WO2016206660A1

WO2016206660A1 - Solid forms of amorphous canagliflozin

Info

Publication number: WO2016206660A1
Application number: PCT/CZ2016/000070
Authority: WO
Inventors: Iva OBADALOVA; Hana TOZICKOVA; Ondrej Dammer; Lukas KREJCIK; Jakub Hert
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2015-06-25
Filing date: 2016-06-24
Publication date: 2016-12-29
Anticipated expiration: 2017-12-25
Also published as: CZ2015435A3

Abstract

The invention relates to novel solid forms of amorphous canagliflozin, having the chemical name (1S)-1,5 -anhydro- 1 - [3 - [[5-(4-fluorophenyl)-2-thienyl]-methyl]-4-methylphenyl]-D- glucitol, their preparation methods and use in a dosage form. These solid forms of amorphous canagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous canagliflozin.

Description

Solid forms of amorphous canagliflozin

Technical Field

The invention relates to novel solid forms of amorphous canagliflozin of formula I, having the chemical name (15)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]-methyl]-4- methylphenyl]-D-glucitol, their preparation methods and use in a dosage form. These solid forms of amorphous canagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous canagliflozin.

(I)

Canagliflozin is a highly selective inhibitor of the common transporter of sodium and glucose of type 2 (SGLT2), responsible for renal reabsorption of glucose. Inhibition of SGLT-2 with the use of canagliflozin increases excretion of glucose by the kidneys, which leads to a decrease of glycaemia and an improvement of diabetes compensation virtually without any increase of the risk of hypoglycaemia. This is a unique action mechanism that is completely independent of the action of insulin. Currently, canagliflozin is approved in the U.S. and in Europe for treatment of type 2 diabetes mellitus in monotherapy (in case of intolerance to metformin), or in combination with other antidiabetic drugs, including insulin. Besides compensation of diabetes, administration of canagliflozin moderately reduces weight and the blood pressure. Thanks to its different action mechanism compared to other orally administered antidiabetic drugs and insulin canagliflozin may be a convenient choice in a combination treatment of diabetes.

Background Art

Canagliflozin and its preparation is described in the patent application WO05012326. The process described in this application provides amorphous canagliflozin. The amorphous form of canagliflozin is characterized by chemical and polymorphic instability. Further, two forms of canagliflozin hemihydrate are known, which are described in the patent applications WO2008069327 and WO2009035969. Canagliflozin hemihydrate described in the application WO2009035969 corresponds to the form that is present in the drug form Invokana . Also, cocrystals of canagliflozin are known, in particular with D- and L-proline, phenylalanine and citric acid, which are described in the patent applications WO2012154812 and WO 2013064909.

Disclosure of Invention

The amorphous form of canagliflozin is easy to obtain with the use of various preparation methods. However, at elevated temperatures and higher relative humidity it recrystallizes to the crystalline hemihydrate form, described in the patent application WO2009035969. For stabilization of the amorphous form of canagliflozin, solid compositions (solid dispersions, amorphous solid dispersions or solid solutions) with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea, preferably especially with polymers, can be used.

The invention provides solid forms of amorphous canagliflozin with at least one pharmaceutically acceptable excipient, which may be selected from the group of polymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea. Especially, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (HPMC AS), polyvinyl pyrrolidone (PVP), derivatives of polymethacrylate (Eudragit LI 00, Eudragit SI 00), the copolymer polyvinyl capro lactam - polyvinyl acetate - polyethylene glycol (PVAc-PVCap- PEG; Soluplus™), copovidone, D-saccharose.

These pharmaceutically acceptable excipients form solid solutions with canagliflozin that have a higher glass transition temperature than amorphous canagliflozin itself, which considerably supports its stability. The prepared solid solutions then exhibit higher polymorphic and chemical stability at elevated temperatures and increased relative humidity.

Detailed description of the invention

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

Thus, compared to crystalline solids, amorphous solids have a different internal structure and a larger surface area, and therefore they exhibit a higher solubility. In case the solubility and bioavailability of pharmaceutically active substances needs to be increased, they should be preferably prepared in an amorphous form.

Since molecules in the amorphous form 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. In case of a low glass transition temperature of an amorphous form there is a higher risk of transition to another form (e.g. crystalline), or increase of the contents of impurities, degradants. The glass transition temperature of an amorphous form can be increased by formation of a solid composition with another, more stable substance. Then, the prepared composition generally exhibits higher polymorphic and chemical stability.

