WO2016169534A1

WO2016169534A1 - Solid forms of amorphous empagliflozin

Info

Publication number: WO2016169534A1
Application number: PCT/CZ2016/000049
Authority: WO
Inventors: Iva OBADALOVA; Hana TOZICKOVA; Ondrej Dammer; Lukas KREJCIK; Jakub Hert
Original assignee: Zentiva, K. S.
Priority date: 2015-04-24
Filing date: 2016-04-21
Publication date: 2016-10-27
Also published as: CZ2015279A3

Abstract

The present invention relates to novel forms of amorphous empagliflozin of formula I, with the systematic name (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]- methyl] phenyl]-6-(hydroxy-methyl)oxane-3,4,5-triol, processes for preparing the same and the use thereof in dosage forms. These solid forms of amorphous empagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous empagliflozin.

Description

Solid forms of amorphous empagliflozin

Technical Field

The invention relates to novel solid forms of amorphous empagliflozin of formula I, with the systematic name (2S,3R,4R,5S,6R)-2-[4-chloro-3- [[4-[(3S)-oxolan-3-yl]oxyphenyl]raethyl]- phenyl]-6-(hydroxy-methyl)oxane-3,4,5-triol, to processes for preparing the same and to use in dosage forms. These solid forms of amorphous empagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous empagliflozin.

00

Empagliflozin is an orally administered antidiabetic, designed for the treatment of type 2 diabetes mellitus. The mechanism of its action consists in inhibition of the sodium glucose co- transporter (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. It 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 empagliflozin 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 amorphous form of empagliflozin is easy obtainable by various preparative processes. However, at elevated temperatures and higher relative humidity it recrystallizes to the only known crystalline form described in the patent application WO2006117359. For stabilization of the amorphous form of empagliflozin, solid compositions (solid dispersions or solid solutions) with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably especially with polymers, can be used. These pharmaceutically acceptable excipients form solid compositions with empagliflozin that have a higher glass transition temperature than amorphous empagliflozin itself, which considerably contributed to its stability. The prepared solid solutions or solid dispersions then exhibit higher polymorphic and chemical stability both at elevated temperatures and increased relative humidity.

The invention provides a composition in the form of a melt, containing empagliflozin and at least one pharmaceutical excipient. The selection of the excipient for this composition is governed by the requirement for stability of the end product. A preferred excipient is such wherein the final composition achieves a glass transition temperature higher than 40°C, even better higher than 70°C. Preferred excipients are especially hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP K30, Soluplus™, PEG 6000 or copovidone VA64.

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.

Thus, 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, they should be preferably prepared in an amorphous form.

Since molecules in the amorphous form have 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 of 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.

A typical "amorphous solid dispersion" then represents a solid composition where both 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, where the number of glass transitions of the matrix depends 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 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".

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. The 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 empagliflozin is 44°C and, in its non-stabilized condition it is subject to crystallization during storage at an elevated temperature and humidity. For this reason, the amorphous form of empagliflozin should be preferably stabilized by increasing of the glass transition temperature (Tg) to prevent re-crystallization. The prepared solid composition of empagliflozin then exhibits polymorphic and chemical stability at elevated temperatures and increased relative humidity.

A possibility of stabilizing amorphous empagliflozin 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 empagliflozin are polyvinyl pyrrolidone (povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol copolymers (Soluplus™), and the like. Typical water-insoluble polymers for stabilization of empagliflozin are methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMC AS), cellulose acetate phthalate, carboxymethyl ethyl 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 empagliflozin. A dissolution process is one of the preparation methods of stabilized amorphous forms of empagliflozin. 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 are solvent-free processes. In these processes the active pharmaceutical ingredient (empagliflozin) 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 - 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, solvent-free fluid bed granulation, etc. may be mentioned as some examples of these processes.

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

The most commonly used polymers in this invention are polyvinyl pyrrolidone (PVP K30) with the molecular weight of approx. 50,000 Da (g/mol), Methocel E5 (HPMC) with the molecular weight of approx. 22,000 Da (g/mol), Eudragit SI 00 with the molecular weight of approx. 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 empagliflozin (API), the method of removing the solvent by means of a rotary vacuum evaporator or lyophilization (freeze-drying of solvents) was 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 results of the X-ray powder analysis showed that empagliflozin forms stable amorphous solid forms with the polymers HPC, HPMC, HPMCAS, PVP K30, Soluplus™, and copovidone VA64.

