WO2016161995A1

WO2016161995A1 - Solid forms of amorphous dapagliflozin

Info

Publication number: WO2016161995A1
Application number: PCT/CZ2016/000037
Authority: WO
Inventors: Iva OBADALOVA; Ondrej Dammer; Lukas KREJCIK; Jakub Hert; Hana TOZICKOVA
Original assignee: Zentiva, K.S.
Priority date: 2015-04-08
Filing date: 2016-04-07
Publication date: 2016-10-13

Abstract

Described is a composition in the form of a melt, containing dapagliflozin and at least one pharmaceutical excipient. The selection of the excipient for this mixture is governed by the requirement for stability of the end product A suitable excipient is such that will make the glass transition temperature of the final mixture higher than 40°C5 preferably higher than 70°C. Preferred excipients are especially hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP K30, Soluplus™, PEG 6000, copovidone VA64, D (+) glucose, D (+) saccharose or urea.

Description

Solid forms of amorphous dapagliflozin

Technical Field

The invention relates to new solid forms of amorphous dapagliflozin of formula I, their preparation methods and use in a dosage form. These solid forms can be advantageously used to increase the chemical and polymorphic stability of amorphous dapagliflozin.

(I) Dapagliflozin is a highly selective inhibitor of SGLT2 (sodium glucose co-transporter 2), which is responsible for renal reuptake of glucose. Inhibition of SGLT2 by means of dapagliflozin leads to increased excretion of glucose by the kidneys and to subsequent reduction of glycaemia and improvement of diabetes compensation. Currently, dapagliflozin is approved in Europe for administration to type 2 diabetic patients in monotherapy (in case of intolerance to metformin), or in combination with other antidiabetics, including insulin. Administration of dapagliflozin leads not only to an improvement of diabetes compensation, but also to a slight reduction of the body weight and reduction of the blood pressure. What is advantageous is its quite unique mechanism of action, complementary to the effect of other types of antidiabetic treatment, as well as the fact that administration of dapagliflozin does not cause hypoglycaemia.

Background Art

Dapagliflozin is first mentioned in the patent application WO2001027128, which does not mention any details of the character of the solid form of the product. The patent application WO2002083066 describes preparation of cocrystals of dapagliflozin with (L)-proline and (L)- phenylalanine. The amorphous form of dapagliflozin is described by the patent applications WO2003099836, WO2004063209 and WO2013064909. The application WO2008002824 describes a crystalline monohydrate of an (^-propylene glycol solvate of dapagliflozin and the patent application WO2013079501 describes crystalline hydrates of dapagliflozin (hydrate and dihydrate). Disclosure of Invention

The amorphous form of dapaghflozin is easy obtainable by various preparatory processes. The glass transition temperature of amorphous dapaglifiozin is low. At higher temperatures and increased relative humidity the amorphous form of dapaglifiozin is not stable and its recrystallization and chemical degradation may occur. For stabilization of the amorphous form, solid solutions and dispersions with chemicals can be used that provide a higher glass transition value and thus higher chemical and polymorphic stability. Chemical compounds that can be used in this manner comprise polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, and preferably polymers. The prepared solid solution or solid dispersion then exhibits higher polymorphic and chemical stability at elevated temperatures and increased relative humidity. The invention provides a composition in the form of a melt, containing dapaglifiozin and at least one pharmaceutical excipient. The selection of the excipient for this rnixture is governed by the requirement for stability of the end product. A suitable excipient is such that will make the glass transition temperature of the final mixture higher than 40°C, preferably higher than 70°C. Preferred excipients are especially hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP K30, Soluplus™, PEG 6000, copovidone VA64, D (+) glucose, D (+) saccharose or urea.

Detailed description of the invention

A crystalline solid substance is characterized by a regular long-distance structure arrangement. On the other hand, amorphous solid substances do not exhibit this arrangement. The molecular arrangement of an amorphous solid substance may be represented by "frozen liquid" with rheological properties of a solid substance.

A solid composition, consisting at least of two components - the pharmaceutically active ingredient (API) and another at least one chemical compound (matrix), can have several forms. To make the explanation of used terms simpler, the matrix for API stabilization is considered to consist of one component only. In fact, this matrix may consist of one, two, or more components (chemical compounds). As components of a matrix for solid compositions, compounds of the type of polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea can be preferably used.

