US009340568B2
`
`a2) United States Patent
`US 9,340,568 B2
`(10) Patent No.:
`Casteelet al.
`(45) Date of Patent:
`May 17, 2016
`
`
`(54) SOLID FORMS OF AN ANTIVIRAL
`COMPOUND
`;
`;
`(71) Applicant: Gilead Pharmasset LLC, Foster City,
`CA (US)
`
`A61K 31/7072 (2013.01); CO7F 9/65586
`(2013.01); CO7H 19/06 (2013.01)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(72)
`
`Inventors: Melissa Jean Casteel, Foster City, CA
`(US); Kathleen Dashner, Foster City,
`CA (US); Hyuk-Jun Jung, Shihcung-si
`(KR); Mun Sik Seo, Shiheung-si (KR);
`;
`shi
`;
`-E
`Bing Shi, RedwoodCity, CA (US); Fang
`ang, Foster City, CA (US), Vahid Zia,
`Foster City, CA (US)
`
`(*) Notice:
`
`(73) Assignee: GILEAD PHARMASSETLLC,Foster
`City, CA (US)
`Subject to any disclaimer, the termofthis
`patent is extended or adjusted under 35
`US.C. 154(b) by 0 days.
`(21) Appl. No.: 14/563,639
`.
`(22)
`Filed:
`Dee. 8 2014
`
`(65)
`
`Prior Publication Data
`US 2015/0175646 Al
`Jun. 25, 2015
`4
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 61/920,371, filed on Dec.
`23, 2013.
`
`(51 )
`
`Int. Cl
`AOIN43/04
`A6IK 31/70
`CO7H 19/10
`AGIK 31/7052
`AGIK 31/7064
`AGIK 31/706
`AGIK 31/7068
`A6LK 31/7072
`CO7F 9/6558
`CO7H 19/06
`(52) U.S.C
`CPO we. CO7H 19/10 (201 3.01): A6LK 31/706
`(2013.01), AGLK 31/7082 (2013.01); A6IK
`31/7064 (2013.01); A6LK 31/7068 (2013.01);
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(56)
`
`References Cited
`
`US. PATENT DOCUMENTS
`7.964.580 B2
`62011 Sofia
`et
`al
`(2
`ofia et al.
`264,
`8.618,076 B2
`12/2013 Rosset al.
`8,642,756 B2*
`2/2014 ROSS essence CO7H19/10
`§36/117
`
`OTHER PUBLICATIONS
`Int’| Search Repost—Writte Opinion Dated Jul. 2, 2015 For PCT/
`US2014/069123.
`K
`ni
`:
`cited by examiner
`Primary Examiner — Patrick Lewis
`7
`r
`67)
`ABSTRACT
`Crystalline solid forms of the anti-HCV compound(S)-iso-
`propyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropy-
`rimidin-1(2H)-y1)-4-fluoro-3-hydroxy-4-methyltetrahydro-
`furan-2-
`yl)methoxy)(phenoxy)phosphorylamino)
`propanoate (CompoundI) are described
`
`(Compound I)
`
`O.
`
`N
`
`
`
`a
`
`Also provided are processes of making and methods of using
`the crystalline forms.
`
`10 Claims, 10 Drawing Sheets
`
`Gilead 2005
`I-MAK v. Gilead
`IPR2018-00126
`
`

`

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`May17, 2016
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`US 9,340,568 B2
`
`2
`One embodiment is a crystalline form of (S)-isopropy]
`2-((S)-((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dibydropyrimi-
`din-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofu-
`ran-2-yl)methoxy)(phenoxy)phosphorylamino) propanoate
`(Compound I) characterized by an XRPD diffractogram com-
`prising at least two peaks chosenfromthe followinglist: 12.6,
`13.5, 16.9, and 17.3 degrees two-theta (°20), +0.2° 20.
`Another embodiment is crystalline Compound I character-
`ized by an XRPDdiffractogram comprising peaksat 12.6 and
`13.5 °2620.2° 20. Another embodimentis crystalline Com-
`pound I characterized by an XRPD diffractogram comprising
`peaks at 12.6, 13.5, and 17.3 °26+0.2° 26. Another embodi-
`ment is crystalline Compound I characterized by an XRPD
`diffractogram comprising peaks at 12.6, 13.5, 16.9, and
`17.3 °2620.2° 20. These crystalline forms of Compound| are
`referred to as Compound |, Form 7.
