USOO9340568B2
`
`(12) United States Patent
`US 9,340,568 BZ
`(10) Patent No.:
`
`Casteel et al.
`(45) Date of Patent:
`May 17, 2016
`
`(54) SOLID FORMS OF AN ANTIVIRAL
`COMPOUND
`_
`'
`(71) Applicant: Gilead Pliarmasset LLC, Foster City.
`CA (US)
`
`A6IK31/7072 (2013.01); C07F 9/65586
`(2013.01); C0711 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);
`-
`.
`1
`,
`.
`(
`an); Sh)” Red‘Yf’Od C‘ty’ CAT (118), ”Eng
`ans) Poster («11% CA (US)1thid Z'a~
`Foster City, CA (US)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`7 964 580 BE
`67011 S 11
`t
`1
`/1.
`o a e a 1
`,
`.
`8,618,076 132
`12/2013 Ross ct 01.
`8,642.756 BZ *
`2/2014 Ross ...................... C0711 10/10
`536/1 17
`
`(73) Assignee: GILEAD PIIARMASSE’I‘ LLC,1"oster
`C‘ty’ CA (US)
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 1540)) by 0 days.
`
`( * ) Notice:
`
`OTHER PUBLICATIONS
`Int’l Search Reponmwnne Opinion Dated Jul, 2. 2015 Per PCT/
`1.152014/069123.
`-
`,1
`.
`Cited by examiner
`
`(21) Appl. No: 14/563,639
`.
`Filed:
`
`Dec. 8, 2014
`
`(22)
`
`(65)
`
`Prior Publication Data
`
`US WIS/0175646 A]
`
`Jun. 25‘ 2015
`_
`_
`Related US. Application Data
`
`(60)
`
`Provisional application No. 61/920,371. filed on Dec.
`235 2013.
`
`(51 )
`
`Int. Cl.
`A01N 43/04
`A61K 31/70
`C07H 19/10
`A61K 31/7052
`A61K 31/7064
`A61K 31/706
`A61K 31/7068
`A61K 31/7072
`C07F 9/6558
`C0711 19/06
`(52) US. (Tl.
`CPC .............. C07f1 19/10 (2013.01): A61K31/706
`(2013.01); A61K 31/7052 (2013.01); A61K
`31/7064 (2013.01); A61K31/7068 (2013.01);
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Primary Examiner «— Patrick Lew1s
`7
`‘
`(5 )
`ABS] RACT
`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)v4-fiuoro-3 —liydroxy—4—metliyltetrahydro-
`furan-2-
`y1)metlioxy)(phenoxy)phosphorylamino)
`propanoate (Compound I) are described
`
`(Compound I)
`
`O.
`
`N
`
`
`
`/
`
`Also provided are processes of making and methods of using
`the crystalline fonns.
`
`10 Claims, 10 Drawing Sheets
`
`Gilead 2005
`
`l-MAK v. Gilead
`
`1PR2018-OO126
`
`

`

`US. Patent
`
`May 17, 2016
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`May 17, 2016
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`US. Patent
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`May 17, 2016
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`May 17, 2016
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`U.S. Patent
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`May 17, 2016
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`US 9,340,568 B2
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`US 9,340,568 B2
`
`1
`SOLID FORMS OF AN ANTIVIRAL
`COMPOUND
`
`CROSS REFERENCE
`
`This application claims the benefits of US. Provisional
`Application No. 61/920,371, filedon Dec. 23, 2013. theentire
`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 elfects 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 I-ICV.
`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)propanoatc,
`designated
`herein
`Compound I, 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 I have been reported, Compound
`I was not heretofore known in the crystalline forms described
`herein.
`
`SUMMARY
`
`The present disclosure relates to crystalline solid forms of
`the compound (S)~isopropyl 2~((S)~(((2R,3R,4R,5R)-5-(2,4—
`dioxo‘3,4-dihydropyrimidin- l (2H)—yl)«4—11uoro-3-hydroxy-
`4-methyltetrahydrofuran—Z—yl)methoxy)(phenoxy)phospho-
`rylamino)propanoate (Compound 1)
`
`10
`
`15
`
`30
`
`35
`
`(Compound I)
`
`40
`
`O
`
`45
`
`50
`
`processes for making the crystalline solid forms of Com— .
