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

AMORPHOUS FORM OF ROCILETINIB HYDROBROMIDE AND ITS SOLID DISPERSION

FIELD OF THE INVENTION
The present application relates to amorphous form of Rociletinib hydrobromide and its solid dispersion and processes for preparation thereof.

BACKGROUND OF THE INVENTION
The compound, N-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide, known as Rociletinib, having the following structure:

Rociletinib is a novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of the cancer-causing mutant forms of epidermal growth factor receptor (EGFR) currently under review with the U.S. and E.U. regulatory authorities for the treatment of advanced non-small cell lung cancer (NSCLC) in patients with activating EGFR mutations, as well as the dominant resistance mutation T790M. Rociletinib is designed to selectively target both the initial activating EGFR mutations and the dominant acquired T790M resistance mutation.
Heterocyclic pyrimidine compounds, such as Rociletinib, administration of the compounds and pharmaceutical compositions containing them are described in WO2012061299A1.
WO2013138502A1 describes various salts of Rociletinib such as benzenesulfonic acid, camphorsulfonic acid, 1,2-ehanedisulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, 1,5-naphthalenedisulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6-trihydroxybenzoic acid. The WO2013138502A1 also describes various polymorphic forms of Rociletinib hydrobromide and Rociletinib benzenesulphonate salts.
There remains a need to provide stable, commercially viable and advantageous amorphous form of Rociletinib hydrobromide (Rociletinib HBr).
SUMMARY
In the first embodiment, the present application provides amorphous form of Rociletinib HBr.
In the second embodiment, the present application provides amorphous form of Rociletinib HBr characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figure 1.
In the third embodiment, the present application provides a process for preparing amorphous form of Rociletinib HBr which comprises;
a) providing a solution of Rociletinib HBr in a solvent or a mixture of two or more solvents;
b) removing solvent from the solution of Rociletinib HBr obtained in step a); and
c) recovering amorphous form of Rociletinib HBr, and
d) optionally, combining the amorphous Rociletinib HBr with an absorbent.
In the fourth embodiment, the present application provides a solid dispersion comprising an amorphous form of Rociletinib HBr and one or more pharmaceutically acceptable carriers.
In the fifth embodiment, the present application provides a solid dispersion comprising an amorphous form of Rociletinib HBr and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figures 2 to Figure 9.
In the sixth embodiment, the present application provides a process for preparing a solid dispersion comprising Rociletinib HBr and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution comprising Rociletinib HBr and one or more pharmaceutically acceptable carriers,
b) removing solvent from a solution obtained in step (a),
c) recovering a solid dispersion comprising an amorphous form of Rociletinib HBr and one or more pharmaceutically acceptable carriers, and
d) optionally, combining the amorphous solid dispersion of Rociletinib HBr with an absorbent, if the pharmaceutically acceptable carrier of step (a) is not an absorbent.
In the seventh embodiment, the present application provides pharmaceutical formulations comprising amorphous Rociletinib HBr or amorphous solid dispersions of Rociletinib HBr together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction ("PXRD") pattern of an amorphous form of Rociletinib HBr prepared according to Example 1.
Figure 2 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of Rociletinib HBr and Syloid (1:1 w/w) prepared according to Example 1.
Figure 3 is powder X-ray power diffraction ("PXRD") pattern of amorphous solid dispersion comprising Rociletinib HBr and PVP K-30 (1:1 w/w) prepared according to Example 3.
Figure 4 is powder X-ray power diffraction ("PXRD") pattern of amorphous solid dispersion comprising Rociletinib HBr, PVP K-30 and Syloid NF (1:1:1 w/w/w) prepared according to Example 3.
Figure 5 is powder X-ray power diffraction ("PXRD") pattern of amorphous solid dispersion comprising Rociletinib HBr and Eudragit (1:1 w/w) prepared according to Example 4.
Figure 6 is powder X-ray power diffraction ("PXRD") pattern of amorphous solid dispersion comprising Rociletinib HBr and Hydroxy Propyl Cellulose (1:1 w/w) prepared according to Example 5.
Figure 7 is powder X-ray power diffraction ("PXRD") pattern of amorphous solid dispersion comprising Rociletinib HBr and Methyl Cellulose (1:1 w/w) prepared according to Example 6.
