WO2011050962A1 - Acid addition salts of lenalidomide - Google Patents

Abstract

The invention relates to acid addition salts of lenalidomide as well as to desirable polymorphic forms of lenalidomide hydrogen sulfate. Furthermore, the invention provides a process for producing acid addition salts of lenalidomide, which optionally can comprise a further step producing lenalidomide in form of the free base.

Description

Acid Addition Salts of Lenalidomide

The invention relates to acid addition salts of lenalidomide and/or pomalidomide as well as to desirable polymorphic forms of lenalidomide hydrogen sulfate. Furthermore, the invention provides a process for producing acid addition salts of lenalidomide and/or pomalidomide, which optionally can comprise a further step producing lenalidomide in form of the free base. Moreover, the application refers to desirable acid addition salts of pomalidomide and blends of lenalidomide and pomalidomide. Finally, the present invention relates to oral dosage forms comprising acid addition salts of lenalidomide and/or pomalidomide.

Lenalidomide, with the chemical name

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

lenalidomide

Unless otherwise stated, the term "lenalidomide" refers within this application either to the racemic mixture of the S- and the R-enantiomer or to the S-enan- tiomer or to the R-enantiomer. The racemic mixture is preferred. 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 racemic lenalidomide in a large scale. Furthermore, the process as disclosed in EP 0 925 294 B l requires large amounts of expensive catalysts.

Furthermore, WO2006 / 028964 A l discloses processes for producing substituted 2-(2 ,6-dioxopiperidin-3-yl) l -oxoisoindolines. However, with regard to racemic lenalidomide, it has to be noted that the suggested preparation process seems to be not sufficiently enabled.

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

However, micronisation entails a number of drawbacks. First of all, the micronisation 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 micronised 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 micronisation increases the susceptibility of the substance towards oxidation. Therefore, a micronised 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 superiour 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 a good bioavailability, especially with regard to bioequivalence to established formulations containing racemic lenalidomide on the market. 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 lenalidomide in form of pharmaceutically acceptable acid addition salts as defined in claim 1 . The acid addition salts enable the preparation of dosage forms having advantageous properties. Moreover, the addition salts enable an advantageous process for the production of racemic lenalidomide in form of the free base. In addition, it was unexpectedly found that, alternatively, the above drawbacks could be overcome by a combination of lenalidomide and pomalidomide or specific salts of pomalidomide. Consequently, a first subject of the present invention is an acid-addition salt of lenalidomide according to the formula (I)

wherein HX is an acid having a pK_a value in water at 25 °C from - 10 to +4. Preferably, HX is not selected from hydrochloric acid, nitric acid, hydrobromic acid, alkylsulfonic acids, arylsulfonic acids, in particular methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid and phosphoric acid. Furthermore, if HX is sulfuric acid, then the resulting acid addition salts preferably are present in a salt form comprising the hydrogen sulfate salt, more preferably as a mixture of sulfate and hydrogen sulfate or as hydrogen sulfate. A further subject of the present invention is a process for producing acid addition salts of lenalidomide, comprising the steps of

i) providing a compound according to formula (II)

ii) hydrogenating the compound according to formula (II),

iii) subsequently adding an acidic compound, preferably having a pK_a value in water at 25 °C from - 10 to +4, and isolating the acid addition salt of lenalidomide;

iv) and, optionally, recrystallizing the resulting acid addition salt of lenalidomide. Further subject of the present invention is the use of an acid addition salt of lenalidomide for producing lenalidomide in form of the free base and thus a process for producing lenalidomide in form of the free base, comprising the steps of i) providing a compound according to formula (II)

ii) hydrogenating the compound according to formula (II), iii) subsequently adding an acid addition salt of lenalidomide by adding an acidic compound, preferably having a pK_a value in water at 25 °C from - 10 to +4,

iv) optionally, recrystallizing the resulting acid addition salt of lenalidomide, and

v) reacting the acid addition salt with a basic compound and isolating lenalidomide in form of the free base.

Moreover, further objects of the present invention are the use of an acid addition salt of lenalidomide according to the present invention for producing a pharmaceutical dosage form and a pharmaceutical dosage form comprising said acid addition salt.

The acid addition salts of the present invention are schematically characterized by formula (I),

wherein HX is an acid having a pK_a value in water at 25 °C from - 10 to +4, preferably a pK_a value from -9.5 to +3, more preferably a pK_a value from -9.0 to + 1 or from -9.0 to -2.

The "pK_a value" is the logarithmic measure to the basis 10 of the acid dissociation constant. In case of acids having more than one dissociable hydrogen atom, the above pK_a values refer to the dissociation constant of the dissociation of the first proton.

The acid dissociation constant, Ka (also known in the art as acidity constant, or acid ionization constant), is a quantitative measure of the strength of an acid in solution, preferably in water, more preferably in pure water. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions. The equilibrium can be written symbolically as: HX H⁺ + X- where HX Is an acid which dissociates by splitting into X^", known as the conjugate base of the acid, and the hydrogen ion or proton, H⁺, which, in the case of aqueous solutions, exists as a solvated hydronium ion.

The dissociation constant is usually written as a quotient of the equilibrium concentrations, denoted by [HX], [X^" ] and [H⁺]:

Due to the many orders of magnitude spanned by K_a values, a logarithmic measure to the basis 10 of the acid dissociation constant is more commonly used in practice. pK_a, which is equal to -log₁₀ K_a, may also be referred to as an acid dissociation constant:

The larger the value of p _a, the smaller the extent of dissociation. An acid having a pK_a value in the approximate range of -2 to 12 in water can be regarded as "weak acid" . An acid with a pK_a value of less than about -2 can be regarded as "strong acid" . Preferably, within the present invention strong acids are used for producing the acid addition salt of lenalidomide.

Generally, the pK_a value is determined at 25 °C by potentiometric titration or by Capillary electrophoresis (CE; capillary zone electrophoresis = CZE).

Examples of suitable acids useful in the present invention are:

HBr, HC1, H₂S0₄, HN0₃, para toluene sulfonic acid, benzenesulfonic acid, (+)- ( l S)-Camphor- l O-sulfonic acid, d-glucuronic acid, lactobionic acid, glucoheptonic acid, d-gluconic acid, lactic acid, Naphtalene- 1 ,5-disulfonic acid, salicylic acid, gentisic acid, embonic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, (+)-L-tartaric acid, alginic acid, (- )-L-malic acid and citric acid. In preferred embodiments HC1 (hydrochloric acid) and H₂S0₄ (sulfuric acid) are used. Hydrochloric acid is particularly preferred.

