DESC:Field of the invention

The present invention relates to substantially pure amorphous forms of Simeprevir sodium and the process for preparation thereof.

Background of the invention

Hepatitis C virus (HCV) is the major etiological agent of 90% of all cases of non-A, non-B hepatitis. The incidence of HCV infection is becoming an increasingly severe public health concern with 2-15% individuals infected worldwide. While primary infection with HCV is often asymptomatic, most HCV infections progress to a chronic state that can persist for decades. Of those with chronic HCV infections, it is believed that about 20-50% will eventually develop chronic liver disease (e.g. cirrhosis) and 20-30% of these cases will lead to liver failure or liver cancer. As the current HCV-infected population ages, the morbidity and mortality associated with HCV are expected to triple.
The use of protease inhibitors, particularly those selectively targeting HCV serine protease, has great potential to be useful in treating HCV infections in patients by inhibiting HCV replication.

Simeprevir (TMC-435) is a new protease inhibitor jointly developed by Janssen and Medivir, therapeutic gene-1 chronic hepatitis C patients with compensated liver diseases. Simeprevir is considered so by blocking HCV protease survive and replicate within host cells to produce effects.

Simeprevir sodium (trade name Olysio) was approved by the USFDA, for treatment in combination therapy with pegylated interferon and ribavirin for chronic hepatitis C genotype -1 virus (HCV) infection. Simeprevir is represented by the following formula (I);

(I)
US20110306634 describes an amorphous form of Simeprevir sodium salt. This application also described the preparation of amorphous Simeprevir sodium salt by spray-drying.
The spray-drying process is difficult to carry out on large scale and also is a time consuming process.

Polymorphism is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties.

Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same molecular structure. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.

Hence there is a need to develop polymorphic forms of Simeprevir sodium and also an industrially feasible process for preparation of amorphous Simeprevir sodium salt.

Description of drawing:

Figure 1: illustrates X-ray powder diffraction pattern of substantially pure amorphous Simeprevir sodium designated as L1.
Figure 2: illustrates Differential Scanning Calorimetry (DSC) of L1.
Figure 3: illustrates X-ray powder diffraction pattern of substantially pure amorphous Simeprevir sodium designated as L2.
Figure 4: illustrates Differential Scanning Calorimetry (DSC) of L2.

Summary of the invention:

In accordance with one embodiment, the present invention provides substantially pure amorphous forms of Simeprevir sodium designated as L1.

In accordance with another embodiment, the present invention provides substantially pure amorphous forms of Simeprevir sodium designated as L2.

In accordance with another embodiment, the present invention provides the process for preparation of substantially pure amorphous forms of simeprevir sodium salt.

In accordance with another embodiment, the present invention provides for pharmaceutical compositions comprising said substantially amorphous forms of Simeprevir sodium.

Detailed description:

The term "substantially pure amorphous" as used herein is intended to mean that amorphous Simeprevir sodium with certain degree of crystallinity.

In one embodiment, the present invention provides Simeprevir sodium in a substantially pure amorphous form designated as L1, characterized by X-ray powder diffraction pattern as depicted in Fig. 1. The PXRD pattern of substantially pure amorphous Simeprevir sodium comprises of crystalline peaks at 8.05o ± 0. 20 2? and 17.96o ± 0.20 2?.

Further characterizing data for substantially pure amorphous Simeprevir sodium form L1 according to the present invention as obtained by differential scanning calorimetry (DSC) is shown in FIG. 2.

In another embodiment, the present invention provides Simeprevir sodium salt in a substantially pure amorphous form designated as L2, characterized by X-ray powder diffraction pattern as depicted in Fig. 3. The PXRD pattern of substantially pure amorphous Simeprevir sodium comprises of crystalline peaks at 8.78o ± 0. 20 2?, 11.36 o ± 0.20 2? and 29.69o ± 0.20 2?.

Further characterizing data for substantially pure amorphous Simeprevir sodium form L2 according to the present invention as obtained by differential scanning calorimetry (DSC) is shown in FIG. 4.

In another embodiment the present invention provides process for preparing substantially pure amorphous Simeprevir sodium comprising:

(i) reacting Simeprevir free base with sodium ethyl hexanoate in an organic solvent;
(ii) adding anti-solvent to the mixture of step (i); and
(iii) isolating substantially pure amorphous Simeprevir sodium salt from reaction mixture thereof.

The organic solvent used in step (i) is selected from but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane and/or mixtures thereof.

The reaction of step (i) is carried out at a temperature of 0oC to reflux temperature of the solvent.

The anti-solvent used in step (ii) is selected from but not limited to n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, and/or water and mixtures thereof.