`Another embodimentis a crystalline form of Compound I
`characterized by an XRPD diffractogram comprising at least
`two peaks chosenfromthe followinglist: 8.6, 9.2, 14.2, 15.6,
`16.0, 17.1, 17.5, 18.1, 19.8, and 25.6 °2020.2° 28. Another
`embodimentis crystalline Compound| characterized by an
`XRPD spectrum comprising peaks
`at
`8.6,
`9.2
`and
`17.1 °20+0.2° 26. These crystalline forms of Compound| are
`referred to as CompoundI, Form 8.
`In another embodiment, provided herein is a method of
`treating a humansubject infected with hepatitis C virus com-
`prising administering to the human subject a therapeutically
`effective amount of Compound I, Form 7 or Compound I,
`Form 8. In another embodiment, provided herein is a method
`of treating a human subject infected with hepatitis C virus
`comprising administering to the human subject a pharmaceu-
`tical composition comprising a therapeutically effective
`amount of CompoundI, Form 7 or Compound I, Form8 and
`a pharmaceutically acceptable excipient.
`Another embodiment
`is a pharmaceutical composition
`comprising CompoundI, Form 7 or Compound I, Form8 and
`a pharmaceutically acceptable excipient.
`Instill a further embodimentis a crystalline compound as
`defined herein or a pharmaceutical composition comprising
`the same for the treatment of a human subject infected by
`hepatitis C virus, use of the crystalline compound as defined
`herein or the pharmaceutical composition comprising the
`samefor the treatment of a human subject infected by hepa-
`titis C virus, use of the crystalline compoundasdefined herein
`or the pharmaceutical composition comprising the same for
`the manufacture of a medicament for the treatment of a
`human subject infected by hepatitis C virus, and use of a
`crystalline compound as defined herein or a pharmaceutical
`composition comprising the same in therapy.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. Lis an XRPD diffractogram of Compound J, Form7.
`FIG. 2 is a ??C SSNMRspectrum of CompoundJ, Form7.
`FIG. 3 is an FT-Raman spectrum of Compound I, Form7.
`FIG. 4 is a DSC plot of CompoundI, Form 7.
`FIG, 5 is a DVS plot of CompoundI, Form 7.
`FIG. 6 is an XRPD diffractogram of Compound I, Form8.
`FIG. 7 isa ‘°C SSNMRspectrum of CompoundI, Form 8.
`FIG. 8 is an FT-Raman spectrum of CompoundI, Form8.
`FIG. 9 isa DSC plot of Compound I, Form 8.
`FIG. 10 is a DVS plot of CompoundI, Form8.
`
`DETAILED DESCRIPTION
`
`As used in the present specification, the following words
`and phrasesare generally intended to have the meanings as set
`forth below, exceptto the extent that the context in which they
`are used indicates otherwise.
`
`30
`
`48
`
`50
`
`5
`
`60
`
`65
`
`1
`SOLID FORMSOF AN ANTIVIRAL
`COMPOUND
`
`CROSS REFERENCE
`
`This application claims the benefits of U.S. Provisional
`Application No. 61/920,371, filed on Dec. 23, 2013, the entire
`disclosure of which is incorporated herein by reference.
`
`BACKGROUND
`
`Hepatitis C is recognized as a chronic viral disease of the
`liver. Although drugs targeting the liver are in wide use and
`have shown efficacy,
`toxicity and other side effects have
`limited their usefulness. Inhibitors ofhepatitis C virus (HCV)
`are useful to limit the establishment and progression of infec-
`tion by HCV as well as in diagnostic assays for HCV.
`The compound (S)-isopropyl 2-((S)-(((2R,3R.4R,5R)-5-
`(2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-4-fluoro-3-hy-
`droxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)
`as
`phosphorylamino)propanoate,
`designated
`herein
`CompoundI, also known as Sofosbuvir, is an effective anti-
`HCV agent and is described in International Publication
`Numbers WO 2008/121634 and WO 2011/123654, and in
`US. Pat. Nos. 7,964,580 and 8,618,076. While certain crys-
`talline forms of Compound J have been reported, Compound
`I was not heretofore knownin the crystalline forms described
`herein.
