Crystalline salts of lisdexamfetamine

FIELD OF THE INVENTION

The present invention relates to salts of pure amphetamine prodrug, in particular, L-lysine-d- amphetamine (known as Hsdexamfetamine) and industrial advantageous process for preparation thereof.

Further the present invention relates to the crystalline salts of Hsdexamfetamine.

Further the present invention relates to a process for preparing the crystalline salts of lisd exarnf etamine .

BACKGROUND OF THE INVENTION

Lisdexamfetamine of formula I, is a conjugate of D -amphetamine and L-lysine and is chemically named as (2S)-2,6-diamino-N-[(lS)-methyl-2-phenylethyl] hexanamide.

Amphetamines stimulate central nervous system (CNS) and prescribed for treatment of various disorders, including attention deficit hyperactivity disorder (ADHD), obesity, nacrolepsy.

It is approved as lisdexamfetamine dimesylate having formula IA, and marketed under trade name Vyvanse for treatment of attention -deficit hyperactivity disorder. L-Lysine-d-amphetamine (lisdexamfetamine) and its pharmaceutically acceptable salts were first disclosed in US patent 7,662,787 wherein it is exemplified as hydrochloride salt.

In equivalent patent US7,659,253, process for preparation of mesylate salt is disclosed and it is prepared by reacting formula II with methane sulfonic acid.

The inventors of the present invention observed that the dimesylate salt of L-lysine-d- amphetamine is very hygroscopic and liquefies at moderate relative humidity levels. Said properties are critical with regard to production, pharmaceutical processing and storage require strict control of the humidity levels of the surrounding atmosphere during all process steps and storage in order to ensure reHable efficacy and safety of the drug product containing L-lysine-d- amphetamine dimesylate.

European patent no. 3459538 disclosed crystaHine salts of L-lysine-d- amphetamine and their polymorphs; wherein the salts were diadipate; ditosylate; difumarate and dioxalate. Further, it disclosed that both the crystaHine diadipate and ditosylate salts of L-lysine-d -amphetamine can exist in two polymorphic forms named as form I and form II.

The dioxalate salt with CAS RN 4907-02-2 for a different stereoisomer of Hsdexamfetamine is disclosed in BE658 748A .

Polymorphism is an influential phenomenon especiaHy in pharmaceutical sciences, as it can significantly influence variety of active pharmaceutical ingredient (API) properties including flowabHity, tableting, dissolution rate, solubihty, stabHity and even biological performance including efficacy and toxicity. This is the reason that detection of polymorphs in the drug manufacturing process and drug discovery is extremely crucial for quahty control and assurance.

There are very few salts of Hsdexamfetamine which are specifically prepared such as hydrochloride, mesylate, diadipate, ditosylate, difumarate and dioxalate. Therefore, there is an urgent need to develop more crystaHine salts of Hsdexamfetamine, which are pharmaceutically acceptable, physically more stable and reproducible at industrial scale.

OBJECT OF THE INVENTION

The principal object of the present invention is to provide salts of Hsdexamfetamine.

Another object of this invention is to provide the crystaHine salts of Hsdexamfetamine. Another object of this invention is to provide an industrial advantageous process for preparation of the crystaHine salts of Hsdexamfetamine.

A further object of this invention is to provide a pharmaceutical composition in oral dosage form comprising the crystaHine pharmaceutically acceptable salt(s) of Hsdexamfetamine and one or more pharmaceuticaHy acceptable additives.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide salt of hsdexamfetamine having Formula IB.

In another aspect, the present invention is to provide the crystalline salts of Hsdexamfetamine having Formula IB .

In another aspect, the present invention relates to a process for the preparation of crystalline salt of hsdexamfetamine having Formula IB, comprising the step of: i) reacting the Boc-protected Hsdexamfetamine having Formula II, with an acid in presence of a suitable solvent to get a reaction mixture and ii) isolating the crystalline salt of hsdexamfetamine having Formula IB.