Hence, a subject of the present invention is an acid addition salt of lenalidomide according to formula (I), wherein HX is selected from the above- mentioned acids, except from hydrochloric acid, nitric acid, hydrobromic acid, alkylsulfonic acids, arylsulfonic acids, in particular methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid and phosphoric acid. Furthermore, if HX is sulfuric acid, then the resulting acid addition salts preferably are present in a salt form comprising the hydrogen sulfate salt, more preferably as a mixture of sulfate and hydrogen sulfate or as hydrogen sulfate.

If acids with more than one dissociable proton are used, the acid addition salts of lenalidomide according to the present invention may comprise anions, which still do contain remaining dissociable protons, and/ or anions, which do not contain remaining dissociable protons.

For example, if in formula (I) the term "HX" refers to sulfuric acid, the resulting acid addition salts of lenalidomide according to the present invention may comprise lenalidomide in form of the sulfate, lenalidomide in form of the hydrogen sulfate , or mixtures thereof.

Hence, preferred subjects of the present inventions are crystalline lenalidomide salts and / or crystalline mixtures of pomalidomide salts and lenalidomide salts, wherein the lenalidomide salts can be illustrated by the following formulae:

As mentioned above, a further subject of the present invention is a process for producing acid addition salts of lenalidomide, comprising the steps of i) providing a compound according to formula (II)

ii) hydrogenating the compound according to formula (II),

iii) subsequently adding an acidic compound, preferably having a pK_a value in water at 25 °C from - 10 to +4, and isolating the acid addition salt of lenalidomide; iv) and, optionally, recrystallizing the resulting acid addition salt of lenalidomide.

In step (i) the compound according to formula (II) (racemic) is provided. Said compound is known from prior art. Alternatively, the compound according to formula (II) (racemic) is obtainable as described below in Precursor-Example 1 .

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 NaBH₄, LiBH₄, KBH₄, NaCNBH₃, Na(AcO)₃BH, 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, 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 0.001 to 0.02 , more preferably from 0.005 to 0.015. 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. Preferably alcohols or alcohol/water mixtures are used as suitable solvents. Particularly, methanol is used. 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. The product resulting in step (ii) can be used in step (iii) with or without an intermittent work-up step. Contrary to the teaching of WO 2009 / 1 14601 it has been found that the hydrogenation step should not be carried out in the presence of acids, in particular not in the presence of methanesulfonic acid. The presence of acids in step (ii) leads to undesired corrosion. Hence, according to the present invention the acid is added subsequently to step (ii). In step (iii) an acid (HX) is added to the product resulting from step (ii). Preferably, an acid having a pK_a value in water at 25 °C from - 10 to +4, preferably a pK_a value from -9.5 to +3 , more preferably a pK_a value from -9.0 to + 1 or from -9.0 to -2 is added in step (iii). Generally, the comments given above for suitable acids apply. Preferably, the acids are added in form of an aqueous solution.

Reaction step (iii) may be carried out in usual organic solvents at usual temperatures. Preferably alcohols or alcohol/water mixtures are used. Alternatively, organic acids, having a pK_a higher than 4, may be used, in particular, acetic acid. Usually the reaction is carried out at temperatures between 0 °C and 100 °C, preferably between 20 °C and 80 °C. The reaction time can range from 0.01 to 5 hours, preferably from 0. 1 to 2 hours.

Usually, the molar ratio of lenalidomide (obtained by hydrogenating the compound according to formula (II)) to dissociable hydrogen atoms of the added acid ranges from 0.5 to 5 , preferably from 0.8 to 2.

In more preferred embodiments HC1 (hydrochloric acid) and/ or H₂S0₄ (sulfuric acid) are used in step (iii). The addition of hydrochloric acid in step (iii) is particularly preferred.

The addition of the acid results in the formation of an acid addition salt of lenalidomide. The resulting acid addition salt preferably is isolated. In a preferred embodiment solvent and temperature are chosen such that the resulting acid addition salt can be isolated by crystallisation and subsequent filtration. Optionally, in a subsequent step (iv) the resulting acid addition salt can be recrystallized. Suitable solvents are water, ethanol, acetic acid and mixtures of water and ethanol, water and acetic acid. Optionally, the catalyst used in step (ii) can be recycled.

In order to illustrate the superior process of the present invention, some aspects are compared with known prior art processes. According to prior art teaching, a hydrogenation is usually carried out in solutions of the starting material in a suitable solvent, which has to be resistant against hydrogenation conditions, and inert against the starting material or product. Usually, it is desired to obtain solutions of the product. Hydrogenation catalysts are usually introduced as solids bound onto carriers with a large surface like charcoal (heterogeneous catalysis). However, products with a low solubility in the chosen hydrogenation medium often are precipitated onto the surface of the catalyst carrier, and the catalyst becomes inactivated. Thus, conversion will be incomplete. According to the teaching of the prior art, in the hydrogenation of nitro arenes to anilins either the addition of stoichiometric amounts of acid (HC1) or the use of acidic solvents (acetic acid) generally opens a possibility to obtain solutions of aniline salts, the bases of which are badly soluble in the hydrogenation medium. However, the reaction conditions are quite corrosive, and usually special equipment (Hastelloy C-22) is required. Under acidic conditions, liberation of ionised species of the noble metal catalyst may be raised. However, the liberation of ionised species of the noble metals generally has to be avoided, especially where hydrogenation is performed as the last step in the synthesis. Furthermore, the complete removal of the noble metal catalyst from the product becomes a necessary requirement, as soluble palladium salts or highly dispersed palladium metal themselves are highly toxic.

We now have unexpectedly found that neither the starting material, which can be introduced to the reaction, even incompletely dissolved, nor the product lenalidomide, which crystallizes from the reaction medium, do inactivate the hydrogenation catalyst. Moreover, we were able to dramatically reduce the amount of catalyst required in the hydrogenation reaction. We unexpectedly have driven the hydrogenation reaction to completion, even if hydrogenation time is kept short (< 16 h). According to the inventive process, it was possible to avoid any liberation of ionised species of the noble metal. Preferably liberation has been limited by only short time contact of extracting hydrochloric acid and catalyst residual, when the product was separated from the heterogeneous catalyst.

Any treatment of the final product with heavy metal/ noble metal absorbents for removal of ionic species of palladium usually implies complete solutions of the product. We now unexpectedly have found that particularly the hydrochloride and the sulfate of lenalidomide have the necessary solubility in water, to allow such a post-processing.

As mentioned above, preferably lenalidomide in form of the hydrochloride (i.e. in formula (I) HX is HC1) is produced. If lenalidomide hydrochloride is produced by the process of the present invention it can be obtained in crystalline form.

