TEPZZ 

688649B_T
(19)

(11) EP 2 688 649 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.:

of the grant of the patent: A61K 31/454 (2006.01)
10.04.2019 Bulletin 2019/15
(86) International application number:
(21) Application number: 12759885.2 PCT/IN2012/000107

(22) Date of filing: 16.02.2012 (87) International publication number:

WO 2012/127493 (27.09.2012 Gazette 2012/39)

(54) A POLYMORPH OF LENALIDOMIDE

EIN POLYMORPH VON LENALIDOMID
FORME POLYMORPHE DE LÉNALIDOMIDE

(84) Designated Contracting States: • RAMAKRISHNA REDDY, Matta

AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Hyderabad 500018
GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Telangana (IN)
PL PT RO RS SE SI SK SM TR • VAMSI KRISHNA, Bandi
Hyderabad 500018
(30) Priority: 23.03.2011 IN CH08992011 Telangana (IN)

(43) Date of publication of application: (74) Representative: Best, Michael et al

29.01.2014 Bulletin 2014/05 Lederer & Keller
Patentanwälte Partnerschaft mbB
(73) Proprietor: Hetero Research Foundation Unsöldstrasse 2
Telangana (IN) 80538 München (DE)

(72) Inventors: (56) References cited:

• PARTHASARADHI REDDY, Bandi WO-A1-2010/056384 WO-A1-2010/061209
Hyderabad 500018 WO-A2-2005/023192 WO-A2-2010/129636
Telangana (IN) US-A1- 2011 021 567
• RATHNAKAR REDDY, Kura
Hyderabad 500018 • CAIRA M R: "CRYSTALLINE POLYMORPHISM OF
Telangana (IN) ORGANIC COMPOUNDS", TOPICS IN CURRENT
• MURALIDHARA REDDY, Dasari CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1
Hyderabad 500018 January 1998 (1998-01-01), pages 163-208,
Telangana (IN) XP001156954, ISSN: 0340-1022, DOI:
10.1007/3-540-69178-2_5
EP 2 688 649 B1

