DESC:FIELD OF THE INVENTION:
The present invention relates to (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide besylate salt represented by following structural formula-Ia, a crystalline form thereof, and methods of preparing the (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide besylate salt, which is a prodrug of dextroamphetamine which requires conversion in the gastrointestinal (GI) tract to release the active drug.
BACKGROUND OF THE INVENTION:
Lisdexamfetamine (L-lysine-d-amphetamine) of formula-I a is an inactive prodrug consisting of the psychostimulant d-amphetamine coupled with the essential amino acid L-lysine. Lisdexamfetamine is a prodrug of dextroamphetamine which requires conversion in the gastrointestinal (GI) tract to release the active drug.

Formula-I a
Lisdexamfetamine marketed under the brand name Vyvanse® is used as part of a treatment program to control symptoms of attention deficit hyperactivity disorder (ADHD; more difficulty focusing, controlling actions, and remaining still or quiet than other people who are the same age) in adults and children. Lisdexamfetamine is in a class of medications called central nervous system stimulants. It works by changing the amounts of certain natural substances in the brain.
The prior art below has suggested references for salts of Lisdexamfetamine and process for the preparation thereof.
The prior art reference NL 6414901 (hereafter NL ‘901) patent discloses various acylated compounds of d-amphetamine, wherein the acyl groups are selected from the optically active amino acids which are optionally protected. The compound includes the oxalate salt of D-lysine-d-amphetamine and also a tosyl protected L-lysine-d-amphetamine. This reference is silent about besylate salt of Lisdexamfetamine.
The US patent application US2004220277A1 (hereafter US ‘277) discloses pharmaceutical combination comprising an effective amount for a day of amphetamine in base and/or salt form, where the amphetamine is an amphetamine salt. Pharmaceutically acceptable salts, e.g., non-toxic, inorganic and organic acid addition salts. This reference is silent about besylate salt of Lisdexamfetamine.
The US patent US7105486B2 (hereafter US ‘486) patent discloses dextro- and levo-isomers i.e., L-lysine-d-amphetamine) a method for treating a patient having attention deficit hyperactivity disorder, comprising orally administering to the patient in need thereof a pharmaceutically effective amount of L-lysine-d-amphetamine, or salts thereof. Pharmaceutically acceptable salts, e.g., mesylate salt of L-lysine-d-amphetamine, hydrochloride salt of L-lysine-d-amphetamine.
The US patent US 7,223,735 (IN 1115/KOLNP/2006 A) (hereafter US ‘735) patent discloses a method for treating a patient having attention deficit hyperactivity disorder, comprising orally administering the patient with a pharmaceutically effective amount of L-lysine-d-amphetamine or its salts. However, this reference too is silent about besylate salt of Lisdexamfetamine.
The US patent US 7,659,253 (hereafter US ‘253) discloses the crystalline form of Lisdexamfetamine dimesylate and its preparation. The crystalline form is characterized by having PXRD peaks at 4.5, 9.0, 12.0, 15.7 and 16.3 ± 0.2.
US ‘253 also discloses the process for the preparation of Lisdexamphetamine dimesylate from di-amine protected Lisdexamphetamine. The di-amine protected Lisdexamphetamine is deprotected and optionally converted to salt. The deprotection and salt conversion are performed in a single reaction. For example, the di-amine protected Lisdexamphetamine reacted with methane sulfonic acid to form Lisdexamphetamine dimesylate. Preferably, this reaction is performed in the presence of an alcohol, such as isopropanol.
US ‘253 also discloses amphetamine is an amphetamine salt. Pharmaceutically acceptable salts, e.g., non-toxic, inorganic and organic acid addition salts, are known in the art. Said document refers to a long list of acid components, wherein among many others besylate is mentioned. However, no further information is given, neither about its method of preparation nor to its properties.
The US patent application US20120157706A1 discloses the process for the preparation of Lisdexamphetamine salts. Wherein LDX is reacted with methanesulfonic acid to yield Lisdexamphetamine dimesylate salt. This reference is silent about besylate salt of Lisdexamfetamine.
The EP patent no. EP 3459538 discloses crystalline salts of L-lysine-d-amphetamine and their polymorphs; wherein the salts are diadipate; ditosylate; difumarate and dioxalate. This reference is silent about besylate salt of Lisdexamfetamine.
After numerous trials and earnest efforts, the present inventors surprisingly found besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide having advantageous properties which is useful and well suitable for the preparation of various pharmaceutical compositions.
Lisdexamfetamine should be provided in a form that shows improved properties with regard to Hygroscopicity. LDB is non-Hygroscopic in nature where-in LDX is Deliquescent in nature. Therefore, Lisdexamfetamine besylate has the advantage of better handling and storage conditions compared to the marketed Lisdexamfetamine dimesylate. Hence, there is no specific requirement of moisture proof packing for storage. However, handling of LDX is very critical, and difficult due to it’s deliquescent nature and it requires specific packing conditions for storage.
The Lisdexamfetamine besylate of the present invention shows an advantageous hygroscopicity (lower), has improved melting point (higher), compared to marketed Lisdexamfetamine dimesylate. Moreover, Lisdexamfetamine besylate being non-hygroscopic has longer shelf-life.

