Blend Comprising S- and R-Lenalidomide

The invention concerns a process for producing S-lenalidomide and polymorphic Forms A and B of S-lenalidomide obtainable by said process. Additionally, the present invention concerns a blend comprising S- lenalidomide and R-lenalidomide. Furthermore, the present invention relates to oral dosage forms comprising polymorphic Forms A and B of S-lenalidomide or a blend comprising S-lenalidomide and R-lenalidomide.

Lenalidomide, with the chemical name

(S)-3-( 1 -oxo-4-amino- 1 ,3-dihydro-2H-isoindoline-2-yl)-piperidine-2,6-dione has the following structure:

In vitro, lenalidomide induces tumour cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti- osteoclastogenic effects, and by immunomodulatory activity. Thus, lenalidomide has a broad range of activities that can be exploited in order to treat many hematologic and solid cancers.

Racemic lenalidomide is marketed under the trade name Revlimid®.

Processes for producing S-lenalidomide are disclosed by Muller et al., Bioorganic & Medicinal Chemistry Letters 9 ( 1999), 1625- 1630 and in EP 0 925 294 B l , see in particular Example 16.

However, it has been found that the synthetic route as suggested in Example 16 of EP 0 925 294 B l for producing S-lenalidomide cannot be carried out in high yield. Furthermore, if racemic lenalidomide is produced in accordance with EP 0 925 294 B l the yield is even lower. That means, the prior art process is not suitable for producing S-lenalidomide in a large scale. Furthermore, the process as disclosed in EP 0 925 294 B l requires large amounts of expensive catalysts.

In WO 2005 /023192 A2 polymorphic forms of racemic lenalidomide are disclosed. In particular, Form B of racemic lenalidomide is described as the desired polymorph for a pharmaceutical formulation. However, the dissolution profile of Form B of racemic lenalidomide shows a still improvable dissolution behaviour.

In addition, it has been found that racemic lenalidomide has some undesirable properties. For example, recrystallization and micronization is necessary in order to ensure blend and content uniformity in pharmaceutical dosage forms, see EMEA, Scientific Discussion of Revlimid ^® , 2007.

However, micronization entails a number of drawbacks. First of all, the micronization of a pharmaceutically active compound often results in a low flowability or pourability of the product formulation. Furthermore, it is more difficult to fill the micronized substance into capsules. This often results in an irregular distribution of the active agent within the capsules. Moreover, the enlargement of the outer surface area due to micronization increases the susceptibility of the substance towards oxidation. Therefore, a micronized agent is more likely to degrade over time.

It is therefore desired to develop lenalidomide in a form that provides a good flowability and pourability, a superior oxidation stability, as well as a superior storage stability and shelf-life. These effects should be achievable with dosage forms having a low as well as a medium or even a high drug load.

For the present pharmaceutical dosage form it is also desired that the number and severity of the side effects, caused by the pharmaceutical dosage forms, are reduced to a minimum, especially taking specific population intolerances towards any of the substances contained therein into account.

In addition, the dosage forms of the present invention should show a superior content uniformity. Furthermore, the formulation should exhibit superior dissolution properties and good bioavailability (in particular before as well as after storage), especially with regard to bioequivalence to established formulations containing racemic lenalidomide on the market. Furthermore, the formulation should release the active pharmaceutical ingredient completely. In conclusion, there is a driving force for a new formulation that overcomes the problems faced in view of the state of the art and provides at the same time a similar or identical bioavailability as prior art compositions or formulations. The inventors of the present invention unexpectedly have found that the above drawbacks can be overcome by providing S-lenalidomide in specific polymorphic forms. The polymorphic forms of S-lenalidomide enable the preparation of dosage forms having advantageous properties. Moreover, the inventors unexpectedly have found that a blend of S-lenalidomide with R- lenalidomide has superior properties when compared to racemic lenalidomide known from prior art.

Consequently, a first subject of the present invention is a process for producing S-lenalidomide according to formula I

comprising the steps i) providing a compound according to formula II

ii) hydrogenating, preferably partially hydrogenating the compound according to formula II,

iii) isolating S-lenalidomide, wherein preferably in step (ii) 55 to 95 % of the compound according to formula II are hydrogenated.

A further subject of the present invention is S-lenalidomide in

polymorphic Form B, wherein an XRPD shows characteristic peaks at 8.03 °, 1 1.76 °, 17.46 ° and 18.84 ⁰ 2-Theta or

polymorphic Form A, wherein an XRPD shows characteristic peaks at 1 1 .73 °, 15.76 °, 18.80 ° and 24.73 ° 2-Theta. Further subjects of the present invention are the use of S-lenalidomide in polymorphic Forms A and/or B for producing a pharmaceutical dosage form and a pharmaceutical dosage form comprising said polymorphic forms of S- lenalidomide. Still a further subject of the present invention is a blend comprising S- lenalidomide and R-lenalidomide.

R-lenalidomide

Therefore, a subject of the present invention is a blend comprising

S-lenalidomide, preferably in polymorphic Form B, wherein an XRPD shows characteristic peaks at 8.03 °,

1 1 .75 °, 1 7.46 ° and 18.84 ⁰ 2-Theta, or

polymorphic Form A, wherein an XRPD shows characteristic peaks at 1 1 .73 °,

15.76 °, 18.80 °, and 24.73 ° 2-Theta, and

R-lenalidomide.

In the blend, Form B of S-lenalidomide is preferred.

Another subject of the present invention is R-lenalidomide in polymorphic Form B, wherein an XRPD shows characteristic peaks at 8.04°, 16. 16 °, 17.308 ° and 24.35 ° 2-Theta.

As mentioned above, a further subject of the present invention is a process for producing S-lenalidomide comprising the steps (i) to (iii), wherein steps (i) to (iii) are explained in more detail below.

In step (i) the compound according to formula II is provided. Said compound is known from prior art. In step (ii) the compound is hydrogenated, i.e. the nitro group is reduced to give an amino group.

