WO2016097173A1

WO2016097173A1 - A process for preparing a crystalline form of sofosbuvir

Info

Publication number: WO2016097173A1
Application number: PCT/EP2015/080271
Authority: WO
Inventors: Nolwenn Martin
Original assignee: Sandoz Ag
Priority date: 2014-12-17
Filing date: 2015-12-17
Publication date: 2016-06-23

Abstract

A process for preparing a 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 7.8°, wherein polyethylene glycol is used as additive for solvent mediated transformation to obtain said crystalline form of sofosbuvir.

Description

A PROCESS FOR PREPARING A CRYSTALLINE FORM OF SOFOSBUVIR

The present invention relates to a process for preparing a solid 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 7.8 ° wherein the process comprises preparing a mixture comprising sofosbuvir provided in crystalline form, semi-crystalline form, or amorphous form, at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, and subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions, obtaining said solid crystalline form of sofosbuvir. Further, the present invention relates to a solid crystalline form of sofosbuvir which is obtainable or obtained by said process, to a pharmaceutical composition comprising the said solid crystalline form of sofosbuvir, and to the use of said pharmaceutical composition for treating hepatitis C in a human. Yet further, the present invention relates to the use of a combination of at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, as a medium for solvent mediated transformation of sofosbuvir under agitation, to obtain sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °.

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)methoxy)(phenoxy)phosphoryl)- amino)propanoate is a drug inhibiting the RNA polymerase used by the hepatitis C virus to replicate its RNA.

WO 2010/135569 Al discloses amorphous sofosbuvir and crystalline forms 1 to 5 as well as processes for their preparation. According to WO 2010/135569 Al , crystalline form 1 is an anhydrate, crystalline forms 2 and 3 are solvates with dichloromethane and chloroform respectively. However, no sufficient data could be collected to determine whether crystalline forms 4 and 5 are unsolvated, hydrated or solvated forms of sofosbuvir. It is further mentioned that all crystalline forms transform to crystalline form 1 on isolation and that crystalline form 1 liquefies when exposed to elevated humidity levels. WO 2011/123645 Al discloses an additional crystalline form, form 6, of sofosbuvir. According to example 21 of WO 2011/123645 Al, crystalline form 6 can be prepared in two different ways. On the one hand, crystalline form 6 is obtained by exposing crystalline form 1 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.

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 crystalline forms of sofosbuvir with improved physicochemical properties; there is a particular need for non-hygroscopic crystalline forms of sofosbuvir with improved behavior upon contact with water and moisture, respectively. Surprisingly, it was found that such a novel crystalline form of sofosbuvir with improved physicochemical properties, in particular exhibiting non-hygroscopic behavior upon contact with moisture and water can be provided. Said novel crystalline form of sofosbuvir, also referred to herein as form 7, can be characterized by the following embodiments and combination of embodiments as indicated by the respective back-references:

1. A crystalline form of sofosbuvir of formula (I) (form 7)

(I)

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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. 2. The crystalline form of embodiment 1, having an X-ray powder diffraction pattern 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 Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

3. The crystalline form of embodiment 1 or 2, exhibiting 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.

4. The crystalline form of any of embodiments 1 to 3, having 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 °.

5. The crystalline form of any of embodiments 1 to 4, having a melting point in the range of from 122 to 126 °C when measured via differential scanning calorimetry at a heating rate of 10 K/min at a pressure in the range of from 0.95 to 1.05 bar.

6. The crystalline form of any of embodiments 1 to 5, comprising at most 0.5 weight-% of organic solvent, based on the weight of the crystalline form, as determined via thermo- gravimetric analysis.

7. The crystalline form of any of embodiments 1 to 6, comprising at most 0.4 weight-% of water based on the weight of the crystalline form 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 %.

This crystalline form 7 of sofosbuvir is the only crystalline form of sofosbuvir showing no peak at 2-theta angles in the range of from 2 to 7.8 ° in the XRPD pattern. All other known crystalline forms according to the prior art show at least one significant peak in this range, as summarized in the following Table: Table 1

XRPD peaks of prior art crystalline forms in the range of from 2 to 7.8° 2-theta

Hence, the absence of an XRPD peak in said range is unique and therefore a characteristic property of this crystalline form of sofosbuvir. Additionally, this crystalline form 7 of sofosbuvir can be, for example, further distinguished from crystalline form 1 of WO 2010/135569 Al by a characteristic XRPD peak at (12.4 ± 0.2) ° 2-theta since the crystalline form 1 shows no such characteristic peak in this range when measured at room temperature with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

An advantageous process for the preparation of this crystalline form 7 of sofosbuvir could be, for example, a process which makes use of seed crystals of a known crystalline form of sofosbuvir, for example of crystalline form 6 of sofosbuvir. Such an advantageous process may comprise, for example

(a) providing sofosbuvir in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms;

(b) preparing seed crystals of crystalline form 7 of sofosbuvir by a method comprising

(b. l) providing sofosbuvir in crystalline form, pseudo-crystalline form, amorphous form, or as a mixture of two or more of these forms;

(b.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) °, (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;

(b.3) preparing a solution of the sofosbuvir provided in (b. l) in a C₂-Ci₀ 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;

(b.4) subjecting the solution provided in (b.3) to crystallization conditions, comprising seeding the solution with the seed crystals provided in (b.2), wherein during crystallization, the solution is not stirred, preferably not mechanically agitated, more preferably not agitated, obtaining the crystalline form 7 of sofosbuvir in its mother liquor;

(b.5) separating at least a portion of the crystalline form 7 of sofosbuvir from its mother liquor;

(c) preparing a solution of sofosbuvir provided in (a) in a C2-C5 alcohol or in a mixture of two or more thereof, and in one or more anti-solvents;

(d) subjecting the solution provided in (c) to crystallization conditions, comprising seeding the solution with the seed crystals prepared in (b), wherein during crystallization, the solution is not stirred, preferably not mechanically agitated, more preferably not agitated, obtaining the crystalline form 7 of sofosbuvir in its mother liquor;

(e) separating the crystalline form 7 of sofosbuvir from its mother liquor.

The term "agitation" as used herein 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 herein relates to any motion of a macroscopic constituent 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 herein 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.

While from this process, the crystalline form 7 of sofosbuvir may be obtained in a reliable manner, the process feature according to which during crystallization, the solution is not stirred, preferably not mechanically agitated, more preferably not agitated. In particular in view of a scaled-up process for the preparation of form 7 wherein, compared to lab-scale processes according to which, for example, from 0.1 to 0.5 g of sofosbuvir are employed as starting material, higher amounts of sofosbuvir have to be employed as starting material, such as at least 0.6 g of sofosbuvir, it may be conceivable that as to the process described above, the essential absence of agitation may lead to a crystallization of at least a portion of the crystalline form 7 at the walls of the respectively used reaction vessel.

CN 104130302 A, published on 05 November 2014, describes the preparation of a crystalline form A of sofosbuvir which is neither a solvate nor a hydrate. According to this process, it is mandatory that in order to obtain said crystalline form, no stirring should be carried out during crystallization. In particular the examples of CN 104130302 A show that as soon as the mixture from which the crystalline form A is crystallized is stirred and not left to stand without any agitation, no pure form A is obtained but a mixture of said form A and form 6. Thus, the process of CN 104130302 A is not suitable for preparing the crystalline form A according to an industrially suitable procedure.

Hence there is a need for providing a process for the preparation of the crystalline form 7 of sofosbuvir which avoids the above-mentioned drawback and which, in particular, allows to be employed not only in a laboratory scale, but also in an scaled up process where a sufficient amount of sofosbuvir, for example at least 0.6 g of sofosbuvir, preferably at least 0.75 g of sofosbuvir, is employed as starting material.

Surprisingly, it was found that this object can be solved if, during solvent-mediated transformation to obtain the solid crystalline form 7 of sofosbuvir, a polyethylene glycol is present in the mixture from which the solid crystalline form 7 of sofosbuvir is obtained.

Therefore, the present invention relates to a process for preparing a solid crystalline form of sofosbuvir of formula (I)

(I)

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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, said 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, at least one organic anti-solvent, and at least one polyethylene glycol;

(iii) subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions, obtaining the solid 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 7.8 ° in its mother liquor.

Further, the present invention relates to solid crystalline form of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, obtainable or obtained by a process according to the present invention. Further, the present invention relates to the use of the solid crystalline form of sofosbuvir of formula (I) obtainable 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, prefer- ably for treating hepatitis C in a human.

Further, the present invention relates to the use of a combination of at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, as medium for solvent mediated transformation of sofosbuvir to obtain sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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.

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 a crystalline form which does not comprise, more preferably which is not, crystalline form 6 of sofosbuvir according to formula (I) 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. More preferably, according to (i), sofosbuvir according to formula (I) is provided in crystalline form 1 , amorphous form, or as a mixture 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, or is provided 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 .

The crystalline form 7 of sofosbuvir having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 ° preferably comprises XRPD 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, and 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; and/or

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; 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; 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; 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 %.

Steps (ii) and (iii) According to (ii), a mixture is prepared comprising the sofosbuvir provided in (i), at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol.

Organic solvent

Preferably, the at least one organic solvent comprises an aliphatic alcohol, more preferably a C₃ alcohol, a C₄ alcohol, a C₅ alcohol, or a mixture of two or more thereof, such as a mixture of two C3 alcohol or a mixture of two or more C₄ alcohols or a mixture of two or more C₅ alcohols or a mixture of at least one C3 alcohol and at least one C₄ alcohol or a mixture of at least one C3 alcohol and at least one C₅ alcohol or a mixture of at least one C₄ alcohol and at least one C5 alcohol or a mixture of at least one C3 alcohol and at least one C₄ alcohol and at least one C₅ alcohol. C3 alcohols include n-propanol or isopropanol. C₄ alcohols include n- butanol, 2-butanol, tert-butanol. C₅ alcohols include 1-pentanol, 2-pentanol, 3-pentanol, 2- methyl-1 -butanol. More preferably, the at least one organic solvent comprises n-propanol, n- butanol, n-pentanol, or a mixture of two or more thereof such as a mixture of n-propanol and n-butanol or a mixture of n-propanol and n-pentanol or a mixture of n-butanol and n-pentanol or a mixture of n-propanol, n-butanol, and n-pentanol. More preferably, the at least one organic solvent comprises a C₄ alcohol, preferably n-butanol. More preferably, the at least one organic solvent is a C₄ alcohol, preferably n-butanol.

Thus, according to (ii), a mixture is preferably prepared comprising the sofosbuvir provided in (i), a C₄ alcohol, preferably n-butanol, as organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol. Further, according to (ii), a mixture is more preferably prepared comprising the sofosbuvir provided in (i), a C₄ alcohol, preferably n-butanol, as the only organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol.

According to the present invention, it was found that it is preferred that the at least organic solvent does not comprise ethanol. Thus, according to (ii), a mixture is preferably prepared comprising the sofosbuvir provided in (i), at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, wherein the mixture does not comprise ethanol. Further, according to (ii), a mixture is preferably prepared comprising the sofosbuvir provided in (i), a C₄ alcohol, preferably n-butanol, as organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, wherein the mixture does not comprise ethanol.

Further according to the present invention, it was found that it is preferred that the at least organic solvent does not comprise, methanol, ethanol, acetone, butanone, acetonitrile, ethyl acetate, isopropylacetate, N-butyl formate, or a mixture of two or more thereof. Thus, according to (ii), a mixture is preferably prepared comprising the sofosbuvir provided in (i), at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, wherein the mixture does not comprise methanol ethanol, acetone, butanone, acetonitrile, ethyl acetate, isopropylacetate, N-butyl formate, or a mixture of two or more thereof. Further, according to (ii), a mixture is preferably prepared comprising the sofosbuvir provided in (i), a C₄ alcohol, preferably n-butanol, as organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, wherein the mixture does not comprise methanol, ethanol, acetone, butanone, acetonitrile, ethyl acetate, isopropylacetate, N-butyl formate, or a mixture of two or more thereof. Organic anti-solvent

Preferably, the at least one anti-solvent comprise an alkane, more preferably a C₅ alkane such as n-pentane, isopentane, neopentane, cyclo-pentane, a C₆ alkane such as n-hexane, 2- methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutanecyclohexane, a C₇ alkane such as n-heptane, cyclo-heptane, a Cg alkane such as n-octane, or a mixture of two or more thereof, more preferably a C₇ alkane. More preferably, the at least one anti-solvent comprises n-heptane. More preferably, the at least one organic anti-solvent is n-heptane.

Thus, according to (ii), a mixture is preferably prepared comprising the sofosbuvir provided in (i), at least one organic solvent, preferably a C₄ alcohol as organic solvent, more preferably n- butanol as organic solvent, a C₇ alkane, preferably n-heptane as at least one organic anti- solvent, and at least one polyethylene glycol. Further, according to (ii), a mixture is more preferably prepared comprising the sofosbuvir provided in (i), a C₄ alcohol, preferably n- butanol, as the only organic solvent, a C₇ alkane, preferably n-heptane as the only organic anti-solvent, and at least one polyethylene glycol.

