DESC:SOLID DISPERSIONS OF SOLRIAMFETOL HCl

FIELD OF THE INVENTION
The present application relates to solid dispersions of Solriamfetol hydrochloride, their preparative methods and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Solriamfetol, has a chemical name (R)-2-amino-3-phenylpropylcarbamate, and is represented by the structure of formula I.

I
Solriamfetol marketed under the brand name Sunosi™ by Jazz pharmaceuticals in the United Sates is a dopamine and norepinephrine reuptake inhibitor (DNRI) indicated for the treatment of daytime sleepiness with narcolepsy or obstructive sleep apnea. 75 mg of Sunosi™ tablet contains 75 mg Solriamfetol (equivalent to 89.3 mg Solriamfetol hydrochloride).
Solriamfetol, its hydrochloride salt, synthetic process and its pharmaceutical compositions are described in US patent No. 5,955,499 B2 (US ‘499). US patent application No. 20190194126 A1 (US ‘126) describes a hydrate form of Solriamfetol hydrochloride salt and their pharmaceutical compositions.
New polymorphic forms, solvates and solid dispersions of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Solriamfetol.

SUMMARY OF THE INVENTION
Aspects of the present application relate to solid dispersions of Solriamfetol, its preparative processes and pharmaceutical compositions thereof.
In one aspect, the present application provides amorphous solid dispersion comprising Solriamfetol hydrochloride and one or more pharmaceutically acceptable excipient.
In another aspect, the present application provides a process for preparation of amorphous solid dispersion comprising Solriamfetol hydrochloride and one or more pharmaceutically acceptable excipient; the process comprising;
a) providing a solution comprising Solriamfetol hydrochloride and one or more pharmaceutically acceptable excipients,
b) removing solvent form the solution obtained in step (a), and
c) recovering the solid dispersion comprising Solriamfetol hydrochloride and one or more pharmaceutically acceptable excipients.
In another aspect, the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Solriamfetol hydrochloride and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction ("PXRD") pattern of amorphous solid dispersion of Solriamfetol hydrochloride prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of amorphous solid dispersion of Solriamfetol hydrochloride prepared according to Example 2.
Figure 3 is powder X-ray diffraction pattern of amorphous solid dispersion of Solriamfetol hydrochloride prepared according to Example 3.

DETAILED DESCRITPION
Aspects of the present application relate to solid dispersions of Solriamfetol hydrochloride, their preparative processes and pharmaceutical compositions thereof. The present application also encompasses the use of solid dispersions of Solriamfetol hydrochloride provided herein for the preparation of pharmaceutical dosage forms.
The present application provides a process for preparing amorphous solid dispersion comprising Solriamfetol hydrochloride and one or more pharmaceutically acceptable excipient, the process comprising;
a) providing a solution comprising Solriamfetol hydrochloride and one or more pharmaceutically acceptable excipients,
b) removing solvent from the solution obtained in step (a), and
c) recovering amorphous solid dispersion comprising Solriamfetol hydrochloride and one or more pharmaceutically acceptable excipient.
Providing a solution in step (a) includes direct use of a reaction mixture containing Solriamfetol hydrochloride that is obtained in the course of its synthesis or dissolving Solriamfetol hydrochloride and pharmaceutically acceptable excipient in a solvent or a mixture of solvents.
Any physical form of Solriamfetol hydrochloride may be utilized for providing the solution of step (a).
Suitable pharmaceutically acceptable excipients 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, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; 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.
In a preferred embodiment, the pharmaceutically acceptable expicients are PVP-K30, PVP-K90 and hydroxypropyl methylcellulose-acetate succinate (HPMC-AS).
Suitable solvent that can be used for dissolving the Solriamfetol hydrochloride is an alcohol solvent such as methanol, ethanol, isopropyl alcohol, n-propanol, 2- butanol and the like. In a specific aspect the solvent used in step (a) is methanol.
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 the 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 such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze -drying, filtration or any other technique known in the art.
Step (c) involves recovering amorphous solid dispersion comprising Solriamfetol hydrochloride and one or more pharmaceutically acceptable excipient. The said recovery can be achieved by using the processes known in the art.
The resulting compound obtained 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 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Solriamfetol hydrochloride is not degraded in its quality. The drying can be carried out for any desired time 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.
When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising Solriamfetol hydrochloride, addition of other carriers 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. Therefore these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous Solriamfetol hydrochloride or solid dispersion to control hygroscopicity and to improve stability.
In another aspect, the present application provides a pharmaceutical composition comprising amorphous Solriamfetol hydrochloride solid dispersion of the present invention and a pharmaceutically acceptable carrier.
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. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. The term “amorphous” refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.
The term "about" when used in the present application 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.
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 solid dispersion of Solriamfetol hydrochloride and Polyvinylpyrrolidone K-30 (PVP K-30)
Solriamfetol hydrochloride (200 mg), Polyvinylpyrrolidone K-30 (PVP K-30, 200 mg), and methanol (25 mL) were charged into a 100 mL rotavapor flask at 27°C. The mixture was heated to 50 °C and stirred for 5 minutes. The mixture was sonicated to get clear solution and the solution was concentrated under reduced pressure at 50°C. The material was dried at 50 °C under reduced pressure. Amorphous solid dispersion was obtained. PXRD pattern is shown in Figure 1.