Generally, the reducing methods known in the art can be used. Suitable reducing agents might be NaBH ₄ , LiBH ₄ , KBH ₄ , NaCNBH ₃ , Na(AcO) ₃ BH, L- Selectride ^® , K-Selectride ^® , N-Selectride ^® , benzyltriethylammonium borohydri- de, lithium dimethylaminoborohydride, lithium morpholinoborohydride, lithium pyrrolidinoborohydride, lithium triethylborohydride, potassium triethylborohydride, potassium triphenylborohydride, sodium triethylborohydride, sodium trimethoxyborohydride, tetrabutylammonium borohydride, tetrabutylammonium cyanoborohydride, tetramethylammonium borohydride, or tetramethylammonium triacetoxyborohydride.

Hydrogenation with complex hydrides (see above) with hydrazine, ammonium formiate, or hydrocarbons as hydrogen donors are carried out in the presence of metals, especially noble metals from the platinum group (platinum, palladium, rhodium, ruthenium), transition metals of the iron group and/or titanium, tin, zinc and copper. Those metals can be used either pure (iron, cobalt and nickel), or alloyed (Raney nickel or nickel boride). Generally, hydrogenation of nitro groups over Raney-nickel and/or palladium, and reductions of the nitro group over metals (Fe, Sn, Zn) in mineral acids (HC1) or organic acid (acetic acid) can be carried out by processes known in the art, see e.g. Richard C. Larock: Comprehensive Organic Transformations: A Guide to Functional Group Preparation, 1989, VCH, Publisher, pp 41 1 - 415).

Preferably, the hydrogenation is carried out by employing a palladium catalyst, preferably palladium on charcoal (Pd/C) in the presence of hydrogen gas. Preferably, the weight ratio of palladium: the compound according to formula (II) is 0.03 to 0. 15, more preferably from 0.05 to 0.010. The term "palladium" refers in this context to the amount of palladium as such, not to the amount of palladium including the weight of the charcoal carrier. Hydrogen can be applied with a pressure ranging from 1 to 10 bar, preferably from 2.5 to 4.0 bar.

The reaction of the compound according to formula (II) with the hydrogenating agent may be carried out in usual organic solvents and at usual temperatures. Usually the reaction is carried out at temperatures between - 50 °C and 50 °C, preferably between 10 °C and 35 °C. The reaction time can range from 0.1 to 20 hours, preferably from 3 to 6 hours.

In a preferred embodiment in step (ii) the compound according to formula II is partially hydrogenated. Preferably, hydrogenation conditions are chosen such that 55 % to 99 % , more preferably 70 % to 95 % , particularly 75 % to 90 % of the compound according to formula II is hydrogenated. Preferably, "%" refers to "mol %". In an alternative embodiment in step (ii) the compound according to formula II is essentially completely hydrogenated. That means, preferably, hydrogenation conditions are chosen such that about 100 % of the compound according to formula II is hydrogenated. Optionally, the catalyst used in step (ii) can be recycled.

After the hydrogenation the resulting S-lenalidomide is isolated in step (iii), preferably by crystallizing from a suitable solvent. Solvents suitable for the use in steps (i), (ii) and/or (iii) generally are polar organic solvents. In a preferred embodiment an organic solvent having a relative permittivity (=ε _Γ ) from > 15 to 50, preferably from 18 to 40, more preferably from 20 to 35, measured at 20 °C, is used. The permittivity of a substance is a characteristic, which describes how it affects any electric field set up in it. A high permittivity tends to reduce any electric field present. The capacitance of a capacitor can be increased by increasing the permittivity of the dielectric material. The permittivity of free space (or a vacuum), ε ₀ , has a value of 8.9 x 10 ^'12 F m ^'1 . The permittivity of a material is usually given relative to that of free space, which is known as relative permittivity, ε _Γ .

In Table 1 below the relative permittivity of several organic solvents (and water), measured at 20 °C, is given. Table 1 :

Generally, suitable organic solvents might be selected from water, C2-C6 alcohol, C3-C6 ketone, C 1 -C4 carboxylic acids, C 1 -C6 carboxylic acid dialkylamides, C2-C6 sulfoxides and C2-C6 sulfons, C2-C4 nitriles, low polymerized liquid ethylene and propylene glycol ethers and mixtures thereof. Methanol is preferred. Furthermore, it is preferred that in steps (i), (ii) and (iii) the same solvent (or solvent mixture) is used. Preferably, in step (iii) S-lenalidomide can be obtained from the filtered reaction mixture by volume reduction through evaporation of volatile solvent amounts. Optionally, purification of S-lenalidomide obtainable by step (iii) can be performed by the use of solvent/ antisolvent systems.

Solvents suitable for the use as a "solvent" component are generally those described for step (iii).

Solvents suitable for the use as a "non-solvent" component are generally organic solvents having a relative permittivity ( = ε _Γ ) from 1 to 15 , preferably from 2 to 12 , more preferably from 3 to 10, measured at 20 °C. Suitable organic solvents for the use as a "non solvent" component might be selected from a C5-C9 aliphatic or aromatic hydrocarbon, optionally substituted e.g. with halogen, a C3 -C6 ester, a C2-C6 ether, C2-C4 nitriles, and mixtures thereof. Ethyl acetate is preferred.

Optionally, in a subsequent step (iv) the resulting acid addition salt can be recrystallized. Solvents suitable for the use in step (iv) generally are non- or slight-polar organic solvents. In a preferred embodiment an organic solvent having a relative permittivity (=ε _Γ ) from 1 to 15 , preferably from 2 to 12, more preferably from 3 to 10, measured at 20 °C, is used. Generally, suitable organic solvents for the use in optional step (iv) might be selected from a C5 -C9 aliphatic or aromatic hydrocarbon, optionally substituted e.g. with halogen, a C3-C6 ester, a C2-C6 ether, C2 -C4 nitriles, and mixtures thereof. Ethyl acetate is preferred. Depending on the reaction conditions chosen in step (ii) and the solvents used in steps (iii) and optionally (iv), different forms of S-lenalidomide can be obtained.