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 1 EP 2 688 649 B1
Description
[0001] This application claims the benefit of Indian Pat-
ent Application No. 899/CHE/2011, filed on March 23,
2011.
Filed of the Invention
[0002] The present invention provides a novel crystal-
line Form of lenalidomide, process for its preparation and
pharmaceutical compositions comprising it. The present
invention also provides a novel N-methylpyrrolidone sol-
vate of lenalidomide and process for its preparation.
Background of the Invention
[0003] Lenalidomide is chemically, 3-(4-amino-1,3-di-
hydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione and
has the structural formula:
[0004] Lenalidomide, a thalidomide analogue, was in-
itially intended for use as a treatment for multiple myelo-
ma, for which thalidomide is an accepted therapeutic mo-
dality. Lenalidomide has also shown efficacy in the he-
matological disorders known as the myelodysplastic syn-
dromes. Lenalidomide is currently marketed under the
trade name REVLIMID® by Celgene.
[0005] Polymorphism is defined as "the ability of a sub-
stance to exist as two or more crystalline phases that
have different arrangement and/or conformations of the
molecules in the crystal Lattice. Thus, in the strict sense,
polymorphs are different crystalline forms of the same
pure substance in which the molecules have different
arrangements and/or different configurations of the mol-
ecules". Different polymorphs may differ in their physical
properties such as melting point, solubility, X-ray diffrac-
tion patterns, etc. Although those differences disappear
once the compound is dissolved, they can appreciably
influence pharmaceutically relevant properties of the sol-
id form, such as handling properties, dissolution rate and
stability. Such properties can significantly influence the
processing, shelf life, and commercial acceptance of a
polymorph. It is therefore important to investigate all solid
forms of a drug, including all polymorphic forms, and to
determine the stability, dissolution and flow properties of
each polymorphic form. Polymorphic forms of a com-
pound can be distinguished in the laboratory by analytical
methods such as X-ray diffraction (XRD), Differential
Scanning Calorimetry (DSC) and Infrared spectrometry
2
(IR).
[0006] Solvent medium and mode of crystallization
play very important role in obtaining a crystalline form
over the other.
5 [0007] Lenalidomide can exist in different polymorphic
forms, which may differ from each other in terms of sta-
bility, physical properties, spectral data and methods of
preparation.
[0008] Lenalidomide and its process were disclosed in
10 U.S. patent no. 5,635,517.
[0009] PCT publication no. WO 2005/023192 dis-
closed crystalline Form A, Form B, Form C, Form D, Form
E, Form F, Form G and Form H of lenalidomide.
[0010] Amorphous lenalidomide was disclosed in PCT
15 publication no. WO 2009/114601.
[0011] PCT publication no. WO 2010/056384 dis-
closed N,N-dimethylformamide solvate and dimethylsul-
foxide solvate of lenalidomide.
[0012] Anhydrous crystalline Form of lenalidomide
20 was disclosed in PCT publication no. WO 2010/061209.
The publication also disclosed a process for preparing
crystalline Form B of lenalidomide.
[0013] PCT publication no. WO 2010/129636 dis-
closed a crystalline Form I of lenalidomide.
25 [0014] We have found a novel crystalline Form of le-
nalidomide. The novel crystalline Form has been found
to be stable over the time and reproducible and so, suit-
able for pharmaceutical preparations.
[0015] The lenalidomide N-methylpyrrolidone solvate
30 as described herein may serve as intermediate for prep-
aration of lenalidomide crystalline Form H1 or other pol-
ymorphs of lenalidomide.
[0016] Thus, object of the present invention is to pro-
vide a novel crystalline Form of lenalidomide, process
