c12) United States Patent
`Hildesheim et al.
`
`I 1111111111111111 11111 1111111111 lllll 111111111111111 111111111111111 IIII IIII
`US007056942B2
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,056,942 B2
`Jun.6,2006
`
`(54) CARVEDILOL
`
`FOREIGN PATENT DOCUMENTS
`
`(75)
`
`Inventors: Jean Hildesheim, Mazkeret Batya (IL);
`Sergey Finogueev, Quiriat Arbaa (IL);
`Judith Aronhime, Rechovot (IL);
`Ben-Zion Dolitzky, Petach Tikva (IL);
`Shoshana Ben-Valid, Sderot (IL); Ilan
`Kor, Shoham (IL)
`
`(73) Assignee: Teva Pharmaceutical Industries Ltd.,
`Petah Tiqva (IL)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 153 days.
`
`(21) Appl. No.: 10/758,025
`
`(22) Filed:
`
`Jan. 16, 2004
`
`(65)
`
`Prior Publication Data
`
`US 2004/0152757 Al Aug. 5, 2004
`
`Related U.S. Application Data
`
`(62)
`
`(60)
`
`(51)
`
`Division of application No. 09/894,798, filed on Jun. 28,
`2001, now Pat. No. 6,699,997.
`Provisional application No. 60/214,356, filed on Jun. 28,
`2000, and provisional application No. 60/246,358, filed on
`Nov. 7, 2000.
`
`Int. Cl.
`C07D 209182
`A61K 311403
`
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl. ........................................ 514/411; 548/444
`
`(58) Field of Classification Search ................. 548/440,
`548/444; 514/411
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,503,067 A
`5,071,868 A
`
`3/1985 Wiedemann et al.
`12/1991 Leinert
`
`EP
`EP
`EP
`WO
`
`12/1984
`0 127 099 A
`5/1987
`0 127 099 Bl
`5/1999
`0 918 055
`WO 99/05105
`2/1999
`OTHER PUBLICATIONS
`Chen et al, "Synthesis and Crystal Structure of Carvedilol"
`Jiegou Huaxue, vol. 17, No. 5, Sep. 1998. pp 325-328. *
`G.M. Wall, "Pharmaceutical Applications of Drug Crystal
`Studies", Pharmaceutical Manufacturing, vol. 3, No. 2, pp.
`33-42, Feb. 1986.
`J.K. Haleblian and W. McCrone, "Pharmaceutical Applica(cid:173)
`tions of Polymorphism", Journal of Pharmaceutical Sci(cid:173)
`ences, vol. 58, No. 8, pp. 911-929, Jul. 1969.
`J.K. Haleblian, "Characterization of Habits and Crystalline
`Modification of Solids and Their Pharmaceutical Applica(cid:173)
`tions", Journal of Pharmaceutical Sciences, vol. 64, No. 8,
`pp. 1269-1288, Jul. 1975.
`Pharmacopeial Forum, vol. 24, No. 1, pp. 5438-5441,
`Jan.-Feb. 1998.
`Senderoff et al., "Synthesis of the Enantiomers and Three
`Racemic Metabolites of Carvedilol Labeled to High Specific
`Activity With Tritium", Journal of Labeled Compounds and
`Radiopharmaceuticals, Dec. 1993, vol. 33, No. 12, pp.
`1091-1105.
`Chen, Wei-Min et al. "Synthesis and Crystal Structure of
`Carvedilol" Jiegou Huaxue, vol. 17, No. 5, Sep. 1998, pp.
`325-328 (abstract included).
`Carey, Francis A. et al. "Advanced Organic Chemistry"
`Third Edition, Part A: Structure and Mechanisms; Plenum
`Press, pp. 232-239.
`* cited by examiner
`Primary Examiner-Kamal A. Saeed
`Assistant Examiner-Janet L Coppins
`(74) Attorney, Agent, or Firm-Kenyon & Kenyon
`ABSTRACT
`(57)
`
`This invention relates to an improved process of preparing
`carvedilol, as well as a new crystalline hydrate and solvate
`and forms of carvedilol, processes for the manufacture
`thereof, and pharmaceutical compositions thereof.