The term "solid dispersion" represents a solid composition of a pharmaceutically active ingredient (API) that is dispersed in a matrix, said matrix manifesting a crystalline character. In the case of dapagliflozin, a solid mixture with the polymer PEG 6000 behaves this way; measured by XRPD, the API shows an amorphous and the polymer a crystalline character.

A typical "amorphous solid dispersion" then represents a solid composition, where the pharmaceutically active ingredient and the matrix show an amorphous character in XRPD.

Measured by differential scanning calorimetry, this "amorphous solid dispersion" exhibits at least two glass transitions (Tg), one for the dispersed component (pharmaceutically active ingredient) and the other one for the matrix, the number of Tg's depending on the number of the components of the matrix.

If both the amorphous components (API and matrix) are mixed on the molecular level and the resulting solid mixture shows just one glass transition temperature (Tg) in differential scanning calorimetry, this is a special solid composition, referred to as a "solid solution".

As mentioned above, compared to crystalline solid substances, amorphous solid substances have a different internal structure and a larger surface area, and therefore they exhibit a higher solubility. If the solubility and bioavailability of pharmaceutically active substances needs to be increased, it is preferable to prepare them in an amorphous form.

If the temperature of a crystalline material reaches the melting point, its phase changes from the solid phase to the liquid phase. When this melt is cooled again, the crystalline structure is restored. However, if the melt is cooled at a sufficiently high rate, crystallization may be prevented by formation of a subcooled solution. The subcooled solution is cooled to achieve the glass transition (Tg), the molecules are kinetically frozen and the subcooled liquid solidifies into glass. Molecules in a subcooled liquid have a much higher mobility than in the vitreous state, as described by Remington in the publication: The Science and Practice of Pharmacy, Pharmaceutical Press, 21^nd edition.

Since molecules in the vitreous state also exhibit certain mobility, it is advantageous for the glass transition temperature to be at least 20°C, preferably 30°C and most preferably at least 40°C above the temperature of the actual storage conditions. For this reason, the amorphous form of the API should be preferably stabilized by increasing of the glass transition temperature (Tg) to prevent re-crystallization and chemical degradation. By preparing a solid mixture we are able to increase this glass transition temperature to prepare the API in a form that will be polymorphically and chemically more stable at elevated temperatures and higher relative humidity.

The glass transition temperature of amorphous dapaghflozin is 24°C and in its non-stabilized condition it is subject to chemical degradation during storage at an elevated temperature and humidity. For this reason, the amorphous form of dapagliflozin should be preferably stabilized by increasing of the glass transition temperature (Tg) to prevent chemical degradation and recrystallization. The prepared solid mixture then exhibits higher polymorphic and chemical stability at elevated temperatures and increased relative humidity.

A possibility of stabilizing amorphous dapagliflozin consists in creating solid compositions with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably especially with polymers. These polymers may come from the group of polymers that are soluble or insoluble in water. Typical water-soluble polymers for stabilization of dapagliflozin are polyvinyl pyrrolidone (povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, copolymers of polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (Soluplus™) and the like. Typical water-insoluble polymers for stabilization of dapagliflozin are methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate, carboxymethyl cellulose and the like. An advantage of these polymers is the fact that their solubility is dependent on the pH value of the solution and their use makes it possible to influence releasing of the pharmaceutically active ingredient depending on pH of the alimentary tract.

There are a number of preparation methods of stabilized amorphous forms of dapagliflozin.

One of the preparation methods of stabilized amorphous forms of dapagliflozin consists in the dissolution process. In a common dissolution process the active substance is dissolved in a solvent or in any mixture of solvents. The solvent may be water or any organic solvent.

Methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, dichloromethane, tetrahydrofuran etc. may be mentioned as examples of suitable organic solvents. In the next step, a substance stabilizing the active pharmaceutical ingredient is added to this solution or suspension. The solvent is quickly removed and amorphous solid matter is produced. The solvent can be removed by means of a rotary vacuum evaporator, fluid granulation, spray drying, electrospinning, solvent freeze-drying etc. Other options of preparation of stabilized amorphous substances are methods without the use of a solvent In these processes the active pharmaceutical ingredient (dapagliflozm) is mixed with a stabilizing substance (for example, a polymer). This mixture is heated up and melted, producing a melt. Common temperatures for the formation of a melt vary in the range of 20°C - 40°C above the Tg temperature, where the mixture is melted and has a suitable viscosity for its processing. The melt is subsequently cooled down, which produces an amorphous solid substance. Hot melt extrusion, hot melt granulation, high shear mixer, fluid bed granulation without the use of a solvent etc. may be mentioned as some examples of these processes.

