USOO8334319B2
`
`(12) United States Patent
`Goldbach et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,334,319 B2
`Dec. 18, 2012
`
`(54) POLYMORPHIC FORMS OF OSELTAMIVIR
`PHOSPHATE
`
`(75) Inventors: Pierre Goldbach, Rixheim (FR): Olaf
`Grassmann, Loerrach (DE); Ines Sauer,
`Mannheim (DE)
`(73) Assignee: Roche Palo Alto LLC, South San
`Francisco, CA (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 705 days.
`(21) Appl. No.: 12/317,157
`
`(*) Notice:
`
`(22) Filed:
`
`Dec. 19, 2008
`
`(65)
`
`(30)
`
`Prior Publication Data
`US 2009/O17688.6 A1
`Jul. 9, 2009
`
`Foreign Application Priority Data
`
`Jan. 4, 2008 (EP) ..................................... 08.150.057
`(51) Int. Cl.
`(2006.01)
`A6 IK3I/25
`(2006.01)
`CD7C 229/248
`(52) U.S. Cl. ........................................ 514/529; 560/125
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,859,284 A
`1/1999 Kent et al.
`2008/0227743 A1* 9/2008 Nguyen et al. .................. 514,44
`FOREIGN PATENT DOCUMENTS
`WO 98.07685 A1
`2, 1998
`2008/112775 A1
`9, 2008
`
`WO
`WO
`
`OTHER PUBLICATIONS
`Shie et al. Journal of the American Chemical Society, Synthesis of
`Tamiflu and it's Phosphonate Congeners Possessing Potent Anti
`Influenza Properties, 2007, 129, pp. 11892-11893.*
`Billinge et al. CrystEngComm, Characterization of Amorphousand
`Nanocrystalline Molecular Materials by Total Scattering, 2010, 12,
`pp. 1366-1368.*
`Green et al. Emerging Infectious Diseases, www.cdc.gov/eid, Deter
`mination of Oseltamivir Quality by Colorimetric and Liquid Chro
`matographic Methods, 2008, 14(4), pp. 552-556.*
`Bedul-Addo, Pharmaceutical Technology, Lyophilization, Under
`standing Lyophilization Formula Development, 2004, pp. 10-18,
`obtained from http://pharmtech.findpharma.com/pharmtech/data
`articlestandard?/pharmtech/072004/84717/article.pdf.*
`Braga et al., “Making crystals from crystals: a green route to crystal
`engineering and polymorphism” ChemComm 2005, 3635-3645.*
`Fututa, Y, et. al. “De Novo Synthesis of Tamiflu via a Catalytic
`Asymmetric Ring-Opening of meso-Aziridines with TMSN3.”
`JACS, Published on Web Apr. 25, 2006, vol. 128, pp. 6312 and 6313.
`Caira, M. R. "Crystalline Polymorphism of Organic Compounds.”
`Topics in Current Chemistry, 1998, vol. 198, pp. 163-208.
`Fukuta, Y, et. al. “De Novo Synthesis of Tamiflu via a Catalytic
`Enantioselective Ring-Opening Reaction of meso-AZiridines with
`TMSN.” Journal of American Chemical Society, 2006, online pp.
`S1-S15.
`Communication Pursuant to Article 94(3) EPC for European Appli
`cation No. 08869959.0-1211 dated Nov. 15, 2011.
`He et al., “Clinical Pharmacokinetics of the prodrug Oseltamivir and
`its active metabolites Ro 64-0802” Clin. Pharmacokinet. 36(7):471
`484 (Dec. 1999).
`* cited by examiner
`Primary Examiner — Paul A Zucker
`(74) Attorney, Agent, or Firm — Brian L. Buckwalter
`(57)
`ABSTRACT
`The present invention relates to polymorphic forms of (3R,
`4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclo
`hex-1-ene-carboxylic acid ethyl ester phosphate, which is a
`potent inhibitor of viral neuraminidase.