Preferably, according to (ii), the at least one organic anti-solvent is not, preferably does not comprise, hexane, n-pentane, cyclohexane, or a mixture of two or more thereof. Thus, according to (ii), a mixture is preferably prepared comprising the sofosbuvir provided in (i), at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, wherein the mixture does not comprise hexane, n-pentane, cyclohexane, or a mixture of two or more thereof. More preferably, the at least one organic anti-solvent is not, preferably does not comprise, hexane, n-pentane, cyclohexane, toluene, petroleum ether, isopropyl ether, or a mixture of two or more thereof. Thus, according to (ii), a mixture is preferably prepared com- prising the sofosbuvir provided in (i), at least one organic solvent, at least one organic anti- solvent, and at least one polyethylene glycol, wherein the mixture does not comprise hexane, n-pentane, cyclohexane, or a mixture of two or more thereof. According to the present invention, it is preferred that the mixture according to (ii) contains the at least one organic solvent and the at least one organic anti-solvent in specific amounts relative to each other. Preferably, in the mixture according to (ii), the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is in the range of from 0.1 : 1 to 1.1 : 1 , preferably of from 0.1 : 1 to 1 : 1 , more preferably of from 0.2: 1 to 0.9: 1 , more preferably of from 0.25: 1 to 0.8:1, more preferably of from 0.3: 1 to 0.7: 1, such as from 0.3: 1 to 0.5: 1 or from 0.4: 1 to 0.6: 1 or from 0.5: 1 to 0.7: 1. If more than one organic solvent is employed, the volume ratio relates to the total volume of all organic solvents. If more than one organic anti-solvent is employed, the volume ratio relates to the total volume of all organic anti-solvents.

According to the present invention, it is preferred that the mixture according to (ii) contains the sofosbuvir according to formula (I) and the at least one organic solvent in specific amounts relative to each other. Preferably, the mixture according to (ii) contains the sofos- buvir according to formula (I), relative to the at least one organic solvent, in an amount in the range of from 100 to 500 mg(sofosbuvir)/mL(organic solvent), preferably of from 110 to 450 mg(sofosbuvir)/mL(organic solvent), more preferably of from 120 to 400 mg(sofosbuvir)/ mL(organic solvent), more preferably of from 130 to 380 mg(sofosbuvir)/mL(organic solvent), more preferably of from 135 to 350 mg(sofosbuvir)/mL(organic solvent). Preferred ranges are, for example, 135 to 200 mg/mL, or 200 to 300 mg/mL, or 300 to 350 mg/rnL, such as from 300 to 330 mg/mL or from 300 to 345 mg/mL or from 300 to 340 mg/mL or from 300 to 335 mg/mL. If more than one organic solvent is employed, the volume relates to the total volume of all organic solvents. Polyethylene glycol

No specific restrictions exist regarding the at least one polyethylene glycol comprised in the mixture according to (ii). For example, the polyethylene glycol can be liquid or solid under ambient conditions. Further, a mixture of at least one polyethylene glycol which is liquid un- der ambient conditions and at least one polyethylene glycol which is solid under ambient conditions can be comprised in the mixture according to (ii). Preferably, the at least one polyethylene glycol has an average molecular weight in the range of from 200 to 8000 g/mol, more preferably of from 300 to 7000 g/mol, more preferably from 400 to 6000 g/mol. More preferably, the at least one polyethylene glycol has an average molecular weight in the range of from 400 to 3000 g/mol, preferably of from 400 to 2000 g/mol, more preferably from 400 to 1000 g/mol, such as from 400 to 900 g/mol or from 400 to 800 g/mol or from 400 to 700 g/mol. More preferably, the at least one polyethylene glycol has an average molecular weight in the range of from 400 to 600 g/mol. According to the present invention, it is preferred that the mixture according to (ii) contains the at least one polyethylene glycol relative to the sofosbuvir according to formula (I) in specific amounts relative to each other. Preferably, in the mixture according to (ii), the weight ratio of the at least one polyethylene glycol relative to the sofosbuvir according to formula (I) is in the range of from 0.01 : 1 to 1 : 1, preferably of from 0.03: 1 to 0.5: 1, more preferably of from 0.04: 1 to 0.4: 1, more preferably of from 0.05: 1 to 0.3: 1, such as from 0.05: 1 to 0.15: 1 or from 0.1 : 1 to 0.2: 1 or from 0.15: 1 to 0.25: 1 or from 0.2: 1 to 0.3:1. If more than one polyethylene glycol is employed, the amount of the polyethylene glycol relates to the total amount of all polyethylene glycols employed.

Therefore, the present invention also relates to the process as defined above, wherein according to (ii), a mixture is prepared comprising the sofosbuvir provided in (i), n-butanol as the at least one organic solvent, n-heptane as the at least one organic anti-solvent, and at least one polyethylene glycol, preferably having an average molecular weight in the range of from 200 to 6000 g/mol, wherein the weight ratio of the at least one polyethylene glycol relative to the sofosbuvir according to formula (I) is in the range of from 0.05: 1 to 0.3: 1, wherein the sofosbuvir according to formula (I), relative to the at least one organic solvent, is comprised in an amount in the range of from 135 to 350 mg/mL, and 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 0.3: 1 to 0.7: 1.

Preferably, at least 95 weight-%, more preferably at least 96 weight-%, more preferably at least 97 weight- %, more preferably at least 98 weight- %, more preferably at least 99 weight- % of the mixture according to (ii) consist of the sofosbuvir according to formula (I), the at least one organic solvent, the at least one organic anti-solvent, and the at least one polyethylene glycol. Further, it is conceivable that at least 99.1 weight-% or at least 99.3 weight-% or at least 99.5 weight-% or at least 99.7 weight-% or at least 99.9 weight-% of the mixture according to (ii) consist of the sofosbuvir according to formula (I), the at least one organic solvent, the at least one organic anti-solvent, and the at least one polyethylene glycol.

Therefore, the present invention also relates to the process as defined above, wherein according to (ii), a mixture is prepared comprising the sofosbuvir provided in (i), n-butanol as the at least one organic solvent, n-heptane as the at least one organic anti-solvent, and at least one polyethylene glycol, preferably having an average molecular weight in the range of from 200 to 6000 g/mol, wherein the weight ratio of the at least one polyethylene glycol relative to the sofosbuvir according to formula (I) is in the range of from 0.05: 1 to 0.3: 1, wherein the sofosbuvir according to formula (I), relative to the at least one organic solvent, is comprised in an amount in the range of from 135 to 350 mg/mL, and 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 0.3: 1 to 0.7: 1, wherein at least 99 weight-% of the mixture consist of the sofosbuvir according to formula (I), the at least one organic solvent, the at least one organic anti-solvent, and the at least one polyethylene glycol. Further, it may be conceivable that instead of the at least one polyethylene glycol or in addition to the at least one polyethylene glycol, at least one polyalkylene glycol other than polyethylene glycol could be employed.

According to the present invention, it is preferred that during preparing the mixture according to (ii), the mixture is at least temporarily agitated, preferably at least temporarily mechanically agitated, more preferably at least temporarily stirred.

The term "agitation" as used in the context of the present invention relates to any motion of a macroscopic constituent of the mixture comprising sofosbuvir which is induced from outside, relative to another macroscopic constituent of the mixture. The term "mechanical agitation" as used in the context of the present invention relates to any motion of a macroscopic constituent of the mixture comprising sofosbuvir which is induced from outside via a device, such as shaking or stirring or sonication, relative to another macroscopic constituent of the mixture. The term "stirring" as used in the context of the present invention relates to any motion of a macroscopic constituent of the mixture comprising sofosbuvir which is induced from outside via a stirring device, relative to another macroscopic constituent of the mixture.

According to (iii), the mixture obtained from (ii) is subjected to solvent-mediated transformation at suitable temperatures, preferably at a temperature of the mixture obtained from (ii) in the range of from 10 to 40 °C, more preferably of from 15 to 35 °C, such as from 15 to 25 °C or from 20 to 30 °C or from 25 to 35 °C.

Solvent-mediated transformation conditions of (iii) according to the present invention, in addition to the solvent, the anti-solvent and the polyethylene glycol of (ii) as disclosed above, are for example the temperature and the agitation conditions.

Solvent-mediated transformation conditions are for example:

1) subjecting the mixture obtained from (ii) at suitable temperature conditions, preferably at a temperature of the mixture obtained from (ii) in the range of from 10 to 40 °C, more prefera- bly of from 15 to 35 °C or 20 to 35 °C, and/or

2) agitating, preferably at least temporarily mechanically agitating, more preferably at least temporarily stirring the mixture obtained in (ii). A temperature range of form 15 to 35 °C is preferred when the mixture in (ii) is a suspension of sofosbuvir with the solvent, the anti-solvent and the polyethylene glycol as disclosed below. A temperature range of form 20 to 35 °C is preferred when sofosbuvir is dissolved in the solvent system as disclosed below.

The agitating, the at least temporarily mechanically agitating, the at least temporarily stirring the mixture obtained in (ii) is preferably carried out in (iii) for a period of time in the range of from 0.3 to 8.0 hours, more preferably from 0.4 to 7.5 hours, even more preferably from 0.5 to 7.0 hours.

According to (iii), the mixture obtained from (ii) is subjected to solvent-mediated transformation from which the crystalline form 7 is obtained in its mother liquor.

Therefore, the present invention also relates to the use of a combination of at least one organic solvent, preferably n-butanol, at least one organic anti-solvent, preferably n-heptane, and at least one polyethylene glycol, as medium for solvent mediated transformation of sofosbuvir to obtain sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, when measured at a temperature in the range of from 15 to 25 °C with

radiation having a wavelength of 0.15419 nm.

As mentioned above, a particular advantage of the process of the present invention is to be seen in the fact that the use of the at least one polyethylene glycol allows a preferred process for subjecting the mixture according to (ii) to solvent-mediated transformation wherein at least partially during solvent-mediated transformation, the mixture from which the crystalline form 7 of sofosbuvir is obtained is agitated. Therefore, it is preferred that subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture.

Therefore, the present invention also relates to the use of a combination of at least one organic solvent, preferably n-butanol, at least one organic anti-solvent, preferably n-heptane, and at least one polyethylene glycol, as medium for solvent-mediated transformation of sofosbuvir to obtain sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, when measured at a temperature in the range of from 15 to 25 °C with

radiation having a wavelength of 0.15419 nm wherein during solvent-mediated transformation, the mixture in which the sofosbuvir is transformed is at least temporarily agitated, preferably at least temporarily mechanically agitated, more preferably at least temporarily stirred.

It was surprisingly found that the combination of the at least one organic solvent, the at least one organic anti-solvent and the at least one polyethylene glycol allows such a robust technique for forming crystalline form 7 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 7 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 more stable crystalline form 7. Therefore, 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 in the context of the present invention.

Suspending sofosbuvir

According to a first preferred embodiment, preparing the mixture according to (ii) comprises suspending the sofosbuvir provided in (i) in a mixture of the at least one organic solvent, the at least one organic anti-solvent, and the at least one polyethylene glycol. According to this embodiment, suspending is preferably carried out at a temperature of the suspension in the range of from 10 to 40 °C, more preferably of from 15 to 35 °C, such as from 15 to 25 °C or from 20 to 30 °C or from 25 to 35 °C.

The thus obtained suspension is subjected to solvent-mediated transformation in (iii) at suitable temperatures, preferably at a temperature of the suspension in the range of from 10 to 40 °C, more preferably of from 15 to 35 °C, such as from 15 to 25 °C or from 20 to 30 °C or from 25 to 35 °C.

Preferably, during the solvent-mediated transformation, the suspension is at least temporarily agitated, preferably at least temporarily mechanically agitated, more preferably at least temporarily stirred. More preferably, during the solvent-mediated transformation, the suspension is agitated, preferably mechanically agitated, more preferably stirred.

Preferably, the agitating, the at least temporarily agitating, preferably the at least temporarily mechanically agitating, more preferably the at least temporarily stirring of (iii) is carried out for a period of time preferably in the range of from 0.3 to 8.0 hours, more preferably from 0.4 to 7.5 hours, even more preferably from 0.5 to 7.0 hours. During solvent-mediated transformation according to (iii), it is possible that seed crystals are added to the suspension. Generally, any seed crystals can be employed which lead to the for- mation of crystalline form 7 of sofosbuvir. If seed crystals are employed, it is preferred that these seed crystals of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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 of crystalline form 7, are used. Further, if seed crystals are employed, it is preferred that based on the amount of sofosbuvir contained in the suspension, seed crystals in an amount in the range of from 0.5 to 20 weight-%, preferably of from 1 to 20 weight-%, more preferably of from 1 to 15 weight-%, more preferably of from 1 to 10 weight- %, more preferably of from 1 to 5 weight-% are added to the suspension. The preferably agitated, more preferably mechanically agitated, more preferably stirred mixture can be optionally cooled to a suitable temperature after the formation of crystalline form 7. If the suspension is cooled, it is preferred to cool it to a temperature in the range of from 0 to 12 °C, preferably of from 2 to 10 °C such as from 5 to 8 °C. The cooling ramp is not subject to any specific restrictions and is preferably in the range of from 5 to 30 K/h, more pref- erably from 7 to 15 K h such as from 7 to 11 K/h or from 9 to 13 K/h or from 11 to 15 K/h. During the cooling the mixture is agitated, preferably mechanically agitated, more preferably stirred.

