DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

CRYSTALLINE FORMS OF LEDIPASVIR AND PROCESS FOR THE PREPARATION THEREOF

INTRODUCTION
Aspects of the present application relates to crystalline forms of ledipasvir, process for the preparation thereof and pharmaceutical formulations of crystalline forms of ledipasvir.
Hepatitis C is recognized as a chouronic viral disease of the liver which is characterized by liver disease. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness. Ledipasvir is useful to limit the establishment and progression of infection by HCV as well as in diagnostic assays for HCV.
The compound (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, also known as ledipasvir, The structure of ledipasvir is shown as formula I

Formula I
U.S. Patent No. U.S.8,088,368 discloses ledipasvir or pharmaceutically acceptable salts thereof and pharmaceutical composition thereof. U.S. Patent No. U.S.8,822,430 discloses ledipasvir, its pharmaceutical composition and method of inhibiting HCV in a human comprising administering a ledipasvir. U.S. Patent No. U.S.8,969,588 discloses crystalline forms of ledipasvir. International Publication No. WO2014/120982A1discloses solid dispersion of ledipasvir.
The occurrences of different solid forms are possible for some compounds. A single compound may exist in different solid forms. Various solid forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, solid forms can affect the quality, safety, and efficacy of the drug product, regulatory authorities require that efforts shall be made to identify all solid forms, e.g., crystalline, amorphous, solvated, etc., of drug substances.
There still remains an unmet need for solid state forms of ledipasvir having good physicochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.
SUMMARY OF THE INVENTION
In an aspect, the present application provides different crystalline forms of ledipasvir, process for the preparation thereof and pharmaceutical formulations of crystalline forms of ledipasvir.
In an aspect, the present application provides a crystalline ledipasvir (Form C2a) having XRPD pattern with characteristic peaks at about 3.17, 6.35, 18.16 and 20.63 ±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C2a), comprising the steps of;
a) providing a solution of ledipasvir in a methyl cyclohexane (or) mixture of methyl cyclohexane and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C2a).
In an aspect, the present application provides a crystalline ledipasvir (Form C2) having XRPD pattern with characteristic peaks at about 12.14, 19.13 and 20.68±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C2) comprises the step of desolvating of crystalline ledipasvir form C2a or crystalline ledipasvir Form C8a.
In an aspect, the present application provides a crystalline ledipasvir (Form C4a) having XRPD pattern with characteristic peaks at about 3.26, 6.53, 9.14, 11.22, 12.19 and 15.50±0.2°2?. Crystalline ledipasvir (Form C4a) further characterized by PXRD pattern comprising peaks at about 8.62, 9.77, 19.39 and 25.79±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C4a), comprising the steps of;
a) providing a solution of ledipasvir in a methyl tert-butyl ether (or) mixture of methyl tert-butyl ether and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C4a).
In an aspect, the present application provides a crystalline ledipasvir (Form C4) having XRPD pattern with characteristic peaks at about 7.80, 13.92, 14.79, 18.55, 19.13 and 20.08±0.2°2?. Crystalline ledipasvir (Form C4) further characterized by PXRD pattern comprising peaks at about 12.04, 21.40 and 24.22±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C4) comprises the step of desolvating of ledipasvir form C4a.
In an aspect, the present application provides a crystalline ledipasvir (Form C5a) having XRPD pattern with characteristic peaks at about 8.66, 9.62 and 12.22±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C5a), comprising the steps of;
a) providing a solution of ledipasvir in cyclo methyl pentyl ether (or) mixture of cyclo methyl pentyl ether and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C5a).
In an aspect, the present application provides a crystalline ledipasvir (Form C5) having XRPD pattern with characteristic peaks at about 7.48, 8.98, 14.97, 17.88 and 19.18±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C5) comprises the step of desolvating of ledipasvir form C5a.