OBJECTIVE OF THE INVENTION
The main object of the present invention is to provide a besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide.
Another object of the present invention is to provide dibesylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide.
Another object of the present invention is to provide a crystalline form of besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I.
One another object of the present invention is to provide a process for the preparation of besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I from {C,C’-Bis(1,1-dimethylethyl) N,N’-[(1S)-1-[[[(1S)-1-methyl-2-phenylethyl]amino]carbonyl]-1,5-pentanediyl]bis[carbamate}.
Another object of the present invention is to provide a process for the preparation of the besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I from Lisdexamfetamine dimesylate.
One another object of the present invention is to provide a form of Lisdexamfetamine besylate showing superior properties e.g., hygroscopicity than the marketed Lisdexamfetamine dimesylate.

SUMMARY OF THE INVENTION
The first aspect of the present invention is to provide a besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide, preferably dibesylate salt.
Another aspect of the present invention is to provide a crystalline form-Z of besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I.
The crystalline form-Z of the present invention can be characterized by one or more of the following characteristics:
a) PXRD pattern of LDB substantially in accordance with figure-01,
b) Powder X-Ray diffractogram having peaks at about 5.65, 6.02, 7.70, 9.60, 10.07, 10.27, 11.36, 12.13, 13.24, 14.77, 15.51, 16.57, 17, 17.27, 18.04, 18.24, 18.93, 19.30, 19.92, 20.37, 20.68, 21.06, 21.4, 21.89, 22.07, 22.89, 23.46, 23.72, 24.41,24.68, 25.07, 25.57, 25.94, 26.44, 26.74, 27.02, 27.42, 28.24, 28.65, 28.96, 29.26,29.97, 30.52,31.36, 31.88, 32.20, 32.53, 33.06, 33.66, 34.10, 34.32, 34.80, 35.54, 36.47, 37.02,37.38, 38.37 and 39.33 ±0.2 degrees of two-theta.
One another aspect of the present invention is to provide a process for the preparation of besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide comprising:
a. dissolving or suspending {C, C’-Bis(1,1-dimethylethyl) N, N’-[(1S)-1-[[[(1S)-1-methyl-2-phenylethyl]amino]carbonyl]-1,5-pentanediyl]bis[carbamate} in a suitable solvent;
b. adding benzene sulfonic acid; and
c. isolating besylate salt of Lisdexamfetamine
Another aspect of the present invention is to provide a process for the preparation of the besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I comprising:
a. dissolving or suspending {C, C’-Bis(1,1-dimethylethyl) N, N’-[(1S)-1-[[[(1S)-1-methyl-2-phenylethyl]amino]carbonyl]-1,5-pentanediyl]bis[carbamate} in a suitable solvent like ethanol, propanol, methanol and Isopropanol preferably Isopropanol;
b. adding benzene sulfonic acid;
c. inducing crystallization of the salt in Isopropyl alcohol: Water, and
d. recovering the crystalline besylate salt.
Yet, another aspect of the present invention is to provide a process for the preparation of the besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I from Lisdexamfetamine dimesylate comprising:
a. dissolving or suspending Lisdexamfetamine dimesylate in a suitable solvent and base;
b. adding benzene sulfonic acid; and
c. isolating crystalline dibesylate salt.
Another aspect of the present invention is to provide a process for the preparation of the besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I from Lisdexamfetamine dimesylate comprising:
a. dissolving or suspending Lisdexamfetamine dimesylate in a suitable solvent and base;
b. optionally isolating Lisdexamfetamine base;
c. dissolving or suspending Lisdexamfetamine base in a suitable solvent;
d. adding Benzene sulfonic acid; and
e. isolating besylate salt of Lisdexamfetamine.
The hygroscopicity of Lisdexamfetamine dimesylate and Lisdexamfetamine besylate powder of this invention was measured, according to EP standard test procedure. When the relative humidity is 80%, the Lisdexamfetamine dimesylate sample deliquesces and becomes an aqueous solution, increase in mass was equal to or greater than 15 per cent. According to the adsorption, the increase mass of Lisdexamfetamine besylate is less than 0.2 per cent, hence, experienced the process of slow water absorption and slow water loss, at 80% relative humidity, confirming that the Lisdexamfetamine besylate is non-hygroscopic. The moisture absorption rate of Lisdexamfetamine besylate was all within 2%, indicating that Lisdexamfetamine and di benzene sulfonic acid salt formation can significantly improve its hygroscopicity.
DEFINITIONS
All temperatures used herein are in degrees Celsius unless specified otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
The term “LDB” refers to Lisdexamfetamine besylate.
The term “LDX” refers to Lisdexamfetamine dimesylate.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure-01: Illustrates the powder X-Ray diffraction pattern of crystalline form of besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide compound of formula-I.
Figure-02: Illustrates the DSC thermogram of crystalline form besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide compound of formula-I.
Figure-03: Illustrates TGA of besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide compound of formula-I.
Figure-04: Illustrates IR spectra of besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide compound of formula-I.