A solid composition, consisting at least of two components, the active pharmaceutical 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, pharmaceutically acceptable excipients, i.e. for example 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 an active pharmaceutical ingredient (API) that is dispersed in a matrix, while this matrix manifests a crystalline character. Thus, in a solid dispersion, the API is present in an amorphous form and the matrix (e.g. polymer) in a crystalline form. In a DSC analysis, a solid dispersion is characterized by the glass transition temperature of the amorphous API and the melting point of the crystalline matrix.

A typical "amorphous solid dispersion" then represents a solid composition where the active pharmaceutical ingredient (API) and the matrix show an amorphous character, measured by XRPD. Measured by differential scanning calorimetry, this "amorphous solid dispersion" exhibits at least two glass transitions (Tg), one for the dispersed component (active pharmaceutical ingredient) and the other one for the matrix, the number of glass transitions of the matrix depending on the number of the components of the matrix.

If both the amorphous components (API and matrix) are thoroughly mixed on the molecular level and the resulting solid composition shows just one glass transition temperature (Tg), measured by differential scanning calorimetry, it is a special solid composition, referred to as a "solid solution". In the case of a solid solution, the components, as mentioned above, are intermixed on the molecular level, which ensures the best stabilization of the amorphous API. The differential scanning calorimetry (DSC) measurement makes it possible to distinguish a solid dispersion, an amorphous solid dispersion and a solid solution. From the stability point of view, the intermixing on the molecular level is ideal as it enables improved stabilization of the API. This means that the solid solution form is more advantageous for stabilization and it is preferred to a dispersion. In the case of a solid solution, the amorphous solid only exhibits one glass transition temperature (Tg) in the record, while in the case of an amorphous solid dispersion the DSC record exhibits two glass transitions, separately for the API and the excipient.

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 down 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^st edition.

As mentioned above, 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. The glass transition temperature of amorphous canaglifiozin is 41°C and in its non-stabilized condition it is subject to crystallization during storage. For this reason, the amorphous form of canaglifiozin should be preferably stabilized by increasing of the glass transition temperature (Tg) to prevent said crystallization. The prepared solid composition of canaglifiozin is then more stable at elevated temperatures and at an increased relative humidity.

A possibility of stabilizing amorphous canaglifiozin consists in creating solid compositions with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or 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 canaglifiozin include polyvinyl pyrrolidone (PVK 30 povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, the copolymer polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (PVAc-PVCap-PEG; Soluplus™), and the like. Typical water-insoluble polymers for stabilization of canagliflozin include methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMC AS), cellulose acetate phthalate, carboxymethylcellulose etc. An advantage of these polymers is represented by 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 canagliflozin. One of the preparation methods of stabilized amorphous forms of canagliflozin 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. As examples of suitable organic solvents, methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, dichloromethane, tetrahydrofuran etc. may be mentioned. 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 include solvent-free processes. In these processes the active pharmaceutical ingredient (canagliflozin) is mixed with a stabilizing substance (e.g. 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 to 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. As some examples of these processes, hot melt extrusion, hot melt granulation, high shear mixer, solvent-free fluid bed granulation, etc., may be mentioned.

This invention is directed to the preparation of a pharmaceutical composition containing amorphous canagliflozin with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea, preferably especially with polymers. The following polymers can be advantageously used for the preparation of polymer-stabilized amorphous solid forms of canagliflozin: polyvinyl pyrrolidone (PVP), copovidone (Kollidon VA64), hydroxypropyl celluloses ( lucel), hydroxypropyl methylcelluloses (Methocel), derivatized hydroxypropyl methylcelluloses (e.g. HPMC AS), derivatives of polymethacrylate (Eudragit LI 00, Eudragit SI 00), and the copolymer polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (PVAc-PVCap- PEG; 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 SI 00 with the molecular weight of approximately 125,000 Da (g/mol), copovidone (KoUidon 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 canagliflozin (API), the method of removing the solvent by means of a rotary vacuum evaporator or lyophilization (freeze-drying of solvents) was used. With regard to relatively high dosage of canagliflozin, the weight ratio of canagliflozin to the excipient of 1 : 1 was preferentially selected. 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 results of the X-ray powder analysis showed that canagliflozin creates stable amorphous solid forms with the polymers HPC, HPMC, HPMC AS, PVP K30, Eudragit SI 00, Soluplus™, PEG 6000 and copovidone VA64.