In an aspect, the present application provides a crystalline ledipasvir (Form C6a) having XRPD pattern with characteristic peaks at about 3.47, 7.06, 10.71 and 12.22±0.2°2?. Crystalline ledipasvir (Form C6a) further characterized by PXRD pattern comprising peaks at about 17.99, 19.85 and 20.34±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C6a), comprising the steps of;
a) providing a solution of ledipasvir in 1,2 dimethoxy ethane (or) mixture of 1,2 dimethoxy ethane and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C6a).
In an aspect, the present application provides a crystalline ledipasvir (Form C6) having XRPD pattern with characteristic peaks at about 7.63, 12.10 and 19.25±0.2°2?. Crystalline ledipasvir (Form C6) further characterized by PXRD pattern comprising peaks at about 13.90, 14.90 and 22.51±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C6) comprises the step of desolvating of ledipasvir form C6a (or) crystalline ledipasvir (Form C9a).
In an aspect, the present application provides a crystalline ledipasvir (Form C7a) having XRPD pattern with characteristic peaks at about 6.47, 9.71, 12.18 and 18.30±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C7a), comprising the steps of;
a) providing a solution of ledipasvir in toulene (or) mixture of toulene and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C7a).
In an aspect, the present application provides a crystalline ledipasvir (Form C7) having XRPD pattern with characteristic peaks at about 7.61, 11.49, 13.10, 19.07 and 23.25±0.2°2?. Crystalline ledipasvir (Form C7) further characterized by PXRD pattern comprising peaks at about 8.91, 12.11, 17.58, 20.63 and 24.49±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C7) comprises the step of desolvating of ledipasvir form C7a.
In an aspect, the present application provides a crystalline ledipasvir (Form-C8a) characterized by an X-ray powder diffractogram comprising the following peaks: 3.22, 6.45, 8.66, 15.43 and 22.94±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form-C8a) characterized by an X-ray powder diffractogram comprising the following peaks: 3.22, 6.45, 8.66, 15.43 and 22.94±0.2°2? comprising the steps of
a) providing a solution of ledipasvir in mixture of cyclohexane and acetone;
b) isolating the crystalline ledipasvir (Form C8a).
In an aspect, the present application provides a crystalline ledipasvir (Form-C9a) characterized by an X-ray powder diffractogram comprising the following peaks: 3.35, 6.66, 20.48, 22.94 and 24.67±0.2°2?.
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form-C9a) characterized by an X-ray powder diffractogram comprising the following peaks 3.35,6.66,20.48, 22.94 and 24.67±0.2°2? comprising the steps of
a) providing a solution of ledipasvir in mixture of xylene and acetone;
b) isolating the crystalline ledipasvir (Form C9a).
In an aspect, the present invention also provides pharmaceutical formulations comprising crystalline forms of ledipasvir together with one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C2a, obtained according to the procedure of example 1.
Figure 2 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C2, obtained according to the procedure of example 2.
Figure 3 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C4a, obtained according to the procedure of example 4.
Figure 4 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C4, obtained according to the procedure of example 5.
Figure 5 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C5a, obtained according to the procedure of example 6.
Figure 6 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C5, obtained according to the procedure of example 7.
Figure 7 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C6a, obtained according to the procedure of example 8.
Figure 8 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C6, obtained according to the procedure of example 9.
Figure 9 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C7a, obtained according to the procedure of example 10.
Figure 10 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C7, obtained according to the procedure of example 11.
Figure 11 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C2, obtained according to the procedure of example 12.
Figure 12 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C8a, obtained according to the procedure of example 13.
Figure 13 illustrates an X-ray powder diffraction pattern of crystalline ledipasvir Form-C9a, obtained according to the procedure of example 15.
DETAILED DESCRIPTION
In an aspect, the present application provides different crystalline forms of Ledipasvir, process for the preparation thereof and pharmaceutical formulations of crystalline forms of ledipasvir.
