DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“NOVEL POLYMORPH OF SOLRIAMFETOL AND SALT THEREOF”

Glenmark Pharmaceuticals Limited;
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the nature of the invention and the manner in which it is to be performed.
PRIORITY
This application claims the benefit to Indian Provisional Application No. 201821007729, filed on 1 March, 2018, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION
The present invention relates to novel polymorph of solriamfetol and its hydrochloride.

BACKGROUND OF THE INVENTION
Solriamfetol, also known as (2R)-2-amino-3-phenylpropyl carbamate, is represented by compound of formula I. The compound of Formula I is also known in its hydrochloride form.

I
The drug is currently in phase III clinical trials for the treatment of excessive daytime sleepiness in patients with narcolepsy or with obstructive sleep apnea

SUMMARY OF THE INVENTION
The present invention provides, a process for the preparation of crystalline solriamfetol, the process comprising:
(a) reacting solriamfetol with ethyl acetate hydrochloride solution to form solriamfetol hydrochloride;
(b) isolating the solriamfetol hydrochloride.
The present invention provides, a process for the preparation of crystalline solriamfetol, the process comprising:
(a) providing solriamfetol in a solvent or a mixture of solvents; and
(b) isolating the crystalline solriamfetol from the step (a).
The present invention provides, crystalline solriamfetol hydrochloride in hydrated form.
The present invention provides, a process for the preparation of crystalline solriamfetol in hydrated form, the process comprising:
(a) providing solriamfetol hydrochloride in water;
(b) lyophilizing the solution obtained in step (a).
The present invention provides, a process for the preparation of crystalline solriamfetol in hydrated form, the process comprising:
(a) dissolving solriamfetol HCl in water, optionally in the presence of a solvent to form a solution; or
(a) (i) providing solriamfetol in an ester, ketone, water or mixtures thereof to form reaction mass;
(ii) adding ethyl acetate-hydrochloric solution to the reaction mass obtained in step (a) to form solriamfetol hydrochloride; and
(b) isolating the crystalline solriamfetol hydrochloride in hydrated form, from the step ‘a’ by (i) removing the solvent from the solution obtained in (a); or (ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or (iii) cooling the solution obtained in (a).
The present invention provides, crystalline solriamfetol characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 8.02, 11.43, 14.71, 18.25, 19.00 ±0.2 degrees 2 theta.
The present invention provides, crystalline solriamfetol characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1, a TGA thermogram as depicted in Figure 2; a DSC thermogram as depicted in Figure 3; and any combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRPD of solriamfetol as obtained in Example 2.
Figure 2 is a TGA thermogram of solriamfetol as obtained in Example 2.
Figure 3 is a DSC thermogram of solriamfetol as obtained in Example 2.
Figure 4 is a characteristic XRPD of solriamfetol hydrochloride as obtained in Example 3.
Figure 5 is a TGA thermogram of solriamfetol hydrochloride as obtained in Example 3.
Figure 6 is a DSC thermogram of solriamfetol hydrochloride as obtained in Example 3.
Figure 7 is a characteristic XRPD of solriamfetol hydrochloride hydrated form as obtained in Example 4.
Figure 8 is a TGA thermogram of solriamfetol hydrochloride hydrated form as obtained in Example 4.
Figure 9 is a DSC thermogram of solriamfetol hydrochloride hydrated form as obtained in Example 4.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a solid form of solriamfetol.
In one embodiment, the present invention provides an amorphous form of solriamfetol.
In one embodiment, the present invention provides a crystalline form of solriamfetol.
In one embodiment, the present invention provides a crystalline solriamfetol characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 8.02, 11.43, 14.71, 18.25, 19.00 ±0.2 degrees 2 theta.
In one embodiment, the present invention provides a crystalline solriamfetol characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 8.02, 11.43, 14.71, 18.25, 19.00, 22.80, 23.02 ±0.2 degrees 2 theta.
In one embodiment, the present invention provides a crystalline solriamfetol characterized by an X-ray powder diffraction (XRPD) spectrum which is substantially in accordance with Figure1.
