WO2016169533A1

WO2016169533A1 - A solid form of apremilast and a process for preparing the same

Info

Publication number: WO2016169533A1
Application number: PCT/CZ2016/000048
Authority: WO
Inventors: Iva OBADALOVA; Ondrej Dammer; Lukas KREJCIK; Jaroslava SVOBODOVA; Marcela Tkadlecova; Robert Klvana; Jan RYMES
Original assignee: Zentiva, K.S.
Priority date: 2015-04-24
Filing date: 2016-04-20
Publication date: 2016-10-27
Also published as: EP3286168A1

Abstract

The invention relates to a solvate of apremilast with tetrahydrofuran - THF of formula 1, wherein the molar ratio of apremilast and THF is 2:1. The THF solvate of apremilast exhibits the characteristic melting point of 79.4°C. Another aspect provides a process for preparing the THF solvate of apremilast. An alternative process for preparing a solvate of apremilast with tetrahydrofuran comprises a reaction of (S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethylamine of formula (S)-3 with 3-acetamidophtalic anhydride of formula 5 in a mixture of tetrahydrofuran and an acid, or a reaction of a diastereoisomeric salt of (S)-1- (3-ethoxy-4-memoxyphenyl)-2-(methylsulfonyl)-ethylamine with tartaric acid or their derivatives of formula (S-6) with a base, producing (S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethylamine of formula (S)-3, and its reaction with 3-acetamidophtalic anhydride of formula 5 in a mixture of tetrahydrofuran and an acid. Another aspect provides a pharmaceutical composition comprising the THF solvate of apremilast and at least one pharmaceutically acceptable excipient selected from the group of lactose, microcrystalline cellulose, sodium crosscarmellose, and magnesium stearate.

Description

A solid form of apremilast and a process for preparing the same

Technical Field The invention relates to a novel solid form of apremilast of formula 2, {¾)-2-[l-(3-ethoxy-4- memoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-l,3-dione,

in particular a solvate of apremilast with tetrahydrofuran, a method of its preparation and use in a dosage form.

Background Art

Apremilast is a novel inhibitor of phosphodiesterase PDE-4, i.e. a representative of a drug group that has tried to assert itself mainly in the treatment of the chronic obstructive pulmonary disease so far. Apremilast causes inhibition of antiinflammatory cytokines and chemokines (TNF-α, IL-23, CXCL9 or CXCLIO). Unlike biological substances exerting a neutralizing action onto already expressed antiinflammation factors, apremilast directly modifies the formation thereof, and also interferes with the production of leukotriene PTB4, inducible NO synthase (iNOS) or metalloproteinases (MMP). It can be used for the treatment of psoriatic arthritis and is also being tested for the treatment of other inflammatory diseases. It represents a new small molecule for oral administration.

Apremilast was first described as a racemic mixture of pharmaceutically active substances (WO0025777 Al; EP1752148 B)_s prepared by refluxing of the amine 3 with the anhydride 5 in acetic acid (Scheme 1).

(rac)-2

Scheme 1 A few years later, in the application WO03080049, a particular enantiomer, (S)-isomer, commonly only referred to as apremilast was described, which itself is the carrier of the biological activity. The application WO03080049 describes a process of chiral resolution of the racemic amine 3 by means of N-acetyl-i-leucine. The obtained diastereoisomeric salt 4 is then refluxed with the anhydride 5 in acetic acid overnight and apremilast (2) was obtained in

Scheme 2 By carrying out the experiment according to the example, Form B was obtained. This is described by means of X-ray powder diffraction and thermal methods in the application in the patent application WO2003080049 by means of 1H, ¹³C NMR and chiral HPLC. An experiment conducted according to an example included in this application provided apremilast Form B. This form is described with the use of X-ray powder diffraction and thermal methods in the following patent application WO2009120167, which describes Forms A to G and an amorphous form. There, Forms A, B and F are described as pure polymorphic forms of apremilast, Forms C, D, E and G as solvates of apremilast (Form C - toluene, Form D - dichloromethane, Form E - acetonitrile, Form G - ethyl acetate). In the patent application WO2009120167, Form C is presented as a toluene solvate that contains 3 molar equivalents of toluene per one mol of apremilast. A reproduction of Form C provided a form that corresponds to the pattern of Form C of the patent application WO2009120167 with its X-ray powder pattern, but with the use of the thermal methods and ^!H NMR measurement the content of toluene was determined to be 0,5 molar equivalent. So according to our conclusions this is the toluene hemisolvate of apremilast In the patent application WO2009120167, Form D is presented as a dichloromethane solvate that contains 2.5 molar equivalents of dichloromethane per one mol of apremilast. A reproduction of Form D provided a form that corresponds to the pattern of Form D of the patent application WO2009120167 with its X-ray powder pattern again, but with the use of the thermal methods and ^lH NMR measurement the content of dichloromethane was determined to be 1 molar equivalent. So according to our conclusions this is a dichloromethane solvate of apremilast in the molar ratio of 1 : 1.