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 substance only exhibits one glass transition value (Tg) in the record. The prepared amorphous solid substances in the weight ratio of 1 : (API : polymer) formed stable solid solutions whose stability increases with an increasing Tg value (Hancock and Zografi, 1997).

Comparison of the Tg values from the DSC measurements has shown that empagliflozin forms the most stable solid solutions with the polymers copovidone VA64 (Tg = 81.5°C) and PVP K30 (Tg = 117.9°C).

Load tests were used to check and compare stability of amorphous empagliflozin and the solid solutions prepared. Amorphous empagliflozin has the glass transition temperature of 44°C. To illustrate the comparison, solid solutions with different glass transition temperatures were selected, namely 61.7°C (HPMC AS), 81.5°C (Copovidone VA64) and 117.9°C (PVP K30). Empagliflozin is highly chemically stable and when loaded, just a slight increase of impurities occurs. Concerning the polymorphic purity, the situation is different.

Non-stabilized amorphous empagliflozin was only stable, in terms of polymorphic stability, at 50°C and under anhydrous conditions. Under all the other conditions, the anhydrous form started to crystallize and either a mixture of the amorphous and crystalline forms or a fully crystalline form was obtained (see Table 2). Table 2:

In the case of amorphous empagliflozin stabilized in the form of a solid solution with HPMC AS, partial crystallization of amorphous empagliflozin occurs at a combination of the conditions of increased humidity and temperature. When the sample is extremely loaded by 100% humidity for 10 days, the substance completely changes its form from amorphous to crystalline. From the chemical point of view the solid solution of empagliflozin - HPMC AS is stable under all conditions (see Table 3).

Table 3:

Amorphous empagliflozin stabilized in the form of a solid solution by Copovidone VA64 exhibits polymorphic and chemical stability under nearly all loading conditions. Only when loaded by 100%» humidity for 10 days, its form completely changes from amorphous to crystalline. From the chemical point of view the solid solution of empagliflozin - Copovidone VA64 is stable under all conditions (see Table 4).

Table 4:

Amorphous empagliflozin stabilized in the form of a solid solution by Povidone PVP K30 is chemically and polymorphically the most stable of all the tested samples and only when loaded by 100% humidity for 10 days, partial crystallization of the amorphous API occurs. The solid solution of empagliflozin - Povidone K30 is chemically stable under all conditions (see Table 5).

Table 5:

The prepared amorphous solid substances containing empagliflozin, stabilized by polymers, saccharides, oligosaccharides, polysaccharides or urea in accordance with this invention, can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets. Such pharmaceutical compositions may 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 coatings, e.g. polyvinyl alcohol or polyethylene glycol.

Brief Description of Drawings

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

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

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

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

Fig. 5: DSC record of the solid solution of empagliflozin - Soluplus™

Fig. 6: DSC record of the solid solution of empagliflozin - Copovidone VA64

Fig. 7: XRPD pattern of the solid solution of empagliflozin - HPC

Fig. 8: XRPD pattern of the solid solution of empagliflozin - HPMC

Fig. 9: XRPD pattern of the solid solution of empagliflozin - HPMC AS

Fig. 10: XRPD pattern of the solid solution of empagliflozin - PVP K30

Fig. 11: XRPD pattern of the solid solution of empagliflozin - Soluplus™

Fig. 12: XRPD pattern of the solid solution of empaglifiozin - Copovidone VA64

Examples

Crystalline empagliflozin was prepared according to the procedure published in the patent application WO2006/117359. The chemical purity of empagliflozin prepared this way was 99.2% (HPLC), after re-purification 99.8% (HPLC).

Example 1

Preparation of an amorphous solid form of empagliflozin with hydroxypropyl cellulose

500 mg of empagliflozin 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 in 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 29.9°C and its X-ray powder pattern is shown in Fig. 7.