In a first preferred embodiment in step (ii) a complete hydrogenation is carried out. Furthermore, in step (iii) S-lenalidomide is isolated by crystallizing from a solvent having a relative permittivity (=e _r ) from > 15 to 50, preferably from methanol. In this embodiment preferably S-lenalidomide in polymorphic Form A (as described in detail below) is obtained. Alternatively, polymorphic Form A can also be obtained if the S-lenalidomide as obtained from above steps (ii) and (iii) (i.e. complete hydrogenation) is subsequently slurried in a solvent having a relative permittivity ( =ε _Γ ) from 1 to 15 , preferably ethylacetate .

In a second preferred embodiment in step (ii) a partial hydrogenation is carried out. Furthermore, in step (iii) S-lenalidomide is isolated by solidification from a solvent having a relative permittivity (=ε _Γ ) from > 15 to 50, preferably from methanol. In this embodiment preferably S-lenalidomide in amorphous form is obtained. In a third embodiment in step (ii) a partial hydrogenation is carried out. Furthermore, in step (iii) S-lenalidomide is isolated by solidification from a solvent having a relative permittivity (=ε _Γ ) from > 15 to 50, preferably from methanol. The obtained solid subsequently is dissolved and crystallized from a solvent having a relative permittivity (=ε _Γ ) from 1 to 15 , preferably ethyl acetate. In this embodiment preferably S-lenalidomide in polymorphic Form B (as described in detail below) is obtained.

That means, if S-lenalidomide is produced by the process of the present invention, it can be obtained in amorphous or different crystallinic forms. Preferably, S-lenalidomide can be obtained in at least two polymorphic forms, namely polymorphic Form A and polymorphic Form B.

In a first preferred embodiment S-lenalidomide is obtained in polymorphic Form A, wherein Form A is characterized by an X-Ray powder diffraction (hereinafter referred to as XRPD) showing characteristic peaks at 1 1 .73 °, 15.76 °, 18.80 °, and 24.73 ° 2-Theta. Further characteristic peaks can be found at 19.38 °, 25.44 ° , 26.68 °, 27.91 ° and/ or 31 .90 ° 2-Theta. Generally, the XRPD measurements are carried out as outlined below in the experimental section. Generally, in all XRPD measurements the margin of error is approximately 0.2 °.

An XRPD of Form A of S-lenalidomide according to the present invention is shown in Figure 1 . In a second preferred embodiment S-lenalidomide is obtained in polymorphic Form B . Form B of S-lenalidomide is characterized by an X-Ray powder diffraction showing characteristic peaks at 8.03 °, 1 1 .75 °, 1 7.46 ° and 18.84 ° 2-Theta. Further characteristic peaks can be found at 15.8 ° , 18.62 °, 19.25 °, 23.98 °, 24.30 °, 24.78 °, 25.32 ° and /or 26.82 ° 2-Theta. An XRPD of Form B of S-lenalidomide according to the present invention is shown in Figure 2. An XRPD of amorphous S-lenalidomide is shown in Figure 3. Preferably, S-lenalidomide according to the present invention is present in particulate form . Preferably, the D ₅₀ -value of the particle size distribution of the particulate S-lenalidomide ranges from 0. 1 to 200 μνα, more preferably from 2.0 to 120 μτη, further more preferably from 15 to 75 μνα, most preferably from 15 to 75 μτη.

Preferably, S-lenalidomide according to the present invention has a D ₉₀ -value of the particle size distribution of 5 to 500 μτη , more preferably of 50 to 350 μτη, further more preferably of 80 to 250 /im, most preferably of 120 to 190 μηι.

Preferably, S-lenalidomide according to the present invention has a D ₁₀ -value of the particle size distribution of 0. 1 to 30 μτη, more preferably of 0.5 to 90 μτη, further more preferably of 1 .0 to 15 μπι, most preferably of 2.0 to 10 μτη.

The volume mean particle size (D ₅₀ ) is determined by the light scattering method, using a Mastersizer 2000 apparatus made by Malvern Instruments (wet measurement, 2000 rpm, ultrasonic waves for 60 sec , data interpretation via Fraunhofer method). The D ₅₀ -value of the particle size distribution of a particulate compound is generally defined as the particle size, where 50 vol. -% of the particles have a smaller particle size than the particle size which corresponds to the D ₅₀ -value. Analogously, the D ₉₀ -value of the particle size distribution of a particulate compound generally is defined as the particle size, where 90 vol. -% of the particles have a smaller particle size than the particle size which corresponds to the D ₉₀ -value. Analogously, the D ₁₀ -value of the particle size distribution of a particulate compound is generally defined as the particle size, where 10 vol. -% of the particles have a smaller particle size than the particle size which corresponds to the D evalue. In a further aspect of the invention it has been unexpectedly found that alternatively the above-mentioned problems could be solved by a blend, comprising S-lenalidomide according to the present invention (i.e. preferably S-lenalidomide in polymorphic Forms A and /or B) and R-lenalidomide. Generally, R-lenalidomide can be prepared according to Example 16 of EP 0 925 294 B l , wherein (R)-3 -( 1 -oxo-4-nitroisoindolin-2-yl)piperidine-2 ,6-dione is used as precursor (which is obtainable by using t-butyl N-( l -oxo-4- nitroisoindolin-2-yl)-R-glutamine as corresponding starting material.

In another embodiment of the invention S and R-lenalidomide were prepared by preparative enantiomer separation using chiral chromatography, preferable as described in Example 5.

Preferably, R-lenalidomide is produced as described below in Example 3. In this case, R-lenalidomide is obtained in polymorphic Form B.

Form B of R-lenalidomide is characterized by an X-Ray powder diffraction showing characteristic peaks at 8.04°, 16.16 °, 17.308 ⁰ and 24.35 ° 2-Theta. Further characteristic peaks can be found at 17.50°, 18.67 °, 19.29 °, 24.03 °, 25.36 ° and/or 26.96 ° 2-Theta. Further peaks can be found in Example 3. An XRPD of Form B of R-lenalidomide according to the present invention is shown in Figure 4.

