PROCESS FOR THE PREPARATION OF BUDESONIDE 21-PHOSPHATE

Abstract

The present invention relates to a new process for the preparation of budesonide 21-phosphate and its disodium salt.

Claims

1-10. (canceled)

11. A process for preparing budesonide 21-phosphate of formula (II) ##STR00007## comprising the steps of: a) reacting budesonide with tetrabutylammonium dihydrogen phosphate and trichloroacetonitrile to obtain the compound of formula (II); b) optionally, satisfying the compound of formula (II) with NaOH to form the corresponding disodium salt.

12. The process according to claim 11, wherein step a) is performed in an aprotic solvent.

13. The process according to claim 12, wherein the aprotic solvent is selected from acetonitrile, acetone, ethyl acetate, dichloromethane, and chloroform.

14. The process according to claim 13, wherein the aprotic solvent is acetonitrile.

15. The process according to claim 11, wherein step a) is performed at room temperature.

16. The process according to claim 11, wherein the pH of step b) is from 7 to 9.

17. The process according to claim 11, further comprising a step of isolating the compound of formula (II).

18. The process according to claim 17, wherein the compound of formula (II) is isolated by crystallization.

19. The process according to claim 18, wherein the compound of formula (II) is isolated by crystallization from ethyl acetate.

20. The process according to claim 11, further comprising a step of isolating the disodium salt of the compound of formula (II).

21. The process according to claim 20, wherein the isolation step of the disodium salt of the compound of formula (II) is carried out by adding an anti-solvent selected from methanol and ethanol.

22. The process according to claim 20, wherein the isolation step of the disodium salt of the compound of formula (II) is carried out by treatment with an opportune solvent.

23. The process according to claim 22, wherein the opportune solvent is selected from diethyl ether, ethyl acetate, and n-hexane.

24. The process according to claim 23, wherein the opportune solvent is diethyl ether.

25. Budesonide 21-phosphate disodium salt having an amount of any single unknown impurity equal to or lower than 0.10% by area % or having an amount of the qualified impurities budesonide (I) or budesonide 21-phosphate (II) equal to or lower than 0.2% by area %.

26. Budesonide 21-phosphate disodium salt having a purity equal to or greater than 98% by area %.

Description

DESCRIPTION OF THE FIGURES

[0024] FIG. 1 shows 1H-NMR (500 MHZ; CD.sub.3OD-d.sub.4) spectrum of Budesonide 21-phosphate.

[0025] FIG. 2 shows 13C-NMR (126 MHZ; CD.sub.3OD-d.sub.4) spectrum of Budesonide 21-phosphate.

[0026] FIG. 3 shows 1H-NMR (500 MHZ; CD.sub.3OD-d.sub.4) spectrum of Budesonide 21-phosphate disodium salt.

[0027] FIG. 4 shows 13C-NMR (126 MHZ; CD.sub.3OD-d.sub.4) spectrum of Budesonide 21-phosphate disodium salt.

[0028] FIG. 5 shows ESI-MS spectrum of Budesonide 21-phosphate.

[0029] FIG. 6 shows the FT-IR spectrum of Budesonide 21-phosphate.

[0030] FIG. 7 shows the FT-IR spectrum of Budesonide 21-phosphate disodium salt.

[0031] FIG. 8 shows the X-Ray Powder Diffraction spectrum of Budesonide 21-phosphate.

[0032] FIG. 9 shows the X-Ray Powder Diffraction spectrum of Budesonide 21-phosphate disodium salt.

[0033] FIG. 10 shows UV spectrum of budesonide 21 phosphate disodium salt.

DETAILED DESCRIPTION OF THE INVENTION

[0034] According to a first aspect, the present invention relates to a new process for preparing budesonide 21-phosphate of formula (II)

##STR00005##

which comprises the steps of: [0035] a) reacting budesonide with tetrabutylammonium dihydrogen phosphate and trichloroacetonitrile to obtain the compound of formula (II); [0036] b) optionally, satisfying the compound of formula (II) with NaOH to form the corresponding disodium salt.

[0037] Advantageously, the one-pot procedure by tetrabutylammonium dihydrogen phosphate and trichloroacetonitrile provides the budesonide 21-phosphate in improved yield (83%).