In the patent application WO2009120167, Form E is presented as an acetonitrile solvate and Form G as an ethyl acetate solvate. Both these solvates are characterized in the patent application with the X-ray powder pattern and the records of the thermal methods.

The patent application WO2009120167 in its description further mentions formation of another form, Form H, but there are no other more detailed data. Form I-l is described in Czech patent application PV 2015-277. This form is a solvate with tetrahydrofuran, wherein a ^LH NMR measurement revealed the molar ratio of apremilast/THF being 1:0.5.

Disclosure of Invention

This invention provides a THF solvate of apremilast (Form I-l), of formula 1, which is characterized especially by high stability and is easy to prepare. In addition, the described Form I-l is excellent in high crystallinity, which makes it very suitable for the preparation of highly pure apremilast.

The invention further provides a process for preparing a solvate of (S)-{2-[l-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylethyl] -4-acetylamraoisoindoline- 1 ,3-dione with tetrahydrofuran (1), comprising a reaction of either the amine (5)-3 with the anhydride 5, or a process comprising a reaction of a diastereoisomeric salt of the (<S)-amine and tartaric acid, or their derivatives (S-6), wherein R¹ a R² are, independently from each other, H, a C1-Q2 alkyl, aryl or heteroaryl with one or more heteroatoms, wherein all these groups may be further substituted with any functional groups, with a base such as an alkaline hydroxide or alkaline carbonate, preferably sodium carbonate or potassium carbonate, producing the free amine (S)- 3, which subsequently reacts with the anhydride 5 in a mixture of tetrahydrofuran/a C2-C5 carboxylic acid. For the purposes of the present invention, the term "any functional group" refers to: (a) halogens, (b) hydroxy, alkoxy or aryloxy groups, (c) amino and nitro groups, (d) CHO and acyl groups (i.e. ketones), (e) derivatives of carboxylic acids. Advantageously, those derivatives can be used wherein R¹ and R² independently stand for R³C(=0) acyl groups, wherein R³ is a Ci-Cn alkyl, a C₆-C₁₄ aryl, a heteroaryl with one or more heteroatoms, wherein all these groups may be further substituted with any functional groups. The Y group in the derivatives 6 can in turn be a hydroxyl OH, O-substituted hydroxyl OR⁴, wherein R⁴ is any C_\- _\ alkyl, C₆-C₁₄ aryl, heteroaryl with one or more heteroatoms, wherein all these groups may be further substituted with any functional groups. The Y group in the derivatives 6 further also stands for NR⁵R⁶ amides, wherein R^s and R⁶ are, independently from each other, H, a Ci-C₁₆ alkyl, a C6-C₁₄ aryl, heteroaryl with one or more heteroatoms, wherein all these groups can be further substituted with any functional groups, preferably C₆-Ci₄ aryls substituted with halogens in any position (Scheme 3).

R^l, R² = H, C_j-C_jg alkyl, aryl, heteroaryl, "Ύ^Κ>

Y = OH, OR*, NR⁵R⁶ O

(S-6)

Scheme 3

The obtained THF solvate (1) is easy to prepare, stable, exhibits high crystallmity and can be advantageously used for the preparation of pure apremilast with HPLC purity exceeding 99.9%. It can also easily be used for the preparation of amorphous apremilast (2).

Detailed description of the invention This invention provides a THF solvate of apremilast (Form I-l) that is highly stable, exhibits high crystallinity and in addition it is easy to prepare.

Form I-l of apremilast exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Fig. 1. Its characteristic diffractions with the use of CuKa radiation are 8.0; 12.7; 15.8; 19.4; 21.3 and 25.2 ± 0.2 °2-theta. Form I-l further exhibits the following characteristic reflections: 8.8; 9.1; 11.8; 15.3; 18.1 and 20.2+ 0.2 °2-theta; Diffraction peaks with a higher relative intensity than 15% are summarized in Table 1. Table 1: Diffraction peaks of apremilast Form I-l

The melting point of the crystalline Form I-l of apremilast determined with the DSC analysis is 79.4°C (Fig. 3). According to the thermogravimetric analysis (TGA), Form I-l of apremilast contains 8.2 % of tetrahydrofuran (Fig. 4). It means that it is the hemisolvate of apremilast with tetrahydrofuran. Since tetrahydrofuran is a highly inert solvent, this Form 1-1 is also suitable for preparation of a dosage form.

Apremilast forms a solvate with tetrahydrofuran, ideally in the molar ratio of apremilast : tetrahydrofuran = 2 : 1.