In the case of stabilization by means of the excipient PEG 6000, a solid dispersion was obtained where the API is present in the composition in an amorphous form and the excipient in a crystalline form. In this case, the DSC record shows the melting point of the crystalline excipient (PEG 6000) and the X-ray powder pattern confirmed absence of crystalline API. In the case of the other excipients conventional solid solutions were obtained whose stability increases with an increasing Tg value (Hancock and Zografi, 1997).

A comparison of the Tg values from the DSC measurements showed that canagliflozin forms the most stable solid solutions with the polymers HPMC AS (Tg = 66.8°C), copovidone VA64 (79.3°C) and the solid solution of canagliflozin - PVP K30 with the glass transition temperature Tg = 101.4°C appears to be the most stable one.

Load tests were used to check and compare stability of amorphous canagliflozin and prepared solid solutions. The glass transition temperature of amorphous canagliflozin is 41°C. To illustrate the comparison, solid solutions with different glass transition temperatures were selected, namely 66.8°C (HPMC AS), 79.3°C (Copovidone VA64) and 101.4°C (PVP K30). During storage of non- stabilized amorphous canagliflozin, higher temperatures and presence of humidity has to be avoided due to its instability; otherwise the amorphous form crystallizes through to a mixture of an amorphous and crystalline form or to a fully crystalline form. At the same time, the molecule of amorphous canagliflozin degrades and the content of impurities increases (see Table 2).

Table 2:

Amorphous canagliflozin stabilized in the form of a solid solution by Copovidone VA64 exhibits polymorphic stability under nearly all loading conditions. Only when loaded by 100% humidity for 10 days, its form changes from amorphous to crystalline. Samples that preserved their amorphous character were also checked for chemical purity and the results, which are summarized in Table 3, indicate a significant influence of humidity. The solid solution of canagliflozin - Copovidone VA64 exhibits chemical stability under anhydrous conditions. Table 3:

Amorphous canagliflozin stabilized in the form of a solid solution by Povidone PVP K30 is the most stable one of all the tested samples from the chemical and polymorphic point of view. Partial crystallization of the amorphous API only occurs when loaded by 100% humidity for 10 days. The solid solution of canaglifozin - Povidone PVP K30 is chemically stable under most conditions. All the samples that preserved their amorphous character were checked for chemical purity and a more significant increase of the content of impurities only occurred under extreme loading by the temperature of 80% and 75% relative humidity (see Table 4).

Table 4:

Amorphous canagliflozin can also be advantageously 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 canagliflozin D-glucose and urea do not form typical solid solutions, but solid dispersions where the amorphous API (canagliflozin) 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 (canagliflozin) 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 temperature in the DSC analysis record. The DSC and X-ray powder analyses of the mixtures of canagliflozin with the saccharides and urea are summarized in Table 5.

Table 5:

Amorphous canagliflozin stabilized in the form of a solid dispersion by D-glucose shows the glass transition temperature of canagliflozin (Tg = 44.3°C) and the melting point of D-glucose (Tm = 136.9°C) in the DSC analysis record (Fig. 9). Then, besides the amorphous halo of the API (canagliflozin), a crystalline form of D-glucose can be seen in the X-ray powder pattern (Fig. 23). This composition of canagliflozin with D-glucose was also successfully prepared in the form of a solid solution; its X-ray powder diffraction pattern is shown in Figure 20.

Amorphous canagliflozin stabilized in the form of a solid solution by D-saccharose exhibits, in the DSC analysis record, one glass transition, Tg = 53.0°C, recrystallization of amorphous D- saccharose to the crystalline form with the melting point of 181.9°C occurring at the temperature T_reCrys ⁼ 100.2°C (Fig. 10). Just the amorphous halo is visible in the X-ray powder diffraction pattern (Fig. 21).

Amorphous canagliflozin stabilized in the form of a solid dispersion by urea shows the glass transition temperature of canagliflozin (Tg = 30.3°C) and the melting point of urea (Tm = 122.8°C) in the DSC analysis record (Fig. 11). In the X-ray powder diffraction record, the crystalline form of urea only can be seen (Fig. 22).