In one embodiment, present invention provides crystalline solriamfetol characterized by TGA thermogram, showing weight loss of about 0.5 to 2.0 weight% up to 100ºC determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
In one embodiment, present invention provides crystalline solriamfetol characterized by TGA thermogram which is substantially in accordance with Figure 2.
In one embodiment, the present invention provides a crystalline solriamfetol characterized by DSC thermogram having endothermic peak at about 49±2°C.
In one embodiment, the present invention provides a crystalline solriamfetol characterized by DSC thermogram having endothermic peak at about 49±2°C which is substantially in accordance with Figure 3.
In one embodiment, the present invention provides a crystalline solriamfetol characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1, a TGA thermogram as depicted in Figure 2; a DSC thermogram as depicted in Figure 3; and any combination thereof.
In one embodiment, the present invention provides a process for the preparation of crystalline solriamfetol, the process comprising:
(a) providing solriamfetol in a solvent or a mixture of solvents; and
(b) isolating the crystalline solriamfetol from the step a.
In (a) of the process for the preparation of crystalline solriamfetol, solriamfetol is mixed with a solvent or a mixture of solvents.
The solvent may be selected from non-polar or polar solvent or a mixture thereof.
In one embodiment, the solvent is a non-polar solvent.
The non-polar solvent may be selected from the group consisting of substituted or un-substituted acyclic or cyclic hydrocarbons etc.
The substituted or un-substituted acyclic or cyclic hydrocarbons may be selected from hydrocarbons containing C4-C18 carbon atoms.
In one embodiment, the solvent is an alkane containing C6-C18 carbon atoms like hexane, heptane, cyclohexane and the like.
In one embodiment, the solvent is an ether, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like.
In (a) of the process for the preparation of crystalline solriamfetol, the solvent includes but not limited to n-heptane.
In (b) of the process for the preparation of crystalline solriamfetol, the isolation is carried out by slurrying or stirring solriamfetol in the solvent.
The slurrying or stirring may be carried out at a temperature in the range of about -15°C to 50°C.
The crystalline form of solriamfetol is then isolated by standard techniques like filtration, decantation or centrifugation.
In one embodiment, the present invention provides a process for the preparation of crystalline solriamfetol, the process comprising:
(a) providing solriamfetol in heptane; and
(b) isolating the crystalline solriamfetol from the step ‘a’, by stirring in heptane.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 6.57, 13.16, 15.30, 15.52, 20.20 ±0.2 degrees 2 theta.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 6.57, 13.16, 15.30, 15.52, 20.20 ±0.2 degrees 2 theta which is substantially in accordance with Figure 4.
In one embodiment, present invention provides crystalline solriamfetol hydrochloride characterized by TGA thermogram, showing weight loss of about 0.5-2.0 weight% up to 100ºC determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
In one embodiment, present invention provides crystalline solriamfetol hydrochloride characterized by TGA thermogram, showing weight loss of about 0.5-2.0 weight% up to 100ºC determined over the temperature range of 0°C to 350°C and heating rate 10°C/min which is substantially in accordance with Figure 5.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride characterized by DSC thermogram having endothermic peaks at about 183±2°C.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride characterized by DSC thermogram having endothermic peak at about 183±2°C and 190±2°C which is substantially in accordance with Figure 6.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 4, a TGA thermogram as depicted in Figure 5; a DSC thermogram as depicted in Figure 6; and any combination thereof.
In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride comprising:
(a) dissolving solriamfetol hydrochloride in a solvent or mixture of solvents;
(b) adding an anti-solvent to obtain crystalline solriamfetol hydrochloride.
In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride comprising:
(a) dissolving solriamfetol hydrochloride in a solvent or mixture of solvents
(b) heating the solution to a temperature of about 50°C to 90°C;
(c) cooling to temperature about 0°C to 10°C.

In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride, process comprising:
(a) reacting solriamfetol with hydrochloride source to form solriamfetol hydrochloride;
(c) isolating the solriamfetol hydrochloride.
