Field of the Invention

The present invention provides an improved process for the preparation of Lisdexamfetamine of formula (I) or its pharmaceutically actable salts. More particularly, the invention provides an improved process for the preparation of polymorphic forms of Lisdexamfetamine of formula (I) and its dimesylate salt of formula (II).

Background of the Invention

Lisdexamfetamine (L-lysine-d-amphetamine) 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.

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.

NL 6414901 (1965) 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. Though this patent does not provide preparation of L-lysine-d-amphetamine, the de-protection of the tosyl protected L-lysine-d-amphetamine inherently yields L-lysine-d-amphetamine.

US 7,223,735 (1115/KOLNP/2006 A) patent claims 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.

The patent also discloses a process for the preparation of L-lysine-d-amphetamine by reacting a solution of Boc-Lys(Boc)-OSu in dioxane and d-amphetamine freebase and DIPEA. The resulting mixture was stirred overnight; excess solvent and base were removed by evaporation under reduced pressure. The crude product was dissolved in ethyl acetate and loaded on to a flash column and eluted with ethyl acetate to obtain purified Boc-Lys(Boc)-Amp. The Boc-Lys(Boc)-Amp obtained was de-protected using HC1 in dioxane as a solvent system. The said process is illustrated by the scheme-1 as provided below.

US 7,687,466 discloses a process for the preparation of Boc protected L-lysine-d-amphetamine, in which the product was isolated by evaporation of the reaction solvent followed by dissolving the residue in ethyl acetate and subsequent chromatographic separation. The final product obtained by this processes is crude which needs additional purification due to contamination with by-product and unreacted starting material. Further the use of chromatography is not viable in large scale preparation.

Scheme-1

US 20090124831 publication claims L-lysine-d-amphetamine dimesylate and discloses a process for the preparation of the same by reacting protected dipeptide succinimidyl ester in 1,4-dioxane with d-amphetamine free base in the presence of N-methylmorpholine. The coupling reaction described in the publication requires a number of purification steps to obtain the protected Lisdexamfetamine of required purity. The yield of the product obtained by the process of this invention is very low, since it involves number of steps to get the required purity which in turn affects the yield of the final product. Further the time required to get the right material is high which is again not viable in large scale preparation. The protected Lisdexamfetamine is deprotected in presence of acid in dioxane and is isolated as its acid addition salt. If required it acid addition salt is converted to its mesylate salt with methane sulfonic acid in presence of dioxane as mentioned in scheme -2

Scheme-2

US 7,659,253 describes the crystalline form of Lisdexamfetamine dimesylate and its preparation. The crystalline form is characterised by having PXRD peaks at 4.5, 9.0, 12.0, 15.7 and 16.3 ± 0.2 20.

In our continued research for developing a process for the preparation of Lisdexamfetamine or its pharmaceutically acceptable salts; we have identified a convenient process which reduces the formation of impurity or by-product and improves the quality and yield of the product and eliminates the foregoing problems like use of chromatography purification associated with prior art processes. The process of the present invention is also an industrially scalable and economically viable process.

In our continued research we have also identified novel crystalline Form of Lisdexamfetamine dimesylate which is call as Form-II. This new form having good stability and purity over conventional product. None of the prior art suggests or even motivates the present invention.

The present inventors also found a novel amorphous form of Lisdexamfetamine dihydrochloride which is useful for the preparation of crystalline Lisdexamfetamine dimesylate Form I and Form II.

The present inventors are isolated chiral pure and new crystalline forms of Lisdexamfetamine free base and its salts preferably its dihydrochloride and dimesylate salts. The reason for obtaining highly chiral pure compound is using starting raw materials such as amphetamine or its acid addition salt used for the reaction is chiral pure.

The other reason is the intermediate compounds such as Boc-protected Lisdexamfetamine of formula (VI) also purified before the deprotection.