`
`SUMMARY
`
`The present disclosure relates to crystalline solid forms of
`the compound(S)-isopropy] 2-((S)-(((2R,3R,4R,5R)-5-(2,4-
`dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)-4-fluoro-3 -hydroxy-
`4-methyltetrahydrofuran-2-yl)methoxy )(phenoxy)phospho-
`rylamino)propanoate (Compound I)
`
`(Compound 1)
`
`0
`
`NH
`|
`Sy So
`cn
`
`CH
`
`paw
`*p
`
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`
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`.
`wiY?
`
`processes for making the crystalline solid forms of Com-
`pound I, and their therapeutic methods ofuse.
`The present disclosure provides two crystalline forms of
`Compound I, referred to herein as Form 7 and Form 8. Forms
`7 and 8 may be characterized and distinguished from other
`solid forms of the same compound using various analytical
`techniques including, but not limited to, X-ray powder dif-
`fraction (XRPD), solid-state nuclear magnetic resonance
`(NMR, or '?C SSNMR), Ramanspectroscopy, differential
`scanning calorimetry (DSC), dynamic vapor sorption (DVS),
`and thermogravimetric analysis (TGA). The disclosure also
`provides processes for making the crystalline forms and
`methods for using them in the treatment of HCV.
`
`

`

`US 9,340,568 B2
`
`20
`
`35
`
`4
`3
`embodiment is crystalline Compound I, Form7, character-
`The term “therapeutically effective amount” refers to an
`ized by an XRPD diffractogram substantially as shown in
`amountthat is sufficient to effect treatment, as defined below,
`FIG. 1.
`when administered to a humanin need of suchtreatment. The
`In another embodiment, CompoundI, Form7is character-
`therapeutically effective amount will vary depending upon
`ized by a '?C SSNMRspectrum comprising peaksat 18.6,
`the humansubject being treated, the weight and age ofthe
`164.5, and 171.8 ppm.
`In another embodiment,
`the °C
`human subject, the severity ofthe disease condition, the man-
`SSNMR spectrum further comprises peaks at 21.5, 68.7,
`ner of administration andthe like, which can readily be deter-
`81.7, 102.8, and 151.4 ppm. In another embodiment, Com-
`mined by oneof ordinary skill in the art.
`pound |, Form 7 is characterized by a ‘*C SSNMRspectrum
`One embodiment
`is crystalline (S)-isopropyl 2-(((S)-
`substantially as shownin FIG. 2.
`((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-|
`In another embodiment, CompoundI, Form7 is character-
`(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)
`ized by an FT-Ramanspectrum comprising peaks at 748, 774,
`methoxy)(phenoxy )phosphoryeamino)
`propanoate
`1006, 1216, and 1717 cm7!. In another embodiment, the
`(Compound I, Form 7) characterized by an X-ray powder
`FT-Raman spectrum further comprises peaks at 545, 616,
`diffractogram comprising atleast three peaks chosen from the
`1027, 1372, 2949, and 2988 cm™’. In another embodiment,
`following list: 8.2, 10.5, 12.6, 17.0, 17.3, 19.5, 20.2, 21.0,
`CompoundI, Form 7 is characterized by an FT-Ramanspec-
`23.4, and 27.3 degrees two-theta (°20)20.2° 20. Another
`trum substantially as shown in FIG. 3.
`embodimentis crystalline Compound I, Form7, character-
`In another embodiment, CompoundI, Form 7 is character-
`ized by an XRPD diffractogram comprisingat least two peaks
`ized by a differential scanning calorimetry (DSC) endotherm
`with an onset at 119-120° C. In another embodiment, Com-
`chosen from the following list: 12.6, 13.5, 16.9, and
`pound I, Form 7 is characterized by a DSC endotherm witha
`17.3 °20#0.2° 26. Another embodimentis crystalline Com-
`peakat about 122° C. In another embodiment, the DSC curve
`pound 1, Form7, characterized by an XRPD diffractogram
`is substantially as shown in FIG. 4.