In (a) of the process for the preparation of crystalline solriamfetol hydrochloride, the solvent is selected from but not limited to alcohol, hydrocarbon, ketone, ester, ether or mixture thereof.
The alcohol, halogenated hydrocarbon, ketone, ester, ether solvent are as described supra.
In (a) of the process for the preparation of crystalline solriamfetol hydrochloride, the hydrochloride source is selected from but not limited to hydrochloride gas, concentrated hydrochloric acid, ethyl acetate hydrochloride and the like.
In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride, process comprising:
(a) reacting solriamfetol with ethyl acetate hydrochloride solution to form solriamfetol hydrochloride;
(b) isolating the solriamfetol hydrochloride.
In (a) of the process for the preparation of crystalline solriamfetol hydrochloride, the solvent is halogenated solvent is selected from dichloromethane, ethylene dichloride, chloroform and ketone solvent is selected from acetone, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof.
In (b) of the process for the preparation of crystalline solriamfetol hydrochloride, the isolation of crystalline solriamfetol hydrochloride is carried out by filtration, centrifugation, distillation of solvent, spray drying or by a method known in the art.
In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride, process comprising:
(a) reacting solriamfetol with ethyl acetate hydrochloride solution in halogenated solvent to form solriamfetol hydrochloride;
(b) isolating the solriamfetol hydrochloride.
In (a) of the process for the preparation of crystalline solriamfetol hydrochloride, the solvent is halogenated solvent is selected from dichloromethane, ethylene dichloride, chloroform and the like.
In one embodiment, solriamfetol hydrochloride obtained in the present invention is isolated by filtration, centrifugation, distillation of solvent, spray drying or by a method known in the art.
In one embodiment, drying may be performed under vacuum at a temperature of about 40-60°C, preferably at about 45-55°C.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride in hydrated form.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride in hydrated form, wherein the molar ratio of solriamfetol hydrochloride and water is in the range of 1:0.5 to 1:6.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride in hydrated form, wherein the molar ratio of solriamfetol hydrochloride and water is in the range of 1:0.5 to 1:3.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride hemihydrate.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride having a water content in the range of 3.5% to 5 % as determined by Karl Fisher.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride having a water content of about 4% as determined by Karl Fisher.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride in hydrated form characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 6.94, 13.56, 17.15, 18.50, 22.89 ±0.2 degrees 2 theta.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride in hydrated form characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 6.94, 13.56, 17.15, 18.50, 22.89 ±0.2 degrees 2 theta which is substantially in accordance with Figure 7.
In one embodiment, present invention provides crystalline solriamfetol hydrochloride in hydrated form characterized by TGA thermogram, showing weight loss of about 3.3 to 4.5 weight% up to 100ºC determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
In one embodiment, present invention provides crystalline solriamfetol hydrochloride in hydrated form characterized by TGA thermogram, showing weight loss of about 3.96 weight% up to 100ºC determined over the temperature range of 0°C to 350°C and heating rate 10°C/min which is substantially in accordance with Figure 8.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride in hydrated form characterized by DSC thermogram having endothermic peak at about 86±2 °C and 183±2 °C.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride in hydrated form characterized by DSC thermogram having endothermic peak at about 86±2 °C and 183±2 °C which is substantially in accordance with Figure 9.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride in hydrated form characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 7, a TGA thermogram as depicted in Figure 8; a DSC thermogram as depicted in Figure 9; and any combination thereof.
In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride in hydrated form, the process comprising:
(a) dissolving solriamfetol hydrochloride in water, optionally in the presence of a solvent, to form a solution; or
(a) (i) providing solriamfetol in a solvent, optionally adding water
(ii) adding hydrochloric acid or aqueous hydrochloric acid to form a solution of
solriamfetol hydrochloride; and
(b) isolating the crystalline solriamfetol hydrochloride in hydrated form, from the
step ‘a’ by
(i) removing the solvent from the solution obtained in (a); or
(ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or
(iii) cooling the solution obtained in (a).