DETAILED DESCRIPTION OF THE INVENTION:
One aspect of the present invention is to provide a besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I, preferably dibesylate salt and crystalline form of besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide, herein after designated as crystalline form-Z.
The crystalline form-Z of the present invention can be characterized by one or more of the following characteristics:
a) PXRD pattern of LDB substantially in accordance with Figure 01,
b) Powder X-Ray diffractogram having peaks at about 5.65, 6.02, 7.70, 9.60, 10.07, 10.27, 11.36, 12.13, 13.24, 14.77, 15.51, 16.57, 17, 17.27, 18.04, 18.24, 18.93, 19.30, 19.92, 20.37, 20.68, 21.06, 21.4, 21.89, 22.07, 22.89, 23.46, 23.72, 24.41,24.68, 25.07, 25.57, 25.94, 26.44, 26.74, 27.02, 27.42, 28.24, 28.65, 28.96, 29.26,29.97, 30.52,31.36, 31.88, 32.20, 32.53, 33.06, 33.66, 34.10, 34.32, 34.80, 35.54, 36.47, 37.02,37.38, 38.37 and 39.33 degrees of two-theta,
In the present application, the XRPD is measured as described further below in the description. Further, unless indicated otherwise, XRPD peaks are reported as degrees 2? values with a standard error of ± 0.2 degrees 2?.
One aspect of the present invention is to provide a process for the preparation of besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide comprising:
a. dissolving or suspending {C, C’-Bis(1,1-dimethylethyl) N, N’-[(1S)-1-[[[(1S)-1-methyl-2-phenylethyl]amino]carbonyl]-1,5-pentanediyl]bis[carbamate} in a suitable solvent;
b. adding benzene sulfonic acid; and
c. isolating besylate salt of Lisdexamfetamine.
The suitable solvent of step A is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol, isopropanol and the like or a mixture thereof. In a preferred aspect, the solvent is selected from isopropanol, and methanol, or a mixture thereof.
Another aspect of the present invention is to provide a process for the preparation of the besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I comprising:
a. dissolving or suspending {C, C’-Bis(1,1-dimethylethyl) N, N’-[(1S)-1-[[[(1S)-1-methyl-2-phenylethyl]amino]carbonyl]-1,5-pentanediyl]bis[carbamate} in a suitable solvent like ethanol, propanol, methanol and Isopropanol preferably Isopropanol;
b. adding benzene sulfonic acid;
c. inducing crystallization of the salt in Isopropyl alcohol: Water, and
d. recovering the crystalline besylate salt.
Yet, another aspect of the present invention is to provide a process for the preparation of the besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I from Lisdexamfetamine dimesylate comprising:
a. dissolving or suspending Lisdexamfetamine dimesylate in a suitable solvent and base;
b. adding benzene sulfonic acid; and
c. isolating crystalline dibesylate salt.
The suitable solvent of step A is Dichloromethane. The suitable base of step A is selected from the group comprising of Sodium Hydroxide, Potassium Hydroxide, and the like or mixture thereof.
Another aspect of the present invention is to provide a process for the preparation of the besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide compound of formula-I from Lisdexamfetamine dimesylate comprising:
a. dissolving or suspending Lisdexamfetamine dimesylate in a suitable solvent and base;
b. optionally isolating Lisdexamfetamine base;
c. dissolving or suspending Lisdexamfetamine base in a suitable solvent;
d. adding Benzene sulfonic acid; and
e. isolating besylate salt of Lisdexamfetamine.
The suitable solvent of step A is Dichloromethane. The suitable base of step A is selected from the group comprising of Sodium Hydroxide, Potassium Hydroxide, and the like or mixture thereof. The suitable solvent of step C is selected from the group comprising of of alcohols such as methanol, ethanol, propanol, butanol, isopropanol and the like or a mixture thereof. In a preferrable aspect, the solvent is selected from isopropanol, and methanol, or a mixture thereof.
The crystalline salt of the present invention may be characterized by any one of the following aspects or by combining two or more of the following aspects.