Objective of the Invention

The main objective of the present invention is to provide a novel process for the preparation of compound of formula (I) or its pharmaceutically acceptable salt with higher chemical purity and yield.

The another objective of the present invention is to provide a novel polymorphic forms of Lisdexamfetamine free base of formula (I) and its salts preferably dichloride and dimesylate salts and its process for the preparation thereof.

Still another objective of the present invention the starting materials and intermediate products used for the preparation of Lisdexamfetamine of formula (I) are purified to get final compounds in higher chemical and chiral purity and enhancement in yield.

Another objective of the present invention is to provide a process which is suitable for large scale production, which avoids chromatographic purifications.

Summary of the Invention

Accordingly, the present invention provides a novel process for the preparation of Lisdexamfetamine or its pharmaceutically acceptable salt comprising the steps of:

(i) reacting N-protected L-Lysine of formula (IV) wherein P represents amino protecting group with d-amphetamine of formula (III) or its acid addition salt, in presence of an acid activating group and a base to obtain a compound of formula (VI);

(ii) isolating compound of formula (VI) in non-polar solvent;

(iii) deprotecting the compound of formula (VI) with an acid to obtain Lisdexamfetamine of Formula (I) or its acid addition salt and polymorphic forms thereof; (iv) converting Lisdexamfetamine of Formula (I) or its acid addition salts to its pharmaceutically acceptable salt; and (v) optionally crystallising Lisdexamfetamine dimesylate of formula (II) to obtain crystalline Lisdexamfetamine dimesylate of formula (II).

Description of Drawings

FIG-1: Powder XRD pattern of an amorphous form of Lisdexamfetamine
dihydrochloride.

FIG-2: Powder XRD pattern of crystalline Boc-protected Lisdexamfetamine.

FIG-3: Powder XRD pattern of crystalline Lisdexamfetamine free base.

FIG-4: Powder XRD pattern of novel crystalline form of Lisdexamfetamine
dimesylate of Form II.

The samples were analyzed by X-Ray Powder Diffractometer of the following features:

Detailed Description of the Invention

In an embodiment of the present invention, the protected group used to protect the amino group of L-Lysine is selected from the group consisting of tert-butyloxycarbonyl, benzyloxyarbonyl, allyoxy carbonyl, tosyl, formyl, benzyl, dibenzyl, phthalyl and the like, preferably tert-butyloxycarbonyl.

In another embodiment of the present invention, the base used for the preparation of protected Lisdexamfetamine is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, dietyhlamine and the like preferably triethylamine.

In another embodiment of the present invention, the salt of d-amphetamine of formula (III) is prepared by reacting amphetamine with optically active acid such as L-tartaric acid.

In another embodiment of the present invention, the acid activation group used for the preparation of diprotected Lisdexamfetamine of formula (VI) in step (i) is selected from the group consisting of 1-Hydroxybenzotriazole (HOBt) ,l-Hydroxy-7-azabenzotriazole (HOAt), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluoro phosphate (BOP), carbonyl diimidazole (CDI), dicyclohexylcarbodiimide (DCC) preferably 1-Hydroxybenzotriazole (HOBt). According to the present invention the acid activating group used to increase the rate of the reaction. The esters formed between the amino acids and the HOBt and HOAt were found to be more reactive than the ester formed with HOSu (1-hydroxysuccinimides) as described in the US 20090124831 publication.

In another embodiment of the present invention, the base used in step (i) is selected from triethylamine, di-isopropyl ethylamine, diethylamine, diisopropyl amine, N-methylmorpholine, N,N,N',N'-tetramethylguanidine (TMG), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN) and the like or mixtures there of preferably triethylamine.

In yet another embodiment of the present invention, the step (i) is conducted in the presence of solvent selected from methylene dichloride, ethylene dichloride, toluene, acetonitrile, n-hexane and cyclohexane, tetrahydrofuran; dimethylether, diethyl ether, butyl ether and methyl tert.-butyl ether, ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate, methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl tert-butyl ketone and the like or mixtures there of.