Therefore, subjecting the mixture to solvent-mediated transformation according to (iii) preferably comprises

(111.1) optionally adding seed crystals, preferably in an amount in the range of from 0.5 to 20 weight-%, more preferably of from 1 to 20 weight-%, more preferably of from 1 to 15 weight-%, more preferably of from 1 to 10 weight-%, more preferably of from 1 to 5 weight-%, based on the amount of sofosbuvir contained in the mixture;

(111.2) agitating, preferably mechanically agitating, more preferably stirring the mixture (suspension) obtained from (ii), optionally from (iii.l), at a temperature in the range of from 10 to 40 °C, more preferably of from 15 to 35 °C, preferably for a period of time in the range of from 0.3 to 8.0 hours, more preferably from 0.4 to 7.5 hours, more preferably from 0.5 to 7.0 hours;

(111.3) optionally cooling the mixture obtained from (iii.2), preferably to a temperature in the range of from 0 to 12 °C, preferably of from 2 to 10 °C, preferably at a cooling rate in the range of from 5 to 30 K/h, more preferably from 7 to 15 K/h; obtaining the solid crystalline form of sofosbuvir preferably having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 ° in its mother liquor.

Therefore, if cooling is carried out, subjecting the mixture to solvent-mediated transformation according to (iii) preferably comprises

(111.3) optionally cooling the mixture obtained from (iii.2), preferably to a temperature in the range of from 0 to 12 °C, preferably of from 2 to 10 °C, preferably at a cooling rate in the range of from 5 to 30 K/h, more preferably from 7 to 15 K/h;

obtaining the solid crystalline form of sofosbuvir preferably having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 ° in its mother liquor.

It is preferred that the agitating, preferably mechanically agitating, more preferably stirring the mixture (suspension) obtained from (ii) is carried out during the whole step (iii) for a period of time in the range of from 0.3 to 8.0 hours, more preferably from 0.4 to 7.5 hours, even more preferably from 0.5 to 7.0 hours. Hence, in case step (iii) comprises only step (iii.2) the agitating, preferably mechanically agitating, more preferably stirring and the time range thereof refer only to (iii.2); in case step (iii) comprises steps (iii.2) and (iii.3) the agitating, preferably mechanically agitating, more preferably stirring and the time range thereof refer to step (iii.2) and (iii.3) together. In case step (iii) comprises steps (iii: 1), (iii.2) and (iii.3) the agitating, preferably mechanically agitating, more preferably stirring and the time range thereof refer to step (iii. l), (iii.2) and (iii.3) together.

Step (iii.2) results in the formation of crystalline form 7 of sofosbuvir as defined above. Gen- erally in step (iii.2) a dense slurry is formed that comprises the crystalline form 7 of sofosbuvir. Optionally step (iii.3) is carried out after the formation of the crystalline form 7 of (iii.2).

Dissolving sofosbuvir According to a second preferred embodiment, preparing the mixture according to (ii) comprises dissolving the sofosbuvir provided in (i) in the at least one organic solvent. Generally, it is possible that in case two or more organic solvents are employed, to dissolve the sofos- buvir provided in (i) in one or more of said solvents and to add one or more solvents after having dissolved the sofosbuvir provided in (i). Further, it is possible to dissolve the sofosbuvir provided in (i) in the at least one organic solvent and to add the at least one polyethylene glycol to the obtained solution. Preferably, the solution is prepared by mixing the sofosbuvir provided in (i) with the at least one organic solvent and the at least one polyethylene glycol. Therefore, the present invention relates to the process as defined above, wherein preparing the mixture according to (ii) comprises

(ii'.l)preparing a solution of the sofosbuvir provided in (i) in the at least one organic solvent, preferably by mixing the sofosbuvir provided in (i) with the at least one organic solvent and the at least one polyethylene glycol.

The temperature at which the mixture is prepared according to (ϋ'.1) is preferably in the range of from 20 to 70 °C, preferably of from 25 to 60 °C, more preferably of from 30 to 55 °C, more preferably of from 35 to 50 °C, such as from 35 to 45 °C or from 40 to 50 °C. Preferably, preparing the mixture according to (ii'.l) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture.

Further, it is preferred that to the mixture (solution of the sofosbuvir in the at least one organic solvent and the at least one polyethylene glycol) obtained from (ii'.l), the at least one organic anti-solvent is added. Thus, the process of the invention preferably comprises

(ii'.l)preparing a solution of the sofosbuvir provided in (i) in the at least one organic solvent, preferably by mixing the sofosbuvir provided in (i) with the at least one organic solvent and the at least one polyethylene glycol;

(ϋ'.2) adding the at least one organic anti-solvent to the solution obtained in (ii'.l). Preferably, according to (ii'.2), the at least one organic anti-solvent is added to the solution at a temperature of the solution in the range of from 20 to 70 °C, preferably of from 25 to 60 °C, more preferably of from 30 to 55 °C, more preferably of from 35 to 50 °C, such as from 35 to 45 °C or from 40 to 50 °C. Preferably, adding the at least one organic anti-solvent according to (ii'.2) comprises agitating, preferably mechanically agitating, more preferably stirring the solution.

The thus obtained solution is subjected to solvent-mediated transformation in (iii) at suitable temperatures. Preferably, during (iii), the thus obtained solution is suitably cooled, preferably to a temperature in the range of from 15 to 40 °C, more preferably of from 20 to 35 °C, such as from 20 to 30 °C or from 25 to 35 °C. The cooling ramp is not subject to any specific restrictions and is preferably in the range of from 30 to 250 K/h, preferably of from 60 to 200 K/h, such as from 60 to 100 K/h or from 80 to 120 K/h or from 100 to 140 K/h or from 120 to 160 K h or from 140 to 180 K/h or from 160 to 200 K/h. Preferably the solvent-mediated transformation according to (iii) comprises temporarily agitating, preferably temporarily mechanically agitating, more preferably temporarily stirring the mixture of (ii) or of (ii'.2) preferably for a period of time in the range of from 0.3 to 8.0 hours, more preferably from 0.4 to 7.5 hours, even more preferably from 0.5 to 7.0 hours.

During and/or after cooling, it is possible to add seed crystals of sofosbuvir. Generally, any seed crystals can be employed which lead to the formation of crystalline form 7 of sofosbuvir. If seed crystals are employed, it is preferred that these seed crystals of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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, in particular of crystalline form 7, are used. Further, if seed crystals are employed, it is preferred that based on the amount of sofosbuvir contained in the mixture, seed crystals in an amount in the range of from 0.5 to 20 weight-%, preferably of from 1 to 20 weight-%, more preferably of from 1 to 15 weight-%, more preferably of from 1 to 10 weight-%, more preferably of from 1 to 5 weight-% are added to the mixture.

During adding the seed crystals, the mixture is preferably agitated, more preferably mechanically agitated, more preferably stirred. Preferably, the seed crystals are added at a temperature of the mixture in in the range of from 15 to 40 °C, preferably of from 20 to 35 °C, such as from 20 to 30 °C or from 25 to 35 °C.

After cooling, preferably after cooling and adding the seed crystals, it is preferred to keep the mixture at a temperature in the range of from 15 to 40 °C, more preferably of from 20 to 35 °C, preferably for a period of time in the range of from 0.3 to 8.0 hours, more preferably of from 0.4 to 7.5 hours, even more preferably of from 0.5 to 7.0 hours wherein during keeping at said temperature, the mixture is at least temporarily agitated, more preferably at least temporarily mechanically agitated, more preferably at least temporarily stirred. Crystalline form 7 of sofosbuvir is formed under these conditions. After cooling, preferably after cooling and adding the seed crystals, more preferably after cooling, adding the seed crystals and keeping the mixture at said temperature to allow formation of crystalline form 7, the mixture can be further suitably cooled. If the mixture is cooled after formation of crystalline form 7, it is preferred to cool it to a temperature in the range of from 0 to 12 °C, preferably of from 2 to 10 °C such as from 5 to 8 °C. The cooling ramp is not subject to any specific restrictions and is preferably in the range of from 5 to 30 K/h, more preferably from 7 to 15 K h such as from 7 to 11 k/h or from 9 to 13 K/h or from 11 to 15 K/h.

Therefore, subjecting the mixture obtained in (ii) to solvent-mediated transformation according to (iii) preferably comprises

(iii'.l) cooling the solution, preferably the solution obtained from (ii.2), preferably to a temperature in the range of from 15 to 40 °C, more preferably of from 20 to 35 °C, preferably at a cooling rate the range of from 30 to 250 K/h, more preferably of from 60 to 200 K/h;

(iii'.2) optionally adding seed crystals, preferably in an amount in the range of from 0.5 to 20 weight-%, more preferably of from 1 to 20 weight-%, more preferably of from 1 to 15 weight-%, more preferably of from 1 to 10 weight-%, more preferably of from 1 to 5 weight-%, based on the amount of sofosbuvir contained in the mixture;

and/or, preferably keeping the mixture at a temperature in the range of from 15 to 40 °C, more preferably of from 20 to 35 °C, preferably for a period of time in the range of 0. 3 to 8.0 hours, more preferably of from 0.4 to 7.5 hours, more preferably of from 0.5 to 7.0 hours wherein during keeping the mixture at said temperature, the mixture is preferably at least temporarily agitated, more preferably at least temporarily mechanically agitated, more preferably at least temporarily stirred;

(iii'.3) optionally cooling the mixture obtained from (iii'. l) or (iii'.2), preferably to a temperature in the range of from 0 to 12 °C, preferably of from 2 to 10 °C, preferably at a cooling rate in the range of from 5 to 30 K/h, more preferably from 7 to 15 K/h;

The temporarily agitating, the temporarily mechanically agitating, the temporarily stirring of solvent-mediated transformation according to (iii) is preferably carried out for a period of time in the range of from 0.3 to 8.0 hours, more preferably from 0.4 to 7.5 hours, even more preferably from 0.5 to 7.0 hours. It is hence preferred that the agitating, preferably mechanically agitating, more preferably stirring the mixture obtained from (ii) or from (ii'.2) is carried out during the whole step (iii) preferably for a period of time in the range of from 0.3 to 8.0 hours, more preferably of from 0.4 to 7.5 hours, even more preferably of from 0.5 to 7.0 hours. The agitating, preferably mechanically agitating, more preferably stirring the mixture is preferably carried out in each of steps (iii'.l), (iii'.2) and (iii'.3) -if present in the process- for an overall period of time in the range of from 0.3 to 8.0 hours, more preferably of from 0.4 to 7.5 hours, even more preferably of from 0.5 to 7.0 hours. Hence, in case step (iii) comprises only step (iii '.2) the agitating, preferably mechanically agitating, more preferably stirring and the time range thereof refer to (iii'.2); in case step (iii) comprises steps (iii'.2) and (iii'.3) the agitating, preferably mechanically agitating, more preferably stirring and the time range thereof refer to steps (iii'.2) and (iii'.3). The same applies to step (iii'. l).

Step (iii'.2) results in the formation of sofosbuvir crystalline form 7 as defined above. Generally in step (iii '.2) a dense slurry is formed that comprises the crystalline form 7 of sofosbuvir. Preferably step (iii'.3) is carried out after the formation of the crystalline form 7 of (iii'.2).

Generally, cooling in (iii'. l) and/or (iii'.3) can be carried out in one or more steps. Preferably, cooling in (iii'.l) is carried out in one step. Preferably, cooling in (iii'.3) is carried out in one step.

Adding seed crystals as well as cooling, as described above are to be understood also as general optional or preferred process steps.

Therefore, the present invention also relates to a process for preparing a solid crystalline form of sofosbuvir of formula (I)

(iii) subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions, obtaining the solid 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 7.8 ° in its mother liquor,

wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises adding seed crystals to the mixture, preferably in an amount in the range of from 0.5 to 20 weight-%, more preferably of from 1 to 20 weight-%, more prefera- bly of from 1 to 15 weight-%, more preferably of from 1 to 10 weight-%, more preferably of from 1 to 5 weight-%, based on the amount of sofosbuvir contained in the mixture.

Further, the present invention relates to a process for preparing a solid crystalline form of sofosbuvir of formula (I)

(I)

wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises, preferably after formation of a dense slurry, cooling the mixture, preferably to a temperature in the range of from 0 to 12 °C, preferably of from 2 to 10 °C, preferably at a cooling rate in the range of from 5 to 30 K/h, more preferably from 7 to 15

K/h.