`pound I, and their therapeutic methods of use.
`The present disclosure provides two crystalline forms of
`Compound I. referred to herein as liorm 7 and l’orm 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 13C SSNMR), Raman spectroscopy, differential
`scanning calorimetry (DSC), dynamic vapor sorption (DVS),
`and thermogravimetrie analysis (TGA), The disclosure also
`provides processes for making the crystalline forms and
`methods for using them in the treatment of HCV’.
`
`60
`
`65
`
`2
`One embodiment is a crystalline form of (S)-isopropyl
`2—((S)-(((2R,3R,4R,5R)-5—(2,4—dioxo-3,4-dihydropyrimi—
`din-l (2II)-yl)-4-fiuoro-3-hydroxy-4-methyltetrahydrol‘ua
`ran—2-yl)methoxy)(phenoxy)phosphorylamino) propanoate
`(Compound 1) characterized by an XRPD diffractogram com-
`prising at least two peaks chosen from the following list: 12 .6,
`13.5, 16.9, and 17.3 degrees two~theta (°20), 10.20 20.
`Another embodiment is crystalline Compound 1 character-
`ized by an XRPD diffraetogram comprising peaks at 12.6 and
`13.5 °20:0.2° 20. Another embodiment is crystalline Com—
`pound I characterized by an XRPD diffractogram comprising
`peaks at 12.6, 13.5, and 17.3 °20:0.2° 20. Another embodi-
`ment is crystalline Compound I characterized by an XRPD
`diffractogram comprising peaks at 12.6, 13.5, 16.9. and
`17.3 °2010.2° 20. These crystalline forms ofCompound l are
`referred to as Compound 1, l’orm 7.
`Another embodiment is a crystalline fomi of Compound 1
`characterized by an XRPD diffractogram comprising at least
`two peaks chosen from the following list: 86, 9.2, 14.2, 15.6,
`16.0, 17.1. 17.5, 18.1, 19.8, and 25.6 °20:0.2° 20, Another
`embodiment is crystalline Compound I characterized by an
`XRPD spectrum comprising peaks
`at
`8.6,
`9.2
`and
`17.1 02030.20 20. These crystalline forms ofCompound l are
`referred to as Compound 1, Form 8.
`In another embodiment, provided herein is a method of
`treating a human subject infected with hepatitis C virus com—
`prising administering to the human subject a therapeutically
`effective amount of Compound I, l’orm 7 or Compound 1,
`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 Compound 1, Form 7 or Compound 1, Form 8 and
`a pharmaceutically acceptable excipient.
`Another embodiment
`is a pharmaceutical composition
`comprising Compound 1. Form 7 or Compound 1, Form 8 and
`a pharmaceutically acceptable excipient.
`In still a further embodiment is 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
`same for the treatment ot‘a human subject infected by hepa—
`titis C virus, use of the crystalline compound as defined 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 DI'iSCRIP'I‘ION OI" THE DRAWINGS
`
`FIG. 1 is an XRPD diffractogram of Compound 1, Form 7.
`FIG. 2 is a ”C SSNMR spectrum ofCompound 1, Form 7.
`FIG. 3 is an FT—Raman spectrum ofCompound 1, Form 7.
`FIG. 4 is a DSC plot ofCompound 1, Form 7.
`FIG. 5 is a DVS plot ofCompound 1, Form 7.
`FIG. 6 is an XRPD diffractogram ofCompound l, Fonn 8.
`FIG. 7 is a 13C SSNMR spectrum ofCompound 1, Form 8.
`FIG. 8 is an FT—Raman spectrum of Compound 1, Form 8.
`FIG. 9 is a DSC plot ofCompound 1, Form 8.
`FIG. 10 is a DVS plot of Compound I, Fomi 8.
