WO2015067223A1

WO2015067223A1 - L-tartrate salt of (1s,3s,5s)-2-[(2s)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and process for preparation thereof

Info

Publication number: WO2015067223A1
Application number: PCT/CZ2013/000145
Authority: WO
Inventors: Violetta Kiss; Ludek Ridvan; Marcela Tkadlecova; Ondrej Dammer; Lukas KREJCIK
Original assignee: Zentiva, K., S.
Priority date: 2013-11-06
Filing date: 2013-11-06
Publication date: 2015-05-14

Abstract

Tartrate salt of (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and a method for the preparation thereof.

Description

L-tartrate salt of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and process for preparation thereof

Background of the invention

1. Field of the invention

The present invention relates to a novel crystalline modification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate of

Formula I,

process for its preparation as well as said solid state form for use in phamaceutical compositions.

2. Background information

Saxagliptin is a dipeptidyl-peptidase-4 (DPP-4) receptor inhibitor used for the treatment of type 2 diabetes controlling the glucose (sugar) level of the blood. DPP-4 is an enzyme that control the incretin hormones. The level of the incretin hormones increases as an effect of saxagliptin and in parallel, pancreas produces more insulin and the amount of glucose produced by the liver decreases. These effects reduce the blood glucose level help in the control of type-2 diabetes.

Saxagliptin is disclosed in patent EP1261586.

Crystalline forms of saxagliptin free base and salts of hydrogen chloride, hydrogen bromide, hydrogen iodide, ammonium sulphate, nitric acid, benzoc acid, R-tartaric acid and fumaric acid various hydrated modifications thereof are discloesd in patent application WO2008131149.

Further crystalline modifications of saxagliptin hydrochloride with water content less than 1.5 % are described in patent application WO2010115974.

The hydrated phosphate salts of saxagliptin are disclosed in patent application WO2012017028. Anhydrous form of pharmaceutically acceptable salts with organic di-acids (maleate, L-malate, succinate) are disclosed in patent application WO2012017029. Further polymorphs (Forms K, T, Z, N S, 0, B, C and D) and the amorphous phase of saxagliptin hydrochloride are described with preparation process thereof in patent application WO2012047871.

Salts with methanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, (ftSj-lactic acid, maleic acid, (RSJ-malic acid, succinic acid and citric acid are disclosed in patent CN102086172.

Process for the preparation of amorphous saxagliptin hydrochloride in the presence of pharmaceutical excipient and organic acid is disclosed in patent WO2013136343.

Organic Process Research and Development 2009; 13; pages 1169-1176 describes saxagliptin as a compound that is unstable in solution and prone to the undergo an intra-molecular cyclization reaction to form a cyclic amidine.

Therefore the objective of the present invention to provide a novel crystalline modification of a L- tartrate salt of saxagliptin with good chemical purity and stability and good processability during its preparation as an active pharmaceutical ingredient or synthesis intermediate for purification purposes. It is very important from economical point of view that the preparation process is suitable for industrial scale application and easily reproducible.

Summary of the invention

The object of the present invention is to provide a novel crystalline modification of (lS,3S,5S)-2-[(2S)- 2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L- tartrate referred to herein as Form I, in particular in a solid form suitable for oral administration which has advantages over the prior art, for example with respect of stability, solubility of the pharmacologically active compound.

The invention also relates to a method for preparing the novel crystalline modification of (lS,3S,5S)-2- t(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3- carbonitrile L-tartrate referred to herein as Form I.

The present invention further relates to pharmaceutical formulations containing the novel crystalline modification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate referred to herein as Form I and the use thereof for the treatment of type 2 diabetes. Brief description of the figures

Figure 1 is an XRPD pattern of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate Form I, prepared according to the below- given example.

Figure 2 is a FTIR spectra of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate Form I, prepared according to the below- given example. Figure 3 is a ssNMR spectra of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate Form I, prepared according to the below- given example.

Figure 4 is a DCS curve of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]- 2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate Form I, prepared according to the below-given example.

Detailed description of the invention

The invention relates to a novel crystalline modification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate referred to herein as Form I, which meet the pharmaceutical requirements regarding the physico- chemical properties and stability and have advantages over the prior art, for example with respect of stability, solubility of the pharmacologically active compound, and which can be produced in reproducible manner even in industrial scale.