Figure 8 is powder X-ray power diffraction ("PXRD") pattern of amorphous solid dispersion comprising Rociletinib HBr and Copovidone (1:1 w/w) prepared according to Example 7.
Figure 9 is powder X-ray power diffraction ("PXRD") pattern of amorphous solid dispersion comprising Rociletinib HBr, Copovidone and Microcrystalline Cellulose (1:1:1 w/w/w) prepared according to Example 7.

DETAILED DESCRIPTION
Rociletinib HBr used as the input in the process for preparation of amorphous form of the present application can be prepared by any process known in the art.
In the first embodiment, the present application provides amorphous form of Rociletinib HBr.
In the second embodiment, the present application provides amorphous form of Rociletinib HBr characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figure 1.
In the third embodiment, the present application provides a process for preparing amorphous form of Rociletinib HBr which comprises;
a) providing a solution of Rociletinib HBr in a solvent or a mixture solvents;
b) removing solvent from a solution of Rociletinib HBr obtained in step a);
c) recovering amorphous form of Rociletinib HBr; and
d) optionally, combining the amorphous Rociletinib HBr with an absorbent.
Providing a solution of Rociletinib HBr in step a) includes direct use of a reaction mixture containing Rociletinib HBr that is obtained in the course of its synthesis; or dissolving Rociletinib HBr in a solvent.
Any physical form of Rociletinib HBr may be utilized for providing the solution of Rociletinib HBr in step a).
Suitable solvents which can be used for dissolving Rociletinib HBr include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like; and any mixtures of two or more thereof.
After dissolution in step (a), the obtained solution may optionally be filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves removing solvent from the solution of Rociletinib HBr.
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, Rotary vacuum paddle dryer, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art. The drying may be carried at normal pressure or under reduced pressure.
Step (c) involves recovering an amorphous form of Rociletinib HBr. The said recovery can be done by using the processes known in the art.
In an embodiment, the isolation of amorphous form of Rociletinib HBr may be carried out by employing any of the techniques known to a person skilled in art. Techniques for the isolation of amorphous form of Rociletinib HBr include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
The resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Rociletinib HBr is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
Step (d) of the process involves optionally combining the amorphous Rociletinib HBr with an absorbent such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like.
In a preferred embodiment, the present application provides the solvent used in step (a) of the process for preparation of amorphous Rociletinib HBr is methanol.
In the fourth embodiment, the present application provides an amorphous solid dispersion comprising Rociletinib HBr and one or more pharmaceutically acceptable carriers.
Solid dispersion as used herein refers to the dispersion of one or more active ingredients in an inert excipient or matrix (carrier), where the active ingredients could exist in amorphous state (Sareen et al., 2012 and Kapoor et al., 2012). Solid dispersion consists of two or more than two components, generally a carrier polymer and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it required very less external energy to dissolve.
In the fifth embodiment, the present application provides a solid dispersion comprising Rociletinib HBr and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figure 2 to 9.
In the sixth embodiment, the present application provides a process for preparing a solid dispersion comprising an amorphous form of Rociletinib HBr and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution of Rociletinib HBr and pharmaceutically acceptable carrier in a solution,
b) removing solvent from a solution obtained in step (a);
c) recovering a solid dispersion comprising an amorphous form of Rociletinib HBr and one or more pharmaceutically acceptable carrier; and
d) optionally, combining the amorphous solid dispersion Rociletinib HBr with an absorbent, if the pharmaceutically acceptable carrier of step (a) is not an absorbent.
Providing a solution in step a) includes: direct use of a reaction mixture containing Rociletinib HBr that is obtained in the course of its synthesis; or dissolving Rociletinib HBr and pharmaceutically acceptable carrier in a solvent.
Any physical form of Rociletinib HBr may be utilized for providing the solution of Rociletinib HBr in step (a).
Suitable pharmaceutically acceptable carriers which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, 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 and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, 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.
Suitable solvents which can be used for dissolving the Rociletinib HBr include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; and any mixtures of two or more thereof.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. 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.
Step (b) involves removing solvent from a solution obtained in step (a);
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other technique known in the art. The drying may be carried out at normal pressure or under reduced pressure.