`9 Claims, 8 Drawing Sheets
`
`Merck Exhibit 2187, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 18, 2012
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`Merck Exhibit 2187, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Merck Exhibit 2187, Page 4
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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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`Dec. 18, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`Merck Exhibit 2187, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 18, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
`
`Dec. 18, 2012
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`Sheet 8 of 8
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`US 8,334,319 B2
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`Merck Exhibit 2187, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

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`1.
`POLYMORPHC FORMS OF OSELTAMVR
`PHOSPHATE
`
`US 8,334,319 B2
`
`2
`TABLE 1
`
`Crystal structure data of form A
`
`CROSS REFERENCE TO PRIORAPPLICATIONS
`
`This application claims the benefit of priority to EP
`08.150057.1 filed Jan. 4, 2008 the contents of which are
`hereby incorporated in their entirety by reference.
`
`FIELD OF THE INVENTION
`
`The present invention relates to new crystalline and amor
`phous forms of oseltamivir phosphate which are useful for the
`inhibition of viral neuramidase and treatment of viral infec
`tions. The new crystalline and amorphous forms of Oselta
`mivir phosphate afford forms that can be conveniently for
`mulated.
`
`10
`
`15
`
`BACKGROUND OF THE INVENTION
`
`Oseltamivir phosphate is (3R,4R,5S)-5-amino-4-acety
`lamino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid
`ethyl ester phosphate ula (I) which is
`
`25
`
`COEt
`
`''',
`
`NH HPO,
`
`30
`
`35
`
`form
`crystal system
`Space group
`crystal habit
`unit cell dimensions
`
`temperature
`cell volume
`molecules in unit cell
`calculated density
`
`A.
`orthorhombic
`P2(1)2(1)2
`needle
`a = 23.8 A
`b = 24.4A
`c = 7.4 A
`C., f, Y = 90.0°
`89°K
`4289 A
`8
`1.27 g/cm
`
`For single crystal structure analysis a single crystal was
`mounted in a loop on agoniometer and measured at ambient
`conditions. Alternatively, the crystal was cooled in a nitrogen
`stream during measurement. Data were collected on a STOE
`Imaging Plate Diffraction System (IPDS) from STOE (Darm
`stadt). In this case Mo-radiation of 0.71 A wavelength was
`used for data collection. Data was processed with STOE
`IPDS-software. The crystal structure was solved and refined
`with the ShelXTL program from Bruker AXS (Karlsruhe).
`Alternatively, synchrotron radiation was used for data col
`lection. A single crystal was mounted in a loop and cooled to
`100 K in a nitrogen stream. Data was collected at the Swiss
`Light Source beamline XIOSA using a MARCCD225 detec
`tor with synchrotron radiation and data processed with the
`program XDS. The crystal structure was solved and refined
`with the ShelXTL program from Bruker AXS (Karlsruhe).
`The active pharmaceutical ingredient of the commercially
`available medicament Tamiflu is in crystalline form A.
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to polymorphic or amorphous
`forms (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-pro
`poxy)-cyclohex-1-ene-carboxylic acid ethyl ester phosphate
`(I), which is a potent inhibitor of viral neuraminidase useful
`for treatment or prevention of influenza. There are provided
`two polymorphic crystalline forms along with amorphous
`oseltamivir phosphate (I) useful for preparing pharmaceutical
`formulations
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`40
`
`45
`
`disclosed by J. C. Rohloffetal, J. Org. Chem. 1998 63:45.45
`4550 and WO 98/07685 has a potent inhibitory activity
`against virus neuraminidase and is useful for prevention and/
`or treatment of influenza virus infections. It is the active
`ingredient of Tamiflu (Registered Trade Mark).
`Crystalline form A of the compound of formula I, is char
`acterized by an X ray powder diffraction pattern comprising
`at least three, preferably five, more preferably seven X-ray
`diffraction peaks (expressed in degrees 20 (degrees 2-theta))
`selected from the group consisting of approximately 5.1,
`approximately 12.4, approximately 13.0, approximately
`14.3, approximately 15.2, approximately 16.1, approxi
`mately 19.0, approximately 19.3, approximately 20.3,
`approximately 20.6, approximately 21.6, approximately 24.4
`and approximately 26.3.