In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride in hydrated form, the process comprising:
(a) dissolving solriamfetol hydrochloride in water, optionally in the presence of a solvent, to form a solution; and
(b) isolating the crystalline solriamfetol hydrochloride in hydrated form from
the step ‘a’ by
(i) removing the solvent from the solution obtained in (a); or
(ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or
(iii) cooling the solution obtained in (a).
The solvent includes but is not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide.
In one embodiment, the crystalline solriamfetol hydrochloride in hydrated form is isolated by removal of solvent in (b) (i) by solvent distillation, concentration, spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.
In one embodiment the crystalline solriamfetol hydrochloride in hydrated form is isolated by addition of an anti-solvent. The antisolvent is selected such that crystalline solriamfetol hydrochloride hydrate is precipitated out from the solution.
The anti-solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, present invention provides a process for preparation of crystalline solriamfetol hydrochloride in hydrated form, process comprising:
(a) providing solriamfetol hydrochloride in water; and
(b) lyophilizing the solution obtained in (a).
In (b) of the process for the preparation of crystalline solriamfetol hydrochloride, the lyophilization is carried out for about 2 to 6 hours and drying is carried out for about 4 to 7 hours.
In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride in hydrated form, the process comprising:
(a) (i) providing solriamfetol in a solvent, optionally adding water
(ii) adding hydrochloric acid or aqueous hydrochloric acid to form a solution of
solriamfetol hydrochloride; and
(b) isolating the crystalline solriamfetol hydrochloride in hydrated form from the step ‘a’ by
(i) removing the solvent from the solution obtained in (a); or
(ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or
(iii) cooling the solution obtained in (a).
The solvent may be selected as discussed supra.
The amount of water used may be in the range of 0.5% to 50% of the amount of solvent used.
In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride in hydrated form, the process comprising:
(a) (i) providing solriamfetol in a solvent and water;
(ii) adding hydrochloric acid to form a solution of solriamfetol hydrochloride;
and
(b) isolating the crystalline solriamfetol hydrochloride in hydrated form, from the step ‘a’ by
(i) removing the solvent from the solution obtained in (a); or
(ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or
(iii) cooling the solution obtained in (a).
In one embodiment, the present invention provides a process for preparation of crystalline solriamfetol hydrochloride in hydrated form, the process comprising:
(a) dissolving solriamfetol HCl in water, optionally in the presence of a solvent to form a solution; or
(a) (i) providing solriamfetol in an ester, ketone, water or mixtures thereof to form reaction mass;
(ii) adding ethyl acetate-hydrochloric solution to the reaction mass obtained in step (a) to form solriamfetol hydrochloride; and
(b) isolating the crystalline solriamfetol hydrochloride in hydrated form, from the step ‘a’ by (i) removing the solvent from the solution obtained in (a); or (ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or (iii) cooling the solution obtained in (a).
In step (a) the solvent may be selected as discussed supra.
In step (a) (i) the ester solvent is methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and ketone solvent is acetone, ethyl methyl ketone, methyl isobutyl ketone.
In one embodiment, the crystalline solriamfetol hydrochloride in hydrated form is isolated by removal of solvent in (b) (i) by solvent distillation, concentration, spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.
In step (b) (ii) the antisolvent may be selected as discussed supra.
In step (b) (iii) cooling is carried out at about 0 0C to about10 0C.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 6.94, 13.56, 17.15, 18.50, 22.89 ±0.2 degrees 2 theta.
In one embodiment, present invention provides process for preparation of (2R)-2-amino-3-phenylpropan-1-ol, the process comprising
(a) providing D-phenylalanine methyl ester or its salt in a solvent or mixture of solvents
(b) basifying the solution and stirring
(c) separating organic layer and distilling it to get oil
(d) treating oil with alkali metal borohydride and stirring
(e) separating organic layer and distilling it to get crude product
(f) purifying crude product
In one embodiment, the present invention provides process for preparation solriamfetol; process comprising contacting (2R)-2amino-3-phenylpropan-1-ol with sodium cyanate under acidic condition and followed by workup under basic conditions. The acid may be selected form organic or inorganic acids like methane sulfonic acid, hydrochloric acid, sulfuric acid and the like. The base may be selected from alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or alkali metal carbonates or bicarbonates.