`
`5 Claims, 7 Drawing Sheets
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`Merck Exhibit 2048, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

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`
`Jun.6,2006
`
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`Merck Exhibit 2048, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
`
`Jun.6,2006
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`
`Jun.6,2006
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`US 7,056,942 B2
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`Merck Exhibit 2048, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`U.S. Patent
`
`Jun.6,2006
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`Jun.6,2006
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Jun.6,2006
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`Merck Exhibit 2048, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 7,056,942 B2
`
`1
`CARVEDILOL
`
`2
`-continued
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a divisional application of application
`Ser. No. 09/894,798 filed Jun. 28, 2001, now U.S. Pat. No.
`6,699,997 and claims the benefit of U.S. provisional appli(cid:173)
`cation Ser. No. 60/349,310, filed Jan. 15, 2002, which is
`incorporated herein by reference.
`
`FIELD OF THE INVENTION
`
`This invention relates to an improved process of preparing
`carvedilol, as well as a new crystalline hydrate and solvate
`and forms of carvedilol, processes for the manufacture
`thereof, and pharmaceutical compositions thereof.
`
`BACKGROUND OF THE INVENTION
`
`Carvedilol is a nonselective ~-adrenergic blocking agent
`with a 1 blocking activity. Carvedilol, also known as (±)
`l -(9H-carbazol-4-yloxy )-3-[[2(2-methoxyphenoxy )ethyl]
`amino ]-2-propanol, (CAS Registry No. 72956-09-3) has the
`structure of formula I.
`
`II
`
`III
`
`Carvedilol has a chiral center and can exist either as
`individual stereoisomers or in racemic form. Racemic
`carvedilol is the active ingredient of COREG®, which is
`indicated for the treatment of congestive heart failure and
`hypertension. The nonselective ~-adrenergic activity of
`carvedilol is present in the S(-) enantiomer and the a,
`blocking activity is present in both the R( +) and S(-)
`enantiomers at equal potency. Both the racemate and stere(cid:173)
`oisomers may be obtained according to procedures well
`known in the art (EP B 0127 099).
`Synthesis of Carvedilol
`U.S. Pat. No. 4,503,067, which is incorporated herein by 50
`reference, discloses a process of preparing carvedilol by the
`following reaction:
`
`o~['f_,"___,,,o--p
`
`'
`
`QOOH
`
`HfO
`
`10
`
`N
`H
`
`in which 4-(oxiran-2-ylmethoxy)-9H-carbazole (formula II)
`is reacted with (2-(2-methoxyphenoxy)ethylamine (formula
`15 III) to form carvedilol (I). The above process produces a low
`yield of carvedilol at least in part because in addition to
`carvedilol, the process leads to the production of a bis
`impurity of the following structure (formula IV):
`
`IV
`
`20
`
`25
`
`30
`
`35
`
`(See EP 918055.)
`In order to reduce the formation of the formula IV and to
`increase the yield of carvedilol, EP 918055 discloses using
`a benzyl protected form of the 2-(2-methoxyphenoxy)
`40 ethylamine (III).
`Carvedilol Polymorphs
`International application No. WO 99/05105, incorporated
`herein by reference, discloses that carvedilol can be isolated
`as two polymorphic forms, depending on the method of
`45 preparation. The two polymorphic forms, designated Form I
`and Form II, are reported to be monotropic and are distin(cid:173)
`guishable by their infrared, Raman and X-ray powder dif(cid:173)
`fraction spectra. No evidence is found in the literature about
`the existence of hydrated solvate states of carvedilol.
`Polymorphism is the property of some molecules and
`molecular complexes to assume more than one crystalline
`form in the solid state. A single molecule may give rise to a
`variety of crystal forms (also called "polymorphs,"
`"hydrates," or "solvates") having distinct physical proper-
`55 ties. For a general review of polymorphs and the pharma(cid:173)
`ceutical applications of polymorphs see Pharm Manuf, 3,
`33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci.,
`58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269
`(197 5), all of which are incorporated herein by reference.
`The existence and physical properties of different crystal
`forms can be determined by a variety of techniques such as
`X-ray diffraction spectroscopy, differential scanning calo(cid:173)
`rimetry and infrared spectroscopy. Differences in the physi(cid:173)
`cal properties of different crystal forms result from the
`65 orientation and intermolecular interactions of adjacent mol(cid:173)
`ecules (complexes) in the bulk solid. Accordingly,
`polymorphs, hydrates and solvates are distinct solids sharing
`
`60
`
`Merck Exhibit 2048, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 7,056,942 B2
`
`4
`of dissolving carvedilol in a solution by heating; heating the
`solution until the crystalline carvedilol is completely dis(cid:173)
`solved; reducing the temperature of the solution; agitating
`the solution for a period of time; further reducing the
`temperature of the solution; further agitating the solution for
`a period of time; and collecting crystalline carvedilol Form
`I.