In yet another embodiment of the present invention the protected Lisdexamfetamine of formula (VI) is isolated by using non-polar solvent selected from diisopropyl ether, diethyl ether, heptane, hexane, cyclohexane, toluene and the like at a temperature in the range of 15 °C to reflux temperature. Since the compound of formula (VI) is isolated using non-polar solvent in pure form; the obtained Lisdexamfetamine by deprotection of the said pure compound is found to be pure even the staring material such as d-amphetamine having the purity in the range of 75% - 99.5%. Prior art process utilizes chromatographic purification technique or vacuum evaporation to isolate the compound of formula (VI), whereas the present invention uses simple process to isolate the product with better yield and enhanced purity.

In another embodiment of the present invention, the protected Lisdexamfetamine obtained in step (ii) is in crystalline form which is characterised by having PXRD peaks at 4.299, 5.353, 7.119, 7.786, 9.096, 11.093, 12.442, 13.038, 15.141, 16.596, 17.833, 19.656, 20.783, 23.520 and 26.412 ±0.2 20.

In yet another embodiment of the present invention, acid used in step (iii) is selected from the group consisting of methane sulfonic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, oxalic acid, fumaric acid, malic acid, maleic acid, phosphoric acid, benzene sulfonic acids preferable methane sulfonic acid and hydrochloric acid.

In yet another embodiment of the present invention, the acid addition salt obtained in step (iii) is converted into its pharmaceutically acceptable salt either by replacement with another salt or by neutralizing the Lisdexamfetamine acid addition salt with base to obtain Lisdexamfetamine free base followed by reacting the said free base with corresponding acid to obtain pharmaceutically acceptable addition salt. If required the second step can be repeated to get pure crystalline Lisdexamfetamine free base and its pharmaceutically acceptable salt.

In yet another embodiment of the present invention, the solvent used for neutralization is selected from the group consisting of water, C1C8 alkyl alcohols, acetonitrile, C3-C6 amides, C3-C6 ketones, C6.C12 aromatic hydrocarbons, C1-C6 aliphatic hydrocarbon, C2-C6 alkyl acetates and C4-C8 ethers. Preferred C1-C8 alkyl alcohols are methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, isobutanol and 2-butanol. Preferred C3-C6 amides are dimethylacetamide and dimethylformamide (DMF). Preferred C3-C6 ketones are acetone, methyl ethyl ketone (MEK) and methyl iso-butyl ketone (MIBK). Preferred C6-C12 aromatic hydrocarbons are benzene, toluene and xylene. Preferred C1-C6 aliphatic hydrocarbons are methylene dichloride (MDC), ethylene dichloride and chloroform. Preferred C2-C6 alkyl acetates are ethyl acetate and isobutyl acetate. Preferred C4-C8 ethers are tetrahydrofuran (THF), diethoxymethane (DEM), isobutyl methyl ether, dibutyl ether and polyethylene glycol (PGME). More preferably the solvent used for neutralization is methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, isobutanol, 2-butanol, most preferably methanol.

In another embodiment of the present invention, the base used for neutralization is an organic or inorganic base wherein the organic base is selected from the group consisting of triethylamine, dimethylamine, tert-butylamine, diisopropylamine, dimethylamine, monomethylamine or diisopropyl ethylamine and the inorganic base is selected from the group consisting of ammonia; hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals. Specific alkali metals are lithium, sodium and potassium, and more specifically sodium and potassium. Specific alkaline earth metals are calcium and magnesium, and more specifically magnesium or mixtures thereof. More preferably the base used for neutralization is sodium carbonate.

In one more embodiment of the present invention, the Lisdexamfetamine free base of formula (I) obtained in step (iii) is in crystalline form which is characterised by having PXRD peaks at 8.02, 11.12, 19.18 and 24.25 ± 0.2 29 which is further characterised by having PXRD peaks at 10.36, 13.11, 15.92, 22.24 and 26.42 +0.2 20.

