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

INTRODUCTION
The present application relates to an improved process for the preparation of lurasidone hydrochloride. In particular, the present application relates to a process for the preparation of substantially pure lurasidone hydrochloride starting from lurasidone free base.
Lurasidone is chemically known as ((3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride (hereinafter referred to by the adopted name “Lurasidone hydrochloride”), and has the structural formula as shown in Formula I.

Formula I
Lurasidone is approved for treating Schizophrenia, and is sold under the trademark LATUDA as 40 mg, 80 mg, and 120 mg oral tablets. US Patent No. US5532372 discloses lurasidone and its related compounds. The patent also exemplifies a process for the preparation of lurasidone HCl starting from lurasidone base wherein the free base is chromatographed on silica gel and treated with HCl-2 propanol solution.
The present application provides an improved process for the preparation of lurasidone hydrochloride which is commercially feasible and easily scalable, and provides lurasidone hydrochloride salt in higher yield with higher purity. The process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield.

SUMMARY
In one aspect, the present application relates to an improved process for the preparation of lurasidone hydrochloride. In particular, the present application relates to a process for the preparation of substantially pure lurasidone hydrochloride from lurasidone free base.
In another aspect, the present application provides a pharmaceutical composition comprising lurasidone hydrochloride prepared according to the process of the present invention either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an X-ray powder diffraction pattern of crystalline Lurasidone HCl prepared in Example 1.

DETAILED DESCRIPTION
In one aspect, the present application provides a process for the preparation of substantially pure lurasidone HCl comprising the steps of:
a) Providing a solution of lurasidone in methanol;
b) adjusting the pH of the solution obtained in step a) with methanolic HCl;
c) optionally treating the solution with activated charcoal;
d) recovering the solid.
By “substantially pure lurasidone hydrochloride” it is meant that lurasidone or the hydrochloride salt of lurasidone in accordance with the present invention contains less than about 0.5%, or less than about 0.1% of the corresponding impurities like the process related impurities of lurasidone or the enantiomeric impurities of lurasidone as characterized by a high performance liquid chromatography (“HPLC”) chromatogram obtained from a mixture comprising lurasidone and one or more of the said impurities. The percentage here refers to the area-% of the peaks representing the said impurities.
The solution of lurasidone in step a) may be obtained by dissolving lurasidone in a methanol, or such a solution may be obtained directly from a reaction in which lurasidone is formed in methanol.
When, the solution in step a) is prepared by dissolving lurasidone in methanol, the dissolution temperatures can range from about 20 to 70 ?C depending on the quantity of solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution of lurasidone is provided.
The Solubility of Lurasidone hydrochloride in methanol is higher than the solubility in isopropanol which has been disclosed in the prior art for recrystallization of Lurasidone HCl, hence, a particle free solution of Lurasidone hydrochloride in methanol is easily obtained using methanol as the solvent; making the recrystallization process easier.
The quantity of solvent used for dissolution depends on the dissolution temperature adopted. The concentration of lurasidone in the solution may generally range from about 0.1 to about 1 g/ml in the solvent.
Concentration of hydrochloric acid in methanol used in step b) may range from about 5% to 50%, or about 10% to 20%, (w/v) of methanol. The mole ratio of hydrochloride acid to that of lurasidone free base may range from about 1.0 to about 2.0.
The methanolic hydrochloric acid solution can be added at temperatures as high as about 30 to about 60 ?C, or addition can be done at lower temperatures of the range of 0 to 30 ?C to attain an acidic pH.
The mixture obtained in step b) can be optionally treated with activated charcoal to enhance the color of the compound followed by filtration through a medium such as through a flux calcined diatomaceous earth (Hyflow) bed to remove the carbon.
The carbon treatment can be given either at the temperatures of the preparation of the mixture or after cooling the solution to lower temperatures.
Optionally, the alcoholic solution of lurasidone hydrochloride obtained in step b) or step c) can be distilled to remove the solvent partially before proceeding to the next stage.
Distillation of the solvent may be conducted under a vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20 ?C to about 70 ?C.
The reaction mixture may be maintained further at temperatures lower than the temperatures of hydrochloric acid addition such as for example below about 10 ?C to about 25 ?C, for a period of time for isolation of the product.
Optionally isolation may be enhanced by methods such as cooling, partial removal of the solvent from the mixture, by adding an anti-solvent to the reaction mixture or a combination thereof.
After isolation, the solid material is recovered from the final mixture, with or without cooling below the operating temperature by any of the techniques such as filtration by gravity, or by suction, centrifugation, and the like. If desired the crystals can be washed on the filter with a solvent to wash out the mother liquor.
The wet cake obtained can be optionally further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, and the like. The drying can be carried out at temperatures of about 35 oC to about 70 oC for any desired time period to achieve a desired result, times from about 1 to 20 hours frequently being suitable.
The dried product can optionally be milled to get the required particle size. Milling or micronization can be performed prior to drying, or after the completion of drying of the product.
Lurasidone HCl obtained according to the process of the present invention is characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 1. Crystalline lurasidone HCl obtained is also characterized by an XRPD pattern having significant peaks at about 8.7, 11.3, 13.8, 15.0, 15.3, 16.3, 17.0, 19.4, 20.6, 21.8, and 24.1 ± 0.2 degrees 2?. The pattern is also characterized by additional XRPD peaks at about 25.2 and 28.2, ± 0.2 degrees 2?.
The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D50 and D10 refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining D10, D50, and D90 include laser light diffraction, such as using equipment sold by Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.
Lurasidone hydrochloride obtained according to process of the present invention have a D10 of less than about 20 ?m or less than 15 ?m, D50 of less than about 150 ?m or less than about 100 ?m, and D90 of less than about 400 ?m or less than about 300 ?m. There is no specific lower limit for any of the D values.
Yet another aspect of the application provides a pharmaceutical composition comprising lurasidone HCl obtained using process of the present invention along with one or more pharmaceutically acceptable carriers, excipients or diluents.
The pharmaceutical composition comprising lurasidone HCl and its combination with a pharmaceutically acceptable carrier of this invention may further formulated as solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and 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 by direct blending, dry granulation or wet granulation or by 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 invention may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and 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 and the like.
In the compositions of present invention lurasidone HCl is a useful active ingredient in the range of 10 mg to 150 mg, per dosage unit.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES
EXAMPLE 1
Preparation of Lurasidone hydrochloride
Lurasidone free base (15 g) and methanol (375 ml) were taken into a round bottom flask and heated to reflux. Methanolic hydrochloric acid solution (17.5%, 11.5 ml) was added to the reaction mixture and heated to reflux. The reaction mass was maintained under reflux for about 45 minutes and then treated with carbon at the same temperature. The solvent was distilled off to 5-7 volumes to that of the starting lurasidone free base and cooloed to 25 to 35 °C. The mixture was maitained at the same temerpature for about 8 hours. The isolated solid was filtered and washed with chilled methanol. The compound was dried at about 50 °C to yeild 10 g of the title compound. (90 % yield)