`
`3
`the same molecular formula yet having distinct advanta(cid:173)
`geous and/or disadvantageous physical properties compared
`to other forms in the polymorph family. The existence and
`physical properties of polymorphs, hydrates and solvates is
`unpredictable.
`One of the most important physical properties of a phar(cid:173)
`maceutical compound which can form polymorphs, hydrates
`or solvates, is its solubility in aqueous solution, particularly
`the solubility in gastric juices of a patient. Other important
`properties relate to the ease of processing the form into 10
`pharmaceutical dosages, such as the tendency of a powdered
`or granulated form to flow and the surface properties that
`determine whether crystals of the form will adhere to each
`other when compacted into a tablet.
`
`5
`
`SUMMARY OF THE INVENTION
`
`The present invention provides a process for preparing
`carvedilol comprising a step of reacting a compound of
`formula II, 4-(oxiran-2-ylmethoxy)-9H-carbazole,
`
`II
`
`0~ QO 0
`
`N
`H
`
`with a compound of formula III, 2-(2-methoxyphenoxy)
`ethylamine
`
`III
`
`20
`
`25
`
`30
`
`The present invention further provides a method for
`preparing crystalline carvedilol Form II, comprising the
`steps of forming a solution of carvedilol by dissolving
`carvedilol in a solvent; precipitating carvedilol Form II by
`cooling the solution; and, isolating crystalline carvedilol
`Form II.
`The present invention further provides a method for
`15 preparing crystalline carvedilol Form II, comprising the
`steps of forming a solution of carvedilol by dissolving
`carvedilol in a solvent mixture; precipitating carvedilol
`Form II by cooling the solution to about -20° C.; and,
`isolating crystalline carvedilol Form II.
`The present invention further provides a method for
`preparing crystalline carvedilol Form III, comprising the
`steps of dissolving carvedilol in a solvent to form a solvent
`solution; and, precipitating crystalline carvedilol Form III
`from the solvent solution using water as an anti-solvent.
`The present invention further provides a method for
`preparing crystalline carvedilol Form III, comprising the
`steps of dissolving carvedilol in a solution by heating;
`cooling the solution mixture; and, collecting crystalline
`carvedilol Form III.
`The present invention further provides a method for
`preparing crystalline carvedilol Form IV, comprising the
`steps of dissolving carvedilol in a solvent to form a solvent
`solution; adding an anti-solvent to the solvent solution; and,
`precipitating crystalline carvedilol Form IV from the solvent
`35 solution.
`The present invention further provides a method for
`preparing crystalline carvedilol Form V, comprising the
`steps of dissolving carvedilol in a solvent to form a solvent
`solution; and, precipitating and isolating crystalline
`40 carvedilol Form V from the solvent solution.
`The present invention further provides a method for
`preparing crystalline carvedilol Form V, comprising the
`steps of dissolving carvedilol in a solvent to form a solvent
`solution; and, precipitating and isolating crystalline
`carvedilol Form V from the solvent solution wherein the
`precipitation step is performed by adding an anti-solvent.
`
`wherein the compound of formula III is at a molar excess
`over the compound of formula II.
`The present invention further provides crystalline
`carvedilol hydrate.
`The present invention further provides crystalline 45
`carvedilol.
`The present invention further provides crystalline
`carvedilol (methyl-ethyl-ketone) solvate.
`The present invention further provides crystalline
`carvedilol Form III characterized by an X-ray powder dif(cid:173)
`fraction pattern having peaks at about 8.4±0.2, 17.4±0.2, and
`22.0±0.2 degrees two-theta.
`The present invention further provides crystalline
`carvedilol Form IV characterized by an X-ray powder dif(cid:173)
`fraction pattern having peaks at about 11.9±0.2, 14.2±0.2, 55
`18.3±0.2, 19.2±0.2, 21.7±0.2, and 24.2±0.2 degrees two(cid:173)
`theta.
