharmaceutical com
`position comprising:
`a) an an alkylammonium salt of ibuprofen selected from
`the group consisting of R-ibuprofen, S-Ibuprofen and
`R.S.-ibuprofen that is capable of complexing with alu
`minum;
`b) an aqueous or a non-aqueous solvent;
`c) optionally an absence of a preservative;
`d) optionally a presence of excipient; and
`e) a Substantial absence of ibuprofen aluminum salt pre
`cipitate;
`wherein the composition is in a unit dosage form in an
`environment for keeping.
`The invention also provides a process for the preparation of
`the pharmaceutical composition of the invention, the process
`comprising:
`(a) mixing an alkylammonium salt of R-ibuprofen, S-ibu
`profen or, S-ibuprofen that is capable of complexing
`with aluminum with an aqueous or a non-aqueous Sol
`vent;
`(b) optionally adjusting the pH of mixture (a) to about 7.0
`with sodium hydroxide or hydrochloric acid;
`(c) filtering mixture (a) or (b) as the case may be:
`(d) aseptically processing filtered mixture (c) while placing
`it in an environment for keeping;
`(e) sealing the environment for keeping; and
`(f) optionally terminally sterilizing.
`The invention also provides a pharmaceutical composition
`comprising:
`(a) an alkylammonium salt of R-ibuprofen, S-ibuprofen or
`R.S.-ibuprofen that is capable of complexing with alu
`minum; and
`(b) an aqueous or a non-aqueous solvent; wherein:
`the composition is:
`(a) in unit dosage form in an environment for keeping;
`(b) preservative-free or in a presence of an excipient; and
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`The present application is a U.S. Nonprovisional Patent
`Application claiming the benefit of U.S. Provisional Appli
`cations No. 61/449,692, filed Mar. 6, 2011, which is herein
`incorporated by reference in its entirety.
`
`10
`
`FIELD OF THE INVENTION
`
`This invention relates to improved pharmaceutical compo
`sitions of alkylammonium salts of ibuprofen, Such as ibru
`profen lysinate, and processes for preparing the pharmaceu
`tical compositions.
`
`15
`
`BACKGROUND OF THE INVENTION
`
`25
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`30
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`35
`
`40
`
`Ibuprofen is a phenylpropionate or 2-arylpropionic acid
`also known as 2-4-(2-methylpropyl)phenylpropanoic acid.
`U.S. Pat. No. 4.279,926 (Bruzzese et al.) discloses phar
`maceutical compositions containing salts of phenylalkanoic
`acids, including the D.L and Llysine salts of ibuprofen and is
`directed to methods of treating inflammation and pain using
`the same.
`U.S. Pat. No. 5,895,789 (Gentile et al) is directed to phar
`maceutical compositions suitable for parenteral administra
`tion that contain an alkylammonium salt of a 2-arylpropionic
`acid, include an aqueous Solution having an osmolarity
`between 270 and 310 mC)sm/kg and a pH in the range of 7.0
`to 7.5, are free of preservatives and of Supporting Substances
`and prepared and kept in an inert gas atmosphere and away
`from light, as well as a process for preparing these pharma
`ceutical compositions.
`U.S. Pat. No. 6,342.530 (L. Darko) is directed to pharma
`ceutical compositions in unit dosage forminavial orampoule
`having storage stability over a period of 2 years and Suitable
`for parenteral administration having anti-inflammatory, anti
`pyretic and analgesic properties, which consists of a thera
`peutically effective amount of the d1 or 1-lysine salt of R.S or
`S-ibuprofen as active ingredient dissolved in sterile water to
`form a solution in the absence of an inert atmosphere and
`Substantially free of any excipient, organic solvent, buffer,
`45
`acid, base, salt other than the active ingredient and capable of
`storage in the absence of an inert atmosphere.
`Surprisingly it now has been found that an ibuprofen alu
`minum salt precipitate can form in these pharmaceutical com
`positions. The presence of the ibuprofen aluminum salt pre
`50
`cipitate may result in the ibuprofen alkylammonium salt
`pharmaceutical composition being unsuitable for therapeutic
`use. An alkylammonium salt ibuprofen pharmaceutical com
`position that is Substantially-free of an ibuprofen aluminum
`salt precipitate would be beneficial since the therapeutic use
`of the pharmaceutical composition would not be compro
`mised. The present invention is directed to these, and other
`important, ends.
