Process for the preparation of aclidinium bromide

Abstract

A process for preparing (3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) comprises reacting 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) yl methyl ester and 3-phenoxypropyl bromide, wherein the reaction takes place in a solvent or mixture of solvents selected from the group of amides and/or the group of solvents with a sulfoxide group. Also provided is a crystalline aclidinium bromide characterized by a powder XRPD pattern having peaks at 7.70.2 2, 10.40.2 2, 13.20.2 2, 13.80.2 2, 19.90.2 2, 20.30.2 2, 20.80.2 2, 24.20.2 2, 25.70.2 2, 26.10.2 2, 29.20.2 2, 30.80.2 2. A pharmaceutical composition comprises aclidinium bromide according to the invention and a pharmaceutically acceptable excipient.

Claims

1. A crystalline aclidinium bromide characterized by a powder XRPD pattern having peaks at 7.70.2 2, 10.40.2 2, 13.20.2 2, 13.80.2 2, 19.90.2 2, 20.30.2 2, 20.80.2 2, 24.20.2 2, 25.70.2 2, 26.10.2 2, 29.20.2 2, 30.80.2 2, characterized by no weight loss by TGA.

2. Aclidinium bromide according to claim 1, further characterized by a DSC thermogram having an endotherm peak at 228 C.

3. A pharmaceutical composition comprising aclidinium bromide according to claim 1 and a pharmaceutically acceptable excipient.

4. A pharmaceutical composition according to claim 3 for inhalation in the form of a dry powder, solution or suspension.

5. A pharmaceutical composition according to claim 3 in the form of a dry powder formulation where the pharmaceutically acceptable excipient is an acceptable dry powder carrier.

6. A pharmaceutical composition according to claim 5 wherein the pharmaceutically acceptable carrier is lactose or -lactose monohydrate.

7. A method of forming a medicine comprising combining aclidinium bromide according to claim 1 and a pharmaceutically acceptable excipient.

8. A method of treating chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof the pharmaceutical composition according to claim 3 as a medicine.

9. A method of treating chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof the aclidinium bromide according to claim 1.

10. A method of treating chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof the pharmaceutical composition of claim 3.

11. A mixture of crystalline and amorphous aclidinium bromide, characterized by a powder XRPD pattern as depicted in FIG. 7.

12. A mixture of crystalline and amorphous aclidinium bromide according to claim 11 wherein 20 wt % or less, as a percentage of the total weight of material, of amorphous aclidinium bromide is present.

13. A pharmaceutical composition comprising a mixture of crystalline and amorphous aclidinium bromide according to claim 11 and a pharmaceutically acceptable excipient.

14. A method comprising utilizing a mixture of crystalline and amorphous aclidinium bromide according to claim 11 in medicine.

15. A pharmaceutical composition according to claim 13 for inhalation in the form of a dry powder, solution or suspension.

16. A pharmaceutical composition according to claim 13 in the form of a dry powder formulation where the pharmaceutically acceptable excipient is an acceptable dry powder carrier.

17. A method comprising utilizing pharmaceutical composition according to claim 13 in medicine.

18. A mixture of crystalline and amorphous aclidinium bromide according to claim 11 wherein 10 wt % or less, as a percentage of the total weight of material, of amorphous aclidinium bromide is present.

19. A method of treating chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof a mixture of crystalline and amorphous aclidinium bromide according to claim 11.

20. A method of treating chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof the pharmaceutical composition according to claim 13.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1depicts the powder XRPD pattern of an anhydrous crystalline form of aclidinium bromide.

(2) FIG. 2depicts the Scanning Electron Microscopy (SEM) of the product with particles presenting plate like shape particles.

(3) FIG. 3depicts the Scanning Electron Microscopy (SEM) of the product with particles presenting cube-shape particles.

(4) FIG. 4depicts the Scanning Electron Microscopy (SEM) of the product with particles presenting very small parallel piped shape particles.

(5) FIG. 5depicts the Thermal Gravimetric Analysis of anhydrous aclidinium bromide.

(6) FIG. 6depicts a Differential Scanning calorimetry (DSC) of anhydrous aclidinium bromide.

(7) FIG. 7depicts a XRPD pattern of a mixture of crystalline form and amorphous aclidinium bromide obtained by spray drying process.

(8) FIG. 8depicts the Scanning Electron Microscopy (SEM) of the product after micronization.

(9) FIG. 9depicts a powder XRPD pattern of a mixture of crystalline and amorphous aclidinimum bromide.

