| WO2011123645A2 | 2011-10-06 | |||
| WO2010135569A1 | 2010-11-25 |
| US20140212491A1 | 2014-07-31 |
| Claims A process for preparing crystalline form 6 of sofosbuvir according to formula (I) (I) having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, the process comprising (i) providing sofosbuvir according to formula (I) in crystalline form, pseudo- crystalline form, amorphous form, or as a mixture of two or more of these forms; (ii) preparing a mixture comprising the sofosbuvir provided in (i) and at least one organic solvent; (iii) subjecting the mixture obtained in (ii) to crystallization conditions, obtaining solid crystalline form 6 of sofosbuvir in its mother liquor. The process of claim 1, wherein according to (i), the sofosbuvir is provided in crystalline form 1 having an X-ray powder diffraction pattern with reflections at 2-theta values of (5.0 ± 0.2) °, (7.3 ± 0.2) °, (9.4 ± 0.2) °, (16.6 ± 0.2) °, (17.3 ± 0.2) °, (18.1 ± 0.2) °, (22.0 ± 0.2) °, (25.0 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, in crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta values in the range of from 2.0 to 7.9 °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm, in amorphous form, or as a mixture of two or three of these forms. The process of claim 1 or 2, wherein (ii) comprises (ii. l) preparing a solution the sofosbuvir provided in (i) in at least one organic solvent, wherein the at least one organic solvent preferably comprises an aliphatic alcohol, more preferably a C2 alcohol, a C3 alcohol, a C4 alcohol, a C5 alcohol, or a mixture of two or more thereof, more preferably a C2 alcohol, a C3 alcohol, a C4 alcohol, or a mixture of two or more thereof, more preferably ethanol, n-propanol, isopropanol, n-butanol, or a mixture of two or more thereof. The process of claim 3, wherein preparing the solution in (ii. l) comprises mixing the sofosbuvir provided in (i) with the at least one organic solvent at a temperature in the range of from 20 to 70 °C, preferably in the range of from 25 to 65 °C, more preferably in the range of from 40 to 60 °C. The process of claim 3 or 4, further comprising (ii.2) adding at least one organic anti-solvent to the solution obtained in (ii. l), wherein the at least one organic anti-solvent preferably comprises an alkane, more preferably a C5 alkane, a C6 alkane, a C7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C7 alkane, more preferably n-heptane. The process of claim 5, wherein in (ii.2), adding the at least one organic anti-solvent to the solution obtained in (ii. l) is carried out a temperature in the range of from 20 to 80 °C, preferably in the range of from 20 to 70 °C, more preferably in the range of from 25 to 70 °C. The process of claim 1 or 2, wherein preparing the mixture in (ii) comprises suspending the sofosbuvir provided in (i) in a mixture of the at least one organic solvent and at least one organic anti-solvent, wherein the at least one organic solvent preferably comprises an aliphatic alcohol, more preferably a C2 alcohol, a C3 alcohol, a C4 alcohol, a C5 alcohol, or a mixture of two or more thereof, more preferably a C2 alcohol, a C3 alcohol, a C4 alcohol, or a mixture of two or more thereof, more preferably ethanol, n-propanol, isopropanol, n-butanol, or a mixture of two or more thereof. The process of claim 7, wherein the at least one organic anti-solvent comprises an alkane, preferably a C5 alkane, a C6 alkane, a C7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C7 alkane, more preferably n-heptane. The process of claim 7 or 8, wherein preparing the mixture in (ii) comprises suspending the sofosbuvir provided in (i) in the mixture of the at least one organic solvent and the at least one organic anti-solvent at a temperature in the range of from 10 to 30 °C, preferably in the range of from 15 to 25 °C. The process of any of claims 5 to 9, wherein the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is in the range of from 0.2 : 1 to 1 : 1 , preferably in the range of from 0.4 : 1 to 0.9 : 1 , and wherein the mixture prepared in (ii) contains the sofosbuvir, relative to the at least one organic solvent, in an amount in the range of from 100 to 500 mg/rnL, preferably in the range of from 200 to 475 mg/rnL, more preferably in the range of from 250 to 450 mg/rnL. 1 1. The process of any of claims 1 to 10, wherein in (iii), the crystallization conditions comprise a crystallization temperature in the range of from 0 to 30 °C, the crystallization conditions preferably further comprising a crystallization time in the range of from 0.1 to 16 h, more preferably in the range of from 0.5 to 9 h, more preferably in the range of from 1 to 6 h. 12. The process of any of claims 1 to 1 1 , further comprising (iv) separating the solid crystalline form 6 of sofosbuvir from its mother liquor; wherein separating in (iv) preferably comprises (iv.1) subjecting the mother liquor containing the solid crystalline form 6 of sofosbuvir to a solids separation process, obtaining the crystalline form 6, wherein the solids separation process comprises filtration, centrifugation, or a combination of thereof, preferably filtration; (iv.2) optionally washing the crystalline form 6 of sofosbuvir obtained from (iv. l), wherein the washing of the crystalline form 6 of sofosbuvir is carried out with at least one organic anti-solvent, wherein the at least one organic anti-solvent preferably comprises an alkane, more preferably a C5 alkane, a C6 alkane, a C7 al- kane, a Cg alkane, or a mixture of two or more thereof, more preferably a C7 alkane, more preferably n-heptane, preferably at a temperature in the range of from 0 to 30 °C; (iv.3) preferably drying the crystalline form 6 of sofosbuvir obtained from (iv. l), optionally from (iv.2), wherein the drying is carried out at a temperature in the range of from 10 to 60 °C, preferably in the range of from 15 to 55 °C, more preferably in the range of from 20 to 50 °C, preferably at a pressure in the range of from 10 to 250 mbar, preferably in the range of from 10 to 100 mbar, more preferably in the range of from 10 to 50 mbar. 13. The process of any of claims 1 to 12, wherein the at least one organic solvent and/or the at least one organic anti solvent of (ii), (ii. l), (ii.2), (iv), (iv.2) is not and/or does not comprise acetonitrile or dichloromethane. 14. An organic suspension comprising crystalline form 6 of sofosbuvir according to formula (I) (I) having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphaii2 radiation having a wavelength of 0.15419 nm, and at least one organic solvent, wherein the at least one organic solvent preferably comprises an aliphatic alcohol, more preferably a C2 alcohol, a C3 alcohol, a C4 alcohol, a C5 alcohol, or a mixture of two or more thereof, more preferably a C2 alcohol, a C3 alcohol, a C4 alcohol, or a mixture of two or more thereof, more preferably ethanol, n-propanol, isopropanol, n- butanol, or a mixture of two or more thereof, the organic suspension preferably additionally comprising at least one organic anti-solvent, wherein the at least one organic anti-solvent preferably comprises an alkane, more preferably a C5 alkane, a C6 alkane, a C7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C7 alkane, more preferably n-heptane, said suspension preferably being obtainable or obtained by a process according to any of claims 1 to 11. The organic suspension of claim 14, wherein the at least one organic solvent and/or the at least one organic anti solvent does not comprise acetonitrile acetonitrile and/or di- chloromethane. Crystalline form 6 of sofosbuvir according to formula (I) (I) having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, obtainable or obtained by a process according to any of claims 1 to 13, preferably according to claim 12. 17. A pharmaceutical composition, comprising crystalline form 6 of sofosbuvir according to claim 16 and at least one pharmaceutically acceptable excipient, preferably for use in a method for treating hepatitis C in a human. 18. Use of a combination of at least one organic solvent and at least one organic anti- solvent as crystallization medium for crystallizing form 6 of sofosbuvir. 19. Use according to claim 18 wherein the at least one organic solvent and the at least one organic anti-solvent is not acetonitrile and/or dichloromethane. |
The present invention relates to a process for preparing crystalline form 6 of sofosbuvir comprising (i) providing sofosbuvir according to formula (I) in crystalline form, pseudo- crystalline form, amorphous form, or as a mixture of two or more of these forms; (ii) preparing a mixture comprising the sofosbuvir provided in (i) and at least one organic solvent; (iii) subjecting the mixture obtained in (ii) to crystallization conditions, obtaining solid crystalline form 6 of sofosbuvir in its mother liquor. Sofosbuvir according to formula (I)
(I)
with IUPAC name(S)-isopropyl 2-(((5)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)me thoxy)(phenoxy)phosphoryl)- amino)propanoate is a drug inhibiting the R A polymerase used by the hepatitis C virus to replicate its RNA.
WO 2011/123645 Al discloses crystalline form 6 of sofosbuvir. According to example 21 of this document, crystalline form 6 can be prepared in two different ways. On the one hand, crystalline form 6 is obtained by exposing crystalline form 1 , described, for example, in WO 2010/135569 Al, to atmospheric humidity for 6 to 10 weeks, whereby a solidified gum is formed which needs to be ground prior to further storage in order to obtain crystalline form 6. On the other hand, crystalline form 6 is prepared by stirring a mixture of crystalline form 1 in water. However, according to WO 2011/123645 Al, a gum- like material is obtained when contacting crystalline form 1 with water, which transforms to an oil upon heating, and only after further stirring form 6 crystallizes from the inhomogeneous mixture. The authors of WO 2011/123645 disclose that a process comprising dissolving form 6 into an organic solvent such as acetonitrile or dichloromethane followed by crystallization provides form 1 even when seeding with crystalline form 6. WO 2010/135569 discloses sofosbuvir crystalline forms 1 to 5.
Sofia et al. J. Med. Chem. 2010 Vol. 53, 7202-7218 discloses sofosbuvir as nucleotide prodrug in the treatment of HCV. Figure 5 discloses the X-ray structure of sofosbuvir prepared according to example 51. The comparison of Figure 5 of Sofia et al. with Figure 12 of WO 2010/135569 and the comparison of the X-ray structure determination of compound 51 of Sofia et al. with table 9 of WO 2010/135569 revealed that the crystalline form of example 51 of Sofia et al. and the crystalline form of Figure 12 of WO 2010/135569 are the same crystal- line form of sofosbuvir, namely the crystalline form 2.
Apparently, there are several drawbacks related to the hygroscopic nature of sofosbuvir having crystalline form 1. Using crystalline form 1 as starting material to prepare crystalline form 6, for example, leads to the appearance of gum-like and oily material which is cumbersome to handle especially on scale. Moreover, crystalline form 1 tends to liquefy at elevated relative humidity and therefore needs to be protected from moisture which requires precautionary measures and consequently renders formulation processes, packaging, and storage complex and costly. Hence there is a need for a new process for preparing crystalline form 6 of sofosbuvir which does not exhibit the significant disadvantages of the prior art processes.