i) X-Ray Diffractograph (XRD)Analysis

The crystalline form of the compound of formula (I), characterised by the following powder X-ray diffraction diagram measured using a diffractometer and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense line):
Table 01: Peak and Relative Intensity Listing (2-theta, peaks with I/I1 value of 10 and over)
Index 2-theta D Value (A) Rel Intensity
1 5.651 15.6258A 71.00%
2 6.026 14.65599A 34.90%
3 7.709 11.45817A 58.00%
4 9.602 9.20341A 23.40%
5 10.072 8.77558A 86.60%
6 10.27 8.60648A 26.60%
7 11.363 7.78113A 33.90%
8 12.135 7.28763A 1.00%
9 13.248 6.67783A 92.10%
10 14.771 5.99265A 22.60%
11 15.512 5.70780A 4.70%
12 16.578 5.34305A 1.60%
13 17 5.21144A 13.60%
14 17.273 5.12967A 20.30%
15 18.048 4.91106A 19.80%
16 18.246 4.85826A 5.20%
17 18.932 4.68380A 35.40%
18 19.309 4.59313A 28.20%
19 19.924 4.45273A 59.70%
20 20.376 4.35494A 9.50%
21 20.68 4.29153A 20.30%
22 21.067 4.21360A 40.30%
23 21.4 4.14875A 32.60%
24 21.893 4.05647A 10.80%
25 22.074 4.02370A 18.10%
26 22.892 3.88177A 100.00%
27 23.46 3.78905A 34.60%
28 23.723 3.74760A 16.40%
29 24.413 3.64313A 32.20%
30 24.688 3.60330A 18.50%
31 25.075 3.54842A 6.80%
32 25.576 3.48017A 2.60%
33 25.942 3.43177A 22.30%
34 26.445 3.36762A 7.20%
35 26.742 3.33099A 17.70%
36 27.022 3.29702A 6.80%
37 27.426 3.24935A 3.10%
38 28.24 3.15755A 7.80%
39 28.657 3.11260A 6.50%
40 28.961 3.08062A 4.20%
41 29.26 3.04974A 4.40%
42 29.972 2.97892A 8.90%
43 30.528 2.92597A 7.50%
44 31.368 2.84945A 2.90%
45 31.884 2.80455A 1.40%
46 32.205 2.77731 A 1.00%
47 32.535 2.74990A 1.10%
48 33.066 2.70694 A 10.00%
49 33.668 2.65991 A 3.40%
50 34.105 2.62678A 3.50%
51 34.324 2.61055 A 3.50%
52 34.805 2.57552 A 5.10%
53 35.546 2.52356 A 4.90%
54 36.478 2.46115 A 2.80%
55 37.028 2.42585 A 1.20%
56 37.388 2.40330 A 1.40%
57 38.378 2.34358A 1.30%
58 39.337 2.28860 A 2.70%
TABLE-01

ii) Differential Scanning Calorimetry (DSC)

The Lisdexamfetamine besylate of this invention was measured by differential scanning calorimetry, and the results are shown in FIG.02.
As can be seen from Figure 02 the endothermic peak of Lisdexamfetamine besylate is at 240.12°C (onset 239.11 °C).