Generally, lenalidomide hydrochloride is obtained in crystalline form A, wherein form A is characterized by an X-Ray powder diffraction (hereinafter referred to as XRPD) showing characteristic peaks at 12. 1 1 °, 24.35°, 24.73° and 26.12° 2-Theta. Further characteristic peaks can be found at 13.29°, 17.1 1 °, 21.67°, 26.77° and/or 31.17° 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°.

In a further embodiment, lenalidomide in form of the sulfate is produced. If lenalidomide sulfate is produced by the process of the present invention it can be obtained in crystalline form.

Generally, lenalidomide sulfate can be obtained in at least two polymorphic forms, namely polymorphic form A and polymorphic form B.

Form A of lenalidomide sulfate is characterized by an X-Ray powder diffraction showing characteristic peaks at 16.69°, 18.85°, 19.68° and 26.25° 2-Theta. Further characteristic peaks can be found at 21.02°, 22.49°, 25.56 and/ or 26.92° 2-Theta.

Form A preferably is obtained by dissolving the product resulting from step (ii) in acetic acid and adding in step (iii) sulfuric acid. Form B of lenalidomide sulfate is characterized by an X-Ray powder diffraction showing characteristic peaks at 16.96°, 17.28°, 18.90° and 25.72° 2-Theta. Further characteristic peaks can be found at 14.32°, 21 .54°, 27.48°, 28.09° and / or 30.3 1 ° 2-Theta.

Form B can be obtained from lenalidomide sulfate, in the Form how it will be obtained by recrystallisation of lenalidomide with half molar equivalent H₂S0₄ per base in acetic acid, by vapor sorption, wherein preferably during sorption the lenalidomide sulfate is contacted with air having a relative humidity of about 75% to 95 % more preferably at 85 % at 25 °C.

In further preferred embodiments of the present invention lenalidomide in form of the hydrogen sulfate or mixtures of hydrogen sulfate and sulfate salts of lenalidomide are produced.

A mixture of lenalidomide sulfate/ hydrogen sulfate is preferably characterized by an X-Ray powder diffraction showing characteristic peaks at 18.88°, 2 1 . 10°, and 25.62° 2-Theta. Further characteristic peaks can be found at 16.96° , 1 7.26°, 2 1 .50°, 26.5 1 and / or 28.09° 2-Theta.

An XRPD of the lenalidomide sulfate / hydrogen sulfate salt is shown in Figure 1 .

A lenalidomide hydrogen sulfate salt preferably is characterized by an X-Ray powder diffraction showing characteristic peaks at 18.92°, 21 . 10° and 25.63° 2-Theta. Further characteristic peaks can be found at 16.71 °, 26.52°, 28.07 and / or 28.55° 2-Theta.

An XRPD of the lenalidomide hydrogen sulfate salt is shown in Figure 2.

These salts are obtainable in crystalline form. For a detailed description of these salts it is referred to the experimental section below.

A further aspect of the present invention is the use of the acid addition salts of lenalidomide for producing lenalidomide in form of the free base. Preferably, acid addition salts of lenalidomide according to formula (I) as defined above are used.

Hence, a further subject of the present invention is a process for producing lenalidomide in form of the free base, comprising the steps of i) providing a compound according to formula (II)

ii) hydrogenating the compound according to formula (II),

iii) subsequently adding an acid addition salt of lenalidomide by adding an acidic compound, preferably having a pK_a value in water at 25 °C from - 10 to

+ 4,

iv) optionally, recrystallizing the resulting acid addition salt of lenalidomide, and

v) reacting the acid addition salt with a basic compound and isolating lenalidomide in form of the free base. Regarding steps (i) to (iv) it is referred to the comments given above for the process for producing the acid addition salts.

In step (v) a "basic compound" is added. Generally, a basic compound is capable of producing a pH of greater than 7 when brought into contact with water. Examples of suitable basic compounds are NaHC0₃, Na₂C0₃, NaOH, KHC0₃, K₂C0₃, KOH, NH₄OH , sodium acetate, potassium acetate. Preferably, sodium hydrogen carbonate (NaHC0₃) is used.

The molar ratio of acid addition salt to basic compound usually ranges from 1 .0 to 10, preferably from 1 .2 to 5. A pH of above 4.0 and below 9.0 might be adjusted, as lenalidomide is a weak base, too.

Reaction step (v) may be carried out in usual organic solvents and / or water at usual temperatures. Preferably water or alcohol /water mixtures are used. Alternatively, organic acids, having a pK_a higher than 4, may be used, in particular, acetic acid. Usually, the reaction is carried out at temperatures between 0 °C and 100 °C, preferably between 40 °C and 80 °C. The reaction time can range from 0.01 to 5 hours, preferably from 0. 1 to 2 hours. In an embodiment of the present invention, lenalidomide resulting from step (v) is recrystallized. Depending on the crystallisation conditions, lenalidomide (free base) can be obtained in crystalline form A or crystalline form B or, alternatively, crystalline Form E, which are known from WO 2005 / 023192.

In WO 2005 / 023 192 crystallisation from hexane, toluene and water is described to obtain form B. Furthermore, crystallisation from butanol, butyl- acetate, EtOH, ethyl acetate , MeOH, methyl ethyl ketone or THF is described to produce form A. However, in the present invention it was found that further advantageous conditions are possible for producing forms A and B of lenalidomide (free base).

Hence, a subject of the present invention is a process for producing polymorphic form A of lenalidomide in form of the free base, wherein acetic acid is used as solvent.

Furthermore, a subject of the present invention is a process for producing polymorphic form B of lenalidomide in form of the free base, wherein

ethanol/water,

dimethylformamide (DMF) /water,

acetic acid /water, or

acetone

are used as solvents. A further aspect of the present invention relates to the separation of enantiomers. It has been found that racemic lenalidomide salts of the present invention can be separated, e.g. by chiral HPLC, as illustrated in the examples. Hence, a subject of the present invention is an acid addition salt of lenalidomide according to the present invention, essentially comprising S- lenalidomide or essentially comprising R-lenalidomide. The term "essentially comprising" indicates that the enantiomeric excess (ee) is preferably more than 90 % , more preferably more than 95 % , in particular more than 99 % .

A further aspect of the present invention relates to a pharmaceutical composition comprising a mixture of lenalidomide and pomalidomide. Unexpectedly, such a composition shows superior properties. As shown in the examples, mixtures of lenalidomide and pomalidomide can be produced by the process of the present invention. Hence, a subject of the present invention is a pharmaceutical composition comprising a) lenalidomide,

β) pomalidomide.

Pomalidomide (brand name: Actimid^®) is known in the art and currently in clinical development. The chemical structure (III) is as follows:

III pomalidomide

Unless otherwise stated, the term "pomalidomide" refers within this application either to the racemic mixture of the S- and the R-enantiomer or to the S-enantiomer or to the R-enantiomer. The racemic mixture is preferred.