This invention focuses on the preparation of a pharmaceutical composition containing dapagliflozin with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably especially with polymers. For the preparation of polymer stabilized amorphous solid forms of dapagliflozin the following polymers can be advantageously used: polyvinyl pyrrolidone (PVP), copovidone ( ollidon VA64), hydroxypropyl celluloses (Klucel), hydroxypropyl methylcelluloses (Methocel), derivatized hydroxypropyl methylcelluloses (e.g. HP C AS), polymethacrylate derivatives (Eudragit LI 00, Eudragit SI 00) and copolymers of polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (Soluplus™).

The most commonly used polymers in this invention are polyvinyl pyrrolidone (PVP K30) with the molecular weight of approximately 50,000 Da (g mol), Methocel E5 (HPMC) with the molecular weight of approximately 22,000 Da (g/mol), Eudragit S100 with the molecular weight of approximately 125,000 Da (g/mol), copovidone (Kollidon VA64), hydroxypropyl cellulose (HPC, Klucel), Soluplus™ and hypromellose acetate succinate (HPMC AS-LF). Out of the group of saccharides and the other substances, glucose, saccharose, galactose or urea can be advantageously used.

For the preparation of the amorphous solid forms of dapagliflozin (API), the methods of removing the solvent by means of a rotary vacuum evaporator or lyophilization (freeze-drying of solvents) have been used. The products prepared this way are summarized in Table 1, together with the results of the DSC and X-ray powder analyses. Table 1:

The differential scanning calorimetry (DSC) measurement makes it possible to distinguish a solid dispersion and a solid solution. In the case of a solid solution an amorphous solid only exhibits one glass transition value (Tg) in the record. The prepared amorphous solids in the weight ratio of 1 : 2 (API : polymer) formed stable solid solutions whose stability increases with an increasing Tg value (Hancock and Zografi, 1997).

The results of the DSC analyses confirmed that dapagliflozin forms more stable solid solutions with HPC (fig. 1), HPMC (fig. 2), HPMC AS (fig. 3), PVP 30 (fig. 4), Soluplus™ (fig. 6) and copovidone VA64 (fig. 7). In the case of PV K30. we managed to prepare both a solid solution characterized by one glass transition temperature (fig. 4), and an amorphous solid dispersion that has two glass transition temperatures (fig. 5).

Comparison of the Tg values from the DSC measurements has shown that dapagliflozin forms the most stable solid solutions with the polymers povidone PVP K30 (Tg = 106.7 °C) and copovidone VA64 (Tg = 76.9 °C).

The results of the X-ray powder analysis showed that dapagliflozin forms stable amorphous solid forms with the polymers HPC (fig. 11), HPMC (fig. 12), HPMC AS (fig. 13), PVP K30 (fig. 14), Soluplus™ (fig. 15) and copovidone VA64 (fig. 16).

Load tests were used to check and compare stability of amorphous dapagliflozin and prepared solid solutions. The glass transition temperature of amorphous dapagliflozin is 24°C. To illustrate the comparison of behaviour under load conditions, solid solutions with different glass transition temperatures were selected, namely 76.9°C (Copovidone VA64) and 106.7°C (PVP K30).

Amorphous dapagliflozin is chemically unstable and under high temperature and humidity load the molecule gets degraded and the contents of impurities increases. Its chemical purity degraded from the original 96.7% (HPLC) to 95.4% (HPLC). In term of polymorphic purity, amorphous dapagliflozin is stable and is not subject to recrystallization (see Table 2).

Table 2:

Amorphous dapagliflozin stabilized in the form of a solid solution with Copovidone VA64 exhibits polymorphic stability under load conditions and no crystallization of the API occurs as in the case of non-stabilized amorphous dapagliflozin. Composition in the form of a solid solution with copovidone VA64 has a positive influence on chemical stability of dapagliflozin (see Table 3).

Amorphous dapagliflozin stabilized in the form of a solid solution with PVP K30 exhibits polymorphic stability under load conditions and only being exposed to extreme humidity (10 days, 100% humidity), partial crystallization of the API occurs. Chemical stability of amorphous dapagliflozin is also significantly improved by composition in the solid solution form and significant increase of the contents of impurities only occurs in case of extreme exposure to humidity (10 days, 100% humidity) (see Table 4).