35 for its preparation and pharmaceutical compositions
comprising it.
Summary of the Invention
40 [0017] The lenalidomide N-methylpyrrolidone solvate
as described herein is characterized by peaks in the pow-
der x-ray diffraction spectrum having 2θ angle positions
at 8.5, 14.0, 14.5, 15.6, 16.1, 17.1, 17.6, 19.6, 21.6, 22.8
and 25.3 6 0.2 degrees.
45 [0018] A process for the preparation of lenalidomide
N-methylpyrrolidone solvate is described herein, which
comprises:
a) suspending lenalidomide in N-methylpyrrolidone;
50 b) heating the suspension obtained in step (a) at
above 50°C;
c) cooling the solution obtained in step (b) at below
15°C;
d) adding solvent to the solution at below 15°C; and
55 e) isolating lenalidomide N-methylpyrrolidone sol-
vate.
[0019] The present invention provides a crystalline
2
 3 EP 2 688 649 B1
Form of lenalidomide designated as Form H1 character-
ized by peaks in the powder x-ray diffraction spectrum
having 2θ angle positions at 10.6, 11.7, 14.9, 16.8, 18.2,
19.1, 22.5, 22.8, 23.6 and 28.2 6 0.2 degrees.
[0020] In another aspect, the present invention pro-
vides a process for the preparation of crystalline Form
H1 of lenalidomide, which comprises:
a) suspending any crystalline, solvated or amor-
phous Form of lenalidomide in N-methylpyrrolidone;
b) heating the suspension obtained in step (a) at
above 50°C;
c) cooling the solution obtained in step (b) at about
15 to 40°C;
d) adding solvent to the solution at about 15 to 40°C;
e) separating the solid;
f) slurring the isolated solid obtained in step (e) with
hydrocarbon solvent; and
g) isolating crystalline Form H1 of lenalidomide.
[0021] Yet in another aspect, the present invention pro-
vides a pharmaceutical composition comprising crystal-
line Form H1 of lenalidomide and pharmaceutically ac-
ceptable excipients.
Brief Description of the Drawing
[0022]
Figure 1 is X-ray powder diffraction spectrum of le-
nalidomide N-methylpyrrolidone solvate.
Figure 2 is X-ray powder diffraction spectrum of crys-
talline Form H1 of lenalidomide.
[0023] X-ray powder diffraction spectrum was meas-
ured on a bruker axs D8 advance X-ray powder diffrac-
tometer having a copper-Ka radiation. Approximately
1gm of sample was gently flattered on a sample holder
and scanned from 2 to 50 degrees two-theta, at 0.02
degrees to theta per step and a step of 10.6 seconds.
The sample was simply placed on the sample holder.
The sample was rotated at 30 rpm at a voltage 40 KV
and current 35 mA.
Detailed Description of the Invention
[0024] The term "room temperature" refers to temper-
ature at about 25 to 35°C.
[0025] The lenalidomide N-methylpyrrolidone solvate
as described herein is characterized by peaks in the pow-
der x-ray diffraction spectrum having 2θ angle positions
at 8.5, 14.0, 14.5, 15.6, 16.1, 17.1, 17.6, 19.6, 21.6, 22.8
and 25.3 6 0.2 degrees. The powdered X-ray diffracto-
gram (PXRD) of lenalidomide N-methylpyrrolidone sol-
vate is shown in figure 1.
[0026] A process for the preparation of lenalidomide
N-methylpyrrolidone solvate as described herein com-
prises:
4
a) suspending lenalidomide in N-methylpyrrolidone;
b) heating the suspension obtained in step (a) at
above 50°C;
c) cooling the solution obtained in step (b) at below
5 15°C;
d) adding solvent to the solution at below 15°C; and
e) isolating lenalidomide N-methylpyrrolidone sol-
vate.
10 [0027] The reaction may preferably be heated in step
(b) at about 55 to 65°C.
[0028] The solution may preferably be cooled in step
(c) at about 0 to 10°C.
[0029] The solvent used in step (d) may preferably be
15 a solvent or mixture of solvents selected from methanol,
ethanol, isopropyl alcohol, n-butanol, ethyl acetate, me-
thyl acetate, isopropyl acetate, tert-butyl methyl acetate,
ethyl formate, tetrahydrofuran, 1,4-dioxane, methyl tert-
