I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US008232265B2
`
`c12) United States Patent
`Rogers et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,232,265 B2
`Jul. 31, 2012
`
`(54) MULTI-FUNCTIONAL IONIC LIQUID
`COMPOSITIONS FOR OVERCOMING
`POLYMORPHISM AND IMPARTING
`IMPROVED PROPERTIES FOR ACTIVE
`PHARMACEUTICAL, BIOLOGICAL,
`NUTRITIONAL, AND ENERGETIC
`INGREDIENTS
`
`(75)
`
`Inventors: Robin D. Rogers, Tuscaloosa, AL (US);
`Daniel T. Daly, Tuscaloosa, AL (US);
`Richard P. Swatloski, Tuscaloosa, AL
`(US); Whitney L. Hough, Albertville,
`AL (US); James Hilliard Davis, Jr.,
`Mobile, AL (US); Marcin Smiglak,
`Tuscaloosa, AL (US); Juliusz Pernak,
`Poznan (PL); Scott K. Spear, Bankston,
`AL (US)
`
`(73) Assignee: Board of Trustees of the University of
`Alabama, Tuscaloosa, AL (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1208 days.
`
`(21) Appl. No.: 11/545,938
`
`(22) Filed:
`
`Oct. 10, 2006
`
`(65)
`
`Prior Publication Data
`
`US 2007 /0093462 Al
`
`Apr. 26, 2007
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/764,850, filed on Feb.
`2, 2006, provisional application No. 60/724,604, filed
`on Oct. 7, 2005, provisional application No.
`60/724,605, filed on Oct. 7, 2005.
`
`(51)
`
`Int. Cl.
`A61K 31/33
`(2006.01)
`A61K 31/445
`(2006.01)
`A61K 31/21
`(2006.01)
`A61K 31/24
`(2006.01)
`A61K 31/16
`(2006.01)
`AOlN 43/90
`(2006.01)
`AOlN 37/30
`(2006.01)
`AOlN 37/18
`(2006.01)
`(52) U.S. Cl. ........ 514/183; 514/306; 514/330; 514/513;
`514/535; 514/555
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
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`
`Primary Examiner - Alton Pryor
`(74) Attorney, Agent, or Firm -McKean, Meunier, Carlin
`& Curfman, LLC
`
`ABSTRACT
`(57)
`Disclosed are ionic liquids and methods of preparing ionic
`liquid compositions of active pharmaceutical, biological,
`nutritional, and energetic ingredients. Also disclosed are
`methods of using the compositions described herein to over(cid:173)
`come polymorphism, overcome solubility and delivery prob(cid:173)
`lems, to control release rates, add functionality, enhance effi(cid:173)
`cacy (synergy), and improve ease of use and manufacture.
`Merck 2018
`Argentum v. Merck
`IPR2018-00423
`
`9 Claims, 6 Drawing Sheets
`
`

`

`US 8,232,265 B2
`Page 2
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`* cited by examiner
`
`

`

`U.S. Patent
`
`Jul. 31, 2012
`
`Sheet 1 of 6
`
`US 8,232,265 B2
`
`Figure 1
`
`[Hex]Sulfacetamide, [Hex]Cl & Na Sulfacetamide Dissolution
`
`1.25
`
`1.00
`
`§ 0.75
`
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`tr)
`N
`@)
`Ill
`
`~ 0.50
`
`0.25
`
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`
`10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160
`
`Time (min)
`
`- - Cation [Hex][Cl]
`- - Anion [Na]Sulfacetamide
`- - Ionic Liquid [Hex]Sulfacetamide
`
`

`

`U.S. Patent
`
`Jul. 31, 2012
`
`Sheet 2 of 6
`
`US 8,232,265 B2
`
`Figure 2
`
`Hex Sulfacetamide and DDA Sulfacetamide Dissolution
`
`0
`
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`
`50
`
`100
`
`150
`
`200
`
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`DOA Sulfacetamide
`
`Time (min)
`
`

`

`U.S. Patent
`U.S. Patent
`
`Jul. 31, 2012
`Jul. 31, 2012
`
`Sheet 3 of 6
`Sheet 3 of 6
`
`US 8,232,265 B2
`US 8,232,265 B2
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`

`U.S. Patent
`
`Jul. 31, 2012
`
`Sheet 4 of 6
`
`US 8,232,265 B2
`
`Figure 4A
`
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`