Surprisingly, it was found that such a process can be provided if a mixture of sofosbuvir, irrespective whether present in crystalline, pseudo-crystalline, or amorphous form, and an organic solvent is prepared, from which mixture the crystalline form 6 is crystallized.
Further, it was surprisingly found that such a process can be provided if a mixture of sofosbuvir, irrespective whether present in crystalline, pseudo-crystalline, or amorphous form, an organic solvent and an anti-solvent is prepared, from which mixture the crystalline form 6 is crystallized.
Yet further, it was surprisingly found that such a process can be provided if a mixture of sofosbuvir, irrespective whether present in crystalline, pseudo-crystalline, or amorphous form, a specific organic solvent and a specific anti-solvent is prepared, from which mixture the crys- talline form 6 is formed.
Therefore, the present invention relates to a process for preparing crystalline form 6 of sofosbuvir according to formula (I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm, the process comprising
(i) providing sofosbuvir according to formula (I) in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms;
(ii) preparing a mixture comprising the sofosbuvir provided in (i) and at least one organic solvent;
(iii) subjecting the mixture obtained in (ii) to crystallization conditions, obtaining solid crys- talline form 6 of sofosbuvir in its mother liquor.
Further, the present invention relates to an organic suspension comprising crystalline form 6 of sofosbuvir according to formula (I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm, and at least one organic solvent.
Further, the present invention relates to crystalline form 6 of sofosbuvir according to formula
(I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm, obtainable or obtained by the process according to the present invention.
Further, the present invention relates to the use of the crystalline form 6 of sofosbuvir obtain- able or obtained by the process according to the present invention, for treating hepatitis C in a human and/or for the preparation of a pharmaceutical composition, preferably for treating hepatitis C in a human.
Further, the present invention relates to the use of the crystalline form 6 of sofosbuvir obtain- able or obtained by the process according to the present invention, as seed crystal material for the preparation of novel crystalline form of sofosbuvir.
Step (i) According to (i), sofosbuvir according to formula (I) is provided in crystalline form, pseudo- crystalline form, amorphous form, or as a mixture of two or more of these forms.
No specific restrictions exist regarding the specific form of sofosbuvir which is employed in (i). Preferably, according to (i), sofosbuvir according to formula (I) is provided in crystalline form, amorphous form, or as a mixture of two or more of these forms. More preferably, according to (i), sofosbuvir according to formula (I) is provided
in crystalline form 1 having an X-ray powder diffraction pattern with reflections at 2-theta angles of (5.0 ± 0.2) °, (7.3 ± 0.2) °, (9.4 ± 0.2) °, (16.6 ± 0.2) °, (17.3 ± 0.2) °, (18.1 ± 0.2) °, (22.0 ± 0.2) °, (25.0 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, in particular determined according to Reference Example 1 ;
or in crystalline form 6 having an X-ray powder diffraction pattern with reflections at 2-theta angles of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm, in particular determined according to Reference Example 1 ;
or in a crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° and preferably comprising reflections at 2-theta angles of (8.1 ± 0.2) °, (10.4 ± 0.2) °, (12.4 ± 0.2) °, (17.3 ± 0.2) °, (19.4 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm, in particular determined according to Reference Example 1;
or in amorphous form;
or as a mixture of two, three, or four of these forms;
preferably in crystalline form 1, in the crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °, in amorphous form, or as a mixture of two or three of these forms.
The crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °preferably
comprises additional XRPD reflections at 2-theta angles of (12.1 ± 0.2) °, (13.5 ± 0.2) °, (16.2 ± 0.2) °, (16.8 ± 0.2) °, (18.0 ± 0.2) °, (18.7 ± 0.2) °, (20.2 ± 0.2) °, (20.9 ± 0.2) °, (22.1 ± 0.2) °, (23.4 ± 0.2) °, (25.4 ± 0.29 °, (28.0 ± 0.2)°, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm
exhibits a Fourier transform infrared spectrum comprising peaks at wavenumbers of (3252 ± 2) cm "1 , (2928 ± 2) cm "1 , (1718 ± 2) cm "1 , (1668 ± 2) cm "1 , (1456 ± 2) cm "1 , when measured at a temperature in the range of from 15 to 25 °C using a ZnSe ATR cell, preferably comprising additional peaks at wavenumbers of (1494 ± 2) cm "1 , (1373 ± 2) cm "1 , (1265 ± 2) cm "1 , (1223 ± 2) cm "1 , (945 ± 2) cm "1 , when measured at a temperature in the range of from 15 to 25 °C using a ZnSe ATR cell, in particular determined according to Reference Example 2; and/or
has the monoclinic space group symmetry P2i and the following unit cell parameters as determined by an X-ray single-crystal structure analysis at 120 K, in particular determined according to Reference Example 6:
a = (5.16 ± 0.04) Angstrom;
b = (16.86 ± 0.12) Angstrom;
c = (14.44 ± 0.10) Angstrom;
alpha = 90.0 °;
beta = (100.2 ± 0.8) °;
gamma = 90.0 °; and/or has a melting point in the range of from 122 to 126 °C when measured via differential scanning calorimetry at a heating rate of 10 °C/min at a pressure in the range of from 0.95 to 1.05 bar, in particular determined according to Reference Example 3; and/or comprises at most 0.5 weight-% of organic solvent, based on the weight of the crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °, as determined via thermogravimetric analysis, in particular determined according to Reference Example 4; and/or
comprising at most 0.4 weight-% of water based on the weight of the crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° as determined via gravimetric moisture sorption / desorp- tion analysis at a temperature of (25.0 ± 0.1) °C and a relative humidity of from 0 to 95 %, in particular determined according to Reference Example 5.
While no specific restrictions exist regarding the process how said crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° is prepared, it is preferred that it is prepared by a process comprising
(al) providing sofosbuvir in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms, wherein the sofosbuvir is preferably provided in crystalline form 1 having an X-ray powder diffraction pattern with reflections at 2- theta angles of (5.0 ± 0.2) °, (7.3 ± 0.2) °, (9.4 ± 0.2) °, (16.6 ± 0.2) °, (17.3 ± 0.2) °, (18.1 ± 0.2) °, (22.0 ± 0.2) °, (25.0 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai ,2 radiation having a wavelength of 0.15419 nm; or in crystalline form 6 having an X-ray powder diffraction pattern with reflections at 2-theta angles of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai i2 radiation having a wavelength of 0.15419 nm; or in a crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.9 ° and preferably comprising reflections at 2- theta angles of (8.1 ± 0.2) °, (10.4 ± 0.2) °, (12.4 ± 0.2) °, (17.3 ± 0.2) °, (19.4 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai j2 radiation having a wavelength of 0.15419 nm; or in amorphous form; or as a mixture of two, three, or four of these forms, more preferably in crystalline form 1, in crystalline form 6, in amorphous form, or as a mixture of two or three of these forms, more preferably in crystalline form 1 or in amorphous form;
(bl) preparing seed crystals of the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °by a method comprising (bl . l) providing sofosbuvir in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms, preferably in crystalline form 1 having an X-ray powder diffraction pattern with reflections at 2-theta values of (5.0 ± 0.2) °, (7.3 ± 0.2) °, (9.4 ± 0.2) °, (16.6 ± 0.2) °, (17.3 ± 0.2) °, (18.1 ± 0.2) °, (22.0 ± 0.2) °, (25.0 ± 0.2) °, when measured at a temperature from 15 to 25 °C with Cu-Kalphai ,2 radiation having a wavelength of 0.15419 nm;
(bl .2) providing seed crystals of crystalline form 6 of sofosbuvir, having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (20.8 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm;
(bl .3) preparing a solution of the sofosbuvir provided in (bl .1) in a C 2 -Cio alcohol or in a mixture of two or more thereof, preferably in a C5-C10 alcohol or in a mixture of two or more thereof, more preferably in a Cg alcohol, more preferably in 2- octanol;
(bl .4) subjecting the solution provided in (bl .3) to crystallization conditions, comprising seeding the solution with the seed crystals provided in (bl .2), wherein during crystallization, the solution is not stirred, preferably not mechanically agitated, more preferably not agitated, obtaining the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °, in its mother liquor, wherein during crystallization in (bl .4), the solution is kept at a temperature in the range of from 15 to 35 °C, preferably from 20 to 30 °C, at a pressure in the range of from 0.95 to 1.05 bar; (bl .5) separating at least a portion of the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 from its mother liquor, preferably comprising
(bl .5.1) subjecting the mother liquor comprising the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no re- flection at 2-theta angles in the range of from 2.0 to 7.9 0 to a solids separation process, preferably to filtration, obtaining the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °; (bl .5.2) optionally washing the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 obtained in (bl .5.1);
(bl .5.3) preferably drying the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 obtained in (bl .5.1) or (bl .5.2); preparing a solution of sofosbuvir provided in (al) in a C2-C5 alcohol or in a mixture of two or more thereof, and in one or more anti-solvents, preferably comprising
(cl . l) preparing a solution of the sofosbuvir provided in (al) the C2-C5 alcohol or in the mixture of two or more thereof, preferably in ethanol, or n-butanol, or n- pentanol, wherein preparing the solution preferably comprises heating, preferably heating the solution to a temperature in the range of from 30 to 70 °C, preferably from 35 to 65 °C;
(c2.2) adding the one or more anti-solvents to the solution obtained in (cl . l), wherein the one or more anti-solvents preferably comprise an alkane, more preferably a C 5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane, more preferably n-heptane;
wherein after (cl . l) and before (cl .2), the solution is preferably cooled, preferably to a temperature in the range of from 15 to 35 °C, more preferably from 20 to 30 °C; and wherein after (cl . l) and before (cl .2), the solution obtained in (cl . l) is optionally subjected to a solids separation process, preferably filtration;
subjecting the solution provided in (cl) to crystallization conditions, comprising seeding the solution with the seed crystals prepared in (bl), wherein during crystallization, the solution is not stirred, preferably not mechanically agitated, more preferably not agitated, obtaining the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 in its mother liquor, wherein during crystallization, the solution is kept at a temperature in the range of from 15 to 35 °C, preferably from 20 to 30 °C, at a pressure in the range of from 0.95 to 1.05 bar ;
preferably separating the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 from its mother liquor, preferably comprising
(el . l) subjecting the mother liquor comprising the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 to filtration, obtaining at least a portion of the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °;
(el .2) preferably washing the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° obtained in (el . l);
(el .3) preferably drying the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 obtained in (el . l) or (el .2). The term "agitation" as used in this context of the present invention relates to any motion of a macroscopic constituent of the solution comprising sofosbuvir which is induced from outside, relative to another macroscopic constituent of the solution. The term "mechanical agitation" as used in this context of the present invention relates to any motion of a macroscopic constit- uent of the solution comprising sofosbuvir which is induced from outside via a device, such as shaking or stirring or sonication, relative to another macroscopic constituent of the solution. The term "stirring" as used in this context of the present invention relates to any motion of a macroscopic constituent of the solution comprising sofosbuvir which is induced from outside via a stirring device, relative to another macroscopic constituent of the solution.