Preparation of apremilast Form 1-1 comprises the following steps:

a dissolution and/or dispersion of apremilast in tetrahydrofuran;

b/ removal of the solvents from the mixture from step a/.

The dissolution or dispersion in tetrahydrofuran can be carried out at a temperature in the range from 20°C to the boiling point of the solvent. Subsequently, the mixture is usually cooled down to a temperature of 0°C to 30°C, preferably to the range of 20°C to 25°C and left to crystallize. The salt can be isolated either directly by filtration, or concentration of the mixture, or evaporation of the solvents may follow.

Form 1-1 of apremilast can also be directly prepared during the formulation process, preferably directly during wet granulation. Apremilast together with the excipients is charged into a homogenizer and Form 1-1 is produced during wet granulation.

A solid state ¹³C NMR measurement confirmed a hitherto undescribed, new Form 1-1 (Fig. 2). A 1H NMR measurement shows the content of tetrahydrofuran in the molar ratio of apremilast : tetrahydrofuran = 2 : 1 (Fig. 5). Form 1-1 can be advantageously used to increase the chemical purity of apremilast. This form crystallizes well and removes impurities from apremilast. Conversion of Form B to Form 1-1 has increased the chemical purity from 99.12% (starting Form B) to 99.59% (final Form 1-1). Also, recrystallization of Form 1-1 itself increases the chemical purity from the initial 99.59% to the final 99.98% (HPLC). Purification of crude apremilast (HPLC purity 98.45%) can be advantageously achieved by recrystallization through Form 1-1 and in such a case the chemical purity of the final apremilast rises to 99.84% (HPLC). The prepared Form 1-1 of apremilast according to this invention can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets. Such pharmaceutical mixtures can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystaliine cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants, etc. These tablets can be coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.

The invention further provides a process for preparing a solvate of (S)-{2-[l-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylemyl]-4-acetylaniinoisoindoline-l_J3-dione with tetrahydrofuran (1), comprising either a reaction of the amine (S)-3 with the anhydride 5 in a mixture of tetrahydrofuran/a C2-C5 carboxylic acid, preferably in a mixture of telrahydrofuran/acetic acid, or a process comprising first a reaction of a diastereoisomeric salt of the amine and tartaric acid or their derivatives (S-6) with a base; preferentially using (R,R)- 4-chlorotartranilate (S-6a) or (^^-O^'-di- -toluoyl-tartrate (S-6b), producing the free amine (5)-3, which subsequently reacts with the anhydride 5 in a mixture of te1rahydrofuran/a C2-C5 carboxylic acid, preferably in a mixture of tetrahydrofuran/acetic acid (Scheme 4). The volume ratio of acetic acid tetrahydrofuran should be suitably selected to be 1:1 to 1:7, preferably

(5-Gb)

Scheme 4 If the diastereoisomeric salts with tartaric acid (S-6a) or (S-6b) are used, the reaction can also be carried out without isolation of the amine (5)-3. The use of new and moderate conditions for the reaction with the anhydride 5 enables preparation of highly pure apremilast exhibiting high HPLC purity (>99.99%), while the product is isolated in Form I-l with a high yield of 78-87%. The THF solvate of apremilast (1) prepared this way exhibits high crystallinity, stability and purifying ability and can serve as an advantageous source for the preparation of amorphous apremilast (2). The latter can be prepared by precipitation into an antisolvent, best water, or into an organic solvent selected from MTBE or heptane, by drying in the temperature range of 60-100°C, or by spray-drying from a solution with methanol, ethanol, dichloromethane or acetone.

An advantage of the process according to the invention is its easy performance, a high yield, low number of the operation steps and high purity of the crude product already.

The term "room temperature" refers, for the purposes of the text below and above, to the temperature range from 22 to 26°C.

Brief Description of Drawings

Fig. 1: XRPD pattern of apremilast Form I-l

Fig. 2: ssNMR record of apremilast Form I-l

Fig. 3: DSC record of apremilast Form I-l

Fig. 4: TGA record of apremilast Form I-l

Fig. 5: 1H NMR record of apremilast Form I-l

The invention is elucidated in a more detailed way using the working examples below. The examples, which illustrate the improvement of the procedure in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect. Examples

Apremilast was prepared according to the procedure published in the patent application WO2003080049. The chemical purity of apremilast prepared this way was 99.4% (HPLC). The 1H and ¹³C NMR spectra confirmed the structure of apremilast. The XRPD and DSC record confirmed Form B as described in the patent applications WO2003080049 and WO2009120167.