Example-2: Preparation of amorphous solid dispersion of Solriamfetol hydrochloride and Hydroxypropyl methyl cellulose Acetate Succinate (HPMC-AS)
Solriamfetol hydrochloride (200 mg), Hydroxypropyl methyl cellulose Acetate Succinate (HPMC-AS-LG, 200 mg), and methanol (25 mL) were charged into a 100 mL rotavapor flask at 27°C. The mixture was heated to 50 °C and stirred for 5 minutes. The mixture was sonicated to get clear solution and the solution was concentrated under reduced pressure at 50°C. The material was dried at 50 °C under reduced pressure. Amorphous solid dispersion was obtained. PXRD pattern is shown in Figure 2.

Example-3: Preparation of amorphous solid dispersion of Solriamfetol hydrochloride and Polyvinylpyrrolidone K-90 (PVP K-90)
Solriamfetol hydrochloride (200 mg), Polyvinylpyrrolidone K-90 (PVP K-90, 200 mg), and methanol (20 mL) were charged into a 100 mL rotavapor flask at 27°C. The mixture was heated to 50 °C and stirred for 5 minutes. The mixture was sonicated to get clear solution and the solution was concentrated under reduced pressure at 50°C. The material was dried at 50 °C under reduced pressure. Amorphous solid dispersion was obtained. PXRD pattern is shown in Figure 3.
,CLAIMS:WE CLAIM:
1. An amorphous solid dispersion comprising Solriamfetol hydrochloride and one or more pharmaceutically acceptable excipient.
2. The amorphous solid dispersion of claim 1, wherein the pharmaceutically acceptable excipient is selected from polyvinylpyrrolidone K-30 (PVP-K30), polyvinylpyrrolidone K-90 (PVP-K90), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate, hydroxypropyl celluloses, hydroxymethyl celluloses, ethylcelluloses or cyclodextrins.
3. A process for the preparation of amorphous solid dispersion comprising the steps of:
a) providing a solution of solriamfetol hydrochloride and the pharmaceutically acceptable excipient in one or more solvents; and
b) isolating the amorphous solid dispersion of solriamfetol hydrochloride.
4. The process of claim 3, wherein the pharmaceutically acceptable excipient is selected from Polyvinylpyrrolidone K-30 (PVP-K30), Polyvinylpyrrolidone K-90 (PVP-K90), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate, hydroxypropyl celluloses, hydroxymethyl celluloses, ethylcelluloses or cyclodextrins.
5. The process of claim 3, wherein the solvent is selected from methanol, ethanol, isopropyl alcohol, n-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran or dichloromethane.

6. A pharmaceutical composition comprising amorphous solid dispersion of Solriamfetol hydrochloride and at least one pharmaceutically acceptable carrier.