[0038] In one preferred embodiment, the step a) is performed in an aprotic solvent, preferably selected from acetonitrile, acetone, ethyl acetate, dichloromethane, or chloroform. More preferably, acetonitrile.

[0039] In another embodiment, the step a) is performed at room temperature.

[0040] According to a preferred embodiment of the process of the invention, budesonide 21-phosphate is isolated by crystallization. The useful solvents for said crystallization are ethyl acetate, n-hexane. More preferably, ethyl acetate.

[0041] In one preferred embodiment, the pH of step b) is from 7 to 9.

[0042] In another embodiment, the process further comprises the step of isolating the disodium salt.

[0043] Budesonide 21-phosphate disodium salt has a much higher water solubility than Budesonide and Budesonide 21-phosphate. Its solubility can be defined freely soluble in water (100-1000 mg/mL) and is equal to 110 mg/ml.

[0044] At the concentration of use (0.25 mg ml-4.0 mg ml), it is rapidly soluble and remains stable at room temperature for long periods of time (12 months) without yellowing or precipitating.

[0045] According to a preferred embodiment of the process of the invention, the isolation step of disodium salt is carried out by adding anti-solvent selected from methanol or ethanol.

[0046] According to a preferred embodiment of the process of the invention, the isolation step of the disodium salt is carried out by treatment with an opportune solvent. The useful solvents for said process are diethyl ether, ethyl acetate, or n-hexane. More preferably, diethyl ether.

[0047] According to a second aspect, the present invention relates to budesonide 21-phosphate disodium salt having an amount of any single unknown impurity equal to or lower than 0.10% (by area %) or having an amount of the qualified impurities budesonide (I) or budesonide 21-phosphate (II) equal to or lower than 0.2% (by area %).

[0048] According to a third aspect thereof, the present invention relates to budesonide 21-phosphate disodium salt having a purity equal to or greater than 98% by area %.

[0049] Purity was assessed through the HPLC method of the European Pharmacopoeia 1075-Budesonide-related substance.

[0050] Budesonide 21-phosphate disodium salt contains only the process impurities, namely budesonide (RRT of 17.8 min) and budesonide 21-phosphate (RRT of 4.3 min), the RRT being measured using the same HPLC method of the European Pharmacopoeia.

Chemistry

Materials and Methods

[0051] All the commercial products have been purchased from Merck-Sigma Aldrich. .sup.1H (500 MHZ) and .sup.13C (125 MHZ) NMR spectra were recorded on an Agilent INOVA spectrometer; chemical shifts were referenced to the residual solvent signal (CD.sub.3OD: ?.sub.H=3.31, ?.sub.C=49.0). ESI-MS spectrum was recorded on a LTQ Orbitrap XL? Fourier transform mass spectrometer (FTMS) equipped with an ESI ION MAX? (Thermo Fisher, San Jos?, USA). X-ray powder diffraction (XRPD) was performed using a Panalytical X'pert PRO diffractometer. Intensity profiles were collected in the 2? range of 4-40? using Ni-filtered CuK? radiation (?=1.5406 ?) at 40 kV and 30 mA, with a step size 0.02?, at a scanning time of 120 s/step. The diffraction patterns were processed using the Highscore Plus suite. IR spectra were recorded on Thermo Nicolet 5700 FT-IR spectrometer. Thermo Fisher GENESYS? 40/50 Vis/UV-Vis Spectrophotometers.

Example 1

Preparation of Budesonide 21-Phosphate

[0052] To a solution of budesonide (200 mg, 0.46 mmol) in acetonitrile (1 mL), trichloroacetonitrile (220 mL, 2.20 mmol) is added, followed by dropwise addition of tetrabutylammonium dihydrogen phosphate (625 mg, 1.84 mmol) in acetonitrile (2 mL). The reaction mixture was monitored by TLC using CHCl.sub.3/MeOH/CH.sub.3COOH (8 mL/2 mL/150 mL) as eluent mixture. The reaction mixture is stirred at room temperature for 24 hours. The reaction was treated with 1 N NaOH and extracted with ethyl acetate. The aqueous phase was made acidic using a 1 N HCl solution and extracted several times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to give 195 mg of budesonide 21-phosphate (yield 83%). M.P. 219-221? C. LRMS (ES) (M+H).sup.+: calcd, 510.5; found, 511.2.

