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

INTRODUCTION
Aspects of the present application relates to amorphous solid dispersions of Evocalcet with polymer matrix and processes thereof.
Evocalcet is useful for the prevention or treatment of diseases such as hyperparathyroidism. The chemical name of Evocalcet is 2- {4-[(3 S ) -3- {[(1 R ) -1- (Naphthalen-1-yl) ethyl] amino} pyrrolidin-1-yl] phenyl} acetic acid, the structural formula is shown below.

US8362274B2 describes Evocalcet and its pharmaceutical composition.
US9643920B2 describes two crystalline forms of Evocalcet (Form A and Form B) and processes thereof.
However, there remains a need for alternate solid forms of Evocalcet and processes thereof, exhibiting desired properties such as bioavailability and stability.
SUMMARY
Aspects of the present application relates to amorphous solid dispersions of Evocalcet with polymer matrix.
In an aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet and polymer matrix, comprising
(a) providing a solution or suspension of Evocalcet and polymer matrix in a solvent;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with HPMC E5 prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with HPMC AS prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with Eudragit L-100 prepared by the method of Example No 3.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with HPMC E5 prepared by the method of Example No 4.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with HPMC AS prepared by the method of Example No 5.
Figure 6 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with PVP K-30 prepared by the method of Example No 6.
Figure 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with PVP K-30 prepared by the method of Example No 7.
Figure 8 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with Co-povidone prepared by the method of Example No 8.
Figure 9 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with PVP K-30 prepared by the method of Example No 9.
Figure 10 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with Copovidone prepared by the method of Example No 10.

DETAILED DESCRIPTION
Aspects of the present application relates to amorphous solid dispersions of Evocalcet with polymer matrix.
In embodiments, polymer matrix may be selected from the group consisting of hydroxypropyl methylcellulose (HPMC; also referred to as hypromellose) such as HPMC E3; hydroxypropyl methylcellulose acetate succinate (HPMC AS; also referred to as hypromellose acetate succinate) such as L, M, and H grades of HPMC AS; eudragit L-100; hydroxypropyl cellulose (HPC); methylcellulose (MC); hypromellose phthalate (HPMC-P); cellulose acetate phthalate; vinylpyrrolidone-vinyl acetate copolymer (copovidone); polyvinyl pyrrolidone (PVP); polymethacrylate-based copolymers; polyvinylcaprolactam-based copolymers, cyclodextrins, chitosan, polyvinyl alcohol, alginic acid or mixture thereof. Preferably, the polymer chosen to form the polymer matrix is HPMC E3, HPMCAS, Eudragit L-100, PVP K-30, Co-povidone (or) mixture thereof.
In an aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet and polymer matrix, comprising
(a) providing a solution or suspension of Evocalcet and polymer matrix in a solvent;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet.
In embodiments, solvent may be selected from the group consisting of methanol, dichloromethane, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone, water or mixtures thereof. Preferably, the solvent is mixture of methanol and dichloromethane.
In embodiments, a solution of Evocalcet and polymer matrix may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of Evocalcet and polymer matrix may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.
In embodiments, amorphous solid dispersion of Evocalcet with polymer, comprising the ratio of Evocalcet and polymer is 1:1 to 1:20 w/w.
In specific aspect, the present application relates to amorphous solid dispersion of Evocalcet with HPMC E3.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with HPMC E3, comprising
(a) providing a solution or suspension of Evocalcet and HPMC E3 in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with HPMC E3.
In embodiments, a solution of Evocalcet and HPMC E3 may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of Evocalcet and HPMC E3 may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor or spray drying.
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with HPMC E5 prepared by the method of Example No 1 and Example No 4.
In specific aspect, the present application relates to amorphous solid dispersion of Evocalcet with HPMC AS.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with HPMC AS, comprising
(a) providing a solution or suspension of Evocalcet and HPMC AS in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with HPMC AS.
In embodiments, a solution of Evocalcet and HPMC AS may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of Evocalcet and HPMC AS may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor or spray drying.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with HPMC AS prepared by the method of Example No 2 and Example No 5.
In specific aspect, the present application relates to amorphous solid dispersion of Evocalcet and Eudragit L-100.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with Eudragit L-100, comprising
(a) providing a solution or suspension of Evocalcet and Eudragit L-100 in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with Eudragit L-100.
In embodiments, a solution of Evocalcet and Eudragit L-100 may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of Evocalcet and Eudragit L-100 may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with Eudragit L-100 prepared by the method of Example No 3.
In specific aspect, the present application relates to amorphous solid dispersion of Evocalcet and PVP K-30.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30, comprising
(a) providing a solution or suspension of Evocalcet and PVP K-30 in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with PVP K-30.
In embodiments, a solution of Evocalcet and PVP K-30 may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of Evocalcet and PVP K-30 may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor.
Figure 6 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with PVP K-30 prepared by the method of Example No 6.
Figure 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with PVP K-30 prepared by the method of Example No 7.
Figure 9 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with PVP K-30 prepared by the method of Example No 9.
In specific aspect, the present application relates to amorphous solid dispersion of Evocalcet and Co-povidone.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with Co-povidone, comprising
(a) providing a solution or suspension of Evocalcet and Co-povidone in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with Co-povidone.
In embodiments, a solution of Evocalcet and Co-povidone may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of Evocalcet and Co-povidone may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor.
Figure 8 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with Co-povidone prepared by the method of Example No 8.
Figure 10 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Evocalcet with Copovidone prepared by the method of Example No 10.