Therefore, a subject of this second aspect of the present invention is a blend comprising

(cx) S-lenalidomide in polymorphic Form B, wherein an XRPD of the S- lenalidomide shows characteristic peaks at 8.03 °, 1 1 .75 °, 17.46 ° and 18.84 ° 2-Theta or

S-lenalidomide in polymorphic Form A, wherein an XRPD of the S- lenalidomide shows characteristic peaks at 1 1.73 °, 15.76 °, 18.80 ° and 24.73 ° 2-Theta, and

(β) R-lenalidomide, preferably R-lenalidomide, in crystalline form.

The term "blend" hereby refers to a physical mixture of S-lenalidomide and R- lenalidomide. Within this application said physical mixture is also designated as "RS-Blend" . The RS-blend is a mixture of two type of crystals, namely a mixture of crystalline R-lenalidomide and crystalline S-lenalidomide. It has been unexpectedly found that the RS-Blend has superior dissolution properties when compared with lenalidomide in form of the racemic compound. Hereby the term "racemic compound" refers to a homogenous composition comprising R-lenalidomide and S-lenalidomide in equal amounts and in form of a single crystalline compound. That means, in the racemic compound R-lenalidomide and S-lenalidomide crystallize within the same crystal, whereas in the RS-Blend S-lenalidomide and R-lenalidomide crystallize in separate crystals. Preferably, the blend according to the second aspect of the invention comprises a weight ratio of S-lenalidomide to R-lenalidomide of 10 : 1 to 1 : 10, more preferably from 5 : 1 to 1 : 5, much more preferably from 3 : 1 to 1 : 3, still more preferably from 2 : 1 to 1 : 2, most preferably of about 1 : 1 .

Preferably, the XRPD of the RS-blend according to the second aspect of the invention shows characteristic peaks at 8.03°, 16. 12°, 17.00° and 22.44° 2- Theta. Further characteristic peaks can be found at 17.47°, 18.25 °, 21 .96°, 24.08 °, 25.32 ⁰ and/ or 38.26° 2-Theta. Further peaks can be found in Example 4. An XRPD of the RS-Blend according to the present invention is shown in Figure 5. The RS-Blend of Example 4 is also designated as Lenalidomide RS-Blend Form I.

In a preferred embodiment, the RS-Blend comprises S-lenalidomide, preferably S-lenalidomide in polymorphic B, and R-lenalidomide, preferably in polymorphic Form B in particulate form. Preferably the D ₅₀ -value of the particle size distribution of the RS-Blend is from 0.1 to 200 μτα, more preferably from 2.0 to 120 μτη, still more preferably of from 5.0 to 90 μτη, most preferably of from 15 to 75 μπι.

Preferably, the RS-Blend according to the present invention has a D ₉₀ -value of the particle size distribution of 5 to 500 μπι, more preferably of 50 to 350 μτη, further more preferably of 80 to 250 μπι, most preferably of 120 to 190 μτη. Preferably, the RS-Blend according to the present invention has a D ₁₀ -value of 0.1 to 30 μιη, more preferably of 0.5 to 20 μπι, further more preferably of 1.0 to 15 μτα, most preferably of 2.0 to 10 μτη.

The RS-Blend shows unexpected superior dissolution properties. Preferably, the RS-Blend shows a dissolution profile, wherein at least 95 wt. % of lenalidomide are dissolved within the first 10 minutes of a dissolution test according to USP Type II (paddle) at 37°C in 0.01 N HC1, pH 2.1 and 50 rpm.

In the above RS-blend preferably R-lenalidomide Form B is used. Preferably, the D ₅₀ -value of the particle size distribution of the R-lenalidomide is from 0.1 to 200 μπι, more preferably from 2.0 to 120 μτη, further more preferably from 5.0 to 90 μτα, most preferably from 15 to 75 μτα.

Preferably, R-lenalidomide Form B has a D ₉₀ -value of the particle size distribution of 5 to 500 μτα, more preferably of 50 to 350 μτη, further more preferably of 80 to 250 μτη, most preferably of 120 to 190 μπι. Preferably, R-lenalidomide Form B has a D ₁₀ -value of the particle size distribution of 0. 1 to 30 /im , more preferably of 0.5 to 20 /im , further more preferably of 1 .0 to 15 μτη , most preferably of 2.0 to 10 μνη.. S-lenalidomide (preferably in polymorphic Forms A and / or B) or R- lenalidomide according to the present invention or a blend comprising S- lenalidomide according to the present invention (i . e . preferably S-lenalidomide in polymorphic Forms A and / or B) and R-lenalidomide can be used for preparing a solid oral dosage form .

Hence , a further subject of the present invention is a pharmaceutical composition, preferably in form of a pharmaceutical dosage form. Preferred dosage forms are tablets or capsules or sachets comprising the pharmaceutical composition in particulate form . Capsules are particularly preferred.

In a preferred embodiment the present invention relates to a dosage form , preferably in form of a capsule , comprising

a) S-lenalidomide , preferably in polymorphic Form A and / or B , or a blend comprising S-lenalidomide according to the present invention (i. e . preferably

S-lenalidomide in polymorphic Forms A and / or B) and R-lenalidomide b) a filler, preferably a lactose-free filler, and / or

c) a solubilizer, and / or

d) a disintegrant.

Generally, fillers b) are used to top up the volume for an appropriate oral deliverable dose , when low concentrations of the active pharmaceutical ingredients (about 70 wt.% or lower) are present. However, in powder formulations they might be useful to enhance the powder flow, so as to guarantee e .g. a uniform filling of the capsules. Fillers are usually relatively chemically inert, but they can have an effect on the bioavailability of the active ingredient. They can influence the solubility of the active ingredient and enable a powder of an insoluble compound to break up more readily on capsule shell disintegration. Typical state of the art formulations employ lactose as a filler.