The above aim has been achieved by the novel crystalline modification of (lS,3S,5S)-2-[(2S)-2-amino- 2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate referred to herein as Form I and the process for the preparation thereof according to the present invention.

The novel crystalline modification of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate referred to herein as Form I can be obtained with good yield and high purity.

The novel crystalline modification of (lS,3S,5S)-2-t(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate according to the invention has the characteristic XRPD pattern as shown in Figure 1. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo- [3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate Form I shows the following powder diffraction peaks as illustrated in Table 1, below:

Pos. [°2Th.] d-spacing [A] Rel. Int. [%]

5.69 15.533 100.0

10.71 8.256 6.0

11.50 7.687 14.0

12.28 7.203 1.7

14.83 5.967 11.6

15.29 5.791 9.7

16.57 5.345 1.6

17.70 5.008 5.3

18.19 4.872 3.0

19.62 4.522 16.5

19.92 4.454 8.5

21.59 4.113 3.8

22.96 3.871 2.2

23.85 3.728 1.6

24.27 3.665 2.2

25.00 3.560 5.8

26.19 3.400 2.2

30.93 2.889 1.9

Table 1

(lS,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3_^

3-carbonitrile L-tartrate Form I can be further characterized by an FTIR and solid state NMR spectroscopy invesitgations. Figure 2 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 3479, 3210, 2933, 1713, 1643, 1504, 1140, 1038, 758 and590 cm^"1 and Figure 4 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.

(lS,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane- 3-carbonitrile L-tartrate Form I can be further described by thermal analytical methods. Figure 5 shows the DSC (Perkin Elmer Pyris 1 DSC) curve measured in the range of 25°C to 300°C and gives a

The present invention also relates to a process for the preparation of (lS,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate Form I. (lS,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo-

[3.1.0]hexane-3-carbonitrile L-tartrate Form I can be prepared by a salt formation and crystallization process comprising the steps of

1) dissolution of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile upon heating;

2) filtering the hot solution (optional);

3) addition of L-tartaric acid solution;

4) cooling the suspension- 5) collection of the crystals obtained by filtration and drying. In step 1) any crystalline solid form of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec- l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile can be used as starting (lS,3S,5S)-2-[(2S)-2- amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and can be dissolved in alcohols, preferably Ci - C₄ alkylalcohols, most preferably in 2-propanol. The temperature applied for dissolution depends on the initial amount and solid form of the starting material, preferably 50°C -55°C.

In step 2) the solution of 50°C - 55°C can be filtered optionally to get rid of the undissolved particles.

In step 3) the crystallization of (lS,3S,5S)-2-[(2S)-a-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate Form I can be initiated by addition of L- tartaric acid solution to the clear solution of the starting material at 50°C - 55°C. Suitable solvents are selected from Ci - C₄ alkylalcohols.

In step 4) the suspension containing (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile L-tartrate Form I can be cooled to a room temperature, i.e. about 25°C, by a controlled cooling profile. Controlled cooling profile means a cooling rate of 10-30°C/h, preferably 20°C/h. After cooling the suspension can be agitated for further 24 to 72 hours, preferably 48 hours.

In step 5) the crystals obtained can be collected by any conventional method, e.g. filtration. The obtained (lS,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo- [3.1.0]hexane-3-carbonitrile L-tartrate Form I can be dried by vacuum suction or at laboratory condition, preferably by vaccum suction.

Example

250 mg (0.793 mmol) of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile was dissolved in 2 mL of 2-propanol by heating to 50°C.

119 mg (0.793 mmol) of L-tartaric acid was dissolved in 2 mL of 2-propanol by heating and the solution of the counterion was drop-wise added to the solution of (lS,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile within 30 minutes.

Precipitation started immediately; the suspension was stirred for additional 30 minutes at 50°C while further 6 ml of 2-propanol was added then cooled back to room temperature by a cooling rate 20°C/h and stirred for 2 days at room temperature.

The precipitate was collected by filtration and dried on air by vacuum suction.