Example 2

Preparation of an amorphous solid form of empagliflozin with hydroxypropyl methylcellulose

500 mg of empagliflozin 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 in a rotary vacuum evaporator. The final product was dissolved in a mixture of the solvents fe -butanol - water, freeze-dried in liquid nitrogen and lyophilized for 20 hours. The glass transition temperature of the solid solution prepared this way is 56.5°C, at approx. 119°C the amorphous API starts to recrystallize to a crystalline form with the melting point Tm 194.0°C. The X-ray powder pattern of the solid solution of empagliflozin - hydroxypropyl methylcellulose is shown in Fig. 8.

Example 3

Preparation of an amorphous solid form of empagliflozin with hypromellose acetate succmate

2.5 mg of empagliflozin 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 in 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 72.1°C. The X-ray powder pattern of the solid solution of empagliflozin - hydroxypropyl methylcellulose acetate succinate is shown in Fig. 9.

Example 4

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

5 mg of empagliflozin 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 in 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 117.9°C. The X-ray powder pattern of the solid solution of empagliflozin - povidone PVP K30 is shown in Fig. 10.

Example 5

Preparation of an amorphous solid form of empagliflozin with Soluplus™

500 mg of empagliflozin 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 in a rotary vacuum evaporator. The final 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 54,1°C. The X-ray powder pattern of the solid solution of empagliflozin - Soluplus™ is shown in Fig. 11.

Example 6

Preparation of an amorphous solid form of empagliflozin with copovidone VA64

500 mg of empagliflozin 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 in 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 56.1°C and its X-ray powder pattern is shown in Fig. 12. Example 7

Pharmaceutical composition of the product - core

The following ingredients were placed into a homogenizer: solid solution of empagliflozin - PVP K30, lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose and water. The mixture was homogenized for 15 min at 20 rpm. Finally, magnesium stearate and Si0₂ 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 250 mg. The obtained cores may possibly be coated (a mixture of hypromellose, titanium oxide, iron oxide).

Outline of analytic methods

Measurement parameters of XRPD: The diffractograms 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: 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 urn particles

- column temperature: 40°C.

Mobile phase: A: 0.1% HCOOH

B: methanol

Gradient elution:

Detection: spectrophotometer 225 nm

Injected amount: 1 μΐ

Sample temperature: 8°C

Sample concentration: 0.7 mg / ml

Claims

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

2. The composition according to claim 1, characterized in that it contains amorphous empagliflozin.

3. The composition according to claim 1, characterized in that the pharmaceutically acceptable excipient is selected from the group consisting of polymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea.

4. The composition according to claim 3, characterized in that the pharmaceutically acceptable excipient is a polymer.

5. The composition according to claim 4, characterized in that the pharmaceutically acceptable excipient is hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP K30, Soluplus™, copovidone VA64, D- (+) glucose, D-(+) saccharose or urea.

6. The composition according to claim 5, characterized in that the pharmaceutically acceptable excipient is povidone PVP 30 and/or copovidone VA64.

7. The composition according to any one of the preceding claims, characterized in that it exhibits the glass transition temperature Tg > 40°C.

8. The composition according to any one of preceding claims, characterized in that it exhibits a characteristic amorphous halo with the use of the CuKa X-ray radiation.

9. The composition according to any one of preceding claims, characterized in that the active pharmaceutical ingredient : pharmaceutically acceptable excipient are prepared in a weight ratio of 1 : 1 to 1 : 5, preferably 1 : 2.

10. A process for preparing the empagliflozin composition as defined in claims 1 to 9, characterized in that it comprises dissolution of a mixture of empagliflozin and a pharmaceutically acceptable excipient in a suitable organic solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran and mixtures thereof, and subsequent removal of the solvent to form an amorphous composition.

11. The process for preparing the empagliflozin composition according to claim 10, characterized in that the solvent is methanol, dichloromethane or their mixture.

12. The process for preparing the empagliflozin composition as defined in claims 1 to 9, characterized in that it comprises mixing of empagliflozin with a pharmaceutically acceptable excipient and subsequent heating up of this mixture to produce a melt and to form an amorphous composition.

13. The process for preparing the empagliflozin composition according to claims 10 and 12, characterized in that the pharmaceutically acceptable excipient is a polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP K30, Soluplus™ and copovidone VA64.

14. Use of the amorphous composition of empagliflozin with a pharmaceutically acceptable excipient according to claims 1 to 9 for the preparation of a pharmaceutically acceptable composition.