Example 1

Preparation of apremilast Fo m I-l

Apremilast (100 mg, 0.22 mmol) was dissolved in 0.4 ml of tetrahydrofuran under moderate reflux (60°C to 75°C). The clear solution was left to slowly cool down to the room temperature and subsequently put in a fridge or freezer to crystallize. The produced crystals were aspirated and dried in a vacuum drier at 40°C for 6 hours. 80 mg of crystalline Form I-l of apremilast was obtained in the molar ratio of apremilast : tetrahydrofuran = 2 : 1 (^]H NMR) with the chemical purity of 99.97% (HPLC).

lH NMR (500 MHz, dms -dS) δ 1.32 (t, J = 6.9 Hz, 3H); 1.76 (m, 2H_} THF); 2.19 (s, 3H); 3.02 (s, 3H); 3.60 (m, 2H, THF); 3.73 (s, 3H); 4.02 (qua_} J = 7.0 Hz, 2H); 4.14 (dd, J = 14,3 Hz, J= 4.5 Hz, 1H); 4.34 (dd, J = 14.3 Hz, J = 10.5 Hz, 1H); 5.78 (dd, J = 10.4 Hz, J= 4.2 Hz, 1H); 6.96 (m, 2H); 7.07 (m, 1H); 7.57 (m, J= 7.4 Hz, 1H); 7.79 (t, J= 7.9 Hz, 1H); 8.44 (d, J= 8.4 Hz, 1H); 9.71 (s, 1H).

Example 2

Preparation of apremilast Form I-l

Apremilast (10 g, 0.022 mol) with the chemical purity of 99.12% (HPLC) was dissolved in 40 ml of tetrahydrofuran under moderate reflux (60°C to 75°C). The clear solution was stirred under moderate reflux (60°C to 75°C) for about 15 minutes and then cooled to the room temperature at the rate of approximately 20°C an hour. The mixture can be inoculated with the crystalline product of Example 1. The reaction mixture was crystallized at 15 to 25 °C for 4 hours. The produced crystals were aspirated and dried in a vacuum drier at 40°C for 12 hours. 8.7 g of crystalline Form I-l of apremilast was obtained in the molar ratio of apremilast : tetrahydrofuran - 2 : 1 (^lH NMR) with the chemical purity of 99.59% (HPLC). Example 3

Recrystallization of apremilast Form 1-1

Apremilast (8,7 g) with the chemical purity of 99.59% (HPLC) was dissolved in 35 ml of tetrahydrofuran under moderate reflux (60°C to 75°C). The clear solution was stirred under moderate reflux (60°C to 75°C) for about 15 minutes and then cooled to the room temperature at the rate of approximately 20°C an hour. The mixture can be inoculated with the crystalline product of Example 1. The reaction mixture was crystallized at 15 to 25 °C for 4 hours. The produced crystals were aspirated and dried in a vacuum drier at 40°C for 12 hours. 8.1 g of crystalline Form 1-1 of apremilast was obtained in the molar ratio of apremilast : tetrahydrofuran = 2 : 1 (1H NMR) with the chemical purity of 99.98% (HPLC).

Example 4

Purification of crude apremilast

Crude apremilast (30 g) with the chemical purity of 98.45% (HPLC) was dissolved in 120 ml of tetrahydrofuran under moderate reflux (60°C to 75°C). The solution was stirred under the same conditions for about 20 minutes and then cooled to the room temperature at the rate of approximately 20 °C an hour. The mixture can be inoculated with the crystalline product of Example 1. The reaction mixture was crystallized at 15°C to 25°C for 4 hours. The produced crystals were aspirated and dried in a vacuum drier at 40°C for 12 hours. 26.9 g of a crystalline product was obtained (Form 1-1, HPLC purity 99.66%). This product was subsequently recrystallized from an ethanol-acetone mixture. 25.7 g of pure Form B of apremilast with the chemical purity of 99.84% (HPLC) was obtained.

Example 5

A preparation process of apremilast - (S)-{2-[l-(3-ethoxy-4-methoxyphenyI)-2-methyl- sulfony lethy 1) -4-acety laminoisoindoline-1 ,3-dione (2)

A 500ml three-neck flask was fitted with a mechanical stirrer, thermometer and cooler. 25 g (56 mmol) of the salt of (5)-2-(3-emoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine with N-acetyl-Z-leucine, 12.1 g (58.8 mmol) of 3-acetamidophtalic anhydride and 250 ml of glacial acetic acid were charged into a reaction vessel. The mixture was refluxed overnight and then cooled down to <50°C. The solvent (250 ml of acetic acid) was removed in vacuo and the residue, having rich yellow colour, was dissolved in 800 ml of ethyl acetate. The obtained solution was washed with water (2 x 250), saturated aqueous NaHC0₃ (2 x 250 ml), brine (2 x 250 ml) and dried with sodium sulphate. The solvent (800 ml of ethyl acetate) was evaporated in vacuo and the residue was recrystallized from a binary solvent containing 150 ml of ethanol and 75 ml of acetone. The solid was isolated by filtration in vacuo and washed with 2 x 100 ml of ethanol. The product was dried in vacuo at 60°C until constant weight, which provided 19.1 g of the title compound; yield 74%, HPLC purity 99.29%, XRPD confirmed Form B.