Table 3:

Solid solution of dapagliflozin - Copovidone VA64, Tg = 76.9°C HPLC = 96.76%

X-ray HPLC

25°C, 0% RH, 10 days amorphous API 96.46%

25°C, 100% RH, 10 days amorphous API 96.76%

50°C, 0% RH, 3 days amorphous API 96.25%

50°C, 75% RH, 3 days amorphous API 96.76% 70°C, 0% RH, 3 days amorphous API 96.01%

70°C, 75% RH, 3 days amorphous API 96.75%

Table 4:

Solid solution of dapagiiflozin - PVPK30, Tg = 106.7°C, HPLC= 96.21%

X-ray HPLC

25°C, 0% RH, 10 days amorphous API 96.21%

25°C, 100% RH, 10 days amorphous API with an admixture of

95.74%

crystalline API

50°C, 0% RH, 3 days amorphous API 96.14%

50°C, 75% RH, 3 days amorphous API 96.20%

70°C, 0% RH, 3 days amorphous API 95.95%

70°C, 75% RH, 3 days amorphous API 96.21%

Amorphous dapagiiflozin can also be stabilized by means of saccharides, oligosaccharides, polysaccharides, fats, waxes or urea. In particular, D-glucose, D-saccharose or urea were tested. D-glucose and urea generally occur in their crystalline form; therefore, in combination with dapagiiflozin D-glucose and urea do not form typical solid solutions, but solid dispersions wherein the amorphous API (dapagiiflozin) is dispersed in a crystalline matrix (D- glucose or urea). Subjected to DSC analysis, these solid dispersions exhibit the glass transition of the amorphous API (dapagiiflozin) and the melting point of D-glucose or urea. In the case of D-saccharose, a typical solid solution is formed showing one glass transition record in the DSC analysis record. The DSC and X-ray powder analyses of the mixtures of dapagiiflozin with the saccharides and urea are summarized in Table 5. Table S:

Amorphous dapaglifiozin stabilized in the form of a solid dispersion with D-glucose shows a glass transition temperature (Tg = 24.9°C) and a melting point (Tm = 132.1°C) in the DSC analysis record (fig. 8). The X-ray powder pattern then, besides the amorphous halo of the API (dapaglifiozin), shows a visible crystalline form of d-glucose (fig. 17).

Amorphous dapaglifiozin stabilized in the form of a solid solution with D- saccharose exhibits, in the DSC analysis record, one glass transition, Tg = 36.7°C, recrystallization occurs at 95.2° C and the melting temperature is 141.1°C (fig. 9). Just an amorphous halo is visible in the X-ray powder diffraction pattern (fig. 18).

Amorphous dapaglifiozin stabilized in the form of a solid dispersion with urea shows a glass transition temperature (Tg = 24.2°C) and a melting point (Tm = 122,3 °C) in the DSC analysis record (fig. 10). The X-ray powder pattern then, besides the amorphous halo (dapaglifiozin), shows a visible crystalline form of urea (fig. 19).

The prepared amorphous solid substances containing dapaglifiozin, stabilized by polymers, saccharides, oligosaccharides, polysaccharides or urea in accordance with this invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets. Such pharmaceutical mixtures can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline 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.

Brief Description of Drawings

Fig. 1: DSC record of the solid solution of dapaglifiozin - HPC

Fig.2: DSC record of the solid solution of dapaglifiozin - HPMC

Fig. 3: DSC record of the solid solution of dapaglifiozin - HPMC AS

Fig. 4: DSC record of the solid solution of dapaglifiozin - PVP K30

Fig. 5: DSC record of the amorphous solid dispersion of dapaglifiozin - PVP K30

Fig. 6: DSC record of the solid solution of dapaglifiozin - Soluplus™

Fig. 7: DSC record of the solid solution of dapaglifiozin - Copovidone VA64

Fig. 8: DSC record of the amorphous solid dispersion of dapaglifiozin - D-(+)-glucose

Fig. 9: DSC record of the solid solution of dapaglifiozin - D-(+)-saccharose

Fig. 10: DSC record of the solid dispersion of dapaglifiozin - urea

Fig. 11: XRPD pattern of the solid solution of dapaglifiozin - HPC Fig. 12: XRPD pattern of the solid solution of dapagliflozin - HPMC

Fig. 13: XRPD pattern of the solid solution of dapagliflozin - HPMC AS

Fig. 14: XRPD pattern of the solid solution of dapagliflozin - PVP K30

Fig. 15: XRPD pattern of the solid solution of dapagliflozin - Soluplus™

Fig. 16: XRPD pattern of the solid solution of dapagliflozin - Copovidone VA64

Fig. 17: XRPD pattern of the solid dispersion of dapagliflozin - D-(+)-glucose

Fig. 18: XRPD pattern of the solid solution of dapagliflozin - D-(+)-saccharose

Fig. 19: XRPD pattern of the solid dispersion of dapagliflozin - urea Examples

Amorphous dapagliflozin was prepared according to the procedure published in the patent application WO2003099836. The chemical purity of dapagliflozin prepared this way was 96.7% (HPLC).