Pomalidomide can be present in form of the free base or in form of a pharmaceutically acceptable salt. The same applies, as mentioned above, to lenalidomide.

Preferably, lenalidomide (a) is present in form of an acid addition salt according to the invention, i.e. an acid addition salt, wherein an acid having a pK_a value in water at 25 °C from - 10 to +4, is used.

Preferably, pomalidomide (β) is present in form of an acid addition salt according to the invention, i.e. an acid addition salt, wherein an acid having a pK_a value in water at 25 °C from - 10 to +4, is used. In a preferred embodiment the composition comprises:

a) 10 to 99.9 wt.%, preferably 50 to 99.9 wt.% , more preferably 90 to 99.5 wt.% , in particular 97 to 99.4 wt.% lenalidomide,

β) 0.1 to 90 wt.%, preferably 0.1 to 50 wt.% , more preferably 0.5 to 10 wt.% , in particular 0.6 to 3.0 wt.% pomalidomide, based on the total weight of the composition.

Generally, all comments regarding preferred embodiments of lenalidomide salts also apply for the pomalidomide salts, e.g. the illustrations given for preferred acids. Furthermore, also the comments for the preparation processes of lenalidomide salts apply for pomalidomide.

Hence, a further subject of the present invention is a process for producing acid addition salts of pomalidomide, comprising the steps of i) providing a compound according to formula (IV)

ii) hydrogenating the compound according to formula (IV),

iii) (preferably subsequently) adding an acidic compound, preferably having a pK_a value in water at 25 °C from - 10 to +4, and preferably isolating the acid addition salt of pomalidomide;

iv) and optionally recrystallizing the resulting acid addition salt of pomalidomide. The compound according to formula IV is known in the art and disclosed in G W Mueller et al, "Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production", BIOORGANIC & MEDICAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, vol. 9 , no. 1 1 , June 7, 1999 , pages 1625- 1630.

The pharmaceutical composition comprising components (a) and (β) shows superior pharmacologic properties. In particular, the combination of components (a) and (β) shows an unexpected additive or even synergistic effect. Especially, the combination of components (a) and (β) shows an unexpected superior effect in the treatment of cancer, immune disorders and / or transplantation therapy.

Specific cancers and immune disorders include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasts leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, leiomyoma, resistant and refractory multiple myeloma, myelofibrosis, sickle cell anemia and myelodysplasia syndrome.

Administration of lenalidomide and pomalidomide to a patient can occur simultaneously or sequentially by the same or different routes of administration. The compounds can be administered orally, intravenously, subcutaneously and/ or intramuscularly. A preferred route of administration for lenalidomide and pomalidomide is orally. Preferably, lenalidomide and pomalidomide are administered simultaneously, more preferably in a single dosage form, still more preferably in a single solid oral dosage form, e.g. a tablet or a capsule, whereas a tablet is preferred.

In one embodiment, lenalidomide can be administered daily in an amount of from about 0. 1 to about 150 mg, preferably from about 1 to about 50 mg, more preferably from about 2 to about 25 mg and most preferably in an amount of 5 mg, 10 mg, 15 mg or 20 mg; whereas pomalidomide can be administered daily in an amount of from about 0.01 to about 150 mg, preferably from about 0. 1 to about 50 mg, more preferably from about 0.5 to about 25 mg and most preferably in an amount of 1 mg, 2 mg, 5 mg or 10 mg. In another preferred embodiment lenalidomide and / or pomalidomide may be administered in a single daily dose or in divided doses two to six times a day. In certain embodiments of the invention lenalidomide and/ or pomalidomide may be administered less frequent then once daily, e.g. every second, third, or fourth day. In certain embodiments, lenalidomide and/ or pomalidomide are cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improves the efficacy of the treatment.

Consequently, in one specific embodiment of the invention, lenalidomide and / or pomalidomide are administered daily in a single or divided doses in a three to six week cycle with a rest period of about a week or two weeks, preferably in a three week cycle with a rest period of one week. The invention further allows the frequency, number, and length of dosing cycles to be increased. Thus, another specific embodiment of the invention encompasses the administration of lenalidomide and/ or pomalidomide for more cycles than are typical when it is administered alone.

In one embodiment, lenalidomide and / or pomalidomide are administered daily and continuously for three or four weeks at a dose of from about 0. 1 to about 150 mg/ d, followed by a break of one or two weeks. Lenalidomide is preferably administered daily and continuously at an initial dose of 0. 1 to 5 mg/ d with dose escalation (every week) by 1 to 10 mg/ d to a maximum dose of 50 mg/ d for as long as therapy is tolerated. In a particular embodiment, lenalidomide is administered in an amount of about 5 mg, 10 mg, 15 mg or 25 mg/ day, preferably in an amount of about 25 mg/ day for three to four weeks, followed by one week or two weeks of rest in a four or six week cycle . Pomalidomide is preferably administered daily and continuously at an initial dose of 0. 1 to 5 mg/ d with dose escalation (every week) by 1 to 10 mg/ d to a maximum dose of 50 mg/ d for as long as therapy is tolerated. In a particular embodiment, pomalidomide is administered in an amount of about 1 mg, 2 mg, 5 mg or 10 mg/ day, preferably in an amount of about 2 mg/ day for three to four weeks, followed by one week or two weeks of rest in a four or six week cycle.

Moreover it has been surprisingly found that the combination of pomalidomide and / or lenalidomide with a glucocorticoid reduces the side effects and improves the efficacy of the treatment in patients suffering from cancer or immune disorders or on transplantation therapy, compared to the treatment of pomalidomide and/ or lenalidomide alone.

Therefore, another embodiment of the invention is a combination of pomalidomide and / or lenalidomide with a glucocorticoid. Dexamethasone and prednisone are the preferred glucocorticoids.

Consequently, a further subject of the present invention is a pharmaceutical composition or a pharmaceutical set comprising

β) pomalidomide, preferably in form of an acid addition salt; and

γ) a glucocorticoid.

Another subject of the present invention is a pharmaceutical composition or a pharmaceutical set comprising

a) lenalidomide, preferably in form of an acid addition salt,

β) pomalidomide, preferably in form of an acid addition salt; and

γ) a glucocorticoid.

The glucocorticoid can be administered orally, intravenously, subcutaneously and/ or intramuscularly. A preferred route of administration for the glucocorticoid is oral.

In a preferred embodiment the glucocorticoid is combined with the lenalidomide salt and / or pomalidomide salt of the present invention within a tablet (hereinafter referred to as combination tablet).