butyl ether, diisopropyl ether and diethyl ether. More pref-
20 erably the solvents are ethanol, ethyl acetate and methyl
tert-butyl ether.
[0030] The isolation of lenalidomide N-methylpyrro-
lidone solvate in step (e) may be carried out by the meth-
ods known such as filtration or centrifugation.
25 [0031] The present invention provides a crystalline
Form of lenalidomide designated as Form H1 character-
ized by peaks in the powder x-ray diffraction spectrum
having 2θ angle positions at 10.6, 11.7, 14.9, 16.8, 18.2,
19.1, 22.5, 22.8, 23.6 and 28.2 6 0.2 degrees. The pow-
30 dered X-ray diffractogram (PXRD) of crystalline Form H1
of lenalidomide is shown in figure 2.
[0032] According to another aspect of the present in-
vention, there is provided a process for the preparation
of crystalline Form H1 of lenalidomide, which comprises:
35
a) suspending any crystalline, solvated or amor-
phous Form of lenalidomide in N-methylpyrrolidone;
b) heating the suspension obtained in step (a) at
above 50°C;
40 c) cooling the solution obtained in step (b) at 15 to
40°C;
d) adding solvent to the solution at 15 to 40°C;
e) separating the solid;
f) slurring the isolated solid obtained in step (e) with
45 hydrocarbon solvent; and
g) isolating crystalline Form H1 of lenalidomide.
[0033] Lenalidomide used in step (a) may be any
known crystalline, solvated or amorphous Forms.
50 [0034] The reaction may preferably be heated in step
(b) at about 55 to 65°C.
[0035] The solution may preferably be cooled in step
(c) at about 25 to 35°C.
[0036] The solvent used in step (d) may preferably be
55 a solvent or mixture of solvents selected from methanol,
ethanol, isopropyl alcohol, n-butanol, ethyl acetate, me-
thyl acetate, isopropyl acetate, tert-butyl methyl acetate,
ethyl formate, tetrahydrofuran, 1,4-dioxane, methyl tert-
3
 5 EP 2 688 649 B1
butyl ether, diisopropyl ether and diethyl ether. More pref-
erably the solvents are ethanol, ethyl acetate and methyl
tert-butyl ether.
[0037] The separation of the precipitated solid in step
(e) may be carried by the methods known in the art such
as filtration or centrifugation.
[0038] The hydrocarbon solvent used in step (f) may
preferably be a solvent or mixture of solvents selected
from cyclohexane, hexane, n-heptane, benzene, toluene
and xylene, and more preferably the hydrocarbon solvent
is toluene.
[0039] The temperature at which slurrying in step (f) is
done is not critical and the slurrying may conveniently be
carried out at about 50°C to 110°C.
[0040] Crystalline Form HI of lenalidomide may be iso-
lated in step (g) by the methods known such as filtration
or centrifugation.
[0041] According to another aspect of the present in-
vention, there is provided a pharmaceutical composition
comprising crystalline Form H1 of lenalidomide and phar-
maceutically acceptable excipients, and optionally other
therapeutic ingredients. The crystalline Form H1 may
preferably be formulated into tablets, capsules, suspen-
sions, dispersions, injectables or other pharmaceutical
forms.
[0042] The invention will now be further described by
the following examples, which are illustrative rather than
limiting.
Reference Examples
Preparation of lenalidomide crystalline Form A
Reference example 1:
[0043] Lenalidomide (100 gm) was dissolved in etha-
nol (1000 ml) and then heated to reflux to obtain a solu-
tion. The solution was maintained for 1 hour at reflux and
then cooled to room temperature. The reaction mass was
stirred for 1 hour at room temperature and filtered. The
solid obtained was dried to give 85 gm of lenalidomide
crystalline form A.
Preparation of lenalidomide crystalline Form B
Reference example 2:
[0044] Lenalidomide (100 gm) was dissolved in a mix-
ture of ethanol (1500 ml) and water (1000 ml). The con-
tents were heated to reflux and then treated with carbon.