`
`DETAILED DESCRIPTION
`
`As used in the present specification, the following words
`and phrases are generally intended to have the meanings as set
`forth below, except to the extent that the context in which they
`are used indicates otherwise.
`
`

`

`US 9,340,568 B2
`
`3
`The term “therapeutically effective amount” refers to an
`amount that is sufficient to effect treatment, as defined below,
`when administered to a human in need of such treatment. The
`therapeutically effective amount will vary depending upon
`the human subject being treated, the weight and age of the
`human subject. the severity of the disease condition, the man-
`ner of administration and the like, which can readily be deter
`mined by one of ordinary skill in the art.
`One embodiment
`is crystalline (S)—isopropyl 2-(((S)-
`(((2R,3R,4R,5R)-5—(2,4—dioxo—3,4—dihydropyrimidin—1
`(211)-yl)-4-fluoro-3-hydroxy—4-methyltetrahydrofuran—Z—yl)
`methoxy)(phenoxy)phosphoryeamino)
`propanoate
`(Compound 1, Form 7) characterized by an X-ray powder
`diffractogram comprising at least three peaks chosen from the
`following list: 8.2, 10.5, 12.6, 17.0, 17.3, 19.5, 20.2, 21.0,
`23.4, and 27.3 degrees two-theta (°26):0.2° 20. Another
`embodiment is crystalline Compound 1, Form 7, character-
`ized by an XRPI ) diffractogram comprising at least two peaks
`chosen from the following list: 12.6, 13.5, 16.9, and
`17.3 02030.2" 20. Another embodiment is crystalline Com~
`pound 1, Form 7, characterized by an XRPD diffractogram
`comprising peaks at 12.6 and 13.5 °20102° 20. Another
`embodiment is crystalline Compound 1, Form 7, character-
`ized by an XRPD diffractogram comprising peaks at 12.6,
`13.5. and 17.3 °20:0.2° 20. Another embodiment is crystal—
`line Compound 1. Form 7, characterized by an XRPD
`diffractogram comprising peaks at 12.6, 13.5, 16.9, and
`17.3 °20t0.2° 20. Another embodiment is crystalline Com—
`pound ], Form 7, characterized by an XRPD diffractogram
`comprising at least three peaks chosen from the following list:
`8.2. 105,126,135,16.9,17.0, 173,195. 20.2, 21.0, 23.4,
`and 27.3 °29:0.2° 26. Another embodiment is crystalline
`Compound 1. Form 7. characterized by an XRPD diffracto-
`gram comprising at least five peaks chosen from the follow-
`inglist:8.2,10.5,126,135,169,17.0,l7.3,19.5,20.2,21.0,
`23.4, and 27.3 °20:O.2° 20. Another embodiment is crystal-
`line Compound 1, Form 7, characterized by an XRPD diffrac—
`togram comprising the following peaks: 8.2, 10.5, 12.6, 13.5,
`16.9, 17.0, 17.3. 19.5, 20.2, 21 .0, 23.4, and 27.3 °20:0.2° 20.
`Another embodiment is crystalline Compound 1, Form 7,
`characterized by an XRPD diffractogram comprising at least
`three d—spacing values from the following list: 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
`another embodiment, the crystalline Compound 1, Form 7 is
`characterized by at least two ofthe following d-spacing val~
`ues: 7.1, 6.6. 5.2. 5.1 angstroms (A). In a further embodiment.
`the crystalline Compound. Form 7 is characterized by d—spac—
`ing values at 7.1 and 6.6 angstroms (A). Another embodiment
`is crystalline Compound 1, Form 7, characterized by an
`XRPD ditlractogram comprising d-spacing values at 7. 1, 6.6,
`and 5.1 angstroms (A). Another embodiment is crystalline
`Compound 1, Form 7, characterized by an XRPD diffracto-
`gram comprising d—spacing values at 7.1. 6.6, 5.2, and 5.1
`angstroms (A). Another embodiment
`is crystalline Com—
`pound 1, Form 7, characterized by an XRPD diffractogram
`comprising at least five d—spacing values from the following
`list: 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). The relationship between peak positions and
`d-spacing values for Form 7 is found in Table 1 and the
`paragraph immediately following it.