Preferred fillers of the invention are calcium phosphate, saccharose , calcium carbonate, calcium silicate , magnesium carbonate , magnesium oxide , maltodextrin , calcium sulfate , dextran , dextrin , dextrose , hydrogenated vegetable oil and / or cellulose derivatives . A pharmaceutical composition according to the invention may comprise an inorganic salt as a filler . Preferably, this inorganic salt is dicalcium phosphate , preferably in form of the dihydrate (dicafos).

Dicalcium phosphate dihydrate is insoluble in water, non-hygroscopic, but still hydrophilic. Surprisingly, this behavior contributes to a high storage stability of the composition. This is in contrast to e.g. lactose , which is readily soluble in water. Furthermore , lactose has the limitation that some people - about 75 % of the world population - have a more or less severe intolerance towards this compound and would therefore find drugs without this compound more agreeable on digestion. Therefore, a pharmaceutical composition comprising dicalcium phosphate dihydrate will not only enhance the storage stability of the resulting product, but will also offer an adequate treatment, which is suitable for lactose-intolerant people. Therefore, in a superior concretization of the invention, the pharmaceutical dosage form of the present invention is essentially free of lactose or derivatives thereof. This can be achieved by employing a filler, which does not comprise lactose or one of its derivatives. The pharmaceutical composition further optionally comprises one or more solubilizers (c). Generally, the term "solubilizer" means any organic excipient, which improves the solubility and dissolution of the active pharmaceutical ingredient. The solubilizers are selected, for example, from the group of known inorganic or organic excipients. In a preferred embodiment the solubilizer is a hydrophilic polymer. Generally, the term "hydrophilic polymer" encompasses polymers comprising polar groups. Examples for polar groups are hydroxy, amino, carboxy, carbonyl, ether, ester and sulfonate. Hydroxy groups are particularly preferred. The hydrophilic polymer usually has a weight average molecular weight ranging from 1 ,000 to 250,000 g/mol, preferably from 2,000 to 100,000 g/mol, particularly from 4,000 to 50,000 g/ mol. Furthermore, a 2 % w/w solution of the hydrophilic polymer in pure water preferably has a viscosity of from 2 to 8 mPas at 25 °C . The viscosity is determined according to the European Pharmacopoeia (hereinafter referred to as Ph. Eur. ), 6 ^th edition, chapter 2.2. 10.

Furthermore, the hydrophilic polymer used as solubilizer preferably has a glass transition temperature (T _g ) or a melting point of 25 °C to 150 °C, more preferably of 40 °C to 100 °C . The glass transition temperature, T _g , is the temperature at which the hydrophilic polymer becomes brittle on cooling and soft on heating. That means, above the T _g , the hydrophilic polymers become soft and capable of plastic deformation without fracture. The glass transition temperature or the melting point are determined with a Mettler-Toledo ^® DSC 1 , wherein a heating rate of 10 °C per minute and a cooling rate of 15 °C per minute is applied.

Examples for suitable hydrophilic polymers useful as solubilizer are derivatives of cellulose, hydrophilic derivatives of cellulose (microcrystalline cellulose, hydroxyproplymethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), preferably sodium or calcium salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone, preferably having an average molecular weight of 10,000 to 60,000 g/mol, copolymers of polyvinylpyrrolidones, preferably copolymers comprising vinylpyrrolidone and vinylacetate units (e.g. Povidon ^® VA 64; BASF), preferably having a weight average molecular weight of 40,000 to 70,000 g/mol, polyoxyethylene alkylethers, polyethylene glycol, co- blockpolymers of ethylene oxide and propylene oxide (Poloxamer, Pluronic ^® ), derivates of methacrylates, polyvinyl alcohol and / or polyethylene glycols or derivatives thereof. The weight average molecular weight is preferably determined by gel permeation chromatography. Moreover, sugar alcohols like isomalt, sorbitol, xylitol or mannitol can be used as solubilizers.

Preferably, microcrystalline cellulose is used as solubilizer, more preferably microcrystalline cellulose having a moisture content of 3 to 5 % and a bulk density from 0.25 to 0.32 g/ cm ³ .

The pharmaceutical composition of this invention optionally further comprises a disintegrant (d), or a combination of more than one disintegrant compound. A disintegrant is generally a compound that accelerates the disintegration of the orally deliverable dose unit - preferably a capsule or tablet - on contact with water. Suitable disintegrants are polacrilin potassium, corn starch, microcrystalline cellulose, starch, pre-agglutinated starch, sodium carboxymethyl starch, sodium carboxymethyl cellulose, croscarmellose sodium and / or cross-linked polyvinylpyrrolidone (crospovidone).

Preferably, so-called "superdisintegrants" are used. These include croscarmellose and more preferably crospovidone. Superdisintegrants either swell many-fold on absorbing water or act as wicks, thereby attracting water into the powder plug so as to disrupt the latter from the inside. Preferably, the disintegrant is an intragranular crospovidone such as Polyplasdone ^® XL 10 or croscarmellose sodium (e.g. Ac-Di-Sol ^® ).

Additionally, the pharmaceutical composition, preferably the pharmaceutical dosage form, may comprise one or more additional excipients as for example lubricant, glidant and / or anti-sticking agent.

In a preferred embodiment of this invention, a lubricant may be used. Lubricants are generally employed to reduce dynamic friction. The lubricant preferably is a stearate, talcum powder or fatty acid, more preferably, hexanedioic acid or an earth alkali metal stearate, such as magnesium stearate . The lubricant is suitably present in an amount of 0. 1 to 3 wt.% , preferably about 0.5 to 1 .5 wt.% of the total weight of the composition. Preferably, the lubricant is applied in a final lubrication step during the powder preparation. The lubricant generally increases the powder flowability.