Yet further, the present invention relates to a process for preparing a solid crystalline form of sofosbuvir of formula (I)

(I)

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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, said 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;

wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises adding seed crystals to the mixture, preferably in an amount in the range of from 0.5 to 20 weight-%, more preferably of from 1 to 20 weight-%, more preferably of from 1 to 15 weight-%, more preferably of from 1 to 10 weight-%, more preferably of from 1 to 5 weight-%, based on the amount of sofosbuvir contained in the mixture, and cooling the mixture, preferably after formation of a dense slurry, preferably to a temperature in the range of from 0 to 12 °C, preferably of from 2 to 10 °C, preferably at a cooling rate in the range of from 5 to 30 K/h, more preferably from 7 to 15 K/h.

Step (iv)

According to the present, it is preferred that the solid 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 7.8 ° which is obtained in (iii) comprised in its mother liquor is suitably separated from said mother liquor. Therefore, the process as described above preferably comprises

(iv) separating the solid crystalline form of sofosbuvir preferably having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 ° from its mother liquor.

Regarding the separation according to (iv), no specific restrictions exist. Preferably, separating according to (iv) comprises subjecting the mother liquor containing the solid crystalline form of sofosbuvir obtained from (iii) to solid-liquid separation, preferably comprising filtration or centrifugation, more preferably filtration. Therefore, separating ac- cording to (iv) preferably comprises

(iv. l) subjecting the mother liquor comprising the solid crystalline form of sofosbuvir to a solid separation process, preferably to filtration.

Preferably, separating according to (iv) comprises washing the solid crystalline form of sofos- buvir obtained from (iii) wherein said washing is preferably carried out after solid-liquid separation as described above. Therefore, separating according to (iv) preferably comprises (iv.2) washing the solid crystalline form of sofosbuvir, preferably the solid crystalline form of sofosbuvir obtained from (iv. l), separated from its mother liquor. Regarding the washing, no specific restrictions exist. Preferably the washing is carried out with at least one organic anti-solvent which 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, the at least one organic anti-solvent is the at least one organic anti-solvent used for preparing the mixture according to (ii). More preferably, the washing is carried out with at least one organic anti-solvent which comprises, more preferably is, n-heptane. The washing can also be carried out with a mixture containing the at least one organic anti-solvent used for preparing the mixture according to (ii) and the at least one organic solvent used for preparing the mixture according to (ii). In addition to the at least one organic anti-solvent, further washing of the filter cake can optionally be carried out with wa- ter. Preferably, the washing is carried out with the at least one organic anti-solvent, followed by optional washing of the filter cake with water, preferably with n-heptane, followed by optional washing of the filter cake with water. More preferably, the washing is carried out with the at least one organic anti-solvent, followed by washing of the filter cake with water, preferably with n-heptane, followed by washing of the filter cake with water.

Regarding the temperature at which the washing is carried out, no specific restrictions exist. Preferably, the washing is carried out at a temperature in the range of from 0 to 30 °C. If, for example, subjecting the mixture obtained from (ii) to solvent-mediated transformation in (iii) comprises cooling, preferably cooling to a temperature in the range of from 0 to 12 °C, more preferably of from 2 to 10 °C, it is preferred that the washing is carried out at a temperature in the range of from 0 to 20 °C, preferably of from 2 to 15 °C wherein the washing temperature relates to the temperature of the washing agents, preferably the at least one organic anti- solvent and, optionally, the water. If, for example, subjecting the mixture obtained from (ii) to solvent-mediated transformation in (iii) does not comprise cooling, preferably does not com- prise cooling to a temperature in the range of from 0 to 12 °C, more preferably of from 2 to 10 °C, it is preferred that the washing is carried out at a temperature in the range of from 15 to 30 °C, preferably of from 20 to 25 °C wherein the washing temperature relates to the temperature of the washing agents, preferably the at least one organic anti-solvent and, optionally the wa- ter.

Step (V)

According to the present invention, it is preferred that the solid 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 7.8 ° which is obtained in (iii) comprised in its mother liquor, preferably obtained from the separation according to (iv), is suitably dried. Therefore, the process as described above preferably comprises

(v) drying the preferably separated solid crystalline form of sofosbuvir preferably having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °.

No specific restrictions exist regarding the drying conditions. Preferably, drying according to (v) is carried at elevated temperatures relative to ambient temperature, more preferably at a temperature of at least 30 °C. More preferably, drying is carried out at a temperature in the range of from 30 to 50 °C, more preferably of from 35 to 45 °C. Preferably, drying according to (v) is carried at a pressure below ambient pressure, preferably at an absolute pressure of at most 500 mbar. More preferably, drying is carried out at an absolute pressure below 1 bar, preferably in the range of from 5 to 500 mbar, more preferably of from 10 to 100 mbar, more preferably of from 15 to 50 mbar. Therefore, more preferably, drying according to (v) is carried out at a temperature in the range of from 30 to 50 °C and an absolute pressure in the range of from 5 to 500 mbar, more preferably at a temperature in the range of from 35 to 45 °C and an absolute pressure in the range of from 15 to 50 mbar. Preferably, drying is carried out for a period of time in the range of from 1 to 48 hours, preferably of from 6 to 24 hours.

Uses

Further, the present invention relates to the use of a combination of at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, as medium for solvent mediated transformation of sofosbuvir to obtain sofosbuvir of formula (I)

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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. Preferably, the solvent me- diated transformation of sofosbuvir comprises agitation, preferably mechanical agitation, more preferably stirring. Preferably, the solvent mediated transformation of sofosbuvir comprises a temperature of the mixture in the range of 10 to 40 °C.

Preferably, the at least one polyethylene glycol has an average molecular weight in the range of from 200 to 8000 g/mol, preferably of from 300 to 7000 g/mol, more preferably from 400 to 6000 g/mol, more preferably of from 400 to 600 g/mol. Preferably, the at least one organic solvent comprises an aliphatic alcohol, preferably a C₃ alcohol, a C₄ alcohol, a C₅ alcohol, or a mixture of two or more thereof, more preferably n-propanol, n-butanol, n-pentanol, or a mixture of two or more thereof, wherein more preferably, the at least one organic solvent comprises, more preferably is, n-butanol. Preferably, 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, wherein more preferably, the at least one organic anti-solvent comprises, preferably is, n-heptane. Therefore, the present invention relates to the use as described above, wherein the at least one organic solvent is n-butanol, the at least one organic anti-solvent is n-heptane, and the at least one polyethylene glycol has an average molecular weight in the range of from 200 to 8000 g/mol, preferably of from 300 to 7000 g/mol, more preferably from 400 to 6000 g/mol, more preferably of from 400 to 600 g/mol. Further, the present invention relates to the use as de- scribed above, wherein the at least one organic solvent is n-butanol, the at least one organic anti-solvent is n-heptane, and the at least one polyethylene glycol has an average molecular weight in the range of from 200 to 8000 g/mol, preferably of from 300 to 7000 g/mol, more preferably from 400 to 6000 g/mol, more preferably of from 400 to 600 g/mol, wherein the solvent mediated transformation of sofosbuvir comprises agitation, preferably mechanical agitation, more preferably stirring. Yet further, the present invention relates to the use of a combination of n-butanol as organic solvent, n-heptane as organic anti-solvent, and a polyethylene glycol having an average molecular weight in the range of from 400 to 600 g/mol, as medium for solvent mediated transformation of sofosbuvir comprising stirring to obtain sofosbuvir of formula (I)

(I)

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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. Preferably, the use of the combination of at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, as medium for solvent mediated transformation of sofosbuvir to obtain sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphai_i2 radiation hav- ing a wavelength of 0.15419 nm, comprises a process according to the present invention as disclosed in the above paragraphs.

Further, the present invention relates to the use of the crystalline form 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 for the preparation of a pharmaceutical composition; to a pharmaceutical composition comprising, in an pharmaceutically effective amount, said crystalline form 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 administering said pharmaceutical composition to a human; to the use of said crystalline form for preparing a medicament for the treatment hepatitis C in a human; to the use of said crystalline form for the treatment of hepatitis C in a human; to said crystalline form for use in the treatment of hepatitis C in a human; to said crystalline form for the treatment of hepatitis C in a human; to a method of treating hepatitis C in a human comprising administering said crystalline form. The present invention is further illustrated by the following embodiments and combinations of embodiments resulting from the given dependencies and back-references:

1. A process for preparing a solid crystalline form of sofosbuvir of formula (I)

(I)

preferably having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.8 °, 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 as described in Reference Example 1.1 herein, said 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;

(iii) subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions, obtaining the solid crystalline form of sofosbuvir preferably having an X- ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 ° in its mother liquor.

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 1.1 ; or in amorphous form;

or as a mixture of these forms.

The process of embodiment 1 or 2, 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 1.1. 4. The process of any of embodiments 1 to 3, wherein according to (ii), the at least one organic solvent comprises an aliphatic alcohol, preferably a C₃ alcohol, a C₄ alcohol, a C5 alcohol, or a mixture of two or more thereof, more preferably n-propanol, n-butanol, n-pentanol, or a mixture of two or more thereof.

5. The process of any of embodiments 1 to 4, wherein according to (ii), the at least one organic solvent comprises, preferably is, a C₄ alcohol. 6. The process of any of embodiments 1 to 5, wherein according to (ii), the at least one organic solvent comprises, preferably is, n-butanol.

7. The process of any of embodiments 1 to 6, wherein according to (ii), the at least one organic solvent is not, preferably does not comprise, ethanol.

8. The process of any of embodiments 1 to 7, wherein according to (ii), the at least one organic solvent is not, preferably does not comprise, methanol, ethanol, acetone, buta- none, acetonitrile, ethyl acetate, isopropylacetate, N-butyl formate, or a mixture of two or more thereof.

9. The process of any of embodiments 1 to 8, wherein according to (ii), the at least one organic anti-solvent comprises an alkane, 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. 10. The process of any of embodiments 1 to 9, wherein according to (ii), the at least one organic anti-solvent comprises, preferably is, n-heptane.

11. The process of any of embodiments 1 to 10, wherein according to (ii), the at least one organic anti-solvent is not, preferably does not comprise, hexane, n-pentane, cyclohex- ane, or a mixture of two or more thereof.

12. The process of any of embodiments 1 to 11, wherein according to (ii), the at least one organic anti-solvent is not, preferably does not comprise, hexane, n-pentane, cyclohex- ane, toluene, petroleum ether, isopropyl ether, or a mixture of two or more thereof.

13. The process of any of embodiments 1 to 12, wherein according to (ii), the at least one organic solvent comprises, preferably is, n-butanol, and the at least one organic anti- solvent comprises, preferably is, n-heptane. The process of any of embodiments 1 to 13, wherein in the mixture according to (ii), the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is in the range of from 0.1 : 1 to 1.1 : 1, preferably of from 0.1 : 1 to 1 : 1, more preferably of from 0.2: 1 to 0.9: 1, more preferably of from 0.25: 1 to 0.8: 1. The process of any of embodiments 1 to 14, wherein in the mixture according to (ii), the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is in the range of from 0.3 : 1 to 0.7: 1. The process of any of embodiments 1 to 15, wherein according to (ii), the at least one organic solvent comprises, preferably is, n-butanol, the at least one organic anti-solvent comprises, preferably is, n-heptane, and wherein in the mixture according to (ii), the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is in the range of from 0.3 : 1 to 0.7: 1. The process of any of embodiments 1 to 16, wherein the mixture according to (ii) contains the sofosbuvir according to formula (I), relative to the at least one organic solvent, in an amount in the range of from 100 to 500 mg/mL, preferably of from 1 10 to 450 mg/mL, more preferably of from 120 to 400 mg/mL, more preferably of from 130 to 380 mg/mL. The process of any of embodiments 1 to 17, wherein the mixture according to (ii) contains the sofosbuvir according to formula (I), relative to the at least one organic solvent, in an amount in the range of from 135 to 350 mg/mL. The process of any of embodiments 1 to 18, wherein according to (ii), the at least one polyethylene glycol has an average molecular weight in the range of from 200 to 8000 g/mol, preferably of from 300 to 7000 g/mol, more preferably from 400 to 6000 g/mol. The process of any of embodiments 1 to 19, wherein according to (ii), the at least one polyethylene glycol has an average molecular weight in the range of from 400 to 3000 g/mol, preferably of from 400 to 2000 g/mol, more preferably from 400 to 1000 g/mol. The process of any of embodiments 1 to 20, wherein according to (ii), the at least one polyethylene glycol has an average molecular weight in the range of from 400 to 600 g/mol. The process of any of embodiments 1 to 21, wherein according to (ii), the at least one organic solvent comprises, preferably is, n-butanol, the at least one organic anti-solvent comprises, preferably is, n-heptane, and the at least one polyethylene glycol comprises, preferably is, a polyethylene glycol having an average molecular weight in the range of from 400 to 600 g/mol. The process of any of embodiments 1 to 22, wherein in the mixture according to (ii), the weight ratio of the at least one polyethylene glycol relative to the sofosbuvir according to formula (I) is in the range of from 0.01 : 1 to 1 : 1, preferably of from 0.03: 1 to 0.5: 1, more preferably of from 0.04: 1 to 0.4:1. The process of any of embodiments 1 to 23, wherein in the mixture according to (ii), the molar ratio of the at least one polyethylene glycol relative to the sofosbuvir according to formula (I) is in the range of from 0.05 : 1 to 0.3 : 1. The process of any of embodiments 1 to 24, wherein according to (ii), the at least one organic solvent comprises, preferably is, n-butanol, the at least one organic anti-solvent comprises, preferably is, n-heptane, and the at least one polyethylene glycol comprises, preferably is, a polyethylene glycol having an average molecular weight in the range of from 400 to 600 g/mol, and wherein in the mixture according to (ii), the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is in the range of from 0.3: 1 to 0.7: 1 and the weight ratio of the at least one polyethylene glycol relative to the sofosbuvir according to formula (I) is in the range of from 0.05: 1 to 0.3: 1, and wherein the mixture according to (ii) contains the sofosbuvir according to formula (I), relative to the at least one organic solvent, in an amount in the range of from 135 to 350 mg/mL. The process of any of embodiments 1 to 25, wherein the solvent-mediated transformation conditions according to (iii) comprises the temperature of the mixture in the range of from 10 to 40 °C. The process of any of embodiments 1 to 26, wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture. The process of embodiment 27, wherein agitating, preferably mechanically agitating, more preferably stirring is carried out for a period of time in the range of from 0.3 to 8.0 hours, preferably from 0.4 to 7.5 hours, more preferably from 0.5 to 7.0 hours. The process of any of embodiments 1 to 28, wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture at a temperature of the mixture in the range of from 10 to 40 °C. The process of any of embodiments 1 to 29, wherein preparing the mixture according to (ii) comprises agitation, preferably mechanical agitation, more preferably stirring. The process of any of embodiments 1 to 30, further comprising

