`
`(12) United States Patent
`US 9,340,568 B2
`(10) Patent No.:
`Casteel et al.
`(45) Date of Patent:
`May 17, 2016
`
`(54) SOLID FORMS OF AN ANTIVIRAL
`COMPOUND
`
`(71) Applicant: Gilead Pharmasset LLC, Foster City,
`CA (US)
`
`(72)
`
`Inventors: Melissa Jean Casteel, Foster City, CA
`(US); Kathleen Dashner, Foster City,
`CA (US); Hyuk-Jun Jung, Shiheung-si
`(KR); Mun Sik Seo, Shiheung-si (KR);
`Bing Shi, Redwood City, CA (US); Fang
`Wang, Foster City, CA (US); Vahid Zia,
`Foster City, CA (US)
`
`(73) Assignee: GILEAD PHARMASSET LLC, Foster
`City, CA (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl.No.: 14/563,639
`
`(22)
`
`Filed:
`
`Dec. 8, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2015/0175646 A1
`
`Jun. 25, 2015
`
`Related US. Application Data
`
`(60) Provisional application No. 61/920,371, filed on Dec.
`23, 2013.
`
`A61K 31/7072 (2013.01); C07F 9/65586
`(2013.01); C07H19/06 (2013.01)
`(58) Field of Classification Search
`None
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`7,964,580 B2
`8,618,076 B2
`8,642,756 B2 *
`
`6/2011 Sofia et a1.
`12/2013 Ross et a1.
`2/2014 Ross ...................... C07H 19/10
`536/117
`
`OTHER PUBLICATIONS
`
`Int’l Search ReportiWritte Opinion Dated Jul. 2, 2015 For PCT/
`US2014/069123.
`
`* cited by examiner
`
`Primary Examiner 7 Patrick Lewis
`
`(57)
`
`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) -yl)-4-fluoro -3 -hydroxy-4-methyltetrahydro-
`furan-2-
`yl)methoxy)(phenoxy)phosphorylamino)
`propanoate (Compound I) are described
`
`(Compound I)
`
`(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 31/70 72
`C07F 9/6558
`C07H 19/06
`(52) us. Cl.
`CPC .............. C07H 19/10 (2013.01); A61K 31/706
`(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)
`
`
`
`Also provided are processes of making and methods of using
`the crystalline forms.
`
`10 Claims, 10 Drawing Sheets
`
`(cid:42)(cid:76)(cid:79)(cid:72)(cid:68)(cid:71)(cid:3)(cid:21)(cid:19)(cid:19)(cid:25)
`Gilead 2006
`(cid:44)(cid:16)(cid:48)(cid:36)(cid:46)(cid:3)(cid:89)(cid:17)(cid:3)(cid:42)(cid:76)(cid:79)(cid:72)(cid:68)(cid:71)
`I-MAK v. Gilead
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:27)(cid:16)(cid:19)(cid:19)(cid:22)(cid:28)(cid:19)
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`US 9,340,568 B2
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`2
`
`1
`SOLID FORMS OF AN ANTIVIRAL
`COMPOUND
`
`CROSS REFERENCE
`
`This application claims the benefits of US. 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
`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— 1 (2H)-yl)-4-fluoro-3 -hydroxy-
`4-methyltetrahydrofuran-2 -yl)methoxy)(phenoxy)pho spho-
`rylamino)propanoate (Compound I)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`(Compound I)
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 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 OiRPD), solid-state nuclear magnetic resonance
`(NMR, or 13C SSNMR), Raman spectroscopy, 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.
`
`One embodiment is a crystalline form of (S)-isopropyl
`2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimi-
`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 chosen from the following list: 12.6,
`13.5, 16.9, and 17.3 degrees two-theta (°20), 102° 20.
`Another embodiment is crystalline Compound I character-
`ized by an XRPD diffractogram 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 °20=0.2° 20. These crystalline forms of Compound I are
`referred to as Compound I, Form 7.
`Another embodiment is a crystalline form of Compound I
`characterized by an XRPD diffractogram comprising at least
`two peaks chosen from the following list: 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 I characterized by an
`XRPD spectrum comprising peaks
`at 8.6,
`9.2
`and
`17.1 °20=0.2° 20. These crystalline forms of Compound I are
`referred to as Compound I, 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, 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 Compound I, Form 7 or Compound I, Form 8 and
`a pharmaceutically acceptable excipient.
`Another embodiment is a pharmaceutical composition
`comprising Compound I, Form 7 or Compound I, 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 of a human subject infected by hepa-
`titis C virus, use ofthe 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 DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is an XRPD diffractogram of Compound I, Form 7.