In an aspect, the present application provides a crystalline ledipasvir (Form C2a) having XRPD pattern with characteristic peaks at about 3.17, 6.35, 18.16 and 20.63 ±0.2°2?. Crystalline ledipasvir (Form C2a) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 1
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C2a), comprising the steps of;
a) providing a solution of ledipasvir in a methyl cyclohexane (or) mixture of methyl cyclohexane and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C2a).
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step b) involves optionally adding acetone to the solution obtained in step a), or adding the solution obtained in step a) to the acetone, wherein the solution is made in step a) with only methyl cyclohexane . After adding acetone, the reaction mass may be maintained from 15 minutes to 24 hours.
In embodiments of step c), the compound obtained from step b) may be collected using techniques such as direct filtration or by scraping, or by shaking the container, or other techniques specific to the equipment used.
In an aspect, the present application provides a crystalline ledipasvir (Form C2). It has an XRPD pattern with characteristic peaks at about 12.14, 19.13 and 20.68±0.2°2?. Crystalline ledipasvir (Form C2) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 2
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C2) comprises the step of desolvating of crystalline ledipasvir form C2a (or) crystalline ledipasvir (Form C8a).
Crystalline ledipasvir (Form C2) was prepared by desolvating of crystalline ledipasvir form C2a (or) form C8a. Method of desolvation can be done by any of the procedures known in the art which include but not limited to drying. Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 120°C, less than about 80°C, less than about 50°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
In an aspect, the present application provides a crystalline ledipasvir (Form C4a) having XRPD pattern with characteristic peaks at about 3.26, 6.53, 9.14, 11.22, 12.19 and 15.50±0.2°2?. Crystalline ledipasvir (Form C4a) further characterized by PXRD pattern comprising peaks at about 8.62, 9.77, 19.39 and 25.79±0.2°2?. Crystalline ledipasvir (Form C4a) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 3
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C4a), comprising the steps of;
a) providing a solution of ledipasvir in a methyl tert-butyl ether (or) mixture of methyl tert-butyl ether and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C4a).
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step b) involves optionally adding acetone to the solution obtained in step a), or adding the solution obtained in step a) to the acetone, wherein the solution is made in step a) with only methyl tert-butyl ether. After adding acetone, the reaction mass may be maintained from 15 minutes to 24 hours.
In embodiments of step c), the compound obtained from step b) may be collected using techniques such as direct filtration or by scraping, or by shaking the container, or other techniques specific to the equipment used.
In an aspect, the present application provides a crystalline ledipasvir (Form C4) having XRPD pattern with characteristic peaks at about 7.80, 13.92, 14.79, 18.55, 19.13 and 20.08±0.2°2?. Crystalline ledipasvir (Form C4) further characterized by PXRD pattern comprising peaks at about 12.04, 21.40 and 24.22±0.2°2?. Crystalline ledipasvir (Form C4) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 4
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C4) comprises the step of desolvating of ledipasvir form C4a.
Crystalline ledipasvir (Form C4) was prepared by desolvating of ledipasvir form C4a. Method of desolvation can be done by any of the procedures known in the art which include but not limited to drying. Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 120°C, less than about 80°C, less than about 50°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
In an aspect, the present application provides a crystalline ledipasvir (Form C5a) having XRPD pattern with characteristic peaks at about 8.66, 9.62 and 12.22±0.2°2?. Crystalline ledipasvir (Form C5a) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 5
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C5a), comprising the steps of;
c) providing a solution of ledipasvir in cyclo methyl pentyl ether (or) mixture of cyclo methyl pentyl ether and acetone;
d) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C5a).
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step b) involves optionally adding acetone to the solution obtained in step a), or adding the solution obtained in step a) to the acetone, wherein the solution is made in step a) with only cyclo methyl pentyl ether. After adding acetone, the reaction mass may be maintained from 15 minutes to 24 hours.
In embodiments of step c), the compound obtained from step b) may be collected using techniques such as direct filtration or by scraping, or by shaking the container, or other techniques specific to the equipment used.