`

`U.S. Patent
`
`Jul. 31, 2012
`
`Sheet 5 of 6
`
`US 8,232,265 B2
`
`Figure 5
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`U.S. Patent
`
`Jul. 31, 2012
`
`Sheet 6 of 6
`
`US 8,232,265 B2
`
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`US 8,232,265 B2
`
`1
`MULTI-FUNCTIONAL IONIC LIQUID
`COMPOSITIONS FOR OVERCOMING
`POLYMORPHISM AND IMPARTING
`IMPROVED PROPERTIES FOR ACTIVE
`PHARMACEUTICAL, BIOLOGICAL,
`NUTRITIONAL, AND ENERGETIC
`INGREDIENTS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This patent application claims the benefit of priority to U.S.
`Provisional Application No. 60/764,850, filed Feb. 2, 2006,
`U.S. Provisional Application No. 60/724,604, filed Oct. 7,
`2005, and U.S. Provisional Application No. 60/724,605, filed
`Oct. 7, 2005, which are each incorporated by reference herein
`in their entireties.
`
`FIELD
`
`The subject matter disclosed herein generally relates to
`ionic liquids and to methods of preparing ionic liquid com(cid:173)
`positions of active pharmaceutical, biological, nutritional,
`and energetic ingredients. Also the subject matter disclosed
`herein generally relates to methods of using the compositions
`described herein to overcome polymorphism, overcome solu(cid:173)
`bility and delivery problems, to control release rates, add
`functionality, enhance efficacy (synergy), and improve ease
`of use and manufacture.
`
`BACKGROUND
`
`Polymorphism is the ability of a substance to exist in two or
`more crystalline forms that have a different arrangement and/
`or conformation of molecules in a crystalline lattice ( see e.g.,
`Chawla and Bansal, CRIPS 2004, 5(1):9-12; Bernstein,
`"Polymorphism in Molecular Crystals," IUCR Monographs
`on Crystallography 14, Oxford Science Publications, 2002,
`pp. 1-28, 240-256). It has been estimated that a large number
`of pharmaceuticals exhibit polymorphism. For example, 70%
`of barbiturates, 60% of sulfonamides, and 23% of steroids are
`believed to exist in different polymorphic forms or "polymor(cid:173)
`phs" (Haleblian et al., J Pharm Sci 1975, 64:1269-1288).
`In some cases, when crystals of a compound are forming
`(e.g., crystallizing from a solution), solvent molecules may
`become entrapped or bound within the crystal lattice. The
`presence of the entrapped solvent molecules may affect the
`three-dimensional crystal lattice that eventually crystallizes.
`The occurrence of a compound (target molecule) crystalliz(cid:173)
`ing in different three-dimensional lattices based upon the
`presence of solvent molecules has been termed "pseudo(cid:173)
`polymorphism." Akin to polymorphs, such "pseudo-poly(cid:173)
`morphs," also known as "solvates" ( or "hydrates" when the
`solvent is water), are crystalline solids containing either sto(cid:173)
`ichiometric (i.e., whole number ratios of target molecules to
`solvent molecules) or non-stoichiometric (i.e., non-whole
`number ratios of target molecules to solvent molecules)
`amounts of a solvent incorporated within the crystal structure.
`In general, different crystalline forms of molecules ( e.g.,
`pharmaceutical compounds) can exist in the same or different
`hydrated or solvated states.
`The Cambridge Structural Database (Allen, "The Cam(cid:173)
`bridge Structural Database: a quarter of a million crystal
`structures and rising," Acta Crystallographica, 2002, B58,
`380-388) is a database of over 300,000 organic crystal struc(cid:173)
`tures and is a widely used reference source in crystallography.
`One survey of the Cambridge Structural Database shows that
`
`2
`pharmaceutical compounds have been reported to exist as
`hemi-hydrates (0.5 water molecules) through decahydrates
`(10 water molecules). (Morris, "Structural Aspect of
`Hydrates and Solvates," Ch. 4 in Polymorphism in Pharma-