Material Name Lisdexamfetamine besylate
Batch No. PPM/LDX-II/1220/001 RS
DSC Analysis Onset = 239.11°C
Delta H = 31.3518 J/g
TABLE-02

iii) Melting point

The results are shown in table 03.

Material Name Lisdexamfetamine besylate
Batch No. PPM/LDX-II/1220/001 RS
Melting point 240.12°C
TABLE-03

iv) Hygroscopicity Study

The hygroscopicity of Lisdexamfetamine dimesylate and Lisdexamfetamine besylate powder of this implementation was measured, and the relative humidity of the control instrument was set at 25 ± 1 deg cen. and 80± 2 per cent relative humidity. The measurement results are shown in TABLE-04, TABLE-05 and TABLE-06.

Standard test procedure (As per EP): This method is to be carried out on a substance that complies with the test for loss on drying or water content of the monograph. Use a glass weighing vessel 50 mm in external diameter and 15 mm high to measure. Weigh the vessel and stopper (m1). Place the amount of substance prescribed for the test for loss on drying or water in the vessel and weigh (m2). Place the unstopped vessel in a desiccator at 25 deg cen. containing a saturated solution of ammonium chloride or ammonium sulphate or place it in a climatic cabinet set at 25 ± 1 deg cen. and 80± 2 per cent relative humidity. Allow to stand for 24 h. Stopper the weighing vessel and weigh (m3).

Material Name LDB LDX
Batch No. PPM/LDX-II/1220/001 RS PPM/LDX-III/1033/137
Status / Material Nature Non-Hygroscopic in nature Deliquescent in nature
Hygroscopicity Study Report No. 23/RPT/LDX/006-00 21/RPT/LDX/025-00
TABLE-04
Note: As per the above data, LDB is non-Hygroscopic in nature where-in LDX is Deliquescent in nature. Therefore, LDB has the advantage of ease of handling and storage. Hence, there is no requirement of specific packaging conditions. However, handling LDX is very critical due to it’s deliquescent nature which requires specific packing conditions for storage.

Observations and Results for Lisdexamfetamine dimesylate:

Weigh (gm)

Vessel and stopper (m1) Weigh (gm)

Vessel and weigh (m2)
Weigh (gm)

A/24 Hrs, Stopper the weighing vessel and weigh (m3) Increase in mass.
(%)
42.65250 43.71412 43.98320 25.35%
TABLE-05
Increase in mass is more than 15 per cent. Hence, Lisdexamfetamine dimesylate (LDX) is Deliquescent.

Observations and Results for Lisdexamfetamine besylate:
Weigh (gm)

Vessel and stopper (m1) Weigh (gm)

Vessel and weigh (m2)
Weigh (gm)

A/24 Hrs, Stopper the weighing vessel and weigh (m3) Increase in mass.
(%)
29.01707 30.13029 30.13091 0.15%
TABLE-06
Increase in mass of Lisdexamfetamine besylate (LDB) is less than 0.2 per cent. Hence, Lisdexamfetamine besylate (LDB) is non-hygroscopic.

When the relative humidity is 80%, the Lisdexamfetamine dimesylate sample deliquesces and becomes an aqueous solution, increase in mass was greater than 15 per cent. According to the adsorption, the increase mass of Lisdexamfetamine besylate is less than 0.2 per cent, hence, experienced the process of slow water absorption and slow water loss, at 80% relative humidity, confirming that the Lisdexamfetamine besylate is non-hygroscopic. The moisture absorption rate of Lisdexamfetamine besylate was all within 2%, indicating that Lisdexamfetamine and di benzene sulfonic acid salt formation can significantly improve its hygroscopicity.

v) Thermogravimetry
Thermogravimetric investigations were performed in a temperature range of 5 °C to about 350°C. and the results are shown in Table 07.
Material Name Lisdexamfetamine besylate
Batch No. PPM/LDX-II/1220/001 RS
TGA Analysis Delta Y: 1.502%
TABLE-07

Note: As per the above TGA data, Lisdexamfetamine besylate is considered as absolute structure. There is no hydrate and solvate form in LDB. The measurement results are shown in Figure 03.

vi) Solubility determination
As per solubility data, the solubility of Lisdexamfetamine besylate is comparable with Lisdexamfetamine dimesylate and the results are shown in Table-08.
Sr No. Solvents LDB LDX
PPM/LDX-II/1220/001 RS LDX3200422
1 Water Freely soluble (1 gm/3 ml) Freely soluble (1 gm/1 ml)
2 Dimethyl sulphoxide Freely soluble (1 gm/3 ml) Freely soluble (1 gm/6 ml)
3 Methanol Freely soluble (1 gm/3 ml) Freely soluble (1 gm/1 ml)
4 Toluene Practically Insoluble Practically Insoluble
TABLE-08

VI) Absolute solubility

As per absolute solubility data, LDB has been observed to have almost comparable solubility to LDX and the results are shown in Table-09.