`
`55
`
`SUMMARY OF DRAWINGS
`
`FIG. 1: FTIR spectrum of particulate matter from a repre
`sentative ibuprofen lysine Solution.
`FIG. 2: FTIR spectrum of a representative aluminum ibu
`profen salt.
`FIG. 3: FTIR spectrum of particulate matter from a repre
`sentative ibuprofen lysine Solution.
`
`60
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`3
`(c) Substantially-free of ibuprofen aluminum salt precipi
`tate;
`prepared by a process comprising the steps:
`(a) mixing an alkylammonium salt of R-ibuprofen, S-ibu
`profen or R.S.-ibuprofen that is capable of complexing
`with aluminum compounds with an aqueous solution,
`Suspension or emulsion, or a non-aqueous Solution, Sus
`pension or emulsion;
`(b) optionally adjusting the pH of mixture (a) to about 7.0
`with sodium hydroxide or hydrochloric acid;
`(c) filtering mixture (a) or (b) as the case may be:
`(d) aseptically processing filtered mixture (c) while placing
`it in an environment for keeping;
`(e) sealing the environment for keeping; and
`(f) optionally terminally sterilizing.
`The invention also provides a pharmaceutical composition
`comprising:
`a) an an alkylammonium salt of ibuprofen selected from
`the group consisting of R-ibuprofen, S-Ibuprofen and
`R.S.-ibuprofen that is capable of complexing with alu
`minum;
`b) an aqueous or a non-aqueous solvent;
`c) optionally an absence of a preservative;
`d) optionally a presence of excipient; and
`e) a Substantial absence of ibuprofen aluminum salt pre
`cipitate;
`wherein the composition is in a unit dosage form in an envi
`ronment for keeping;
`prepared by a process comprising the steps:
`f) mixing an alkylammonium salt of R-ibuprofen, S-ibu
`profen or R.S.-ibuprofen that is capable of complexing
`with aluminum compounds with an aqueous solution,
`Suspension or emulsion, or a non-aqueous Solution, Sus
`pension or emulsion;
`g) optionally adjusting the pH of mixture (a) to about 7.0
`with sodium hydroxide or hydrochloric acid;
`h) filtering mixture (a) or (b) as the case may be:
`i) aseptically processing filtered mixture (c) while placing
`it in an environment for keeping;
`j) sealing the environment for keeping; and
`k) optionally terminally sterilizing.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`4
`j) a Substantial absence of ibuprofen aluminum salt pre
`cipitate.
`The present invention also provides a pharmaceutical com
`position comprising:
`f) an an alkylammonium salt of ibuprofen selected from the
`group consisting of R-ibuprofen, S-Ibuprofen and R.S.-
`ibuprofen that is capable of complexing with aluminum;
`g) an aqueous or a non-aqueous Solvent;
`h) optionally an absence of a preservative;
`i) optionally a presence of excipient; and
`j) a Substantial absence of ibuprofen aluminum salt pre
`cipitate;
`wherein the composition is in a unit dosage form in an
`environment for keeping.
`Though injectable pharmaceutical compositions often
`contain subvisible extraneous particles (such as cellulose and
`elastomers) when examined under a microscope, which fre
`quently come from container-closure components and/or
`manufacturing, it now Surprisingly has been found that the
`predominant particulate in ibuprofen alkylammonium salt
`compositions of the prior art is an organo-aluminum salt.
`Without being bound by any one theory, it is possible that the
`salt of the ibuprofen alkylammonium salt composition
`extracts aluminum from the glass vial or ampoule in which
`the pharmaceutical composition typically is contained being
`that it is known that the elemental composition of glass
`includes aluminum (see e.g., G. Zadora, "Classification of
`Glass Fragments Based on Elemental Analysis and Refractive
`Index. J. Forensic Sci., (2009) 54(1): 49-59), resulting in an
`aluminum-lysine complex. Further, ibuprofen of the pharma
`ceutical composition may extract aluminum from the glass
`vial or glass ampoule since it is a carboxylic acid, as well as
`be in equilibrium with the aluminum-lysine complex where
`aluminum is exchanged between the two acids.