Example 6

Preparation of the THF solvate of (S)-{2-[l-(3-ethoxy-4-methoxyphenyl)-2-methyl- sulfonylethyl]-4-acetylaminoisoindoline-l,3-dione (1)

11.0 g (40.241 mmol) of (S)-l-(3-emoxy-4-memoxyphenyl)-2-(methylsmfonyl)-emylamine (S)-3 and 8.65 g of (3-acetamidophtalic anhydride (42.253 mmol) 5 were refluxed in a mixture of 8 ml of AcOH and 50 ml of THF for 21 h. Then, the reaction mixture was gradually cooled down to 26°C, seeded, subsequently slowly cooled down to 0°C and stirred overnight. The obtained product was filtered off, washed with icy MTBE and dried at 40°C in vacuo. 16.56 g of a white crystalline substance was obtained with the yield of 83%, HPLC 99.99%, NMR apremilast/THF 1:0.5, XRPD - THF solvate.

Example 7

11.0 g (40.241 mmol) of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine (S)-3 and 8.65 g (42.253 mmol) of 3-acetamidophtalic anhydride 5 were refluxed in a mixture of 8 ml of butyric acid and 50 ml of THF for 21 h. Then, the reaction mixture was gradually cooled down to 26°C, seeded, subsequently slowly cooled down to 0°C and stirred overnight. The separated product was filtered off, washed with icy MTBE and dried at 40°C in vacuo. 15.52 g of a white crystalline substance was obtained; yield 78%, HPLC 99.2%, NMR apremilast/THF 1:0.5, XRPD - THF solvate.

Example 8

Preparation of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyIamine (S)-3

192.0 g (1.389 mol) of K2CO3 and 3180 ml of demineralized water were charged into a reactor. After dissolution, 600.0 g (1.126 mol) of (i^H-cWorotartranilate of (5)-l-(3-ethoxy- 4-memoxyphenyl)-2-(methylsulfonyl)-ethylamine (S-6a) and subsequently 3000 ml of CH₂C1₂ were added. The resulting mixture was intensively stirred at 30-33°C for ca. 30 min. The organic phase was separated and the aqueous phase was gradually extracted with 1 x 1500 ml of CH₂C1₂ (30-33°C) and then with 1 x 900 ml of CH₂C1₂ (30-33°C). The combined dichloromethane phases were concentrated to the volume of ca. 1400-1600 ml and then 2400 ml of THF was added. Then, at the atmospheric pressure, ca. 2300 ml of the solvent was removed by distillation, the mixture was cooled down to 60°C and 500 ml of MTBE was added. After that, the mixture was gradually cooled down to -10°C during 1.5 h, seeded and stirred at -10°C for another 1.5 h. The separated product was filtered off, washed with 2 x 120 ml of cooled THF and dried in a vacuum drier at 45-50°C. 254.5 g (83%) of white crystals of the title compound of formula (S)-3 was obtained.

Example 9

Preparation of the THF solvate of (S)-{2-[l-(3-ethoxy-4-methoxypheiiyI)-2-methyi- sulfonyIethyl]-4-acetylaminoisoindoline-l,3-dione (1)

600 g (2.195 mol) of (S)-l-(3-emoxy-4-memoxyphenyi)-2-(memylsulfonyl)-e larnine (S)-3 and 468 g (2.281 mmol) of 3-acetamidophtalic anhydride (5) were refluxed in a mixture of 1200 ml of acetic acid and 2220 ml of THF for 4 h. Then, the reaction rnixture was gradually cooled down to 40°C and 2100 ml of MTBE was added. At 30°C, the mixture was seeded and subsequently cooled down to -5°C during 1.5 h and stirred at -5°C for another two hours. The separated product was filtered off, washed with 3 x 850 ml of icy MTBE and dried at 40-45X in vacuo. 964.3 g of white crystals of the title compound was obtained; yield 87%, HPLC >99.99%, NMR apremilast/THF 1:0.6, XRPD - THF solvate.

