Technical Field The invention relates to novel solid forms of empagliflozin of formula I, with the systematic name ( S^R^R^S^Ri-l-^-chloro-S-t^-tCSSi-oxolan-S-y^oxyphenyllmethyl lphenyl]^- (hydroxy-methy oxane-S^^-triol

(I)

Described is an amorphous or crystalline complex of empagliflozin with proline, a method of its preparation and use for the manufacture of a dosage form. The crystalline complex of empagliflozin with proline can be advantageously used to increase the purity of empagliflozin and its stabilization in terms of chemical and polymorphic purity. The invention further relates to an amorphous form of empagliflozin and a method of its preparation.

Empagliflozin is a new oral antidiabetic, designed for the treatment of type 2 diabetes mellitus. The mechanism of its action consists in inhibition of the sodium glucose cotransporter (SGLT2), which results in glycosuria and decrease of glycaemia. In clinical studies, administration of empagliflozin led to a decrease of glycated haemoglobin both in monotherapy and in combination with metformin, sulfonylurea, pioglitazone and insulin, which means that empagliflozin represents an effective drug especially for combination treatment of diabetes. Background Art

Empagliflozin is first mentioned in the patent application WO2005092877, which does not mention any details of the character of the solid form of the product. A crystalline form of empagliflozin is first described in the patent application WO2006117359. This application also describes preparation methods of this crystalline form by crystallization from ethyl acetate, isopropanol or an ethanol-water mixture. Then, the same crystalline form of empagliilozin is prepared in the patent application WO2011039107 by crystallization from a mixture of at least two solvents. This only known crystalline form of empagliflozin so far is characterized by X-ray powder diffraction patterns and differential scanning calorimetry records.

Disclosure of Invention

The invention relates to an amorphous or crystalline complex of empagliflozin with proline, a method of its preparation and use for the manufacture of a dosage form. The crystalline complex of empagliflozin with proline can be advantageously used to increase the purity of empagliflozin and its stabilization in terms of chemical and polymorphic purity. The invention further relates to an amorphous form of empagliflozin and a method of its preparation. Detailed description of the invention

Empagliflozin very readily forms a complex with proline, which shows a high crystallization tendency and is stable. During its crystallization, the chemical purity of the product is considerably increased. Proline binds to empagliflozin in the molar ratio of proline to empagliflozin of 4:1 to 1:4, preferably 2:1 to 1:2, but ideally in the molar ratio of 1:1. The complex of empagliflozin with proline tends to be formed in many solvents.

The complex is formed both by a reaction in a solution and by stirring in a suspension. For example, CI to C8 hydrocarbons (aliphatic and aromatic), CI to C4 alcohols, CI to C8 ketones, CI to C4 nitriles, CI to C8 esters, CI to C6 ethers (acyclic or cyclic) or their mixtures can be used for the reaction. Methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, butyl acetate, toluene or their mixtures can be advantageously used. The benefit of using this complex consists in the possibility to increase the chemical purity during crystallization and possible re-crystallizations. Thus, empagliflozin gets stabilized in terms of chemical as well as polymorphic purity. Table 1 summarizes chemical purity values of the starting empagliflozin and its complex with proline prepared in various solvents. Table 1: Chemical purity of empaglifiozin and its complex with proline

The complex of empaglifiozin with proline was also studied with the use of load tests and subsequent verification of their chemical purity. The results of these tests are summarized in Table 2.

Table 2: Chemical purity (HPLC) or empaglifiozin before and after the load tests

Formation of the complex of empaglifiozin with proline was confirmed with the use of analytic methods, X-ray powder diffraction, differential scanning calorimetry and by means of the solid-state nuclear magnetic resonance. The solid-state nuclear magnetic resonance (ssNMR) spectrum is shown in Fig. 1. The X-ray powder diffraction record (XRPD) is shown in Fig. 2. The complex of empaglifiozin with proline exhibits a crystalline character. The characteristic diffraction peaks are 6.9; 15.9 and 18.8 + 0.2 °2-theta, other characteristic diffraction peaks are 9.6; 17.3 and 20.7 ± 0.2° 2-theta. Diffraction peaks with a higher relative intensity than 15% are shown in Table 3. Table 3: Diffraction peaks of the crystalline complex of empagliflozin with proline