Absolute solubility condition LDB LDX
PPM/LDX-II/1218/027 LDX3200422
0.1 N HCl 915.55 mg/ml 1026.20 mg/ml
0.1 N NaOH 967.53 mg/ml 990.77 mg/ml
Buffer pH 6.8 760.92 mg/ml 1000.34 mg/ml
Buffer pH 7.4 817.53 mg/ml 1033.96 mg/ml
Buffer pH 4.5 843.87 mg/ml 1067.65 mg/ml
water 1044.80 mg/ml 1024.08 mg/ml
TABLE-09

VII) pH Analysis (1% solution in water)
Material Name LDB
Batch No. PPM/LDX-II/1220/001 RS
pH analysis 4.829
TABLE-10

VIII) Benzene sulfonic acid content (By Potentiometry)
Material Name LDB
Benzene sulfonic acid content Theoretical value 54.57% w/w
PPM/LDX-II/1220/001 RS 54.44% w/w (ODB)
TABLE-11
Note: As per the above Benzene sulfonic acid content data by potentiometric titration, it is concluded that Lisdexamfetamine contains two molecules of Benzene sulfonic acid. So, it is dibesylate salt (1:2). Dibesylate salt is also supported based on 1H NMR spectra.

IX) Mass Spectroscopy of Lisdexamfetamine
As per the mass analysis data, it is concluded Lisdexamfetamine exists as a salt of Benzene sulfonic acid (LDB) the results are shown in Table-12.
Molecular weight of Lisdexamfetamine besylate : 579.73
Molecular weight of Lisdexamfetamine free base : 263.37
Molecular weight of Benzene sulfonic acid : 158.18

LDB Observed Mass Mode
PPM/LDX-II/ 1220/001 RS 264.10 (M+H) Positive
157.10 (M-H) Negative
TABLE-12

X) NMR Spectroscopy- LDB
The above 1H-NMR and D2O exchange spectrum supports the structure of LDB.
1) 1H NMR analysis
Structural Formula: -

No. (d) PPM Number of Proton Number Type of Hydrogen Type of Proton
1 0.8642-1.0517 2H 3 -CH2 aliphatic m
2 1.1116-1.1281 3H 8 -CH3 aliphatic d
3 1.3453-1.4865 4H 2, 4 -CH2 aliphatic m
4 2.6054-2.6746 3H 1,7 -CH2 aliphatic m
5 2.7264-2.7743 1H 7 -CH2 aliphatic m
6 3.5969-3.6274 1H 5 -CH aliphatic t
7 4.0590-4.1325 1H 6 -CH aliphatic m
8 7.1942-7.2924 5H 11,12,13,14,15 -CH aromatic m
9 7.3052-7.3578 6H 17,18,19,22,23,24 -CH aromatic m
10 7.5858-7.6466 4H 16,20,21,25 -CH aromatic m
11 7.6556 2H 26 -NH2 bs
12 7.9607 2H 9 -NH2 bs
13 8.2805-8.3015 1H 10 -NH amide d
TABLE-13
2) 1H NMR + D2O exchange analysis (PPM/LDX-II/1220/001 RS)
No. (d) PPM Number of Proton Number Type of Hydrogen Type of Proton
1 0.7808-1.0133 2H 3 -CH2 aliphatic m
2 1.1389-1.1554 3H 8 -CH3 aliphatic d
3 1.3441-1.4884 4H 2, 4 -CH2 aliphatic m
4 2.6054-2.6568 3H 1,7 -CH2 aliphatic m
5 2.7687-2.8161 1H 7 -CH2 aliphatic m
6 3.5733-3.6044 1H 5 -CH aliphatic t
7 4.0826-4.1520 1H 6 -CH aliphatic m
8 7.2051-7.3102 5H 11,12,13,14,15 -CH aromatic m
9 7.3784-7.4139 6H 17,18,19,22,23,24 -CH aromatic m
10 7.6405-7.6733 4H 16,20,21,25 -CH aromatic m
TABLE-14