DETAILED DESCRIPTION OF THE INVENTION

(10) This invention concerns a process for preparing (3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting (3R)-1-azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate and 3-phenoxypropyl bromide, wherein the reaction takes place in a solvent or mixture of solvents that are selected from the group of amides and/or other solvents or mixture of solvents with a sulfoxide group at a temperature below their boiling point. The reaction temperature is below 100 C., preferably below 50 C., and in preferred aspects the reaction temperature is from about 30 C. to about 2 C., suitably about 30 C., or about 20 C.

(11) In a preferred aspect, the reaction takes place under a flow of an inert gas, suitably a dry inert gas, preferably under a flow of dry nitrogen, dry helium or a mixture thereof.

(12) In a preferred aspect, the reaction takes place at a pressure below the atmospheric pressure. Standard atmospheric pressure is 101325 Pa (equivalent to 760 mmHg), and preferably the pressure is below this. Alternatively, the pressure may be below the ambient atmospheric pressure, based on the location where the reaction is taking place.

(13) Preferably, any alcohol formed during the reaction is removed from the reaction mixture.

(14) Preferably, the reaction solvent is DMF or is a mixture of solvents containing DMF, DMA or a mixture of solvents containing DMA, DMSO or a mixture of solvents containing DMSO. One preferred solvent is DMSO or a mixture of solvents containing DMSO.

(15) For example, when using DMSO as solvent the purity achieved is above 99.5% without the need for any crystallization step. For other solvents a crystallization step may be needed in order to achieve the desired purity.

(16) In a preferred aspect, the process of the invention is such that the equivalent mole ratio of 3-phenoxypropyl bromide to (3R)-1-azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate is in the range of from 1.2 to 2.0, preferably from 1.5 to 2.0, more preferably about 1.8.

(17) The content of the genotoxic impurity 3-phenoxypropyl bromide in the final product is always below 500 ppm, more preferably below 200 ppm.

(18) The process of the invention preferably has a total reaction time is not more than 8 hours. In a preferred aspect, the reaction time is not more than 6 hours, more preferably not more than 4 hours.

(19) The process of the invention may if desired further comprise the step of purification of aclinidium bromide by dissolving the product in DMSO (or another suitable solvent) and using acetonitrile (or another suitable solvent) as co-solvent to precipitate the purified product.

(20) In a preferred process according to the invention, the aclidinium bromide obtained is crystalline.

(21) In one preferred aspect of the process according to the invention, the aclidinium bromide obtained is a mixture of crystalline and amorphous material.

(22) In a preferred aspect of the invention, an anhydrous crystalline form of aclidinium bromide is obtained. This form is characterized by the powder XRPD pattern depicted in the FIG. 1 and having characteristic diffraction peaks at 7.70.2 2, 10.40.2 2, 13.20.2 2, 13.80.2 2, 19.90.2 2, 20.30.2 2, 20.80.2 2, 24.20.2 2, 25.70.2 2, 26.10.2 2, 29.20.2 2, 30.80.2 2.

(23) This anhydrous crystalline form can be obtained with different crystal habits and morphologies.

(24) This crystalline form of aclidinium bromide is preferably further characterized by no weight loss by TGA, and also preferably further characterized by a DSC thermogram having an endotherm peak at 228 C.

(25) In one aspect, the crystalline form of aclidinium bromide provided may comprise a minor amount of amorphous aclidinium bromide. Suitably, the amount is less than 2% by weight, preferably less than 10% by weight, more preferably less than 5% by weight (% by weight being expressed with respect to the total amount of material).

(26) Different morphology was observed when anti-solvent crystallization technique was conducted. The particles exhibited a plate like shape by Electro Scanning Microscopy (SEM) analysis as shown in FIG. 2.

(27) When a thermocycling process is used to crystallize the product, cube-shape particles are obtained, as shown in FIG. 3.

(28) And when crystallization is carried out by cooling the reaction mixture, the product morphology consists of very small parallel piped shape particles, as shown in FIG. 4.

(29) Anhydrous crystalline aclidinium bromide obtained according to the process described herein is further characterized by no weight loss until melting and decomposition by Thermal Gravimetric Analysis (TGA) FIG. 5.

(30) Anhydrous crystalline aclidinium bromide is further characterized by a Differential Scanning calorimetry (DSC) thermogramFIG. 6having a single endothermic transition, at a temperature given by the onset of the transition (Tonset) of 227 C. This transition corresponds to the melting of the crystalline form.

(31) The invention also concerns a process to obtain aclidinium salts, preferably aclidinium bromide, by drying a solution of the aclidinium salt in a solvent or in a mixture of solvents by lyophilization or spray drying or by another suitable drying method. Preferably the drying step is a spray drying step.