The reaction mass was filtered and then cooled to 0 to
5°C. The reaction mass was stirred for 1 hour at 0 to 5°C
and filtered. The solid obtained was dried to give 84 gm
of lenalidomide crystalline form B.
6
Examples
Preparation of lenalidomide N-methylpyrrolidone
solvate
5
Example 1 (Reference):
[0045] Lenalidomide (25 gm) was suspended in N-
methylpyrrolidone (75 ml) and then heated to 60°C to
10 obtain a solution. The solution was then cooled to 0 to
5°C and then added ethanol (125 ml). The reaction mass
was stirred for 1 hour 30 minutes at 0 to 5°C and filtered.
The solid obtained was dried to obtain 20 gm of lenalid-
omide N-methylpyrrolidone solvate.
15
Example 2 (Reference):
[0046] Example 1 was repeated using ethyl acetate
solvent instead of ethanol solvent to obtain lenalidomide
20 N-methylpyrrolidone solvate.
Example 3 (Reference):
[0047] Example 1 was repeated using methyl tert-butyl
25 ether solvent instead of ethanol solvent to obtain lenal-
idomide N-methylpyrrolidone solvate.
Preparation of lenalidomide crystalline Form H1
30 Example 4:
[0048] Lenalidomide (25 gm) was suspended in N-
methylpyrrolidone (75 ml) at room temperature and then
heated to 60°C to obtain a solution. The solution was
35 then cooled to room temperature and then added ethanol
(125 ml). The reaction mass was stirred for 1 hour at
room temperature, filtered and dried to obtain a solid. To
the solid was added toluene (180 ml) and then heated to
90 to 95°C. The reaction mass was maintained for 1 hour
40 at 90 to 95°C and then cooled to room temperature. The
reaction mass was stirred for 1 hour at room temperature
and filtered. The solid obtained was dried under vacuum
at 95 to 100°C for 36 hours to obtain 17 gm of lenalido-
mide crystalline Form H1.
45
Example 5:
[0049] Example 4 was repeated using ethyl acetate
solvent instead of ethanol solvent to obtain lenalidomide
50 crystalline Form H1.
Example 6:
[0050] Example 4 was repeated using methyl tert-butyl
55 ether solvent instead of ethanol solvent to obtain lenal-
idomide crystalline Form H1.
4
 7 EP 2 688 649 B1
Example 7:
[0051] Lenalidomide N-methylpyrrolidone solvate
(100 gm) as obtained in example 1 was suspended in N-
methylpyrrolidone (300 ml) at room temperature. The
contents were heated to 60°C to obtain a solution. The
solution was then cooled to room temperature and then
added ethyl acetate (500 ml). The reaction mass was
stirred for 1 hour at room temperature. The separated
solid was filtered and dried to obtain a solid. To the solid
was added toluene (720 ml) and then heated to 90 to
95°C. The reaction mass was maintained for 1 hour at
90 to 95°C and then cooled to room temperature. The
contents were stirred for 1 hour at room temperature,
filtered and then dried under vacuum at 95 to 100°C for
40 hours to obtain 67 gm of lenalidomide crystalline Form
H1.
Example 8:
[0052] Example 7 was repeated using lenalidomide
N,N-dimethylformamide solvate instead of lenalidomide
N-methylpyrrolidone solvate to obtain lenalidomide crys-
talline Form H1.
Example 9:
[0053] Example 7 was repeated using lenalidomide N-
methylsulfoxide solvate instead of lenalidomide N-meth-
ylpyrrolidone solvate to obtain lenalidomide crystalline
Form H1.
Example 10:
[0054] Example 7 was repeated using ethanol solvent
instead of ethyl acetate solvent to obtain lenalidomide
crystalline Form H1.
Example 11:
[0055] Example 7 was repeated using methyl tert-butyl
ether solvent instead of ethyl acetate solvent to obtain
lenalidomide crystalline Form H1.
Example 12:
[0056] Lenalidomide crystalline Form B (15 gm) as ob-
tained in reference example 2 was suspended in N-meth-
ylpyrrolidone (45 ml) at room temperature and then heat-
ed to 60°C to obtain a solution. The solution was then
cooled to room temperature and then added methyl tert-
butyl ether (105 ml). The reaction mass was stirred for 1