`A single crystal structural analysis of form A was con
`ducted. Table 1 lists the crystal structure data. The experimen
`tal X-ray powder diffraction (XRPD) pattern collected with
`the form A corresponds to the theoretical pattern calculated
`from crystal structure data. The absolute configuration of the
`molecules was determined from single crystal structure data.
`The crystal packing of form. A shows hydrogen bonds of the
`protonated amino group to three phosphate molecules. The
`amide oxygen accepts a hydrogen from another phosphate
`molecule. Consequently, the phosphate molecule forms
`hydrogen bonds to four different molecules of the active
`molecule. This results a hydrogen bonding pattern of tightly
`bond columns parallel to the crystallographic c-axis. A ther
`mal ellipsoid plot of the crystal structure is shown in FIG. 8.
`
`50
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`FIG. 1 shows a XRPD pattern of form A of (3R,4R,5S)-4-
`acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-en
`ecarboxylic acid ethyl ester phosphate.
`FIG. 2 shows an IR (InfraRed spectroscopy) spectrum of
`form A of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl
`propoxy)-cyclohex-1-enecarboxylic acid ethyl ester phos
`phate.
`FIG.3 shows a XRPD pattern of form B of (3R,4R,5S)-4-
`acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-en
`ecarboxylic acid ethyl ester phosphate.
`FIG. 4 shows an IR spectrum of form B of (3R,4R,5S)-4-
`acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-en
`ecarboxylic acid ethyl ester phosphate.
`FIG. 5.1 shows a XRPD pattern of form C of (3R,4R,5S)-
`4-acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-
`enecarboxylic acid ethyl ester phosphate.
`FIG. 5.2 rescaled XRPD pattern of FIG. 5.1.
`FIG. 6 shows an IR spectrum of an amorphous form of
`(3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-
`cyclohex-1-enecarboxylic acid ethyl ester phosphate.
`
`Merck Exhibit 2187, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`US 8,334,319 B2
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`3
`FIG. 7 shows a XRPD pattern of an amorphous form of
`(3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-
`cyclohex-1-enecarboxylic acid ethyl ester phosphate.
`FIG. 8 shows a thermal ellipsoid plot of the crystal struc
`ture of form A
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`4
`Bragg's law describes the diffraction of crystalline mate
`rial with the equation:
`
`2d sin 0=n.
`wherein d perpendicular distance between pairs of adjacent
`planes in a crystal (d-spacing), 0 (theta)-Bragg angle, W
`(lambda) wavelength and ninteger.
`When Bragg's law is fulfilled, the reflected beams are in
`phase and interfere constructively so that Bragg diffraction
`peaks are observed in the X-ray diffraction pattern. At angles
`of incidence other than the Bragg angle, reflected beams are
`out of phase and destructive interference or cancellation
`occurs. Amorphous material does not satisfy Bragg's law and
`no Bragg diffraction peaks are observed in the X-ray diffrac
`tion pattern.
`An “amorphous halo' is an approximately bell-shaped dif
`fraction maximum in the X-ray powder diffraction pattern of
`an amorphous substance. The FWHM of an amorphous halo
`is in principle bigger than the FWHM of a peak of crystalline
`material.
`“FWHM' means full width at half maximum, which is a
`width of a peak appearing in an XRPD pattern at its half
`height.
`“Form A' is used herein as abbreviation for the crystalline
`form A of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl
`propoxy)-cyclohex-1-enecarboxylic acid ethyl ester phos
`phate.
`“Form B is used herein as abbreviation for the crystalline
`form B of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl
`propoxy)-cyclohex-1-enecarboxylic acid ethyl ester phos
`phate.
`“Form C is used herein as abbreviations for the crystalline
`form C of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl
`propoxy)-cyclohex-1-enecarboxylic acid ethyl ester phos
`phate.