Hence, a further subject of the present invention is a tablet comprising a glucocorticoid and a pharmaceutical acceptable salt of lenalidomide. Another subject of the present invention is a tablet comprising a glucocorticoid and a pharmaceutical acceptable salt of pomalidomide. Still another subject of the present invention is a tablet comprising a glucocorticoid, a pharmaceutical acceptable salt of lenalidomide salt and a pharmaceutical acceptable salt of pomalidomide. In such a combination tablet preferably dexamethasone or prednisone is used as glucocorticoid. Further, in such a combination tablet preferably lenalidomide hydrochloride or hydrogensulfate is used. Further, in such a combination tablet pomalidomide hydrochloride, sulfate or hydrogen sulfate salt is used. Preferably, the combination tablet comprises the above described active ingredients and pharmaceutical excipients, preferably the below described pharmaceutical expients, e.g. b) a filler, preferably a lactose-free filler, and/ or c) a solubilizer, and/ or d) a disintegrant.

Preferably, the combination tablet is prepared by a direct compression process.

Alternatively, the combination tablet can be prepared by a granulation process (wet or dry, wherein wet is preferred). Preferably, the lenalidomide salt and / or pomalidomide salt is present in the intragranular phase, whereas the glucocorticoid is present in the extragranular phase. Alternatively, the lenalidomide salt and/ or pomalidomide salt is present in the extragranular phase, whereas the glucocorticoid is present in the intragranular phase.

Alternatively, the combination tablet can be prepared by a pellet layering process or by a melt granulation process.

The combination tablet preferably comprises

0. 1 to 150 mg, more preferably 1 to 50 mg glucocorticoid, and

1 to 150 mg, more preferably 5 to 50 mg pomalidomide salt; or

0. 1 to 150 mg, more preferably 1 to 50 mg glucocorticoid, and

1 to 150 mg, more preferably 5 to 50 mg lenalidomide salt; or

0. 1 to 150 mg, more preferably 1 to 50 mg glucocorticoid,

1 to 150 mg, more preferably 5 to 50 mg pomalidomide salt and

1 to 150 mg, more preferably 5 to 50 mg lenalidomide salt.

In one embodiment, dexamethasone can be administered daily in an amount of from about 0. 1 to about 150 mg, preferably from about 1 to about 50 mg, more preferably in an amount of 20 mg or 40 mg; whereas prednisone can be administered daily in an amount of from about 0.01 to about 150 mg, preferably from about 0. 1 to about 50 mg, more preferably in an amount of 20 mg, 30 mg or 40 mg. In a specific embodiment, patients with relapsed or refractory multiple myeloma are treated by the administration of from about 5 to about 25 mg/ day of lenalidomide and / or from about 0.01 to about 5 mg/ day of pomalidomide accompanied by the administration of 40 mg/ day of dexamethasone.

It has been found that the pharmaceutical composition comprising pomalidomide (preferably in form of the above described acid addition salt) and optionally lenalidomide (preferably in form of the above described acid addition salt) and optionally a glucocorticosteroid is unexpectedly superior for the treatment of cancer, immune disorders and /or transplantation therapy, wherein patients are treated, who do not sufficiently respond to a thalidomide treatment.

A further aspect of the present invention is the use of an acid addition salt of lenalidomide and/or pomalidomide according to the present invention for producing a pharmaceutical 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) an acid addition salt or a combination of acid addition salts according to the present invention, preferably lenalidomide hydrogen sulfate,

b) a filler, preferably a lactose-free filler, and/ or

c) a solubilizer, and/or

d) a disintegrant.

In a preferred embodiment the active ingredient (a) (lenalidomide acid addition salt and/ or pomalidomide acid addition salt) is employed in particulate form. More preferably, the active ingredient (a) of the pharmaceutical composition of the present invention has a volume mean particle size (D₅₀) of 0. 1 to 100 μτα., more preferably of 0.3 to 50 μτη, further more preferably of 1 to 20 μπι, most preferably of 2 to 10 μτα. The volume mean particle size (D₅₀) 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).

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, dextrate, 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 behaviour 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 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 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), polyvinyl - pyrrolidone, 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/ cm³. 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 carboxy- methyl 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: a lubricant, a glidant and/ or an 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.

The glidant can for example be colloidal silicone dioxide (e.g. Aerosil^®}. 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. Preferably, the silicone dioxide has a specific surface area of 50 to 400 m²/ g, measured according to Ph. Eur. , 6th edition, chapter 2.9.26.

The anti-sticking agent is for example talcum and may be present in amounts of 0.05 to 5 wt.% , more preferably in an amount of 0.5 to 3 wt.% of the total weight of the composition.

In this context, it is generally noted that, due to the nature of pharmaceutical excipients, it cannot be excluded that a certain compound meets the functional requirements of more than one of the above mentioned excipient classes. However, in order to enable an unambiguous distinction and terminology in the present application, the same pharmaceutical compound can only be subsumed as one of the functional excipient classes presented above. For example, if dicalcium phosphate dihydrate is described as a filler, it cannot additionally classify as a solubiliser or as a disintegrant. Generally, in the pharmaceutical composition of the present invention the active ingredient (a) (lenalidomide acid addition salt and/or pomalidomide acid addition salt) 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

Differential Scanning Calorimetry (DSC)

B) Reactions

Precursor-Example 1 : 3-(4-nitro- 1 -oxo- 1 ,3-dihydro-isoindol-2-yl)piperidi- ne-2,6-dione

A. Methyl 2-bromomethyl-3-nitrobenzoate

A stirred mixture of methyl-3-nitro-o-toluate ( 1 7.04 g, 87. 1 mmol) and N- bromosuccinimide ( 18.9 g, 105 mmol) in carbon tetrachloride (243 ml, 388.03 g) was heated under gentle reflux (bath temperature 90 °C, bottom temperature 70°C) for 4 hours, but no conversion was detected.

Dibenzoylperoxide (0.2 g) was added and reflux continued for 72h. Within this time, conversion reached about 80 % . Additional NBS (2.2 g) was added and the reflux continued. After 93 h a conversion of 86 % was reached. The reaction mixture was cooled to room temperature and filtered. The residual from the filter was discarded and the filtrate was transferred to a separatory funnel, washed with water (2 x 120 ml), with brine ( 120 ml) and finally dried over anhydrous MgS0₄. After filtration the solvent was removed in vacuo to give a honey yellow colored, partially crystallizing oil (24.2 1 g).

The remaining oily semi-crystalline mass was repeatedly digested with hot heptane aliquots at 70 °C (4 x 500 ml), which were chilled to 10 °C, first crop crystals were filtered off (6.39 g from first extract) and the filtrates were collected; from the filtrates the heptane was distilled off. In total, 22 g (93 %) of methyl 2-bromomethyl-3 -nitrobenzoate were collected from 4 fractions as light yellow solid (mp 71.9 °C).