`Another embodiment is crystalline Compound 1, Form 7,
`characterized by an XRPD diffractogram having peak posi—
`tions (20 values) substantially as listed for Form 7 in Table 1.
`Another embodiment is crystalline Compound 1, Form 7,
`characterized by an XRPD diffractogram having d—spacing
`values substantially as listed for Form 7 in Table 1. Anoflier
`
`4
`embodiment is crystalline Compound 1, Form 7, character-
`ized by an XRPD diffractogram substantially as shown in
`FIG. 1.
`In another embodiment, Compound 1, Form 7 is character-
`ized by a 13C SSNMR spectrum comprising peaks at 18.6,
`164.5, and 171.8 ppm.
`In another embodiment,
`the 13C
`SSNMR spectrum further comprises peaks at 21.5, 68.7,
`81.7, 102.8, and 151.4 ppm. In another embodiment, Com-
`pound 1, Form 7 is characterized by a 13C SSNMR spectrum
`substantially as shown in FIG. 2.
`In another embodiment. Compound 1, Form 7 is character-
`ized by an FT—Raman spectrum comprising peaks at 748, 774,
`1006, 1216, and 1717 cm“. In another embodiment, the
`FT—Raman spectrum further comprises peaks at 545, 616,
`1027, 1372, 2949, and 2988 cm". In another embodiment,
`Compound 1, Form 7 is characterized by an FT—Raman spec-
`trum substantially as shown in FIG. 3.
`In another embodiment, Compound I, Form 7 is character—
`ized by a differential scanning calorimetry (DSC) endotherm
`with an onset at 1 19-120" C. In another embodiment, Com—
`pound 1, Form 7 is characterized by a DSC endotherm with a
`peak at about 122° C. In another embodiment, the DSC curve
`is substantially as shown in FIG. 4.
`In another embodiment, Compound 1, Form 7 is character—
`ized by a change in mass ofabout 0.1 5% at a relative humidity
`(RH) of 90% (sorption cycle 1) as measured by dynamic
`vapor sorption (DVS). In another embodiment, the DVS is
`substantially as shown in FIG. 5.
`In another embodiment. Compound 1, Form 7 is character-
`ized by at least two ofthe following:
`an XRPD spectrum comprising peaks at 12.6 and 13.5 °20;
`at
`'3C SSNMR spectrum comprising peaks at 18.6, 164.5.
`and 171.8 ppm;
`an FT—Raman spectrum comprising peaks at 748, 774,
`1006, 1216, and 1717 cm“; and
`a DSC endotherm with an onset at 119-120° C.
`In another embodiment, Compound 1, Form 7 is characterized
`by an XRPD spectrum comprising peaks at 12.6 and 13.5, and
`a 13C SSNMR spectrum comprising peaks at 18.6, 164.5, and
`171.8 ppm. In another embodiment, Compound 1, Form 7 is
`characterized by an XRPD spectrum comprising peaks at
`12.6, 13.5, and 17.3, and a 13C SSNMR spectrum comprising
`peaks at 18.6, 164.5, and 171.8 ppm. In another embodiment,
`Compound 1, Form 7 is characterized by an XRI’D spectrum
`comprising peaks at 12.6, 13.5, 16.9, and 17.3 °26, and a ”C
`SSNMR spectrum comprising peaks at 18.6, 21.5, 68.7, 81.7,
`102.8,164.5,151.4 and 171.8 ppm.
`One embodiment is a process for making Compound 1,
`Form 7, comprising contacting (S)—isopropy1 2-(((S)—(((2R,
`3R,4R,5R)~5—(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4—
`tluoro-3—hydroxy—4-methyltetrahydrofuran-2-yl)methoxy)
`(phenoxy)phosphoryl)amino) propanoate with a solvent
`comprising isopropyl acetate and heptane, whereby Com—
`pound 1. Form 7 is formed. In another embodiment, the sol-
`vent comprises THF. In another embodiment, the process
`further comprises seeding with a seed crystal of Compound 1,
`Form 7. In another embodiment, the process further com—
`prises isolating Compound 1 Form 7.