`comprising peaks at 12.6 and 13.5 °2020.2° 20, Another
`In another embodiment, CompoundI, Form7 is character-
`embodimentis crystalline Compound I, Form 7, character-
`ized by achangein mass ofabout 0.15%ata relative humidity
`ized by an XRPD diftractogram comprising peaks at 12.6,
`(RH) of 90% (sorption cycle 1) as measured by dynamic
`13.5, and 17.3 °20+0.2° 28. Another embodimentis crystal-
`vapor sorption (DVS). In another embodiment, the DVS is
`line Compound I, Form 7, characterized by an XRPD
`substantially as shown in FIG. 5.
`diffractogram comprising peaks at 12.6, 13.5, 16.9, and
`In another embodiment, CompoundI, Form7is character-
`17.3 °20+0.2° 20. Another embodimentis crystalline Com-
`ized byat least two of the following:
`pound |, Form 7, characterized by an XRPD diffractogram
`an XRPDspectrum comprising peaksat 12.6 and 13.5 °20,
`comprisingat least three peaks chosenfrom the followinglist:
`a °C SSNMRspectrum comprising peaksat 18.6, 164.5,
`8.2, 10.5, 12.6, 13.5, 16.9, 17.0, 17.3, 19.5, 20.2, 21.0, 23.4,
`and 171.8 ppm;
`and 27.3 °2020.2° 26. Another embodiment is crystalline
`an FT-Raman spectrum comprising peaks at 748, 774,
`Compound |, Form 7, characterized by an XRPD diffracto-
`1006, 1216, and 1717 cm7’; and
`gram comprising at least five peaks chosen from the follow-
`a DSC endotherm with an onset at 119-120° C.
`ing list: 8.2, 10.5, 12.6, 13.5, 16.9, 17.0, 17.3, 19.5, 20.2, 21.0,
`In another embodiment, CompoundI, Form7 is characterized
`23.4, and 27.3 °20+0.2° 20. Another embodimentis crystal-
`by an XRPDspectrum comprising peaks at 12.6 and 13.5, and
`line CompoundI, Form7, characterized by an XRPDdiffrac-
`a'°C SSNMRspectrum comprising peaks at 18.6, 164.5, and
`togram comprisingthe following peaks: 8.2, 10.5, 12.6, 13.5,
`171.8 ppm. In another embodiment, Compound I, Form 7 is
`16.9, 17.0, 17.3, 19.5, 20.2, 21.0, 23.4, and 27.3 °20+0.2° 20.
`characterized by an XRPD spectrum comprising peaks at
`Another embodiment is crystalline Compound |, Form7,
`12.6, 13.5, and 17.3, anda !2C SSNMR spectrum comprising
`characterized by an XRPDdiffractogram comprising at least
`peaks at 18.6, 164.5, and 171.8 ppm. In another embodiment,
`three d-spacing values from the followinglist: 10.8, 8.4, 7.1,
`6.6, 5.2, 5.1, 4.6, 4.4, 4.2, 3.8 and 3.3 angstroms (A).
`In
`CompoundI, Form 7 is characterized by an XRPD spectrum
`comprising peaks at 12.6, 13.5, 16.9, and 17.3 °28, and a °C
`another embodiment, the crystalline Compound I, Form7 is
`SSNMRspectrum comprising peaks at 18.6, 21.5, 68.7, 81.7,
`characterized byat least twoof the following d-spacing val-
`102.8, 164.5, 151.4 and 171.8 ppm.
`ues: 7.1, 6.6, 5.2, 5.1 angstroms (A). Ina further embodiment,
`One embodiment is a process for making Compound],
`the crystalline Compound, Form7 is characterized by d-spac-
`Form 7, comprising, contacting (S)-isopropyl 2-(((S)-(((2R,
`ing valuesat 7.1 and 6.6 angstroms(A). Another embodiment
`3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-
`is crystalline Compound I, Form 7, characterized by an
`fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)
`XRPDdiffractogram comprising d-spacing valuesat 7.1, 6.6,
`(phenoxy)phosphory])amino) propanoate with a solvent
`and 5.1 angstroms (A). Another embodimentis crystalline
`comprising isopropyl acetate and heptane, whereby Com-
`Compound I, Form 7, characterized by an XRPDdiffracto-
`pound I, Form 7 is formed. In another embodiment,the sol-
`gram comprising d-spacing values at 7.1, 6.6, 5.2, and 5.1
`5 vent comprises THF. In another embodiment, the process
`angstroms (A). Another embodiment
`is crystalline Com-
`further comprises seeding with a seed crystal of Compound J,
`pound 1, Form 7, characterized by an XRPD diffractogram
`Form 7. In another embodiment, the process further com-
`comprisingat least five d-spacing values from the following
`prises isolating Compound| Form 7.