More preferably, according to (al), sofosbuvir according to formula (I) is provided in crystalline form 1 or in amorphous form. The crystalline form 1 and the amorphous form of sofosbuvir can be prepared, for example, as disclosed in WO 2010/135569 Al . Step (if)
According to a first preferred embodiment of the present invention, (ii) comprises
(ii. l) preparing a solution of the sofosbuvir provided in (i) in at least one organic solvent. Preferably in step (ii) the at least one organic solvent does not comprise acetonitrile and/or dichloromethane. Preferably, the at least one organic solvent comprises at least one alcohol in which the sofosbuvir can be dissolved. More preferably, the at least one organic solvent comprises an aliphatic alcohol, more preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, a C5 alcohol, or a mixture of two or more thereof, more preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, or a mixture of two or more thereof. C 2 alcohols include ethanol. C 3 alcohols include n-propanol or isopropanol. C 4 alcohols include n-butanol, 2-butanol, tert-butanol. C 5 alcohols include 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-butanol.
More preferably, the at least one organic solvent comprises ethanol, n-propanol, isopropanol, n-butanol, or a mixture of two or more thereof. More preferably, the at least one organic solvent comprises ethanol, n-butanol, or a mixture of thereof. More preferably, the at least one organic solvent comprises is ethanol or n-butanol.
Therefore, the present invention relates to the process as described above, wherein (ii) com- prises
(ii.1 ) preparing a solution of the sofosbuvir provided in (i) in ethanol.
Therefore, the present invention relates to the process as described above, wherein (ii) comprises (ii.1 ) preparing a solution of the sofosbuvir provided in (i) in n-butanol.
No specific restrictions exist how the solution in (ii) is prepared. Preferably, during preparing the solution, the sofosbuvir is admixed with the at least one organic solvent at room tempera- ture or a temperature elevated with respect to room temperature. More preferably, during preparing the solution, the sofosbuvir is admixed with the at least one organic solvent at a temperature in the range of from 20 to 80 °C, preferably in the range of from 20 to 70 °C, more preferably in the range of from 25 to 70 °C. More preferably, during preparing the solution, the sofosbuvir is admixed with the at least one organic solvent at a temperature in the range of from 30 to 70 °C, preferably in the range of from 40 to 65 °C, more preferably in the range of from 50 to 60 °C.
Preferably, during mixing, preparing the solution in (ii.1 ) comprises agitating, preferably mechanical agitating, more preferably stirring, subjecting to sonication, or a combination thereof.
While it is generally conceivable that from the solution prepared in (ii. l), crystalline form 6 of sofosbuvir can be crystallized, it is preferred that to the solution prepared in (ii. l), at least one organic anti-solvent is added. Therefore, the present invention relates to the process as described above, further comprising
(ii.2) adding at least one organic anti-solvent to the solution obtained in (ii. l).
Regarding the one or more organic anti-solvents employed in (ii.2), no specific restrictions exist, provided the crystalline form 6 of sofosbuvir crystallizes. Preferably, the one or more organic anti-solvents does not comprise acetonitrile or dichloromethane. Preferably, the one or more anti-solvents comprises an alkane, more preferably a C 5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane. More preferably, the one or more anti-solvents comprise n-heptane. More preferably, n-heptane is used as the only anti-solvent in (ii. l). Therefore, the present invention relates to the process as described above, wherein (ii) comprises
(11.1) preparing a solution of the sofosbuvir provided in (i) in ethanol;
(11.2) adding n-heptane as anti-solvent to the solution obtained in (ii.1). Therefore, the present invention relates to the process as described above, wherein (ii) comprises
(ii.1 ) preparing a solution of the sofosbuvir provided in (i) in n-butanol;
(ii.2) adding n-heptane as anti-solvent to the solution obtained in (ii. l). No specific restrictions exist how the at least one organic anti-solvent is added in (ii.2). Preferably, the anti-solvent is added at room temperature or a temperature elevated with respect to room temperature. More preferably, the anti-solvent is added at a temperature in the range of from 20 to 80 °C, preferably in the range of from 20 to 70 °C, more preferably in the range of from 25 to 70 °C. More preferably, the anti-solvent is added at a temperature in the range of from 30 to 70 °C, preferably in the range of from 40 to 65 °C, more preferably in the range of from 50 to 60 °C. These temperatures refer to the temperature of the mixture resulting from adding the anti-solvent. Preferably, during adding the anti-solvent, preparing the solution in (ii. l) comprises agitating, preferably mechanical agitating, more preferably stirring, subjecting to sonication, or a combination thereof.
According to a second preferred embodiment of the present invention, (ii) comprises suspend- ing the sofosbuvir provided in (i) in a mixture of the at least one organic solvent and at least one organic anti-solvent. Thus, it was surprisingly found that in particular the combination of at least one organic solvent and at least one organic anti-solvent allows such a robust technique for forming crystalline form 6 of sofosbuvir so that it is irrelevant whether the sofosbuvir is dissolved or suspended. If the sofosbuvir is suspended and from said suspension, the crystalline form 6 is obtained, this solvent mediated transformation can be also seen as a continuous dissolution / recrystallization process on a microscopic scale which proceeds until all metastable form, under the respective conditions, has transformed to the stable crystalline form 6. Therefore, regarding this second embodiment comprising (ii) suspending the sofosbuvir provided in (i) in a mixture of the at least one organic solvent and the at least one organ- ic anti-solvent, the terms "crystallization" and "solvent mediated transformation", "crystallization conditions" and "solvent mediated transformation conditions", "crystallization temperature" and "solvent mediated transformation temperature", "crystallization time" and "solvent mediated transformation time", and "crystallized" and "solvent mediated transformed", are used synonymously. As disclosed below, the crystallization of step (iii) is preferably carried out and is performed under agitation/stirring conditions.
Therefore, the present invention also relates to the use of a combination of at least one organic solvent and at least one organic anti-solvent as crystallization medium for crystallizing form 6 of sofosbuvir. Preferably, the present invention also relates to the use of a combination of a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, a C 5 alcohol, or a mixture of two or more thereof and a C 5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, as crystallization medium for crystallizing form 6 of sofosbuvir. More preferably, the present invention also relates to the use of a combination of a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, or a mixture of two or more thereof, and a C 7 alkane, as crystallization medium for crystallizing form 6 of sofosbuvir. More preferably, the present invention also relates to the use of a combination of ethanol and n-heptane as crystallization medium for crystallizing form 6 of sofosbuvir. Also more preferably, the present invention also relates to the use of a combination of n- butanol and n-heptane as crystallization medium for crystallizing form 6 of sofosbuvir.
Therefore, the present invention also relates to a process for preparing crystalline form 6 of sofosbuvir according to formula (I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai i2 radiation having a wavelength of 0.15419 nm, the process comprising
(i) providing sofosbuvir according to formula (I) in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms;
(ii) preparing a mixture comprising the sofosbuvir provided in (i), at least one organic solvent and at least one organic anti-solvent;
(iii) subjecting the mixture obtained in (ii) to crystallization conditions, obtaining solid crystalline form 6 of sofosbuvir in its mother liquor.
Further, the present invention also relates to the use of a combination of at least one organic solvent and at least one organic anti-solvent as medium for a solvent mediated transformation of sofosbuvir to obtain crystalline form 6 of sofosbuvir. Preferably, according to this embodiment the at least one organic solvent and the at least one anti-solvent do not comprise ace- tonitrile and/or dichloromethane. Preferably, the present invention also relates to the use of a combination of a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, a C 5 alcohol, or a mixture of two or more thereof and a C 5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, as medium for a solvent mediated transformation of sofosbuvir to obtain crystalline form 6 of sofosbuvir. More preferably, the present invention also relates to the use of a combination of a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, or a mixture of two or more thereof, and a C 7 alkane, as medium for a solvent mediated transformation of sofosbuvir to obtain crystalline form 6 of sofosbuvir. More preferably, the present invention also relates to the use of a combination of ethanol and n-heptane as medium for a solvent mediated transformation of sofosbuvir to obtain crystalline form 6 of sofosbuvir. Also more preferably, the present invention also relates to the use of a combination of n-butanol and n-heptane as medium for a solvent mediated transformation of sofosbuvir to obtain crystalline form 6 of sofosbuvir. Therefore, the present invention also relates to a process for preparing crystalline form 6 of sofosbuvir according to formula (I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai, 2 radiation having a wavelength of 0.15419 nm, the process comprising
(i) providing sofosbuvir according to formula (I) in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms;
(ii) preparing a mixture comprising the sofosbuvir provided in (i), at least one organic solvent and at least one organic anti-solvent;
(iii) subjecting the mixture obtained in (ii) to solvent mediated transformation conditions, obtaining solid crystalline form 6 of sofosbuvir in its mother liquor.
With regard to the preparation of the suspension, the at least one organic solvent preferably comprises at least one alcohol. Preferably, the at least one organic solvent does not comprise acetonitrile and/or dichloromethane. More preferably, the at least one organic solvent comprises an aliphatic alcohol, more preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, a C 5 alcohol, or a mixture of two or more thereof, more preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, or a mixture of two or more thereof. C 2 alcohols include ethanol. C 3 alcohols include n-propanol or isopropanol. C 4 alcohols include n-butanol, 2-butanol, tert-butanol. C 5 alcohols include 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-butanol.
More preferably, the at least one organic solvent comprises ethanol, n-propanol, isopropanol, n-butanol, or a mixture of two or more thereof. More preferably, the at least one organic solvent comprises ethanol, n-butanol, or a mixture of thereof. More preferably, the at least one organic solvent comprises is ethanol or n-butanol. Therefore, the present invention relates to the process as described above, wherein (ii) comprises suspending the sofosbuvir provided in (i) in a mixture of ethanol and at least one organic anti-solvent. Therefore, the present invention relates to the process as described above, wherein (ii) comprises suspending the sofosbuvir provided in (i) in a mixture of n-butanol and at least one organic anti-solvent.