3) 13C NMR (APT) analysis (PPM/LDX-II/1220/001 RS)
Structural Formula: -

No Peak position
Chemical Shift (d) ppm No. of Carbon Identification of carbon
1 21.18 01 8
2 21.25 01 3
3 26.99 01 2
4 30.89 01 4
5 39.01 01 1
6 42.22 01 7
7 46.81 01 6
8 52.47 01 5
9 125.93 01 13
10 126.59 02 12, 14
11 128.16 02 11, 15
12 128.54 04 16, 20, 21, 25
13 128.99 04 17, 19, 22, 24
14 129.60 02 19, 23
15 139.28 01 28
16 148.58 02 29, 30
17 167.76 01 27
TABLE-15

XI) Infra-Red Spectra analysis of LDB
IR illustration data
Sr.
No. Characteristic Absorption (cm-1) Type of vibration Intensity Functional group
1 3352.09 N-H stretching 55.55 -primary amine
2 1654.02 C=O stretching 34.64 -primary amide
3 2970.29 C-H stretching 41.96 -alkane
4 1446.43 C-H bending 42.75 -methyl
5 1095.13 C-N stretching 54.89 -amine
TABLE-16

XII) Elemental analysis of LDB

Material Name LDB
Elemental Analysis Theoretical Value PPM/LDX-II/1120/001 RS
C 55.94 55.93
H 6.43 6.42
N 7.25 7.22
S 11.06 11.04
O 19.32 19.312
TABLE-17

Note: From 1H NMR, 13C NMR (APT), IR and Elemental analysis data and the results are shown in Table-13, Table-14, Table-15, Table-16 and Table-17. It is concluded that the probable structure of Lisdexamfetamine besylate (LDB) is as given below.

The present invention is demonstrated via examples cited below, which are provided as illustration only and therefore should not be construed as limitation of the scope of the invention in any manner.

EXAMPLES:
The following examples are illustrative of some of the aspects of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Preparation of Lisdexamfetamine dimesylate:
L-Lysine monohydrochloride and process water were added to a clean vessel and then heated. Tert-butoxycarbonyl (Boc) anhydride and sodium hydroxide solution were then charged to the vessel. The pH of the mixture was adjusted using sodium hydroxide solution.
The reaction mixture was then heated until reaction completion. The mixture was cooled followed by dilution with dichloromethane. The pH of the mixture was adjusted using concentrated hydrochloric acid, followed by phase separation.
The mixture containing the non-isolated intermediate L-Lys (Boc)-OH was charged on top of a N-hydroxysuccinimide solution in a clean vessel. The original vessel was then rinsed with solvent and the washings were combined with the mixture. The temperature of the mixture was adjusted. A solution of N,N'-Dicyclohexyl carbodiimide and Dichloromethane heated was then added to protected amino acid succinimidyl ester. The temperature of the reaction mixture was maintained until reaction completion. The mixture was cooled followed by filtration.
The filtrate was washed with saturated sodium bicarbonate solution. The reaction mixture was concentrated by vacuum distillation to give the intermediate LDX-I.
Methane sulfonic acid and Isopropyl alcohol, process water was added to the filtrate and the mixture was heated. When complete, pre-heated IPA was added to the mixture while the temperature was maintained, followed by cooling. The mixture was then cooled.
The product was collected by filtration. The filter-cake was washed with a mixture of IPA and dried in vacuo. The dried material was screened to yield the final product of Lisdexamfetamine dimesylate.