`The phrase “environment for keeping or simply “environ
`ment' is defined herein, unless otherwise Stated, as a means
`for containing the unit dosage form. Non-limiting examples
`of an environment for keeping are a vial, ampoule, blister
`pack, and prefillable delivery systems such as Syringes and
`cartridges.
`As used herein, the phrases “substantially-free of ibupro
`fen aluminum salt precipitate' and “substantial absence of
`ibuprofen aluminum salt precipitate' mean that the pharma
`ceutical composition has at least no visible or subvisible
`particulate matter, Such as at least less than about 5 g/L of
`ibuprofen aluminum salt precipitate.
`In some embodiments, the alkylammonium salt is selected
`from a group consisting of d.l-lysine, 1-lysine, d-lysine,
`tromethamine and meglumine. In some embodiments, the
`alkylammonium salt is d.l-lysine, l-lysine, or d-lysine. In
`Some embodiments, the salt is d-lysine. In some embodi
`ments, the salt is l-lysine.
`In some embodiments, the environment for keeping is
`selected from a group consisting of a vial, an ampoule, a
`blister pack and a prefilable delivery system. In some
`embodiments, the environment is a vial or an ampoule. In
`Some embodiments, it is a vial. In some embodiments, it is an
`ampoule. In some embodiments, it is a blister pack. In some
`embodiments, it is a prefillable delivery system. In some
`embodiments, the prefillable delivery system is a Syringe or a
`cartridge.
`The environment for keeping is comprised of a material, or
`combination of materials, that is inert to the complexing of
`any aluminum content it may have with the R-ibuprofen,
`S-ibuprofen or R.S.-ibuprofen alkylammonium salt composi
`tion it contains.
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`
`The invention provides a pharmaceutical composition
`comprising:
`(a) an alkylammonium salt of R-ibuprofen, S-ibuprofen or
`R.S.-ibuprofen that is capable of complexing with alu
`minum; and
`(b) an aqueous, or a non-aqueous solvent, wherein:
`the composition is:
`(a) in unit dosage form in an environment for keeping;
`(b) preservative-free or in a presence of an excipient; and
`(c) Substantially-free of ibuprofen aluminum salt precipi
`tate.
`The present invention also provides a pharmaceutical com
`position comprising:
`f) an an alkylammonium salt of ibuprofen selected from the
`group consisting of R-ibuprofen, S-ibuprofen and R.S.-
`ibuprofen that is capable of complexing with aluminum;
`and
`g) an aqueous or a non-aqueous solvent; wherein:
`the composition is in a unit dosage form in an environment for
`keeping comprising:
`h) optionally an absence of preservative;
`i) optionally a presence of an excipient; and
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`5
`In some embodiments, the environment for keeping is
`comprised of glass, such as a vial or an ampoule. In some
`embodiments, the aluminum content of the glass environment
`is negligible Such that the ibuprofen Salt composition in it is
`substantially-free of ibuprofen aluminum salt precipitate. In
`Some embodiments, the glass environment further comprises
`a coating disposed on the inner wall of it that inhibits or
`reduces the aluminum content of it from complexing with the
`R-ibuprofen, S-ibuprofen or R.S.-ibuprofen alkylammonium
`salt composition it contains. In some such embodiments, the
`coating is comprised of silicon dioxide, Teflon R, or any other
`inert material that inhibits or reduces the aluminum content of
`the glass environment from complexing with the R-ibupro
`fen, S-ibuprofen or R.S.-ibuprofen alkylammonium salt com
`position the glass environment contains. For example, Schott
`15
`Type I Plus(R) vials (Schott North America, Inc., Lebanon, Pa.,
`U.S.A.), which are glass vials having an inert quartz-like
`non-porous coating consisting of 100% SiO2 that covalently
`bonds to the inner surface of the vial and a thickness of
`100-200 nm.
`In some embodiments, the coating is silicon dioxide. In
`Some embodiments, the coating is Teflon R. In some embodi
`ments, the coating is an inert polymer.
`In some embodiments, the environment for keeping is
`comprised of an inert polymeric material. For example, Dal
`kyo Crystal Zenith R. vials and prefillable delivery systems
`(West Pharmaceutical Services, Lionville, Pa., U.S.A., the
`U.S. affiliate of Dalkyo Seiko, Ltd., Tokyo, Japan), which are
`comprised of a proprietary cyclic olefin polymer material.