Step (c) involves recovering the amorphous solid dispersion comprising Rociletinib HBr and one or more pharmaceutically acceptable carriers. The said recovery can be by using the processes known in the art.
In an embodiment, the isolation of amorphous solid dispersion of Rociletinib HBr may be carried out by employing any of the techniques known to a person skilled in art. Techniques for the isolation of the amorphous solid dispersion include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
The resulting compound obtained in step (c) may be optionally further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as Rociletinib HBr is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
Step (d) of the process involves optionally combining the amorphous solid dispersion of Rociletinib HBr with an absorbent such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like.
An absorbent may also be necessary when the formulation contains a hygroscopic ingredient, especially when adsorption of moisture produces a cohesive powder that will not feed properly to the tablet press. In such instances use of an absorbent such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value.
The dried product 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.
In another embodiment, the amorphous form of Rociletinib HBr obtained according to the present application can be used as an intermediate for making any crystalline form of Rociletinib HBr or solid dispersion of Rociletinib HBr along with the other pharmaceutically acceptable excipients.
In another aspect, the present application provides pharmaceutical formulations comprising amorphous form of Rociletinib HBr, together with one or more pharmaceutically acceptable excipients. Amorphous form of Rociletinib HBr 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.
Amorphous Rociletinib HBr and its solid dispersion of the present application are characterized by its PXRD pattern. All PXRD data reported herein were obtained using Cu Ka radiation, having the wavelength 1.541 Å, and were obtained using a PANalytical, Powder X-ray Diffractometer.
Although the exemplified procedures herein illustrate the practice of the present invention in some of its embodiments, the procedures should not be construed as limiting the scope of the invention. Modifications from consideration of the specification and examples within the ambit of current scientific knowledge will be apparent to one skilled in the art.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
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 1 1 , preferably within the range of 9.5to 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 .
“Amorphous form” as used herein refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, isoamyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater 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 application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
Example 1: Preparation of amorphous form of Rociletinib HBr and its solid dispersion with Syloid.
Rociletinib HBr (1 g) and methanol (50 mL) were charged into a 100 mL round bottom flask at 25°C and stirred for 15 min. The clear solution was filtered and the filtrate was taken into a Buchi® flask and completely evaporated under reduced pressure at 45°C. The solid was dried under reduced pressure at 25°C to afford the title compound. PXRD pattern is shown in Fig. 1.
300 mg of the above amorphous Rociletinib HBr was blended with Syloid (300 mg) in a mortar pestle for 30 minutes at 30° C and analyzed PXRD. Amorphous solid dispersion was obtained. PXRD pattern is shown in Fig. 2.
Example 2: Preparation of amorphous form of Rociletinib HBr and its solid dispersion with Syloid.
Rociletinib HBr (4.0 g) and 200 mL of methanol were taken in 500 mL conical flask and stirred for 10 min at 30°C. The solution was filtered to remove un-dissolved particles and the filtrate was evaporated by spray drying, using a Büchi® MINI Spray Dryer B-290 with Büchi® Inert Loop B-295 at 75°C to afford 1.8 g of amorphous Rociletinib HBr.
PXRD pattern matches with Fig. 1.
Parameters for the spray drier of the above experiment:
Aspirator: 70 %; Feed rate: 9 mL/ minute; Inlet temperature: 75°C; Outlet temperature: 52°C.
300 mg of the above amorphous Rociletinib HBr was blended with Syloid (300 mg) in a mortar pestle for 30 minutes at 30° C and analyzed PXRD. Amorphous solid dispersion was obtained. PXRD pattern matches with Fig. 2.
Example 3: Preparation of amorphous solid dispersion of Rociletinib HBr with PVP-K30.
Rociletinib HBr (500 mg), PVP K-30 (500 mg) and methanol (100 mL) were charged into a 250 mL round bottom flask and stirred for 15 minutes at 30°C. The resultant clear solution was filtered and the filtrate was taken into a Buchi® flask and completely evaporated under reduced pressure at 50°C. The solid was dried under reduced pressure at 30°C to afford the title compound. PXRD pattern is shown in Fig. 3.
300 mg of the above amorphous solid dispersion was blended with Syloid (300 mg) in a mortar pestle for 30 minutes at 30° C and analyzed PXRD. Amorphous solid dispersion was obtained. PXRD pattern is shown in Fig. 4.