`The present invention further provides crystalline
`carvedilol (methyl-ethyl-ketone) solvate Form V character(cid:173)
`ized by an X-ray powder diffraction pattern having peaks at
`about 4.1±0.2, 10.3±0.2, and 10.7±0.2 degrees two-theta.
`The present invention further provides carvedilol HCl
`Hydrate characterized by an X-ray powder diffraction pat(cid:173)
`tern having peaks at about 6.5±0.2, 10.2±0.2, 10.4±0.2,
`15.8±0.2,16.4±0.2 and 22.2±0.2 degrees two-theta.
`The present invention further provides a method for
`preparing crystalline carvedilol Form I, comprising the steps
`
`BRIEF DESCRIPTION OF THE FIGURES
`FIG. 1. shows the X-ray diffraction pattern of carvedilol
`50 Form III.
`FIG. 2. shows the DTG thermal profile of carvedilol Form
`III.
`FIG. 3. shows the X-ray diffraction pattern of carvedilol
`Form IV.
`FIG. 4. shows the DTG thermal profile of carvedilol Form
`IV.
`FIG. 5. shows the X-ray diffraction pattern of carvedilol
`Form V.
`FIG. 6. shows the DTG thermal profile of carvedilol Form
`
`60 V.
`
`FIG. 7. shows the X-ray diffraction pattern of carvedilol
`HCI.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`As used herein, the term "carvedilol" includes hydrates
`and solvates of carvedilol. The term "water content" refers
`
`65
`
`Merck Exhibit 2048, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 7,056,942 B2
`
`10
`
`with a compound of formula III, 2-(2-methoxyphenoxy)
`20 ethylamine
`
`III
`
`30
`
`II
`
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`
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`
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`H
`
`6
`As used herein, the term "neat" conditions refers to
`conditions of a reaction wherein the solvent of the reaction
`is one of the reactants.
`Synthesis of Carvedilol
`According to one embodiment, the present invention is a
`process for preparing carvedilol comprising a step of react(cid:173)
`ing a compound of formula II, 4-(oxiran-2-ylmethoxy)-9H(cid:173)
`carbazole,
`
`5
`to the content of water, based upon the Loss on Drying
`method (the "LOD" method) as described in Pharmacopeia
`Forum, Vol. 24, No. 1, p. 5438 (January-February 1998), the
`Karl Fisher assay for determining water content or thermo(cid:173)
`gravimetric analysis (TGA). The term "equivalents of 5
`water" means molar equivalents of water. All percentages
`herein are by weight unless otherwise indicated. Those
`skilled in the art will also understand that the term
`"anhydrous", when used in reference to carvedilol, describes
`carvedilol which is substantially free of water. One skilled in
`the art will appreciate that the term "hemihydrate", when
`used in reference to carvedilol, describes a crystalline mate(cid:173)
`rial having a water content of about 2.2% w/w. One skilled
`in the art will appreciate that the term "hydrate",in reference
`to carvedilol hydrochloride a crystalline material having a
`water content of about or above 2% w/w. One skilled in the 15
`art will also appreciate that the term "solvate of methyl(cid:173)
`ethyl-ketone" refers to carvedilol in which solvent is con(cid:173)
`tained within the crystal lattice in quantities above 1 %. One
`skilled in the art will also appreciate that the term "solvate
`of methyl-ethyl-ketone" which contains one mole of is
`characterized by a methyl-ethyl-ketone content of about
`14% by weight.
`Hydrate and solvate forms of carvedilol are novel and
`distinct from each other in terms of their characteristic
`powder X-ray diffraction patterns and their thermal profiles. 25
`For the purposes of this specification, ambient tempera(cid:173)
`ture is from about 20° C. to about 25° C.
`All powder X-ray diffraction patterns were obtained by
`methods known in the art using a Philips X-ray powder
`The new procedure results in a higher yield of carvedilol
`diffractometer. Copper radiation of A=l.5418 A was used.
`than has been reported in the prior art. In addition, the
`Measurement of thermal analysis are conducted for the
`product of the new procedure is nearly free of bis impurities
`purpose of evaluating the physical and chemical changes
`and the reaction is more rapid.