Example 10

Preparation of the THF solvate of (S)-{2-[l-(3-ethoxy-4-methoxyphenyl)-2-methyl- sulf onylethy 1] -4-acetylarninoisoindoline-l ,3-dione (1)

96.0 g (0.695 mol) of K2CO3 and 1590 ml of demineralized water were charged into a reactor. After dissolution, 300.0 g (0.563 mol) of (i.,i -4-cWorotartranilate of (5)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)-ethylamine (S-6a) and subsequently 1500 ml of CH2CI2 were added. The obtained mixture was intensively stirred at 30-33°C for ca. 30 min. The organic phase was separated and the aqueous phase was extracted with 2 x 750 ml of CH2CI2 (30-33 °C). The combined dichloromethane phases were concentrated at a reduced pressure to the volume of ca. 450-480 ml, then 660 ml of THF was added and the residue of CH₂Ci₂ was removed by distillation at a reduced pressure. After that, 110.7 g (0.540 mol) of 3- acetamidophtalic anhydride (5), 240 ml of acetic acid were added to the reaction mixture and the reaction mixture was refluxed for 4-5 h. After cooling to 40 °C, 600 ml of MTBE were added dropwise. At the temperature of 28-30°C, the mixture was seeded, then cooled down to -8°C during 2 h and it was stirred at -8°C for another 2 h. The separated white crystalline substance was filtered off, washed with 3 x 150 ml of cold MTBE and dried at 40-45 °C in vacuo. 223.59 g of the title compound of formula 1 was obtained; yield 83%, HPLC >99.99%, NMR apremilast/THF 1 :0.5, XRPD - THF solvate. Example 11

Preparation of the THF solvate of (S)-{2-[l-(3-ethoxy-4-methoxyphenyl)-2-inethyl- sulfonylethyl]-4-acetyIaminoisoindolinc-l,3-dionc (1)

9.6 g (0.0695 mol) of K2CO3 and 159 ml of demineralized water were charged into a reactor. After dissolution, 38.04 g (0.0563 mol) of (/.,i?)-di- ?-toluoyl-tartrate of (5)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)-ethylamine (S-6b) and subsequently 150 ml of CH2CI2 were added. The obtained mixture was intensively stirred at 30-33°C for ca. 30 min. The organic phase was separated and the aqueous phase was extracted with 2 x 75 ml of CH2CI2 (30-33°C). The combined dichloromethane phases were concentrated at a reduced pressure to the volume of ca. 45-48 ml, then 66 ml of THF was added and the residue of CH2CI2 was removed by distillation at a reduced pressure. After that, 11.07 g (0.0540 mol) of 3- acetamidophtalic anhydride (5), 24 ml of acetic acid were added to the reaction mixture and the reaction mixture was refluxed for 4-5 h. After cooling to 40°C, 60 ml of MTBE were added dropwise. At the temperature of 28-30 °C, the mixture was seeded, then cooled down to -8°C during 2 h and stirred at -8°C for another 2 h. The separated white crystalline substance was filtered off, washed with 3 x 15 ml of cold MTBE and dried at 40-45 °C in vacuo. 21.26 g of the title compound of formula 1 was obtained; yield 79%, HPLC >99.95%, NMR apremilast/THF 1:0.5, XRPD - THF solvate.

Example 12

Preparation of amorphous apremilast, (S)-{2-[l-(3-ethoxy-4-metb.oxyphettyl)-2-methyI- sulfonylethyl] -4-acelyIaminoisoindoIine-l ,3-dione (2)

40 g of (5 -{2-[l-(3-emoxy-4-memoxyphenyl)-2-memylsulfonylemyl]-4-acetylaminoiso- indoline-l,3-dione · ½THF (1) were dissolved in 120 ml of acetone and the obtained solution was filtered. Then, during 15 minutes, the filtrate was added to icy water (0°C) dropwise and stirred at 0-5 °C for 15-20 minutes. The produced amorphous substance was filtered off, washed with 50 ml of cold water, dried on frit and subsequently in a drier at 40°C in vacuo. 33.9 g of the title compound was obtained in an amorphous form; yield 91%, HPLC 99.99%, XRPD - amorphous form.

Example 13

Preparation of amorphous apremilast, (S)-{2-Il-(3-ethoxy-4-methoxyphenyl)-2-methyl- sulfonyIethyl]-4-acetylaminoisoindoline-l,3-dione (2)

50.0 g of (S)-{2-[l-(3-emoxy-4-memoxyphenyl)-2-memylsulfonylemyl]-4-acetylaniinois indoline-l,3-dione · ½THF (1) were suspended in 200 ml of acetone. The mixture being stirred, its temperature was adjusted to 35-40°C and after dissolution in the hot state it was filtered through a filter with the pore size of 0.2-0.4 μπι. The clear filtrate at a temperature of 25-30°C was added dropwise to heptane (1200 ml), pre-cooled to the temperature of 0 to -3°C, during 30-35 min. During the addition, the temperature was maintained in the range of -3 to +2°C. The precipitate was further stirred at 0°C for 15-20 min. The slightly yellowish substance was filtered off and then washed with 1x50 ml of cooled heptane. The product was dried in a vacuum drier at 35-45°C for 12-24 h. 40.2 g of an amorphous substance was obtained; yield 87%, sum of impurities according to HPLC <0.03%, optical purity <0.05%, XRPD - amorphous form.