`The aqueous solvent of the pharmaceutical composition
`can be any grade of water Suitable for parenteral applications.
`For example, Water for Injection, USP.
`The non-aqueous solvent of the pharmaceutical composi
`tion can be ethanol, a propylene glycol, glycerol, and the like,
`or a mixture of one or more of these non-aqueous solvents
`with water.
`In some embodiments, a preservative is absent (i.e., pre
`servative-free or an absence of preservative). In some
`embodiments, a preservative is present (i.e., a presence of
`preservative). In some embodiments, excipient is present
`40
`(i.e., there is a presence of excipient). In some embodiments,
`excipient is absent (i.e., an absence of excipient).
`The invention also provides a pharmaceutical composition
`as defined herein, wherein the unit dosage form is liquid. In
`Some embodiments, the liquid unit dosage form is a mixture
`selected from the group consisting of a solution, a Suspension,
`a dispersion and an emulsion.
`The invention also provides a pharmaceutical composition
`as defined herein, wherein the unit dosage form is solid. In
`Some embodiments, the Solid unit dosage form is a lyo
`philized powder. In some embodiments, the Solid unit dosage
`form is a quick dissolve strip or tablet. In some embodiments,
`it’s a fast melt strip or tablet.
`The invention also provides a process for the preparation of
`the pharmaceutical composition of the invention. The process
`comprises:
`(a) mixing an alkylammonium salt of R-ibuprofen, S-ibu
`profen or R.S.-ibuprofen that is capable of complexing
`with aluminum with an aqueous or a non-aqueous sol
`vent;
`(b) optionally adjusting the pH of mixture (a) to about 7.0
`with sodium hydroxide or hydrochloric acid;
`(c) filtering mixture (a) or (b) as the case may be:
`(d) aseptically processing filtered mixture (c) while placing
`it in an environment for keeping;
`(e) sealing the environment for keeping; and
`(f) optionally terminally sterilizing.
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`6
`The pharmaceutical composition of the invention also can
`be made by processes known in the art for preparing ibupro
`fen alkylammonium salts. See e.g., U.S. Pat. Nos. 4.279,926,
`5,895,789 and 6,342,530.
`The invention also provides a pharmaceutical composition
`comprising:
`(a) an alkylammonium salt of R-ibuprofen, S-ibuprofen or
`R.S.-ibuprofen that is capable of complexing with alu
`minum; and
`(b) an aqueous or a non-aqueous solvent; wherein:
`the composition is:
`(a) in unit dosage form in an environment for keeping;
`(b) preservative-free or in a presence of an excipient; and
`(c) Substantially-free of ibuprofen aluminum salt precipi
`tate;
`prepared by a process comprising the steps:
`(a) mixing an alkylammonium salt of R-ibuprofen, S-ibu
`profen or R.S.-ibuprofen that is capable of complexing
`with aluminum compounds with an aqueous solution,
`Suspension or emulsion, or a non-aqueous solution, Sus
`pension or emulsion;
`(b) optionally adjusting the pH of mixture (a) to about 7.0
`with sodium hydroxide or hydrochloric acid;
`(c) filtering mixture (a) or (b) as the case may be:
`(d) aseptically processing filtered mixture (c) while placing
`it in an environment for keeping;
`(e) sealing the environment for keeping; and
`(f) optionally terminally sterilizing.
`The invention also provides a pharmaceutical composition
`comprising:
`1) an an alkylammonium salt of ibuprofen selected from the
`group consisting of R-ibuprofen, S-Ibuprofen and R.S.-
`ibuprofen that is capable of complexing with aluminum;
`m) an aqueous, or a non-aqueous solvent;
`n) optionally an absence of a preservative;
`o) optionally a presence of excipient; and
`p) a Substantial absence of ibuprofen aluminum salt pre
`cipitate;
`wherein the composition is in a unit dosage form in an envi
`ronment for keeping;
`prepared by a process comprising the steps:
`q) mixing an alkylammonium salt of R-ibuprofen, S-ibu
`profen or R.S.-ibuprofen that is capable of complexing
`with aluminum compounds with an aqueous solution,
`Suspension or emulsion, or a non-aqueous solution, Sus
`pension or emulsion;
`r) optionally adjusting the pH of mixture (a) to about 7.0
`with sodium hydroxide or hydrochloric acid;
`S) filtering mixture (a) or (b) as the case may be:
`t) aseptically processing filtered mixture (c) while placing
`it in an environment for keeping;
`u) sealing the environment for keeping; and
`V) optionally terminally sterilizing.