The solid solution of canagliflozin - D-saccharose was also monitored by load tests. Partial conversion of the amorphous form of canagliflozin to a crystalline form was observed under the load of increased humidity. In case of anhydrous conditions (e.g. use of a desiccant or packing under nitrogen) this prepared solid solution of canagliflozin - D-saccharose is polymorphically stable even at elevated temperatures. Only the samples that preserved their amorphous character were tested for chemical purity; chemical purity only got worse in the case of the sample loaded by 80°C. The results of the tests are summarized in Table 6.

Table 6

Pharmaceutically acceptable excipients from the group of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (HPMC AS), polyvinyl pyrrolidone (PVP), derivatives of polymethacrylate (Eudragit LI 00, Eudragit SI 00), the copolymer polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (PVAc-PVCap- PEG; Soluplus™), copovidone, D-saccharose, with which a solid solution where the ingredients are mixed on the molecular level was successfully prepared, thus ensuring the best stabilization of the amorphous API, have proved to be especially suitable.

The solid solutions according to the invention can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets. Such pharmaceutical compositions 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 canagliflozin - HPC

Fig. 2: DSC record of the solid solution of canagliflozin - HPMC Fig. 3: DSC record of the solid solution of canagliflozin - HPMC AS

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

Fig. 5: DSC record of the solid solution of canagliflozin - Eudragit SI 00

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

Fig. 7: DSC record of the solid dispersion of canagliflozin - PEG6000

Fig. 8: DSC record of the solid solution of canagliflozin - Copovidone VA64

Fig. 9: DSC record of the solid dispersion of canagliflozin - D-glucose

Fig. 10: DSC record of the solid solution of canagliflozin - D-saccharose

Fig. 11: DSC record of the solid dispersion of canagliflozin - urea

Fig. 12: XRPD pattern of the solid solution of canagliflozin - HPC

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

Fig. 14: XRPD pattern of the solid solution of canagliflozin - HPMC AC

Fig. 15: XRPD pattern of the solid solution of canagliflozin - PVP K30

Fig. 16: XRPD pattern of the solid solution of canagliflozin - Eudragit SI 00

Fig. 17: XRPD pattern of the solid solution of canagliflozin - Soluplus™

Fig. 18: XRPD pattern of the solid dispersion of canagliflozin - PEG6000

Fig. 19: XRPD pattern of the solid solution of canagliflozin - Copovidone VA64

Fig. 20: XRPD pattern of the solid solution of canagliflozin - D-glucose

Fig. 21: XRPD pattern of the solid solution of canagliflozin - D-saccharose

Fig. 22: XRPD pattern of the solid dispersion of canagliflozin - urea

Fig. 23: XRPD pattern of the solid dispersion of canagliflozin - D-glucose

Examples

Crystalline canagliflozin was prepared according to the procedure published in the patent application WO05012326. The chemical purity of canagliflozin prepared this way was 99.9% (HPLC). Example 1

Preparation of an amorphous solid form of canagliflozin with hydroxypropyl cellulose

500 mg of canagliflozin was weighed into a 50ml flask together with 500 mg 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 at an elevated temperature for another 30 minutes and subsequently it was completely evaporated in a rotary vacuum evaporator. The evaporation product was dissolved in a mixture of the solvents tert-butanol - water, freeze-dried in liquid nitrogen and lyophilized for 20 hours. The glass transition temperature of the solid solution prepared this way is 40.5°C (Fig. 1) and its X-ray powder pattern is shown in Figure 12.

Example 2

Preparation of an amorphous solid form of canagliflozin with hydroxypropyl methylcellulose

500 mg of canagliflozin was weighed into a 50ml flask together with 500 mg 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 at an elevated temperature for another 30 minutes and subsequently it was completely evaporated in a rotary vacuum evaporator. The final product was dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 54.6°C (Fig. 2). The X-ray powder pattern of the solid solution of canagliflozin - hydroxypropyl methylcellulose is shown in Figure 13.

Example 3

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

2.5 g of can canagliflozin was weighed into a 250ml flask together with 2.5 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 at an elevated temperature for another 45 minutes and subsequently it was completely evaporated in a rotary vacuum evaporator. The final product was dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 66.8°C (Fig. 3). The X-ray powder pattern of the solid solution of canagliflozin - hydroxypropyl methylcellulose acetate succinate is shown in Figure 14. Example 4

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

5 g of canagliflozin was weighed into a 500ml flask together with 5 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 at an elevated temperature for another 50 minutes and subsequently it was completely evaporated in a rotary vacuum evaporator. The final product was dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 101.4°C (Fig. 4). The X- ray powder pattern of the solid solution of canagliflozin - povidone PVP K30 is shown in Figure 15.