In yet another embodiment of the present invention, treating Lisdexamfetamine free base with methane sulfonic acid in a solvent at a temperature in the range of 20 °C to reflux temperature of the solvent used.

In yet another embodiment of the present invention also provides a process for the preparation of novel crystalline polymorph of Lisdexamfetamine dimesylate Form-II by crystallizing Lisdexamfetamine dimesylate by the solvent which is selected from the group consisting of methanol, isopropanol, ethyl acetate, dichloromethane, diisopropyl ether, methyl isobutyl ketone, dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF) or mixtures thereof.

In one more embodiment of the present invention also provides a process for the isolation of Lisdexamfetamine dimesylate directly from the reaction mixture after deprotection of the protecting group from Lisdexamfetamine of formula (VI) by reacting with methanesulfonic acid in an alcoholic solvent selected from the group consisting of methanol, ethanol, and the like or mixtures there of more preferably methanol.

In still another embodiment of the present invention also provides a process for the preparation of novel crystalline polymorph of Lisdexamfetamine dimesylate Form-II by treating Lisdexamfetamine free base with methane sulfonic acid in a solvent which is selected from the group consisting of methanol, isopropanol, ethyl acetate, dichloromethane, diisopropyl ether, methyl isobutyl ketone, dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF) or mixtures thereof.

In yet another embodiment of the present invention also provides an improved process for the preparation of Lisdexamfetamine dimesylate Form I by treating Lisdexamfetamine dihydrochloride with methane sulfonic acid in a solvent which is selected from the group consisting of methanol, isopropanol, ethyl acetate, dichloromethane, diisopropyl ether, methyl isobutyl ketone, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and mixtures thereof.

In one more embodiment of the present invention, Lisdexamfetamine dimesylate obtained by the present invention is 99.8 % pure. The chiral purity of the d-amphetamine or its salt used in the present invention ranges from 70 % to 99.9 %. The chiral purity of Lisdexamfetamine dimesylate obtained from present invention is 99.8 %, even the chiral purity of d-amphetamine tartrate salt is 80 %. Thus the present invention provides an effective process for the preparation of Lisdexamfetamine dimesylate even with the low quality of d-amphetamine and also it avoids chromatography purification.

Still another embodiment of the present invention, an amorphous form of Lisdexamfetamine dimesylate was prepared by spray drying or by agitated thin film drying a solution of Lisdexamfetamine dimesylate in a suitable solvent preferably from water.

The starting material amphetamine can be prepared by the technique known in prior art or by following the Reference example and is illustrated in Scheme-3

Scheme-3

The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
Example 1: Preparation of bis-(tert-buryIoxycarbonyl)-Lisdexamfetamine (VI):

A solution of bis-(tert-butyloxycarbonyl)-L-lysine in DMF was cooled to 5 to 10 °C, to the cold solution were added triethylamine (10 g), HOBt (4.2 g) and EDC1.HC1 (7.9 g) and stirred. To the above reaction mixture was added D-amphetamine-L-tartrate salt (chiral purity in the range of 70-99.9 %) and stirred at room temperature. To the reaction mass was added water and ethyl acetate, stirred and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 10 % sodium carbonate solution, diluted with HC1, water and then with the brine solution. The solvent were distilled out completely under vacuum, followed by the addition of IPE (15V) and heated to reflux, the reaction mass was cooled to 25 to 35 °C, stirred and the solid was filtered. The solid obtained was washed with IPE and dried under vacuum. Purity by chiral HPLC 99.5% Purity by HPLC 99.5%
Advantages;

Irrespective of the starting material chiral purity (D-amphetamine) the present invention yield the final product with chiral purity greater than 99 % whereas the prior art process utilizes highly pure D-amphetamine to get good chiral purity.