`“IR” is used hereinas an acronym of Infrared spectroscopy.
`IR spectra were recorded as film of a Nujol suspension of
`approximately 5 mg of sample and few Nujol between two
`sodium chloride plates, with an FTIR spectrometer in trans
`mittance. The Spectrometer is a NicoletTM20SXB or equiva
`lent (resolution 2 cm, 32 or more coadded scans, MCT
`detector).
`“XRPD (is used herein as an acronym of X-Ray Powder
`Diffraction) X-ray diffraction patterns were recorded at
`ambient conditions in transmission geometry with a STOE
`STADI P diffractometer (Cu KC. radiation, primary mono
`chromator, position sensitive detector, angular range 3' to 42°
`20, approximately 60 minutes total measurement time). The
`samples were prepared and analyzed without further process
`ing (e.g. grinding or sieving) of the Substance.
`“Excipient” and “pharmaceutically acceptable excipient'
`mean inactive pharmaceutically acceptable ingredients that
`are, other than drug Substances, not intended to treat and/or
`prevent illnesses. It is to be understood that the excipients,
`including, but not limited to, diluents, Surfactants, wetting
`agents, binders, lubricants, disintegrating agents, carriers,
`fillers, etc. are of pharmaceutically acceptable grade.
`"Pharmaceutically active drug substance(s) and “drug
`Substance(s) are used interchangeably to denote a pharma
`ceutically active principle which is intended to treat and/or
`prevent illnesses.
`“Micronization” means the process whereby the particle
`size of a single drug Substance, is diminished by the aid of a
`Suitable mill, e.g. an air-jet mill.
`
`The phrase “a” or “an entity as used herein refers to one or
`more of that entity; for example, a compound refers to one or
`more compounds or at least one compound. As such, the
`terms “a” (or “an”), “one or more', and “at least one' can be
`used interchangeably herein.
`The specific crystalline forms of (3R,4R,5S)-4-acety
`lamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecar
`boxylic acid ethyl ester phosphate (I) are herein referred to as
`“crystalline form A', 'crystalline form B' and “crystalline
`form C.
`In an embodiment of the present invention there is provided
`a new crystalline form B of the compound of formula I, which
`is characterized by an XRPD pattern comprising at least three
`peaks (expressed in degrees 20) selected from the group
`consisting of approximately 5.3, approximately 6.0, approxi
`mately 7.4, approximately 12.1, approximately 12.8,
`approximately 13.6, approximately 16.1, approximately
`18.0, approximately 18.7, approximately 21.4, approxi
`mately 23.8 and approximately 24.3. In another embodiment
`of the present invention there is provided a crystalline Form B
`characterized by at least five XRPD peaks from the above list.
`In still another embodiment of the present invention there is
`provided a crystalline Form B characterized by at least seven
`XRPD peaks from the above list.
`In an embodiment of the present invention there is provided
`a new crystalline form C of the compound of formula (I),
`which is characterized by an XRPD comprising at least one
`XRPD peak (expressed in degrees 20) selected from the
`group consisting of approximately 4.5, approximately 9.1
`and approximately 13.6. In another embodiment of the
`present invention there is provided a crystalline Form C char
`acterized by at least two XRPD peaks from the above list. In
`still another embodiment of the present invention there is
`provided a crystalline Form C characterized by at least three
`XRPD peaks from the above list.
`In an embodiment of the present invention there is provided
`an amorphous form of the compound of formula I, which is
`characterized by an XRPD pattern lacking a Bragg diffraction
`peak. This amorphous form is also characterized by an XRPD
`pattern comprising one or more amorphous halos.
`In an embodiment of the present invention there is provided
`a pharmaceutical compositions comprising crystalline form
`B and/or crystalline form C or the above mentioned amor
`phous of the compound of formula I and a pharmaceutically
`acceptable excipient.
`In an embodiment of the present invention there is provided
`a method for inhibiting influenza viruses, in particular the
`selective inhibition of viral neuraminidases comprising
`administering a therapeutically effective amount of a crystal
`line form Band/or crystalline form C or the above mentioned
`amorphous form of the compound of formula I to a patient in
`need thereof.