In one embodiment, the present invention provides an amorphous form of solriamfetol hydrochloride.
In one embodiment, the present invention provides solriamfetol or hydrochloride thereof substantially free of other isomer i.e. S form of solriamfetol.
In one embodiment, the present invention provides pharmaceutical compositions comprising solriamfetol or hydrochloride salt, or solvate thereof obtained by the processes herein described, having a D50 and D90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state solriamfetol or hydrochloride or solvate thereof into any of the foregoing desired particle size range.
The present invention provides solriamfetol and hydrochloride, obtained by the above processes, as characterized and analyzed by following techniques:
A. X-ray powder diffraction profiles were obtained using an X-ray Diffractometer (Philips X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X’Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV; tube current 40mAmp. The samples were scanned in the full 2? range of 2-50° with a “time-per-step” optimized to 50 sec.
B. DSC (Mettler Toledo 822e): Temperature range is “30°C to 350°C” and heating rate is 10°C/minute.
C. Thermo Gravimetric Analyzer: TGA Q500 V6.5. Thermogram was recorded at 30-350°C at the rate of 10°C/min.
D. Karl Fischer: The water content was calculated by the following formula:
water content (%) = Burette reading × KF Factor × 100
Weight of sample in mg
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLES
EXAMPLE 1: Preparation of (2R)-2-amino-3-phenylpropan-1-ol
In a round bottom flask, D-Phenylalanine methyl ester hydrochloride (100g) and water (300mL) were charged. Dichloromethane (500mL) was added to the reaction mass. The reaction mass was basified using saturated sodium carbonate solution (200mL). The reaction mass was stirred for about 15 min; followed by separation of aqueous and organic layers. The obtained aqueous layer was extracted with dichloromethane. Both the organic layers were combined and distilled at about 40°C to get 81 g of oil. The obtained oil was transferred to 2 L round bottom flask and methanol was charged to it. The reaction mass was cooled to about 0 to 10°C and sodium borohydride (32g) was added to the reaction mass. After complete addition of sodium borohydride the temperature of the reaction mass was raised to about 20°C to 30°C. The reaction mass was stirred and maintained for about 2 to 3 hours. After completion of the reaction, the reaction mass was distilled at temperature below about 50°C; followed by addition of water to the reaction mass. The aqueous layer was extracted with dichloromethane. The obtained organic layer was washed with water followed by distillation at temperature below about 40°C; white solid was formed. The solid obtained was heated with dichloromethane at temperature about 40°C and n-heptane was added to the reaction mass. The reaction mass was stirred for 2 hours at temperature about 20°C to 30°C. The reaction mass was then filtered, the solid obtained was then dried at temperature about 40°C to 50°C to obtain (2R)-2-amino-3-phenylpropan-1-ol. Yield: 60.2g.

EXAMPLE 2: Preparation of crystalline (2R)-2-amino-3-phenylpropyl carbamate (Solriamfetol)
In a dry round bottom flask dichloromethane (224mL) was charged followed by addition of (2R)-2-amino-3-phenylpropan-1-ol (28g) and sodium cyanate (23.59g). The reaction mixture was cooled to about 0°C to 5°C and methane sulfonic acid (62.28g) was slowly added to the reaction mass. After completion of the addition of methane sulfonic acid, temperature of the reaction mass was raised to about 20°C to 30°C and stirred for about 3hrs at about same temperature. After completion of the reaction, the reaction mass cooled to about 0°C to 5°C and 20% aqueous sodium hydroxide solution was added at temperature below about 5°C. The aqueous and organic layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water and brine and dried over sodium sulfate overnight followed by filtration. The filtrate was concentrated under vacuum to obtain 29.5 g solriamfetol as oil. The obtained oil was taken in 300 mL n-heptane and stirred for 5 hours at about 0°C to 10°C. The precipitated solid was filtered and dried under vacuum at about 20°C to 30°C to obtain solriamfetol. Yield: 27g.