Example 14

Preparation of amorphous apremilast, (5)-{2-[l-(3-ethoxy-4-methoxyphenyl)-2-methyI- sulfbnylethy I] -4-acetylaminoisoindoline-l ,3-dione (2)

20.0 g of (S)-{2-[l-(3-emoxy-4-memoxyphenyl)-2-memylsulfonylethyl]-4-acetylaminoiso- indoline-l,3-dione · ½THF (1) were suspended in 120 ml of acetone. The mixture being stirred, its temperature was adjusted to 35-40°C and after dissolution in the hot state it was filtered through a filter with the pore size of 0.2-0.4 μιη. The clear filtrate at a temperature of 20-25°C was spray-dried (Buchi B290, Tin=65-80°C). 18 g of an amorphous substance was obtained; sum of impurities according to HPLC <0.03%, optical purity <0.05%, XRPD - amorphous form. Example 15

Preparation of amorphous apremilast, (5)-{2-[l-(3-ethoxy-4-methoxyphenyl)-2-methyl- sulfonylethyl]-4-acetylaminoisoindoUne-l,3-dione (2)

20.0 g of (-?)-{2-[l-(3-emoxy-4-memoxyphenyl)-2-memylsulfonylemyl]-4-acetylaminoiso- indoline-l,3-dione · ½THF (1) were suspended in 120 ml of methanol. The mixture being stirred, its temperature was adjusted to 35-40°C and after dissolution in the hot state it was filtered through a filter with the pore size of 0.2-0.4 μπι. The clear filtrate at a temperature of 20-25°C was spray-dried (Buchi B290, Tin=65-80°C). 18 g of an amorphous substance was obtained; sum of impurities according to HPLC <0.03%_? optical purity <0.05%, XRPD - amorphous form.

Example 16

Pharmaceutical composition of the product - core

The following ingredients were charged into a homogenizer: apremilast Form 1-1, lactose, microcrystalline cellulose and sodium crosscarmellose. The mixture was homogenized at 20 rpm for 15 min. Finally, magnesium stearate was added and the mixture was homogenized at 20 rpm for another 3 min. The tabletting matter produced in the above mentioned way was compressed in a rotary tabletting machine and used for the production of cores with the approximate weight of 305 mg.

Overview of analytical methods

Measurement parameters of XRPD: The diffractograms were measured using an X'PERT PRO MPD PANalytical diffxactometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40" 20, increment: 0,01° 20, the measurement was carried out on a flat powder sample that was applied on a Si plate. For the setting of the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a ¼° anti-diffusion slit were used. For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.

The nuclear magnetic resonance (NMR) spectra were measured using a Bruker Avance 500 device. The ^lH spectra were measured at the frequency of 500.13 MHz, ¹³C at the frequency of 125.8 MHz. The sample was measured in a deuterated solvent specified for the particular analysis, normally at 25°C (unless specified otherwise for a particular analysis). The chemical shift δ is expressed as ppm, the interaction constants J are specified in Hz. The spectra were normally referenced to the residual solvent content.

Carbon spectra of solid-state nuclear magnetic resonance (ssNMR) were measured with the use of an Avance 400 WB Bruker device, using the CP/MAS method in a 4mm rotor at the speed of 13 kHz, normally at 25°C.

The records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device made by the company Perkin Elmer. The sample charge in a standard Al pot (40 μΐ,) was between 2-4 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 min stabilization at the temperature of 20°C and then of heating up to 250°C at the heating rate of 10 °C/min. As the carrier gas 4.0 N₂ was used at the flow of 20 ml/min. The records of the therniogravimetric analysis (TGA) were measured using a TGA 6 device made by the company Perkin Elmer, The sample charge in a corundum pot was 20 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 minute's stabilization at the temperature of 20°C and then of heating up to 300°C at the heating rate of 10°C/min. As the carrier gas 4.0 N₂ was used at the flow of 20 ml/min.

Chemical purity was measured with the use of liquid chromatography (HPLC):

Device: Waters Acquity UPLC, PDA detection

Sample preparation: Dissolve 6.0 mg of the tested sample in 10.0 ml of 100% acetonitrile Column: - dimension; 1 = 0.10 m, 0 = 2.1 mm

- stationary phase: Acquity UPLC BEH Fenyl, 1.7 μηι particles

- column temperature: 30°C.

Mobile phase: A: 10 raM (NH^HPC^ at pH 6.8

B: acetonitrile

Gradient elution:

Detection: spectrophotometer 230 nm

Injected amount: 1.0 μΐ

Sample temperature: 15°C

Sample concentration: 0.6 mg/ml

Claims

1. A solvate of apremilast with tetrahydrofuran - THF of formula 1

2. The THF solvate according to claim 1, where the molar ratio of apremilast and THF is

2:1.