[0053] .sup.1H NMR (500 MHZ, CD.sub.3OD-d.sub.4) ? 7.47 (d, J=10.1 Hz, 1H), 6.26 (d, J=10.1 Hz, 1H), 6.01 (s, 1H), 5.18 (dd, J=13.1, 6.2 Hz, 1H), 4.96-4.83 (m, 2H), 4.72-4.62 (m, 2H), 4.41 (d, J=3.5 Hz, 1H), 2.64 (dt, J=13.0, 6.7 Hz, 1H), 2.37 (d, J=11.0 Hz, 1H), 2.24-2.09 (m, 3H), 1.94 (dd, J=17.8, 9.7 Hz, 1H), 1.70 (dd, J=14.1, 6.6 Hz, 1H), 1.60 (dd, J=12.1, 7.0 Hz, 3H), 1.51-1.39 (m, 4H), 1.04-0.89 (m, 7H).

[0054] .sup.13C NMR (126 MHZ, CD.sub.3OD-d.sub.4): ? 210.89, 209.55, 188.85, 174.28, 159.86, 127.84, 122.55, 109.41, 105.45, 99.88, 98.97, 84.01, 82.92, 70.53, 70.48, 69.96, 69.68, 57.17, 57.08, 54.22, 51.33, 47.07, 45.98, 45.94, 41.34, 40.97, 38.27, 36.17, 35.50, 35.35, 34.34, 33.83, 33.01, 32.47, 31.75, 21.55, 18.44, 17.98, 17.82, 17.54, 14.40, 14.26.

Example 2

Preparation of Budesonide 21-Phosphate Disodium Salt

[0055] ##STR00006##

[0056] Budesonide 21-phosphate (100 mg, 0,196 mmol) was suspended in water (10 mL) and titrated with 2N NaOH to pH 7.94, obtaining a completely clear solution. Then the solvent was removed, and the residue was treated with methanol (5 mL) keeping the suspension at the boiling point of the solvent for 30 min. After cooling, the insoluble solid was filtered off and the solvent was removed in vacuo. The residue was then treated with diethyl ether affording budesonide 21-phosphate disodium salt as a white solid (86 mg, yield 79%), M.P. 245-246? C. 1H NMR (500 MHZ, CD.sub.3OD-d.sub.4) ? 7.47 (d, J=10.1 Hz, 1H), 6.26 (d, J=10.1 Hz, 1H), 6.01 (s, 1H), 5.18 (dd, J=13.1, 6.2 Hz, 1H), 4.96-4.83 (m, 2H), 4.72-4.62 (m, 2H), 4.41 (d, J=3.5 Hz, 1H), 2.64 (dt, J=13.0, 6.7 Hz, 1H), 2.37 (d, J=11.0 Hz, 1H), 2.24-2.09 (m, 3H), 1.94 (dd, J=17.8, 9.7 Hz, 1H), 1.70 (dd, J=14.1, 6.6 Hz, 1H), 1.60 (dd, J=12.1, 7.0 Hz, 3H), 1.51-1.39 (m, 4H), 1.04-0.89 (m, 7H).

[0057] .sup.13C NMR (126 MHZ, CD.sub.3OD-d.sub.4): ? 210.89, 209.55, 188.85, 174.28, 159.86, 127.84, 122.55, 109.41, 105.45, 99.88, 98.97, 84.01, 82.92, 70.53, 70.48, 69.96, 69.68, 57.17, 57.08, 54.22, 51.33, 47.07, 45.98, 45.94, 41.34, 40.97, 38.27, 36.17, 35.50, 35.35, 34.34, 33.83, 33.01, 32.47, 31.75, 21.55, 18.44, 17.98, 17.82, 17.54, 14.40, 14.26.

Stability Testing

[0058] According to ICH guidelines (STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Q1A (R2) Current Step 4 version dated 6 Feb. 2003), studies on budesonide 21-phosphate disodium salt were conducted at 25? C./60% RH (relative humidity) and 30? C./65% RH for a period of 12 months (m). Accelerated tests were also conducted under conditions of 40? C./75% RH for 6 months (m), as shown in the following Tables.