`that may take place in a heated sample. Thermal reactions
`Preferably, the compound of formula III is at a molar
`can be endothermic ( e.g., melting, boiling, sublimation,
`excess over the compound of formula II. The compound of
`vaporization, desolvation, solid-solid phase transitions, 35
`formula III and the compound of formula II are preferably
`chemical degradation, etc.) or exothermic (e.g.,
`at a molar ratio from about 1.5:1 to about 100:1. More
`crystallization, oxidative decomposition, etc.) in nature.
`preferably, the compound of formula III and the compound
`Such methodology has gained widespread use in the phar(cid:173)
`of formula II are at a molar ration from about 2.8:1 to about
`maceutical industry in characterization of polymorphism.
`10: 1. Most preferably, the compound of formula III and the
`Thermal measurements have proven to be useful in the 40
`compound of formula II are at a molar ratio from about 2.8:1
`characterization of polymorphic systems. The most com(cid:173)
`to about 6: 1.
`monly applied techniques are thermogravimetry (TGA),
`In one embodiment of the present invention, the reacting
`differential thermal analysis (DTA), and differential scan(cid:173)
`step is performed in a solvent. The solvent is preferably
`ning calorimetry (DSC).
`selected from the group consisting of toluene, xylene and
`The DTA and TGA curves presented herein were obtained 45 heptane. In an alternative embodiment, the reacting step is
`by methods known in the art using a DTG Shimadzu model
`performed in a solvent mixture wherein the solvent mixture
`DTG-50 (combined TGA and DTA). The weight of the
`comprises multiple solvents. Preferably, a solvent of the
`samples was about 9 to about 13 mg. The samples were
`solvent mixture is selected from the group consisting of
`scanned up to about 300° C. or above at a rate of 10° C./min.
`toluene, xylene and heptane.
`Samples were purged with nitrogen gas at a flow rate of 20 50
`The reacting step is preferably performed at a temperature
`ml/min. Standard alumina crucibles covered lids with one
`from about 25° C. and about 150° C. Most preferably, the
`hole.
`reacting step is performed at a temperature from about 60°
`Thermogravimetry analysis (TGA) is a measure of the
`C. and about 120° C.
`thermally induced weight loss of a material as a function of
`In an alternative embodiment, the reacting step is per(cid:173)
`the applied temperature. TGA is restricted to transitions that 55
`formed under neat conditions. The neat conditions may
`involve either a gain or a loss of mass, and it is most
`obtained by melting a solid form of the compound of
`commonly used to study desolvation processes and com(cid:173)
`formula III to form a liquid and, dissolving the compound of
`pound decomposition.
`formula II in the liquid to form a reaction mixture.
`Karl Fisher analysis, which is well known in the art, is
`The reaction performed under neat conditions may further
`also used to determine the quantity of water in a sample.
`60 comprise a step of reducing the temperature of the reaction
`As used herein, a solvent is any liquid substance capable
`mixture after dissolving the compound of formula II. The
`of dissolving carvedilol. As used herein, the term "anti(cid:173)
`temperature is preferably reduced to about 70° C.
`solvent" means a liquid in which a compound is poorly
`The reaction performed under neat conditions may further
`soluble. The addition of an anti-solvent to a solvent reduces
`comprise a step of adding an organic solvent: water mixture
`to the reaction mixture. The organic solvent is preferably
`the solubility of a compound. As used herein a mixture of 65
`solvents refers to a composition comprising more than one
`selected from the group consisting of ethyl acetate, methyl
`solvent.
`isobutyl ketone, methyl ethyl ketone and butyl acetate.
`
`Merck Exhibit 2048, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 7,056,942 B2
`
`7
`The reaction performed under neat conditions may further
`comprise a step of adjusting the pH of the organic solvent:
`water mixture after it is added to the reaction mixture. The
`pH is preferably adjusted to less than about pH 5. More
`preferably, the pH is adjusted from about pH 3 to about pH 5
`5.
`
`20
`
`8
`Optionally, the solvent is selected from the group con(cid:173)
`sisting of methanol, absolute ethanol, 1-propanol,
`isopropanol, n-butanol, ethylene glycol, butyl acetate, isobu(cid:173)
`tyl methyl ketone, dichloromethane, dichloroethane,
`acetonitrile, acetone, isoamylalcohol, xylene and toluene.
`Optionally, the precipitated carvedilol Form II is isolated
`by filtration.
`Another aspect of the present invention provides a method
`for preparing crystalline carvedilol Form II, comprising the
`steps of: forming a solution of carvedilol by dissolving
`carvedilol in a solvent mixture, precipitating carvedilol
`Form II by cooling the solution to about -20° C., and
`isolating crystalline carvedilol Form II.