hour at room temperature, filtered and dried to obtain a
solid. To the solid was added toluene (100 ml) and then
heated to 90 to 95°C. The reaction mass was maintained
for 1 hour at 90 to 95°C and then cooled to room tem-
perature. The reaction mass was stirred for 1 hour at
room temperature and filtered. The solid obtained was
8
dried under vacuum at 95 to 100°C for 36 hours to obtain
10 gm of lenalidomide crystalline Form H1.
Example 13:
5
[0057] Example 12 was repeated using lenalidomide
crystalline Form A as obtained in reference example 1
instead of lenalidomide crystalline Form B to obtain le-
nalidomide crystalline Form H1.
10
Example 14:
[0058] Example 12 was repeated using ethanol solvent
instead of methyl tert-butyl ether solvent to obtain lena-
15 lidomide crystalline Form H1.
Example 15:
[0059] Example 12 was repeated using ethyl acetate
20 solvent instead of methyl tert-butyl ether solvent to obtain
lenalidomide crystalline Form H1.
Claims
25
1. A crystalline Form HI of lenalidomide which is char-
acterized by peaks in the powder x-ray diffraction
spectrum having 2θ angle positions at about 10.6,
11.7, 14.9, 16.8, 18.2, 19.1, 22.5, 22.8, 23.6 and 28.2
30 6 0.2 degrees.
2. A process for the preparation of crystalline Form H1
of lenalidomide as claimed in claim 1, which com-
prises:
35
a. suspending any crystalline, solvated or amor-
phous Form of lenalidomide in N-methylpyrro-
lidone;
b. heating the suspension obtained in step (a)
40 at above 50°C;
c. cooling the solution obtained in step (b) at 15
to 40°C;
d. adding solvent to the solution at 15 to 40°C;
e. separating the solid;
45 f. slurring the isolated solid obtained in step (e)
with hydrocarbon solvent; and
g. isolating crystalline Form H1 of lenalidomide.
3. The process as claimed in claim 2, wherein in step
50 (b) the reaction is heated to 55-65°C.
4. The process as claimed in claim 2, wherein the sol-
vent used in step (d) is a solvent or mixture of sol-
vents selected from methanol, ethanol, isopropyl al-
55 cohol, n-butanol, ethyl acetate, methyl acetate, iso-
propyl acetate, tert-butyl methyl acetate, ethyl for-
mate, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl
ether, diisopropyl ether and diethyl ether.
5
 9 EP 2 688 649 B1
5. The process as claimed in claim 4, wherein the sol-
vent is selected from ethanol, ethyl acetate and me-
thyl tert-butyl ether.
6. The process as claimed in claim 2, wherein the hy-
drocarbon solvent used in step (f) is a solvent or mix-
ture of solvents selected from cyclohexane, hexane,
n-heptane, benzene, toluene and xylene.
7. The process as claimed in claim 6, wherein the hy-
drocarbon solvent is toluene.
8. A pharmaceutical composition in tablet or capsule
form that comprises crystalline lenalidomide Form
H1 as claimed in claim 1 and pharmaceutically ac-
ceptable excipients, and optionally other therapeutic
ingredients.
Patentansprüche
1. Kristalline Form H1 von Lenalidomid, die durch
Peaks im Pulver-Röntgenbeugungsspektrum mit
2θ-Winkelpositionen bei 10,6, 11,7, 14,9, 16,8, 18,2,
19,1, 22,5, 22,8, 23,6 und 28,2 6 0,2 Grad gekenn-
zeichnet ist.
2. Verfahren zur Herstellung der kristallinen Form H1
von Lenalidomid nach Anspruch 1, das umfasst:
a. Suspendieren einer kristallinen, solvatisierten
oder amorphen Form von Lenalidomid in N-Me-
thylpyrrolidon;
b. Erwärmen der in Schritt (a) erhaltenen Sus-
pension auf über 50°C;
c. Abkühlen der in Schritt (b) erhaltenen Lösung
auf 15 bis 40°C;
d. Zugeben eines Lösungsmittels zu der Lösung
bei 15 bis 40°C;
e. Abtrennen des Feststoffes;
f. Aufschlämmen des in Schritt (e) erhaltenen
isolierten Feststoffes mit einem Kohlenwasser-
stofflösungsmittel und
g. Isolieren der kristallinen Form H1 von Lena-
lidomid.
3. Verfahren nach Anspruch 2, wobei in Schritt (b) die
Reaktion auf 55 - 65°C erwärmt wird.