3. The THF solvate according to claims 1 or 2, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 8.0; 12.7; 15.8; 19.4; 21.3 and 25.2 + 0.2 °2-theta.

4. The THF solvate according to claim 3, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 8.8; 9.1; 11.8; 15.3; 18.1 and 20.2± 0.2 °2-theta.

5. The THF solvate according to any one of the preceding claims, exhibiting the characteristic melting point of 79.4°C.

6. A process for preparing the THF solvate of apremilast as defined in claims 1 to 5, wherein the process comprises the following steps:

a) dissolution and/or dispersion of apremilast in tetrahydrofuran;

b) removal of the solvent from the mixture from step a).

7. The process according to claim 6, characterized in that lyophilization, spray drying or filtration is used for the removal of the solvent from the mixture.

The process according to claim 6, characterized in that the THF solvate of apremilast produced in situ during the formulation process.

9. A process for preparing of apremilast, wherein the process comprises preparation of the THF solvate of apremilast as defined in claims 1-5 and its recrystallization.

10. Use of the THF solvate of apremilast as defined in claims 1 to 5 for the preparation of apremilast with a chemical purity higher than 99.80% according to HPLC.

11. A pharmaceutical composition, wherein the composition comprises the THF solvate of apremilast as defined in claims 1 to 5 and at least one pharmaceutically acceptable excipient selected from the group consisting of lactose, microcrystalline cellulose, sodium crosscarmellose, and magnesium stearate.

12. A process for manufacturing the pharmaceutical composition accordmg to claim 11, characterized in that the process comprises the wet granulation procedure.

13. The process for manufacturing the pharmaceutical composition according to claim 12, characterized in that the composition is in the form of tablets.

14. A process for preparing a solvate of apremilast with tetrahydrofuran, wherein the process comprises a reaction of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)- ethylamine of formula (S)-3

(S)-3 with 3-acetamidophtalic anhydride of formula 5

5 in a mixture of tetrahydrofuran and an acid, or a reaction of a diastereoisomeric salt of (S)-l-(3-ethoxy-4-memoxyphenyI)-2-(memylsulfonyl)-ethylamine with tartaric acid or

R¹, R² - H,

(S-6) with a base, producing (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)- ethylamine of formula (S 3, and its reaction with 3-acetamidophtalic anhydride of formula 5 in a mixture of tetrahydrofuran and an acid.

15. The process according to claim 14, characterized in that the acid is selected from the group consisting of organic acids, preferably C2-C5 organic acids, more preferably acetic, propionic or butyric acid.

16. The process according to claims 14 or 15, characterized in that the mixture of the acid and tetrahydrofuran is in the volume ratio of 1: 1 to 1:7, preferably 1 : 1.85.

17. The process according to any one of claims 14-16, characterized in that the diastereoisomeric salt of (iS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)- ethylamine with tartaric acid is (i-,/-)-4-chlorotartranilate of formula S-6a or (R,R)-di-p- toluoyl-tartrate of formula S-6b.

(S-6b)

18. The process according to any one of claims 14-17, characterized in that the base is selected from the group consisting of KOH, NaOH, K2CO3 and Na₂C0₃, and preferably from K₂C03 or Na₂C03.

19. The process according to claim 14, wherein the process comprises a reaction of (S)-l- (3-emoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine of formula (S -3 with 3- acetamidophtalic anhydride of formula 5 in a mixture of acetic acid and tetrahydrofuran in the volume ratio of ί :1.85.

20. The process according to claim 14, characterized in that it comprises a reaction of (R, i?)-4-chlorotartranilate of (S)- 1 -(3 -ethoxy-4-methoxyphenyl)-2-(methylsulfonyI)- ethylamine or (i-,i?)~di- j-toluoyl-tartrate of (5)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)-ethylamine with a base selected from K2CO3 or Na₂C⁽¼, producing (S)-l-(3-emoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine of formula (S)-3, which is further reacted with 3-acetamidophtalic anhydride of formula 5 in a mixture of acetic acid and tetrahydrofuran in the volume ratio of 1:2.75.

21. The process according to any one of claims 14-20, wherein the process further comprises preparation of amorphous apremilast by the procedure of precipitation into an antisolvent or organic solvent, drying in the temperature range of 60 - 100°C, or spray-drying.

22. The process according to claim 21, characterized in that the antisolvent is water.

23. The process according to claim 21, characterized in that the organic solvent is MTBE or heptane.

24. The process according to claim 21, characterized in that a suspension of the solvate of apremilast with tetrahydrofuran in methanol, ethanol, dichloromethane or acetone is used for the spray-drying.