Example 2; Preparation of Lisdexamfetamine dimesvlate (ID

The Boc-protected Lisdexamfetamine obtained in example 2 was dissolved in methanol (25 mL) and to the above solution was added methane sulphonic acid (2.18 g) and heated to 70 °C. After completion of the reaction, the reaction mass was cooled to 50 °C and distilled out the solvent to 1V under vacuum and further cooled to 25 to 30 °C. To the mass was added ethyl acetate slowly and stirred for 2 hours. The solid was filtered, washed with ethyl acetate and dried under vacuum. Purity by chiral HPLC 99% Purity by
HPLC 99.8%

Example 3: Preparation of Lisdexamfetamine dimesvlate

The Boc-protected Lisdexamfetamine was dissolved in methanol (5V) and to the above solution was added methane sulphonic acid and refluxed till completion of the reaction. Methanol was distilled completely; to the residual mass was added ethyl acetate slowly and stirred. The solid formed was filtered and dried to afford free flowing, crystalline Lisdexamfetamine dimesylate.

The crystalline Lisdexamfetamine dimesylate was prepared similarly by using condition given in the table.

Example 4; Process for the preparation of Lisdexamfetamine dihydrochloride
Boc-protected Lisdexamfetamine was dissolved in (5v) methanol and added IPA.HC1 (3 eq) at room temperature for about 30 minutes. The reaction mass was heated to reflux temperature and maintained till completion of reaction. The reaction mass was cooled and distilled off methanol completely under vacuum at temperature 45-50 °C. The obtained pasty mass was dried under high vacuum at temperature 60 °C for about 5-6 hours.

Example 5: Process for the preparation of Lisdexamfetamine free base Method A:
Lisdexamfetamine dimesylate (1 g) was dissolved in methanol (15V) and was added sodium carbonate (3 eq) to the above solution. The pH was adjusted to 7-9 and stirred. The obtained solid was filtered, washed with methanol and distilled the solvent completely under vacuum to obtain Lisdexamfetamine freebase. The PXRD of the obtained solid shows essentially as given in the figure-3.

Method B:

Lisdexamfetamine dihydrochloride (2 g) was dissolved in methanol (15V) and was added sodium carbonate (3 eq) to the above solution the stirred at room temperature. The pH was adjusted to 7-9 and stirred. The obtained solid was filtered, washed with methanol and distilled the solvent completely under vacuum to obtain Lisdexamfetamine freebase.

Example 6: Process for the preparation of Lisdexamfetamine dimesylate Lisdexamfetamine hydrochloride was dissolved in methanol and sodium carbonate was added to the above solution. The pH was adjusted to 7-9 and stirred. The obtained solid was filtered, washed with methanol and distilled the solvent completely under vacuum to obtain Lisdexamfetamine freebase. To the obtained solid was added ethyl acetate and methane sulfonic acid and stirred for a time sufficient to convert its dimesylate salt. The obtained solid was filtered, washed with ethyl acetate and dried to afford crystalline Lisdexamfetamine dimesylate.

Example 7; Recrystallization of Lisdexamfetamine dimesylate

Method A:

Lisdexamfetamine dimesylate was stirred with dimethyl sulfoxide at room temperature for 15 minutes. To the above solution was added ethyl acetate at room temperature, stirred for 1 hour, the obtained solid was filtered and dried to afford crystalline Lisdexamfetamine Dimesylate (free flowing crystalline)

Method B:

Lisdexamfetamine dimesylate was stirred with tetrahydrofuran for 3 hours. The solid was filtered and dried to afford crystalline Lisdexamfetamine dimesylate.
In a similar manner crystalline Lisdexamfetamine dimesylate was prepared by using methanol and ethanol instead of tetrahydrofuran.

Method C:

A solution of Lisdexamfetamine dimesylate in acetonitrile was prepared at 65 °C. The solution was cooled to room temperature; the obtained solid was filtered and dried to afford crystalline Lisdexamfetamine dimesylate.

Reference Example 1: Preparation of bis-(tert-butyloxycarbonyl)-L-lysine (IV)
L-Lysine monohydrate was stirred in presence of water at room temperature and cooled to 5 to 10 °C and added sodium hydroxide solution. To the reaction mass was added di-(tert-butylloxycarbonyl) slowly for 30 minutes at 5 to 10 °C and stirred the reaction mass at 25 to 30 °C. The aqueous layer was washed with hexane and the layers were separated.
The pH of the aqueous layer was adjusted with dilute HC1 till 4, extracted with ethyl acetate and the combined organic layer was washed with water and brine solution. The solvents were distilled out to obtain a pasty mass, which was dissolved in DMF and taken to the next step.

We claim,

1. An improved process for the preparation of Lisdexamfetamine of formula (I)

or its pharmaceutically acceptable salt comprising the steps of: (i) reacting TV-protected L-Lysine of formula (IV)

where P is protecting group; with the d-amphetamine of formula (III) or its salt

in presence of an acid activating and a base to obtain a compound of formula (VI);


(ii) isolating compound of formula (VI) in non-polar solvent;

(iii) deprotecting the compound of formula (VI) with an acid to obtain Lisdexamfetamine of Formula (I) or its acid addition salt and polymorphic forms thereof; (iv) converting Lisdexamfetamine of Formula (I) or its acid addition salts to its pharmaceutically acceptable salt; and (v) optionally crystallising Lisdexamfetamine dimesylate of formula (II) to obtain crystalline Lisdexamfetamine dimesylate of formula (II), wherein the improvement consisting the isolation protected Lisdexamfetamine of formula (IV) in a non-polar solvent.

2. The process according to the claim 1, wherein the protecting group is selected from the group consisting of tert-butyloxycarbonyl, benzyloxyarbonyl, allyoxy carbonyl, tosyl, formyl, benzyl, dibenzyl, phthalyl, preferably tert-butyloxycarbonyl.

3. The process according to the claim 1, wherein the acid activating group selected from 1-Hydroxybenzotriazole (HOBt), l-Hydroxy-7- azabenzotriazole (HOAt), benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluoro phosphate (BOP), carbonyl diimidazole (CDI) and dicyclohexylcarbodiimide (DCC).

4. The process according to the claim 1, wherein the base is selected from triethyl amine, di-isopropyl ethyl amine, diethyl amine, diisopropyl amine, N-methylmorpholine, TMG, DBU, DBN or mixtures there of.

5. The process according to the claim 1, wherein the non-polar solvent selected from the group consisting of diisopropyl ether, diethyl ether, heptane, cyclohexane or the mixture thereof

6. The process according to the claim 1, wherein the d-amphetamine used in step (i) having the chiral purity in the range of 70-99 %.

7. The process according to the claim 1, protected Lisdexamfetamine of formula (VI) obtained in step (ii) having the chiral purity greater than 99.5.

8. An improved process for the process for the purification of protected Lisdexamfetamine of formula (VI) which comprises:

(i) treating the compound of formula (VI) with non-polar solvent selected from group consisting of diisopropyl ether, diethyl ether, heptane, hexane, cyclohexane, toluene at a temperature which is suitable for compound completely dissolve;

(ii) stirring the solution;

(iii) cooling the solution; and

(iv) isolating pure protected Lisdexamfetamine of formula (VI).

9. The protected Lisdexamfetamine of formula (VI) prepared according to the claim 8 used for the preparation of Lisdexamfetamine of formula (I) or its pharmaceutically acceptable salt.

10. The process for the preparation of Form II of Lisdexamfetamine dimesylate of formula (II) which comprises the steps of:

(i) dissolving Lisdexamfetamine dimesylate of formula (II) in a solvent selected from the group consisting of methanol, isopropanol, ethyl acetate, dichloromethane, diisopropyl ether, methyl isobutyl ketone, dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF) or mixtures thereof;

(ii) cooling the solution; and

(iii) isolating Form II of Lisdexamfetamine dimesylate.