Yield: 80%

HPLC: 99.5%

Ee.: >99.7%

¹H-NMR analysis confirmed the structure with a stoichiometry of 1:1.

Water content determination resulted in 0.33% of water content. Analysis - XRPD (X-Ray Powder Diffractometry)

Diffractograms were obtained with laboratory X^'PERT PRO MPD PANalytical diffractometer with CuKa (λ = 1.542A) radiation.

Generator settings:

- excitation voltage 45 kV

anodic current 40 mA.

Scan description:

scan type - go nio

measurement range 2 - 40⁹ 2Θ

- step size 0.012 2Θ

time per step: 0.5s.

Sample was measured as received (not grinded) on Si substrate (zero-background holder).

Incident beam optics: programmable divergence slits (irradiated length 10 mm), 10 mm mask, 1/42 anti-scatter fixed slit, 0.02 rad Soller slits.

Diffracted beam optics: X'Celerator detector, scanning mode, active length 2.1222, 0.02 rad Soller slits, anti-scatter slit 5.0 mm, Ni filter.

Analysis - FTIR (Fourier-Transformed Infra-Red) spectroscopy

FTIR spectra were recorded by Nicolet Thermo 6700 spectrometer.

General settings:

Number of sample scans: 45

Number of background scans: 45

Resolution: 4.000

Sample gain: 4.0

Optical velocity: 0.6329

Aperture: 100.00

Analysis - NMR

For HH NMR spectra the Bruker NMR spectrometer AVANCE 500 MHz and DMSO as solvent were used. The stoichiometry of salts were determinated from integrals of corresponding signals of API and counterion.

^UC CP-MAS ss NMR spectra were meausred on Bruker 400 WB spectrometer in 4 mm rotors with 13 kHz spinning frequency. The spectra of salts were compared with the spectrum of initial API because the formation of a salt should be accompanied by changes of positions of signals of API and by the presence of signals of counterion. Analysis - DSC (Differential Scanning Calorimetry)

DSC measurements were performed on a Mettler Toledo DSC822e/700 DSC.

The sample were weighed in aluminium pans and covers (20 μί) and measured in a nitrogen flow (50 mL/min). Investigations were performed in a temperature range of 25 °C to 300 °C with a heating rate of 10°C/min. The temperatures specified in relation to DSC analyses are the temperatures of the peak maxima and onset temperature of peaks. The specific heat is given in J/g.

The weight sample was about 2-3 mg.

Claims

Claims:

1) Tartarate salt of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile.

2) Tartarate salt of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile, exhibiting the following characteristic diffraction peaks in XRPD pattern: 5.7, 11.5, 14.8, 15.3, 19.6 and 25.0 ± 0.2° 2-theta.

3) A method of preparation of tartarate salt of (lS,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, comprising

a) dissolution of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]- 2-azabicyclo[3.1.0]hexane-3-carbonitrile in a solvent selected from Ci - C₄ alkylalcohols, or a mixture thereof, upon heating;

b) optionally filtering the hot solution;

c) dissolution of L-tartaric acid in a solvent selected from Ci - C₄ alkylalcohols, or a mixture thereof, upon heating;

d) mixing said hot solution of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec- l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile with said hot solution of L-tartaric acid to form a suspension;

e) cooling the resulting suspension to a room temperature;

f) collection of the crystals obtained by filtration and drying.

4) A method according to claim 3, characterised in that (lS,3S,5S)-2-[(2S)-2-amino-2-(3- hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile is dissolved in 2-propanol upon heating to 50-55°C.

5) A method according to claim 3, characterised in that L-tartaric acid is dissolved in 2-propanol upon heating to 50-55°C

6) A method of preparation according to claim 3, characterised in that the suspension is cooled to a room temperature by a cooling rate 20°C/h.

7) Tartarate salt of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile according to any one of claims 1 or 2 or obtained by the method of any one of claims 3-6 for use in a preparation of a pharmaceutical composition.

8) Tartarate salt of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile according to any one of claims 1 or 2 or obtained by the method of any one of claims 3-6 for use in a preparation of any other pharmaceutically acceptable salt of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyl]- 2-azabicyclo[3.1.0]hexane-3-carbonitrile or free base thereof.