XRD peaks of crystalline solriamfetol obtained are listed in Table 1
Table 1:
Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]
4.60 0.66 22.80 56.82 32.30 5.15
8.02 8.53 23.02 52.32 32.62 6.29
11.43 5.09 23.24 38.34 34.18 2.50
12.06 2.53 24.30 7.26 35.96 1.62
12.55 8.72 24.68 19.12 36.94 4.44
13.37 0.40 25.50 13.32 37.88 3.94
14.71 31.94 25.98 9.29 38.91 6.21
16.12 75.34 26.97 6.76 40.10 1.58
16.30 62.59 27.19 3.86 40.79 1.02
17.74 6.36 27.81 4.44 42.17 1.98
18.25 34.39 28.14 4.73 42.67 2.17
18.63 9.01 28.61 7.30 44.31 3.84
19.00 100.00 29.14 3.23 45.51 3.37
19.22 17.80 29.80 6.92 46.73 1.90
20.59 28.77 30.95 6.62 48.79 1.12
20.94 17.77 31.36 7.03
21.55 25.23 31.83 2.51
TGA analysis of solriamfetol shows a weight loss of about 0.8 weight% up to 100°C determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
DSC analysis of solriamfetol shows endothermic peak at about 49.28°C.

EXAMPLE 3: Preparation of crystalline solriamfetol hydrochloride Solriramfetol (1g) was dissolved in dichloromethane (5mL) in round bottom flask. The reaction mass cooled to about 0°C to 5°C and ethyl acetate hydrochloride (3mL) was added at temperature about 0°C to 5°C. The reaction mixture was stirred for 1 hour, a white precipitated formed. The obtained precipitate was filtered and dried in vacuum at about 50°C to obtained solriamfetol hydrochloride. Yield 1.0g.
XRD peaks of crystalline solriamfetol hydrochloride obtained are listed in Table 2
Table 2:
Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]
6.57 24.03 26.19 26.99 35.66 4.88
12.24 18.66 26.84 3.92 36.24 12.58
12.34 16.64 27.12 5.50 37.55 1.48
13.16 25.03 27.45 1.46 39.01 3.33
15.30 16.92 28.55 17.20 39.64 1.66
15.52 14.29 29.15 20.86 40.09 2.24
16.02 32.83 29.95 3.99 41.01 1.83
17.29 8.10 30.57 2.38 41.57 2.61
19.17 17.90 30.91 24.32 42.40 2.39
19.64 40.45 31.34 5.92 43.09 2.11
19.79 42.86 32.37 14.61 44.12 1.19
20.20 39.40 32.75 3.75 44.81 1.25
21.25 17.53 33.29 4.07 45.34 3.24
22.23 10.36 33.99 5.12 46.61 2.09
22.80 21.26 34.43 4.57 47.20 1.25
23.78 63.94 34.97 4.50 48.45 1.35
24.63 100.00 35.34 5.62

TGA analysis of solriamfetol hydrochloride shows a weight loss of about 1.8 weight% up to 100°C determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
DSC analysis of solriamfetol hydrochloride shows endothermic peaks at about 182.74°C and 189.66°C.