(iv) separating the solid crystalline form of sofosbuvir preferably having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 ° from its mother liquor;

(v) drying the separated solid crystalline form of sofosbuvir preferably having an X- ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °. The process of any of embodiments 1 to 31, wherein preparing the mixture according to (ii) comprises suspending the sofosbuvir provided in (i) in a mixture of the at least one organic solvent, the at least one organic anti-solvent, and the at least one polyethylene glycol. The process of embodiment 32, wherein preparing the mixture in (ii) comprises suspending the sofosbuvir provided in (i) in the mixture of the at least one organic solvent, the at least one organic anti-solvent, and the at least one polyethylene glycol at a temperature in the range of from 10 to 40 °C, preferably in the range of from 15 to 35 °C. The process of embodiment 32 or 33, wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture at a temperature of the mixture in the range of from 10 to 40 °C, preferably in the range of from 15 to 35 °C. The process of embodiment 34, wherein agitating, preferably mechanically agitating, more preferably stirring is carried out for a period of time in the range of from 0.3 to 8.0 hours, preferably from 0.4 to 7.5 hours, more preferably from 0.5 to 7.0 hours. The process of embodiment 34 or 35, wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) does not comprise adding seed crystals of sofosbuvir of formula (I)

(I)

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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 to the mixture, preferably does not comprise adding seed crystals of sofosbuvir of formula (I).

The process of embodiment 34 or 35, wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises adding seed crystals of sofosbuvir of formula (I)

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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 to the mixture.

The process of embodiment 37, wherein, based on the amount of sofosbuvir contained in the mixture, seed crystals in an amount in the range of from 0.5 to 20 weight-%, preferably of from 1 to 20 weight-%, more preferably of from 1 to 15 weight-%, more preferably of from 1 to 10 weight-%, more preferably of from 1 to 5 weight-% are added to the mixture.

The process of any of embodiments 34 to 38, comprising cooling the agitated mixture to a temperature of the mixture in the range of from 0 to 12 °C, preferably of from 2 to 10 °C, preferably after formation of a dense slurry. 40. The process of embodiment 39, wherein the mixture is cooled at a cooling rate in the range of from 5 to 30 K/h, preferably from 7 to 15 K/h.

The process of any of embodiments 34 to 38, which does not comprise cooling the preferably agitated mixture to a temperature of the mixture in the range of from 0 to 12 °C, preferably of from 2 to 10 °C, preferably does not comprise cooling the agitated mixture.

The process of any of embodiments 32 to 41, further comprising

(v) drying the separated solid crystalline form of sofosbuvir preferably having an X- ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °.

43. The process of embodiment 37 or 38, wherein the seed crystals are prepared by a process according to embodiment 36, preferably according to embodiment 42. 44. The process of embodiment 37 or 38, comprising preparing the seed crystals by a process according to embodiment 36, preferably according to embodiment 42.

45. The process any of embodiments 1 to 31, wherein preparing the mixture according to (ii) comprises

46. The process of embodiment 45, wherein preparing the solution in (ii'. l) comprises mix- ing the sofosbuvir provided in (i) with the at least one organic solvent and the at least one polyethylene glycol at a temperature of the mixture in the range of from 20 to 70 °C, preferably of from 25 to 60 °C, more preferably of from 30 to 55 °C.

47. The process of embodiment 45 or 46, wherein preparing the solution in (ii'. l) comprises mixing the sofosbuvir provided in (i) with the at least one organic solvent and the at least one polyethylene glycol at a temperature in the range of from 35 to 50 °C. The process of any of embodiments 45 to 47, wherein mixing the sofosbuvir provided in (i) with the at least one organic solvent and the at least one polyethylene glycol comprises agitating, preferably mechanically agitating, more preferably stirring. The process of any of embodiments 45 to 48, further comprising

(ϋ'.2) adding the at least one organic anti-solvent to the solution obtained in (ii'.l). The process of embodiment 49, wherein in (ii'.2), adding the at least one organic anti- solvent to the solution obtained in (ii'. l) is carried out at a temperature of the mixture in the range of from 20 to 70 °C, preferably of from 25 to 60 °C, more preferably in the range of from 30 to 55 °C. The process of embodiment 49 or 50, wherein in (ii'.2), adding the at least one organic anti-solvent to the solution obtained in (ii'. l) is carried out at a temperature of the mixture in the range of from 35 to 50 °C. The process of any of embodiments 49 to 51, wherein in (ii'.2), adding the at least one organic anti-solvent to the solution comprises agitating, preferably mechanically agitating, more preferably stirring. The process of any of embodiments 49 to 52, wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises (iii'.l) cooling the mixture obtained from (ii'.2). The process of embodiment 53, wherein according to (iii'.l), the mixture obtained from (ii'.2) is cooled to a temperature of the mixture in the range of from 15 to 40 °C, preferably of from 20 to 35 °C. The process of embodiment 53 or 54, wherein in (iii'.l), the mixture is cooled at a cooling rate in the range of from 30 to 250 K/h, preferably of from 60 to 200 K/h. The process of any of embodiments 53 to 55, wherein during and/or after cooling according to (iii'.l), preferably after cooling according to (iii'. l), the process further comprises

(iii'.2) adding seed crystals of sofosbuvir of formula (I)

(I)

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, when measured at a temperature in the range of from 15 to 25 °C with

radiation having a wavelength of 0.15419 nm, to the mixture. The process of embodiment 56, wherein the seed crystals are prepared by a process according to embodiment 36, preferably according to embodiment 42. The process of embodiment 56, comprising preparing the seed crystals by a process according to embodiment 36, preferably according to embodiment 42. The process of any of embodiments 56 to 58, wherein, based on the amount of sofos- buvir contained in the mixture, seed crystals in an amount in the range of from 0.5 to 20 weight-%, preferably of from 1 to 20 weight-%, more preferably of from 1 to 15 weight-%, more preferably of from 1 to 10 weight-%, are added to the mixture. The process of any of embodiments 56 to 59, wherein, based on the amount of sofos- buvir contained in the mixture, seed crystals in an amount in the range of from 1 to 5 weight-% are added to the mixture. The process of any of embodiments 56 to 60, wherein the seed crystals are added to the mixture at a temperature of the mixture in the range of from 15 to 40 °C, preferably of from 20 to 35 °C. The process of any of embodiments 56 to 61, wherein adding the seed crystals according to (iii'.2) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture. The process of any of embodiments 53 to 62, preferably of any of embodiments 56 to 62, wherein after cooling, preferably after cooling and adding the seed crystals, the mixture is kept at the temperature in the range of from 15 to 40 °C, preferably of from 20 to 35 °C, preferably for a period of time in the range of 0.3 to 8.0 hours, preferably of from 0.4 to 7.5 hours, more preferably of from 0.5 to 7.0 hours.

64. The process of embodiment 63, wherein keeping the mixture at the temperature in the range of from 15 to 40 °C, preferably of from 20 to 35 °C comprises agitating, preferably mechanically agitating, more preferably stirring the mixture.

65. The process of any of embodiments 53 to 64, preferably of any of embodiments 56 to 64, optionally further comprising

(iii.'3) cooling the mixture obtained from (iii'. l), preferably from (iii'.2).

66. The process of embodiment 65, wherein cooling according to (iii.'3) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture. 67. The process of embodiment 65 or 66, wherein in (iii.'3), the mixture is cooled to a temperature of the mixture in the range of from 0 to 12 °C, preferably of from 2 to 10 °C.

68. The process of any of embodiments 65 to 67, wherein in (iii'.3) the mixture is cooled to the temperature of the mixture in the range of from 0 to 12 °C, preferably of from 2 to 10 °C in one step.

69. The process of embodiment 67, wherein in (iii.'3), the mixture is cooled at a cooling rate in the range of from 5 to 30 K/h, preferably of from 7 to 15 K/h. 70. The process of any of embodiments 65 to 67, wherein in (iii.'3), the mixture is cooled to the temperature of the mixture in the range of from 0 to 12 °C, preferably of from 2 to 10 °C in two or more steps, preferably in two steps.

71. The process of embodiment 70, wherein in (iii.'3), the mixture is cooled to the tempera- ture of the mixture in the range of from 0 to 12 °C, preferably of from 2 to 10 °C in two or more steps, preferably in two steps, more preferably in two steps comprising

(iii'.3.1) cooling the mixture obtained from (iii'.2) to a temperature in the range of from 20 to 30 °C, preferably of from 20 to 25 °C;

(iii'.3.2) cooling the mixture obtained from (iii'.3.1) to the temperature in the range of from 0 to 12 °C, preferably of from 2 to 10 °C.

72. The process of embodiment 71, wherein in (iii'.3.1), the cooling rate is in the range of from 5 to 15 K/h, preferably of from 6 to 15 K h. 73. The process of embodiment 71 or 72, wherein in (iii' .3.2), the cooling rate is in the range of from 5 to 10 K/h, preferably of from 7 to 10 K/h.

74. The process of any of embodiments 53 to 64, which does not comprise cooling the pref- erably agitated mixture to a temperature of the mixture in the range of from 0 to 12 °C, preferably of from 2 to 10 °C, preferably does not comprise cooling the preferably agitated mixture.

75. The process of any of embodiments 49 to 74, wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture obtained in (ii), preferably for period of time in the range of 0.3 to 8.0 hours, preferably of from 0.4 to 7.5 hours, more preferably of from 0.5 to 7.0 hours. 76. The process of any of embodiments 45 to 75, further comprising

77. The process of any of embodiments 31 or 42 or 76, wherein separating according to (iv) comprises

(iv.1) subjecting the mother liquor comprising the solid crystalline form of sofosbuvir to a solid separation process, preferably to filtration.

78. The process of embodiment 77, wherein separating according to (iv) comprises

(iv.2) washing the solid crystalline form of sofosbuvir.

79. The process of embodiment 78, wherein the washing according to (iv.2) is carried out with at least one organic anti-solvent and optionally with water, 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.

80. The process of embodiment 78 or 79, wherein the washing according to (iv.2) is carried out with at least one organic anti-solvent and optionally with water, wherein the at least one organic anti-solvent comprises, preferably is, n-heptane. The process of any of embodiments 78 to 80, wherein washing according to (iv.2) is carried out at a temperature in the range of from 0 to 30 °C. The process of embodiment 81 insofar as embodiment 81 is dependent on embodiment 41 or 75, wherein washing according to (iv.2) is carried out at a temperature of the at least one organic anti-solvent and/or the water, preferably of the at least one organic anti-solvent and the water, in the range of from 15 to 30 °C. The process of embodiment 81 insofar as embodiment 81 is dependent on embodiment 39 or 40, or on any of embodiments 65 to 73, wherein washing according to (iv.2) is carried out at a temperature of the at least one organic anti-solvent and/or the water, in the range of from 0 to 20 °C, preferably of from 2 to 15 °C. The process of any of embodiments 31 or 42 or 76, preferably of any of embodiments 77 to 83, wherein according to (v), drying is carried out at a temperature in the range of from 30 to 50 °C, preferably of from 35 to 45 °C. The process of any of embodiments 31 or 42 or 76, preferably of any of embodiments 77 to 84, wherein according to (v), drying is carried out at an absolute pressure below 1 bar, preferably in the range of from 5 to 500 mbar, more preferably of from 10 to 100 mbar, more preferably of from 15 to 50 mbar. The process of any of embodiments 31 or 42 or 76, preferably of any of embodiments 77 to 85, wherein according to (v), drying is carried out for a period of time in the range of from 1 to 48 hours, preferably of from 6 to 24 hours. The process of any of embodiments 1 to 86, wherein the crystalline form of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.8 °, comprises 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, and preferably comprises additional 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 Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm, in particular as described in Reference Example 1.1 herein. 88. The process of any of embodiments 1 to 87, wherein the crystalline form of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.8 ° 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 as described in Reference Example 1.2 herein.

