FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10 and rule 13)
ADDUCTS OF 2-AMINO-2-[2-(4-OCTYLPHENYL) ETHYL] PROPANE-1,3-DIOL HYDROCHLORIDE WITH SUCROSE
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at 17/B, Mahal Industrial Estate, Mahakali Caves Road, Andheri (E), Mumbai-400093. Maharashtra,
India
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed

ADDUCTS OF 2-AMINO-2-[2-(4-OCTYLPHENYL) ETHYL] PROPANE-1,3-DIOL HYDROCHLORIDE WITH SUCROSE
The present invention relates to adducts of 2-amino-2-[2-(4-octylphenyl) ethyl] propane-1,3-diol hydrochloride with sucrose.
BACKGROUND OF THE INVENTION
Fingolimod, chemically 2-amino-2-[2-(4-octylphenyl) ethyl] propane-1,3-diol, compound of formula (I), is an immunosuppressive drug. It has been approved for treating multiple sclerosis in USA and Russia in 2010 and in Europe, Canada and Australia in 2011.

formula (I) formula (Ia)
Fingolimod is commercially marketed as its hydrochloride salt (formula Ia). WO 2010/055028 discloses the different crystalline forms (Form I, II, III and hydrate) of fingolimod hydrochloride. It has been reported that fingolimod hydrochloride exists in a particular crystalline form (Form I) at room temperature. The crystalline Form I undergoes a change to an alternative crystalline form (Form II) at a transition temperature of approximately 40 °C. The crystalline Form II can also undergo a transition to a third crystalline form (Form III) at a temperature of approximately 66 °C and at a temperature of approximately 107 °C, fingolimod hydrochloride forms a phase with lower crystalline order.
WO 2012/041358 (the '358 application) discloses the process for preparation of fingolimod hydrochloride Form I, II and III.

It has been found that fingolimod hydrochloride forms an adduct of formula (Ib) with sucrose,

The fingolimod hydrochloride sucrose adducts of the present invention can be obtained and isolated in crystalline and stable form showing good handling properties such as flowability and filterability.
SUMMARY OF THE INVENTION
The present invention relates to fingolimod hydrochloride sucrose adducts, particularly adducts of formula (Ib),

The present invention also relates to the process for preparation of fingolimod hydrochloride sucrose adducts, particularly adducts of formula (Ib).
According to the process of the present invention a solution of fingolimod hydrochloride in a water miscible organic solvent is mixed with an aqueous solution of sucrose, a water miscible antisolvent is added and the fingolimod hydrochloride sucrose adduct is isolated. Preferably, the adduct is isolated in a crystalline form.

DESCRIPTION OF THE INVENTION
The present invention relates to fingolimod hydrochloride sucrose adducts. In preferred embodiments the adduct is a compound of formula (Ib),

More preferably, the sucrose adduct of formula (Ib) is isolated in a crystalline form. In preferred embodiments, the crystalline sucrose adduct of Formula (Ib) is characterized by x-ray powder diffraction peaks at 8.8, 9.4, 15.2 and 19.3 degrees 2-theta. In yet another preferred embodiment of the present invention, fingolimod hydrochloride sucrose adduct obtained by the process of the present invention shows characteristic XRPD as depicted below in table 1, 2 or 3.
According to the process of the present invention, in step (a), a solution of fingolimod hydrochloride in a water miscible organic solvent is mixed with an aqueous sucrose solution, in step (b), a water miscible antisolvent is added, and in step (c) fingolimod hydrochloride sucrose adduct is isolated.
The "water miscible organic solvent" used in step (a) is a solvent for fingolimod hydrochloride, at room temperature or higher temperature, and is miscible in at least some proportion or in all proportions with water. Preferably, the water miscible organic solvent is selected from a C1-C6 aliphatic alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and mixtures thereof; more preferably, methanol and ethanol.
According the process of the present invention, step (a) may be carried out at room temperature or at higher temperature, at least 30 °C. more particularly 40-60 °C. The mole ratio of fingolimod hydrochloride to sucrose in step (a) is 1:0.5 to 1:10; and in a preferred embodiment, it is 1:1. In a preferred embodiment of the process of the present invention,

in step (a) the mixture is concentrated by distillation, preferably under vacuum, more preferably, at temperature below 50 °C.
In step (b) of the process of the present invention, a water miscible antisolvent is added to the mixture of step (a), preferably a concentrated mixture. In preferred embodiments, the water miscible antisolvent is acetone. The mixture of solvents is removed by co-distillation. The fingolimod hydrochloride sucrose adduct obtained as a residue is suspended in the water miscible antisolvent. The water miscible antisolvent may be pre¬heated to 45-50 °C, before suspending the residue. The suspension is stirred at room temperature for 30 minutes to 4 hour, more preferably for 1 hour.
The resulting suspension of fingolimod hydrochloride sucrose adduct is cooled, filtered, washed with a non-solvent and dried to give crystalline fingolimod hydrochloride sucrose adduct. Preferably, the suspension is cooled to 0-20 °C before filtration. More preferably, the suspension is cooled to 5-10 °C.
Preferably, the non-solvent used for washing is acetone. More preferably, acetone used for washing is pre-cooled to 5-10 °C.
Preferably fingolimod hydrochloride sucrose is dried by vacuum drying. More preferably the vacuum drying is carried out at 50 °C.
The present invention is illustrated by following non-limiting examples.
Example 1: Preparation of Fingolimod hydrochloride, formula (Ia).
To 9.0 g of fingolimod free base in a round bottom flask, was added 10 ml of isopropyl alcoholic HCI (IPA. HC1) at 25-30 °C and stirred for 10-20 minutes. The reaction mixture was heated to 65-73 °C and stirred for further 60-120 minutes. The solution was slowly cooled to 0-5 °C over a period of 1-2 hours and further stirred at same temperature for 1 hour. The slurry was filtered at 0-5 °C and washed with 196 ml of pre-chilled (0-5 °C) and pre filtered IPA, to yield 8.0 g of fingolimod hydrochloride.

Example 2: Preparation of Sucrose ad duct of Fingolimod hydrochloride, compound of formula (lb).
The wet fingolimod hydrochloride (8.0 g) obtained as above was placed in a round bottom flask. One volume of methanol was added to it and stirred at 45-50 °C to form a solution. Meanwhile 8.0 g of sucrose was dissolved in 8 ml of dimineralized water and added into the solution of fingolimod hydrochloride at 45-50 °C. followed by addition of 4 ml of methanol. The resulting solution was stirred at 45-50 °C for 10-20 minutes. The solvents were distilled off under vacuum at temperature below 50 °C. Acetone was added to the obtained mixture and residual solvents were co-distilled with acetone. The residue obtained was suspended again in acetone at 45-50 °C, stirred at room temperature for 1 hour, cooled to 5-10 °C and stirred for 30-60 minutes. The slurry containing fingolimod hydrochloride sucrose adduct was filtered, washed with pre-cooled (5-10 °C) & pre-filtered acetone (5-10 °C). The wet cake was suck dried under nitrogen for 1 hour followed by vacuum drying at 50 °C for 2-3 hours to yield 13.62 g of fingolimod hydrochloride sucrose adduct.
The preparation of the sucrose adduct, compound of formula (Ib), was repeated by the above procedure in three different batches. The product obtained in these individual batches was characterized by XPR.D, the values for which are depicted below in Table 1, 2 and 3 and Figure 1, 2 and 3.
Table 1: XRPD pattern of Fingolimod Hydrochloride Sucrose adduct

Position [2θ] d-spacing Relative Intensity [%]
3.6495 24.21076 100
7.1892 12.29642 3.26
8.4354 10.48232 2.07
8.7532 10.10242 2.58
9.4006 9.40808 1.91
10.7291 8.24598 4.53
11.7543 7.52901 7.11
12.8181 6.90642 4.45

13.237 6.68878 7.04
14.842 5.96888 2.55
15.1659 5.84214 1.89
15.5792 5.68806 3.28
16.4052 5.40349 1.17
16.7991 5.27766 1.91
18.2209 4.86892 1.37
18.9183 4.69098 14.29
19.349 4.58753 3.16
19.6789 4.51136 11.86
20.0642 4.42558 2.31
20.4725 4.33825 4.91
20.9406 4.2423 7.08
21.5321 4.12709 1.4
22.1314 4.01666 5.28
22.5875 3.93658 2.05
22.9349 3.87773 1.04
23.6269 3.76571 2.55
24.8304 3.58585 15.53
25.289 3.52182 6.57
25.9607 3.43223 1.56
26.5198 3.36112 1.69
27.4704 3.24694 1.67
28.6958 3.11102 1.54
29.3676 3.04136 0.89
30.6093 2.92075 1.04
31.0785 2.87772 4.11
32.0317 2.79423 3.4
32.6744 2.74072 1.94
33.5503 2.67115 1.5
34.8814 2.5722 0.91
36.2261 2.47975 1.29
36.9945 2.41999 1.12
37.328 2.40904 1.45
38.2718 2.35178 2.98

Table 2: XRPD pattern of Fingolimod Hydrochloride Sucrose adduct

Position [2θ] d-spacing Relative Intensity [%]
3.719 23.75891 100
5.9805 14.77864 0.65
7.2446 12.20247 3.9
8.5057 10.39592 1.88
8.8074 10.04044 3.93
9.4872 9.32245 2.2
10.798 8.19351 5.21
11.8443 7.47198 4.91
12.8784 6.87422 3.08
13.3137 6.65043 5.67
14.893 5.94857 3.36
15.2224 5.82058 2.07
15.6424 5.66522 2.7
16.4393 5.39235 0.77
16.8737 5.2545 1.87
18.3883 4.82499 1.54
18.975 4.67708 13.21
19.4261 4.5695 4.07
19.7491 4.49548 11.2
20.1231 4.41276 3.24
20.4676 4.33926 4.91
20.9926 4.23191 7.85
21.6043 4.11345 1.18
22.2127 4.00215 4.37
22.685 3.91988 1.98
23.6881 3.75611 2.22
24.9184 3.57339 13.83
25.3351 3.51554 7.23
25.9988 3.42728 1.41
26.6081 3.35017 1.46
27.5373 3.2392 0.95

28.7662 3.10356 1.13
29.3755 3.04056 0.49
30.674 2.91474 0.71
31.1468 2.87156 3.38
32.0593 2.79188 3.26
32.7327 2.73597 2.01
33.5607 2.67034 1.66
34.9331 2.56852 0.79
36.2809 2.47613 1.14
37.3834 2.4056 1.14
38.3359 2.34799 2.64
38.5395 2.33606 2.15
Table 3: XRPD pattern of Fingolimod Hydrochloride Sucrose adduct

Position [20] d-spacing Relative Intensity [%]
3.6683 24.08711 100
7.201 12.27625 3.48
8.4534 10.46008 2.3
8.7566 10.09849 2.77
9.4339 9.37498 1.91
10.7563 8.22518 4.38
11.7815 7.51167 5.4
12.8193 6.90581 3.17
13.251 6.68176 5.71
14.8176 5.97865 2.18
15.1613 5.84389 1.65
15.594 5.68269 2.66
16.3828 5.41082 0.81
16.8198 5.27122 1.83
18.2693 4.85614 1.23
18.929 4.68837 11.31
19.3743 4.58159 3.05
19.6916 4.50847 10.39
20.0727 4.42374 2.68

20.4748
4.33775 4.36
20.9261 4.24521 6.22
21.6154 4.11138 1.56
22.1557 4.01231 4.54
22.6038 3.93379 2.05
22.9366 3.87745 1.14
23.6552 3.76126 2.26
24.1942 3.67868 0.72
24.8531 3.58262 12.77
25.2972 3.52072 7.37
25.969 3.43116 1.59
26.5668 3.35529 1.33
27.492 3.24443 1.08
28.7214 3.1083 1.16
29.3096 3.04724 0.69
31.0788 2.8777 3.13
32.0282 2.79452 3.33
32.6867 2.73971 1.59
33.5143 2.67394 1.4
34.8467 2.57468 0.69
36.2276 2.47965 0.96
37.3605 2.40702 1.01
38.2836 2.35109 2.27
38.4963 2.33858 1.62
38.9396 2.31298 0.35
i

We Claim:
1. An adduct of fingolimod hydrochloride with sucrose, having the formula

2. An adduct as claimed in claim 1 in crystalline form characterized by x-ray powder diffraction pattern with peaks at 8.8, 9.4, 15.2 and 19.3 degrees 2-theta.
3. An adduct as claimed in claim 1, characterized by an x-ray powder diffraction pattern as depicted in table 1 or table 2 or table 3.
4. A process for preparation of fingolimod hydrochloride sucrose adduct, comprising,
a. mixing a solution of fingolimod hydrochloride in an water miscible organic
solvent with an aqueous sucrose solution,
b. adding a water miscible antisolvent,
c. isolating fingolimod hydrochloride sucrose adduct from the mixture.
5. A process according to claim 4, wherein the water miscible organic solvent used is selected from methanol.
6. A process according to claim 4 wherein the mole ratio of fingolimod hydrochloride and sucrose is from 1:1 and the adduct isolated is an adduct of formula (Ib).
7. A process according to claim 4, wherein the water miscible antisolvent is acetone.
8. A process according to claim 4 wherein the mixture formed in step (a) is concentrated by distilling out the solvents and the slurry formed after step (b) is subjected to co-distillation to isolate the fingolimod hydrochloride sucrose adduct.