Example 5

Preparation of an amorphous solid form of canagliflozin with Eudragit S100

500 mg of canagliflozin was weighed into a 50ml flask together with 500 mg Eudragit SI 00. The mixture was dissolved in a mixture of dichloromethane and methanol at an elevated temperature and under stirring. The completely clear solution was stirred at an elevated temperature for another 30 minutes and subsequently it was completely evaporated in a rotary vacuum evaporator. The final product was dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 56.4°C (Fig. 5). The X- ray powder pattern of the solid solution of canagliflozin - Eudragit SI 00 is shown in Figure 16.

Example 6

Preparation of an amorphous solid form of canagliflozin with Soluplus™

500 mg of canagliflozin was weighed into a 50ml flask together with 500 mg 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 at an elevated temperature for another 30 minutes and subsequently it was completely evaporated in a rotary vacuum evaporator. The final product was dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 51.1 °C (Fig. 6). The X- ray powder pattern of the solid solution of canagliflozin - Soluplus™ is shown in Figure 17. Example 7

Preparation of an amorphous solid form of canagliflozin with PEG6000

500 mg of canagliflozin was weighed into a 50ml flask together with 500 mg of PEG6000. The mixture was dissolved in a mixture of dichloromethane and methanol at an elevated temperature and under stirring. The completely clear solution was stirred at an elevated temperature for another 30 minutes and subsequently it was completely evaporated in a rotary vacuum evaporator. The evaporation product was dissolved in a mixture of the solvents tert- butanol - water, freeze-dried in liquid nitrogen and lyophilized for 20 hours. In the DSC record the obtained solid dispersion exhibits the melting point of PEG6000 of 28.5°C (Fig. 7) and its X-ray powder pattern is shown in Figure 18.

Example 8

Preparation of an amorphous solid form of canagliflozin with copovidone VA64

500 mg of canagliflozin was weighed into a 50ml flask together with 500 mg 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 at an elevated temperature for another 30 minutes and subsequently it was completely evaporated in a rotary vacuum evaporator. The evaporation product was dissolved in a mixture of the solvents tert-butanol - water, freeze-dried in liquid nitrogen and lyophilized for 20 hours. In the DSC record the obtained solid solution exhibits the glass transition temperature of 79.3°C (Fig. 8) and its X-ray powder pattern is shown in Figure 19.

Example 9

Preparation of an amorphous solid form of canagliflozin with D-saccharose

2.5 g of canagliflozin was weighed into a 250ml flask together with 2.5 g of D-saccharose. The mixture was dissolved in a mixture of dichloromethane and methanol at an elevated temperature and under stirring. The completely clear solution was stirred at an elevated temperature for another 45 minutes and subsequently it was completely evaporated in a rotary vacuum evaporator. The final product was dried in a vacuum drier at 40°C for 12 hours. The glass transition temperature of the solid solution prepared this way is 53.0°C, at 100.2°C the amorphous saccharose starts to recrystallize to its crystalline form with the melting point of 181.9°C (Fig. 10). The X-ray powder pattern of the solid solution of canagliflozin - D- saccharose is shown in Figure 21. Example 10

Pharmaceutical composition of the product - core

The following ingredients were charged into a homogenizer: solid solution of canagliflozin - povidone PVP K30, lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium crosscarmellose and water. The mixture was homogenized at 20 rpm for 15 min. Finally, magnesium stearate and Si0₂ 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 255 mg. The obtained cores may possibly be coated (a mixture of hypromellose, titanium oxide, 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 to 40° 20, increment: 0.02°/300 s, 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 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 rate of 50 ml/min.

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

Device-. Waters Acquity UPLC, PDA detection

Sample preparation: Dissolve 10.0 mg of the tested sample in 20.0 ml of 80% methanol Column: - dimension: 1 = 0.10 m, 0 = 2.1 mm

- stationary phase: Pinnacle Biphenyl (Restek), 1.9 μηι particles

- column temperature: 60°C.