89. The process of any of embodiments 1 to 88, wherein the crystalline form of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.8 ° 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 °.

90. The process of any of embodiments 1 to 89, wherein the crystalline form of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.8 ° 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 K/min at a pressure in the range of from 0.95 to 1.05 bar, in particular as described in Reference Example 1.3 herein.

91. The process of any of embodiments 1 to 90, wherein the crystalline form of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.8 ° comprises at most 0.5 weight-% of organic solvent, based on the weight of the crystalline form, as determined via thermogravimet- ric analysis, in particular as described in Reference Example 1.4 herein.

The process of any of embodiments 1 to 91, wherein the crystalline form of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2- theta angles in the range of from 2.0 to 7.8 ° comprises at most 0.4 weight-% of water based on the weight of the crystalline form as determined via gravimetric moisture sorp- tion / desorption analysis at a temperature of (25.0 ± 0.1) °C and a relative humidity of from 0 to 95 %, in particular as described in Reference Example 1.5 herein.

A solid crystalline form of sofosbuvir of formula (I)

(I),

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, obtainable or obtained by a process according to any of embodiments 1 to 92, preferably according to any of embodiments 31 or 42 or 76, more preferably according to any of embodiments 77 to 92.

94. Use of the crystalline form of sofosbuvir according to embodiment 93 for the preparation of a pharmaceutical composition.

95. A method of using the crystalline form of sofosbuvir according to embodiment 94 for the preparation of a pharmaceutical composition.

96. A pharmaceutical composition, comprising the crystalline form of sofosbuvir according to embodiment 93 and at least one pharmaceutically acceptable excipient.

97. The pharmaceutical composition of embodiment 96 for use in a method for treating hepatitis C in a human.

98. Use of the pharmaceutical composition of embodiment 97 for treating hepatitis C in a human.

99. A method of treating hepatitis C in a human comprising administering the pharmaceutical composition of embodiment 97 to a human.

100. Use of the crystalline form of sofosbuvir according to embodiment 93 for preparing a medicament for the treatment of hepatitis C in a human. 101. Use of the crystalline form of sofosbuvir according to embodiment 93 for the treatment of hepatitis C in a human.

102. The crystalline form of sofosbuvir according to embodiment 93 for use in the treatment of hepatitis C in a human.

103. The crystalline form of sofosbuvir according to embodiment 93 for the treatment of hepatitis C in a human.

104. A method of treating hepatitis C in a human comprising administering the crystalline form of sofosbuvir according to embodiment 93 to a human.

105. Use of a combination of at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol, as medium for solvent mediated transformation of sofosbuvir to obtain sofosbuvir of formula (I)

having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, 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.

106. The use of embodiment 105, wherein the at least one organic solvent is n-butanol, the at least one organic anti-solvent is n-heptane, and the at least one polyethylene glycol is a polyethylene glycol having a molecular weight in the range of from 400 to 600 g/mol. 107. The use of embodiment 105 or 106, wherein the solvent mediated transformation of sofosbuvir comprises agitation, preferably mechanical agitation, more preferably stirring of the combination of at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol. 108. The use of any of embodiments 105 to 107, wherein the solvent-mediated transformation of sofosbuvir comprises a temperature in the range of from 10 to 40 °C of the combination of at least one organic solvent, at least one organic anti-solvent, and at least one polyethylene glycol.

109. The use of any of embodiments 105 to 108, wherein the solvent-mediated transformation of sofosbuvir comprises agitation, preferably mechanical agitation, more preferably stirring at a temperature of the mixture in the range of from 10 to 40 °C.

110. The use of any of embodiments 107 to 109, wherein agitation, preferably mechanical agitation, more preferably stirring is preferably carried out for a period of time in the range of from 0.3 to 8.0 hours, more preferably from 0.4 to 7.5 hours, more preferably from 0.5 to 7.0 hours.

111. The use of any of embodiments 105 to 110, wherein the use comprises a process according to any of embodiments 1 to 92.

The present invention is further illustrated by the following reference examples, examples, and comparative examples.

Examples

Crystalline Form 7 of Sofosbuvir

In this Example section, reference is made to crystalline form 7 of sofosbuvir. This crystalline form 7 is the crystalline form described throughout this invention as the crystalline form of sofosbuvir having an X-ray powder diffraction pattern which comprises no reflection at 2- theta angles in the range of from 2.0 to 7.8 °, which preferably comprises 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) °, and which more preferably comprises additional 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 Cu-Kalphai_i2 radiation having a wavelength of 0.15419 nm, in particular as described in Reference Example 1.1 herein.

Reference Example 1: Determination of physical parameters

1.1 X-ray powder diffraction (XRPD) patterns

XRPD patterns were obtained with an X'Pert PRO diffractometer (PANalytical, Alme- lo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder,

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 diffractogram was recorded at room temperature at a tube voltage of 40 kV, tube current of 40 mA, applying a step size 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 8.1 ° 2-theta can appear between 7.9 and 8.3 ° 2-theta on most X-ray diffrac- tometers under standard conditions. 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 infrared peak that appears for example at 1668 cm^-1 can appear between 1666 and 1670 cm^-1 on most infrared spectrometers under standard conditions. Melting point

Differential scanning calorimetry (DSC) was performed with a DSC 7 (Perkin-Elmer, Norwalk, 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 ultramicrobalance, 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 K/min. Dry nitrogen was used as the purge gas (purge: 20 mL/min). Organic solvent content

Thermogravimetric analysis (TGA) was performed using the following equipment/conditions: Thermogravimetric-system TGA-7, Pyris-Software for Windows NT, (Perkin-Elmer, Norwalk, 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 K/min; heating range: 25-145 °C. 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 novel crystalline form according to the present invention 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 measurement cycles for form 1 were started at 43 % RH, decreased to 40 % RH, 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 91 % 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. Unit cell

Intensity data for the crystal structure were recorded at 120 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 F² using SHELXL97. All non-hydrogen atoms were refined anisotropically. Examples 1: Preparation of the crystalline form of sofosbuvir according to the present invention (suspending sofosbuvir)

Example 1.1: Preparation of the crystalline form of sofosbuvir according to the present invention (suspending 0.90 g sofosbuvir in 6.5 mL solvent and 0.30 g PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 0.90 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 6.5 mL of n-butanol (> 99.5 %, Merck KGaA), 0.30 g of PEG 400 and 12.0 mL of n-heptane (> 99 %, Sigma-Aldrich). The mixture was stirred (300 r.p.m.) at 20 °C. After 5.5 hours, a dense slurry was obtained and filtered on a medium- porosity glass fritted funnel. The solid residue was successively washed with n-heptane and water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 16 h, yielding 0.77 g of pure crystalline form 7 of sofosbuvir. Representative characteristics of pure crystalline form 7 accordingly prepared are shown in Figures 1-6 hereinbelow.

Example 1.2: Preparation of the crystalline form of sofosbuvir according to the present invention (suspending 1.00 g sofosbuvir in 6.0 mL solvent and 0.11 g PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 6.0 mL of n-butanol (> 99.5 %, Merck KGaA), 0.11 g of PEG 400 and 14.0 mL of n-heptane (> 99 %, Sigma-Aldrich). The mixture was stirred (300 r.p.m.) at 20 °C. After 4.0 hours, a dense slurry was obtained and filtered on a medium- porosity glass fritted funnel. The solid residue was successively washed with n-heptane and water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 18 h, yielding 0.82 g of pure crystalline form 7 of sofosbuvir.

Example 1.3: Preparation of the crystalline form of sofosbuvir according to the present invention (suspending 1.00 g sofosbuvir in 6.0 mL solvent and 55 mg PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 6.0 mL of n-butanol (> 99.5 %, Merck KGaA), 55 mg of PEG 400 and 14.0 mL of n-heptane (> 99 %, Sigma-Aldrich). The mixture was stirred (300 r.p.m.) at 20 °C. After 6.0 hours, a dense slurry was obtained and filtered on a medium- porosity glass fritted funnel. The solid residue was successively washed with n-heptane and water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 18 h, yielding 0.82 g of pure crystalline form 7 of sofosbuvir.

Example 1.4: Preparation of the crystalline form of sofosbuvir according to the present invention (suspending 1.00 g sofosbuvir in 3.0 mL solvent and 0.30 g PEG) A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 3.0 mL of n-butanol (> 99.5 %, Merck KGaA), 0.30 g of PEG 400 and 6.0 mL of n-heptane (> 99 %, Sigma-Aldrich). The mixture was stirred (300- 400 r.p.m.) at 25 °C. After 90 minutes, a dense slurry was obtained. A sample was taken and filtered. The solid residue was washed with n-heptane and water, followed by drying under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 16 h. XRPD pattern of the product corresponded to crystalline form 7 of sofosbuvir.

Examples 2: Preparation of the crystalline form of sofosbuvir according to the pre- sent invention (dissolving sofosbuvir)

Example 2.1: Preparation of the crystalline form of sofosbuvir according to the invention (dissolving 1.00 g sofosbuvir in 6.0 mL solvent; 0.30 g PEG) A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 6.0 mL of n-butanol (> 99.5 %, Merck KGaA) and 300 mg of PEG 400. The solution was heated to a temperature of 40 °C under stirring conditions (300 r.p.m.) to allow solid dissolution.14.0 mL of n-heptane (> 99 %, Sigma-Aldrich) were added and the solution was cooled to 25 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300 r.p.m. at 25 °C. After 90 minutes white slurry was formed and cooled to 5 °C for 165 minutes, followed by filtration on a medium-porosity glass fritted funnel. The solid residue was successively washed with cold n-heptane and water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 16 h, yielding 0.87 g of pure crystalline form 7 of sofosbuvir. Example 2.2: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 6.0 iriL solvent; 0.30 g PEG) A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 6.0 mL of n-butanol (> 99.5 %, Merck KGaA) and 300 mg of PEG 400. The solution was heated to a temperature of 40 °C under stirring conditions (300 r.p.m.) to allow solid dissolution.14.0 mL of n-heptane (> 99 %, Sigma- Aldrich) were added and the solution was cooled to 25 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300 r.p.m. at 25 °C. After 90 minutes white slurry was formed and cooled to 20 °C for 45 minutes and to 5 °C for 120 minutes, followed by filtration on a medium-porosity glass fritted funnel. The solid residue was successively washed with n-heptane and water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 16 h, yielding 0.87 g of pure crystalline form 7 of sofosbuvir.

Example 2.3: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 6.0 mL solvent; 0.20 g PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 6.0 mL of n-butanol (> 99.5 %, Merck KGaA) and 200 mg of PEG 400. The solution was heated to a temperature of 40 °C under stirring conditions (300 r.p.m.) to allow solid dissolution. 14.0 mL of n-heptane (> 99 %, Sigma-Aldrich) were added and the solution was cooled to 25 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300 r.p.m. at 25 °C. After 90 minutes white slurry was formed and cooled to 5 °C over 165 min, followed by filtration on a medium-porosity glass fritted funnel at 25 °C. The solid residue was successively washed with n-heptane and water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 18 h, yielding 0.85 g of crystalline form 7 of sofosbuvir.

Example 2.4: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 3.0 mL solvent; 0.30 g PEG) A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 3.0 mL of n-butanol (> 99.5 %, Merck KGaA) and 0.30 g of PEG 400. The solution was heated to a temperature of 50 °C under stirring condi- tions (300-400 r.p.m.) to allow solid dissolution. 6.0 mL of n-heptane (> 99 %, Sigma- Aldrich) were added and the solution was cooled to 25 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300-400 r.p.m. at 25 °C. After 2 hours, a dense slurry was obtained. A sample was taken and filtered. The solid residue was washed with n-heptane and water, followed by drying under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 16 h. XRPD pattern of the product corresponded to crystalline form 7 of sofosbuvir.

Example 2.5: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 5.0 mL solvent; 0.30 g PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 5.0 mL of n-butanol (> 99.5 %, Merck KGaA) and 0.30 g of PEG 400. The solution was heated to a temperature of 50 °C under stirring conditions (300-400 r.p.m.) to allow solid dissolution. 13.0 mL of n-heptane (> 99 %, Sigma- Aldrich) were added and the solution was cooled to 25 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300-400 r.p.m. at 25 °C. After 2.5 hours, a dense slurry was obtained. The sus- pension was cooled to 5 °C over 160 min and filtered on a medium-porosity glass fritted funnel. The solid residue was successively washed with cold n-heptane and cold water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 18 h, yielding 0.88 g of crystalline form 7 of sofosbuvir. Example 2.6: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 5.0 mL solvent; 0.30 g PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 5.0 mL of n-butanol (> 99.5 %, Merck KGaA) and 0.30 g of PEG 400. The solution was heated to a temperature of 40-45 °C under stirring conditions (300-400 r.p.m.) to allow solid dissolution. 13.0 mL of n-heptane (> 99 %, Sigma- Aldrich) were added and the solution was cooled to 30 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300-400 r.p.m. at 30 °C. After 0.5 hour, a dense slurry was obtained. The suspension was cooled to 5 °C over 3 hours and filtered on a medium-porosity glass fritted funnel. The solid residue was successively washed with n-heptane and water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 19 h, yielding 0.88 g of crystalline form 7 of sofosbuvir.