In an aspect, the present application provides a crystalline ledipasvir (Form C5) having XRPD pattern with characteristic peaks at about 7.48, 8.98, 14.97, 17.88 and 19.18±0.2°2?. Crystalline ledipasvir (Form C5) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 6
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C5) comprises the step of desolvating of ledipasvir form C5a.
Crystalline ledipasvir (Form C5) was prepared by desolvating of ledipasvir form C5a. Method of desolvation can be done by any of the procedures known in the art which include but not limited to drying. Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 120°C, less than about 80°C, less than about 50°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
In an aspect, the present application provides a crystalline ledipasvir (Form C6a) having XRPD pattern with characteristic peaks at about 3.47, 7.06, 10.71 and 12.22±0.2°2?. Crystalline ledipasvir (Form C6a) further characterized by PXRD pattern comprising peaks at about 17.99, 19.85 and 20.34±0.2°2?. Crystalline ledipasvir (Form C6a) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 7
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C6a), comprising the steps of;
a) providing a solution of ledipasvir in 1,2 dimethoxy ethane (or) mixture of 1,2 dimethoxy ethane and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C6a).
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step b) involves optionally adding acetone to the solution obtained in step a), or adding the solution obtained in step a) to the acetone, wherein the solution is made in step a) with only 1,2 dimethoxy ethane. After adding acetone, the reaction mass may be maintained from 15 minutes to 24 hours.
In embodiments of step c), the compound obtained from step b) may be collected using techniques such as direct filtration or by scraping, or by shaking the container, or other techniques specific to the equipment used.
In an aspect, the present application provides a crystalline ledipasvir (Form C6) having XRPD pattern with characteristic peaks at about 7.63, 12.10 and 19.25±0.2°2?. Crystalline ledipasvir (Form C6) further characterized by PXRD pattern comprising peaks at about 13.90, 14.90 and 22.51±0.2°2?. Crystalline ledipasvir (Form C6) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 8
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C6) comprises the step of desolvating of ledipasvir form C6a (or) ledipasvir (Form C9a).
Crystalline ledipasvir (Form C6) was prepared by desolvating of ledipasvir form C6a form C9a. Method of desolvation can be done by any of the procedures known in the art which include but not limited to drying. Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 120°C, less than about 80°C, less than about 50°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
In an aspect, the present application provides a crystalline ledipasvir (Form C7a) having XRPD pattern with characteristic peaks at about 6.47, 9.71, 12.18 and 18.30±0.2°2?. Crystalline ledipasvir (Form C7a) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 9
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C7a), comprising the steps of;
a) providing a solution of ledipasvir in toluene (or) mixture of toulene and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C7a).
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step b) involves optionally adding acetone to the solution obtained in step a), or adding the solution obtained in step a) to the acetone, wherein the solution is made in step a) with only toulene. After adding acetone, the reaction mass may be maintained from 15 minutes to 24 hours.
In embodiments of step c), the compound obtained from step b) may be collected using techniques such as direct filtration or by scraping, or by shaking the container, or other techniques specific to the equipment used.
In an aspect, the present application provides a crystalline ledipasvir (Form C7) having XRPD pattern with characteristic peaks at about 7.61, 11.49, 13.10, 19.07 and 23.25±0.2°2?. Crystalline ledipasvir (Form C7) further characterized by PXRD pattern comprising peaks at about 8.91, 12.11, 17.58, 20.63 and 24.49±0.2°2?. Crystalline ledipasvir (Form C7) is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 10
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form C7) comprises the step of desolvating of ledipasvir form C7a.
Crystalline ledipasvir (Form C7) was prepared by desolvating of ledipasvir form C7a. Method of desolvation can be done by any of the procedures known in the art which include but not limited to drying. Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 120°C, less than about 80°C, less than about 50°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
In an aspect, the present application provides a crystalline ledipasvir (Form-C8a) characterized by an X-ray powder diffractogram comprising the following peaks: 3.22, 6.45, 8.66, 15.43 and 22.94±0.2°2?. Form-C8a of ledipasvir is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 12
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form-C8a) characterized by an X-ray powder diffractogram comprising the following peaks: 3.22, 6.45, 8.66, 15.43 and 22.94±0.2°2? comprising the steps of
a) providing a solution of ledipasvir in mixture of cyclohexane and acetone;
b) isolating the crystalline ledipasvir (Form C8a).