4. Verfahren nach Anspruch 2, wobei das in Schritt (d)
verwendete Lösungsmittel ein Lösungsmittel oder
ein Gemisch aus Lösungsmitteln ist, ausgewählt aus
Methanol, Ethanol, Isopropylalkohol, n-Butanol,
Ethylacetat, Methylacetat, Isopropylacetat, tert-Bu-
tylmethylacetat, Ethylformiat, Tetrahydrofuran, 1,4-
Dioxan, Methyl-tert-butylether, Diisopropylether und
Diethylether.
10
5. Verfahren nach Anspruch 4, wobei das Lösungsmit-
tel ausgewählt ist aus Ethanol, Ethylacetat und Me-
thyl-tert-butylether.
5 6. Verfahren nach Anspruch 2, wobei das in Schritt (f)
verwendete Kohlenwasserstofflösungsmittel ein Lö-
sungsmittel oder ein Gemisch aus Lösungsmitteln
ist, ausgewählt aus Cyclohexan, Hexan, n-Heptan,
Benzol, Toluol und Xylol.
10
7. Verfahren nach Anspruch 6, wobei das Kohlenwas-
serstofflösungsmittel Toluol ist.
8. Pharmazeutische Zusammensetzung in Tabletten-
15 oder Kapselform, die die kristalline Lenalidomidform
H1 nach Anspruch 1 und pharmazeutisch akzeptab-
le Hilfsstoffe und gegebenenfalls andere therapeu-
tische Inhaltsstoffe umfasst.
20
Revendications
1. Forme cristalline H1 de lénalidomide qui est carac-
térisée par des pics du spectre de diffractométrie
25 de rayons X sur poudres présentant des positions
d’angle 2θ à 10,6, 11,7, 14,9, 16,8, 18,2, 19,1, 22,5,
22,8, 23,6 et 28,2 6 0,2 degrés.
2. Procédé de préparation de la forme cristalline H1 de
30 lénalidomide selon la revendication 1, qui comprend
les étapes consistant à :
a. mettre en suspension toute forme cristalline,
solvatée ou amorphe de lénalidomide dans de
35 la N-méthylpyrrolidone ;
b. chauffer la suspension obtenue à l’étape (a)
au-dessus de 50 °C ;
c. refroidir la solution obtenue à l’étape (b) entre
15 et 40 °C ;
40 d. ajouter du solvant à la solution entre 15 et 40
°C ;
e. séparer le solide ;
f. étaler le solide isolé obtenu à l’étape (e) avec
un solvant hydrocarboné ; et
45 g. isoler la forme cristalline H1 de lénalidomide.
3. Procédé selon la revendication 2, dans lequel dans
l’étape (b), la réaction est chauffée à 55- 65 °C.
50 4. Procédé selon la revendication 2, dans lequel le sol-
vant utilisé dans l’étape (d) est un solvant ou un mé-
lange de solvants choisis parmi le méthanol, l’étha-
nol, l’alcool isopropylique, le n-butanol, l’acétate
d’éthyle, l’acétate de méthyle, l’acétate d’isopropyle,
55 l’acétate de méthyle de tert-butyle, le formiate d’éthy-
le, le tétrahydrofuranne, le 1,4-dioxane, l’éther de
méthyle de tert-butyle, l’éther diisopropylique et
l’éther diéthylique.
6
 11 EP 2 688 649 B1 12

5. Procédé selon la revendication 4, dans lequel le sol-

vant est choisi parmi l’éthanol, l’acétate d’éthyle et
l’éther de méthyle de tert-butyle.

6. Procédé selon la revendication 2, dans lequel le sol- 5

vant hydrocarboné utilisé dans l’étape (f) est un sol-
vant ou un mélange de solvants choisis parmi le cy-
clohexane, l’hexane, le n-heptane, le benzène, le
toluène et le xylène.
10
7. Procédé selon la revendication 6, dans lequel le sol-
vant hydrocarboné est le toluène.

8. Composition pharmaceutique sous forme de com-

primé ou de gélule, qui comprend la forme cristalline 15
H1 de lénalidomide selon la revendication 1, et des
excipients pharmaceutiquement acceptables et
éventuellement d’autres ingrédients thérapeutiques.

20

25

30

35

40

45

50

55

7
EP 2 688 649 B1

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EP 2 688 649 B1

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 EP 2 688 649 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European
patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be
excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• IN 899CHE2011 [0001] • WO 2010056384 A [0011]

• US 5635517 A [0008] • WO 2010061209 A [0012]
• WO 2005023192 A [0009] • WO 2010129636 A [0013]
• WO 2009114601 A [0010]

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