Regarding the one or more organic anti-solvents employed together with the at least one or- ganic solvent for preparing the suspension, no specific restrictions exist, provided the crystalline form 6 of sofosbuvir crystallizes. Preferably, the one or more organic anti-solvents does not comprise acetonitrile and/or dichloromethane. Preferably, the one or more anti-solvents comprise an alkane, more preferably a C 5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane. More preferably, the one or more anti-solvents comprises n-heptane. More preferably, n-heptane is used as the only anti- solvent used for preparing the suspension.
Therefore, the present invention relates to the process as described above, wherein (ii) comprises suspending the sofosbuvir provided in (i) in a mixture of ethanol and n-heptane.
Therefore, the present invention relates to the process as described above, wherein (ii) comprises suspending the sofosbuvir provided in (i) in a mixture of n-butanol and n-heptane.
No specific restrictions exist how the sofosbuvir is suspended. Preferably, the sofosbuvir is added to the mixture of the at least one organic solvent and the at least one organic anti- solvent at a temperature in the range of from 5 to 35 °C, more preferably in the range of from 10 to 30 °C, more preferably in the range of from 15 to 25 °C. These temperatures refer to the temperature of the mixture to which the sofosbuvir is added. Preferably, during adding the sofosbuvir to the mixture, (ii) comprises agitating, preferably mechanical agitating, more preferably stirring.
During suspending the sofosbuvir in the mixture of the at least one organic solvent and the at least one organic anti-solvent, it is possible to add additional organic anti-solvent or a mixture of additional organic solvent and organic anti-solvent, for example to make the suspension more agitatable, preferably more stirrable.
According to the present invention, it is preferred that the mixture from which the crystalline form 6 is crystallized in (iii) contains the at least one organic solvent and the at least one or- ganic anti-solvent in specific amounts relative to each other. Preferably, in the mixture from which the crystalline form 6 is crystallized in (iii), the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is at most 1 : 1, more preferably less than 1 : 1. More preferably, in the mixture from which the crystalline form 6 is crystallized in (iii), the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is in the range of from 0.2 : 1 to 1 : 1, more preferably in the range of from 0.3 : 1 to 0.95 : 1, more preferably in the range of from 0.4 : 1 to 0.9 : 1. If more than one organic solvent is employed, the molar ratio relates to the total molar amount of all organic solvents. If more than one organic anti-solvent is employed, the molar ratio relates to the total molar amount of all organic anti-solvents.
Further, it is preferred that the mixture prepared in (ii) from which the crystalline form 6 is crystallized in (iii) contains the sofosbuvir, relative to the at least one organic solvent, in an amount in the range of from 100 to 500 mg/mL, preferably in the range of from 200 to 475 mg/mL, more preferably in the range of from 250 to 450 mg/mL. If more than one organic solvent is employed, the amount relates to the total amount of all organic solvents.
It is preferred that the at least one organic solvents does not comprise acetonitrile and/or dichloromethane. It is preferred that the organic solvent is not acetonitrile or dichloromethane.
It is preferred that one or more organic anti-solvents does not comprise acetonitrile and/or dichloromethane. It is preferred that the anti-solvent is not acetonitrile or dichloromethane
Step (iii)
No specific restrictions exist concerning the crystallization in (iii). Preferably, in (iii), the crystallization conditions comprise a crystallization temperature in the range of from 0 to 30 °C. Preferred temperature ranges are from 0 to 20 °C or from 10 to 25 °C or from 20 to 30 °C. The term "crystallization temperature" as used in this context refers to the temperature of the mixure in which the crystalline form 6 is formed during (iii).
Preferred crystallization times are in the range of from 0.1 to 24 h, more preferably from 0.1 to 16 h, more preferably from 0.2 to 12 h, more preferably from 0.5 to 9 h, more preferably from 1 to 6 h.
During crystallization, it is generally possible to add at least one organic anti-solvent to the mixture in which crystalline form 6 of sofosbuvir crystallizes. Preferably, the one or more organic anti-solvents does not comprise acetonitrile and/or dichloromethane. Preferably, the at least one organic anti-solvent comprises an alkane, more preferably a C5 alkane, a C 6 alkane, a C 7 alkane, a C% alkane, or a mixture of two or more thereof, more preferably a C 7 alkane, more preferably n-heptane. More preferably, it at least one anti-solvent is added during crystallization, the at least one anti-solvent is n-heptane.
Preferably, crystallization in (iii) comprises agitating, preferably mechanical agitating, more preferably stirring, subjecting to sonication, or a combination thereof, of the mixture in which crystalline form 6 of sofosbuvir crystallizes.
From (iii), solid crystalline form 6 is obtained in its mother liquor, the mother liquor comprising the at least one organic solvent and preferably the at least one organic anti-solvent. Hence, the present invention also relates to said suspension, obtainable or obtained by the process as described above, comprising (i) to (iii). Therefore, the present invention also relates to an organic suspension comprising crystalline form 6 of sofosbuvir according to formula (I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai i2 radiation having a wavelength of 0.15419 nm, and at least one organic solvent, wherein the at least one organic solvent does not comprises acetonitrile and/or dichloromethane, wherein the at least one organic solvent preferably comprises an aliphatic alcohol, more preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, a C 5 alcohol, or a mixture of two or more thereof, more preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, or a mixture of two or more thereof, more preferably ethanol, n-propanol, isopropanol, n-butanol, or a mixture of two or more thereof.
More preferably, said suspension additionally comprises at least one organic anti-solvent, wherein preferably the at least one organic solvent does not comprise acetonitrile and/or dichloromethane, wherein the at least one organic anti-solvent preferably comprises an alkane, preferably a C5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane.
Thus, the present invention also relates to an organic suspension comprising crystalline form 6 of sofosbuvir according to formula (I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm, said suspension further comprising either n-butanol and n-heptane, or ethanol and n-heptane.
Generally, it is possible to use this mother liquor, optionally after concentration or dilution, or after removal of the one or more anti-solvents as defined above or the one or more organic solvents as defined above. Preferably, the crystalline form 6 of sofosbuvir is suitably separated from its mother liquor.
Step (iv)
Therefore, the present invention also relates to the process as described above, further comprising
(iv) separating the solid crystalline form 6 of sofosbuvir from its mother liquor. Regarding the separating step in (iv), no specific restrictions exist. Preferably, in (iv), the separating step comprises subjecting the mother liquor comprising the crystalline form 6 of sofosbuvir to a solids separation process, such as centrifugation, filtration, spray drying, or a combination of two or more of these methods, preferably to filtration. Optionally, the thus separated crystalline form 6 of sofosbuvir can be subjected to washing. While there are no specific restrictions concerning the washing agent, it is preferred that washing of the crystalline form 6 of sofosbuvir is carried out with at least one organic anti- solvent, wherein the at least one organic anti-solvent preferably comprises an alkane, more preferably a C5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane, more preferably n-heptane, preferably at a temperature in the range of from 0 to 30 °C. Preferably, wherein the washing agent and the at least one organic anti-solvent is not acetonitrile and/or dichloromethane. Preferably, the thus separated crystalline form 6 of sofosbuvir, optionally after washing, is subjected to drying. While there are no specific restrictions concerning this drying, it is preferred that the drying is carried out at a temperature in the range of from 10 to 60 °C, preferably in the range of from 15 to 55 °C, more preferably in the range of from 20 to 50 °C, preferably at a pressure in the range of from 10 to 250 mbar, more preferably in the range of from 10 to 100 mbar, more preferably in the range of from 10 to 50 mbar.
Therefore, the present invention also relates to the process as described above, wherein (iv) comprises
(iv. l) subjecting the mother liquor containing the solid crystalline form 6 of sofosbuvir to a solids separation process, obtaining the crystalline form 6;
(iv.2) optionally washing the crystalline form 6 of sofosbuvir obtained from (iv.l);
(iv.3) preferably drying the crystalline form 6 of sofosbuvir obtained from (iv. l), optionally from (iv.2).
Hence, the present invention also relates to a process for the preparation of crystalline form 6 of sofosbuvir, comprising
(i) providing sofosbuvir according to formula (I) in crystalline form 1 or in amorphous form;
(ii) preparing a mixture comprising the sofosbuvir provided in (i), n-heptane and either n- butanol or ethanol, either comprising
(11.1) preparing a solution of the sofosbuvir provided in (i) in ethanol or n-butanol at a temperature in the range of from 50 to 60 °C;
(11.2) adding n-heptane to the solution obtained in (ii.l) at a temperature in the range of from 50 to 60 °C;
or comprising suspending the sofosbuvir provided in (i) in a mixture of n-heptane and either n-butanol or ethanol at a temperature in the range of from 15 to 25 °C, wherein in the mixture prepared in (ii), the volume ratio of ethanol or n-butanol relative to n-heptane is in the range of from 0.4 : 1 to 0.9 : 1 and wherein the mixture prepared in (ii) contains the sofosbuvir, relative to the ethanol or the n-butanol in an amount in the range of 250 to 450 mg/rnL;
(iii) subjecting the mixture obtained in (ii) to crystallization conditions comprising a crystallization temperature in the range of from 0 to 30 °C, comprising a crystallization time of from 1 to 6 h, and comprising stirring, obtaining solid crystalline form 6 of sofosbuvir in its mother liquor;
(iv) separating the solid crystalline form 6 of sofosbuvir from its mother liquor, comprising (iv.1) subjecting the mother liquor containing the solid crystalline form 6 of sofosbuvir to filtration, obtaining the crystalline form 6; (iv.2) washing the crystalline form 6 of sofosbuvir obtained from (iv. l) with n- heptane;
(iv.3) drying the crystalline form 6 of sofosbuvir obtained from (iv.2) at a temperature in the range of from 20 to 50 °C at a pressure in the range of from 10 to 50 mbar.
Further, the present invention also relates to crystalline form 6 of sofosbuvir according to formula (I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm, which is obtainable or obtained by the process as described above, comprising (i) to (iii), preferably (i) to (iv), more preferably (i) to (iv.3).
Generally, the crystalline form 6 of sofosbuvir obtainable or obtained by the process according to the present invention can be used for each conceivable purpose.
For example, it can be used as seed crystal material in a process for the preparation of crystal- line form of sofosbuvir, having an X-ray powder diffraction pattern comprising no reflection at 2-theta values in the range of from 2.0 to 7.9 °and preferably comprising reflections at 2- theta values of (8.1 ± 0.2) °, (10.4 ± 0.2) °, (12.4 ± 0.2) °, (17.3 ± 0.2) °, (19.4 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm.