Generally, in the pharmaceutical composition of the present invention the active ingredient (a) can be present in an amount of 0. 1 to 50 wt.% , preferably 0.5 to 20 wt.% , more preferably 2 to 15 wt.% , and particularly preferred between 3 and 10 wt.% , based on the total weight of the dosage form. The dosage forms of the present invention may contain dosage amounts of 0. 1 - 50 mg, preferably 0.5 - 25 mg, more preferable 5 - 25 mg, e.g. 5 mg, 10 mg, 15 mg or 25 mg of the active pharmaceutical ingredient, based on the weight of lenalidomide in form of the free base.

Generally, in the pharmaceutical composition of the present invention the filler (b) can be present in an amount of 0 to 90 wt.% , preferably 10 to 85 wt.% , more preferably 15 to 80 wt.% , based on the total weight of the composition.

Generally, in the pharmaceutical composition of the present invention the solubilizer (c) can be present in an amount of 0 to 90 wt.% , preferably 10 to 85 wt.% , more preferably 15 to 80 wt.% , based on the total weight of the composition.

In a preferred embodiment components (b) and (c) together are present in an amount of 50 to 99 wt.% , more preferably of 60 to 95 wt.% , still more preferably of 70 to 95 wt.% . The disintegrant (d) is suitably present in an amount of 0 to 20 wt.% , more preferably at about 1 to 15 wt.% of the total weight of the composition. The lubricant is suitably present in an amount of 0 to 2 wt.% , preferably about 0.5 to 1 .5 wt.% of the total weight of the composition.

Preferably, the glidant agent is present in an amount of 0 to 8 wt.% , more preferably at 0. 1 to 3 wt.% of the total weight of the composition.

The anti-sticking agent may be present in amounts of 0 to 5 wt.% , more preferably in an amount of 0.5 to 3 wt.% of the total weight of the composition.

Where it is referred to the total weight of the pharmaceutical composition or the pharmaceutical dosage form, the total weight is the combined weight of the components present in the dosage form excluding, if applicable, the weight of any coating, capsule shell or sachet.

The pharmaceutical dosage form generally is produced by blending the above- mentioned ingredients and subsequently transferring the blend into the desired dosage form, e.g. by filling into capsules or sachets or by compressing into tablets. The blending can be carried out in conventional blenders. Suitable examples are tumble blenders such as Turbula TC 10 B.

In addition, the inventive capsules display a high content uniformity. Typically, these parameters indicate the relative deviation in the amount of content of the capsules. The content uniformity is determined according to Ph. Eur. 6.0, chapter 2.9.40 and provided in terms of the acceptance value. The latter parameter is calculated according to table 2.9.40. -2 , Ph. Eur. 6.0, and pages 328 and 329. Generally, the maximum allowed acceptance value is 15.0 (Ph. Eur. 6.0). The present invention provides acceptance values of 7.0 or lower, more preferably of 5.0 or lower, in particular, of 3.0 or lower.

In addition, the present compositions and formulations display a high storage stability, which is preferably higher than for previous formulations. The storage stability is ascertained for at least 12 months at 40 °C and 75% humidity. The incurred deterioration and / or impurities after this timespan are less than 2.5 wt.% .

The pharmaceutical dosage forms of the present invention comprise formulations showing "immediate release". Within the scope of this patent application, immediate release formulations having a Q value of not less than 75 % , preferably having a Q value from 80 % to 100 % , more preferably a Q value from 90 % to 100 % . The Q value is determined as described in USP 32- NF 27 method II (paddle, chapter <71 1 >). In case of tablets, these values refer to the uncoated tablet.

The invention is hereinafter illustrated by the following examples.

EXAMPLES

A] Equipment

IR-spectroscopy

HPLC-methods

For the determination of the purity of the intermediates and the final product, the following HPLC methods were used.

Reversed Phase (RP) HPLC

Chiral HPLC

Melting Point

B) Reactions Example 1 : (S)- 3-(l -Oxo-4-aminoisoindolin-2-yl)piperidine-2,6-dione;

Form A

A mixture of (S)-3 -( 1 -oxo-4-nitroisoindolin-2-yl)piperidine-2 ,6-dione (6.20 g, 21 .4 mmol), and 5 % Pd / C wet (3.74 g, wetted with 50 % water, 0.08 equiv. ) in methanol (3 ,700.00 ml, was completely hydrogenated in a hydrogenation reactor (Kilo Clave from Biichi, with BPC equipment) at 50 psi of hydrogen at RT.

As in process control (IPC) analysis showed full conversion of starting material, the reaction medium was released from the reactor, filtered through filter paper on a Buchner filter, which had been covered with diatomaceous earth (40 g) to remove catalyst and then the clear, colorless filtrate was concentrated in vacuo (on a Rotavapor). During evaporation of the volatiles a crystalline solid separated, which was filtered from the concentrated mother liquor ( 10 ml) and dried on air to obtain 4.98 g. A sample was taken and characterized and analyzed for reference (0. 180 g, sample 1 - 1 ).

The solid (4.8 g) was put back to the flask, ethyl acetate (EA, 100 ml) was added and warmed up in a water bath, set to about 65 °C. The flask with the slurry of the solid in hot ethyl acetate (EA) was slowly rotated in a water bath (Rotavapor) for 30 min. After that time an amber suspension has been formed, which had been filtered through a glass sinter filter (G3) leaving a light yellow solid. When dried on the filter at 50 °C at 200 mbar 4.19 g (75.4 % from theory) of the product were obtained as a light yellow solid (sample 1-2), slowly melting under degradation between 235 °C and 242 °C, and solid from MeOH mother liquor melted/decomposed in the same range between 235 -245 °C (sample 1-1). When analyzed by DSC the crystalline solid from evaporation of MeOH (sample 1-1) could be characterized with melting endotherm peak at 241.46 °C, with onset and offset temperatures at 234.75 °C and 247.38°C, respectively (norm. 56.00 J/g), the sample from the slurry (sample 1-2) had similar values (peak: 242.68°C, onset: 235.98°C, offset: 248.51 (norm.54.35 J/g).