Example 1:
Preparation of Lisdexamfetamine Besylate
A solution of 50 g of {C,C’-Bis(1,1-dimethylethyl) N,N’-[(1S)-1-[[[(1S)-1-methyl-2-phenylethyl]amino]carbonyl]-1,5-pentanediyl]bis[carbamate} in 450 ml Isopropyl alcohol was cooled to 10°C, 37.6 g Benzene sulfonic acid was added lot-wise over a period of 30 mins, maintaining the temperature below 20°C. The solution was then heated for 24 hours at 50-60°C. After cooling at 25-30°C, the material was isolated by filtration to give 46.9 g crude Lisdexamfetamine dibesylate. A solution of 46 g crude Lisdexamfetamine dibesylate in 250 ml IPA:Water (97.5:2.5) mixture was heated for 1 hour at reflux temperature. After cooling to 0-5°C, the material was isolated by filtration to give 38.9 g pure Lisdexamfetamine dibesylate.
Purity: 98.56%.
Example 2:
Preparation of Lisdexamfetamine Besylate
A 5 Lit 4 necked round bottom flask fitted with a thermometer pocket, overhead stirrer and double surface condenser was taken. Added Lisdexamfetamine Dimesylate salt (180 gms), Dichloromethane (900ml) and water (180ml). The reaction mass was stirred at Room temperature. Added Aqueous sodium Hydroxide solution (34.7gms dissolved in 60ml water) to adjust pH above 12.0 and continued stirring at the same temperature for 15mins. The layers were seperated and the aqueous layer was extracted with Dichloromethane. The combined organic layers were distiled out to get Lisdexamfetamine base as a residue. Isopropyl alcohol (900 ml) was added to the residue and stirred the reaction mass at room temperature. Added an Isopropyl alcohol solution of benzene sulfonic acid (128.2 gms dissolved in 900ml IPA) and the reaction mass was stirred at 65o C for 2 hrs. Cooled the reaction mass to 25-30o C and filtered. Dried the material to obtain 190gms of Lisdexamfetamine Dibesylate.
The prepared Lisdexamfetamine Di-Besylate salt was studied for its stability and the results are as below:

Note: Compared to initial data, there is no significant change observed in quality of the product when subjected to 1 M, 3M, and 6 months stability at 2-8°C ± 2°C; 25 °C± 2°C; and 40°C ± 2°C. ,CLAIMS:We Claim:
1. A Lisdexamphetamine Besylate salt.
2. A crystalline Lisdexamfetamine Besylate salt, characterized by having a powder X-ray diffractogram comprising reflections at 2-theta angles comprising at 22.892, 13.248, 10.072, 5.651, 7.709 ±0.2 degrees 2?.
3. A crystalline Lisdexamfetamine Dibesylate salt, characterized by Differential scanning calorimetry comprising onset peak in the range of 236 °C - 241 °C.
4. A process for preparation of Lisdexamfetamine salt comprising the steps of:
a. dissolving or suspending {C, C’-Bis(1,1-dimethylethyl) N, N’-[(1S)-1-[[[(1S)-1-methyl-2-phenylethyl]amino]carbonyl]-1,5-pentanediyl]bis[carbamate} in a suitable solvent;
b. adding benzene sulfonic acid; and
c. isolating besylate salt of Lisdexamfetamine.
5. The process as claimed in claim 4, wherein the step A solvent is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol, isopropanol and the like, preferably isopropanol, and methanol or a mixture thereof.
6. A process for preparation of Lisdexamfetamine salt comprising the steps of:
a. dissolving or suspending {C, C’-Bis(1,1-dimethylethyl) N, N’-[(1S)-1-[[[(1S)-1-methyl-2-phenylethyl]amino]carbonyl]-1,5-pentanediyl]bis[carbamate} in a suitable solvent like ethanol, propanol, methanol and Isopropanol preferably Isopropanol or mixture thereof;
b. adding benzene sulfonic acid;
c. inducing crystallization of the salt in Isopropyl alcohol: Water, and
d. recovering the crystalline besylate salt.
7. A process for preparation of Lisdexamfetamine salt comprising the steps of:
a. dissolving or suspending Lisdexamfetamine dimesylate in a suitable solvent and base;
b. adding benzene sulfonic acid; and
c. isolating crystalline dibesylate salt.
8. The process of claim 7, wherein the step A solvent is Dichloromethane, and the step A base is selected from the group comprising Sodium Hydroxide, Potassium Hydroxide, and the like or mixture thereof.
09. A process for the preparation of the besylate salt of (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide comprising steps of:
a. dissolving or suspending Lisdexamfetamine dimesylate in a suitable solvent and base;
b. optionally isolating Lisdexamfetamine base;
c. dissolving or suspending Lisdexamfetamine base in a suitable solvent;
d. adding Benzene sulfonic acid; and
e. isolating besylate salt of Lisdexamfetamine.
10. The process of claim 9, wherein the step A solvent is Dichloromethane, and the step A base is selected from the group comprising of Sodium Hydroxide, Potassium Hydroxide, and the like or mixture thereof; the suitable solvent of step C is selected from the group comprising of of alcohols such as methanol, ethanol, propanol, butanol, isopropanol and the like or a mixture thereof.