Further, the present invention relates to the use of the crystalline form 6 of sofosbuvir obtainable or obtained by the process according to the present invention for the preparation of a pharmaceutical composition; to a method of using said crystalline form 6 of sofosbuvir for the preparation of a pharmaceutical composition; to a pharmaceutical composition comprising, in an pharmaceutically effective amount, said crystalline form 6 of sofosbuvir and at least one pharmaceutically acceptable excipient; to said pharmaceutical composition for use in a method for treating hepatitis C in a human; to the use of said pharmaceutical composition for treating hepatitis C in a human; to a method of treating hepatitis C in a human comprising admin- istering said pharmaceutical composition to a human; to the use of said crystalline form 6 of sofosbuvir for preparing a medicament for the treatment hepatitis C in a human; to the use of said crystalline form 6 of sofosbuvir for the treatment of hepatitis C in a human; to said crystalline form 6 of sofosbuvir for use in the treatment of hepatitis C in a human; to said crystalline form 6 of sofosbuvir for the treatment of hepatitis C in a human; to a method of treating hepatitis C in a human comprising administering said crystalline form 6 of sofosbuvir.
The present invention is illustrated by the following embodiments and combinations of embodiments resulting from the given dependencies and back-references:
1. A process for preparing crystalline form 6 of sofosbuvir according to formula (I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, in particular determined according to Reference Example 1 , the process comprising
(i) providing sofosbuvir according to formula (I) in crystalline form, pseudo- crystalline form, amorphous form, or as a mixture of two or more of these forms;
(ii) preparing a mixture comprising the sofosbuvir provided in (i) and at least one organic solvent;
(iii) subjecting the mixture obtained in (ii) to crystallization conditions, obtaining solid crystalline form 6 of sofosbuvir in its mother liquor.
2. The process of embodiment 1, wherein according to (i), the sofosbuvir is provided
in crystalline form 1 having an X-ray powder diffraction pattern with reflections at 2- theta angles of (5.0 ± 0.2) °, (7.3 ± 0.2) °, (9.4 ± 0.2) °, (16.6 ± 0.2) °, (17.3 ± 0.2) °, (18.1 ± 0.2) °, (22.0 ± 0.2) °, (25.0 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm, in particular determined according to Reference Example 1 ;
or in crystalline form 6 having an X-ray powder diffraction pattern with reflections at 2- theta angles of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, in particular determined according to Reference Example 1 ;
or in a crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °and preferably comprising reflections at 2-theta angles of (8.1 ± 0.2) °, (10.4 ± 0.2) °, (12.4 ± 0.2) °, (17.3 ± 0.2) °, (19.4 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, in particular determined according to Reference Example 1 ;
or in amorphous form;
or as a mixture of two, three, or four of these forms;
preferably in crystalline form 1 , in crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °, in amorphous form, or as a mixture of two or three of these forms.
The process of embodiment 2, wherein according to (i), the sofosbuvir is provided in crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °, wherein the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° preferably
exhibits a Fourier transform infrared spectrum comprising peaks at wavenumbers of (3252 ± 2) cm "1 , (2928 ± 2) cm "1 , (1718 ± 2) cm "1 , (1668 ± 2) cm "1 , (1456 ± 2) cm "1 , when measured at a temperature in the range of from 15 to 25 °C using a ZnSe ATR cell, in particular determined according to Reference Example 2; and/or
has the monoclinic space group symmetry P2i and the following unit cell parameters as determined by an X-ray single-crystal structure analysis at 120 K:
a = (5.16 ± 0.04) Angstrom;
b = (16.86 ± 0.12) Angstrom;
c = (14.44 ± 0.10) Angstrom;
alpha = 90.0 °;
beta = (100.2 ± 0.8) °;
gamma = 90.0 °.; and/or
has a melting point in the range of from 122 to 126 °C when measured via differential scanning calorimetry at a heating rate of 10 °C/min at a pressure in the range of from 0.95 to 1.05 bar, in particular determined according to Reference Example 3; and/or comprises at most 0.5 weight-% of organic solvent, based on the weight of the crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °, as determined via thermo- gravimetric analysis, in particular determined according to Reference Example 4; and/or
comprising at most 0.4 weight-% of water based on the weight of the crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.9 ° as determined via gravimetric moisture sorption / desorption analysis at a temperature of (25.0 ± 0.1) °C and a relative humidity of from 0 to 95 %, in particular determined according to Reference Example 5.
The process of embodiment 3, wherein the crystalline form of sofosbuvir having an X- ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° is prepared by a process comprising, or wherein the process of embodiment 2 or 3 comprises preparing the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° by a process comprising
(al) providing sofosbuvir in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms, wherein the sofosbuvir is preferably provided in crystalline form 1 having an X-ray powder diffraction pattern with reflections at 2-theta angles of (5.0 ± 0.2) °, (7.3 ± 0.2) °, (9.4 ± 0.2) °, (16.6 ± 0.2) °, (17.3 ± 0.2) °, (18.1 ± 0.2) °, (22.0 ± 0.2) °, (25.0 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm; or in crystalline form 6 having an X- ray powder diffraction pattern with reflections at 2-theta angles of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm; or in a crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° and preferably comprising reflections at 2-theta angles of (8.1 ± 0.2) °, (10.4 ± 0.2) °, (12.4 ± 0.2) °, (17.3 ± 0.2) °, (19.4 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai i2 radiation having a wavelength of 0.15419 nm; or in amorphous form; or as a mixture of two, three, or four of these forms, more preferably in crystalline form 1 , in crystalline form 6, in amorphous form, or as a mixture of two or three of these forms, more preferably in crystalline form 1 or in amorphous form; (bl) preparing seed crystals of the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° by a method comprising
(bl . l) providing sofosbuvir in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms, preferably in crystalline form 1 having an X-ray powder diffraction pattern with reflections at 2-theta values of (5.0 ± 0.2) °, (7.3 ± 0.2) °, (9.4 ± 0.2) °, (16.6 ± 0.2) °, (17.3 ± 0.2) °, (18.1 ± 0.2) °, (22.0 ± 0.2) °, (25.0 ± 0.2) °, when measured at a temperature from 15 to 25 °C with Cu-Kalphai, 2 radiation having a wavelength of 0.15419 nm or in amorphous form;
(bl .2) providing seed crystals of crystalline form 6 of sofosbuvir, having an X- ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (20.8 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu- Kalphai i2 radiation having a wavelength of 0.15419 nm;
(bl .3) preparing a solution of the sofosbuvir provided in (bl . l) in a C 2 -Cio alcohol or in a mixture of two or more thereof, preferably in a C5-C10 alcohol or in a mixture of two or more thereof, more preferably in a Cg alcohol, more preferably in 2-octanol;
(bl .4) subjecting the solution provided in (bl .3) to crystallization conditions, comprising seeding the solution with the seed crystals provided in (bl .2), wherein during crystallization, the solution is not stirred, preferably not mechanically agitated, more preferably not agitated, obtaining the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °, in its mother liquor, wherein during crystallization in (bl .4), the solution is kept at a temperature in the range of from 15 to 35 °C, preferably from 20 to 30 °C, at a pressure in the range of from 0.95 to 1.05 bar;
(bl .5) separating at least a portion of the crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 from its mother liquor, preferably comprising (b 1.5.1) subjecting the mother liquor comprising the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 to a solids separation process, preferably to filtration, obtaining the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °; (bl .5.2) optionally washing the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.9 ° obtained in (bl .5.1);
(bl .5.3) preferably drying the crystalline form of sofosbuvir having an
X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.9 ° obtained in (bl .5.1) or (bl .5.2);
preparing a solution of sofosbuvir provided in (al) in a C 2 -C 5 alcohol or in a mixture of two or more thereof, and in one or more anti-solvents, preferably comprising
(cl .l) preparing a solution of the sofosbuvir provided in (i) the C 2 -C 5 alcohol or in the mixture of two or more thereof, preferably in ethanol, or n-butanol, or n-pentanol, wherein preparing the solution preferably comprises heating, preferably heating the solution to a temperature in the range of from 30 to 70 °C, preferably from 35 to 65 °C;
(c2.2) adding the one or more anti-solvents to the solution obtained in (cl .l), wherein the one or more anti-solvents preferably comprise an alkane, more preferably a C5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane, more preferably n- heptane;
wherein after (cl .l) and before (cl .2), the solution is preferably cooled, preferably to a temperature in the range of from 15 to 35 °C, more preferably from 20 to 30 °C; and wherein after (cl . l) and before (cl .2), the solution obtained in (cl . l) is optionally subjected to a solids separation process, preferably filtration;
subjecting the solution provided in (cl) to crystallization conditions, comprising seeding the solution with the seed crystals prepared in (bl), wherein during crystallization, the solution is not stirred, preferably not mechanically agitated, more preferably not agitated, obtaining the crystalline form of sofosbuvir having an X- ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 in its mother liquor, wherein during crystallization, the solution is kept at a temperature in the range of from 15 to 35 °C, preferably from 20 to 30 °C, at a pressure in the range of from 0.95 to 1.05 bar ;
preferably separating the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 0 from its mother liquor, preferably comprising
(el .l) subjecting the mother liquor comprising the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.9 0 to filtration, obtaining at least a portion of the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °;
(el .2) preferably washing the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° obtained in (el .l);
(el .3) preferably drying the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° obtained in (el . l) or (el .2).
5. The process of embodiment 2, wherein according to (i), the sofosbuvir is provided in crystalline form 1.
6. The process of embodiment 2, wherein according to (i), the sofosbuvir is provided in amorphous form.
7. The process of any of embodiments 1 to 6, wherein (ii) comprises
(ii. l) preparing a solution of the sofosbuvir provided in (i) in at least one organic solvent.
8. The process of embodiment 7, wherein the at least one organic solvent in (ii) comprises an aliphatic alcohol, preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, a C 5 alcohol, or a mixture of two or more thereof, more preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, or a mixture of two or more thereof, more preferably ethanol, n-propanol, iso- propanol, n-butanol, or a mixture of two or more thereof.
9. The process of embodiment 8, wherein the at least one organic solvent in (ii) comprises, preferably is, n-butanol. 10. The process of embodiment 8, wherein the at least one organic solvent in (ii) comprises, preferably is, ethanol.
11. The process of any embodiments 7 to 10, wherein preparing the solution in (ii.l) comprises mixing the sofosbuvir provided in (i) with the at least one organic solvent at a temperature in the range of from 20 to 80 °C, preferably in the range of from 20 to 70
°C, more preferably in the range of from 25 to 70 °C.