`Optionally, the carvedilol is dissolved in a solution at a
`temperature from about 40° C. to about the boiling tem-
`15 perature of the solvent.
`Optionally, the carvedilol Form II is isolated by filtration.
`Optionally, the step of cooling the reaction is performed
`by cooling the solution to a temperature from about -20° C.
`to ambient temperature.
`Optionally, the solvent mixture is selected from the group
`consisting
`of
`acetone:cyclohexane,
`chloroform:cyclohexane, dichloroethane:cyclohexane,
`dichloromethane:cyclohexane, pyridine:cyclohexane,
`tetrahydrofuran: cyclohexane, dioxane: cyclohexane,
`25 acetone:hexane, chloroform:hexane, dichloroethane:hexane,
`dichloromethane:hexane, tetrahydrofuran:hexane and etha(cid:173)
`nol:hexane.
`Novel Carvedilol Polymorphs
`In another aspect the present invention provides new
`30 crystalline forms of carvedilol, designated Forms III, IV, V
`and processes for the manufacture thereof. Moreover, the
`present invention provides a new hydrate form of carvedilol,
`having water content of about 2% by weight and processes
`for their manufacture. In another embodiment, the present
`35 invention provides new solvate forms of carvedilol, having
`solvent content up to about 14% by weight, wherein the
`solvent is methyl ethyl ketone, and processes for their
`manufacture. These hydrate/solvate forms of carvedilol are
`useful as intermediates for the synthesis of carvedilol drug
`40 substances.
`Procedures for Crystallizing Novel Forms of Carvedilol
`The novel hydrates/solvates forms provided herein are
`optionally formed by precipitating carvedilol as a crystalline
`solid from a solvent or a solvent mixture. It will be under-
`45 stood by those of skill in the art, that other methods may also
`be used to form the hydrate/solvates form disclosed herein.
`Alternatively the polymorphs may be formed by routine
`modification of the procedures disclosed herein.
`Formation of Crystalline Carvedilol Form III
`One embodiment of the present invention provides a
`method for preparing crystalline carvedilol Form III, which
`comprises the steps of forming a solvent solution containing
`carvedilol; and, precipitating crystalline carvedilol Form III
`from the solvent solution using water as an anti-solvent. The
`55 invention provides for a dissolving step wherein water is
`present in the solvent solution during the dissolving step.
`The invention also provides for a precipitation step wherein
`water is added to the solution after carvedilol is fully
`dissolved in a solvent.
`Optionally, to form the solvent solution containing
`carvedilol, carvedilol may be dissolved in a solvent at
`elevated temperature. The preferred elevated temperature is
`from about 40 to about 90° C. Most preferably the elevated
`temperature is about 55° C. Alternatively, carvedilol may be
`65 dissolved in a solvent at ambient temperature.
`Another embodiment of the present invention provides,
`forming the solvent solution containing carvedilol, by dis-
`
`10
`
`Optionally, the process further comprises the steps of
`isolating carvedilol hydrochloride after adjusting the pH,
`and purifying carvedilol.
`Carvedilol hydrochloride is optionally isolated as a
`hydrate. Carvedilol HCl isolated as a hydrate typically has
`an XRD peaks are found at about 6.5±0.2, 10.2±0.2,
`10.4±0.2, 14.2±0.2, 14.7±0.2, 16.4±0.2, 17.7±0.2, 20.0±0.2,
`21.9±0.2, 25.2±0.2 degrees to 2-theta.
`The reaction preformed under neat conditions may further
`comprise steps of, isolating carvedilol from the reaction
`mixture after adjusting the pH, and purifying carvedilol.
`Optionally, carvedilol may be purified by methods well
`known in the art. (See EP B 0127 099.)
`Novel Methods for Preparing Crystalline Carvedilol Form I
`and Form II
`One aspect of the present invention provides a method for
`preparing crystalline carvedilol Form I, by dissolving
`carvedilol in a solvent until the crystalline carvedilol is
`completely dissolved, reducing the temperature of the solu(cid:173)
`tion and agitating the solution for a period of time, further
`reducing the temperature of the solution and agitating the
`solution for a period of time and, collecting crystalline
`carvedilol Form I.