`In some embodiments, the pharmaceutical composition is
`administered parenterally, such as intravenously. In some
`embodiments, the pharmaceutical composition is adminis
`tered orally, Such as buccally and Sublingually.
`The following examples are meant to illustrate the inven
`tion without in any way limiting it.
`
`EXAMPLE 1.
`
`Aluminum Content in Ibuprofen Lysine Solution
`
`Total aluminum content was measured in multiple batches
`of Ibuprofen Lysine Solution (i.e., pharmaceutical composi
`tion) in Wheaton Type 1 glass vials stored at 25°C. and 60%
`
`Eton Ex. 1048
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`
`

`

`US 8,415,337 B1
`
`8
`EXAMPLE 3
`
`7
`relative humidity (RH). The aluminum content was measured
`using inductively coupled plasma mass spectrometry (ICP
`MS). The ICP-MS methodology used is well known by those
`skilled in the art, and it was validated with a limit of quanti
`fication (LOQ) of 9 ppb (9 g/L) established. The ICP-MS 5
`method measured the total amount of aluminum present in the
`vial, i.e., soluble and insoluble. Table 1 shows the storage
`time of a batch at the time of analysis and the aluminum
`content measured. The gradual increase in aluminum content 10
`over time Suggests that the aluminum is continuously being
`extracted from the inner surface of the vial.
`
`TABLE 1.
`
`Aluminum Content in Various
`Batches of Ibuprofen Lysine Solution
`
`Batch
`
`Storage Time
`(months)
`
`Aluminum Content
`(Lig/L)
`
`1
`2
`3
`4
`5
`6
`
`65
`52
`34
`25
`17
`14
`
`112
`141
`98
`108
`26
`71
`
`EXAMPLE 2
`
`15
`
`2O
`
`25
`
`30
`
`Aluminum Content in Ibuprofen Lysine Active
`
`Aluminum content in multiple lots of Ibuprofen Lysine 35
`active was measured using inductively coupled plasma mass
`spectrometry (ICP-MS) method of Example 1 to estimate the
`aluminum content contribution from the ibuprofen lysine
`active to formation of an ibuprofen aluminum salt precipitate
`in the Ibuprofen Lysine solutions of Example 1 and others. 40
`The Ibuprofen Lysine active was prepared in water at a con
`centration of 17 mg/mL, which is the same concentration of
`the Ibuprofen Lysine solution. As can be seen from the results
`in Table 2, the contribution from the ibuprofen lysine active to 45
`the formation of the ibuprofen aluminum salt precipitate is
`negligible. Therefore, the ibuprofen lysine active is not a
`significant source of aluminum in the Ibuprofen Lysine Solu
`tion.
`
`TABLE 2
`
`Aluminum Content in Various
`Lots of Ibuprofen Lysine Active
`
`50
`
`Accelerating Visible Ibuprofen Aluminum Salt
`Particulate Formation
`
`Three different concentrations of Ibuprofen Lysine in
`water were prepared (1.7 mg/mL, 17 mg/mL and 170
`mg/mL). The equivalent Ibuprofen concentrations are 1.0
`mg/mL, 10 mg/mL and 100 mg/mL, respectively. The solu
`tions were filtered through a 0.2 um filter, filled into clear
`borosilicate glass vials commonly used for Such solutions
`(Type I, Wheaton Science Packaging, a division of Wheaton
`Industries, Inc., Millville, N.J., U.S.A.). The fill volumes
`were 1 mL, 2 mL and 3 mL for each concentration. The vials
`were stoppered with a commonly used stopper (Dalkyo Fluo
`rotec(R) (D777-1 S2-451), West Pharmaceutical Services,
`Lionville, Pa., U.S.A.) and capped. The filled vials were
`stored at 25°C., 60° C. and 90° C. and 60% relative humidity.