`Another embodiment is crystalline (S)-isopropy1 2-(((S)—
`(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4~dihydropyrimidin—1
`(2H)-yl)—4-fluoro—3-hydroxy—4—methyltetrahydrofuran-Z~y1)
`methoxy)(phenoxy)phosphoryl)amino)
`propanoate
`(Compound 1, Form 8) characterized by an X—ray powder
`diffractogram comprising at least three of the following peaks
`chosen from the followinglist: 8.6, 9.2, 14.2, 15.6, 16.0, 17.1.
`17.5, 18.1, 19.8, and 25.6 °20::0.2° 20.Another embodiment
`is crystalline Compound 1. Form 8, characterized by an
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`XRPD diffractogram comprising at least 5 peaks chosen from
`the followinglist: 8.6, 9.2, 14.2, 15.6, 16.0, 17.1, 17.5, 18.1,
`19.8, and 25.6 °20:0.2° 20. Another embodiment is crystal-
`line Compound 1, Form 8, characterized by an XRPD diffrac-
`togram comprising peaks at 8.6, 9.2 and 17.1 °20:0.2° 20.
`Another embodiment is crystalline Compound 1, l’orm 8,
`characterized by an XRPD diffractogram comprising dvspac-
`ing values at 10.3, 9.6, and 52 angstroms (A). In yet another
`embodiment, the crystalline Compound 1, Form 8 has at least
`three of 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). In still another embodi—
`ment, the crystalline Compound 1, Form 8 has at least five of
`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
`positions and d-spacing values for Form 8 is found in Table 1.
`Another embodiment is crystalline Compound I, Fomi 8,
`characterized by an XRPD diffractogram having peak posi—
`tions (20 values) substantially as listed for Form 8 in Table 1.
`Another embodiment is crystalline Compound 1, Form 8,
`characterized by an XRPD diffractogram having d—spacing
`values substantially as listed for Form 8 in Table 1. Another
`embodiment is crystalline Compound 1, Form 8. character-
`ized by an XRPD diffractogram substantially as shown in
`FIG. 6.
`In another embodiment, Compound 1, Penn 8 is character—
`ized by a 13C SSNMR spectrum comprising peaks at 23.5,
`70.1, and 152.4 ppm.
`In another embodiment,
`the 13C
`SSNMR spectrum further comprises peaks at 22.2, 71.6,
`78.8, 118.6 and 172.2 ppm. In another embodiment, Com-
`pound 1, Form 8 is characterized by a 13C solid state nuclear
`magnetic resonance spectrum substantially as shown in FIG.
`7.
`
`In another embodiment, Compound 1, Form 8 is character-
`ized by an FT—Raman spectrum comprising peaks at 628, 759,
`1029, 1224, and 1701 cm“.
`In another embodiment,
`the
`FTLRaman spectrum further comprises peaks at 221, 290,
`543, 1397, 2994, and 3076 cm”. In another embodiment,
`Compound 1, Form 8 is characterized by an FT—Raman spec-
`trum substantially as shown in FIG. 8.
`In another embodiment, Compound 1, Form 8 is character—
`ized by a differential scanning calorimetry (DSC) endotherm
`with an onset at 131-132° C. In another embodiment, Com—
`pound 1, Form 8 is characterized by a DSC endotherm with a
`peak at about 133° C. In another embodiment, the DSC curve
`is substantially as shown in FIG. 9.
`In another embodiment, Compound 1, Form 8 is character-
`ized by a change in mass ofabout 0. 1 7% at a relative humidity
`of 90% relative humidity, (sorption cycle 1) as measured by
`dynamic vapor sorption (DVS). In another embodiment, the
`DVS is substantially as shown in FIG. 10.