`list: 10.8, 8.4, 7.1, 6.6, 5.2, 5.1, 4.6, 4.4, 4.2, 3.8 and 3.3
`Another embodimentis crystalline (S)-isopropy! 2-(((S)-
`angstroms (A). The relationship betweenpeak positions and
`(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1
`d-spacing values for Form 7 is found in Table | and the
`(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)
`paragraph immediately following it.
`methoxy)(phenoxy)phosphory!)amino)
`propanoate
`Another embodimentis crystalline Compound J, Form7,
`(Compound I, Form 8) characterized by an X-ray powder
`characterized by an XRPD diffractogram having peak posi-
`diffractogram comprising atleast three ofthe following peaks
`tions (26 values) substantially as listed for Form 7 in Table 1.
`chosen fromthe following list: 8.6, 9.2, 14.2, 15.6, 16.0, 17.1,
`Another embodiment is crystalline Compound I, Form 7,
`17.5, 18.1, 19.8, and 25.6 °20+0,.2° 26. Another embodiment
`characterized by an XRPD diffractogram having d-spacing
`is crystalline Compound I, Form 8, characterized by an
`values substantially as listed for Form 7 in Table 1. Another
`
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`US 9,340,568 B2
`
`6
`5
`One embodiment is a process for making Compound 1,
`XRPDdiffractogram comprisingat least 5 peaks chosen from
`Form 8, comprising contacting (S)-isopropyl 2-(((S)-(((2R,
`the followinglist: 8.6, 9.2, 14.2, 15.6, 16.0, 17.1, 17.5, 18.1,
`3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-y!)-4-
`19.8, and 25.6 °2020.2° 26. Another embodimentis crystal-
`fluoro-3-hydroxy-4-methy]tetrahydrofuran-2-yl)methoxy)
`line CompoundI, Form 8, characterized by an XRPDdiffrac-
`(phenoxy)phosphoryljamino) propanoate with a solvent
`togram comprising peaksat 8.6, 9.2 and 17.1 °2640.2° 20.
`comprising isopropyl acetate, whereby CompoundI, Form 8
`Another embodimentis crystalline Compound I, Form 8,
`is formed. In another embodiment, the process further com-
`characterized by an XRPDdiffractogram comprising d-spac-
`ing values at 10.3, 9.6, and 5.2 angstroms(A). In yet another
`prises seeding with a seed crystal of CompoundI, Form 8. In
`another embodiment, the process further comprisesisolating
`embodiment, the crystalline CompoundI, Form 8 hasat least
`Compound I, Form 8.
`three ofthe following d-spacing: 10.3, 9.6, 6.3, 5.7, 5.5, 5.2,
`5.1, 4.9, 4.5, and 3.5 angstroms(A). In still another embodi-
`Forms7 and 8 of CompoundI provided in accordance with
`the present disclosure may be administered in the form of
`ment, the crystalline CompoundI, Form8has atleastfive of
`pharmaceutical compositions. This disclosure therefore pro-
`the following d-spacing: 10.3, 9.6, 6.3, 5.7, 5.5, 5.2, 5.1, 4.9,
`4,5, and 3.5 angstroms (A). The relationship between peak
`vides pharmaceutical compositionsthat contain, as the active
`ingredient, one or more of Forms 7 and 8 of Compound I and
`positions and d-spacing values for Form8 is foundin Table 1.
`one or more pharmaceutically acceptable excipients, carriers,
`Another embodiment is crystalline Compound 1, Form8,
`including inert solid diluents and fillers, diluents, including
`characterized by an XRPD diffractogram having peak posi-
`sterile aqueous solution and various organic solvents, perme-
`tions (26 values) substantially as listed for Form 8 in Table 1.
`ation enhancers, solubilizers and adjuvants. The pharmaceu-
`Another embodiment is crystalline Compound J, Form 8,
`tical compositions may be administered aloneor in combina-
`characterized by an XRPD diffractogram having d-spacing
`tion with other therapeutic agents. Such compositions are
`values substantially as listed for Form 8 in Table 1. Another
`prepared in a manner well known in the pharmaceutical art
`embodiment is crystalline Compound I, Form8, character-
`(see, e.g., Remington’s Pharmaceutical Sciences, Mace Pub-
`ized by an XRPDdiffractogram substantially as shown in
`FIG. 6.
`lishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern
`Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker &
`In another embodiment, Compound J, Form8 is character-
`C. T. Rhodes, Eds.).
`ized by a °C SSNMR spectrum comprising peaksat 23.5,
`70.1, and 152.4 ppm.
`In another embodiment,
`the '°C
`In one embodiment, provided herein is a pharmaceutical
`composition comprising CompoundI, Form 7 and a pharma-
`SSNMR spectrum further comprises peaks at 22.2, 71.6,
`ceutically acceptable carrier. In another embodiment, pro-
`78.8, 118.6 and 172.2 ppm. In another embodiment, Com-
`pound I, Form8 is characterized by a '°Csolid state nuclear
`vided herein is a pharmaceutical composition comprising
`CompoundI, Form 8 and a pharmaceutically acceptable car-
`magnetic resonance spectrumsubstantially as shownin FIG.
`7,
`rier. In various embodiments, a pharmaceutical composition
`can comprise CompoundI in more than onesolid form. For
`In another embodiment, CompoundI, Form8is character-
`example, a pharmaceutical composition can comprise Com-
`ized by an FT-Ramanspectrum comprising peaks at 628, 759,
`pound I, Form 7 at about 1 to about 100 percent(wt/wt) of the
`1029, 1224, and 1701 cm™!.
`In another embodiment,
`the 3:
`total amount of Compound1. For example, a pharmaceutical
`FT-Raman spectrum further comprises peaks at 221, 290,
`composition can comprise CompoundI, Form 7 at about | to
`543, 1397, 2994, and 3076 cm™!. In another embodiment,
`about 40 percent of the total amount of Compound 1. For
`CompoundI, Form8 is characterized by an FT-Raman spec-
`example, a pharmaceutical composition can comprise Com-
`trumsubstantially as shownin FIG. 8.
`pound |, Form 7 at about | to about 20 percent(i.e. about 1
`In another embodiment, Compound I, Form 8 is character-
`percent, about 2 percent, about 3 percent, about 4 percent,
`ized by a differential scanning calorimetry (DSC) endotherm
`with an onset at 131-132° C. In another embodiment, Com-
`about 5 percent, about 6 percent, about 7 percent, about 8
`percent, about 9 percent, about 10 percent, about 11 percent,
`poundI, Form8 is characterized by a DSC endothermwith a
`about12 percent, about13 percent, about14 percent, about 15
`peak at about 133° C. In another embodiment, the DSC curve
`percent, about 16 percent, about 17 percent, about 18 percent,
`is substantially as shownin FIG. 9.
`about 19 percent, about 20 percent) of the total amount of
`in another embodiment, CompoundI, orm8 is character-
`Compound |. By wayof further example, a pharmaceutical
`ized by achange in mass ofabout 0.17% atarelative humidity
`composition can comprise Compound J, Form8 at about | to
`of 90% relative humidity, (sorption cycle 1) as measured by
`about 100 percent (wt/wt) ofthe total amount ofCompound1.
`dynamic vaporsorption (DVS). In another embodiment, the
`For example, a pharmaceutical composition can comprise
`DVSis substantially as shown in FIG. 10.
`CompoundI, Form 8 at about | to about 40 percentofthetotal
`In another embodiment, CompoundI, Form 8 is character-
`amount of CompoundI. For example, a pharmaceutical com-
`ized byat least two ofthe following:
`position can comprise Compound 1, Form 8 at about
`1
`to
`an XRPD spectrum comprising peaks at 8.6, 9.2 and
`17.1 °28,
`about 20 percent(i.e. about | percent, about 2 percent, about
`3 percent, about 4 percent, about 5 percent, about 6 percent,
`a ‘°C SSNMRspectrum comprising peaks at 23.5, 70.1,
`about 7 percent, about 8 percent, about 9 percent, about 10
`and 152.4 ppm,
`percent, about 11 percent, about 12 percent, about 13 percent,
`an FT-Raman spectrum comprising peaks at 628, 759,
`about 14 percent, about 15 percent, about 16 percent, about 17
`1029, 1224, and 1701 cm7’; and
`a DSC endothermwith an onset at 131-132°C.