EXAMPLE 2
Preparation of Lurasidone hydrochloride
Lurasidone free base (20 g) and methanol (600 ml) were taken into a round bottom flask and stirred at 25 to 35 °C. Methanolic hydrochloric acid solution (16.0%, 16.2 ml) was added to the reaction mixture at the same temeprature and stirred for about 20 minutes. The reaction mass was then heated to reflux and maintained under reflux for about 30 minutes. The reaction mass was filtered under hot condition and the solvent was distilled off to 5-7 volumes to that of the starting lurasidone free base and cooloed to 25 to 35 °C. The mixture was maitained at the same temerpature for about 8 hours. The isolated solid was filtered and washed with chilled methanol. The compound was dried at about 50 °C to yeild 19.9 g of the title compound. (92.3 % yield).
Purity by HPLC: 99.86%
,CLAIMS:We Claim:
1. A process for the preparation of substantially pure Lurasidone hydrochloride, wherein the process comprises:
a) providing a solution of Lurasidone in methanol;
b) adjusting the pH of solution obtained in step a) with methanolic HCl;
c) optionally, treating the solution with activated charcoal;
d) isolating the solid obtained in step (b) or step (c).

2. The process according to claim 1, wherein the concentration of hydrochloric acid in methanol used in step (b) is about 5% to 50%, or about 10% to 20%, (w/v) of methanol.

3. The process according to claim 1, wherein the mole ratio of hydrochloric acid to that of Lurasidone free base is about 1.0 to about 2.0.

4. Lurasidone hydrochloride obtained according to any one of the preceding claims is in crystalline form.

5. The crystalline form of Lurasidone hydrochloride of claim 4, characterized by XRPD peaks at about 8.7, 11.3, 13.8, 15.0, 15.3, 16.3, 17.0, 19.4, 20.6, 21.8 and 24.1 ± 0.2 degrees 2?.

6. The crystalline form of Lurasidone hydrochloride of claim 5, further characterized by XRPD peaks at about 25.2 and 28.2 ± 0.2 degrees 2?.

7. The process according to claim 1, wherein the substantially pure Lurasidone hydrochloride is having less than about 0.5% (w/w) of the corresponding process related impurities of Lurasidone hydrochloride.

8. The Lurasidone hydrochloride obtained according to any one of the preceding claims, is having a D10 of less than about 20 µm, D50 of less than about 150 µm, and D90 of less than about 400 µm.

9. A pharmaceutical composition comprising Lurasidone Hydrochloride obtained according to any one of the preceding claims and one or more of pharmaceutically acceptable carrier, diluent or excipient.

10. Use of Lurasidone hydrochloride obtained according to any one of the preceding claims for the treatment of schizophrenia.