`In another embodiment, Compound 1, Form 8 is character—
`ized by at least two of the following:
`an XRPD spectrum comprising peaks at 8.6, 9.2 and
`17.1 °20;
`a 13C SSNMR spectrum comprising peaks at 23.5, 70.1,
`and 152.4 ppm;
`an FT—Raman spectrum comprising peaks at 628, 759,
`1029, 1224, and 1701 cm“; and
`a DSC endotherm with an onset at l31—l32° C.
`In another embodiment, Compound 1, Form 8 is characterized
`by an XRPD spectrum comprising peaks at 8.6, 9.2 and 17.1
`020 and a 13C SSNMR spectrum comprising peaks at 23.5,
`70.1. and 152.4 ppm. In another embodiment, Compound 1,
`Form 8 is characterized by an XRPD spectrum comprising
`peaks at 8.6, 9.2 and 17.1 020 and a DC SSNMR spectrum
`comprising peaks at 22.2, 23.5, 70.1. 71.6, 78.8, 1 18.6, 152.4
`and 172.2 ppm.
`
`6
`One embodiment is a process for making Compound 1,
`Form 8, comprising contacting (S)-isopropyl 2—(((S)—(((2R,
`3R,4R,5R)-5-(2,4-dioxo~3,4-dihydropyrimidin-1(2IwI)~yl)-4-
`fluoro—3—hydroxy-4-methy1tetrahydrofiJran-Z-ylhnethoxy)
`(phenoxy)phosphoryl)amino) propanoate with a solvent
`comprising isopropyl acetate, whereby Compound 1, I’orm 8
`is formed. In another embodiment, the process further com-
`prises seeding with a seed crystal oi‘Compound 1, Form 8. In
`another embodiment, the process further comprises isolating
`Compound 1, Form 8.
`Forms 7 and 8 of Compound I provided in accordance with
`the present disclosure may be administered in the form of
`pharmaceutical compositions. This disclosure therefore pro—
`vides pharmaceutical compositions that contain, as the active
`ingredient, one or more of Forms 7 and 8 of Compound I and
`one or more pharmaceutically acceptable excipients, carriers,
`including inert solid diluents and fillers, diluents, including
`sterile aqueous solution and various organic solvents, perme—
`ation enhancers, solubilizers and adjuvants. The pharmaceu~
`tical compositions may be administered alone or in combina~
`tion with other therapeutic agents. Such compositions are
`prepared in a manner well known in the pharmaceutical art
`(see, e.g., Remington’s Pharmaceutical Sciences, Mace Pub-
`lishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modem
`Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker &
`C. T. Rhodes, Eds).
`In one embodiment, provided herein is a phannaceutical
`composition comprising Compound 1, Form 7 and a pharma—
`ceutically acceptable carrier. In another embodiment, pro—
`vided herein is a pharmaceutical composition comprising
`Compound 1, Form 8 and a pharmaceutically acceptable car—
`rier. In various embodiments, a pharmaceutical composition
`can comprise Compound I in more than one solid form. For
`example, a pharmaceutical composition can comprise Com—
`pound 1, Form 7 at about 1 to about 100 percent (wt/wt) ofthe
`total amount of Compound 1. For example, a pharmaceutical
`composition can comprise Compound 1, Form 7 at about 1 to
`about 40 percent of the total amount of Compound 1. For
`example, a phannaceutical composition can comprise Com-
`pound 1, Form 7 at about 1 to about 20 percent (i.e. about 1
`percent, about 2 percent. about 3 percent, about 4 percent,
`about 5 percent, about 6 percent, about 7 percent, about 8
`percent, about 9 percent, about 10 percent, about 11 percent,
`about 12 percent, about 13 percent, about 14 percent, about 15
`percent, about 16 percent, about 17 percent, about 18 percent,
`about 19 percent, about 20 percent) ofthe total amount of
`Compound 1. By way of further example, a pharmaceutical
`composition can comprise Compound 1, Form 8 at about 1 to
`about 100 percent (wt/wt) ofthe total amount ofCompound 1 .