In another aspect, the present invention relates to a process for the preparation of the crystaHine salt of Hsdexamfetamine having Formula IB, comprising the step of: i) reacting lisdexamfetamine of Formula I, with suitable acid in presence of a solvent to get a reaction mixture and ii) isolating the crystalline salt of lisdexamfetamine having Formula IB.

In another aspect, the present invention relates to a pharmaceutical composition in oral dosage form comprising i) crystalline salt of Hsdexamfetamine having Formula IB and ii) one or more pharmaceutically acceptable additives.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: X-ray diffraction (XRD) pattern of Hsdexamfetamine dibesylate

Figure 2: Differential scanning calorimetry (DSC) thermogram pattern of lisdexamfetamine dibesylate

Figure 3: Proton NMR spectrum of Hsdexamfetamine dibesylate

Figure 4: Infrared (IR) spectrum of Hsdexamfetamine dibesylate

Figure 5: Mass spectrum of Hsdexamfetamine dibesylate

Figure 6: X-ray diffraction (XRD) pattern of Hsd examphetamine sulfate salt (Form-1)

Figure 7: X-ray diffraction (XRD) pattern of Hsd examphetamine sulfate salt (Form-2)

Figure 8: X-ray diffraction (XRD) pattern of Hsdexamphetamine difumarate salt

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides salt of Hsdexamfetamine having Formula IB wherein the salt is selected from pharmaceutically acceptable salts .

In one embodiment, the pharmaceutically acceptable salts can be selected from the group comprising of di-benzene sulfonate (dibesylate/dibesilate), hydrogen sulfate and difumarate.

The present inventors have tried many pharmaceutically acceptable salts for preparing corresponding salt of Hsdexamfetamine and observed that either many acids do not form salt with Hsdexamfetamine or some acid addition salts do not crystallize out or isolate from the reaction mixture. However, the inventors of the present invention are able to discover some more crystalline salts of Hsdexamfetamine having Formula IB with their immense efforts and optimization in process. The present invention crystaHine salts of Hsdexamfetamine having Formula IB are physically more stable and reproducible at industrial scale.

In one embodiment, the present invention provides a crystaHine salt of Hsdexamfetamine having Formula IB .

In one embodiment, the present invention provides a crystaHine salt of Hsdexamfetamine having Formula IB, which may be characterized by analytical methods known in the art such as X-ray powder diffraction ("PXRD") pattem/X-ray diffraction (XRD), melting point, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), UV spectrum, Proton NMR spectrum, IR spectrum and mass spectrum.

In one specific embodiment, the present invention provides a di-benzene sulfonate (dibesylate/dibesilate) salt of Hsdexamfetamine having Formula IC.

2

The compound of Formula IC is characterized by analytical techniques known in the art such as X-ray diffraction (XRD) 2-theta values comprising reflections at 5.6, 7.7, 10.1, 13.3, 19.9, 21.1, 22.9 ±0.2 degrees 29. According to one embodiment, the crystalline form of Formula IC is characterized by X-ray diffraction (XRD) 2-theta values comprising reflections at 5.6, 6.0, 7.7, 9.6, 10.1, 10.3, 11.4, 13.3, 14.8, 15.5,17.0, 17.3, 18.1, 19.0, 19.3, 19.9, 20.4, 20.7, 21.1, 21.4, 22.1, 22.9, 23.5, 23.7, 24.4, 24.7, 25.1, 25.9 ±0.2 degrees 20.

The compound of Formula IC is characterized by X-ray diffraction as shown in Figure 1.

The compound of Formula IC is characterized by differential scanning calorimetry (DSC) comprising of two endothermic peaks, one onset peak in the range of 160-170°C and the other onset peak in the range of 230-240°C.

In a specific embodiment, the compound of Formula IC may be characterized by differential scanning calorimetry (DSC) as shown in Figure 2 or characterized by two endothermic onset peaks, one at about 164.86°C and the other at about 236.51°C.

The inventors of the present invention observed that the dimesylate salt of L-lysine-d- amphetamine is very hygroscopic and liquefies at moderate relative humidity levels. Said properties are critical with regard to production, pharmaceutical processing and storage require strict control of the humidity levels of the surrounding atmosphere during all process steps and storage in order to ensure reHable efficacy and safety of the drug product containing L-lysine-d- amphetamine dimesylate.