Example 2.7: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 5.0 mL solvent; 0.20 g PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 5.0 mL of n-butanol (> 99.5 %, Merck KGaA) and 0.20 g of PEG 400. The solution was heated to a temperature of 40-45 °C under stirring conditions (300-400 r.p.m.) to allow solid dissolution. 13.0 mL of n-heptane (> 99 %, Sigma- Aldrich) were added and the solution was cooled to 30 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300-400 r.p.m. at 30 °C. After 0.5 hour, a dense slurry was obtained. The sus- pension was cooled to 5 °C over 3 hours and filtered on a medium-porosity glass fritted funnel. The solid residue was successively washed with n-heptane and water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 19 h, yielding 0.89 g of crystalline form 7 of sofosbuvir. Example 2.8: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 5.0 mL solvent; 0.30 g PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 5.0 mL of n-butanol (> 99.5 %, Merck KGaA) and 0.30 g of PEG 400. The solution was heated to a temperature of 40-45 °C under stirring conditions (300-400 r.p.m.) to allow solid dissolution. 13.0 mL of n-heptane (> 99 %, Sigma- Aldrich) were added and the solution was cooled to 35 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300-400 r.p.m. at 35 °C. After 0.5 hour, a dense slurry was obtained. The suspension was cooled to 30 °C over 10 min and to 5 °C over 3 hours and filtered on a medium- porosity glass fritted funnel. The solid residue was successively washed with cold n-heptane and with water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 18 h, yielding 0.88 g of crystalline form 7 of sofosbuvir.

Example 2.9: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 5.0 mL solvent; 0.30 g PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 5.0 mL of n-butanol (> 99.5 %, Merck KGaA) and 0.30 g of PEG 400. The solution was heated to a temperature of 40-45 °C under stirring conditions (300-400 r.p.m.) to allow solid dissolution. 13.0 mL of n-heptane (> 99 %, Sigma- Aldrich) were added and the solution was cooled to 40 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture fur- ther stirred at 300-400 r.p.m. at 40 °C. After 0.5 hour, a dense slurry was obtained. The suspension was cooled to 25 °C over lhour and filtered on a medium-porosity glass fritted funnel. 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 18 h, yielding 0.88 g of crystalline form 7 of sofosbuvir.

Example 2.10: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 3.3 mL solvent; 0.30 g PEG) A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 3.3 mL of n-butanol (> 99.5 %, Merck KGaA) and 0.30 g of PEG 400. The solution was heated to a temperature of 45-50 °C under stirring conditions (300-400 r.p.m.) to allow solid dissolution. 8.7 mL of n-heptane (> 99 %, Sigma- Aldrich) were added and the solution was cooled to 30 °C. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300-400 r.p.m. at 30 °C. After 0.5 hour, a dense slurry was obtained. The suspension was cooled to 5 °C over 2 hours and filtered on a medium-porosity glass fritted funnel. The solid residue was successively washed with n-heptane and water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 17 h, yielding 0.87 g of crystalline form 7 of sofosbuvir. Example 2.11: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 5.00 g sofosbuvir in 25 mL solvent; 1.50 g PEG)

A 100 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 5.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and a solution containing 25 mL of n-butanol (> 99.5 %, Merck KGaA) and 1.50 g of PEG 400. The solution was heated to a temperature of 40-45 °C under stirring conditions (300-400 r.p.m.) to allow solid dissolution. 65 mL of n-heptane (> 99 %, Sigma-Aldrich) were added and the solution was cooled to 30 °C over 10 minutes. Sofosbuvir form 7 seed crystals (150 mg, prepared according to Example 1.1 above) were added when the mixture temperature reached 35 °C and the mixture further cooled to 30 °C under stirring conditions (300-400 r.p.m.). After 1 hour at 30 °C, a dense slurry was obtained. The suspension was cooled to 5 °C over 2 hours and filtered on a medium-porosity glass fritted funnel. The solid residue was successively washed with cold n-heptane and with water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 17 h, yielding 4.51 g of crystalline form 7 of sofosbuvir.

Example 2.12: Preparation of the crystalline form of sofosbuvir according to the present invention (dissolving 1.00 g sofosbuvir in 5.0 mL solvent and 0.30 g PEG)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of amorphous sofosbuvir prepared by dissolving 9.6 g of crystalline form 6 of sofosbuvir - prepared according to Comparative Example 2.2 below - in 100 mL of acetone, followed by solvent removal in rotary evaporator at 40 °C (pressure of from 700 mbar to 50 mbar) and drying in vacuum at 40 °C for 19 hours (pressure of from 20-30 mbar). A solution containing 5.0 mL of n-butanol (> 99.5 %, Merck KGaA), 0.30 g of PEG 400 and 13.0 mL of n-heptane (> 99 %, Sigma-Aldrich) were added to amorphous sofosbuvir and the mixture was heated to a temperature of 35 °C under stirring conditions (300-400 r.p.m.) to allow solid dissolution. Thereafter, sofosbuvir form 7 seed crystals (50 mg, prepared according to Example 1.1 above) were added and the mixture further stirred at 300-400 r.p.m. at 35 °C. After 0.5 hour, a dense slurry was obtained. The suspension was successively cooled to 20 °C over 1.0 hour and to 5 °C over 1.5 hours and filtered on a medium-porosity glass fritted funnel. The solid residue was successively washed with cold n-heptane and with water and dried under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 17 h, yielding 0.90 g of crystalline form 7 of sofosbuvir. Comparative Examples 1: Preparation of a crystalline form of sofosbuvir (suspending sofosbuvir)

Comparative Example 1.1: Preparation of a crystalline form of sofosbuvir (suspend- ing 0.10 g sofosbuvir in 0.75 ml solvent; no PEG added)

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 and 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 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 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 20 h, yielding crystalline form 6 of sofosbuvir.

Comparative Examples 2: Preparation of a crystalline form of sofosbuvir (dissolving sofosbuvir)

Comparative Example 2.1: Preparation of a crystalline form of sofosbuvir (dissolving

0.135 g sofosbuvir in 1.0 mL solvent; no PEG added) Sofosbuvir of crystalline form 1 (0.135 g, prepared according to WO 2011/123645 Al, example 10) was dissolved in 1.0 mL n-butanol (> 99.5 %, Merck KGaA) upon heating to a temperature of 40 °C. The hot solution was filtered and allowed to cool to room temperature. Thereafter, 2.6 mL n-heptane (> 99 %, Sigma-Aldrich) were added to the solution, followed by addition of seed crystals of crystalline form 7 of sofosbuvir (7 mg, prepared according to Example 1.1 above). The mixture was stirred (400-500 r.p.m.) at a temperature of 25 °C for 14 h. The obtained slurry was filtered 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 30 to 40 °C for 15 h, yielding crystalline form 6 of sofosbuvir. Comparative Example 2.2: Preparation of a crystalline form of sofosbuvir (dissolving

1.00 g sofosbuvir in 6.0 mL solvent; no PEG added)

A 50 mL reactor equipped with a pitched-blade stirrer and a temperature sensor was charged with 1.00 g of sofosbuvir of crystalline form 1 (prepared according to WO 2011/123645 Al, Example 10) and 6.0 mL of n-butanol (> 99.5 %, Merck KGaA). The solution was heated to a temperature of 40 °C under stirring conditions (300 r.p.m.) to allow solid dissolution, followed by cooling to 25 °C for 10 minutes. 12.0 mL of n-heptane (> 99 %, Sigma-Aldrich) were added. After 5 minutes seed crystals of form 7 of sofosbuvir (50 mg, prepared according to Example 1) were added. The mixture was stirred at 25 °C for 6 hours 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 14 h, yielding crystalline form 6 of sofosbuvir.

Comparative Example 2.3: Preparation of a crystalline form of sofosbuvir (dissolving

45 mg sofosbuvir in ethanol; 15 mg PEG) To sofosbuvir of crystalline form 1 (45 mg, prepared according to WO 2011/123645 Al, example 10) was added a solution containing 330 microL of ethanol (99.9 %, Lichrosolv®, Merck KGaA), 15 mg of PEG 400 and 660 microL of n-heptane (> 99 %, Sigma-Aldrich). A clear solution was obtained and stirred with a magnetic bar (800 r.p.m.) at 20 °C. After 50 minutes crystallization started. After 2 hours, a dense slurry was obtained and a sample was taken and filtered. The solid residue was washed with n-heptane and water, followed by drying under vacuum at a pressure of from 20 to 30 mbar and a temperature of 40 °C for 6 h. XRPD pattern of the product corresponds to crystalline form 6 of sofosbuvir.

Example 3 and Comparative Example 3: Influence of the polyethylene glycol as addi- tive

In the following Table 1 , experimental results are listed which illustrate again the significant influence of the polyethylene glycol as used in the process of the present invention on the solvent mediated transformation of sofosbuvir. In particular, different polyethylene glycols were used (PEG 6000, PEG 4000, and PEG 400). All experiments were carried out according to Example 1.1 hereinabove (in about 50 mg scale in a vial equipped with a magnetic bar), including a weight ratio of sofosbuvir relative to additive of 3 : 1 and a crystallization temperature of 20 °C.

Table 1

Influence of the Polyethylene Glycol and Other Additives

# Starting Material Additive Crystalline Form of Sofosbuvir obtained (Crystalline Form from solvent mediated transformation of Sofosbuvir) after 2 h after 4 h after 6-7 h 1 1 PEG 6000 (solid) 7 7 7

2 1 PEG 4000 (solid) 7 7 7

3 1 PEG 400 (liquid) n.d. 7 7

4 1 1 ,2-propanediol 7 + 6 6 6

5 1 mannitol 6 6 6

6 1 PVP 10 no crystal. no crystal. no crystal.

7 1 PVP 40 no crystal. no crystal. no crystal.

8 1 HPMC E5 no crystal. no crystal. 7 + 6

For all polyethylene glycols, formation of pure crystalline form 7 of sofosbuvir was observed after a crystallization time of 2 hours, 4 hours as well as 6-7 hours. In contrast thereto, the use of a whole variety of other additives, i.e. polyols like polyethylene glycol (in particular 1,2- propanediol, mannitol, and hydroxypropylmethyl cellulose (HPMC E5; commercially available from Dow Chemical Co. under the trade name Methocel® E5) and also other additives (polyvinylpyrrolidone, in particular PVP 10 (average molecular weight 10,000 g/mol) and PVP 40 (average molecular weight 40,000 g/mol); commercially available from Sigma- Aldrich), either resulted in no crystallization at all (#6 and #7 and #8), or in the crystallization of another crystalline form of sofosbuvir (#4 and #5), or in a non-pure crystalline form 7 of sofosbuvir containing other crystalline form(s) (#4 and #8).

Summary of the Examples and Comparative Examples Examples 1.1 to 1.4 show that the process according to the present invention comprising the use of polyethylene glycol, wherein the polyethylene glycols are employed in different amounts relative to the amount of the sofosbuvir starting material, and wherein the sofosbuvir starting material is suspended in mixture of organic solvent, organic anti-solvent, and polyethylene glycol, leads to pure crystalline form 7 of sofosbuvir. Example 1.1 and 1.4 show that the amount of solvent can be varied in case polyethylene glycol is used. In particular Examples 2.1 to 2.12 show that the process according to the present invention comprising the use of polyethylene glycol, wherein the polyethylene glycols are employed in different amounts relative to the amount of the sofosbuvir starting material, and wherein the sofosbuvir starting material is dissolved in organic solvent and polyethylene glycol, and organic anti-solvent is add- ed to the resulting mixture, leads to pure crystalline form 7 of sofosbuvir. In particular Examples 1.4, and e.g. 2.5 and 2.6 show that irrespective whether the sofosbuvir is suspended or dissolved in the organic solvent, also a high sofosbuvir concentration can be used, relative to the organic solvent, which is very advantageous in view of an industrial-scale process. All Examples 1.1 to 1.4 and 2.1 to 2.12 show that the inventive process according to which a pol- yethylene glycol is employed, comparatively high amounts of sofosbuvir can be prepared, with sofosbuvir employed as starting material in an amount of above 0.6 g, in particular above 0.75 g . Example 2.11, for example, shows that the process according to the present invention even in a 5.00 g scale. Comparative Example 1.1 shows that according to a process which is essentially carried out as described in the examples 1.1 to 1.4 described above wherein crystalline form 1 of sofosbuvir is suspended in n-butanol and n-heptane, and wherein the crystallization is carried out under stirring, the absence of polyethylene glycol as additive results in a solvent mediated transformation of crystalline form 1 of sofosbuvir to crystalline form 6 of sofosbuvir. Crystal- line form 7 of sofosbuvir was not obtained. Comparative Examples 2.1 and 2.2 show that according to a process which is essentially carried out as described in the examples 2.1 to 2.12 described above wherein crystalline form 1 of sofosbuvir is dissolved in n-butanol and n- heptane is added as anti-solvent to the resulting solution, and wherein the crystallization is carried out under stirring, the absence of polyethylene glycol as additive results in a solvent mediated transformation of crystalline form 1 of sofosbuvir to crystalline form 6 of sofosbuvir. Crystalline form 7 of sofosbuvir was not obtained. Comparative Example 2.3 shows that according to a process which is essentially carried out as described in the examples 2.1 to 2.12 described above wherein crystalline form 1 of sofosbuvir is dissolved in n-butanol and n- heptane is added as anti-solvent to the resulting solution, and wherein the crystallization is carried out under stirring, the use of ethanol as solvent, instead of n-butanol, results in a solvent mediated transformation of crystalline form 1 of sofosbuvir to crystalline form 6 of sofosbuvir. Crystalline form 7 of sofosbuvir was not obtained.