`Unless otherwise indicated, the following definitions are
`set forth to illustrate and define the meaning and scope of the
`various terms used to describe the invention herein.
`Amorphous forms' or “amorphous' denote a material that
`does not show a Bragg diffraction peak. The XRPD pattern of
`an amorphous material is also characterized by one or more
`amorphous halos.
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`US 8,334,319 B2
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`5
`"Co-micronization” means that a mixture comprising at
`least one drug Substance and at least one excipient is micron
`ized in a suitable mill to obtain a diminished particle size of
`the drug Substance.
`Throughout this application the term “approximately” in
`the context of XRPD patterns means that there is an uncer
`tainty in the measurements of the degrees 20 of +0.2 degrees
`20. The term “approximately” means, in the context of an
`infra-red spectra, indicates an uncertainty in the measure
`ments of the wavenumbers of +3 cm'.
`Crystalline forms and amorphous forms of the present
`invention can be prepared, for example, by the general prepa
`ration procedures described below.
`Preparation of form A of (3R,4R.5S)-4-acetylamino
`5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecar
`boxylic acid ethyl ester phosphate
`
`10
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`6
`ethyl ester phosphate may surprisingly also be obtained by
`micronization of an initially crystalline sample of (3R,4R,
`5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex
`1-enecarboxylic acid ethyl ester phosphate in a agate ball
`mill.
`Alternatively the amorphous form is obtained by spray
`drying a solution of (3R,4R,5S)-4-Acetylamino-5-amino-3-
`(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester
`phosphate in organic solvents such as ethanol.
`The crystalline form(s) and the amorphous forms of the
`present invention can be used as medicaments, e.g. in the
`form of pharmaceutical preparations for enteral, parenteral or
`topical administration. They can be administered, for
`example, perorally, e.g. in the form of tablets, coated tablets,
`dragees, hard and softgelatine capsules, solutions, emulsions
`or Suspensions, rectally, e.g. in the form of Suppositories,
`parenterally, e.g. in the form of injection solutions or Suspen
`sions or infusion solutions, or topically, e.g. in the form of
`ointments, creams or oils. Oral administration is preferred.
`The production of the pharmaceutical preparations can be
`effected in a manner which will be familiar to any person
`skilled in the art by bringing the described crystalline forms or
`the amorphous of the compounds of formula I, optionally in
`combination with other therapeutically valuable substances,
`into a galenical administration form together with Suitable,
`non-toxic, inert, therapeutically compatible Solid or liquid
`carrier materials and, if desired, usual pharmaceutical adju
`VantS.
`Suitable carrier materials are not only inorganic carrier
`materials, but also organic carrier materials. Thus, for
`example, lactose, corn starch or derivatives thereof, talc,
`Stearic acid or its salts can be used as carrier materials for
`tablets, coated tablets, dragees and hard gelatine capsules.
`Suitable carrier materials for soft gelatine capsules are, for
`example, vegetable oils, waxes, fats and semi-solid and liquid
`polyols (depending on the nature of the active ingredient no
`carriers might, however, be required in the case of soft
`gelatine capsules). Suitable carrier materials for the produc
`tion of Solutions and syrups are, for example, water, polyols,
`Sucrose, invert Sugar. Suitable carrier materials for injection
`Solutions are, for example, water, alcohols, polyols, glycerol
`and vegetable oils. Suitable carrier materials for suppositories
`are, for example, natural or hardened oils, waxes, fats and
`semi-liquid or liquid polyols. Suitable carrier materials for
`topical preparations are glycerides, semi-synthetic and Syn
`thetic glycerides, hydrogenated oils, liquid waxes, liquid par
`affins, liquid fatty alcohols, Sterols, polyethylene glycols and
`cellulose derivatives.