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step b), the compound obtained from step a) may be collected using techniques such as direct filtration or by scraping, or by shaking the container, or other techniques specific to the equipment used.
In an aspect, the present application provides a crystalline ledipasvir (Form-C9a) characterized by an X-ray powder diffractogram comprising the following peaks: 3.35, 6.66, 20.48, 22.94 and 24.67±0.2°2?. Form-C9a of ledipasvir is also characterized by its full X-ray powder diffractogram as substantially shown in FIG. 13
In an aspect, the present application provides a process for the preparation of crystalline ledipasvir (Form-C9a) characterized by an X-ray powder diffractogram comprising the following peaks3.35,6.66,20.48, 22.94 and 24.67±0.2°2? comprising the steps of
a) providing a solution of ledipasvir in mixture of xylene and acetone;
b) isolating the crystalline ledipasvir (Form C9a).
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step b), the compound obtained from step a) may be collected using techniques such as direct filtration or by scraping, or by shaking the container, or other techniques specific to the equipment used.
The obtained crystalline forms of ledipasvir may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills. etc., to produce a desired particle size distribution. Crystalline forms of ledipasvir obtained according to certain processes of the present application has a particle size distribution wherein: d(0.5) is less than about 100 µm, or less than about 25 µm, or less than about 10 µm; and d(0.9) is less than about 200 µm, or less than about 50 µm, or less than about 30 µm. Particle size distributions can be determined using any means, including laser light diffraction equipment sold by Malvern Instruments limited, Malvern, Worcestershire, United Kingdom, Coulter counters, microscopic procedures, etc. The term d(x) means that a particular fraction has particles with a maximum size being the value given; 0.5 represents 50% of the particles and 0.9 represents 90% of the particles.
Any crystalline forms (or) amorphous form of ledipasvir used as the input material for the processes of the present invention.
In an aspect, the present invention also provides pharmaceutical formulations comprising crystalline forms of ledipasvir together with one or more pharmaceutically acceptable excipients. Crystalline forms of ledipasvir together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, or capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, or emulsions; or injectable preparations such as, but not limited to, solutions, dispersions, or freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, or modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
Different solid forms are characterized by scattering techniques, e.g., x-ray powder diffraction pattern, by spectroscopic methods, e.g., infra-red, 13C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:911-929. Crystalline forms of ledipasvir can be further processed to modulate particle size. For example, crystalline forms of ledipasvir can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation or formulation.
In an aspect of the application, crystalline forms of ledipasvir prepared according to the processes of the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chouromatography (HPLC).
Crystalline forms of ledipasvir described herein are solvated or partially solvated or desolvated.
DEFINITIONS
The term “solvate” refers to a complex formed by the combining of ledipasvir and a solvent.
The term “desolvated” refers to a ledipasvir form that is a solvate as described herein, and from which solvent molecules have been partially or completely removed. Desolvation techniques to produce desolvated forms include, without limitation, exposure of a ledipasvir form (solvate) to a vacuum, subjecting the solvate to elevated temperature, exposing the solvate to a stream of gas, such as air or nitrogen, or any combination thereof. Thus, a desolvated ledipasvir form can be anhydrous, i.e., completely without solvent molecules, or partially solvated wherein solvent molecules are present in stoichiometric or non-stoichiometric amounts.
The term "about" when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1 .
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.

EXAMPLES
EXAMPLE 1: Preparation of Ledipasvir Form-C2a.