`FIG. 2 is a 13C SSNMR spectrum ofCompound I, Form 7.
`FIG. 3 is an FT—Raman spectrum of Compound I, Form 7.
`FIG. 4 is a DSC plot of Compound I, Form 7.
`FIG. 5 is a DVS plot of Compound I, Form 7.
`FIG. 6 is an XRPD diffractogram of Compound I, Form 8.
`FIG. 7 is a 13C SSNMR spectrum ofCompound I, Form 8.
`FIG. 8 is an FT—Raman spectrum of Compound I, Form 8.
`FIG. 9 is a DSC plot of Compound I, Form 8.
`FIG. 10 is a DVS plot of Compound I, Form 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 sufiicient 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
`(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)
`methoxy)(phenoxy)phosphoryeamino)
`propanoate
`(Compound I, 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 (°20)=0.2° 20. Another
`embodiment is crystalline Compound I, Form 7, character-
`ized by an XRPD diffractogram comprising at least two peaks
`chosen from the following list: 12.6, 13.5, 16.9, and
`17.3 °20=0.2° 20. Another embodiment is crystalline Com-
`pound I, Form 7, characterized by an XRPD diffractogram
`comprising peaks at 12.6 and 13.5 °20=0.2° 20. Another
`embodiment is crystalline Compound I, 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 I, Form 7, characterized by an XRPD
`diffractogram comprising peaks at 12.6, 13.5, 16.9, and
`17.3 °20=0.2° 20. Another embodiment is crystalline Com-
`pound I, Form 7, characterized by an XRPD diffractogram
`comprising at least three peaks chosen from the following list:
`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 I, Form 7, characterized by an XRPD diffracto-
`gram comprising at least five peaks chosen from the follow-
`inglist: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 crystal-
`line Compound I, 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 I, 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 I, Form 7 is
`characterized by at least two of the 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 I, Form 7, characterized by an
`XRPD diffractogram comprising d-spacing values at 7.1, 6.6,
`and 5.1 angstroms (A). Another embodiment is crystalline
`Compound I, 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 I, 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 I, 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 I, Form 7,
`characterized by an XRPD diffractogram having d-spacing
`values substantially as listed for Form 7 in Table 1. Another
`
`10
`
`15
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`20
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`25
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`35
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`65
`
`4
`
`embodiment is crystalline Compound I, Form 7, character-
`ized by an XRPD diffractogram substantially as shown in
`FIG. 1.
`
`In another embodiment, Compound I, 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 13 C
`SSNMR spectrum further comprises peaks at 21.5, 68.7,
`81.7, 102.8, and 151.4 ppm. In another embodiment, Com-
`pound I, Form 7 is characterized by a 13 C SSNMR spectrum
`substantially as shown in FIG. 2.
`In another embodiment, Compound I, Form 7 is character-
`ized by an FT—Raman spectrum comprising peaks at 748, 774,
`1006, 1216, and 1717 cm'l. In another embodiment, the
`FT—Raman spectrum further comprises peaks at 545, 616,
`1027, 1372, 2949, and 2988 cm'l. In another embodiment,
`Compound I, 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 119-1200 C. In another embodiment, Com-
`pound I, 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 I, 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 I, Form 7 is character-
`ized by at least two of the following:
`an XRPD spectrum comprising peaks at 12.6 and 13.5 °20;
`a 13C 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‘lg and
`a DSC endotherm with an onset at 119-1200 C.
`
`In another embodiment, Compound I, 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 I, 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 I, Form 7 is characterized by an XRPD spectrum
`comprising peaks at 12.6, 13.5, 16.9, and 17.3 °20, and a 13C
`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 I,
`Form 7, comprising contacting (S)-isopropyl 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)phosphoryl)amino) propanoate with a solvent
`comprising isopropyl acetate and heptane, whereby Com-
`pound I, 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 I,
`Form 7. In another embodiment, the process further com-
`prises isolating Compound I Form 7.
`Another embodiment is crystalline (S)-isopropyl 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)phosphoryl)amino)
`propanoate
`(Compound I, Form 8) characterized by an X-ray powder
`diffractogram comprising at least three ofthe following peaks
`chosen from the following list: 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 I, Form 8, characterized by an
`
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`XRPD diffractogram comprising at least 5 peaks chosen from
`the following list: 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 I, 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 I, Form 8,
`characterized by an XRPD diffractogram comprising d-spac-
`ing values at 10.3, 9.6, and 5.2 angstroms (A). In yet another
`embodiment, the crystalline Compound I, Form 8 has at least
`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-
`ment, the crystalline Compound I, 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, Form 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 I, 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 I, Form 8, character-
`ized by an XRPD diffractogram substantially as shown in
`FIG. 6.