Example 4: Preparation of amorphous solid dispersion of Rociletinib HBr with Eudragit.
Rociletinib HBr (500 mg), Eudragit (500 mg) and methanol (50 mL) were charged into a 100 mL conical flask and shaken solution for complete dissolution at 30°C. The resultant clear solution was filtered and the filtrate was taken into a Buchi® flask and completely evaporated under reduced pressure at 50°C. The solid was collected from the Buchi® flask to afford the title compound. PXRD pattern is shown in Fig. 5.
Example 5: Preparation of amorphous solid dispersion of Rociletinib HBr with Hydroxy Propyl Cellulose (HPC).
Rociletinib HBr (500 mg), HPC (500 mg) and methanol (50 mL) were charged into a 100 mL conical flask and shaken solution for complete dissolution at 30°C. The resultant clear solution was filtered and the filtrate was taken into a Buchi® flask and completely evaporated under reduced pressure at 50°C. The solid was collected from the Buchi® flask to afford the title compound. PXRD pattern is shown in Fig. 6.
Example 6: Preparation of amorphous solid dispersion of Rociletinib HBr with Methyl Cellulose.
Rociletinib HBr (500 mg), Methyl Cellulose (500 mg) and methanol (50 mL) were charged into a 100 mL conical flask and shaken solution for complete dissolution at 30°C. The resultant clear solution was filtered and the filtrate was taken into a Buchi® flask and completely evaporated under reduced pressure at 50°C. The solid was collected from the Buchi® flask to afford the title compound. PXRD pattern is shown in Fig. 7.
Example 7: Preparation of amorphous solid dispersion of Rociletinib HBr with Copovidone.
Rociletinib HBr (500 mg), Copovidone (500 mg) and methanol (50 mL) were charged into a 100 mL conical flask and shaken solution for complete dissolution at 30°C. The resultant clear solution was filtered and the filtrate was taken into a Buchi® flask and completely evaporated under reduced pressure at 50°C. The solid was collected from the Buchi® flask to afford the title compound. PXRD pattern is shown in Fig. 8.
150 mg of the above amorphous solid dispersion was blended with Microcrystalline Cellulose (150 mg) in a mortar pestle for 30 minutes at 30° C and analyzed PXRD. Amorphous solid dispersion was obtained. PXRD pattern is shown in Fig. 9.
,CLAIMS:We claim
1. Amorphous Rociletinib HBr.
2. The amorphous Rociletinib HBr according to claim 1, characterized by PXRD pattern as shown in Figure 1.
3. A process for preparation of amorphous Rociletinib HBr according to claim 1, comprising:
(a) providing a solution of Rociletinib HBr in a solvent or a mixture solvents;
(b) removing solvent from the solution of Rociletinib HBr obtained in step a); and
(c) recovering amorphous form of Rociletinib HBr.
4. The process according to claim 3, the solvent used in step (a) is methanol.
5. Amorphous solid dispersion comprising Rociletinib HBr and one or more pharmaceutically acceptable carriers.
6. The pharmaceutically acceptable carrier of the amorphous solid dispersion of claim 5, is selected form the group comprising pregelatinized starch, lactose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium starch glycolate, crospovidone, croscarmellose sodium, colloidal silicon dioxide hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose and methylcellulose.
7. A process for preparing a solid dispersion according to claim 5, comprises;
(a) providing a solution of Rociletinib HBr and pharmaceutically acceptable carrier in a solution,
(b) removing solvent from a solution obtained in step (a);
(c) recovering a solid dispersion comprising an amorphous form of Rociletinib HBr and one or more pharmaceutically acceptable carrier; and
(d) optionally, combining the amorphous solid dispersion Rociletinib HBr with an absorbent, if the pharmaceutically acceptable carrier of step (a) is not an absorbent.
8. A pharmaceutical composition comprising amorphous Rociletinib HBr according to any of claims 1 to 4, characterized that it contains at least one pharmaceutically acceptable excipient.
9. A pharmaceutical composition comprising amorphous solid dispersion according to any of claims 5 or claim 6, characterized that it contains at least one pharmaceutically acceptable excipient.
10. Use of amorphous Rociletinib HBr as an intermediate for making any crystalline form of Rociletinib HBr or solid dispersion of Rociletinib HBr.