12. The process of any of embodiments 7 to 11, wherein preparing the solution in (ii. l) comprises agitating, preferably stirring, subjecting to sonication, or a combination thereof, wherein (ii. l) optionally comprises subjecting the solution to a solids separation process, preferably comprising filtration or centrifugation. The process of any of embodiments 7 to 12, further comprising
(ii-2) adding at least one organic anti-solvent to the solution obtained in (ii.1). The process of embodiment 13, wherein the at least one organic anti-solvent comprises an alkane, preferably a C 5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane. The process of embodiment 14, wherein the at least one organic anti-solvent comprises, preferably is, n-heptane. The process of any of embodiments 13 to 15, wherein in (ii.2), adding the at least one organic anti-solvent to the solution obtained in (ii. l) is carried out a temperature in the range of from 20 to 80 °C, preferably in the range of from 20 to 70 °C, more preferably in the range of from 25 to 70 °C. The process of any of embodiments 13 to 16, wherein in (ii.2), adding the at least one organic anti-solvent comprises stirring, subjecting to sonication, or a combination thereof. The process of any of embodiments 1 to 6, wherein preparing the mixture in (ii) comprises suspending the sofosbuvir provided in (i) in a mixture of the at least one organic solvent and at least one organic anti-solvent. The process of embodiment 18, wherein the at least one organic solvent comprises an aliphatic alcohol, preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, a C 5 alcohol, or a mixture of two or more thereof, more preferably a C 2 alcohol, a C 3 alcohol, a C 4 alco- hoi, or a mixture of two or more thereof, more preferably ethanol, n-propanol, iso- propanol, n-butanol, or a mixture of two or more thereof. The process of embodiment 19, wherein the at least one organic solvent in (ii) comprises, preferably is, n-butanol. The process of embodiment 19, wherein the at least one organic solvent in (ii) comprises, preferably is, ethanol.
The process of any of embodiments 18 to 21 , wherein the at least one organic anti- solvent comprises an alkane, preferably a C 5 alkane, a C 6 alkane, a C 7 alkane, a Cs al- kane, or a mixture of two or more thereof, more preferably a C 7 alkane.
The process of embodiment 22, wherein the at least one organic anti-solvent comprises, preferably is, n-heptane. The process of any of embodiments 18 to 23, wherein preparing the mixture in (ii) comprises suspending the sofosbuvir provided in (i) in the mixture of the at least one organic solvent and the at least one organic anti-solvent at a temperature in the range of from 10 to 30 °C, preferably in the range of from 15 to 25 °C. The process of any of embodiments 13 to 24, wherein the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is in the range of from 0.2 : 1 to 1 : 1 , preferably in the range of from 0.4 : 1 to 0.9 : 1. The process of any of embodiments 11 to 21, wherein the mixture prepared in (ii) contains the sofosbuvir, relative to the at least one organic solvent, in an amount in the range of from 100 to 500 mg/rnL, preferably in the range of from 200 to 475 mg/rnL, more preferably in the range of from 250 to 450 mg/rnL. The process of any of embodiments 1 to 26, wherein in (iii), the crystallization conditions comprise a crystallization temperature in the range of from 0 to 30 °C. The process of any of embodiments 1 to 27, wherein in (iii), the crystallization condi- tions comprise a crystallization time in the range of from 0.1 to 16 h, preferably in the range of from 0.5 to 9 h, more preferably in the range of from 1 to 6 h. The process of any of embodiments 1 to 29, wherein in (iii), the crystallization conditions comprise adding at least one anti-solvent to the mixture being subjected to crystal- lization conditions, wherein the at least one organic anti-solvent preferably comprises an alkane, more preferably a C5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane, more preferably n-heptane.
The process of any of embodiments 1 to 29, further comprising
(iv) separating the solid crystalline form 6 of sofosbuvir from its mother liquor.
The process of embodiment 30, wherein separating in (iv) comprises
(iv.1) subjecting the mother liquor containing the solid crystalline form 6 of sofosbuvir to a solids separation process, obtaining the crystalline form 6. The process of embodiment 31, wherein in (iv.l), the solids separation process comprises filtration, centrifugation, or a combination of thereof, preferably filtration. The process of embodiment 31 or 32, wherein separating in (iv) further comprises (iv.2) washing the crystalline form 6 of sofosbuvir obtained from (iv.l). The process of embodiment 33, wherein in (iv.2), the washing of the crystalline form 6 of sofosbuvir is carried out with at least one anti-solvent, wherein the at least one organic anti-solvent preferably comprises an alkane, more preferably a C 5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane, more preferably n-heptane. The process of embodiment 33 or 34, wherein in (iv.2), the washing is carried out at a temperature in the range of from 0 to 30 °C. The process of any of embodiments 30 to 35, wherein separating in (iv) further comprises
(iv.3) drying the crystalline form 6 of sofosbuvir obtained from (iv.l), optionally from (iv.2). The process of embodiment 36, wherein in (iv.3), the drying is carried out at a temperature in the range of from 10 to 60 °C, preferably in the range of from 15 to 55 °C, more preferably in the range of from 20 to 50 °C. The process of embodiment 36 or 37, wherein in (iv.3), the drying is carried out at a pressure in the range of from 10 to 250 mbar, preferably in the range of from 10 to 100 mbar, more preferably in the range of from 10 to 50 mbar. The process of any of embodiments 1 to 38, wherein the organic solvent of and the anti- solvent of (ii), (ii. l), (ii.2), (iii), (iv), (iv. l), (iv.2) are not selected from acetonitrile and/or dichloromethane An organic suspension comprising crystalline form 6 of sofosbuvir according to formula (I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai i2 radiation having a wavelength of 0.15419 nm, and at least one organic solvent.
The suspension of embodiment 40, wherein the at least one organic solvent comprises an aliphatic alcohol, preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, a C5 alcohol, or a mixture of two or more thereof, more preferably a C 2 alcohol, a C 3 alcohol, a C 4 alcohol, or a mixture of two or more thereof, more preferably ethanol, n-propanol, isopropa- nol, n-butanol, or a mixture of two or more thereof. 42. The suspension of embodiment 40 or 41 , wherein the at least one organic solvent comprises n-butanol, preferably is n-butanol.
43. The suspension of embodiment 40 or 41, wherein the at least one organic solvent comprises ethanol, preferably is ethanol.
44. The suspension of any of embodiments 40 to 43, additionally comprising at least one organic anti-solvent.
45. The suspension of embodiment 44, wherein the at least one organic anti-solvent com- prises an alkane, preferably a C5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane.
46. The suspension of embodiment 44 or 45, wherein the at least one organic anti-solvent comprises, preferably is, n-heptane.
47. The suspension of any of embodiments 40 to 46, obtainable or obtained by a process according to any of embodiments 1 to 29. The suspension of any embodiments 40 to 47 wherein the at least one organic solvent does not comprise acetonitrile and/or dichloromethane. The suspension of any embodiments 44 to 47, wherein the at least one organic anti- solvent does not comprise acetonitrile and/or dichloromethane.
Crystalline form 6 of sofosbuvir according to formula (I)
(I)
having an X-ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, (23.3 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm, obtainable or obtained by a process according to any of embodiments 1 to 38, preferably according to any of embodiments 30 to 38, more preferably according to any of embodiments 36 to 38.
Use of the crystalline form 6 of sofosbuvir according to embodiment 47 as seed crystal material for the preparation of crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta values in the range of from 2.0 to 7.9 °and preferably comprising reflections at 2-theta values of (8.1 ± 0.2) °, (10.4 ± 0.2) °, (12.4 ± 0.2) °, (17.3 ± 0.2) °, (19.4 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm. The use of embodiment 51, wherein the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° is prepared by a process comprising
(al) providing sofosbuvir in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms, wherein the sofosbuvir is preferably provided in crystalline form 1 having an X-ray powder diffraction pat- tern with reflections at 2-theta angles of (5.0 ± 0.2) °, (7.3 ± 0.2) °, (9.4 ± 0.2) °,
(16.6 ± 0.2) °, (17.3 ± 0.2) °, (18.1 ± 0.2) °, (22.0 ± 0.2) °, (25.0 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with ra- diation having a wavelength of 0.15419 nm; or in crystalline form 6 having an X- ray powder diffraction pattern with reflections at 2-theta angles of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (17.2 ± 0.2) °, (17.7 ± 0.2) °, (18.0 ± 0.2) °, (18.8 ± 0.2) °, (19.4 ± 0.2) °, (19.8 ± 0.2) °, (20.1 ± 0.2) °, (20.8 ± 0.2) °, (21.8 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm; or in a crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° and preferably comprising reflections at 2-theta angles of (8.1 ± 0.2) °, (10.4 ± 0.2) °, (12.4 ± 0.2) °, (17.3 ± 0.2) °, (19.4 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai i2 radiation having a wavelength of 0.15419 nm; or in amorphous form; or as a mixture of two, three, or four of these forms, more preferably in crystalline form 1 , in crystalline form 6, in amorphous form, or as a mixture of two or three of these forms, more preferably in crystalline form 1 or in amorphous form;
(bl) preparing seed crystals of the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° by a method comprising
(bl . l) providing sofosbuvir in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms, preferably in crystalline form 1 having an X-ray powder diffraction pattern with reflections at 2-theta values of (5.0 ± 0.2) °, (7.3 ± 0.2) °, (9.4 ± 0.2) °, (16.6 ± 0.2) °, (17.3 ± 0.2) °, (18.1 ± 0.2) °, (22.0 ± 0.2) °, (25.0 ± 0.2) °, when measured at a temperature from 15 to 25 °C with Cu-Kalphai i2 radiation having a wavelength of 0.15419 nm or in amorphous form;
(bl .2) providing seed crystals of crystalline form 6 of sofosbuvir, having an X- ray powder diffraction pattern with reflections at 2-theta values of (6.1 ± 0.2) °, (8.2 ± 0.2) °, (10.4 ± 0.2) °, (12.7 ± 0.2) °, (20.8 ± 0.2) °, when measured at a temperature in the range of from 15 to 25 °C with Cu- Kalphai i2 radiation having a wavelength of 0.15419 nm;
(bl .3) preparing a solution of the sofosbuvir provided in (bl . l) in a C 2 -Ci 0 alcohol or in a mixture of two or more thereof, preferably in a C5-C10 alcohol or in a mixture of two or more thereof, more preferably in a Cg alcohol, more preferably in 2-octanol;
(bl .4) subjecting the solution provided in (bl .3) to crystallization conditions, comprising seeding the solution with the seed crystals provided in (bl .2), wherein during crystallization, the solution is not stirred, preferably not mechanically agitated, more preferably not agitated, obtaining the crystalline form of sofosbuvir having an X-ray powder diffraction pattern com- prising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °, in its mother liquor, wherein during crystallization in (bl .4), the solution is kept at a temperature in the range of from 15 to 35 °C, preferably from 20 to 30 °C, at a pressure in the range of from 0.95 to 1.05 bar;
(bl .5) separating at least a portion of the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° from its mother liquor, preferably comprising
(b 1.5.1) subjecting the mother liquor comprising the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° to a solids separation process, preferably to filtration, obtaining the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °;
(bl .5.2) optionally washing the crystalline form of sofosbuvir having an
X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.9 ° obtained in (bl .5.1);
(bl .5.3) preferably drying the crystalline form of sofosbuvir having an
X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.9 ° obtained in (bl .5.1) or (bl .5.2);
preparing a solution of sofosbuvir provided in (al) in a C2-C5 alcohol or in a mixture of two or more thereof, and in one or more anti-solvents, preferably comprising
(cl . l) preparing a solution of the sofosbuvir provided in (al) the C 2 -C 5 alcohol or in the mixture of two or more thereof, preferably in ethanol, or n-butanol, or n-pentanol, wherein preparing the solution preferably comprises heating, preferably heating the solution to a temperature in the range of from 30 to 70 °C, preferably from 35 to 65 °C;
(c2.2) adding the one or more anti-solvents to the solution obtained in (cl . l), wherein the one or more anti-solvents preferably comprise an alkane, more preferably a C 5 alkane, a C 6 alkane, a C 7 alkane, a Cg alkane, or a mixture of two or more thereof, more preferably a C 7 alkane, more preferably n- heptane;
wherein after (cl . l) and before (cl .2), the solution is preferably cooled, preferably to a temperature in the range of from 15 to 35 °C, more preferably from 20 to 30 °C; and wherein after (cl . l) and before (cl .2), the solution obtained in (cl . l) is optionally subjected to a solids separation process, preferably filtration;
subjecting the solution provided in (cl) to crystallization conditions, comprising seeding the solution with the seed crystals prepared in (bl), wherein during crystallization, the solution is not stirred, preferably not mechanically agitated, more preferably not agitated, obtaining the crystalline form of sofosbuvir having an X- ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° in its mother liquor, wherein during crystallization, the solution is kept at a temperature in the range of from 15 to 35 °C, preferably from 20 to 30 °C, at a pressure in the range of from 0.95 to 1.05 bar ;
preferably separating the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° from its mother liquor, preferably comprising
(el .l) subjecting the mother liquor comprising the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.9 ° to filtration, obtaining at least a portion of the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 °;
(el .2) preferably washing the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° obtained in (el .l);
(el .3) preferably drying the crystalline form of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° obtained in (el . l) or (el .2). Use of the crystalline form 6 of sofosbuvir according to embodiment 50 for the preparation of a pharmaceutical composition. A method of using the crystalline form 6 of sofosbuvir according to embodiment 50 for the preparation of a pharmaceutical composition. A pharmaceutical composition, comprising crystalline form 6 of sofosbuvir according to embodiment 50 and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of embodiment 55 for use in a method for treating hepatitis C in a human. 57. Use of the pharmaceutical composition of embodiment 55 for treating hepatitis C in a human.