`Usual stabilizers, preservatives, wetting and emulsifying
`agents, consistency-improving agents, flavour-improving
`agents, salts for varying the osmotic pressure, buffer Sub
`stances, solubilizers, colorants and masking agents and anti
`oxidants come into consideration as pharmaceutical adju
`VantS.
`The dosage of the described crystalline forms or the amor
`phous of the compounds of formula I can vary within wide
`limits depending on the disease to be controlled, the age and
`the individual condition of the patient and the mode of admin
`istration, and will, of course, be fitted to the individual
`requirements in each particular case. For adult patients a daily
`dosage of about 1 to 1000 mg, especially about 1 to 100 mg is
`effective. Depending on severity of the disease and the precise
`pharmacokinetic profile the crystalline forms or amorphous
`forms of the present invention could be administered with one
`or several daily dosage units, e.g. in 1 to 3 dosage units.
`
`Form A may be formed upon spontaneous or seeded solu
`tion mediated phase transformation or upon spontaneous or
`seeded crystallization in organic solvents such as methanol,
`ethanol, acetonitrile, isopropanol, ethyl acetate, methyl
`acetate, isopropyl acetate, acetone, benzyl alcohol, methyl
`cyclohexane and others eventually mixture thereof or other
`low polarity solvents. Form A is obtained after drying. The
`accessibility may be influenced by the impurity profile of the
`compound and the choice of solvent.
`Preparation of form B of (3R,4R,5S)-4-acetylamino
`5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecar
`boxylic acid ethyl ester phosphate
`
`Form B may be formed by adding (3R,4R,5S)-4-acety
`lamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecar
`boxylic acid ethyl ester to the phosphoric acid and cooling the
`supersaturated solution from 50° C. to -40° C. as fast as
`possible (without seeding).
`Preparation of form C of (3R,4R,5S)-4-acetylamino
`5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecar
`boxylic acid ethyl ester phosphate
`
`25
`
`30
`
`35
`
`40
`
`Crystalline form C of (3R,4R,5S)-4-acetylamino-5-
`amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid
`ethyl ester phosphate may be formed by the method compris
`ing following steps: Step a) dissolving compound of formula
`(I) into water and adjusting pH to 4.0; step b) sterile filtering
`the Solution through a sterilized 0.22 Lum membrane; step c)
`aseptic filling the solution into sterile depyrogenated vial and
`stoppering the vial with a sterile stopper; step d) lyophilizing
`the solution in a steam-sterilized freeze-dryer.
`An injectable pharmaceutical formulation may comprises
`a pharmaceutically effective amount of crystalline form C of
`compound of formula (I) and a pharmaceutically acceptable
`carrier.
`
`45
`
`50
`
`55
`
`Preparation of the amorphous form of (3R,4R,5S)-4-
`Acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclo
`hex-1-enecarboxylic acid ethyl ester phosphate
`
`Evaporation of a solution of (3R,4R,5S)-4-acetylamino-5-
`amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid
`ethyl ester phosphate in organic solvents such as dichlo
`romethane, ethyl acetate or others leading to amorphous Solid
`state usually as a foam.
`A amorphous form of (3R,4R,5S)-4-acetylamino-5-
`amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid
`
`60
`
`65
`
`Merck Exhibit 2187, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 8,334,319 B2
`
`7
`The pharmaceutical preparations conveniently contain
`about 1-500 mg, preferably 1-100 mg. of the crystalline
`form(s) or the amorphous forms of the compound of formula
`I.
`
`To prepare the pharmaceutical preparations, containing the
`crystalline form(s) or the amorphous forms of the compound
`of formula I, these materials are often micronized. Microni
`Zation is a commonly used and well known process in the
`pharmaceutical industry to reduce the particle size of drug
`Substances. The reason for micronization is usually to
`increase the bioavailability of the drug substance or to
`improve its overall technical processability.
`The following examples illustrate the preparation of the
`polymorphic and amorphous material within the scope of the
`invention. These examples and preparations which follow are
`provided to enable those skilled in the art to more clearly
`understand and to practice the present invention. They should
`not be considered as limiting the scope of the invention, but
`merely as being illustrative and representative thereof.