`For example, a phannaceutieal composition can comprise
`Compound 1, Form 8 at about 1 to about 40 percent ofthe total
`amount ofCompound I. For example, a pharmaceutical com-
`position ean comprise Compound 1, I‘orm 8 at about
`1
`to
`about 20 percent (i.e. about 1 percent, about 2 percent, about
`3 percent, about 4 percent, about 5 percent, about 6 percent,
`about 7 percent, about 8 percent, about 9 percent, about 10
`percent, about 11 percent, about 12 percent, about 13 percent,
`about 14 percent, about 15 percent, about 16 percent, about 17
`percent, about 18 percent, about 19 percent, about 20 percent)
`of the total amount of Compound 1.
`Form 7 and Form 8 of Compound I may be administered
`orally or formulated for oral administration. Administration
`may be via capsule or enteric coated tablets or the like. In
`making the pharmaceutical compositions that include at least
`one compound described herein, the active ingredient is usu-
`ally diluted by an excipient and/or enclosed within such a
`carrier that can be in the form ofa capsule, sachet, paper or
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`US 9,340,568 B2
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`other container. When the excipient serves as a diluent, it can
`be in the fomi of a solid, semi-solid or liquid material (as
`above), which acts as a vehicle, carrier or medium for the
`active ingredient. Thus, the compositions can be in the form
`of tablets, pills, powders, lozenges, sachets, cachets, elixirs,
`suspensions, emulsions, solutions, syrups, aerosols (as a solid
`or in a liquid medium), ointments, soft and hard gelatin cap—
`sules, sterile injectable solutions and sterile packaged pow-
`ders.
`Some examples of suitable excipients include lactose, dex-
`trose, sucrose, sorbitol, mannitol, starches, gum acacia, cal—
`cium phosphate, alginates, tragacanth, gelatin, calcium sili—
`cate, microcrystalline
`cellulose,
`polyvinylpyrrolidone,
`cellulose, sterile water, syrup and methyl cellulose. The for-
`mulations can additionally include: lubricating agents such as
`talc, magnesium stearate and mineral oil; wetting agents;
`emulsifying and suspending agents; preserving agents such
`as methyl and propylhydroxy—benzoates; sweetening agents;
`and flavoring agents.
`In some embodiments, the compositions are formulated in
`a unit dosage form. The term “unit dosage forms" refers to
`physically discrete units suitable as unitary dosages for
`human subjects and other mammals, each unit containing a
`predetermined quantity of active material calculated to pro-
`duce the desired therapeutic effect, in association with a suit-
`able phannaceutical excipient
`(e.g.,
`a
`tablet, capsule,
`ampoule). The compounds are generally administered in a
`pharmaceutically effective amount. In seine embodiments,
`each dosage unit contains from 1 mg to 2 g ofa Compound 1,
`Form 7 or Form 8, and for parenteral administration, in some
`embodiments, from 0.1 to 700 mg of Compound 1, Form 7 or
`Form 8. In some embodiments, each dosage unit contains
`about 400 mg of Compound I, Form 7 or Form 8. It will be
`understood, however, that the amount of the compound actu-
`ally administered usually will be determined by a physician,
`in the light of the relevant circumstances, including the con—
`dition to be treated, the chosen route ofadministration, the
`actual compound administered and its relative activity, the
`age, weight and response ofthe individual subject, the sever-
`ity ofthe subject’s symptoms, and the like.
`For preparing solid compositions such as tablets, the prin—
`cipal active ingredient is mixed with a pharmaceutical exeipi—
`ent to form a solid preformulation composition containing a
`homogeneous mixture of a compound of the present disclo-
`sure. When referring to these preformulation compositions as
`homogeneous, it is meant that the active ingredient is dis-
`persed evenly throughout the composition so that the compo-
`sition may be readily subdivided into equally effective unit
`dosage forms such as tablets, pills and capsules.