Differential scanning calorimetry (DSC) was applied to measure the melting point of the complex of empagliflozin with proline of 180.7°C (Fig. 3). According to the thermogravimetnc analysis (TGA) the complex of empagliflozin with proline contains 1% of water (Fig. 4). Preparation of the complex of empagliflozin with proline in accordance with variant A comprises the following steps: a/ dissolution and/or dispersion of a mixture of empagliflozin and proline in a solvent or mixture of solvents;

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

Preparation of the complex of empagliflozin with proline in accordance with variant B comprises the following steps: a/ dissolution and/or dispersion of empagliflozin in a solvent or a mixture of solvents; b/ addition of proline in the solid form or in the form of a solution;

c/ removal of the solvents from the mixture from step b/. The dissolution or dispersion according to the preparation variants A and B may be carried out in an organic solvent selected from CI to C8 hydrocarbons (aliphatic or aromatic), CI to C4 alcohols, CI to C8 esters, CI to C8 ketones, CI to C6 ethers (acyclic or cyclic), CI to C4 nitriles or their mixtures in the range from 20°C to the boiling point of the solvent or solvents. It is preferably carried out in methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile, ethyl acetate, butyl acetate, toluene or their mixtures. Subsequently, the mixture is usually cooled down, preferably to the range of -20°C to 30°C, and left to crystallize. The complex can be isolated either directly by filtration, or concentration of the mixture, or evaporation of the solvents may follow.

If the lyophilization or spray drying method is used for isolation of the complex, the result is an amorphous complex of empagliflozin with proline.

Preparation of the complex of empagliflozin with proline according to variant C is directly carried out during the formulation process, e.g. during wet granulation. Then, besides empagliflozin itself and excipients, proline is also placed into a homogenizer in the respective equivalent proportion. The complex of empagliflozin and proline is then formed directly during the wet granulation. The complex of empagliflozin and proline is generally produced in an at least 80% yield, usually 90% yield, while the chemical purity, measured with HPLC, is not lower than that of the input empagliflozin. On the contrary, what often happens is that the chemical purity of the complex is considerably higher than the purity of the input empagliflozin. Thus, the complex of empagliflozin with proline can be advantageously used to purify crude empagliflozin.

Empagliflozin forms the complex with proline in the molar ratios of proline to empagliflozin of 4: 1 to 1 :4, preferably 2: 1 to 1 :2, most preferably 1:1. The invention further provides amorphous empagliflozin. Figure 5 shows the XRPD pattern of the amorphous form of empagliflozin prepared by lyophilization. The lyophilization took 20 hours and it was carried out from a mixture of ter/-butanol and water. The glass transition temperature was determined to be 47 to 48 °C. Amorphous empagliflozin can also be prepared by spray drying of a solution of empagliflozin, or by evaporation in a vacuum evaporator, e.g. from the solvent dichloromethane.

Brief Description of Drawings Fig. 1: ssNMR record of the complex of empagliflozin with proline

Fig.2: XRPD pattern of the complex of empagliflozin with proline

Fig. 3: DSC record of the complex of empagliflozin with proline

Fig. 4: TGA record of the complex of empagliflozin with proline

Fig. 5: XRPD pattern of amorphous empagliflozin

Examples

Crystalline empagliflozin was prepared according to the procedure published in the patent application WO2006/U7359. The chemical purity of empagliflozin prepared this way was 99.2% (HPLC). Example 1

Preparation of the complex of empagliflozin with proline in methanol

Empagliflozin (200 mg) was dissolved together with (L)-proline (51 mg) in 1 ml of methanol at an elevated temperature. The resulting clear solution was slowly cooled down to the laboratory temperature and left to freely evaporate at the laboratory temperature. The resulting white crystalline substance was identified as a cocrystal of empagliflozin with (L)-proline.

Example 2

Preparation of the complex of empagliflozin with proline in ethanol

Empagliflozin (5 g) was stirred up together with (L)-proline (1.3 g) in 40 ml of ethanol. This mixture was heated up to moderate reflux until dissolution. The resulting clear solution was then left to cool down to the laboratory temperature and crystallize overnight in a refrigerator. The solid fraction was filtered. 5.9 g of a white crystalline substance was obtained. Example 3

Preparation of the complex of empagliflozin with proline in acetonitrile

Empagliflozin (0.5 g) was stirred up in 2 ml of acetonitrile and this mixture was heated up until dissolution. Subsequently, (L)-proline (127 mg) was added. The mixture was stirred at an elevated temperature for another 5 minutes and then left to freely cool down to the laboratory temperature and crystallize overnight. The next day, the solid fraction was filtered. 570 mg of a white crystalline substance was obtained.