`The higher temperature conditions were used to accelerate
`the effect one would likely observe over a longer period of
`time at ambient temperature. This practice, with these condi
`tions, often is used in the pharmaceutical art to determine
`feasibly of long term storage conditions in a shorter than
`actual period of time. Over a 4-week period, one vial from
`each condition was visually inspected 2x per week for visible
`particulate appearance and solution color. The vials were
`inspected in a light box and observations recorded. The same
`vial was observed each time for consistency over the 4-weeks.
`A sample was drawn weekly over the 4-weeks from one vial
`of each type and the sample tested for aluminum content
`using inductively coupled plasma mass spectrometry (ICP
`MS). The ICP-MS methodology used is well known by those
`skilled in the art.
`As can be seen from the results in Tables 3-4, the 17 mg/mL
`solution samples stored at 60° C. for 2-weeks produced vis
`ible particulate matter with no change in the color of the
`Solution. This finding Suggests that a 17 mg/mL Ibuprofen
`Lysine solution stored for 14 days at 60° C. produces an
`ibuprofen aluminum salt precipitate. A higher concentration
`solution (170 mg/mL) at 60° C. or 90° C. produced visible
`particulate matter, but a change in Solution color also was
`observed, which most probably was due to the formation of
`degradation products.
`Also, the total aluminum content results presented in Table
`5 show an increase in aluminum content as a function of both
`temperature and solution concentration. The amount of alu
`minum extracted is highest for the most concentrated Solution
`stored at 90° C. Moderate amounts of aluminum were
`extracted with the 17 mg/mL solution at 60° C.
`
`TABLE 3
`
`Visible Particulate Matter Results'
`
`Conc.
`(mg/mL)
`
`Temp.
`(°C.)
`
`Fill Vol.
`(mL)
`
`7 days 14 days 21 days 28 days
`
`Lot
`
`Ref.
`
`A.
`B
`C
`D
`D
`D - E
`E
`F
`
`Batch
`
`1
`2
`3
`4
`5
`6
`7
`8
`
`Aluminum Content
`
`55
`
`gig
`
`O.18
`O.32
`O.15
`O.18
`O.18
`0.25* *
`O.32
`O.21
`
`Jig?L
`
`<9
`<9
`<9
`<9
`<9
`<9
`<9
`<9
`
`Lug of aluminum per gram of Ibuprofen Lysine,
`**value average of Lots D and Eindividually measured values,
`
`1.7
`
`60
`
`65
`
`25
`
`60
`
`90
`
`25
`
`1
`2
`3
`1
`2
`3
`1
`2
`3
`1
`2
`3
`
`None
`None
`None
`None
`None
`None
`None
`None
`None
`None
`None
`None
`
`None
`Fiber
`None
`Yes
`Fiber
`Fiber
`Yes
`Yes
`Yes
`None
`Fiber
`None
`
`Yes
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`None
`
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`Fiber
`
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`
`

`

`US 8,415,337 B1
`
`9
`TABLE 3-continued
`
`Visible Particulate Matter Results'
`
`10
`TABLE 5-continued
`
`Aluminum Content Results
`
`Conc.
`(mg/mL)
`17
`
`Temp.
`(°C.)
`60
`
`90
`
`25
`
`170
`
`60
`
`90
`
`Fill Vol.
`(mL)
`1
`2
`3
`1
`2
`3
`1
`2
`3
`1
`2
`3
`1
`2
`3
`
`7 days 14 days 21 days 28 days 5
`None
`Yes
`Yes
`Yes
`None
`Yes
`Yes
`Yes
`None
`Yes
`Fiber
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`None
`Fiber
`Yes
`Fiber
`None
`Fiber
`Fiber
`Fiber
`None
`Fiber
`Yes
`Fiber
`None
`Yes
`Yes
`Yes
`None
`Yes
`Yes
`Yes
`None
`Yes
`Yes
`Yes
`None
`Yes
`Yes
`Yes
`None
`Yes
`Yes
`Yes
`None
`Yes
`Yes
`Yes
`
`15
`
`10
`
`W
`Yes = particulates visible, i.e., precipitate found; Fiber = fiber-like particulates observed,
`i.e., precipitate found.