EXAMPLE 4: Preparation of crystalline solriamfetol hydrochloride hydrate
Solriamfetol hydrochloride (1g) dissolved in water (10mL). The solution was lyophilized for about 4 hours and then dried under vacuum for about 5 hours at temperature about 500C to afford crystalline solriamfetol hydrochloride hydrate. Yield 1gm. XRD peaks of crystalline solriamfetol hydrochloride hydrate obtained are listed in Table 3
Table 3:
Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]
6.94 18.81 24.07 28.01 34.12 8.78
11.12 3.19 24.49 14.34 35.23 2.90
12.63 1.35 25.95 13.47 35.90 2.14
13.56 42.82 26.18 14.60 36.19 1.86
16.14 6.15 26.88 5.19 37.30 8.77
17.15 31.54 27.32 49.34 37.88 15.81
17.42 12.65 28.01 10.13 38.59 1.54
17.75 4.09 29.39 2.35 39.34 1.51
18.50 15.38 30.08 0.84 41.50 3.28
20.92 45.33 30.55 1.19 41.90 1.62
21.09 7.17 31.02 5.09 42.65 4.15
21.64 14.28 31.40 3.60 43.22 3.12
22.34 5.19 31.87 16.72 45.58 5.67
22.62 26.03 31.97 16.28 46.13 3.30
22.89 100.00 32.30 8.25 46.74 1.85
23.29 2.59 32.61 3.30 47.51 1.16
23.92 24.98 33.24 9.80

TGA analysis of crystalline solriamfetol hydrochloride hydrate shows a weight loss of about 3.9 weight% up to 100°C determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
DSC analysis of crystalline solriamfetol hydrochloride hydrate shows endothermic peak at about 86°C and 183°C.
The water content in the solriamfetol obtained is 4.1%
EXAMPLE 5: Preparation of crystalline solriamfetol hydrochloride hydrate
Solriamfetol (1g) was dissolved in ethyl acetate containing 10-20% water and the solution was cooled to temperature about 0°C to 5°C. To the obtained reaction mass, ethyl acetate hydrochloride (3mL) was added at temperature about 0°C to 5°C. The reaction mass was stirred for 1 hour to obtain a white precipitated. The precipitate was filtered and dried in vacuum at temperature about 50°C to obtain crystalline solriamfetol hydrochloride hydrate. Yield 1.0g.
EXAMPLE 6: Preparation of crystalline solriamfetol hydrochloride
Solriamfetol hydrochloride (1g) was dissolved in methanol (4mL) at temperature about 20°C to 30°C. Methyl tertiary butyl ether (MTBE; 10mL) was slowly added to the reaction mass. The reaction mass was stirred for about 30min at temperature about 20°C to 30°C, the solid was obtained. Obtained solid was filtered and washed with MTBE. The solid was then dried at temperature about 50°C under vacuum to obtained crystalline solriamfetol hydrochloride. Yield 0.8 g.
EXAMPLE 7: Preparation of crystalline solriamfetol hydrochloride
In a round bottom flask solriamfetol (10g) and ethyl acetate (50mL) were charged to obtain a clear solution at temperature about 20°C to 30°C. Then 20ml of 10-12% ethyl acetate: HCl was added drop wise and reaction mass was stirred for about 1 hour at 20°C to 30°C. The reaction mass was filtered to obtain solid and dried at temperature about 50°C to obtain crystalline solriamfetol hydrochloride. Yield 11g.
EXAMPLE 8: Preparation of crystalline solriamfetol hydrochloride In a round bottom flask solriamfetol (1g) and acetone (20mL) were charged to obtain clear solution at temperature about 20°C to 30°C. Then 10-12% ethyl acetate: HCl (3mL) was added drop wise. The reaction mass was stirred for about 1 hour at temperature about 0°C to 10°C. The reaction mass was filtered to obtain solid and dried at temperature about 50°C to obtain crystalline solriamfetol hydrochloride. Yield: 0.7g.
EXAMPLE 9: Preparation of crystalline solriamfetol hydrochloride In a round bottom flask solriamfetol (1g) and tetrahydrofuran (10mL) were charged to obtain a clear solution at temperature about 20°C to 30°C. To the reaction mass, 10-12% ethyl acetate: HCl (3 mL) was added drop wise. The reaction mass was stirred for about 1 hour at temperature about 0°C to 10°C. After completion of reaction, the reaction mass was filtered to obtain solid; the solid was dried at temperature about 50°C to obtain crystalline solriamfetol hydrochloride. Yield 0.9g.
EXAMPLE 10: Preparation of crystalline solriamfetol hydrochloride In a round bottom flask solriamfetol (1g) and tetrahydrofuran (20mL) was charged to obtain a clear solution at temperature about 20°C to 30°C. Concentrated hydrochloric acid (3mL) was added drop wise, the reaction mass was stirred for about 1 hour at temperature about 0°C to 10°C. After completion of reaction, the reaction mass was filtered to obtain solid; the solid was dried at temperature about 50°C to obtain crystalline solriamfetol hydrochloride. Yield: 0.7g.