Stability data:
ASD with Eudragit L-100 ASD with HPMC E5 ASD with HPMC AS ASD with PVP K-30 ASD with Copovidone
Ratio of API: Polymer 1:4 1:4 1:4 1:10 1:10
Initial PXRD Amorphous Amorphous Amorphous Amorphous Amorphous
Stability in 2-8oC (1 Month) Amorphous Amorphous Amorphous Amorphous Amorphous
Stability in 2-8oC (3 Months) Amorphous Amorphous Amorphous Amorphous Amorphous
Stability at 25oC and 60% RH (1 Month) Amorphous Amorphous Amorphous Amorphous Amorphous
Stability at 25oC and 60% RH (3 Months) Amorphous Amorphous Amorphous Amorphous Amorphous
Stability in 40oC and 75% RH (1 Month) Amorphous Amorphous Amorphous Amorphous Amorphous
Stability in 40oC and 75% RH (3 Months) Amorphous Amorphous Amorphous Amorphous Amorphous

Examples
Example-1: Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC E5
Evocalcet (250 mg) and HPMC E5 (1 g) were dissolved in methanol (25 mL) and dichloromethane (25 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was evaporated under reduced pressure at 55°C to obtain amorphous solid dispersion of Evocalcet with HPMC E5.

Example-2: Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC AS
Evocalcet (250 mg) and HPMC AS (1 g) were dissolved in methanol (25 mL) and dichloromethane (25 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was evaporated under reduced pressure at 55°C to obtain amorphous solid dispersion of Evocalcet with HPMC-AS.

Example-3: Process for the preparation of amorphous solid dispersion of Evocalcet with Eudragit L-100
Evocalcet (250 mg) and Eudragit L-100 (1 g) were dissolved in methanol (25 mL) and dichloromethane (25 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was evaporated under reduced pressure at 55°C to obtain amorphous solid dispersion of Evocalcet with Eudragit L-100.

Example-4: Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC E5
Evocalcet (2 g) and HPMC E5 (8 g) were dissolved in methanol (100 mL) and dichloromethane (100 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with HPMC E5.

Example-5: Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC AS
Evocalcet (2 g) and HPMC AS (8 g) were dissolved in methanol (100 mL) and dichloromethane (100 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with HPMC AS.

Example-6: Process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30.
Evocalcet (1 g) and PVP K-30 (20 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with PVP K-30.

Example-7: Process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30.
Evocalcet (1 g) and PVP K-30 (10 g) were dissolved in methanol (100 mL) and dichloromethane (100 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with PVP K-30.

Example-8: Process for the preparation of amorphous solid dispersion of Evocalcet with Co-povidone.
Evocalcet (1 g) and Co-povidone (20 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with Co-povidone.

Example-9: Process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30.
Evocalcet (2 g) and PVP K-30 (10 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with PVP K-30.

Example-10: Process for the preparation of amorphous solid dispersion of Evocalcet with Co-povidone.
Evocalcet (2 g) and Co-povidone (10 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with Co-povidone.

,CLAIMS:We claim:
1. Amorphous solid dispersion of Evocalcet comprising an amorphous Evocalcet and polymer matrix.
2. The amorphous solid dispersion of claim 1, wherein the polymer matrix is selected from of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), eudragit, vinylpyrrolidone-vinyl acetate copolymer (copovidone), polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose (MC), hypromellose phthalate (HPMC-P), cellulose acetate phthalate, polymethacrylate-based copolymers; polyvinylcaprolactam-based copolymers, cyclodextrins, chitosan, polyvinyl alcohol, alginic acid or mixture thereof.
3. The amorphous solid dispersion of claim 1, wherein the polymer selected from HPMC E3, HPMCAS, eudragit L-100, PVP K-30, Co-povidone (or) mixture thereof.
4. A process for the preparation of amorphous solid dispersion of Evocalcet and polymer matrix, comprising
(a) providing a solution or suspension of Evocalcet and polymer matrix in a solvent;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet.
5. The process of claim 4, where in the polymer matrix is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), eudragit, vinylpyrrolidone-vinyl acetate copolymer (copovidone), polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose (MC), hypromellose phthalate (HPMC-P), cellulose acetate phthalate, polymethacrylate-based copolymers; polyvinylcaprolactam-based copolymers, cyclodextrins, chitosan, polyvinyl alcohol, alginic acid or mixture thereof.
6. The process of claim 4, wherein the solvent is selected from methanol, dichloromethane, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, water or mixtures thereof.
7. The process of claim 4, wherein the solvent is selected from methanol, dichloromethane or mixtures thereof.