`
`8
`poxy)-cyclohex-1-enecarboxylic acid ethyl ester in 250 mL
`of ethanol was added to the phosphoric acid solution within 3
`to 5 minutes under stirring. The result clear solution was
`cooled to -40° C. within 1 hour without seeding. The
`obtained crystal suspension was slowly stirred at -40°C. over
`night. The suspension was filtered and washed with 240 mL
`of acetone and 300 mL of n-heptane. The crystal was then
`dried in vacuum under maximal temperature of 50° C. 53 g of
`fine white crystal form B was obtained, correspond to a yield
`of 88.6%.
`Characterization of Crystal Form B
`Form B can be characterized by an XRPD pattern obtained
`with a Cu KO. radiation having characteristic peaks expressed
`in degrees 20 at approximately: approximately 5.3, 6.0. 7.4.
`12.1, 12.8, 13.6, 16.1, 18.0, 18.7, 21.4, 23.8 and 24.3 or by an
`infrared spectrum having sharpbands at approximately: 3347.
`3172,2719, 1728, 1713, 1661, 1619, 1552, 1377, 1335, 1293,
`1262,1245, 1199, 1132, 1072, 1031,968,953,938,875,851,
`730 cm.
`
`10
`
`15
`
`EXAMPLE1
`
`EXAMPLE 3
`
`Preparation of Crystalline form A of the Compound of For
`mula I
`0.2 g of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl
`propoxy)-cyclohex-1-enecarboxylic acid ethyl ester phos
`phate was heated to reflux in the quantity of solvent stated in
`table 1 until it was dissolved. The solution was then allowed
`to cool slowly in an oil bath and then place in a refrigerator at
`approximately 4°C. overnight. All samples were dried in a
`Vacuum at room temperature.
`The crystals obtained were analyzed and did not exhibit
`significant differences between the samples and the reference
`Substance.
`
`25
`
`30
`
`35
`
`TABLE 1.
`
`Experimental conditions of crystallization of form A of formula I
`
`Solvent (incl. temperatures range)
`
`Volume of solvent
`
`40
`
`Ethanol (78° C. to RT)
`Ethanol/acetone (59° C. to RT)
`Isopropanol (83°C. to RT)
`Ethanol/ethyl acetate (77° C. to 4°C.)
`Methanol/acetonitrile (80° C. to 4°C.)
`Methanol/acetone (36° C. to 4°C.)
`Dimethyl formamide (125° C. to RT)
`Benzyl alcohol/methyl cyclohexane (120° C. to 4
`Ethanol (60° C. to RT)
`Methanol/acetone (50° C. to RT)
`
`6.7 mL.
`16 mL/72 mL
`32.5 mL.
`25 mL/40 mL.
`16 mL/60 mL.
`2 mL.7 mL
`1 mL
`1 mL 5 mL.
`7 mL.
`2 mL.7 mL
`
`Characterization of Crystal Form A
`Form A can be characterized by an XRPD pattern obtained
`with a Cu KC radiation having characteristic peaks expressed
`in degrees 20 at approximately: approximately 5.1, 12.4.
`13.0, 14.3, 15.2, 16.1, 19.0, 19.3, 20.3, 20.6, 21.6, 24.4 and
`26.3 or by an infrared spectrum having sharp bands at
`approximately: 3352, 3162, 1724, 1663, 1623, 1551, 1376,
`1337,1263, 1173, 1132, 1071, 1027,953,880, 854,731 cm
`EXAMPLE 2
`
`Preparation of Crystalline Form B of the Compound of For
`mula I
`16.9 g of phosphoric acid were mixed with 700 mLethanol
`in a nitrogen purged 1000 mL. glass reactor fitted with a
`mechanic stirrer and heated to 50 to 55° C. A solution of 45.8
`g of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-pro
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Preparation of Crystalline form C of the Compound of For
`mula I
`The bulk solution was prepared by dissolution of (3R,4R,
`5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex
`1-enecarboxylic acid ethyl ester phosphate into water for
`injection followed by pH adjustment with 0.1N hydrochloric
`acid (HCl) to pH 4.0.