TABLE-US-00001 ICH study at 25? C. and 60% RH Specification Time 0 Time 3 m Time 6 m Time 9 m Time 12 m Title 95.0-105.0% 98.22% 98.10% 98.08% 97.85% 97.45% known ?0.2% 0.14% 0.14% 0.14% 0.15% 0.15% impurities unknown ?0.1% 0.05% 0.05% 0.05% 0.08% 0.08% impurities

TABLE-US-00002 ICH study at 30? C. and 65% RH Specification Time 0 Time 3 m Time 6 m Time 9 m Time 12 m Title 95.0-105.0% 98.22% 97.50% 97.28% 97.00% 94.55% known ?0.2% 0.14% 0.20% 0.25% 0.25% 0.30% impurities unknown ?0.1% 0.05% 0.15% 0.15% 0.40% 0.40% impurities

TABLE-US-00003 ICH study at 40? C. and 75% RH Specification Time 0 Time 3 m Time 6 m Title 95.0-105.0 % 98.22 % 96.50 % 93.28 % known ?0.2 % 0.14 % 0.30 % 0.45 % impurities unknown ?0.1 % <0.05 % 2.45 % 2.80 % impurities

Formulation Studies

[0059] The following formulations were prepared to test the stability of the budesonide 21-phosphate disodium salt in aqueous solution.

TABLE-US-00004 Budesonide disodium phosfate Ingredient Formula I Formula II Function Active substance Budesonide 0.25 mg 4.0 mg Active substance (disodium phosphate) Excipients Disodium edetate 0.10 mg 0 Chelating agent Sodium chloride 8.50 mg 3.0 Tonicity agent Citric acid, anhydrous 0.28 mg 0 Buffering agent Sodium citrate 0.50 mg 10.0 Buffering agent tribasic dihydrate Water for injections q. s. to 1.00 ml q. s. to 1.00 ml Solvent HCl q. s. to pH 4.5 q. s. to pH 7.75

[0060] The same formulations were tested according to ICH guidelines in the stability studies at 25? C. and 40? C. and the results are reported below.

TABLE-US-00005 ICH study at 25? C. and 60% RH FORMULA I Specification Time 0 Time 3 m Time 6 m Time 9 m Time 12 m Aspect Clear solution Compliant Compliant Compliant Compliant Compliant free from visible particles Title 95.0-105.0% 100.5% 100.2% 100.2% 100.0 99.8% known ?0.2% 0.10% 0.10% 0.10% 0.15% 0.15% impurities unknown ?0.1% 0.05% 0.05% 0.05% 0.10% 0.10% impurities pH 4.0-5.0 4.5 4.5 4.5 4.5 4.5

TABLE-US-00006 ICH study at 40? C. and 75% RH FORMULA I Specification Clear solution free from visible Time 0 Time 3 m Time 6 m Aspect particles Compliant Compliant Compliant Title 95.0-105.0 % 100.5 % 100.2 % 100.2 % known ?0.2 % 0.10 % 0.15 % 0.20 % impurities unknown ?0.1 % <0.05 % 0.1 % 0.1 % impurities pH 4.0-5.0 4.5 4.5 4.5

TABLE-US-00007 ICH study at 25? C. and 60% RH FORMULA II Specification Time 0 Time 3 m Time 6 m Time 9 m Time 12 m Aspect Clear solution Compliant Compliant Compliant Compliant Compliant free from visible particles Title 95.0-105.0% 101.2% 101.2% 101.0% 100.6% 99.8% known ?0.2% 0.10% 0.10% 0.10% 0.10% 0.20% impurities unknown ?0.1% 0.05% 0.05% 0.10% 0.10% 0.10% impurities pH 7.25-8.25 7.75 7.75 7.75 7.75 7.75

TABLE-US-00008 ICH study at 40? C. and 75% RH FORMULA II Specification Clear solution free from visible Time 0 Time 3 m Time 6 m Aspect particles Compliant Compliant Compliant Title 95.0-105.0 % 101.2 % 100.5 % 99.6 % known ?0.2 % 0.10 % 0.20 % 0.20 % impurities unknown ?0.1 % 0.05 % 0.10 % 0.10 % impurities pH 7.25-8.25 7.75 7.80 7.90