EXAMPLE 11: Preparation of crystalline solriamfetol hydrochloride In a 50mL round bottom flask solriamfetol (1g) and isopropyl alcohol (10mL) was charged to obtain a clear solution at temperature about 20°C to 30°C. Concentrated hydrochloric acid (3 mL) was added dropwise, the reaction mass was stirred for about 1 hour at temperature about 0°C to 10°C. After completion of reaction, the reaction mass was filtered to obtain solid; the solid was dried at temperature about 50°C to obtain crystalline solriamfetol hydrochloride. Yield: 0.6g.
EXAMPLE 12: Preparation of crystalline solriamfetol hydrochloride Solriamfetol hydrochloride (2g) was dissolved in methanol (4mL) at temperature about 60°C to 70°C and the reaction mass was cooled temperature about to 0°C to 5°C to obtain crystalline solriamfetol hydrochloride. Yield: 1.3g
EXAMPLE 13: Preparation of crystalline solriamfetol hydrochloride Solriamfetol hydrochloride (2g) was dissolved in methanol (4mL) at temperature about 80°C to 90°C and the reaction mass was cooled temperature about to 0°C to 5°C to obtain crystalline solriamfetol hydrochloride. Yield: 0.8g.
EXAMPLE 14: Preparation of crystalline solriamfetol hydrochloride Solriamfetol hydrochloride (5g) was dissolved in 50mL methanol to get a clear solution. The solution was spray dried with inlet temperature about 70 0C and outlet temperature about 45 to 50 0C to obtain crystalline solriamfetol hydrochloride. Yield: 2.0 g.
,CLAIMS:We Claims:
1. A process for the preparation of crystalline solriamfetol hydrochloride, the process comprising
(a) reacting solriamfetol with ethyl acetate hydrochloride solution to form solriamfetol hydrochloride;
(c) isolating the solriamfetol hydrochloride.
2. The process as claimed in claim 1, wherein solvent used in step (a) is halogenated solvent selected from dichloromethane, ethylene dichloride, chloroform and ketone solvent selected from acetone, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof.
3. Crystalline solriamfetol hydrochloride in hydrated form.
4. The crystalline solriamfetol hydrochloride as claimed in claim 3, wherein the molar ratio of solriamfetol hydrochloride and water is in the range of 1:0.5 to 1:6.
5. A process for the preparation of crystalline solriamfetol hydrochloride in hydrated form, the process comprising:
(a) providing solriamfetol hydrochloride in water;
(b) lyophilizing the solution obtained in step (a).
6. The process as claimed in claim 5, wherein in lyophilization is carried out for about 2 to 6 hours and drying is carried out for about 4 to 7 hours.
7. A process for the preparation of crystalline solriamfetol hydrochloride in hydrated form, the process comprising:
(a) dissolving solriamfetol HCl in water, optionally in the presence of a solvent to form a solution; or
(a) (i) providing solriamfetol in an ester solvent, ketone solvent, water or mixtures to form reaction mass;
(ii) adding ethyl acetate-hydrochloric solution to the reaction mass obtained in step (a) to form solriamfetol hydrochloride; and
(b) isolating the crystalline solriamfetol hydrochloride in hydrated form, from the step ‘a’ by (i) removing the solvent from the solution obtained in (a); or (ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or (iii) cooling the solution obtained in (a).
8. The process as claimed in claim 7, wherein in step (a) is methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and ketone solvent is acetone, ethyl methyl ketone, methyl isobutyl ketone.

9. The process as claimed in claim 7, wherein the removal of solvent in (b)(i) is carried out by solvent distillation, concentration, spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.

10. The process as claimed in claim 7,wherein in step (b)(ii) the antisolvent is haloalkanes, ketones, alcohols, ethers, esters, hydrocarbons, dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.

Dated this 19th day of February, 2019

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED