CZ2015834A3 - The solid form of dapagliflozin - Google Patents

Abstract

The present invention relates to a solid form of dapagliflozin of formula I, in particular dapagliflozin co-crystal form I-4 with L-proline, a process for its preparation and use in a dosage form. This solid form may advantageously be used to increase chemical and polymorphic purity. At the same time, this form increases both chemical and polymorphic stability and prevents dapagliflozin degradation. Another solution is a pharmaceutical composition comprising dapagliflozin co-crystal form I-4 with L-proline.

Description

Solid form of dapagliflozin

Technical field

The invention relates to a new solid form of dapagliflozin of formula I, to a process for its preparation and to its use in a dosage form. This solid form can advantageously be used to increase chemical and polymorphic purity. At the same time, this form increases both chemical and polymorphic stability and prevents dapagliflozin degradation.

(AND)

Dapagliflozin is a highly selective inhibitor of the SGLT2 (sodium glucose co-transporter 2) transporter, which is responsible for renal glucose reabsorption. Inhibition of SGLT2 by dapagliflozin results in increased renal glucose excretion and consequently reduced glycemia and improved diabetes compensation. Dapagliflozin is currently approved in Europe for use in type 2 diabetics in monotherapy (for metformin intolerance), possibly in combination with other antidiabetics, including insulin. Administration of dapagliflozin not only results in improved diabetes control, but also in a slight decrease in body weight and a decrease in blood pressure. The advantage is a completely unique mechanism of action complementary to that of other types of antidiabetic therapy and also the fact that the administration of dapagliflozin does not induce hypoglycaemia.

BACKGROUND OF THE INVENTION

For the first time, dapagliflozin-like substances are mentioned in patent application WO2001027128, in which nothing is more specific to the nature of the solid form of the product.

WO2002083066 describes the preparation of co-crystals of substances similar to dapagliflozin with amino acids, in particular L-proline 1: 2 and L-phenylalanine 1: 1. These types of co-crystals in this publication were not applied to dapagliflozin alone.

The amorphous form of dapagliflozin is described in WO2003099836, WO2004063209 and WO2013064909.

WO2008002824 describes crystalline dapagliflozin (S ' -propylene glycol solvate) and crystalline dapagliflozin hydrates in patent application WO2013079501.

A ······························································· ··············································· (hydrate and dihydrate). At the same time, WO2008002824 mentions co-crystals with L-proline and L-phenylalanine. For co-crystals with L-phenylalanine, the patent application only mentions preparation, the solid form being characterized only by a 1: 1 ratio of pharmaceutically active substance (API): L-phenylalanine. For L-proline co-crystals, the patent application describes both the preparation of co-crystals and the solid forms of the obtained products. Forms N1 (molar ratio API: L-proline = 1: 2), N1 (molar ratio API: L-proline = 1: 1) and form H5-2 (molar ratio API: L-proline = 1: 2) are described herein. ). These three forms are described in the patent application by XRPD.

SUMMARY OF THE INVENTION

The present invention provides a new solid form of the co-crystal of dapagliflozin and L-proline in a molar ratio of API: L-proline = 1: 2 of formula II.

COOH

(Π)

This form is chemically stable and did not show chemical degradation and impurity growth even under stress conditions. Its water solubility is very good and is therefore suitable for use in a dosage form. This new solid form also has good crystallinity and is therefore suitable for purifying the product.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a new solid form of the co-crystal of dapagliflozin and L-proline (1-4), which is stable and excels in good crystallinity.

Form 1-4 exhibits a distinctly crystalline nature. An X-ray powder pattern of this salt is shown in Figure 1. Characteristic diffraction patterns using CuKα radiation are 4.3; 14.3; 18,2 a

23.2 ± 0.2 ° 2-theta. Form 1-4 further exhibits these characteristic reflections of 6.2; 13.2; 16.0; 18,9 a

24.5 ± 0.2 ° 2-theta. Diffraction peaks with relative intensity greater than 15% are shown in Table 1.

Table 1: Diffraction peaks of Form 1-4

Location [° 2Th.] Interplanar distance [Á] []] = 0.1 nm Rel. intensity [%] 4.32 20,419 100.0 6.21 14,224 31.9 8.49 10,407 11.5 13.19 6,708 17.6 14.29 6,195 31.2 16.04 5,522 19.0 16.79 5,277 10.7 17.17 5,162 6.1 18.23 4,862 34.4 18.87 4,698 20.5 19.81 4,477 17.9 20.06 4,422 15.4 20.46 4,337 15.8 22.36 3,973 6.2 23.24 3,824 14.6 23.64 3,761 5.8 24.53 3,626 11.7 25.65 3,470 5.1 26.59 3,350 3.5 27.39 3,253 2.4 27.76 3,211 2.9 29.12 3,064 1.9 29.86 2,990 1.9 30.24 2,953 2.4 32.19 2,778 3.6

DSC analysis showed the melting point of the form 1-4 103 ° C. According to thermogravimetric analysis (TGA), Form 1-4 contains 1.34% water.

The dapagliflozin-L-proline form 1-4 co-crystals showed a molar ratio of dapagliflozin: L-proline = 1: 2, which was confirmed by NMR analysis.

···· · ··· · ··· · ·

Dapagliflozin forms a 1-4 co-crystal with proline in a molar ratio of dapaglifiosin to proline of 1: 2. It is therefore ideal to use substances in this ratio at approximately this ratio. The range may range from a molar ratio of dapagliflozin to proline of 0.5: 2 to 1.5: 2, preferably 0.9: 2

1.1: 2.

Preparation of Form 1-4 comprises the following steps:

and / mixing dapagliflozin and L-proline in the form of solutions;

b) removing solvents from the mixture of step a).

Dapagliflozin dissolution may range from 20 ° C to the boiling point of the solvent. Conventional organic solvents such as alcohols, preferably methanol, ethanol, 2-propanol or 1-propanol, are suitable for dissolving dapagliflozin. The dissolution of L-proline can take place in a mixture of water and an organic solvent, e.g. water and alcohol, at a temperature of from 20 ° C to the boiling point of the solvent. The two solutions are mixed at elevated temperature, ideally at 50 ° C to 90 ° C. Subsequently, the mixture is stirred for 10-60 minutes at this temperature and then slowly cooled to 0 ° C to 30 ° C, preferably in the range of 20 ° C to 25 ° C and allowed to crystallize. During cooling, crystallization can be initiated by seeding. Advantageously, the co-crystal yield can be increased by the addition of an antisolvent, e.g., a target, butyl methyl ether. The co-crystal may be isolated either directly by filtration, or may be followed by concentration of the mixture or evaporation of the solvents.

The rate of addition of the dapagliflozin solution is important for the formation of crystalline Form 1-4. The addition must be carried out so that the concentration of the two reactants is constant at all times in the mixing vessel throughout the addition. In other words, there must be no concentration difference between the individual sites in the stirred vessel. In practice, for example, about 500 ml, a solution of 50-100 g / l dapagliflozin is added at a rate of 20-80 ml / minute.

When the reaction is carried out in aqueous isopropanol, Form 1-4 is already precipitated during the addition of the dapagliflozin solution to the proline solution. At the beginning of the addition, the reaction mixture is in the form of a clear solution. At the end of the addition, however, the reaction mixture began to harden and the product began to precipitate as a white precipitate. The advantage of this procedure is not the necessity to inoculate the reaction mixture.

Form 1-4 of dapagliflozin and proline is generally produced in at least 80% yield, preferably in 90% yield, whereby the chemical purity, as measured by HPLC, is not lower than the chemical purity of the input dapagliflozin. Conversely, the chemical purity of Form 1-4 is significantly higher than that of the input dapagliflozin. Therefore, dapagliflozin Form 1-4 with proline can advantageously be used to purify crude dapagliflozin.

Form 1-4 can be advantageously used to enhance the chemical purity of dapagliflozin. This form crystallizes well and frees dapagliflozin impurities. At formation of Form 1-4 from the amorphous form of dapagliflozin, the chemical purity increased from 99.00% (starting amorphous form) to 99.92% (final form 1-4). Also, the recrystallization of Form 1-4 alone increases chemical purity from the original 99.51% to the final 99.98% (HPLC).

Compared to the amorphous form, Form 1-4 is far more chemically stable. Under load conditions (70 ° C, 75% RH, 3 days), the chemical purity (HPLC) of the amorphous form changed from the original 99.83% to the final 97.41%. Under the same conditions, the chemical purity remained unchanged and retained an input value of 99.89% (HPLC).

The prepared form L-proline dapagliflozin 1-4 co-crystal of the present invention can be used in 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 (eg lactose), binders (eg microcrystalline cellulose), disintegrants (eg croscarmellose sodium), lubricants (eg magnesium stearate), surfactants, etc. These tablets may be coated with conventional coatings such as polyvinyl alcohol or polyethylene glycol.

Two forms of co-crystal of dapagliflozin with L-phenylalanine were also prepared. Both forms, forms 1-5 in a ratio of 1: 2 and 1-6 in a ratio of 1: 8, exhibit a distinctly crystalline nature.

The dapagliflozin cocrystal with L-phenylalanine has several advantages over the amorphous form, the SC-3 form (the (S) -1,2-propanediol solvate form of WO2008002824) as well as the Lproline cocrystal. First, it does not excel in such high hygroscopicity as the other mentioned forms. The amorphous form is very hygroscopic, the maximum water sorption is 12% and shows flowability. Form SC-3 is stable up to 50% relative humidity, containing less than 1% water. At conditions above 50% relative humidity, its maximum water sorption is 29%. The L-proline co-crystal is stable up to 60% relative humidity, absorbing 41% water above this level. The dapagliflozin-L-proline co-crystal contains under 0.5% water under standard conditions up to 60% relative humidity. The water absorption of the co-crystal of dapagliflozin with L-phenylalanine is constant. At a common humidity of 50 - 60%, this co-crystal contains 1.5% of water and its maximum water sorption is only 2.2%.

The co-crystal of dapagliflozin with L-phenylalanine shows high physical and chemical stability. In the stress tests (80 ° C / 75% RH / 3 days), its solid form (XRPD) and chemical purity (HPLC) remain unchanged.

The X-ray powder pattern of dapagliflozin Form L-phenylalanine Form 1-5 is shown in Figure 2. The characteristic diffraction patterns of Form 1-5 using CuKα radiation are 3.9; 6.2; 11.8; 17.2;

20.7 ± 0.2 ° 2-theta. Form 1-5 further exhibits these characteristic reflections of 5.7; 15.1; 19,7 a

21.3 ± 0.2 ° 2-theta. The diffraction peaks of Form 1-5 with a relative intensity greater than 15% are shown in Table 2.

Table 2: Diffraction peaks of Form 1-5

Location [° 2Th.J Interplanar distance []] []] - 0.1 nm Rel. intensity [%] 3.92 22,520 100.0 5.68 15,543 13.4 6.18 14,286 21.8 8.67 10,191 3.4 11.80 7,491 6.1 14.56 6,079 2.7 15.14 5,847 6.5 16.38 5,406 4.0 16.72 5,300 2.4 17.24 5,139 33.0 18.07 4,904 7.5 19.26 4,605 5.1 19.71 4,500 14.8 20.07 4,420 6.8 20.68 4,293 18.8 21.34 4,161 14.8 22.82 3,895 4,5 23.18 3,834 6.0 23.49 3,784 4.1 23.71 3,749 4.4 24.18 3,678 4.3 25.28 3,520 3.8 25.58 3,479 2.5 27.11 3,286 5.4 27.75 3,212 4.4 29.31 3,045 2.1 31.05 2,878 4.0

DSC analysis showed the melting point of dapagliflozin-L-phenylalanine co-crystal form 1-5.

132 [deg.] C. According to thermogravimetric analysis (TGA), form 1-5 of the dapagliflozin-L-phenylalanine co-crystal contains 2.5% water.

The X-ray powder pattern of dapagliflozin Form 1-6 with L-phenylalanine is shown in Figure 3. The characteristic diffraction patterns of Form 1-6 using CuKα radiation are 6.5; 14,8 a

21.4 ± 0.2 ° 2-theta. Form 1-6 further exhibits these characteristic reflections of 8.9; 10.6; 17,2 a

26.2 ± 0.2 ° 2-theta. The diffraction peaks of Form 1-6 with a relative intensity greater than 15% are shown in Table 3.

Table 3: Diffraction peaks of Form 1-6

Location [° 2Th.J Interplanar distance []] []] = 0.1 nm Rel. intensity [%] 6.48 13.62 79.9 8.94 9.88 20.6 10.64 8.30 19.6 14.78 5.99 100.0 16.05 5,52 14.1 17.18 5.16 19.3 17.56 5,05 13.3 17.95 4.94 11.1 19.54 4.54 10.3 19.74 4.49 7.4 21.38 4.15 63.5 23.77 3.74 12.1 24.30 3.66 13.3 25.57 3.48 9.9 26.18 3.40 27.4 27.61 3.23 13.0 32.92 2.72 11.4

Molar ratios were determined by NMR measurements.

For the purposes of the following and the foregoing, the term "room temperature" means a temperature range from ° C to 26 ° C.

Overview of pictures

Giant. 1: XRPD form record 1-4

Giant. 2: XRPD pattern record 1-5

Giant. 3: XRPD pattern of Form 1-6

The invention is illustrated by the following examples. These examples, which illustrate the improvement of the process according to the invention, are purely illustrative and do not limit the scope of the invention in any way.

Examples

Dapagliflozin was prepared according to the procedure disclosed in patent application WO2003099836. The chemical purity of the dapagliflozin thus prepared was 99.0% (HPLC). ¹ H and ¹³ C NMR spectra confirmed the structure of dapagliflozin. Both XRPD and DSC record confirmed amorphous form.

Example 1

Preparation of Form 1-4

L-proline (269 mg, 2.34 mmol) was dissolved in 0.24 mL of water at elevated temperature (80-85 ° C). To the clear solution was slowly added dapagliflozin solution (500 mg,

1.23 mmol) in 2.34 ml of 2-propanol. The resulting solution was slowly cooled (10 ° C per hour) to room temperature. Allow to stir overnight at room temperature. The crystals were aspirated, washed with 2-propanol and dried in a vacuum oven at 40 ° C overnight. Form 1-4 crystals with a chemical purity of 99.94% (HPLC) were obtained.

Example 2

Preparation of Form 1-4

L-proline (2.69 g, 23.4 mmol) was dissolved in 2.4 mL of water at elevated temperature (80-85 ° C). A solution of dapagliflozin (5 g, 12.2 mmol) in 23.5 mL of 2-propanol was slowly added to the clear solution with rapid stirring. The resulting solution was slowly cooled (20 ° C per hour) to room temperature. At 45-50 ° C, the solution was seeded with Form 1-4 prepared according to Example 1. Stir at room temperature overnight. The crystals were aspirated, washed with 2-propanol and dried in a vacuum oven at 40 ° C overnight. 6.0 g of Form 1-4 crystals with a chemical purity of 99.89% (HPLC) were obtained.

Example 3

Preparation of Form 1-4

L-proline (538 mg, 4.67 mmol) was dissolved in a mixture of 3 mL of ethanol and 0.4 mL of water. A solution of dapagliflozin (1 g, 2.45 mmol) in 3 mL of ethanol was slowly added to the clear solution with rapid stirring. The resulting solution was stirred at 80 ° C for 10 minutes, then cooled slowly (20 ° C per hour) to 30 ° C. At 45-50 ° C, the solution was seeded with Form 1-4 prepared according to Example 1. At 30 ° C, the mixture was stirred for 2 hours and then 15 ml of tert-butyl methyl ether was added dropwise over 15 minutes with rapid stirring. The mixture was cooled in an ice bath and stirred for 2 hours. The resulting crystals were filtered, washed with a target, butyl methyl ether and dried in a vacuum oven at 40 ° C overnight. 1.4 g of Form 1-4 crystals with a chemical purity of 99.87% (HPLC) were obtained.

Example 4

Preparation of Form 1-4

L-proline (11 g, 0.096 mol) was dissolved in a mixture of 10 ml water and 50 ml 2-propanol at 80 ° C. A solution of dapagliflozin (20 g, 0.049 mol) in 250 ml of 2-propanol was added dropwise to the clear solution with rapid stirring over 5 minutes. Towards the end of the dropwise addition, the reaction mixture became cloudy and solid product began to precipitate. After dropwise addition of the dapagliflozin solution, the reaction mixture was stirred for 30 minutes at 80 ° C, followed by slow cooling (20 ° C per hour) to room temperature. The mixture was allowed to crystallize at room temperature for 2 hours. The resulting crystals were filtered, washed with 2-propanol and dried in a vacuum oven at 40 ° C overnight. 27 g of Form 1-4 crystals with a chemical purity of 99.91% (HPLC) were obtained.

Example 5

Preparation of the mold 1-5

L-phenylalanine (4.04 g, 24.46 mmol) dissolved at 80 ° C in 100 mL water. A solution of dapagliflozin (5 g, 12.23 mmol) in 20 mL of ethanol was added dropwise with rapid stirring. The resulting reaction mixture was stirred for an additional 20 minutes at 85-90 ° C and then cooled (20 ° C per hour) to room temperature. Over the weekend let it crystallize in the fridge. The solid was aspirated, washed with ethanol and dried in a vacuum oven at 40 ° C overnight. 8.2 g of form 1-5 co-crystals of dapagliflozin with L-phenylalanine in molar porn 1: 2 were obtained.

Example 6

Preparation of mold 1-6 · · ··· · ··· · ··· · · ··· · · · · · · · · · · · · · · · · · · · · · · · · · «·····

L-phenylalanine (202 mg, 1.22 mmol) was dissolved in 4 mL of water at 80 ° C. To this solution was added a solution of dapagliflozin (500 mg, 1.22 mmol) in 2 mL of ethanol. Stir 10 min at 80 ° C, then allow to cool (10 ° C per hour) to room temperature and then cool in an ice bath for 1 hour. The solid was filtered and dried in a vacuum oven at 40 ° C overnight. 80 mg of dapagliflozin-L-phenylalanine co-crystal form 1-6 were obtained in a molar ratio of 1: 8.

Example 7

Pharmaceutical product composition - core

Substance Amount - core / mg / dapagliflozin-L-proline co-crystal 15.6 Lactose anhydrous 60.0 Microcrystalline cellulose 160.0 Kollidon CL 10.0 Magnesium stearate 2.5 SiO ₂ 2.5

Raw materials were added to the homogenizer: dapagliflozin-L-proline cocrystal, anhydrous lactose, microcrystalline cellulose, Kollidon CL and water. The mixture was homogenized for 15 min at 20 rpm. Finally, magnesium stearate and SiO ₂ were added and the mixture was homogenized for an additional 3 min at 20 rpm. The above-formed tablet was compressed on a rotary tablet and used to produce cores of approximately 250 mg. The resulting cores may optionally be coated (a mixture of hypromellose, PEG, talc, titanium dioxide, iron oxide).

List of analytical methods

XRPD measurement parameters: Diffractograms were measured on X'PERT PRO MPD PANalytical diffractometer, CuKa radiation (λ = 1.542 Å), excitation voltage: 45 kV, anode current: 40 mA, measuring range: 2 - 40 ° 20, step size: 0.01 ° 20, the measurement was performed on a flat powder sample that was applied to a Si plate. Programmable divergence orifices with irradiated sample area of 10 mm, Soller 10 were used for primary optics adjustment

• 0.02 rad iris diaphragms and anti-scatter iris' λ ⁰ . The XOelerator detector with a maximum opening of the detection slot, a 0.02 rad Soller diaphragm and a 5.0 mm anti-scattering aperture were used for secondary optics adjustment.

Differential Scanning Calorimetry (DSC) records were recorded on a DSC Pyris 1 instrument from Perkin Elmer. The sample weighed into a standard Al crucible (40 µL) was between 2-3 mg and a heating rate of 10 ° C / min. The temperature program used was composed of a stabilization minute at 20 ° C and then from heating to 260 ° C at a heating rate of 10 ° C / min. 4.0 N ₂ at a flow rate of 20 ml / min was used as the carrier gas.

Thermogravimetric analysis (TGA) records were recorded on a TGA 6 instrument from Perkin Elmer. The sample weighed into the corundum crucible was 19-21 mg and the heating rate was 10 ° C / min. The temperature program that was used consists of 1 stabilization minute at 20 ° C and then heating to 300 ° C at a heating rate of 10 ° C / min. 4.0 N ₂ at a flow rate of 20 ml / min was used as the carrier gas.

Chemical purity was measured by liquid chromatography (HPLC):

Apparatus'. Waters Acquity UPLC, PDA detection Sample preparation: Dissolve 12.0 mg of the test sample in 20.0 ml of 20% acetonitrile Column: - dimension: 1 = 0.10 m, 0 = 2.1 mm

- stationary phase: Kinetex C1 8 (Phenomenex), 1.7 µm particles

column temperature: 15 ° C.

Mobile Phase: A: 10 mM Ammonium dihydrogen phosphate, pH 2.5

B: Acetonitrile

Gradient elution:

IN Time (min) Flow rate (ml / min) % A % B 0 0.30 90 10 15 Dec 0.30 50 50 18 0.30 20 May 80 20 May 0.30 20 May 80 21 0.30 90 10 23 0.30 90 10

Detection:

Injection:

Sample temperature:

spectrophotometer 225 nm

1.0 μΐ ° C

Sample concentration: 0.6 mg / ml

Claims (9)

PATENT CLAIMS A dapagliflozin-L-proline co-crystal form 1-4 showing characteristic reflections in an X-ray powder record using CuKα radiation of 4.3; 14.3; 18.2 and 23.2 ± 0.2 ° 2-theta. The dapagliflozin-L-proline co-crystal form 1-4 of claim 1, exhibiting further characteristic reflections in an X-ray powder record using CuKα radiation 6.2; 13.2; 16.0; 18.9 and 24.5 ± 0.2 ° 2-theta. The dapagliflozin-L-proline co-crystal form 1-4 of claims 1 and 2, wherein its melting point is 101.5 to 104.5 ° C. A process for preparing Form 1-4 as defined in claims 1 to 3, comprising the steps of: a) mixing dapagliflozin and L-proline in the form of solutions; b) removing solvents from the mixture of step a). Process according to claim 4, characterized in that the solvents in step a) are conventional organic solvents and / or water, preferably mixtures of alcohols and water. The method according to claim 4 or 5, characterized in that the alcoholic solution of dapagliflozin is gradually added to the aqueous or aqueous-alcoholic L-proline solution. The process according to claim 6, wherein the solvent is an alcohol C1 to C4. Method according to claims 6 or 7, characterized in that the alcoholic solution of dapagliflozin is added at a rate such that the concentrations of both proline and dapagliflozin in the whole volume are the same throughout the addition. Method according to claims 4 to 8, characterized in that filtration, spray-drying is used to remove the solvent from the mixture in step b) or it can be followed by concentration of the mixture or evaporation of the solvents.