The XRPD from both solids were recorded. Crystalline solid from evaporation of MeOH (sample 1-1), showing reflections which match with those from the XRPD of the solid from EA-slurry (sample 1-2). IR-spectra were congruently overlapping.

Sample 1 - 1 :

IR-spectrum: V [cm ¹ ] (intensity): 1661,9 (0,600), 1702,8 (0,513), 1195,3 (0,430), 1624,8 (0,335), 1322,3 (0,287), 1605,0 (0,275), 753,6 (0,277), 1175,0 (0,265), 3367,6 (0,260), 1265,3 (0,256), 1463,7 (0,231), 1353,8 (0,209), 1297,5 (0,202), 1425,3 (0,185), 3079,7 (0,184), 1494,6 (0,174), 810,0 (0,161), 3475,5 (0,138), 870,0 (0,133).

XRPD: (°2theta/rel. Int. %): 11.727 (76.3), 15.764 (57.1), 17.019 (8.8), 18.795 (100), 19.382 (32.6), 19.772 (13.1), 23.017 (14.7), 23.37 (9.5), 23.646 (9.4), 24.729 (67.2), 25.438 (29.9), 26.005 (19.9), 26.684 (52.2), 27.909 (37.9), 28.61 (9.7), 31.898 (17.6), 33.239 (13.2), 36.196 (8.7), 36.63 (9.5), 38.924 (7.3);

The respective XRPD is shown in Figure 1.

Sample 1-2:

IR-spectrum: v [cm ¹ ] (intensity): 1662,3 (0,405), 1703,2 (0,360), 1195,6 (0,288), 1624,8 (0,235), 1605,1 (0,206), 1322,4 (0,199), 3367,5 (0,194), 753,7 (0,189), 1175,1 (0,187), 1265,4 (0,180), 1463,7 (0,165), 1353,8 (0,155), 1297,5 (0,148), 3078,1 (0,141), 1494,2 (0,137), 1425,1 (0,135), 810,1 (0,114), 3475,3 (0,112), 870,0 (0,0953) ST09030601-2 (09031602-3. dif)

XRPD: (°2theta/rel. Int. %): 8.029 (72.5), 9.377 (27.8), 11.751 (100), 15.8

(50.3) , 16.127 (12.5), 17.026 (39.3), 17.284 (60.1), 17.46 (71.6), 18.616 (55.7), 18.836 (87.8), 19.245 (49.5), 23.403 (13), 23.983 (44.7), 24.303 (59.1), 24.777

(53.4) , 25.323 (51.7), 26.034 (15.4), 26.824 (54.4) 27.937 (20), 31.881 (14.1);

Chiral HPLC:

9.466 min. (99.2580 %, S-lenalidomide); 18.9 min. (R-lenalidomide not detected), 6.288 min. (0.7420 %).

Example 2: (S)- 3-(l-Oxo-4-aminoisoindolin-2-yl)piperidine-2,6-dione;

amorphous and Form B A mixture of (S)-3-( 1 -oxo-4-nitroisoindolin-2-yl)piperidine-2,6-dione (5.61 g , 19.4 mmol), and 5 % Pd/C wet (3.38 g, wetted with 50 % water, 0.08 equiv.) in methanol (3,363.18 ml, was partially hydrogenated in a hydrogenation reactor (Kilo Clave from Biichi, with BPC equipment). The reaction was monitored by measuring online and recording stirrer speed, inner temperature, pressure and gas consumption. The reaction was stopped after 5 hours (50 psi, 20-21 °C IT, when gas consumption had ceased.

Through the sampling unit of the reactor 3 aliquots of 5 ml sample were taken from the supernatant. The third sample was filtered from catalyst through membrane filter unit (Pall ^® GHP, 0.2 μτη), diluted with Methanol and analyzed by HPLC.

As in process control (IPC) analysis showed incomplete conversion of starting material, the reaction medium in the reactor was kept for a whole of 23 h under hydrogenation conditions. After that time a second IPC showed no more starting material and an amount of 80 %-87 % of product in the supernatant. The reaction was stopped the reactor inertized and the reaction mixture was released from the reactor. This was filtered through filter paper covered with diatomaceous earth (40 g) on a Buchner funnel to remove catalyst. The clear, colorless filtrate was concentrated in vacuo (on a Rotavapor). On evaporation of the volatiles no crystal solid was separated. First a syrupy liquid, then, when concentrated further, a glassy solid (100 % amorphous, see Figure 3) resulted, which was sticking on the walls of the flask. Ethyl acetate (100 ml) was added to the flask and warmed up in a water bath, set to about 65 °C, the glassy film became turbid and recrystallized. The solid was slurried in hot ethyl acetate for 30 min while slowly rotating on the water bath (Rotavapor). After that time an amber suspension had been formed, which had been filtered through a glass sinter filter (G3) leaving a light yellow solid. When dried on the filter at 50 °C at 200 mbar 4.09 g (81 .3 % from theory) of the product were obtained as a light yellow solid.

This solid was melting slowly under degradation between 229 °C and 233 °C, while solids according to example 1 (sample 1 - 1 from MeOH and sample 1 -2 from ethyl acetate) melted between 235-245 °C.

When analyzed by DSC the crystalline solid could be characterized with melting endotherm peak at 232.95 °C, with onset and offset temperatures at 220.77 °C and 238.91 °C, respectively (norm. 77. 17 J/g). The XRPD from this solid was recorded, showing reflections of a crystalline solid different to that from Example 1 (Form A). Differences to these samples were observed in IR spectra, too.