B. N-Benzyloxycarbonylamino-3-Amino-piperidine-2, 6-dione

A 3 necked 10-L RBF was charged with (S)-N-benzyloxycarbonylamino-4- carbamoylbutyric acid (43 1 .6 g, 1.54 Mol). THF (5L) and 4- dimethylaminopyridine ( 1 .88 g, 15.4 mmol) were added. Within 1 h CDI was added (total 273.43 g, 1 .69 Mol, l . l equiv. ). Then the mixture was heated to reflux of THF and kept for 20 h under these conditions.

The reflux condenser was replaced by a distillation bridge and THF was distilled from the mixture until about 4.5 L distillate were collected. The residue was allowed to come to 30-40 °C , and then treated with 2 L of cold water ( 10°C). The slurry was stirred overnight at RT ( 15 h). The crystalline mass was filtered and sucked to dryness on a Buchner filter funnel under vacuum.

The mass was taken into 1 L of dry isopropanol and stirred overnight at RT, filtered and dried in a vacuum drying cabinet at 50°C / 200 mbar for 3 h. 3 10.4 g (76.9 % yield) of anhydrous, solvent free product was obtained having a m.p. of 124.3 °C.

C. 3-Amino-piperidine-2, 6-dione HCI

In a 10 L, 3 necked RBF N-benzyloxycarbonyl-3-amino-3-methylpiperidine- 2 , 6-dione, ( 175.40 g) was suspended in methanol (203 1 .69 mL). To this suspension was added 4 N HCI ( 1 73.88 mL), followed by 10% Pd / C catalyst (5g, 0.0075 eq). The mixture was hydrogenated under 1 atm of hydrogen (balloon) for 23 hours.

Hydrogenation was stopped and the suspension was vacuum filtered through a weighed Buchner funnel. The clear filtrate was fed to a pre-weighed flask on a rotary evaporator and evaporated to an aqueous crystal slurry.

The solid from the filter funnel was suspended in hot water. After evaporation Isopropanol ( 150 mL) was added to the aqueous slurry and the slurry was filtered. After drying (4h at 60°C) 89.02 g (80.9% ) of the title compound was obtained.

The aqueous crystal suspension from the evaporated methanol filtrates were combined with the aqueous isopropanol filtrate from solid workup, and to this additional dry Isopropanol ( 100.00 mL) was added. The slurry was concentrated again on the rotavapor and filtered.

The wet solid (28.31 g) was dried in vacuum for 74 h to a mass of 16.61 g. A total mass of 105.61 (96% ) of pure rac-3-Amino-piperidine-2, 6-dione HCI was obtained.

D. 3-(4-nitro- l -oxo-l ,3-dihydro-isoindol-2-yl)piperidine-2,6-dione rac-a-Amino-glutarimide hydrochloride (41 .2 g, 0.25 mole), and methyl 2- bromomethyl-3-nitrobenzoate (69.0 g , 0.25 mole) were charged to the dry 3- necked RBF and dry acetonitrile (300 ml, 252. 1 g) was added. The homogeneous suspension was stirred at room temperature for about 15 min. In the meantime diisopropyl-ethyl-amine (DIPEA, 71 g, 94 ml) was diluted with dry acetonitrile (300 ml, 241 .6 g) and the solution was filled into the dropping funnel (500 ml), from which it was added drop-wise to the suspension over 40 min.

After 3 h stirring the mixture was slowly heated. The temperature of the oil bath was set to 85 °C, shortly above the boiling point of acetonitrile (80 °C). Reflux started after 20 min. and was maintained for further 3 hours.

The mixture was allowed to come to RT, while further stirred over night at RT. After this, the dark blue-violet suspension was filtered on a Buchner filter, the colored residual was suspended in water (200mL) for 15 min to remove ionic species (Amine salts). Then it was suspended in dichloromethane ( 100 ml) for 30 min, followed by thorough washing with this solvent (800 ml) on the filter after filtration.

A light lilac to light mauve colored solid remained, which had 54.5 g (75 % from theory 72.3 g) in 97.6 % purity by HPLC after drying. Example 1 : Preparation of Racemic Lenalidomide according to

Example 16E of EP 0 925 294 Bl

A suspension of 28.9 g (0. 1 mol) rac-3-( 1 -oxo-4-nitroisoindoline-2- yl)piperidine-2 ,6-dione and 9g 10% Pd / C (0.09 eq. Pd) in 3 1 methanol (725 equiv. ) was hydrogenated under hydrogen pressure at 3. 15 bar (50 psi) for 42 h in a hydrogenation autoclave ( 10 1). Hydrogenation was extended to 42 h as hydrogenation was found to be incomplete after 5 h. The mixture was filtered on a Buchner filter under vacuum, and the solid on the filter rinsed with MeOH (250 ml). The light yellow colored filtrate was concentrated on a Rotavapor ( 1000 ml) flask to a residual volume of 150 ml. A light beige colored, crystalline solid with a melting point of 265 °C was obtained (7.6 g, 29% ), which turned to light grey color on standing.

Peak positions from XRPD obtained for rac-lenalidomide, which crystallized from MeOH when reaction solvent was evaporated, were matching to those from XRPD given in Figure 1 of WO 2005 / 023192 for lenalidomide anhydrous Form A.

Example 2: Preparation of Lenalidomide HCl

A suspension of 253. 1 g rac-3-( 1 -oxo-4-nitroisoindoline-2-yl)piperidine-2 ,6- dione (0.875 mol) in 6.2 1 (4.75 kg) MeOH was charged into the hydrogenation reactor (Kiloclave Buchi 10 1). Thereafter, 10. 15 g 10% Pd (0.01 eq. Pd) on charcoal, suspended in 500 ml MeOH was added, the stirrer was set to 400 rpm, and hydrogen gas supply (bpc Biichi-Glas Uster) was regulated to keep a constant pressure of 50 psi (3.2 bar). After an induction period of 5 min. the inner temperature raised within the first 5 hours continuously from 2 1 °C to 35 °C , while hydrogen was continuously charged to maintain the preset pressure. After 2 h the speed of the stirrer was set to 600 rpm and the reaction was terminated after 18 h.

The reaction mixture was released from the reactor and equipment rinsed with additional MeOH (793.9 g/ 1 1). The combined suspension was filtered under vacuum on a pre-weighed Buchner Funnel equipped with a filter paper. 245.6 g wet solid was collected on the filter paper and after air drying for 16 h at RT, 214g were obtained. This mass was transferred into hot aqueous hydrochloric acid (prepared from 600 g water and 86 ml 32% HCl), immediately transferred onto a pre-weighed Buchner funnel, equipped with filter paper and filtered under vacuum. A light yellow colored filtrate was obtained, from which a light solid started to crystallize immediately. The crystal suspension was chilled in an ice bath for 60 min, the obtained crystals were collected by vacuum filtration through a Buchner funnel on filter paper. The cake of crystals was rinsed with 100 ml of cold MeOH sucked to dryness on the filter, and dried on air overnight. 216.5 g dry lenalidomide hydrochloride was collected (83.5% from theory 258.8g).