`
`Conc.
`
`Temp. Fill Vol.
`
`Aluminum Content (ugL
`
`(mg/mL)
`17
`
`(C.)
`25
`
`60
`
`90
`
`170
`
`25
`
`60
`
`(mL)
`1
`2
`3
`1
`2
`3
`1
`2
`3
`1
`2
`3
`1
`2
`3
`
`7 days
`14
`6
`8
`18
`13
`11
`28
`14
`6
`17
`14
`25
`50
`60
`59
`
`14 days
`8
`3
`3
`28
`9
`1
`21
`2
`4
`33
`125
`31
`61
`2O
`83
`
`21 days
`11
`5
`4
`38
`23
`2O
`33
`17
`15
`35
`19
`15
`64
`104
`8O
`
`28 days
`11
`
`2
`52
`12
`9
`34
`23
`22
`38
`21
`39
`84
`160
`153
`
`TABLE 4
`
`Solution Color Results
`
`7 days
`
`14 days
`
`21 days
`
`28 days
`
`Conc.
`(mg/mL)
`
`Temp. Fill Vol.
`(C.)
`(mL)
`
`1.7
`
`25
`
`2
`3
`
`2
`3
`
`2
`3
`
`2
`3
`
`2
`3
`
`60
`
`90
`
`17
`
`25
`
`60
`
`90
`
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Colorless
`Pale Yellow
`Pale Yellow Pale Yellow PaleYellow
`Pale Yellow
`Pale Yellow Pale Yellow PaleYellow
`Pale Yellow
`Pale Yellow Pale Yellow PaleYellow
`Pale Yellow
`Colorless
`Colorless
`Colorless
`Pale Yellow
`Colorless
`Colorless
`Colorless
`Pale Yellow
`Colorless
`Colorless
`Colorless
`Yellow
`Pale Yellow
`Yellow
`Yellow
`Yellow
`Pale Yellow
`Yellow
`Yellow
`Yellow
`Pale Yellow
`Yellow
`Yellow
`Yellow
`Dark Yellow Dark Yellow Dark Yellow
`Yellow
`Dark Yellow Dark Yellow Dark Yellow
`Yellow
`Yellow
`Dark Yellow Dark Yellow
`
`170
`
`25
`
`60
`
`90
`
`2
`3
`
`2
`3
`
`2
`3
`
`2
`3
`
`TABLE 5
`
`Aluminum Content Results
`
`TABLE 5-continued
`
`Conc.
`
`Temp. Fill Vol.
`
`Aluminum Content (ugL
`
`55
`
`Aluminum Content Results
`
`(mg/mL)
`
`(C.)
`
`(mL)
`
`7 days
`
`14 days
`
`21 days
`
`28 days
`
`Conc.
`
`Temp. Fill Vol.
`
`Aluminum Content (gL)
`
`1.7
`
`25
`
`60
`
`90
`
`1
`2
`3
`1
`2
`3
`1
`2
`3
`
`11
`17
`5
`10
`5
`4
`408
`59
`70
`
`5
`2
`3
`7
`8
`4
`100
`81
`36
`
`5
`6
`1
`6
`17
`7
`Not Tested
`15
`32
`
`12
`3
`13
`15
`11
`18
`33
`7
`24
`
`60 (mg/mL) (C.)
`
`(mL)
`
`7 days
`
`14 days
`
`21 days
`
`28 days
`
`90
`
`1
`2
`
`3
`
`301
`416
`
`286
`
`40S
`435
`
`328
`
`316
`388
`
`312
`
`276
`731
`
`472
`
`65
`
`Eton Ex. 1048
`11 of 15
`
`

`

`US 8,415,337 B1
`
`11
`EXAMPLE 4
`
`12
`TABLE 6-continued
`
`Determination of Visible Precipitate from Example 3
`
`To determine whether the observed particulate material in
`the 17 mg/mL Ibuprofen Lysine solution stored for 14 days at
`60° C. in EXAMPLE 2 was ibuprofen aluminum salt, the
`particulate matter was tested by Fourier transform infrared
`(FTIR) spectroscopy. Aluminum salts of ibuprofen (1:1, 2:1
`and 3:1) were