Ledipasvir (1 g) and methyl cyclohexane (50 mL) were charged into an easymax reactor at 25°C. The reaction mass was stirred for 15hours at 25°C. Acetone (5 mL) was added to the above obtained reaction mass and stirred for 7 hours at 25°C. The resulting slurry was filtered to produce Ledipasvir form-C2a.
EXAMPLE 2: Preparation of Ledipasvir Form-C2.
Ledipasvir Form-C2a (the preparation of ledipasvir form-C2a as described above in Example 1) was dried at 50ºC for 40 minutes that resulted in the discovery of Ledipasvir form-C2.
EXAMPLE 3: Preparation of crystalline Ledipasvir Form-C2a.
Ledipasvir (2 g), methyl cyclohexane (50 mL), acetone (10 mL) were charged into an easymax reactor at 25°C. The reaction mass was stirred for 7hours at 25°C. The resulting slurry was filtered to produce Ledipasvir form-C2a.
EXAMPLE 4: Preparation of Ledipasvir Form-C4a.
Ledipasvir (1 g), methyl tert-butyl ether (25 mL), acetone (5 mL) were charged into an easymax reactor at 25°C. The reaction mass was stirred for 8hours at 25°C. The resulting slurry was filtered to produce Ledipasvir form-C4a.
EXAMPLE 5: Preparation of Ledipasvir Form-C4.
Ledipasvir Form-C4a (the preparation of Ledipasvir form-C4a as described above in Example 4) was dried at 100ºC for 1hour, that resulted in the discovery of Ledipasvir form-C4.
EXAMPLE 6: Preparation of Ledipasvir Form-C5a.
Ledipasvir (1 g), cyclo methyl pentyl ether (10 mL), acetone (20 mL) were charged into an easymax reactor at 25°C. The reaction mass was stirred for 12hours at 25°C. The resulting slurry was filtered to produce Ledipasvir form-C5a.
EXAMPLE 7: Preparation of Ledipasvir Form-C5.
Ledipasvir Form-C5a (the preparation of Ledipasvir form-C5a as described above in Example 6) was dried at 100ºC for 2hours, that resulted in the discovery of Ledipasvir form-C5.
EXAMPLE 8: Preparation of Ledipasvir Form-C6a.
Ledipasvir (1 g), 1,2 dimethoxy ethane (10 mL), acetone (20 mL) were charged into an easymax reactor at 25°C. The reaction mass was stirred for 12hours at 25°C. The resulting slurry was filtered to produce Ledipasvir form-C6a.
EXAMPLE 9: Preparation of Ledipasvir Form-C6.
Ledipasvir Form-C6a (the preparation of Ledipasvir form-C6a as described above in Example 8) was dried at 100ºC for 2hours that resulted in the discovery of Ledipasvir form-C6.
EXAMPLE 10: Preparation of Ledipasvir Form-C7a.
Ledipasvir (0.5 g), toulene (5 mL), acetone (10 mL) were charged into an easymax reactor at 25°C. The reaction mass was stirred for 8hours at 25°C. The resulting slurry was filtered to produce Ledipasvir form-C7a.
EXAMPLE 11: Preparation of Ledipasvir Form-C7.
Ledipasvir Form-C7a (the preparation of Ledipasvir form-C7a as described above in Example 10) was dried at 100ºC for 3hours that resulted in the discovery of Ledipasvir form-C7.
EXAMPLE 12: Preparation of crystalline Ledipasvir Form-C2.
Ledipasvir Form-C2a (the preparation of Ledipasvir form-C2a as described above in Example 3) was kept at 25ºC for 2 days and dried at 100ºC for 5hours that resulted in the discovery of Ledipasvir form-C2.
EXAMPLE 13: Preparation of Ledipasvir Form-8a.
Ledipasvir (0.5 g), cyclohexane (10 mL) and acetone (20 mL) were charged into an easymax reactor at 25°C. The reaction mass was stirred for 24hours at 25°C. The resulting slurry was filtered to produce Ledipasvir form-8a.
EXAMPLE14: Preparation of Ledipasvir Form-C2.