`percent, about 18 percent, about 19 percent, about 20 percent)
`of the total amount of Compound1.
`In another embodiment, CompoundI, Form8 is characterized
`Form 7 and Form 8 of Compound | may be administered
`by an XRPD spectrumcomprising peaksat 8.6, 9.2 and 17.1
`orally or formulated for oral administration. Administration
`°26 and a ‘°C SSNMRspectrum comprising peaksat 23.5,
`may be via capsule or enteric coated tablets or the like. In
`70.1, and 152.4 ppm. In another embodiment, CompoundI,
`making the pharmaceutical compositionsthat includeat least
`Form8 is characterized by an XRPD spectrum comprising
`peaks at 8.6, 9.2 and 17.1 °20 and a °C SSNMRspectrum
`one compound described herein, the active ingredient is usu-
`ally diluted by an excipient and/or enclosed within such a
`comprising peaks at 22.2, 23.5, 70.1, 71.6, 78.8, 118.6, 152.4
`carrier that can be in the form of a capsule, sachet, paper or
`and 172.2 ppm.
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`US 9,340,568 B2
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`w
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`25
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`30
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`35
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`20
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`7
`8
`tical unit dosage forms comprise from about 10 mg to about
`other container. When the excipient serves as a diluent,it can
`1000 mg of CompoundI, which may contain from about | to
`be in the form of a solid, semi-solid or liquid material (as
`above), which acts as a vehicle, carrier or medium for the
`about 99 percent of Form 7 or Form 8. In various embodi-
`ments, the pharmaceutical dosage form comprises about 50,
`active ingredient. Thus, the compositions can be in the form
`or about 100, or about 150, or about 200, or about 250, or
`oftablets, pills, powders, lozenges, sachets, cachets, elixirs,
`about 300, or about 350, or about 400, or about 450, or about
`suspensions, emulsions, solutions, syrups, aerosols (as a solid
`500, or about 550, or about 600,or about 650, or about 700, or
`or ina liquid medium), ointments, soft and hard gelatin cap-
`about 750, or about 800 mg of CompoundI. In a further
`sules, sterile injectable solutions andsterile packaged pow-
`ders.
`embodiment,
`the pharmaceutical dosage form comprises
`about 400 mg of CompoundI. In one embodiment, a phar-
`Some examples of suitable excipients include lactose, dex-
`maceutical dosage form comprises about 400 mg of Com-
`trose, sucrose, sorbitol, mannitol, starches, gumacacia, cal-
`pound I, wherein the amount of Form 7 is from about 1
`to
`cium phosphate, alginates, tragacanth, gelatin, calcium sil-
`about 100 percent of the total amount of Compound J. In one
`cate, microcrystalline
`cellulose,
`polyvinylpyrrolidone,
`embodiment, a pharmaceutical dosage form comprises about
`cellulose, sterile water, syrup and methyl cellulose. The for-
`400 mg ofCompound |, wherein the amount of Form7 is from
`mulations canadditionally include: lubricating agents such as
`about| to about 40 percentof the total amount of Compound
`talc, magnesium stearate and mineral oil; wetting agents:
`I, In one embodiment, a pharmaceutical dosage form com-
`emulsifying and suspending agents; preserving agents such
`prises about 400 mg of CompoundI, wherein the amount of
`as methy! and propylhydroxy-benzoates: sweetening agents;
`Form 7 is from about
`|
`to about 20 percent (i.e. about
`|
`and flavoring agents.