`The tablets or pills of the present disclosure may be coated
`or otherwise compounded to provide a dosage form affording
`the advantage of prolonged action or to protect from the acid
`conditions of the stomach. l‘or example, the tablet or pill can
`comprise an inner dosage and an outer dosage component, the
`latter being in the form of an envelope over the former. The
`two components can be separated by an enteric layer that
`serves to resist disintegration in the stomach and permit the
`inner component to pass intact into the duodenum or to be
`delayed in release. A variety of materials can be used for such
`enteric layers or coatings, such materials including a number
`of polymeric acids and mixtures of polymeric acids with such
`materials as shellac, eetyl alcohol and cellulose acetate. In
`one embodiment, the film coating is a polyvinylalcohol~based
`coating.
`In other embodiments, provided herein are pharmaceutical
`unit dosage forms comprising the pharmaceutical composi-
`tions provided herein. In some embodiments, the pharmaceu-
`
`8
`tical unit dosage forms comprise from about 10 mg to about
`1000 mg of Compound I, which may contain from about 1 to
`about 99 percent of Fomi 7 or Form 8. In various embodi-
`ments, the pharmaceutical dosage form comprises about 50,
`or about 100, or about 150, or about 200, or about 250, or
`about 300, or about 350, or about 400, or about 450, or about
`500, or about 550, or about 600, or about 650, or about 700, or
`about 750, or about 800 mg of Compound I. In a further
`embodiment,
`the pharmaceutical dosage form comprises
`about 400 mg of Compound I. In one embodiment, a phar—
`maceutical dosage form comprises about 400 mg of Com—
`pound I, wherein the amount of Form 7 is from about 1
`to
`about 100 percent ofthe total amount ofCompound 1. In one
`embodiment, a pharmaceutical dosage form comprises about
`400 mg ofCompound I, wherein the amount ofForm 7 is from
`about 1 to about 40 percent of the total amount of Compound
`I. In one embodiment, a pharmaceutical dosage form com-
`prises about 400 mg of Compound I, wherein the amount of
`Form 7 is from about
`1
`to about 20 percent (i.e. about
`1
`percent, about 2 percent, about 3 percent, about 4 percent.
`about 5 percent, about 6 percent. about 7 percent, about 8
`percent, about 9 percent, about 10 percent, about 11 percent,
`about 12 percent, about 13 percent, about 14 percent, about 15
`percent, about 16 percent, about 17 percent, about 18 percent.
`about 19 percent, about 20 percent) of the total amount of
`Compound I. In one embodiment, a pharmaceutical dosage
`form comprises about 400 mg of Compound I, wherein the
`amount ofForm 8 is from about 1 to about 100 percent of the
`total amount of Compound I. In one embodiment, a pharma-
`ceutical dosage form comprises about 400 mg of Compound
`I, wherein the amount of Fomi 8 is from about 1 to about 40
`percent of the total amount of Compound I. In one embodi-
`ment, a pharmaceutical dosage form comprises about 400mg
`of Compound I, wherein the amount of Form 8 is from about
`1 to about 20 percent (i.e. about 1 percent, about 2 percent,
`about 3 percent, about 4 percent, about 5 percent, about 6
`percent, about 7 percent, about 8 percent, about 9 percent,
`about 10percent, about 1 1 percent, about 12 percent, about 13
`percent, about 14 percent, about 15 percent, about 16 percent,
`about 17 percent, about 18 percent, about 19 percent. about 20
`percent) of the total amount of Compound 1.
`Compound 1, Form 7 or Form 8 described herein may be
`administered to a human subject suffering from hepatitis C
`virus (HCV) in either single or multiple doses by any ofthe
`accepted modes of administration known to those who are
`skilled in the art and as detailed above. In one embodiment,
`provided herein is a method of treating a human subject
`infected with hepatitis C virus comprising administering to
`the human subject a therapeutically effective amount ofCom~
`pound I Form 7. 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 thera-
`peutically effective amount of Compound I,
`l-‘orm 8.
`In
`another embodiment, provided herein is a method of treating
`a litunan subject infected with hepatitis C virus comprising
`administering to the human subject a pharmaceutical compo-
`sition comprising a therapeutically effective amount of Com-
`pound l, lior