Example 1

Preparation of an amorphous solid form of dapagliflozin with hydroxypropyl cellulose

500 mg of dapagliflozin was weighed into a 50ml flask together with 1 g of hydroxypropyl cellulose. The mixture was dissolved in a mixture of dichloromethane and methanol at an elevated temperature and under stirring. The completely clear solution was stirred for another 30 minutes at an elevated temperature and subsequently it was completely evaporated on a rotary vacuum evaporator. The final product was further dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 27.9°C and its X-ray powder pattern is shown in fig. 11.

Example 2

Preparation of an amorphous solid form of dapagliflozin with hydroxypropyl methylcellulose

500 mg of dapagliflozin was weighed into a 50ml flask together with 1 g of hydroxypropyl methylcellulose. The mixture was dissolved in a mixture of dichloromethane and methanol at an elevated temperature and under stirring. The completely clear solution was stirred for another 30 minutes at an elevated temperature and subsequently it was completely evaporated on a rotary vacuum evaporator. The final product was dissolved in a mixture of the solvents terf-butanol - water, freeze-dried in liquid nitrogen and lyophilized for 20 hours. The glass transition temperature of the solid solution prepared this way is 54.9°C, at approx. 118.4°C the amorphous API starts to recrystallized to a crystalline for with the melting point Tm 213.4°C. The X-ray powder pattern of the solid solution of dapagliflozin - hydroxypropyl methylcellulose is shown in fig. 12.

Example 3

Preparation of an amorphous solid form of dapagliflozin with hypromellose acetate succinate

2.5 mg of dapagliflozin was weighed into a 250ml flask together with 5 g of hydroxypropyl methylcellulose acetate succinate The mixture was dissolved in a mixture of dichloromethane and methanol at an elevated temperature and under stirring. The completely clear solution was stirred for another 30 minutes at an elevated temperature and subsequently it was completely evaporated on a rotary vacuum evaporator. The final product was further dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 52.5°C. The X-ray powder pattern of the solid solution of dapagliflozin - hydroxypropyl methylcellulose acetate succinate is shown in fig. 13.

Example 4

Preparation of an amorphous solid form of dapagliflozin with povidone PVP K30

5 mg of dapagliflozin was weighed into a 500ml flask together with 10 g of povidone PVP K30. The mixture was dissolved in a mixture of dichloromethane and methanol at an elevated temperature and under stirring. The completely clear solution was stirred for another 30 minutes at an elevated temperature and subsequently it was completely evaporated on a rotary vacuum evaporator. The final product was further dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 106.7°C. The X-ray powder pattern of the solid solution of dapagliflozin - povidone PVP K30 is shown in fig. 14.

Example s

Preparation of an amorphous solid form of dapagliflozin with Soluplus™

500 mg of dapagliflozin was weighed into a 50ml flask together with 1 g of Soluplus™. The mixture was dissolved in a mixture of dichloromethane and methanol at an elevated temperature and under stirring. The completely clear solution was stirred for another 30 minutes at an elevated temperature and subsequently it was completely evaporated on a rotary vacuum evaporator. The final product was dissolved in a mixture of the solvents teri-butanol - water, freeze-dried in liquid nitrogen and lyophilized for 20 hours. The glass transition temperature of the solid solution prepared this way is 52.6°C. The X-ray powder pattern of the solid solution of dapagliflozin - Soluplus™ is shown in fig. 15.

Example 6

Preparation of an amorphous solid form of dapagliflozin with copovidone VA64

500 mg of dapagliflozin was weighed into a 50ml flask together with 1 g of copovidone VA64. The mixture was dissolved in a mixture of dichloromethane and methanol at an elevated temperature and under stirring. The completely clear solution was stirred for another 30 minutes at an elevated temperature and subsequently it was completely evaporated on a rotary vacuum evaporator. The final product was further dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 76.9°C and its X-ray powder pattern is shown in fig. 16.