The Hsdexamfetamine di-benzene sulfonate salt having Formula IC of present invention is less hygroscopic as compared to innovator’s di-mesylate salt of lisdexamfetamine and results of hygroscopicity study are tabulated below: In other specific embodiment, the present invention provides a crystalhne salt of Hsdexamfetamine having Formula IB, wherein the crystalline salt is selected from the group comprising of

• Lisdexamfetamine benzene sulfonate (dibesylate/dibesilate) and

• Lisdexamfetamine hydrogen sulfate wherein the crystalline salt of Hsdexamfetamine having Formula IB may be characterized by the analytical methods known in the art such as X-ray powder diffraction ("PXRD") pattem/X-ray diffraction (XRD), melting point, differential scanning calorimetry (DSC), UV spectrum, Proton NMR spectrum, IR spectrum and mass spectrum.

In other embodiment, crystalline salt of Hsdexamfetamine having Formula IB may exist in one or more polymorphic forms and may be characterized by the analytical methods known in the art.

In a specific embodiment, crystalhne Hsdexamfetamine hydrogen sulfate may exist in two polymorphic forms named Form-1 and Form-2 and characterized by XRD as shown in Figure 6 and Figure 7 respectively.

In one embodiment, the crystalhne Form-1 of Hsdexamfetamine hydrogen sulfate is characterized by X-ray diffraction (XRD) 2-theta values comprising reflections at 5.2, 10.4, 17.9, 18.1, 19.2, 20.8 ±0.2 degrees 29.

In another embodiment, the crystaHine Form-1 of Hsdexamfetamine hydrogen sulfate is characterized by X-ray diffraction (XRD) 2-theta values comprising reflections at 5.2,10.2, 10.4, 16.5, 17.7, 17.9, 18.1, 19.2, 19.6, 20.8, 23.5, 24.8, 26.2 ±0.2 degrees 29.

According to another embodiment, the crystaHine Form-2 of Hsdexamfetamine hydrogen sulfate is characterized by X-ray diffraction (XRD) 2-theta values comprising reflections at 4.5, 8.5, 14.6, 17.2, 22.2, 22.8, 23.0, 24.0 ±0.2 degrees 29.

According to another embodiment, the crystaHine Form-2 of Hsdexamfetamine hydrogen sulfate is characterized by X-ray diffraction (XRD) 2-theta values comprising reflections at 4.5, 8.0, 8.5, 12.5, 14.6, 15.2, 16.1, 17.2, 20.0, 21.2, 22.2, 22.8, 23.0, 24.0, 24.3, 25.2, 27.0, 27.8 ±0.2 degrees 20.

In one embodiment, the present invention provides a process for the preparation of crystalline salt of lisdexamfetamine having Formula IB, wherein the salt is selected from dibesilate and hydrogen sulfate comprising the step of: i) reacting the Boc-protected Hsdexamfetamine having Formula II, with an acid selected from benzene sulfonic acid and sulfuric acid in presence of a suitable solvent to get a reaction mixture and ii) isolating the crystaHine salt of lisdexamfetamine having Formula IB.

The said process step i) to step ii) may be proceeded as follow: a solution of Boc-protected Hsdexamfetamine having Formula II is made with a suitable solvent at a temperature in the range of 40°C to 70°C and then acid is added to the solution to get a reaction mixture. Then, the reaction mixture is stirred at a suitable temperature for a suitable time to obtain the product.

The suitable solvent used for making solution of Boc-protected lisdexamfetamine having Formula II may be selected from the group comprising of alcohol, ester and/or mixture thereof.

The alcohols solvent used in the present invention are selected from but not Hmited to methanol, ethanol, isopropanol, n-butanol and the like or mixture thereof.

The esters solvent used in the present invention are selected from but not limited to ethyl acetate, methyl acetate isopropyl acetate and the like or mixture thereof. The acid of the present invention which are solid/powdered in nature may be added in the reaction in the form of solution and the solution is prepared by using the suitable solvent as mentioned above.