Example 3: Preparation of Lenalidomide Base

Lenalidomide hydrochloride (345 g, 1 . 1 7 mol), obtained according to Example 2 , was charged to a 3 1 beaker and suspended in water ( 1500 ml). With stirring by a magnetic stirring bar, the suspension was heated to about 85°C. When most of the solid had dissolved, charcoal ( 10 g) was added in portions and stirring continued for 30 min at 80°C. The black suspension was filtered through a Buchner funnel into a preheated round bottom flask (3 1) under vacuum. The clear solution was kept at 70°C and 350 ml of a saturated NaHC0₃ sol. was added dropwise until pH 8. The measured inner temperature was 65°C .

While stirring (50 rpm) the suspension was allowed to cool to RT overnight. The formed crystals were collected by filtration on a Buchner funnel and dried for 16 h at 40°C under vacuum ( 100 mbar). 258 g of lenalidomide base in the form of its hemihydrate (Form B according to WO 2005 / 023192 ) was obtained (98.9% pure, 82% from 314.77 g theory). Example 4: Recrystallization of Lenalidomide Base

In a beaker a mixture of EtOH ( 1 .5 1, 1 , 185.04 g) and H₂0 ( 1 1, 1 ,007 g) was heated to 65° under stirring. Raw 3-( 1 -oxo-4-amino-isoindoline-2- yl)piperidine-2 ,6-dione hemihydrate , as obtainable by Example 3 (50.0 g, 0. 186 mol, 98.9 % purity) , was dissolved under stirring with a magnetic stirrer. Within 5 min. a slightly turbid solution was formed, to which charcoal was added ( 1 .5 g) and stirring continued for another 5 min.

The hot suspension was vacuum-filtered into a preheated flask. The flask was allowed to come to RT overnight. On the next morning, the crystal suspension was filtered under vacuum and the crystals collected were sucked on the filter to dryness.

The filter cake was dried in a vacuum drying cabinet at 100 mbar/ 40°C overnight. After drying, 39.60 g of coarse lenalidomide hemihydrate with high purity (99.7 % purity, 76.48 % from 5 1 .78 g, theoretical yield) were obtained in the first crop. This material was used for seeding in example 5.

The aqueous EtOH mother liquor was evaporated on a rotavapor to a residual volume of about 0.5 1 and chilled in the refrigerator overnight. After filtration and drying, a second crop could be obtained (3.2 g, 6. 18% ).

Finally, the filtrate was evaporated hardly to dryness. From the aqueous slurry a third crop could be filtered off by vacuum filtration (5.00 g, 9.66% ).

From the first and second crop a total of 42.80 g (82.66% yield) of lenalidomide hemihydrate of acceptable purity > 98.8 % was obtained. Even the third crop material could be used for recycling. Example 5: Recrystallisation of Lenalidomide Base with Seeding

In a beaker a mixture of EtOH (61, 4, 746.0 g) and H₂0 (4 1, 4 ,000.0 g) was heated to 66 °C and raw 3-( 1 -oxo-4-amino-isoindoline-2-yl)piperidine-2 ,6- dione hemihydrate, as obtainable by Example 3 ( 197.0 g, 0.734 mol, 98.9 % purity) was dissolved under stirring. Within 15 min. , a slightly turbid solution was formed, to which charcoal was added (6.0 g) and the stirring continued for another 30 min. Into a 10 1 vacuum bottle , equipped with a magnetic stirring bar and Buchner funnel with filter paper, covered with 10 diatomaceous earth, finely ground seeding material of pure lenalidomide hemihydrate (39.00 g, 0. 145 mol, 99.45 % pure) obtainable according to example 4 had been placed. The bottle had been joined to the vacuum , set to 200 mbar, and the hot suspension was filtered through a Buchner funnel into the bottle to the seeding material, while stirring with the magnetic stirrer. The bottle was vented, closed and stirred slowly for crystallization overnight, while slowly reaching RT.

After filtration and drying in the vacuum drying cabinet (40 °C, 150 mbar, 16 h), 185 g lenalidomide hemihydrate (75.98 % from a total of 243.49 g) had been obtained with 99.56 % purity, having a melting point of 268.6 °C. After the mother liquor from the filtration had been chilled in a refrigerator overnight, a second crop of 25.00 g ( 10.27 % ) could be collected by vacuum filtration.

From the first and the second crop a total of 210 g (86.24% yield) of lenalidomide hemihydrate of acceptable purity > 98.8 % were obtained.

Example 6: Recrystallisation of Lenalidomide Hydrochloride

In a 3-necked round bottom flask EtOH ( 1 .2 1, 950 g) was placed and raw 3-( l - oxo-4-amino-isoindoline-2-yl)piperidine-2 ,6-dione hydrochloride (31 .7 g total, 0. 108 mol, 99.08 % pure), obtainable by Example 2, was added while stirring and heating to reflux. Within 15 min. a slightly turbid solution was formed, to which first 1 ml HC1 32 % was given, followed by charcoal (2.0 g), and stirring and heating was continued for another 30 min. The suspension was filtered on a Buchner funnel, equipped with filter paper, covered with 10 g diatomaceous earth. The filtrate was allowed to cool to RT overnight, and the crystals were filtered off by vacuum filtration. A first crop of pure lenalidomide hydrochloride ( 18 g, 56.8 % , 0.0613 mol, 99.03 % pure) had been obtained after drying in a vacuum drying cabinet for 16 h at 200 mbar and at 40°C.

To obtain a second crop, the mother liquor was reduced to one third of the volume and chilled in a refrigerator. Another 4.0 g ( 12.6 % yield) of lenalidomide hydrochloride was obtained, having 98.6 % purity. A third crop of crystals (4.5 g, 14.2 %) of the same quality (98.6 %) could be separated from the mother liquor after standing over the weekend in the cold (4°C).

Thus, with a total yield of 26.5 g, 83.6 % recovery was achieved.