Example 7

Pharmaceutical composition of the product

The following ingredients were placed into a homogenizer: solid solution of dapagliflozin - povidone PVP 30, anhydrous lactose, microcrystalline cellulose, ollidon CL and water. The mixture was homogenized for 15 min at 20 rpm. Finally, magnesium stearate and S1O2 was added and the mixture was homogenized for another 3 min at 20 rpm. 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 270 mg. The obtained cores may possibly be coated (a mixture of hypromellose, PEG, talc, titanium dioxide, iron oxide).

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: 0,02° 2Θ, 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 records of differential scanning calorimetry (DSC) were measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 μΐ.) was between 4-5 and 5 mg and the heating rate was 5°C/min, The temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 220°C at the heating rate of 5°C/min (amplitude = 0.8°C and period = 60 s). As the carrier gas 5.0 N₂ was used at the flow of 50 ml/min.

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

Device'. Waters Acquity UPLC, PDA detection

Sample preparation: 12.0 mg of the tested sample is dissolved in 20.0 ml of 20% acetonitrile

Column: - dimension: 1 = 0.10 m,□ = 2.1 mm

- stationary phase: Kinetex CI 8 (Phenomenex), 1.7 μιη particles

- column temperature: 15 °C.

Mobile phase: A: lOmM Ammonium dihydrogen phosphate, pH 2.5

B Acetonitrile

Gradient elution:

Time Flow rate % A % B

(min) (ml / min)

0 0.30 90 10 15 0.30 50 50

18 0.30 20 80

20 0.30 20 80

21 0.30 90 10

23 0.30 90 10

Detection: spectrophotometer 225

Injected quantity: 1.0 μΐ

Sample temperature: 20°C

Sample concentration: 0.6 mg / ml

Claims

1. A composition in the form of a melt, characterized in that it contains dapagliflozin and at least one pharmaceutically acceptable excipient.

2. The composition in accordance with claim 1, characterized in that it contains amorphous dapagliflozin.

3. The composition in accordance with claim 1 or 2, characterized in that the glass transition temperature of the melt is at least 40°C.

4. The composition in accordance with claim 1 or 2, characterized in that the glass

transition temperature of the melt is at least 70°C.

5. The composition in accordance with claim 1 or 2, characterized in that the glass

transition temperature of the melt is at least 100°C.

6. The composition in accordance with claims 3 to 5, characterized in that the pharmaceutically acceptable excipient is selected from the group consisting of polymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea.

7. The composition in accordance with claim 6, characterized in that the pharmaceutically acceptable excipient is a polymer, saccharide or urea.

8. The composition in accordance with claim 7, characterized in that the pharmaceutically acceptable excipient is hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP K30, Soluplus™, PEG 6000, copovidone VA64, D-(+) glucose, D-(+) saccharose or urea.

9. The composition in accordance with claim 8, characterized in that the pharmaceutically acceptable excipient is copovidone VA64 or PVP K30.

10. The composition in accordance with any one of the preceding claims, characterized in that dapagliflozin contained therein exhibits a characteristic amorphous halo with the use of the CuKa X-ray radiation.

11. The composition in accordance with any one of the preceding claims, characterized in that the content of the active pharmaceutical ingredient to the pharmaceutically acceptable excipient is in a weight ratio of 1 : 1 to 1 : 5, preferably 1 : 2.

12. A process of preparing the composition in the form of a melt as defined in claims 1 to 11, comprising dissolution of dapagliflozin with a suitable polymer, saccharide or urea in a suitable organic solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran and their mixtures, and subsequent removal of the solvent to produce an amorphous mixture.

13. A process of preparing a dapagliflozin composition in accordance with claim 12, characterized in that the solvent is methanol, dichloromethane or their rnixture.

14. A process of preparing the composition in the form of a melt as defined in claims 1 to 11, comprising mixing of dapagliflozin with a suitable polymer, saccharide or urea and subsequent heating up of this mixture to give a melt and to form an amorphous mixture.

15. A process of preparing a dapagliflozin composition in accordance with claim 14, characterized in that the polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP 30, Soluplus™, PEG 6000, copovidone VA64, D-(+) glucose, D-(+) saccharose and urea.

16. Use of amorphous dapagliflozin with a polymer, saccharide or urea in accordance with claims 1 to 8 for the preparation of a pharmaceutically acceptable composition.