The reaction mixture is stirred at a temperature in the range of 15°C to 60 °C for few minutes to several hours or till the reaction completion.

After the completion of the reaction, the salt of Hsdexamfetamine or crystalline lisdexamfetamine having Formula IB is isolated from the reaction mixture of step i) by techniques known in the prior art such as distillation, centrifugation, filtration or cooling the reaction mixture followed by filtration, decantation and the like.

Optionally, the isolated salt having Formula IB may be further purified by any techniques known in the art. The purification of the isolated salt having Formula IB may be done by any techniques known in the art such as precipitation, washing or crystallization by using solvent or mixture of solvent or by using solvent and anti-solvent or combination of the said techniques thereof.

In one embodiment, the purification of isolated salt having Formula IB may be done by using solvent selected from the group comprises of alcohol, ester, and/or mixture thereof.

In other embodiment, the present invention provides a process for the preparation of crystalline salt of lisdexamfetamine having Formula IB, wherein salt is selected from dibesilate, hydrogen sulfate and difumarate, comprising the step of: i) reacting the lisdexamfetamine of Formula I, with suitable acid selected from benzene sulfonic acid, sulfuric acid and fumaric acid in presence of a solvent to get a reaction mixture and ii) isolating the crystalline salt of lisdexamfetamine having Formula IB. The said process step i) to step ii) may be proceeded as follow: a solution of Hsdexamfetamine of Formula I is made with a solvent and the acid is added slowly to the solution to get a reaction mixture. Then, the reaction mixture is stirred at a suitable temperature for a suitable time and isolating crystalline salt of Hsdexamfetamine having Formula IB.

The solvent used for making solution of lisdexamfetamine having Formula I may be selected from the group comprising of alcohols, esters and the like and/or mixture thereof.

The alcohols solvent used in the present invention are selected from but not limited to methanol, ethanol, isopropanol, n-butanol and the like or mixture thereof.

The esters solvent used in the present invention are selected from but not limited to ethyl acetate, methyl acetate isopropyl acetate and the like or mixture thereof.

The acid of the present invention which are solid/powdered in nature may be added in the reaction in the form of solution and the solution is prepared by using the solvent as mentioned above.

The reaction is stirred at a temperature in the range of 10 °C to 60 °C for few minutes to several hours or till the reaction completion.

The isolation of crystalline salt of Hsdexamfetamine having Formula IB may be done by any techniques known in the art.

In a preferred embodiment, the isolation of crystaHine salt of lisdexamfetamine having Formula IB from reaction mixture may be done by distillation, centrifugation, filtration, decantation or by precipitation or by crystalhzation or combination of the said techniques thereof and the like.

In one embodiment, the crystalhzation may be facilitated by addition of another solvent in the reaction mixture of the step i), wherein acid is selected from benzene sulfonic acid and sulfuric acid. After addition of another solvent to the reaction mixture of the step i), the resulting mixture is heated at suitable temperature ranging from 25 °C to 60 °C and then cooled at temperature ranging from 10°C to 30 °C to obtain corresponding crystalline salts of Hsdexamfetamine. The another solvent added in the reaction mixture to facihtate the crystalhzation is selected from the group comprising of ester, ether and/or mixture thereof. The esters solvent used in the present invention are selected from but not limited to ethyl acetate, methyl acetate isopropyl acetate and the like or mixture thereof. The ethers solvent used in the present invention are selected from but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, t-butyl methyl ether and the like or mixture thereof.

The crystalline salt of lisdexamfetamine having Formula IB of present invention may be used to prepare a pharmaceutical composition in oral dosage form comprises one or more pharmaceutically acceptable additives.

The crystalline salt of lisdexamfetamine having Formula IB of present invention may be used to prepare hsdexamfetamine free base or its other pharmaceutically acceptable salt selected from hydrochloride, mesylate, diadipate, dioxalate and alike. In one embodiment, the present invention provide a process for preparing lisdexamfetamine free base and/or its pharmaceutically acceptable salt selected from hydrochloride, mesylate, diadipate, dioxalate and alike comprises reacting crystalline salt of hsdexamfetamine, wherein salt is selected from dibesilate, hydrogen sulfate and difumarate, with a base and/or converting lisdexamfetamine free base to its pharmaceutically acceptable salt.