`percent, about 2 percent, about 3 percent, about 4 percent,
`In some embodiments, the compositions are formulated in
`about 5 percent, about 6 percent, about 7 percent, about 8
`a unit dosage form. The term “unit dosage forms” refers to
`percent, about 9 percent, about 10 percent, about 11 percent,
`physically discrete units suitable as unitary dosages for
`about12 percent, about 13 percent, about 14 percent, about 15
`human subjects and other mammals, each unit containing a
`percent, about 16 percent, about 17 percent, about 18 percent,
`predetermined quantity of active material calculated to pro-
`about 19 percent, about 20 percent) of the total amount of
`duce the desired therapeutic effect, in association with a suit-
`Compound I. In one embodiment, a pharmaceutical dosage
`able pharmaceutical excipient
`(e.g.,
`a
`tablet, capsule,
`form comprises about 400 mg of CompoundJ, wherein the
`ampoule). The compounds are generally administered in a
`amount of Form8is from about| to about 100 percentofthe
`pharmaceutically effective amount. In some embodiments,
`total amount of Compound I. In one embodiment, a pharma-
`each dosage unit contains from 1 mg to 2 g of a CompoundI,
`ceutical dosage form comprises about 400 mg of Compound
`Form 7 or Form8, and for parenteral administration, in some
`1, wherein the amount of Form 8 is from about | to about 40
`embodiments, from 0.1 to 700 mg of CompoundI, Form7 or
`percent of the total amount of CompoundI. In one embodi-
`Form 8. In some embodiments, each dosage unit contains
`ment, a pharmaceutical dosage form comprises about 400 mg
`about 400 mg of Compound I, Form 7 or Form 8. It will be
`of Compound I, wherein the amount of Form 8 is from about
`understood, however, that the amount of the compound actu-
`1 to about 20 percent (i.e. about 1 percent, about 2 percent,
`ally administered usually will be determined by a physician,
`about 3 percent, about 4 percent, about 5 percent, about 6
`in the light of the relevant circumstances, including the con-
`dition to be treated, the chosen route of administration, the
`percent, about 7 percent, about 8 percent, about 9 percent,
`about 10 percent, about 11 percent, about 12 percent, about 13
`actual compound administered and its relative activity, the
`percent, about 14 percent, about 15 percent, about 16 percent,
`age, weight and responseofthe individual subject, the sever-
`about 17 percent, about 18 percent, about 19 percent, about 20
`ity of the subject’s symptoms, andthelike.
`percent) of the total amount of CompoundI.
`For preparing solid compositions such as tablets, the prin-
`CompoundI, Form 7 or Form 8 described herein may be
`cipal active ingredient is mixed with a pharmaceutical excipi-
`administered to a human subject suffering from hepatitis C
`ent to forma solid preformulation composition containing a
`virus (HCV)in either single or multiple doses by any of the
`homogeneous mixture of a compoundof the present disclo-
`accepted modes of administration known to those who are
`sure. Whenreferring to these preformulation compositions as
`skilled in the art and as detailed above. In one embodiment,
`homogeneous, it is meant that the active ingredient is dis-
`provided herein is a method oftreating a human subject
`persed evenly throughout the compositionso that the compo-
`infected with hepatitis C virus comprising administering to
`sition may be readily subdivided into equally effective unit
`the humansubject a therapeutically effective amount of Com-
`dosage forms such as tablets, pills and capsules.
`pound I Form7. In another embodiment, provided hereinis a
`Thetablets orpills of the present disclosure may be coated
`methodoftreating a human subject infected with hepatitis C
`or otherwise compoundedto provide a dosage formaffording
`virus comprising administering to the human subject a thera-
`the advantage of prolonged action or to protect from the acid
`peutically effective amount of CompoundI, Form 8.
`In
`conditions ofthe stomach. lor example, the tablet or pill can
`another embodiment, provided herein is a methodoftreating
`comprise an inner dosage and anouter dosage component, the
`a humansubject infected with hepatitis C virus comprising
`latter being in the form of an envelope over the former. The
`administering to the human subject a pharmaceutical compo-
`two components can be separated by an enteric layer that
`sition comprising a therapeutically effective amount of Com-
`serves to resist disintegration in the stomach and permit the
`pound I, Form7 and a pharmaceutically acceptable carrier.In
`inner component to pass intact into the duodenumarto be
`another embodiment, provided herein is a methodof treating
`delayed in release. A variety of materials can be used for such
`a humansubject infected with hepatitis C virus comprising
`enteric layers or coatings, such materials inchiding a number
`administering to the humansubject a pharmaceutical compo-
`of polymeric acids and mixtures of polymeric acids with such
`sition comprising a therapeutically effective amount of Com-
`materials as shellac, cetyl alcohol and cellulose acetate. In
`pound I, Form 8 and a pharmaceutically acceptable carrier. In
`one embodiment, the film coating is a polyvinylalcohol-based
`still another embodiment, provided herein is a crystalline
`coating.
`for