Example 3 shows that in addition to examples 1 and 2 above, the inventive concept of using a polyethylene glycol as additive in the solvent mediated transformation of sofosbuvir to obtain crystalline form 7 of sofosbuvir is not restricted to (liquid) PEG 400 but also works with (solid) PEG 4000 and PEG 6000. Thus, it is shown that the inventive use of polyethylene glycol is a broad and general concept. Further, Comparative Example 3 shows that the inventive use of polyethylene glycol in a process for preparing crystalline form 7 of sofosbuvir is a decisive factor, in particular in view of an industrially advantageous process which includes stirring during crystallization, due to the fact that when using a variety of other additives, crystallization of another crystalline form of sofosbuvir, crystallization of a non-pure crystalline form 7 of sofosbuvir containing other crystalline form(s), and no crystallization at all were observed. Short Description of the Figures

Fig. 1 shows a representative X-ray powder diffraction (XRPD) pattern of the crystalline form 7 prepared according to the present invention, as determined according to Reference Example 1.1. The x-axis shows the 2-theta angle / °, with tick marks, from left to right, at 10, 20, 30 ° 2-theta. The y-axis shows the intensity / counts, with tick marks, from bottom to top, at 500, 1000.

Fig. 2 shows a representative Fourier transform infrared (FTIR) spectrum of the crystalline form 7 of sofosbuvir prepared according to the present invention, as determined according to Reference Example 1.2. The x-axis shows the wavenumber / cm^"1, with tick marks, from left to right, at 3000, 2000, 1000 cm^"1. The y-axis shows the trans- mittance / %, with tick marks, from bottom to top, at 40, 60, 80, 100.

Fig. 3 shows the unit cell of the crystalline form 7 of sofosbuvir prepared according to the present invention, as determined according to Reference Example 1.6. At the upper left hand corner of the unit cell, the indices "a" (left) and "0" (right), at the upper right hand corner, the index "b", and at the lower left hand corner, the index "c" are shown.

Fig. 4 shows a representative differential scanning calorimetry (DSC) curve of the crystalline form 7 of sofosbuvir prepared according to the present invention, as determined according to Reference Example 1.3. The x-axis shows the temperature / °C, with tick marks, from left to right, at 25, 50, 75,100, 125, 150 °C. The y-axis shows the heat flow (endo up), with tick marks, from bottom to top, at 4, 5, 6, 7, 8, 9, 10.

Fig. 5 shows a representative thermogravimetric analysis (TGA) curve of the crystalline form 7 of sofosbuvir prepared according to the present invention, as determined according to Reference Example 1.4. The x-axis shows the temperature / °C, with tick marks, from left to right, at 15, 25, 35, 45, 55, 65, 75, 85, 95, 105, 115, 125, 135, 145, 155 °C. The y-axis shows the weight/ %, with tick marks, from bottom to top, at 95, 96, 97, 98, 99, 100, 101 weight-%.

Fig. 6 shows a representative gravimetric moisture sorption / desorption isotherm of the crystalline form 7 of sofosbuvir prepared according to the present invention, as determined according to Reference Example 1.5. The x-axis shows the relative humidity (RH) / %, with tick marks at 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 %. The left y-axis shows the net change in mass (dm) / %, with tick marks at 0.0, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 %. The right y-axis shows the mole ratio (water), with tick marks at 0.0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6. shows a representative X-ray powder diffraction (XRPD) pattern of the crystalline form 6 of sofosbuvir, prepared according to Comparative Example 1 , determined according to Reference Example 1.1 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. Cited Prior Art

WO 2010/135569 Al

WO 2011/123645 Al

CN 104130302 A

Claims

(I)

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 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_i2 radiation having a wavelength of 0.15419 nm, or in amorphous form; or as a mixture of these forms.

The process of claim 1 or 2, wherein according to (ii), the at least one organic solvent comprises an aliphatic alcohol, preferably a C₃ alcohol, a C₄ alcohol, a C5 alcohol, or a mixture of two or more thereof, more preferably n-propanol, n-butanol, n-pentanol, or a mixture of two or more thereof, 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, wherein more preferably, the at least one organic solvent comprises, preferably is, n-butanol and the at least one organic anti- solvent comprises, preferably is, n-heptane.

4. The process of any of claims 1 to 3, wherein in the mixture according to (ii), the volume ratio of the at least one organic solvent relative to the at least one anti-solvent is in the range of from 0.1 : 1 to 1.1 : 1, preferably of from 0.1 : 1 to 1 : 1, more preferably of from 0.2: 1 to 0.9: 1, more preferably of from 0.25: 1 to 0.8: 1, more preferably of from 0.3: 1 to

0.7: 1.

5. The process of any of claims 1 to 4, wherein the mixture according to (ii) contains the sofosbuvir according to formula (I), relative to the at least one organic solvent, in an amount in the range of from 100 to 500 mg/mL, preferably of from 110 to 450 mg/mL, more preferably of from 120 to 400 mg/mL, more preferably of from 130 to 380 mg/mL, more preferably of from 135 to 350 mg/mL.

6. The process of any of claims 1 to 5, wherein according to (ii), the at least one polyeth- ylene glycol has an average molecular weight in the range of from 200 to 8000 g/mol, preferably of from 300 to 7000 g/mol, more preferably of from 400 to 6000 g/mol, more preferably of from 400 to 600 g/mol.

7. The process of any of claims 1 to 6, wherein in the mixture according to (ii), the weight ratio of the at least one polyethylene glycol relative to the sofosbuvir according to formula (I) is in the range of from 0.01 : 1 to 1 : 1, preferably of from 0.03: 1 to 0.5: 1, more preferably of from 0.04: 1 to 0.4: 1, more preferably of from 0.05: 1 to 0.3: 1.

8. The process of any of claims 1 to 7, wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture.

9. The process of any of claims 1 to 8, wherein the solvent-mediated transformation conditions according to (iii) comprises a temperature of the mixture in the range of from 10 to 40 °C.

10. The process of any of claims 1 to 9, wherein subjecting the mixture obtained in (ii) to solvent-mediated transformation conditions according to (iii) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture at a temperature of the mixture in the range of from 10 to 40 °C.

11. The process of any of claims 1 to 10, wherein in solvent-mediated transformation according to (iii), the agitating, preferably mechanically agitating, more preferably stirring of the mixture obtained in (ii) is carried out for a period of time in the range of from 0.3 to 8.0 hours, preferably from 0.4 to 7.5 hours, more preferably from 0.5 to 7.0 hours.

12. The process of any of claims 1 to 11, wherein preparing the mixture according to (ii) comprises suspending the sofosbuvir provided in (i) in a mixture of the at least one organic solvent, the at least one organic anti-solvent, and the at least one polyethylene glycol, preferably at a temperature in the range of from 10 to 40 °C, preferably in the range of from 15 to 35 °C.

13. The process of claim 12, wherein subjecting the mixture obtained in (ii) to solvent- mediated transformation conditions according to (iii) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture of (ii) preferably for a period of time in the range of from 0.3 to 8.0 hours, more preferably from 0.4 to 7.5 hours, even more preferably from 0.5 to 7.0 hours.

14. The process any of claims 1 to 11, wherein preparing the mixture according to (ii) comprises

(ii'.l) preparing a solution of the sofosbuvir provided in (i) in the at least one organic solvent containing the at least one polyethylene glycol;

(ii'.2) adding the at least one organic anti-solvent to the solution obtained in (ii'. l), wherein preparing the solution in (ii'. l) preferably comprises mixing the sofosbuvir provided in (i) with the at least one organic solvent and the at least one polyethylene glycol at a temperature of the mixture in the range of from 20 to 70 °C, preferably of from 25 to 60 °C, more preferably of from 30 to 55 °C, more preferably of from 35 to 50 °C, and wherein in (ii'.2), adding the at least one organic anti-solvent to the solution obtained in (ii'.l) is preferably carried out at a temperature of the mixture in the range of from 20 to 70 °C, preferably of from 25 to 60 °C, more preferably in the range of from 30 to 55 °C, more preferably of from 35 to 50 °C.

15. The process of claim 14, wherein subjecting the mixture obtained in (ii) to solvent- mediated transformation conditions according to (iii) comprises

(iii'.l) cooling the mixture obtained from (ii'.2), preferably to a temperature of the mixture in the range of from 15 to 40 °C, more preferably in the range of from 20 to 35 °C.

16. The process of claim 14 or 15, wherein after cooling according to (iii'. l), the process further comprises

(iii'.2) adding seed crystals of sofosbuvir of formula (I)

(I)

radiation having a wavelength of 0.15419 nm, to the mixture, wherein, based on the amount of sofosbuvir contained in the mixture, seed crystals in an amount preferably in the range of from 0.5 to 20 weight-%, more preferably of from 1 to 20 weight-%, more preferably of from 1 to 15 weight-%, more preferably of from 1 to 10 weight- %, more preferably of from 1 to 5 weight-% are added to the mixture.

17. The process of claim 15 or 16, wherein after cooling of (iii'.l), preferably after cooling of (iii'. l) and adding the seed crystals of (iii'.2) the mixture is kept at the temperature in the range of from 15 to 40 °C, preferably of from 20 to 35 °C.

18. The process of claim 17, wherein keeping the mixture at the temperature in the range of from 15 to 40 °C, preferably of from 20 to 35 °C comprises agitating, preferably mechanically agitating, more preferably stirring the mixture.

19. The process of any of claims 15 to 18, further comprising

(iii'.3) cooling the mixture obtained from (iii'.l), preferably from (iii'.2), preferably to a temperature of the mixture in the range of from 0 to 12 °C, preferably of from 2 to 10 °C.

20. The process of claim 19, wherein (iii'.3) further comprises agitating, preferably mechanically agitating, more preferably stirring the mixture obtained from (iii'.l), preferably from (iii'.2).

21. The process of any of claims 15 to 20, wherein the solvent-mediated transformation conditions according to (iii) comprises agitating, preferably mechanically agitating, more preferably stirring the mixture of (ii) preferably for a period of time in the range of from 0.3 to 8.0 hours, more preferably from 0.4 to 7.5 hours, even more preferably from 0.5 to 7.0 hours.

22. The process of any of claims 1 to 21, further comprising

(iv) separating the solid crystalline form of sofosbuvir preferably having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 ° from its mother liquor, preferably comprising

(iv. l) subjecting the mother liquor comprising the solid crystalline form of sofosbuvir to a solid separation process, preferably to filtration;

(iv.2) washing the solid crystalline form of sofosbuvir;

wherein the washing according to (iv.2) is carried out with at least one organic anti-solvent and optionally water, wherein the at least one organic anti-solvent preferably comprises an alkane, more preferably a C₅ alkane, a C₆ alkane, a C₇ alkane, a C8 alkane, or a mixture of two or more thereof, more preferably a C₇ alkane, wherein more preferably the at least one organic anti-solvent comprises, preferably is, n-heptane;

(v) drying the separated solid crystalline form of sofosbuvir preferably having an X- ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °;

wherein the drying according to (v) is preferably carried out at a temperature in the range of from 30 to 50 °C, preferably of from 35 to 45 °C, and at an absolute pressure below 1 bar, preferably in the range of from 5 to 500 mbar, more preferably of from 10 to 100 mbar, more preferably of from 15 to 50 mbar.

23. The process of any of claims 1 to 22, wherein the crystalline form of sofosbuvir of formula (I) having an X-ray powder diffraction pattern comprising no reflection at 2-theta angles in the range of from 2.0 to 7.8 °, comprises 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, and preferably comprises additional 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 Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

24. A solid crystalline form of sofosbuvir of formula (I)

(I),

obtainable or obtained by a process according to any of claims 1 to 23.

Use of a combination of at least one organic solvent, preferably n-butanol, at least one organic anti-solvent, preferably n-heptane, and at least one polyethylene glycol, as medium for solvent mediated transformation of sofosbuvir under agitation, preferably under mechanical agitation, more preferably under stirring, to obtain sofosbuvir of formula

(I)

(I)

The use of claim 25, wherein the solvent-mediated transformation of sofosbuvir comprises a temperature of the combination in the range of from 10 to 40 °C.

The use of claim 25 or 26, wherein the use comprises a process according to any of claims 1 to 23.