The hsdexamfetamine of Formula I and Boc -protected lisdexamfetamine having Formula II are used in the present invention may be prepared by any method known in the prior art. The Boc- protected hsdexamfetamine used in the present invention may be purified with ethanol, water or a mixture thereof. The said purification is carried out at a temperature in the range of 40°C to 70°C.

The completion and monitoring of the reaction of the present invention is checked by any analytical techniques known in the prior art.

EXAMPLE 1: Preparation of Form-1 of crystalline lisdexamfetamine sulfate salt from lisdexamfetamine free base

To hsdexamfetamine free base (10.5 g) ethanol (60 ml) was added at 20-30°C and stirred to get a clear solution. The solution was cooled to 15-20 °C and sulfuric acid (2.3 ml) was added dropwise to the reaction solution to get as reaction mixture. The reaction mixture was stirred for 2 hours and isopropyl ether (100 ml) was added and the reaction mixture again stirred for 2 hours to get a solid product. The solid was then filtered under nitrogen atmosphere and washed with isopropyl ether (40 ml). The resulting solid was dried under vacuum at 45-50°C for 12 hours to give crystalline hsdexamfetamine sulfate. EXAMPLE 2: Preparation of crystalline Form-1 of lisdexamfetamine sulfate salt from lisdexamfetamine free base

To Lisdexamfetamine free base (10g) ethanol (20 ml) was added at 20-30 °C and stirred to get a clear solution. The solution was then cooled to 15-20 °C and sulfuric acid (3.7 g) was added slowly into it, temperature was raised to 25-30 °C and stirred for 3 hours to obtain a suspension. To the suspension isopropyl ether (85 ml) was added slowly, stirred and solid was then filtered under nitrogen atmosphere and washed with isopropyl ether (30 ml). The solid was dried under vacuum at 50-55 °C for 12 hours to give crystalline lisdexamfetamine sulfate salt.

EXAMPLE 3: Preparation of crystalline Form-2 of lisdexamfetamine sulfate salt from Boc- protected lisdexamfetamine

Boc-protected Lisdexamfetamine (50g) was added to methanol (200 ml) at 20-30°C and stirred to get a clear solution. The solution was cooled to 0-5 °C and sulfuric acid (31.85 g) was added slowly into the solution to get a reaction mixture. The temperature of the reaction mixture was raised to 25-30 °C and stirred for 4 hours. After completion of the reaction, methanol was distilled under vacuum to get crude. Ethyl acetate (150 ml) was added to the crude and solvent was distilled and degassed under vacuum. To this crude ethanol (75 ml) was added and the temperature was raised to 50-55°C. Then, ethyl acetate (500 ml) was added and stirred for 18 hours at 25-30°C. Reaction mixture was cooled to 10-15°C, stirred for 30 minutes, filtered under nitrogen atmosphere and washed with ethyl acetate (150 ml). The solid was dried under vacuum at 50-55°C for 12 h to give crystalline Hsdexamfetamine sulfate.

EXAMPLE 4: Preparation of crystalline lisdexamfetamine dibesilate salt from Boc- protected lisdexamfetamine

Boc-protected Hsdexamfetamine (20g) was added to ethanol (140 ml) at 25-35°C and stirred to get a clear solution. To this solution benzenesulfonic acid (30.72g) in ethanol (20 ml) was added slowly under nitrogen atmosphere and temperature of the resulting reaction mixture was raised to 30-40 °C. The reaction mixture was stirred for 24 hours. After completion of the reaction, ethanol was distilled under vacuum to get a crude. Ethyl acetate (20 ml) was added to the crude and distiHed degassed under vacuum and ethyl acetate (100 ml) was added at 25 -30 °C to get a reaction mixture. The reaction mixture was stirred, cooled, filtered under nitrogen atmosphere and washed with chilled ethyl acetate (20 ml) to obtain wet solid. The wet solid was dried under vacuum at 50-55°C for 12 hours to give crystalline Hsdexamfetamine dibesilate salt.