`5 ceutical Solids, in Brittain, H. G., Ed., Vol. 95 of Drugs and
`the Pharmaceutical Sciences, Marcel Dekker, Inc., New
`York, N.Y., 1999, 125-181.)
`The possibility of polymorphism or pseudo-polymorphism
`may exist for any particular compound, but the conditions
`10 required to prepare as yet unknown polymorphs or pseudo(cid:173)
`polymorphs are not easily determined (see e.g., Bernstein,
`"Crystal Structure Prediction and Polymorphism," Am Crys(cid:173)
`tallographic Assoc Trans, 2004, 39:14-23). The knowledge
`that one type of polymorph or pseudo-polymorph of a crys-
`15 talline form of a compound exists, or that a given set of
`crystallization conditions leads to the production of one type
`of polymorph or pseudo-polymorph, does not typically allow
`researchers to predict what other types of polymorph or
`pseudo-polymorph might exist, or what type of polymorph or
`20 pseudo-polymorph would be produced by other crystalliza(cid:173)
`tion conditions (Guillory, "Generation of Polymorphs,
`Hydrates, Solvates, and Amorphous Solids," Ch. 5 in Poly(cid:173)
`morphism in Pharmaceutical Solids, Brittain, H. G., Ed., Vol.
`95 of Drugs and the Pharmaceutical Sciences, Marcel Dek-
`25 ker, Inc., New York, N.Y., 1999, pp. 183-226).
`The existence of various polymorphs or pseudo-polymor(cid:173)
`phs can greatly affect a pharmaceutical's performance since
`each form can have different physical and chemical proper(cid:173)
`ties. For example, one particular polymorph pseudo-poly-
`30 morph may be more bioavailable, more stable ( e.g., longer
`shelflife ), or more easily formulated or tableted than another
`polymorph. Similarly, one polymorph pseudo-polymorph
`may be more active or less toxic than another. Some specific
`examples of the dramatic difference that can exist between
`35 various pharmaceutical polymorphs are described in, e.g.,
`Brittain et aL, J Pharm Sci 2002, 91:1573-1580 and Moris(cid:173)
`sette et al., Proc Natl Acad Sci USA 2003, 100:2180-2184.
`The effects of polymorphism and pseudo-polymorphism
`on quality and performance of a drug is widely recognized.
`40 The exact solid state polymorph ( or pseudo-polymorph) of a
`compound determines its physical properties such as disso(cid:173)
`lution rate, solubility, bioavailability, crystal habit, mechani(cid:173)
`cal strength, etc. (Datta et al., Nature Reviews-Drug Discov(cid:173)
`ery, 2004, 3:42-57). The delivery of an exact dosage in
`45 manufacture and the manufacturing process itself often
`depend on which of several possible polymorphs or pseudo(cid:173)
`polymorphs are present.
`The variation in properties among different polymorphs ( or
`pseudo-polymorphs) usually means that one crystalline form
`50 is desired or preferred over other forms. Obtaining a particu(cid:173)
`lar form can be difficult, however. Typically, researchers have
`to experiment with a multitude of variables in crystallization
`conditions, such as aqueous solvent mixtures, amount of
`water, amount of target compound, relative humidity, tem-
`55 perature of incubation, incubation time, etc., in a process
`characterized by trial and error. Further, the search for salts of
`crystalline forms (usually sought after to control dissolution
`rate and solubility) can require extensive experimentation.
`Each salt of a drug or each different solvent used to crystallize
`60 the drug or a salt of the drug may lead to polymorphs or
`pseudo-polymorphs that have to be fully investigated and that
`have different properties (see e.g., Reutzel-Edens et al.,
`"Anhydrates and hydrates of olanzapine: Crystallization,
`solid-state characterization, and structural relationships,"
`65 Crystal Growth & Design, 2003, 3:897-907).
`Moreover, the inadvertent production of an undesired poly(cid:173)
`morph (or pseudo-polymorph), or the spontaneous transfor-
`
`