`The dissolving step is optionally performed by heating the
`solvent.
`The dissolving step is optionally performed by heating
`crystalline carvedilol at a temperature from about 50° C. to
`about 60° C. for about 6 hours.
`The dissolving step is optionally performed by suspend(cid:173)
`ing the crystalline carvedilol in ethyl acetate.
`The dissolving step is optionally performed by heating the
`solution to about 77° C.
`The step of reducing the temperature of the solution is
`optionally performed by cooling the solution to about 50° C.
`in a time period of 15 min.
`The step of agitating solution is optionally performed at
`about 50° C. for about 48 hours.
`The step of further reducing the temperature of the
`solution is optionally performed by cooling the solution to
`about 10° C. in about 0.75 hours with agitation.
`The step of further agitating the solution is optionally
`performed by stirring the suspension for more than 5 hours.
`The step of further agitation may optionally be performed by
`stirring the suspension for about 24 hours.
`The drying step may be performed by heating crystalline
`carvedilol at a temperature from about 50° C. to about 60° 50
`C. for about 6 hours.
`The suspending step may be performed by suspending the
`crystalline carvedilol in ethyl acetate.
`The heating step may be performed by heating the solu(cid:173)
`tion to about 77° C.
`Another aspect of the present invention provides a method
`for preparing crystalline carvedilol Form II, comprising the
`steps of forming a solution of carvedilol by dissolving
`carvedilol in a solvent, precipitating carvedilol Form II by
`cooling the solution, and isolating crystalline carvedilol 60
`Form II.
`Optionally, the step of dissolving carvedilol is performed
`at a temperature from about 40° C. to about the boiling temp
`of the solvent.
`Optionally, the step of cooling the solution is performed
`by reducing the temperature from about -20° C. to about
`ambient temperature.
`
`Merck Exhibit 2048, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 7,056,942 B2
`
`9
`solving carvedilol in a solvent and inducing precipitation of
`crystalline carvedilol Form III by the addition of an anti(cid:173)
`solvent. Solvents are optionally selected from the group
`which includes pyridine, dioxane, isopropanol and chloro(cid:173)
`form. Anti-solvents are optionally selected from the group 5
`which includes water and hexane.
`An alternative embodiment of the present invention
`provides, forming the solvent solution containing carvedilol
`by dissolving carvedilol in an organic solvent and water and
`precipitating crystalline carvedilol Form III. In this embodi(cid:173)
`ment the organic solvent is optionally an alcohol. The
`alcohol is preferably selected from the group consisting of
`methanol and ethanol. Alternatively, the organic solvent may
`be selected from the group of solvents consisting of
`pyridine, dioxane, and ethyl acetate and tetrahydrofuran.
`An alternative embodiment of the present invention
`provides, a method for preparing crystalline carvedilol Form
`III, comprising the steps of: drying crystalline carvedilol at
`elevated temperature, suspending crystalline carvedilol in a
`solution mixture, heating the solution mixture until the 20
`crystalline carvedilol is completely dissolved, cooling the
`solution mixture, and collecting crystalline carvedilol Form
`III.
`Optionally, the drying step may be performed by heating
`crystalline carvedilol at a temperature from about 50° C. to 25
`about 60° C. for about 6 hours.
`Optionally, the suspending step may be performed by
`suspending the crystalline carvedilol in a solution mixture of
`ethyl acetate: water (150:40).
`Optionally, the heating step may be performed by heating
`the solution mixture from about 60 to about 70° C. with
`agitation until the crystalline carvedilol is completely dis(cid:173)
`solved.
`Optionally, the cooling step may be performed by cooling
`the solution mixture to about to 10° C. for a period of about 35
`3 hours with agitation.
`Formation of Crystalline Carvedilol Form IV
`The present invention also provides a method for prepar(cid:173)
`ing crystalline carvedilol Form IV by forming a solvent
`solution containing carvedilol and inducing precipitation of 40
`crystalline carvedilol Form IV by the addition of an "anti(cid:173)
`solvent". In this embodiment, solvents are optionally
`selected from the group which includes methyl ethyl ketone,
`and methyl isobutyl ketone. Anti-solvents are optionally
`selected from the group which includes cylcohexane and 45
`heptane.
`Optionally, to form crystalline carvedilol Form IV
`carvedilol may be dissolved in a solvent at from below
`ambient temperature to