Example 7: Preparation of Lenalidomide Sulfate (Form A)

In a round bottom flask acetic acid (AcOH, 5 ml) was placed and 3-( l -oxo-4- amino-isoindoline-2-yl)piperidine-2,6-dione ( 1.0 g, 98.8 % pure) was added while stirring. Sulfuric acid (H₂S0₄, 0. 1 ml, 96% ) was added. Immediately, a yellow coloured viscous oil was settled. After heating to 70 °C, a turbid solution was formed, while stirring and heating was continued for another 45 min. During that time, a crystalline solid precipitated. The suspension was filtered on a Buchner funnel, equipped with filter paper. The collected crystals were washed with 15 ml acetic acid and dried at 40 °C in vacuum drying cabinet at 100 mbar. The solids had a weight of 1 .16 g ( 100 % yield). Example 8: Preparation of Lenalidomide Sulfate (Form B)

Lenalidomide sulfate, obtained according to example 7 (0.25 g) was exactly weighed into a tared weighing bottle and this was placed into a hygrostat chamber over saturated C1 solution for equilibration (85% r.H. at 20°C) within 4 weeks. Within the first 16 hours the mass of the sample had grown by about 6-7 % (hygroscopicity) but during further exposure the mass of the substance was lowered again below 99 % from starting value (desolvation). DSC and XRPD had changed completely after this time. Example 9: Preparation of Lenalidomide sulfate /Hydrogen Sulfate

In a round bottom flask 3 -( 1 -oxo-4-amino-isoindoline-2-yl)piperidine-2 , 6-dione ( 1 .0 g, 98.8 % pure) was placed. Water (5.2 ml) was added, and the mixture was heated to 50°C while stirring. Sulfuric acid (H₂S0₄, 0. 1 ml, 96 % ) was added and a clear solution was obtained. The aqueous phase was concentrated to leave a viscous oil. THF (30 ml) was added and the crystal suspension, which had been formed, was decanted from the supernatant, slurried with two aliquots of THF ( 10 ml each) for 10 min. The washed solid was collected on a filter by vacuum filtration and dried at 40 °C in vacuum drying cabinet at 100 mbar. The solids had a weight of 1 . 10 g ( 100 % yield).

Example 10: Preparation of Lenalidomide Hydrogen Sulfate In a round bottom flask 3-( 1 -oxo-4-amino-isoindoline-2-yl)piperidine-2 ,6-dione ( 1 .0 g, 98.8 % pure) was placed. Water ( 10.07 ml) was added and the mixture was heated to 50 °C while stirring. Sulfuric acid (H₂S0₄, 0.24 ml, 96% was added and a clear solution was obtained. The aqueous phase was concentrated to leave a viscous oil. THF (30 ml) was added and stirred for 15 min. , but no solid was obtained. Thus, the supernatant was decanted and slurried with three additional aliquots of THF ( 10 ml each) for 15 min. The washed oil was treated with MeOH (20 ml) and stirred for 10 min. when it became a suspension of crystals. The solid formed was collected on a filter by vacuum filtration and dried at 40 °C in vacuum drying cabinet at 100 mbar. The solids had a weight of 0.68 g (49.3 % yield).

C) Physical Data

Data of Lenalidomide Hydrochloride Obtained by Example 6

Pomalidomide: 8.684 min. (0.99%)

Data of Lenalidomide Sulfate (form A) Obtained by Example

Data of Lenalidomide Sulfate (form B) Obtained by Example 8

Data of Lenalidomide Sulfate /Hydrogen Sulfate Obtained by Example 9

Data of Lenalidomide Hydrogen Sulfate Obtained by Example

D) 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

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, a blend comprising lenalidomide and pomalidomide according to the present invention can be used as active pharmaceutical ingredient in formulation example 1 , 2 , 3 or 4 with the indicated weight ratio. 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

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.

Claims

Claims

Acid-addition salt of lenalidomide according to the form

wherein HX is an acid having a pK_a value in water at 25 °C from - 10 to +4, provided that HX is not selected from hydrochloric acid, nitric acid, hydrobromic acid, alkylsulfonic acids, arylsulfonic acids, in particular methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid and phosphoric acid,

provided further that if HX is sulfuric acid, then lenalidomide is present in a salt form comprising a hydrogen sulfate salt.

2. Acid addition salt of lenalidomide according to claim 1 comprising a crystalline hydrogen sulfate salt, characterized by an XRPD as shown in Figure 1 or 2.

3. Acid addition salt of lenalidomide according to the formula (I)

wherein HX is an acid having a pK_a value in water at 25 °C from - 10 to +4, said acid addition salt essentially comprising the S-enantiomer of lenalidomide or essentially comprising the R-enantiomer of lenalidomide.

4. Pharmaceutical composition comprising

a) lenalidomide, preferably in form of an acid addition salt according to claim 1 or 2;

and

β) pomalidomide, preferably in form of an acid addition salt.

5. Pharmaceutical composition according to claim 4, comprising

a) 50 to 99.9 wt.% , preferably 90 to 99.5 wt.% lenalidomide,

β) 0. 1 to 50 wt.% , preferably 0.5 to 10 wt.% pomalidomide,

based on the total weight of the composition.

6. Pharmaceutical composition according to claim 4 or 5 , further comprising

γ) a glucocorticoid, preferably dexamethasone or prednisone.

7. Acid-addition salt of pomalidomide according to the formula (III)

wherein HX is an acid having a pK_a value in water at 25 °C from - 10 to +4.

8. Acid-addition salt according to claim 7, in form of the hydrochloride, sulfate or hydrogen sulfate salt.

9. Use of an acid addition salt of lenalidomide according to any one of claim 1 to 3 for producing lenalidomide in form of the free base.

10. Process for producing acid addition salts of lenalidomide , comprising the steps of i) providing a compound according to formula (II)

ii) hydrogenating the compound according to formula (II),

iii) subsequently adding an acidic compound, preferably having a pK_a value in water at 25 °C from - 10 to +4, and isolating the acid addition salt of lenalidomide;

iv) and optionally recrystallizing the resulting acid addition salt of lenalidomide.

1 1 . Use of an acid addition salt according to any one of claims 1 to 3 or 7 to 8 , or use of a pharmaceutical composition according to claims 4 to 6 for producing a pharmaceutical dosage form.

12. Pharmaceutical dosage form, wherein preferably the dosage form is in form of a capsule, comprising

a) an acid addition salt according to any one of claims 1 to 3 or 7 to 8 , or a pharmaceutical composition according to claims 4 to 6,

b) a filler, preferably a lactose-free filler, and / or

c) a binder, and / or

d) a disintegrant.

13. Pharmaceutical composition according to claim 4 to 6 or pharmaceutical dosage form according to claim 12 for the treatment of cancer, immune disorders and / or transplantation therapy.

14. Pharmaceutical composition or pharmaceutical dosage form according to claim 13 , wherein lenalidomide is administered in a daily amount of from 0. 1 to 150 mg, and pomalidomide is administered in a daily amount of from about 0.01 to about 150 mg.