`Before freeze-drying the bulk solution is sterile filtered
`through a sterilized 0.22 um membrane filter using a nitrogen
`pressure of approx. 0.5 bar (maximum 0.7 bar). The filtrate is
`collected into a sterile depyrogenated vessel, for example
`consisting of borosilicate glass.
`Under aseptic conditions, the sterile bulk solution is filled
`into sterile depyrogenated vials which are then stoppered
`with sterile stoppers in lyo-position and Subsequently lyo
`philized in a steam-sterilized freeze-dryer.
`After freeze-drying the vial headspace is overlaid with
`sterile filtered nitrogen, the vials are fully stoppered and
`finally sealed with aluminum flip-off caps.
`The following lyophilisation cycle was developed.
`
`Ramp Holding
`Ramp
`Shelf
`temperature temperature time
`time
`(° C.)
`(C./min) (min)
`(min)
`+5
`O
`60
`45
`-40
`1
`18O
`35
`-5
`1
`240
`30
`-40
`1
`120
`70
`-5
`O.S
`1100
`Secondary drying optimal
`by -8°C. product temperature
`O.S
`S4
`300
`234
`2000
`2234 min = 37.2hrs
`
`+30
`
`Vacum
`(mTorr)
`
`200
`
`100
`
`Pre-cooling
`Freezing?
`Annealing
`
`Primary drying
`
`Secondary drying
`
`Total process
`time
`
`Characterization of Crystallin Form C
`Form C can be characterized by an XRPD pattern obtained
`with a Cu KO. radiation having characteristic peaks expressed
`in degrees 20 at approximately: approximately 4.5, 9.1 and
`13.6. The term “approximately” means in this context that
`there is an uncertainty in the measurements of the degrees 20
`of +0.2 degrees 20.
`
`Merck Exhibit 2187, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 8,334,319 B2
`
`9
`EXAMPLE 4
`
`10
`ethyl ester phosphate (I) which is characterized by an XRPD
`pattern comprising at least one X-ray diffraction peak (ex
`pressed in degrees 20) selected from the group consisting of
`approximately 4.5, approximately 9.1 and approximately
`13.6.
`2. The crystalline form C according to claim 1, wherein
`XRPD pattern comprising at least of two X-ray diffraction
`peaks (expressed in degrees 20) selected from the group
`consisting of approximately 4.5, approximately 9.1 and
`approximately 13.6.
`3. The crystalline form C according to claim 1, wherein
`XRPD pattern comprising three X-ray diffraction peaks (ex
`pressed in degrees 20) selected from the group consisting of
`approximately 4.5, approximately 9.1 and approximately
`13.6.
`4. A method for therapeutic treatment and/or prophylaxis
`of a disease associated with a viral neuramidase comprising
`administering a therapeuically effective amount to a patient
`in need thereof of a crystalline form C of (3R,4R,5S)-4-
`acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-en
`ecarboxylic acid ethyl ester phosphate (I) according to claim
`1.
`5. A pharmaceutical composition containing a crystalline
`form C of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl
`propoxy)-cyclohex-1-enecarboxylic acid ethyl ester phos
`phate (I) according to claim 1 and at least one pharmaceuti
`cally acceptable carrier, diluent or excipient.
`6. An injectable pharmaceutical formulation comprising a
`composition according to claim 5 and a pharmaceutically
`acceptable carrier.
`7. An injectable pharmaceutical formulation according to
`claim 6, which formulation contains 60 to 120 mg of Form C
`of compound of formula (I) dissolved in an aqueous solution
`at a pH of 3.0 to 7.0.
`8. An injectable pharmaceutical formulation according to
`claim 7, which formulation contains Form C of compound of
`formula (I) dissolved in an aqueous solution at a pH of 3.5 to
`4.5.
`9. A method for preparing the crystalline form C of 3R.4R,
`5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy