NOVEL PROCESSES FOR THE PREPARATlON OF VARIOUS POLYMORPHIC
FORMS OF ALISKIREN HEMWUMARATE
FIELD OF INVENTION: :
The present invention relates to novel processes fm the pepmation of various polymorphic
j forms of Aliskiin Hemifbmarate.
BACKGROUD OF INVENTION
. . @ . _ -
~liskirerhi e ~ i f h m t[eC AS Registry Number: 173334-58-21, having the chemical n e e : (2S,
- -3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate and structural formula as given below
as Formula I' I(
#
FORMULA I
which is indicated for treatment of hypertension, acting as a renin inhibitor, and
marketed by Novartis as TekturnaQ as a once-daily formuiation. Aliskiren and its related
compounds are referred to in U.S. Patent No, 5,559,111, while synthesis, pharmacological
actions, pharmacokineics and clinical studies of -~liskirena nd its related compounds are
referred to in Lindsay, K.B. et. al, J Org. Chem, vo1.71, pp 4766-4777 (2006) and in Drugs
of the Future, VoL 26, No.12, pp 1 139-1 148 (2Wf).
@ U.S. 'patent No. 5,559,111 describes the prepdon if nystaKne form of Aliskiren
Hemifumarate in ethanollacetonitrile mixture which is r e k e d to as crystalline form I of
Aliskiren Hemibarate in the later patent application WO 2009/064479,
W020051089729 refers to the solid oral dosage forms comprising aliskiren obtained by a
process comprising; wet granulation of the API, drying the obtained granulate, nixing
i with an outer phase excipient and further compressing to obtain a tablet. W020051089729
69 discusses the difficuIties in formulation of aliskiren due to the needle shaped crystals.
Moreover, it claims that the compression behavior of the drug substance is poor and therefore
. . -
direct compression is a difficult option for routine production.
I
1 U.S. Patent No. 6,730,798 refers to the preparation of Aliskiren Hemi'fiunarate using Aliskiren
I
base and Fumaric acid in ethanoYacetonitrile.
?-
WO 2008/06 1622 or US 8,119,84 1 B2 describes amorphous Aliskiren Hemifumarate and
several crystalline forms including Modification A, Modification By Solvate SA (also called
form E), Solvate Ss, Solvate S,, Solvate SO, Type I,.Type 11, Type 111, Type N ,Type V and Type
VI of aliskiren hemifmarate. It describes the preparation of a solvate crystalline form of
Aliskiren Hemifiunarte using Acetonitrile / E t h d in the ratio (75:25' or 90:lO). This solvate
crystalline form of Aliskiren Hemifumarate is qmkd to have characteristic peaks in the XRD
- . .
[:*\ at 2 theta values 3.5,6.5,7.7,8.0 13.8, 14.5,15-6and 17.4.
..= Zf
WO 2009/064479 Patent application filed by Teva claims various new polymorphic forms of
Aliskiren Hemifumarate. It also describes novel processes for the preparation of various
polymorphic forms. Aliskiren Hemifumarate Form I is prepared by dissolution of Aliskiren
Base and Fumaric acid in ethanol followed by crystallization in acetonitrile as per basic patent.
-
This patent describes the preparation of Form 11 by dissolution of dissolution of Aliskiren base
and Fumaric acid in isobutyl acetate. Polymorphic Form I11 is prepared by stirring of Form I in
t'-- 7
THF, methyl acetate & 2-butanol whereas polymorphic Form V is prepared by dissolution of
base and fharic acid in acetonitrile. Polymorphic Form VII is formed by dissolution of
Aliskiren Hemifumarte in tert-butanol 'whereas polymorphic Form VIII is prepared by
dissolution of amorphous Aliskiren Hemibarate in acetonitrile by RT for 40 hrs followed it
vaccurn drying. Polymorphic Form IX is obtained by dissolution of Aliskiren Base and fiunaric
acid in diethyl carbonate followed by stirring at RT for 40 hrs whereas Form X is obtained by
stirring of amorphous Aliskiren Hemifumarate in isopropanol fix 4 days.
Patent application W02011028919 filed by Teva again claims process for amorphous Aliskiren
Hemifbmarate comprising dissolution of AIiskiren H e m i h t e in methylene chloride &
crystallization by addition of diisopropyl ether. Besides the amorphous Aliskiren Hemifumarate
polymorph preparation, it dso describes the formation of different polymorphs referred herein as
T1, T3, T4, T5, T6, T7 ... & T8.
Though various polymorphic forms of Aliskiren Hemibarate & their method of preparations
are reported, but there still remain scope to develop new processes for various crystalline forms
of Aliskiren Hemifumarate which produces same polymorphic form consistently and can be '
used for commercial purpose.
SUMMARY OF INVENTION:
.--- ' . !
This present invention provides novel processes for the prepdon of polymorphic crystalline
polymorphic form I (designated as per US 5,559,111) or form B (as per US 8,119,841),
crystalline polymorphic form I1 (designated as per W0200W79 of Teva) & crystalline
polymorphic form A (designated as per US 8,119,841 of NovadjsJDETAILED
DESCRIPTION OF THE INVENTION:
According to the first embodiment of present invention, process for the preparation of Aliskiren
Hernifurnarate polymorphic fomF confirmed by its XRD Pattern (Figure I), which comprises
a) dissolving any form of Aliskiren Hemiharate in an aliphatic halogenated
hydrocarbon to get a c k solution.
".A'* b) recry$allization of p&t by adding suitable anti-solvent
@.k3
c) isolation of Aliskiren Hemifumarate polymorphic form I by routine filtration &
drying.
According to one aspect of the present invention, the aliphatic halogenated hydrocarbon used in
step (a) above is selected from methylene dichloride, chloroform, carbon tetrachloride or a
mixture thereof.
F') According toanother aspect of the present invention, the most preferred diphatic halogenated
hydrocarbon used is methylene dichloride.
According to still another aspect of the present invention, the anti-solvent used'in step (b) above
is selected from C4-Cs straight or branched chain aliphatic hydrocarbons like-butane, pentane,
hexane, heptane, octane or a mixture thereof.
(b) is 20-30 OC.
According to yet another aspect of the present invention, the drying time for product in step (d) is
24-72 hrs, more preferably 36-60 hrs, most preferably 36-48 hrs.
According to the s.tzcond embodiment of ihe present invention, a novel process for the fgg
preparation of AlisRiren Hemiharate form I confirmed by its XRD pattern (Figure IT), which
comprises:
a) dissolving any form of Aliskiren Hemifumarate in an aliphatic or aromatic
hydrocarbon & stirring
b) filtering the resulting organic layer through hyflow.
C) recrystallization of material by stirring the filtrate of step (5)
d) isolating Aliskiren Hemifumarate polymorphic fwm I by routine filtration &
drying.
According to one aspect of present invention, the aromatic hydrocarbons used in step (a) are
selected from Toluene, o-xylene, m-xylem, p-xylene or a mixture thereof.
According to other aspect of present invention, the stirring time in step (c) in 48-72 hours.
According to yet another aspect of present invention, the temperature in step (c) is 20-30 "C.
According to another aspect of present inventiou, the aliphatic hydrocarbon used in step (a) are
selected from cyclohexane, hexane, heptane or a mixture thereof.
According to yet another aspect of thi: present invention, the most preferred aromatic
hydrocarbon used in step (a) is ToIueae; -
@
According to yet another aspect of the present invention, the drying time for product in step (d) is
24-72 hrs, more preferably 36-60 hrs, most preferably 36-48 hrs.
According to the third embodiment of present invention, a novel process for the preparation of
Aliskiren Hemifharate polymorphic form I1 confirmed by its XRD pattern (Figure 111), which
comprises:
fl:! a) dissolving any form of Aliskiren Hemharate in - aliwtic ketone
b) recrystallization of product by stirring the resulting solution of step (a)
c) isolation of Aliskiren Hemibarate polymorphic farm I1 by routine filtration &
drying.
- ?.
According to one aspect of present invention, the aliphatic ketone used in step (a) above may be
selected horn acetone, methyl ethyl. keone, 2-butanone, methyl isobutyl ketone, diethyl ketone,
dipropyl ketone, dibutyl ketone or a mixtures thereof.
According to another aspect of present invention, the most suitable al'lphatic ketone used is
acetone.
. According to still another aspect o f t k p s e n t invention, the stirring temperature in step (b) is
According to yet another aspect of the present invention, the drying time for product in step (c) is
24-72 hrs, more preferably 36-60 hrs, most preferably 36-48 hrs. .
According to the fourth embodiment of present invention, amvel prows for the preparation of
Aliskiren Hemiharate p o l y m o ~ fco rm A confirmed by its XRD pattern (Figure IV), which
6:::
b) Recrystallization of product using suitable anti-solvent
c) Isolation of Aliskiien Hemiharate polymorphic form I1 by routine filtration &
drying.
According to one aspect ofthe present invention, the aliphatic halogenated hydrocarbon used in
step (a) above may be selected from methylene dichloride, c h l o r s h , carbon tetrachloride or a
mixture thereof.
According to yet another aspect of present invention, most prefmed of all aliphatic halogenated
hydrocarbons used is methyfene &chloride.
-
According to still another aspect of present invention, th antdmlvent used in step (b) can be
c.2
selected from acetonitrile, uryIonitrile or propionitrile or a mixme thereof. Acetonitrile being
the most suitable due to its relative lower toxicity.
According to still another aspect of the present invention, the crystallization temperatute in step
(b) is 20-30 "C.
According to yet another aspect of the present invention, the dryii time for product in step,(c) is
24-72 hrs, more preferably 36-60 hrs, most preferably 36-48 hrs.
-
. .
The present invention, wRich reports novel processes for preparation of various polymorphic
forms of Aliskiren hemiharate, will be explained in more detail with reference to the
following non limiting examples, which are provided by the way of illustration only and should
not be constructed as a limif to the swpe of the invention.
- 4
Note -
Form I designated / referred herein refers ta Aliskiren Hemifiunarate prepared as per US
5,559,111, the basic product patent of Aliskiren Hemiharate.
Form I1 designated 1 referred herein refers to Aliiren Hemiharate form II reported in
patent application WO 2009/064479 filed by Teva,
62 Form A & B designated / referred herein refers to Aliskiren Heraifwnarate Form A & B
reported in patent US 8,119,84 1 of its innovator Novartis.
EXAMPLES:
Example 1:
Process for the preparation of (2S,IS,5S,7S)-N-(2-Carbamoyl-2-methylpromino-4-
hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl~~namide
t .:I
hemifitmarate or Aliskiren hemifumarate poIymorphic form I (Process I).
100 g of ( 2 S , 4 S , 5 S , 7 S ) - N - ( 2 - C a r b a m o y l - 2 - m e t h y l ~ i s opr opyl -
8-[4-methoxy-3-(3-methoxypropoxy)pheny1]-0~tanamide hemifbarate (Aliskiren
Hemifumarate) was dissolved in methylene chloride (500 ml). The material is recrystallized by
slow addition of n-heptane (500 ml) at 20-30 "C. The solid, thus obtained, is filtered & dried at
20-30 "C for 2-3 hours followed by further drying at 40-50 "C under vacuum for 24-48 hours to
get 90 g crystalline Form I which is confirmed by its XRD Pattern (Figure I).
Example 2:
Pro. c.e ss for the preparation of (2S,4~~7~)-~-(2-~a~~moyl-2-methyl~ropyl)-5-amino-4-
hemifumarate or Aliskiren Hemifumarite polymorphic form I (Process 11).
100 g of (2S,4S,5S,7S)-N-(2-CarbamoyI-2-me~flpmpy1~5-amino-4-hydroxy-2,7-diipsoro pyl-
8-[4-methoxy-3-(3-methoxn>ropoxy)phenyl]-octanamide hemifumarate (Aliskiren
hemihmarate) is dissolved in toluene (1000 mI)1 The resulting toluene solution was stirred at 20-
30 "C for 2-3 days. The solid, thus obtained, was filtered and dried at 20-30 "C under vacuum for
2-3 hours followed by further drying-at 40-50 'C under vacuum for 24-48 hours to get 90 g
p :;\ crystalline Form I which is confirmed by its XRD Pattern (Figure 11).
Process for the preparation of (2S,4S,5S,7S)-N-(2-Carba1110yl-2-methylpropyl)-5-amino-4-
Hemifumarate or Aliskiren Hemifumarate polyarorpbic Farm 11.
8-[4-methoxy-3-(3-methoxypropoxy)phenyl~-octanamide hemifumarate (Aliskiren
hemiharate) is dissoIved in acetone (1000 d) and stirred at 20-30 "C for 2-3 days . The solid,
thus obtained, was filtered and dried at 20% 'C under vacuum for 2-3 hours followed by further
drying at 40-50 OC under vacuum for 2448 Bours to get 50 g crystalline form 11. XRD (Figure
Process for the preparation of (2S,4S,5S,?S~-(2-Carbamoy1-2-methylpropy1)-5-amino-4-
Hemifumarate or Aliskiren Hemifumarate polymorphic Form A
100 g of (2S,4S,5S,7S)-N.(2~amoyI-2-methylpropy)-5-mino-4-hydroxy-2y7sporo pyl -
8-f4-methoxy-3-(3-methoxypropoxy)~enyl]-octanamide hemiharate (Aliskiren
f? hemiharate) is dissotved in methylene chloride (300 ml) and recrystallized by slow addition
of-acetonitrile (1000 ml] to the resulting methylene chloride solution at 20-30 "C. The solid, thus
obtained, was filtered and dried at 20-30 "C under vacuum for 2-3 hours followed by fixther
drying at 40-50 OC under vacuum for 24-48 hours to get 70 g crystalline Form A XRD (Figure
Example 5:
Process for the preparation of (2&~S,5S,7S)-N-(2-Carbamoyl-2-methylp~-5-amino-4-
Hemifumarte or Aliskiren Hemifurname polymorphic Form I.
. -
8-[4-methoxy-3-(3-methoxypropoq~ph~-o~tanamide . het&biakte' (Aliskiren
g5.J
hemifurnarate) is dissoived in methflene &chloride (300 ml) and recrystallized by slow addition
of diisopropyl ether (500 ml) at 20-30 "C. The solid thus obtained, was filtered and dried at 20-30
"C under vacuum' for 2-3 hours f a w e d by Mer drying at 40-50 "C under vacuum for 24-48
hours to get 80 g crystalline Form L XRD (Figure V).

We Claim:
1. A novel process for the preparation of AIiskiren hemibarate Form I which comprises
i) dissolving any form of Aliskisen hemiharate in an aliphatic halogenated
hydrocarbon to get clear solution.
ii) recrystallizing of product by slow addition of aliphatic straight /branched chain
hydrocarbon
iii) filtration of resulting solid & drying -at 20-30 "C for 2-3 hours under vacuum
followed by hrther drying at 40-50 ?C d e r vacuum .for 24-48 hours to get
Aliskiren Hemibarate form I.
2. A process according to claim 1 wherein the aliphatic halogenated hydrocarbon is selected
from methylene chloride, chloroform or carbon tetrachloride or a mixture thereof.
3. A process according to claim 1 wherein the aIiphatic hydrocarbon in step (iii) is selected
from butane, pentane, hexane or heptane or a mixture thereof.
4. A process according to claim 1 wherein the crystallization temperature in step (ii) is 20-
5. Another novel' process for the preparation of Ahkiren hemifiumrarate Form I which
comprises:
i) dissoIving Aliskiren hemibarate in an aromatic or aliphatic hydrocarbon &
stirring
. ---
- - 5
0
- - f ii) filtering*ther esulting organic layer thm@ hyfiow
iii) recrystallization of mated by cooling the filtrate of step (ii)
iv) filtration & drying at 20-30 OC for 2-3 hours under vacuum followed by drying at
.. 40-50 O Cu nder vacuumfm 3648 hours ".. ..- - - --- -
T
. -
6. A process according to claim 5 wherein the aromatic hydrocarbon used in step (i) is
i - -
selected from toluene, o-xylene, m-xylene, p*ne or a mixture thereof.
Q . . 7. A process according to claim 5 wherein the aliphatic hydrocarbon used in step 4(i) is .
. . . - . .
selected from cyclohexaae, hexane, heptane or a mixture thereof.
8. Xprocess according to claim 5 wherein the stirring time in step (ii) is 48-72 hours, most
preferably 60-72 hours.
lo
9. A process accordcng to claim 5 wherein the coaling temperature of step (iii) is 20-30 'C.
10. A hovel process for tfie prepamtion of Aliskim hemifumarate Form I1 which comprises
-
i) dissolving Aliskiren hemIfUmarate in aliphatic ketone -
6 ii) stirring for crystallization of product
iii) filtration & dryingat 2 k 3 ~ - 0for~ 2 -3 hours under vacuum followed by drying at
40-50 "C under vacuum for 2448 hours,
11. The process according to claim 10 wherein the aliphatic ketone used in step (i) can be -
I
I I - -f
12. The process according to claim 10 wherein the stirring time in step (ii) of claim 10 is 48-
72 hours & temperature is 20-30 "C,
13. A novel process for the preparation of Aliskiren hemifumarate Form A which comprises
i) dissolving Alisfdren hemiharate'in halogenated hydrocarbon
ii) recrystallizatbn Pry slow addilk of suitable anti-solvent
iii) filtration & d q i q at 20-30 "C fix 2-3 hours under vacuum followed by drying at
49 40-50 O C undes- for24-48 hours. -
14. A process according to c h 13, wherein the aliphatic halogenated hydrocarbon used can
be selectedfrom methyhe chloride, chloroform or carbon tetrachloride or mixture
thereof.
15. A process according to claim 13, wherein the anti-solvent used in step (ii) of claim 10 is
acetonitrile, propionitrile or a mixture thereof.
16. A process according to claim 13, wherein the recrystallization temperature of step (ii) in