Example 4

Preparation of the complex of empagliflozin with proline in an acetonitrile / toluene mixture

To a solution of empagliflozin (8 g) in a mixture of acetonitrile and toluene (in the 3 :7 ratio), a solution of (L)-proline (2.1 g) in the same mixture of solvents was added. The mixture was stirred at an elevated temperature for another 15 minutes at and then left to cool down to the laboratory temperature and crystallize overnight. The solid fraction was filtered. 9.7 g of a white crystalline substance was obtained. Example 5

Preparation of the complex of empagliflozin with proline during wet granulation

The following ingredients were charged into a homogenizer: crystalline empagliflozin, L- proline, lactose monohydrate, microcrystalHne cellulose, hydroxypropyl cellulose, sodium crosscarmellose and water. The mixture was homogenized at 20 rpm for 60 min. Finally, magnesium stearate and Si0 ₂ was added and the mixture was homogenized at 20 rpm for another 10 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 200 mg. The obtained cores may possibly be coated (a mixture of hypromellose, titanium oxide, iron oxide) .

Example 6

Pharmaceutical composition of the product - core

The following ingredients were charged into a homogenizer: the complex of empagliflozin with L-proline, lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium crosscarmellose and water. The mixture was homogenized at 20 rpm for 15 min. Finally, magnesium stearate and Si0 ₂ 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 200 mg. The obtained cores may possibly be coated (a mixture of hypromellose, titanium oxide, iron oxide).

Example 7

Preparation of the amorphous form of empagliflozin by Iyophilization

Empagliflozin (50 mg) was dissolved in 50 ml of a mixture of teri-butanol and water (1:1) 304572. The resulting clear solution was frozen and subsequently lyophilized. The produced white substance was identified as the amorphous form of empagliflozin. 45 mg of the product was obtained.

Example 8

Preparation of the amorphous form of empagliflozin by spray drying

Empagliflozin (5 g) was dissolved in 150g of dichloromethane. The resulting clear solution was spray dried in a Buechi spray drier (model B290) under the following conditions:

Inlet temperature: 55°C

Dosage: 20%

Aspirator: 100%

Condenser: -20°C.

2.6 g of the product was obtained, whose amorphous form was confirmed.

Example 9

Preparation of the amorphous form of empagliflozin in a vacuum evaporator

Empagliflozin (2 g) was dissolved in dichloromethane at an elevated temperature. The resulting clear solution was quickly evaporated in a rotary vacuum evaporator until dry. The produced amorphous foam was identified as the amorphous form of empagliflozin. 2 g of the product was obtained.

List of analytic methods Measurement parameters of XRPD: The diffraction patterns were measured using an X'PERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0,01° 2Θ, the measurement was carried out on a flat powder sample that was applied on a Si plate. 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 primary 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 for the setting of the secondary optical equipment.

The nuclear magnetic resonance (NMR) spectra were measured using a Bruker Avance 500 device. The 1H spectra were measured at the frequency of 500.13 MHz, ^I3 C 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 3-4 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 N ₂ was used at the flow of 20 ml/min. The records of the thermogravimetric analysis (TGA) were measured using a TGA 6 device made by the company Perkin Elmer. The sample charge in a corundum pot was 14.5 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 250°C at the heating rate of 10°C/min. As the carrier gas 4.0 N ₂ 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 7.0 mg of the tested sample in 10.0 ml of 50% acetonitrile Column: - dimension: 1 = 0.10 m, 0 = 2.1 mm

- stationary phase: Acquity UPLC BEH CI 8 (Waters), 1.7 μπι particles - column temperature: 40°C.

Mobile phase: A: 0.1% HCOOH

B: methanol

Gradient elution:

Detection: spectrophotometer 225 nm

Injected quantity: 1 μΐ

Sample temperature: 8°C

Sample concentration: 0.7 mg / ml