`

`US 8,232,265 B2
`
`4
`solubility are possible. Methods of preparing and using such
`compositions are also needed. Further methods of converting
`a compound that is difficult to solubilize into a more soluble
`form are also desired. The compositions and methods dis-
`5 closed herein meet these and other needs including the intro(cid:173)
`duction of enhanced or new functionality.
`
`3
`mation from the desired crystalline form to an undesired
`form, can result in crystalline forms of a drug that are less
`effective or even toxic. Thus, the existence and control of
`polymorphism and pseudo-polymorphism can be the biggest
`challenge to obtaining a drug product of constant quality.
`Another important issue regarding polymorphism and
`pseudo-polymorphism is that there can be considerable regu(cid:173)
`latory hurdles for a drug that exists in various crystalline
`forms. The FDA' s regulatory guidelines emphasize control of
`crystal form and the use of appropriate techniques to detect 10
`and characterize different forms of a drug ( see Guidance for
`Industry ANDAs: Pharmaceutical Solid Polymorphism
`Chemistry, Manufacturing, and Controls Information, U.S.
`Department of Health and Human Services, FDA, 2004).
`Thus, an applicant seeking FDA approval of a drug must 15
`demonstrate the ability to maintain a constant crystalline
`form throughout the life of the product. Such an endeavor is
`costly and can be extremely difficult or even impossible.
`Similar challenges can exist when one seeks approval of a
`generic product by filing an Abbreviated New DrugApplica- 20
`tion (ANDA), in which case the applicant must show equiva(cid:173)
`lence between the generic drug and an approved drug. Such a
`showing can be complicated when various polymorphic and/
`or pseudo-polymorphic forms exist for the drug.
`Amorphous forms of drugs are now being studied because 25
`they are higher energy forms that have higher dissolution
`rates and solubilities since there is no lattice structure to
`overcome or to inhibit salvation (Bernstein, "Polymorphism
`in Molecular Crystals," IUCR Monographs on Crystallogra(cid:173)
`phy 14, Oxford Science Publications, 2002, pp. 240-256). 30
`This increasing attention to amorphous forms has also shown,
`however, that the amorphous forms have a tendency to crys(cid:173)
`tallize spontaneously to a lower energy crystalline form, usu(cid:173)
`ally at inopportune times.
`The phenomenon of polymorphism and pseudo-polymor- 35
`phism is not limited to pharmaceuticals as many other (if not
`all) organic and inorganic compounds can crystallize into
`different forms. Thus, the existence of various forms of a
`given compound ( e.g., a pesticide, herbicide, nutraceutical,
`cosmetic, food additive, explosive, etc.) can result in the same 40
`synthetic, analytical, regulatory, and commercial difficulties
`that plague the pharmaceutical industry because of polymor(cid:173)
`phic and pseudo-polymorphic drugs. In each of these indus(cid:173)
`tries, it is not currently possible to simply alter the chemical
`nature of the active compound in order to tune the chemical 45
`(e.g., rate of dissolution and solubility) or physical (crystal
`habit, mechanical strength) properties. Rather, it is often the
`strategy to search for polymorphs or pseudo-polymorphs that
`have the most desirable "obtainable" properties.
`Another common problem that exists with many pharma- 50
`ceuticals is low solubility. Low solubility can make formu(cid:173)
`lating a particular compound difficult, and generally low solu(cid:173)
`bility translates into low bioavailability. Much research is
`conducted on finding ways to improve a compound's solubil-
`ity and availability. Typically methods include complex deliv- 55
`ery devices and chemical modifications of the drug.
`Given that polymorphism and pseudo-polymorphism can(cid:173)
`not be predicted; that the exact crystalline state affects chemi-
`cal properties (e.g., dissolution rate, solubility), biological
`properties ( e.g., bioavailability, pharmacokinetics ), mechani- 60
`cal and physical properties, and manufacturing processes,
`and that polymorphs and pseudo-polymorphs can inconve(cid:173)
`niently interconvert, what are needed are compositions that
`are at least effective for their intended purpose, but can also
`have controlled and tunable chemical, biological, and physi- 65
`cal properties, are in a form that is not subject to polymor(cid:173)
`phism, and for which controlled, tunable dissolution and
`
`SUMMARY
`
`In accordance with the purposes of the disclosed materials,
`compounds, compositions, devices, and methods, as embod(cid:173)
`ied and broadly described herein, the disclosed subject mat(cid:173)
`ter, in one aspect, relates to compounds and compositions and
`methods for preparing and using such compounds and com(cid:173)
`positions. In a further aspect, the disclosed subject matter
`relates to ionic liquid compositions that can be used for or in
`biological, pharmaceutical, nutritional, cosmetic, industrial,
`and commercial compositions. Methods for making the dis(cid:173)
`closed ionic liquid compositions are also disclosed. Also
`disclosed are methods of preparing ionic liquid compositions
`of active pharmaceutical, biological, nutritional, and ener(cid:173)
`getic ingredients. Also the disclosed are methods of using the
`compositions described herein to overcome polymorphism,
`overcome solubility and delivery problems, to control release
`rates, add functionality, enhance efficacy (synergy), and
`improve ease of use and manufacture.
`Additional advantages will be set forth in part in the
`description that follows, and in part will be obvious from the
`description, or may be learned by practice of the aspects
`described below. The advantages described below will be
`realized and attained by means of the elements and combina(cid:173)
`tions particularly pointed out in the appended claims. It is to
`be understood that both the foregoing general description and
`the following detailed description are exemplary and
`explanatory only and are not restrictive.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`The accompanying Figures, which are incorporated in and
`constitute a part of this specification, illustrate several aspects
`described below.
`FIG. 1 is a graph of ab