Mobile phase: A: 10 mM Ν¾Η₂Ρ0₄ pH 2.50

B: methanol

Gradient elution:

Detection: spectrophotometer 220

Injection: 1.0 μΐ

Sample temperature: 20°C

Sample concentration: 0.5 mg / ml

Claims

1. A solid solution of amorphous canagliflozin, characterized in that it contains at least one pharmaceutically acceptable excipient.

2. The solid solution according to claim 1, characterized in that the pharmaceutically acceptable excipient is selected from the group comprising polymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea.

3. The solid solution according to claim 2, characterized in that it exhibits a glass transition temperature higher than 40°C (Tg > 40°C).

4. The solid solution according to claim 1 to 3, characterized in that the pharmaceutically acceptable excipient is selected from the group comprising hydroxypropyl cellulose - HPC, hydroxypropyl methylcellulose - HPMC, hypromellose acetate succinate - HPMC AS, polyvinyl pyrrolidone - PVP K30, derivatives of polymethacrylate - Eudragit L100, Eudragit SI 00, the copolymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol - PVAc-PVCap-PEG; Soluplus™, copovidone, and D-saccharose.

5. The solid solution according to claim 4, characterized in that the pharmaceutically

acceptable excipient is the polymer HPMC AS.

6. The solid solution according to claim 5, characterized in that it exhibits the glass

transition temperature of 66.8 (± 3)°C (Tg = 66.8 ± 3°C).

7. The solid solution according to claim 4, characterized in that the pharmaceutically

acceptable excipient is the polymer copovidone.

8. The solid solution according to claim 7, characterized in that it exhibits the glass

transition temperature of 79.3 (± 3)°C (Tg = 79.3 ± 3°C).

9. The solid solution according to claim 4, characterized in that the pharmaceutically

acceptable excipient is the polymer PVP K30.

10. The solid solution according to claim 9, characterized in that it exhibits the glass

transition temperature of 101.4 (± 3)°C (Tg = 101.4 ± 3°C).

11. The solid solution according to claim 4, characterized in that the pharmaceutically

acceptable excipient is the polymer hydroxypropyl cellulose HPC.

12. The solid solution according to claim 11, characterized in that it exhibits the glass

transition temperature of 40.5 (± 3)°C (Tg = 40.5 ± 3°C).

13. The solid solution according to claim 4, characterized in that the pharmaceutically

acceptable excipient is the polymer hydroxypropyl methylcellulose HPMC.

14. The solid solution according to claim 13, characterized in that it exhibits the glass transition temperature of 54.6 (± 3)°C (Tg = 54.6 ± 3°C).

15. The solid solution according to claim 4, characterized in that the pharmaceutically

acceptable excipient is the polymer Eudragit S 100.

16. The solid solution according to claim 15, characterized in that it exhibits the glass

transition temperature of 56.4 (± 3)°C (Tg = 56.4 ± 3°C).

17. The solid solution according to claim 4, characterized in that the pharmaceutically

acceptable excipient is the polymer PVAc-PVCap- PEG - Soluplus™.

18. The solid solution according to claim 17, characterized in that it exhibits the glass

transition temperature of 51.1 (± 3)°C (Tg = 51.1 ± 3°C).

19. The solid solution according to claim 4, characterized in that the pharmaceutically

acceptable excipient is the oligosaccharide D-saccharose.

20. The solid solution according to claim 19, characterized in that it exhibits the glass

transition temperature of 53.0 (± 3)°C (Tg = 53.0 ± 3°C).

21. The solid solution according to any one of the preceding claims, characterized in that it contains the active pharmaceutical ingredient - API and a pharmaceutically acceptable excipient in the weight ratio of 1 : 0.5 to 1 : 5, preferably 1 : 1 to 1 : 2 (API : pharmaceutically acceptable excipient).

22. A method for preparing the solid solution as defined in claims 1-21, characterized in that it comprises dissolution of the canagliflozin and a pharmaceutically acceptable excipient in a solvent selected from the group comprising methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, water and mixtures thereof, and subsequent removal of the solvent to produce a solid solution.

23. The method according to claim 22, characterized in that the solvent is methanol, dichloromethane or a mixture thereof.

24. A method for preparing the solid solution as defined in claims 1-21, characterized in that it comprises mixing of canagliflozin with a pharmaceutically acceptable excipient, subsequent heating of this mixture, producing a melt, and cooling the melt to produce a solid solution.

25. Use of the solid solution according to any one of the preceding claims for the preparation of a pharmaceutically acceptable composition.