EXAMPLE 5: Preparation of lisdexamfetamine dibesilate salt from Boe -protected Lisdexamfetamine

Boc-protected Hsdexamfetamine (1kg) was added to ethyl acetate (11L) at 25-35°C and stirred at 50-60°C to get a clear solution. To the reaction mixture solution of benzenesulf onic acid (1.43kg) in ethyl acetate (2L) was added slowly into the reaction mixture under nitrogen atmosphere at a temperature of 35-40 °C and stirred for 15 hours. After completion of the reaction, the resulting reaction mixture was filtered under nitrogen atmosphere to give wet Hsdexamfetamine dibesilate salt. The resulting wet salt was successively washed with ethyl acetate (20L) and dried under vacuum to give crystahine lisdexamfetamine dibesilate.

EXAMPLE 6: Preparation of crystalline lisdexamfetamine dibesilate salt from lisdexamfetamine free base

To Hsdexamfetamine free base (10g) ethanol (20 ml) was added at 20-30 °C and stirred to get a clear solution. To the solution, a solution of benzenesulfonic acid (13.2g) in ethanol (20 ml) was added slowly. The temperature of the resulting reaction mixture was raised to 50-55 °C, stirred for 30 minutes and ethyl acetate (150 ml) was added slowly to the reaction mixture. To the reaction mixture ethyl acetate (150 ml) was added, stirred for 1 hour and cooled to 20-25 °C. The reaction mixture was further stirred for 2 hours and the resulting sohd was then filtered under nitrogen atmosphere and washed with ethyl acetate (20 ml). The sohd was dried under vacuum at 50-55°C for 12 hours to give crystalhne lisdexamfetamine dibesHate salt.

EXAMPLE 7: Preparation of crystalline lisdexamfetamine dibesilate salt from lisdexamfetamine free base

To Hsdexamfetamine free base (10g) ethyl acetate (40 ml) and ethanol (30 ml) were added at 20- 30 °C and stirred to get a clear solution. A solution of benzenesulfonic acid (13.2g) in ethyl acetate (15 ml) was added slowly into the solution and temperature was raised to 50-55 °C to get a reaction mixture. The reaction mixture was stirred for 1 hour, ethyl acetate (100 ml) was added slowly and stirred for 1 hour. Then, the reaction mixture was cooled to 20-25 °C, ethyl acetate (40 ml) was added and stirred for 2 hours to obtain a solid. The solid was then filtered under nitrogen atmosphere, washed with ethyl acetate (20 ml) and dried under vacuum at 50-55°C for 12 hours to give crystalline lisdexamfetamine dibesilate salt.

EXAMPLE 8: Preparation of crystalline lisdexamfetamine difumarate salt from lisdexamfetamine free base

To Hsdexamfetamine free base (10g) ethanol (15ml) was added at 20-30 °C and stirred to get a clear solution. The solution was then cooled to 15-20 °C and suspension of fumaric acid (8.8g) in ethanol (88ml) was added slowly into the solution to give a reaction mixture. The reaction mixture was stirred for 4 hours to give a solid. The solid was then filtered under nitrogen atmosphere, washed with ethanol (30 ml) and dried under vacuum at 50-55 °C for 12 hours to give crystalline lisdexamfetamine difumarate salt.

EXAMPLE 9. Preparation of crystalline lisdexamfetamine difumarate salt from lisdexamfetamine free base

To Hsdexamfetamine free base (10g) ethanol (15 ml) was added at 20-30 °C and stirred to get a clear solution. The solution was then cooled to 15-20 °C and suspension of fumaric acid (8.8g) in ethanol (88 ml) was added slowly into the solution to give a reaction mixture. The reaction mixture was stirred for 4 hours to give a sohd. The sohd was then filtered under nitrogen atmosphere, washed with ethanol (15 ml) and dried under vacuum at 50-55 °C for 12 hours to give crystaHine lisdexamfetamine difumarate salt.