58. A method of treating hepatitis C in a human comprising administering the pharmaceutical composition of embodiment 55 to a human.
59. Use of the crystalline form 6 of sofosbuvir according to embodiment 50 for preparing a medicament for the treatment of hepatitis C in a human.
60. Use of the crystalline form 6 of sofosbuvir according to embodiment 50 for the treatment of hepatitis C in a human.
61. The crystalline form 6 of sofosbuvir according to embodiment 50 for use in the treatment of hepatitis C in a human.
62. The crystalline form 6 of sofosbuvir according to embodiment 50 for the treatment of hepatitis C in a human.
63. A method of treating hepatitis C in a human comprising administering the crystalline form 6 of sofosbuvir according to embodiment 50, to a human.
64. Use of a combination of at least one organic solvent and at least one organic anti- solvent as crystallization medium for crystallizing form 6 of sofosbuvir.
65. Use of a combination of at least one organic solvent and at least one organic anti- solvent as medium for solvent mediated transformation of sofosbuvir to obtain crystalline form 6 of sofosbuvir.
66. Use of embodiment 64 or 65 wherein the one organic solvent and at least one organic anti-solvent are not acetonitrile and/or dichloromethane.
The present invention is further illustrated by the following reference examples and examples.
Reference Example 1: Characterization of the crystalline forms of Sofosbuvir - X- ray powder (XRPD) diffraction patterns
XRPD were obtained with an X'Pert PRO diffractometer (PANalytical, Almelo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-Kalphai i2 radiation source (wavelength 0.15419 nm) with a focusing mirror, a 0.5 ° divergence slit, a 0.02 ° soller slit collimator and a 0.5 ° anti- scattering slit on the incident beam side, a 2 mm anti-scattering slit, a 0.02 ° soller slit collimator, a Ni-filter and a solid state PIXcel detector on the diffracted beam side. The diffracto- gram was recorded at room temperature at a tube voltage of 40 kV, tube current of 40 mA, applying a stepsize of 0.013 ° 2-theta with 40 sec per step in the angular range of 2 ° to 40 ° 2- theta. A typical precision of the 2-theta values is in the range of ± 0.2 ° 2-theta. Thus, a diffraction peak that appears for example at 9.4 ° 2-theta can appear between 9.2 and 9.6 ° 2- theta on most X-ray diffractometers under standard conditions. Reference Example 2: FTIR spectra
Fourier transform infrared (FTIR) spectra were recorded with a Bruker IFS 25 spectrometer (Bruker Analytische Messtechnik GmbH, Karlsruhe, D) connected to a Bruker IR microscope I (15x-Cassegrain-objective). The samples were prepared on ZnSe-disks and measured at room temperature in transmission mode (spectral range (4000-600) cm "1 , resolution 4 cm "1 , 64 interferograms per spectrum). To record a spectrum a spatula tip of a sample was applied to the surface of the ZnSe in powder form. Then the sample was pressed onto the ZnSe and the spectrum was recorded. A spectrum of the clean ZnSe was used as background spectrum. A typical precision of the wavenumber values is in the range of about ± 2 cm "1 . Thus, an in- frared peak that appears for example at 1668 cm -1 can appear between 1666 and 1670 cm -1 on most infrared spectrometers under standard conditions.
Reference Example 3: Melting point Differential scanning calorimetry (DSC) was performed with a DSC 7 (Perkin-Elmer, Nor- walk, Ct., USA) using a Pyris 2.0 software and with a DSC 204F1 (Netzsch GmbH & Co. Holding AG, Selb, Germany). Approximately (1 to 5 ± 0.005) mg sample (using a UM3 ul- tramicrobalance, Mettler, Greifensee, CH) was weighed into an Al-pan (30 microL), sealed with a cover, which was perforated by a needle and heated from 25 to 150 °C at a rate of 10 °C/min. Dry nitrogen was used as the purge gas (purge: 20 mL/min).
Reference Example 4: Organic solvent content
Thermogravimetric analysis (TGA) was performed using the following equipment/conditions: Thermogravimetric-system TGA-7, Pyris-Software for Windows NT, (Perkin-Elmer, Nor- walk, Ct., USA), Platinum-sample holder (50 microL), nitrogen as the purge gas (sample purge: 20 mL/min, balance purge: 40 mL/min). Heating rate: 10 °C/min; heating range: 25- 145 °C. Reference Example 5: Water content
The moisture sorption desorption isotherms were acquired using a SPS-11 moisture sorption analyzer (MD Messtechnik, Ulm, D). The samples were weighed into Aluminium sample holders. The measurement cycles for the crystalline form having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.9 ° were started at 43 % RH, decreased to 40 % RH (relative humidity), further decreased in 10 % steps to 10 % RH, decreased in 5 % steps to 0 % RH, increased in 5 % steps to 10 % RH, further increased in 10 % steps to 90 % RH and subsequently increased to 95 % RH, decreased again to 90 % RH, decreased in 10 % steps to 10 % RH, further decreased in 5 % steps to 0 % RH, again increased in 5 % steps to 10 %, subsequently increased in 10 % steps to 40 % RH and finally increased to 43 % RH. The equilibrium condition for each step was set to a mass constancy of ± 0.005 % over 60 min. The temperature was (25 ± 0.1) °C. The water content of the samples was determined after the moisture sorption/ desorption experiments with a TGA 7 system (Perkin Elmer, Norwalk, Ct., USA) using the Pyris 2.0 software. The samples were weighed into aluminium pans (50 microL). Dry nitrogen was used as purge gas (purge rate: 20 mL/min). The samples were heated from 25 to 200 °C using a heating rate of 10 K/min.
Reference Example 6: Unit cell
Intensity data for the crystal structure were recorded at 100 K on a Rigaku AFC 12 goniometer driven by the CrystalClear-SM Expert 3.1 b27 software (Rigaku, 2012) and equipped with an enhanced sensitivity (HG) Saturn724+ detector mounted at the window of an FR-E+ Super Bright Mo rotating anode generator (lambda = 0.71075 Angstrom) with HFVarimax optics. The structure was solved using the direct methods procedure in SHELXS97 and refined by full-matrix least squares on F 2 using SHELXL97. All non-hydrogen atoms were refined ani- sotropically.
Example 1: Preparation of crystalline form 6 of sofosbuvir
519 mg of sofosbuvir (crystalline form 1 prepared according to WO 2011/123645 A, Example 10) were added in different portions (300 mg, 106 mg, 113 mg) to 1.0 mL of n-butanol (> 99.5 %, Merck KGaA). The solution was heated to a temperature between 50 and 60 °C and sonicated (2 to 5 min in a VWR Ultrasonic Cleaner apparatus) to allow solid dissolution, fol- lowed by filtration with a 0.45 micrometer syringe filter.
To 25 mL of the filtrate, 0.5 mL of w-heptane (> 99%, Sigma- Aldrich) were added at 40 °C under stirring conditions with a magnetic bar at a speed of about 500 r.p.m. (rounds per minute), which allowed the dissolution of the fine, white precipitate formed during n-heptane addition and lead to a clear solution. The solution was stirred at 25 °C for 2 h at a speed of from 300 to 400 r.p.m., leading to the formation of a white suspension. The slurry was filtered on a medium-porosity glass fritted funnel and washed with 1.0 mL n-heptane. The solid residue was dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 25 °C for 16 h, yielding crystalline form 6 of sofosbuvir.
The XRPD pattern is shown in Figure 1.
Example 2: Preparation of crystalline form 6 of sofosbuvir
519 mg of sofosbuvir (crystalline form 1 prepared according to WO 2011/123645 A, Example 10) were added in different portions (300 mg, 106 mg, 113 mg) to 1.0 mL of n-butanol (> 99.5 %, Merck KGaA). The solution was heated to a temperature between 50 and 60 °C and sonicated (2 to 5 min in a VWR Ultrasonic Cleaner apparatus) to allow solid dissolution, fol- lowed by filtration with a 0.45 micrometer syringe filter.
25 mL of the filtrate was put into an open vial and stirred with a magnetic bar at a speed of 300 to 400 r.p.m. at a temperature of 25 °C for 2 h allowing crystallization to occur. The obtained suspension was filtered on a medium-porosity glass fritted funnel, and the solid residue was dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 25 °C for 16 h, yielding crystalline form 6 of sofosbuvir.
The XRPD pattern is shown in Figure 2. Example 3: Preparation of crystalline form 6 of sofosbuvir
To a 100 mL round bottom flask equipped with a magnetic stirring bar were added 4.98 g of sofosbuvir (crystalline form 1 prepared according to WO 2011/123645 A, Example 10) and 10 mL of n-butanol (> 99.5 %, Merck KGaA). The solution was heated to a temperature of from 50 to 60 °C and sonicated (2 to 5 min in a VWR Ultrasonic Cleaner apparatus) to allow solid dissolution. 20 ml of n-heptane (> 99 %, Sigma- Aldrich) were added under stirring conditions (500 r.p.m.) at a temperature of from 25 to 50 °C, yielding a slightly turbid solution.
The solution was let cooled to a temperature of 25 °C under stirring conditions (300 to 400 rpm) and further stirred at this temperature for 3 h to allow crystallization to take place. Then, 30 mL of n-heptane were added to facilitate the stirring of the dense slurry. After 1 h, stirring was stopped. The dense suspension was filtered on a medium-porosity glass fritted funnel and the solid residue was washed with n-heptane and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of from 40 to 50 °C for 4 h where after heating was stopped and the temperature of the solid residue was allowed to decrease slowly to 25 °C at a pressure of from 20 to 30 mbar for 43 h, yielding 4.88 g (98 % yield) of crystalline form 6 of sofosbuvir.
The XRPD pattern is shown in Figure 3.
Example 4: Preparation of crystalline form 6 of sofosbuvir
In a vial equipped with a magnetic stirring bar were added 1.00 g of sofosbuvir (crystalline form 1 prepared according to WO 2011/123645 A, Example 10) and 2.5 mL of n-butanol (> 99.5 %, Merck KGaA). The solution was heated to a temperature of from 50 to 60 °C to allow solid dissolution. 5.0 mL of n-heptane (> 99 %, Sigma- Aldrich) were added under stirring conditions (500 r.p.m.) at a temperature of from 50 to 60 °C.
The solution was further stirred at a velocity of from 300 to 400 r.p.m. and a temperature of from 25 to 28 °C for 6 h to allow crystallization to take place. The obtained suspension was filtered on a medium-porosity glass fritted funnel and the solid residue was washed with n- heptane and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 3 h whereafter heating was stopped and the temperature of the solid residue was allowed to decrease slowly to 25 °C at a pressure of from 20 to 30 mbar for 12 h, yielding 0.96 g (96 % yield) of crystalline form 6 of sofosbuvir. The XRPD pattern is shown in Figure 4.
Example 5: Preparation of crystalline form 6 of sofosbuvir
Amorphous sofosbuvir was prepared according to the following recipe: To 400 mg of sofos- buvir crystalline form 1 prepared according to WO 2011/123645 A, Example 10, 3.5 mL eth- anol were added, followed by 12 mL DI water. The mixture was subjected to sonication (2 to 5 min at room temperature in a VWR Ultrasonic Cleaner apparatus) to accelerate the dissolution of the solid material. The homogeneous solution was frozen in a bath of liquid nitrogen and lyophilized at -36 °C at a pressure of from 0 to 2 mbar, yielding amorphous sofosbuvir.
In a vial equipped with a magnetic stirring bar were added 200 mg of the amorphous sofosbuvir and 0.5 mL of n-butanol (> 99.5 %, Merck KGaA). The solution was heated to a temperature of from 40 to 50 °C to allow solid dissolution. 1.0 mL of n-heptane (> 99 %, Sigma- Aldrich) was added under stirring conditions (500 r.p.m.) at a temperature of from 50 to 60 °C. The solution was further stirred at a velocity of from 300 to 400 r.p.m. and a temperature of from 25 to 28 °C for 4 h to allow crystallization to take place. The obtained suspension was filtered on a medium-porosity glass fritted funnel and the solid residue was washed with n- heptane and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 2 h whereafter heating was stopped and the temperature of the solid residue was allowed to decrease slowly to 25 °C at a pressure of from 20 to 30 mbar for 16 h, yielding 180 mg (90 % yield) of crystalline form 6 of sofosbuvir.
Example 6: Preparation of crystalline form 6 of sofosbuvir
In a vial equipped with a magnetic stirring bar were added 200 mg of sofosbuvir (crystalline form 1 prepared according to WO 2011/123645 A, Example 10) and 0.5 mL of ethanol (99.9 %, Lichrosolv®, Merck KGaA). The solution was heated to a temperature of from 50 to 60 °C to allow solid dissolution. 1.0 mL of n-heptane (> 99 %, Sigma- Aldrich) was added under stirring conditions (500 r.p.m.) at a temperature of from 50 to 60 °C.
The solution was further stirred at a velocity of from 300 to 400 r.p.m. and a temperature of from 25 to 28 °C for 16 h to allow crystallization to take place. The obtained suspension was filtered on a medium-porosity glass fritted funnel and the solid residue was washed with n- heptane and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 2 h whereafter heating was stopped and the temperature of the solid residue was allowed to decrease slowly to 25 °C at a pressure of from 20 to 30 mbar for 13 h, yielding 162 mg (81 % yield) of crystalline form 6 of sofosbuvir. The XRPD pattern is shown in Figure 5.
Example 7: Preparation of crystalline form 6 of sofosbuvir
100 mg of sofosbuvir (crystalline form 1 prepared according to WO 2011/123645 A, Example 10) were suspended in 0.75 mL of a solution containing n-butanol (> 99.5 %, Merck KGaA) and n-heptane (> 99 %, Sigma-Aldrich) with a volume ratio of n-butanol : n-heptane of 0.5 : 1. The slurry was stirred at a temperature of from 25 to 27 °C. After 1.5 h, 1.25 mL of the mixture containing n-butanol and n-heptane (volume ratio 0.5 : 1) was added to allow better stirring of the slurry, which was stirred further 0.5 h. The suspension was filtered on a medi- um-porosity glass fritted funnel and the solid residue was washed with n-heptane and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 2 h whereafter heating was stopped and the temperature of the solid residue was allowed to decrease slowly to 25 °C at a pressure of from 20 to 30 mbar for 20 h, yielding crystalline form 6 of sofosbuvir. The XRPD pattern is shown in Figure 6.
Example 8: Preparation of crystalline form 6 of sofosbuvir
1.00 g of sofosbuvir (crystalline form 1 prepared according to WO 2011/123645 A, Example 10) were suspended in 10 mL of a solution of ethanol (99.9%, Lichrosolv®, Merck KGaA) and n-heptane (> 99 %, Sigma- Aldrich) with a volume ratio of ethanol : n-heptane of 0.5 : 1. The slurry was stirred at a temperature of from 25 to 27 °C. After 1.5 h, the suspension was filtered on a medium-porosity glass fritted funnel and the solid residue was washed with n- heptane and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 4 h whereafter heating was stopped and the temperature of the solid residue was allowed to decrease slowly to 25 °C at a pressure of from 20 to 30 mbar for 16 h, yielding 0.80 mg (80 % yield) of crystalline form 6 of sofosbuvir.
The XRPD pattern is shown in Figure 7.
Short Description of the Figures
Fig. 1 shows the XRPD, determined according to Reference Example 1 above, of sofosbuvir of crystalline form 6 prepared according to Example 1 above. The x axis shows the 2-theta / ° values, with tick marks, from left to right, at 5, 10, 15, 20, 25, 30, 35 °. The y axis shows the intensity in counts, with tick marks, from bottom to top, at 0, 200, 400, 600, 800, 1000.
Fig. 2 shows the XRPD, determined according to Reference Example 1 above, of sofosbuvir of crystalline form 6 prepared according to Example 2 above. The x axis shows the 2-theta / ° values, with tick marks, from left to right, at 5, 10, 15, 20, 25, 30, 35 °. The y axis shows the intensity in counts, with tick marks, from bottom to top, at 0, 500, 1000, 1500, 2000.
Fig. 3 shows the XRPD, determined according to Reference Example 1 above, of sofosbuvir of crystalline form 6 prepared according to Example 3 above. The x axis shows the 2-theta / ° values, with tick marks, from left to right, at 5, 10, 15, 20, 25, 30, 35 °. The y axis shows the intensity in counts, with tick marks, from bottom to top, at 0, 200, 400, 600, 800, 1000.
Fig. 4 shows the XRPD, determined according to Reference Example 1 above, of sofosbuvir of crystalline form 6 prepared according to Example 4 above. The x axis shows the 2-theta / ° values, with tick marks, from left to right, at 5, 10, 15, 20, 25, 30, 35 °. The y axis shows the intensity in counts, with tick marks, from bottom to top, at 0, 500, 1000, 1500, 2000, 2500, 3000.
Fig. 5 shows the XRPD, determined according to Reference Example 1 above, of sofos- buvir of crystalline form 6 prepared according to Example 6 above. The x axis shows the 2-theta / ° values, with tick marks, from left to right, at 5, 10, 15, 20, 25, 30, 35 °. The y axis shows the intensity in counts, with tick marks, from bottom to top, at 0, 500, 1000, 1500, 2000, 2500, 3000.
Fig. 6 shows the XRPD, determined according to Reference Example 1 above, of sofos- buvir of crystalline form 6 prepared according to Example 7 above. The x axis shows the 2-theta / ° values, with tick marks, from left to right, at 5, 10, 15, 20, 25, 30, 35 °. The y axis shows the intensity in counts, with tick marks, from bottom to top, at 0, 500, 1000, 1500.
Fig. 7 shows the XRPD, determined according to Reference Example 1 above, of sofos- buvir of crystalline form 6 prepared according to Example 8 above. The x axis shows the 2-theta / ° values, with tick marks, from left to right, at 5, 10, 15, 20, 25, 30, 35 °. The y axis shows the intensity in counts, with tick marks, from bottom to top, at 0, 200, 400, 600, 800, 1000, 1200.
Cited Prior Art
US 2010298257 Al
US 2011251152 Al
WO 2011/123645 A2
WO 2010/135569 Al
Sofia et al. J. Med. Chem. 2010 Vol. 53, 7202-7218