Ledipasvir Form-8a (the preparation of ledipasvir form-8a as described above in Example 13) was dried at 100ºC for 60 minutes that resulted in the discovery of Ledipasvir form-C2.
EXAMPLE 15: Preparation of Ledipasvir Form-9a.
Ledipasvir (0.5 g), xylene (10 mL) and acetone (20 mL) were charged into an easymax reactor at 25°C. The reaction mass was stirred for 24hours at 25°C. The resulting slurry was filtered to produce Ledipasvir form-9a.
EXAMPLE16: Preparation of Ledipasvir Form-C6.
Ledipasvir Form-9a (the preparation of ledipasvir form-9a as described above in Example 15) was dried at 100ºC for 60 minutes that resulted in the discovery of Ledipasvir form-C2.
,CLAIMS:We Claim:
1. Crystalline ledipasvir (Form-C2a) characterized by an X-ray powder diffractogram comprising the peaks at 3.17, 6.35, 18.16 and 20.63 ±0.2°2?.
2. A process for the preparation of crystalline ledipasvir (Form-C2a) characterized by an X-ray powder diffractogram with the peaks at 3.17, 6.35, 18.16 and 20.63 ±0.2°2? comprising the steps of
a) providing a solution of ledipasvir in a methyl cyclohexane (or) mixture of methyl cyclohexane and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form-C2a).
3. Crystalline ledipasvir (Form-C2) characterized by an X-ray powder diffractogram comprising the peaks at 12.14, 19.13 and 20.68±0.2°2?.
4. A process for the preparation of crystalline ledipasvir (Form-C2) characterized by an X-ray powder diffractogram with the peaks at 12.14, 19.13 and 20.68±0.2°2? comprises the step of desolvating the crystalline ledipasvir Form C2a (or) crystalline ledipasvir Form C8a.
5. Crystalline ledipasvir (Form-C6a) characterized by an X-ray powder diffractogram comprising the peaks at 3.47, 7.06, 10.71 and 12.22±0.2°2?.
6. A process for the preparation of form crystalline ledipasvir (Form-C6a) characterized by an X-ray powder diffractogram with the peaks at 3.47, 7.06, 10.71 and 12.22±0.2°2? comprising the steps of;
a) providing a solution of ledipasvir in 1,2 dimethoxy ethane (or) mixture of 1,2 dimethoxy ethane and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C6a).
7. Crystalline ledipasvir (Form-C6) characterized by an X-ray powder diffractogram comprising the peaks at 7.63, 12.10 and 19.25±0.2°2?.
8. A process for the preparation of crystalline ledipasvir (Form-C6) characterized by an X-ray powder diffractogram with the peaks at 7.63, 12.10 and 19.25±0.2°2? comprises the step of desolvating the crystalline ledipasvir Form C6a (or) crystalline ledipasvir Form C9a.
9. Crystalline ledipasvir (Form-C7a) characterized by an X-ray powder diffractogram comprising the peaks at 6.47, 9.71, 12.18 and 18.30±0.2°2?.
10. A process for the preparation of crystalline ledipasvir (Form-C7a) characterized by an X-ray powder diffractogram with the peaks at 6.47, 9.71, 12.18 and 18.30±0.2°2? comprising the steps of
a) providing a solution of ledipasvir in toulene (or) mixture of toulene and acetone;
b) optionally adding acetone to the solution obtained in step a);
c) isolating the crystalline ledipasvir (Form C7a).
11. Crystalline ledipasvir (Form-C7) characterized by an X-ray powder diffractogram comprising the peaks at 7.61, 11.49, 13.10, 19.07 and 23.25±0.2°2?.
12. A process for the preparation of crystalline ledipasvir (Form-C7) characterized by an X-ray powder diffractogram with the peaks at 7.61, 11.49, 13.10, 19.07 and 23.25±0.2°2? comprises the step of desolvating the crystalline ledipasvir (Form C7a).