IR-spectrum: V [cm ¹ ] (intensity): 1671 ,0 (0,730), 1623,6 (0,625), 1 199,4 (0,443), 1359, 1 (0,363), 739,0 (0,331 ), 1492,5 (0,320), 1236,4 (0,319), 3213, 1 (0,290), 1324,8 (0,286), 3368,5 (0,282), 1441 ,3 (0,248), 1735,7 (0,235), 3471 ,2 (0,232), 1 148,9 (0,230), 1297,8 (0,222), 1462,6 (0,201 ), 1264,5 (0, 192), 800,6 (0, 180), 937,0 (0, 129), 1047,5 (0, 128) XRPD: (°2theta/rel. Int.%): 8.029 (72.5), 9.377 (27.8), 1 1.751 ( 100), 15.8

(50.3) , 16. 127 ( 12.5), 17.026 (39.3), 17.284 (60.1 ), 17.46 (71 .6), 18.616 (55.7), 18.836 (87.8), 19.245 (49.5), 23.403 ( 13), 23.983 (44.7), 24.303 (59.1 ), 24.777

(53.4) , 25.323 (51 .7), 26.034 ( 15.4), 26.824 (54.4) 27.937 (20), 31.881 ( 14.1 ); The respective XRPD is shown in Figure 2.

Chiral HPLC:

9.582 min. (94 % , S-lenalidomide); 10.298 min. , (4.8 % ), 7.064 min. (0.18 %), 7.35 min. (0.42 %), 19.177 min. (R-lenalidomide not detected). Example 3: (R)- 3-(l-Oxo-4-aminoisoindolin-2-yl)piperidine-2,6-dione,

Form B

(R)-3-( 1 -oxo-4-aminoisoindolin-2-yl)piperidine-2,6-dione was synthesized, starting from (R)-3-( 1 -oxo-4-nitroisoindolin-2-yl)piperidine-2,6-dione accor- ding to Example 2. The XRPD from this solid was recorded, showing reflections of a crystalline solid as followed:

XRPD: (°2theta/rel. Int.%): 8.037 (100.0%), 16.164 (21.3%), 16.998 (4.8%), 17.308 (19.0%), 17.503 (13.2%), 18.666 (13.7%), 19.299 (14.1%), 23.403 (5.3%), 24.033 (13.8%), 24.353 (20.1%), 25.36 (16.4%), 26.957 (18.8%), 29.741 (10.3%), 31.593 (4.7%), 34.355 (5.0%), 37.887 (4.8%), 41.136 (8.6%), 41.24 (4.7%), 48.756 (4.7%), 49.872 (4.9%). Example 4: Physical RS-Blend Lenalidomide Form I

Equal amounts of (S)-3-( 1 -oxo-4-aminoisoindolin-2-yl)piperidine-2,6-dione Form B according to Example 2 and (R)-3-( 1 -oxo-4-aminoisoindolin-2- yl)piperidine-2,6-dione Form B were mixed and comminuted.

The XRPD from this solid was recorded, showing reflections of a crystalline solid as followed:

XRPD: (°2theta/rel. Int.%): 8.025 (100.0%), 16.123 (22.4%), 17.002 (13.6%), 17.47 (12.1%), 18.248 (9.7%), 21.956 (9.0%), 22.436 (13.9%), 24.008 (10.9%), 25.332 (12.4%), 27.744 (6.6%), 31.9 (3.3%), 35.398 (3.4%), 38.259 (12.2%), 43.285 (3.5%), 43.917 (7.4%), 44.772 (3.2%), 45.402 (2.9%), 46.208 (11.7%), 48.771 (3.4%), 49.851 (6.6%). Example 5: (R)- and (S) 3-(l-Oxo-4-aminoisoindolin-2-yl)piperidine-2,6- dione, Preparation by Preparative Enantiomer Separation

About 150 g of rac-lenalidomide were separated into optically pure enantiomers by continuous batch chromatography using Chiralcel IA (20 μτη, Daicel) as chiral phase in a column with 250 mm length and 50 mm diameter. A flow of 140 mL/min and feedconc. 10 g / 1 in MeOH was used for chromatography eluting with MeOH.

After evaporation of MeOH, three fractions of solids were isolated:

peak 1 62.60 g ee=99.6 rt = 2.5 min. (S-lenalidomide) peak 2 46.15 g ee=99.6 rt = 5.0 min. (R-lenalidomide) peak 3 8.22 g ee=99.6 rt = 5.0 min. (R-lenalidomide) C) Pharmaceutical Formulations

Formulation Example 1

The above shown components, except magnesium stearate, were blended in a Turbula ^® blender for 5 minutes, subsequently magnesium stearate was added and blending was continued for 1 minute. The resulting blend was filled into capsules.

Formulation Example 2

The above shown components, except magnesium stearate, were blended in a Turbula ^® blender for 5 minutes, subsequently magnesium stearate was added and blending was continued for 1 minute . The resulting blend was filled into capsules. Formulation Example 3

The above shown components, except magnesium stearate, were blended in a Turbula ^® blender for 5 minutes, subsequently magnesium stearate was added and blending was continued for 1 minute. The resulting blend was filled into capsules.

Formulation Example 4

The above shown components, except magnesium stearate, were blended in a Turbula ^® blender for 5 minutes, subsequently magnesium stearate was added and blending was continued for 1 minute. The resulting blend was filled into capsules.

Alternatively, S-lenalidomide in polymorphic Form B or a blend comprising S- lenalidomide according to the present invention (i.e. preferably S-lenalidomide in polymorphic Forms A and/or B) and R-lenalidomide can be used as active pharmaceutical ingredient in formulation Example 1 , 2 , 3 or 4.

Formulation Example 5

The above shown components, except magnesium stearate , were blended in a Turbula ^® blender for 5 minutes, subsequently magnesium stearate was added and blending was continued for 1 minute. The resulting blend was filled into capsules.

Formulation Example 6 (Comparison)

Formulation Example 5 was repeated, wherein instead of the RS-Blend a lenalidomide racemate in polymorphic Form B as disclosed in WO 2005 / 023192 was used.

Dissolution Test The dissolution profile of Formulation Example 5 and comparative Formulation Example 6 was tested (according to USP Type II (paddle) at 37 °C in 0.01 N HCl, pH 2. 1 and 50 rpm for the first 60 minutes, 100 rpm after 60 minutes). The results (average value of 6 samples each) are shown in Figure 6. It was unexpectedly found that the dissolution properties of the RS-Blend are superior to the racemate known from the prior art.