`
`In another embodiment, Compound I, Form 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 I, Forrn 8 is characterized by a 13C solid state nuclear
`magnetic resonance spectrum substantially as shown in FIG.
`7.
`
`In another embodiment, Compound I, Form 8 is character-
`ized by an FT-Raman spectrum comprising peaks at 628, 759,
`1029, 1224, and 1701 cm‘l. In another embodiment, the
`FT-Raman spectrum further comprises peaks at 221, 290,
`543, 1397, 2994, and 3076 cm'l. In another embodiment,
`Compound I, Form 8 is characterized by an FT-Raman spec-
`trum substantially as shown in FIG. 8.
`In another embodiment, Compound I, Form 8 is character-
`ized by a differential scanning calorimetry (DSC) endotherm
`with an onset at 131-1320 C. In another embodiment, Com-
`pound I, Forrn 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 I, 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 I, 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'lg and
`a DSC endotherm with an onset at 131-1320 C.
`
`In another embodiment, Compound I, Form 8 is characterized
`by an XRPD spectrum comprising peaks at 8.6, 9.2 and 17.1
`°20 and a 13C SSNMR spectrum comprising peaks at 23.5,
`70.1, and 152.4 ppm. In another embodiment, Compound I,
`Form 8 is characterized by an XRPD spectrum comprising
`peaks at 8.6, 9.2 and 17.1 °20 and a 13C SSNMR spectrum
`comprising peaks at 22.2, 23.5, 70.1, 71.6, 78.8, 118.6, 152.4
`and 172.2 ppm.
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`One embodiment is a process for making Compound I,
`Form 8, comprising contacting (S)-isopropyl 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)phosphoryl)amino) propanoate with a solvent
`comprising isopropyl acetate, whereby Compound I, Form 8
`is formed. In another embodiment, the process further com-
`prises seeding with a seed crystal of Compound I, Form 8. In
`another embodiment, the process further comprises isolating
`Compound I, 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 Modern
`Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker &
`C. T. Rhodes, Eds.).
`In one embodiment, provided herein is a pharmaceutical
`composition comprising Compound I, Form 7 and a pharma-
`ceutically acceptable carrier. In another embodiment, pro-
`vided herein is a pharmaceutical composition comprising
`Compound I, 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 I, Forrn 7 at about 1 to about 100 percent (wt/wt) ofthe
`total amount of Compound 1. For example, a pharmaceutical
`composition can comprise Compound I, Form 7 at about 1 to
`about 40 percent of the total amount of Compound 1. For
`example, a pharmaceutical composition can comprise Com-
`pound I, Forrn 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) of the total amount of
`Compound 1. By way of further example, a pharmaceutical
`composition can comprise Compound I, Form 8 at about 1 to
`about 100 percent (wt/wt) ofthe total amount ofCompound 1 .
`For example, a pharmaceutical composition can comprise
`Compound I, Form 8 at about 1 to about 40 percent ofthe total
`amount of Compound I. For example, a pharmaceutical com-
`position can comprise Compound I, Form 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 of a capsule, sachet, paper or
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`other container. When the excipient serves as a diluent, it can
`be in the form 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 pharmaceutical excipient
`(e.g.,
`a tablet, capsule,
`ampoule). The compounds are generally administered in a
`pharmaceutically effective amount. In some embodiments,
`each dosage unit contains from 1 mg to 2 g of a Compound I,
`Form 7 or Form 8, and for parenteral administration, in some
`embodiments, from 0.1 to 700 mg of Compound I, 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 of administration, the
`actual compound administered and its relative activity, the
`age, weight and response of the individual subject, the sever-
`ity of the subject’s symptoms, and the like.
`For preparing solid compositions such as tablets, the prin-
`cipal active ingredient is mixed with a pharmaceutical excipi-
`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. For example, the tablet or pill can
`comprise an inner do sage and an outer do sage 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 ofmaterials can be used for such
`enteric layers or coatings, such materials including a number
`ofpolymeric acids and mixtures ofpolymeric acids with such
`materials as shellac, cetyl 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-
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`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 Form 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 of the total amount of Compound I. 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 of Form 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 Form 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 400 mg
`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 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.
`Compound I, 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 of the
`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 of Com-
`pound I Form 7. In another embodiment, provided herein is a
`method of treating a human subject infected with hepatitis C
`virus comprisin