The isolation of the substantially pure amorphous Simeprevir sodium salt is carried out by conventional techniques known in the prior art such as filtration, concentration, evaporation etc.; and drying the product include all techniques known to those skilled in the art, such as heating, applying vacuum, circulating air or gas, adding a desiccant, evaporation, or the like, or any combination thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising substantially pure amorphous form L1 and form L2 of Simeprevir sodium with pharmaceutically acceptable excipients. Substantially pure amorphous form L1 and form L2 of Simeprevir sodium can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

Pharmaceutically acceptable excipients may be utilized as required for conversion of the substantially amorphous form of Simeprevir sodium salt into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations.

Examples:

The following examples describe the present invention in detail, but are not to be construed to be in any way limiting for the present invention.

Example 1:
Process for Preparation of substantially pure amorphous form L1 of Simeprevir sodium

To the slurry of Simeprevir freebase (0.5 g, 0.66 mmol) in Tetrahydrofuran (2.5 ml) was added a solution of sodium-2-ethyl hexanoate (0.166 g, 0.99 mmol) in Tetrahydrofuran (2.0 ml). Reaction mass was stirred for 45 mins followed by addition of n-Heptane (25 ml). Stirring was continued for additional 60 mins. The product was obtained by filtration and washing with n-Heptane (2.0 ml). The product was dried under vacuum to yield (0.38 g) Simeprevir Sodium.

Example 2:

To the slurry of Simeprevir (0.5 g, 0.66 mmol) in Acetone (5.0 ml), added a solution of sodium-2-ethyl hexanoate (0.166 g, 0.99 mmol) in Acetone (2.0 ml). Reaction mass was stirred for 20 mins followed by addition of n-Heptane (16 ml). Reaction mass was heated and stirred at 55°C for 60 mins. Reaction mass was then cooled to room temperature and stirred for 180 mins. The product is obtained by filtration and washing with n-Heptane (1.0 ml). The product was dried under vacuum to yield (0.32 g) Simeprevir Sodium.

Example 3:
Process for Preparation of substantially pure amorphous form L2 of Simeprevir sodium

To the slurry of Simeprevir freebase (35 g, 0.0466 mmol) in Tetrahydrofuran (140ml) was added a solution of sodium-2-ethyl hexanoate (11.6 g, 0.0699 mmol) in Tetrahydrofuran (105 ml). Reaction mass was stirred for 45 mins followed by addition of n-Heptane (1750 ml). Stirring was continued for additional 60 mins. The product was obtained by filtration and washing with n-Heptane (175 ml). The product was dried under vacuum to yield (35.8 g) Simeprevir Sodium.
,CLAIMS:1. Substantially pure amorphous Simeprevir sodium salt designated as L1.
2. The substantially pure amorphous Simeprevir sodium salt L1 according to the claim 1 is characterized by X-Ray diffraction pattern comprising crystalline peaks at 8.05o ± 0. 20 2? and 17.96o ± 0.20 2?.
3. The substantially pure amorphous Simeprevir sodium salt L1 of claim 1, characterized as having X-ray powder diffraction pattern substantially the same as that shown in FIG. 1.
4. The substantially pure amorphous Simeprevir sodium salt according to claim 1 having Differential Scanning Calorimetry (DSC) curve as shown in Fig 2.
5. Substantially pure amorphous Simeprevir sodium salt designated as L2.
6. Substantially pure amorphous Simeprevir sodium salt L2 according to claim 5 is characterized by X-Ray diffraction pattern comprising crystalline peaks at 8.78o ± 0. 20 2?, 11.36 o ± 0.20 2? and 29.69o ± 0.20 2?.
7. The substantially pure amorphous Simeprevir sodium salt L2 of claim 5, characterized as having X-ray powder diffraction pattern substantially the same as that shown in FIG. 3.
8. Substantially pure amorphous Simeprevir sodium salt according to claim 5 having Differential Scanning Calorimetry (DSC) curve as shown in Fig 4.
9. A process for the preparation of substantially pure amorphous Simeprevir sodium salt L1 and L2 comprising:
(i) reacting Simeprevir free base with sodium ethyl hexanoate in an organic solvent;
(ii) adding anti-solvent to the mixture of step (i); and
(iii) isolating amorphous Simeprevir sodium salt from reaction mass thereof.
10. The improved process according to claim 9, wherein the organic solvent used in step (i) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane and/or mixtures thereof.
11. The improved process according to claim 9, wherein the anti-solvent used in step (ii) is selected from n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, and/or water and mixtures thereof.
12. A pharmaceutical composition comprising substantially pure amorphous form L1 or form L2 of Simeprevir sodium and a pharmaceutically acceptable carrier, excipients or diluent.
13. The pharmaceutical composition of claim 12 wherein said pharmaceutical composition is suitable for oral administration to patient.