(32) In one preferred aspect, said solvent or a mixture of solvents are selected from solvents with a sulfoxide group. Preferably the said mixture contains DMSO and most preferably the solvent is DMSO.

(33) In a preferred aspect, when the drying step is a spray drying process, the product obtained can either be crystalline, crystalline with a minor content of amorphous product, pure amorphous, amorphous with a minor content of a crystalline form or a mixture of amorphous and crystalline forms in different ratios.

(34) The XRPD pattern (FIG. 7) depicts a mixture of a crystalline form and amorphous aclidinium bromide obtained by a spray drying process.

(35) The invention also concerns a pharmaceutical composition comprising aclidinium, preferably in the form of a dry powder, solution or suspension of a pharmaceutical acceptable salt, which can for example be anhydrous, a hydrate or a solvate as described above in admixture with a pharmaceutical excipient, preferably an acceptable dry powder carrier.

(36) Preferably, the pharmaceutical acceptable salt form is aclidinium bromide.

(37) Suitably, the pharmaceutical acceptable carrier is lactose or -lactose monohydrate.

(38) The invention also provides a pharmaceutical composition as described herein for inhalation comprising aclidinium in the form of a dry powder, solution or suspension of a pharmaceutically acceptable salt as described in herein or as obtained by a process as described herein, together with a pharmaceutically acceptable excipient.

(39) Preferably, the pharmaceutical composition is in the form of a dry powder formulation where the pharmaceutically acceptable excipient is an acceptable dry powder carrier. The pharmaceutically acceptable carrier is preferably lactose or -lactose monohydrate.

(40) The invention can encompass a pharmaceutical composition as described herein wherein aclidinium bromide is replaced with an alternative pharmaceutically acceptable salt form of aclidinium. However, the salt form used is preferably aclidinium bromide.

(41) For example, the chloride or the iodide salts may be used. The synthetic route for these salts is essentially identical to the process for making the bromide salt, except that a suitable chloride or iodide reagent should be used. For example, 3-phenoxypropyl chloride may be used instead of 3-phenoxypropyl bromide.

EXAMPLES

(42) This invention is illustrated by the following examples. These examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.

(43) HPLC analysis of the products of the following examples was conducted on a Zorbaz SB-C3 column (150 mm3.0 mm3.5 m).

(44) The mobile phase at a flow of 1.2 ml/min was a binary system of water (containing sodium methanesulfonate and potassium dihydrogenphosphate at pH3.0Phase A) and a mixture of methanol:acetonitrile:phase A (10:40:50 v/v/v). The total run time was 50 minutes.

Example 1

Transesterification Reaction

Synthesis of (3R)-azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (Compound IV)

(45) To a solution of (3R)-quinuclidinol (10.30 g, 81.0 mmol) in 500 ml of toluene was added methyl di(2-thienyl) glycolate (MDTG) (20 g, 78 mmol). The solution was refluxed with continuous distillation of toluene and replacement with fresh toluene.

(46) After distillation was added sodium methoxide (1.70 g, 31 mmol) and distillation was carried out at 80/90 C. under a flow of nitrogen, until the reaction is considered complete. The reaction is considered complete when MDTG content is 2.0% in area by HPLC.

(47) The reaction mixture is washed with water and with brine until the content of the impurity 2-hydroxy-2,2-bis(2-thienyl) acetic acid (DTG) was 1.5%.

(48) The organic solution is concentrated under vacuum at a temperature equal to, or lower than, 50 C. until a final volume of 50 ml.

(49) The suspension was cooled to 20/25 C. and stirred at this temperature over, at least, 2 hours.

(50) The suspension was cooled to a temperature between 10 C. and 15 C. and stirred at this temperature over, at least, 4 hours.

(51) The product was filtered and washed with isopropyl ether previously cooled to a temperature between 10 C. and 15 C.

(52) The desired product (18.4 g) was obtained with a purity of, not less than 99.2% in area, by HPLC.

Example 2

Transesterification Reaction

Synthesis of (3R)-azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (Compound IV)

(53) A solution of (3R)-quinuclidinol (5.15 g, 40.5 mmol) in 250 ml of toluene is heated until a temperature between 65 C. and 70 C. and sodium methoxide (0.65 g, 11.8 mmol) was added.

(54) Under a flow of nitrogen at a temperature between 75 C. and 85 C. a solution of MDTG (10.0 g; 39.3 mmol) in 100 ml of toluene was added during around 1 hour.

(55) Under a flow of nitrogen and at a temperature between 75 C. and 85 C. the azeotrope of toluene and methanol was removed by distillation (with replacement of fresh toluene) until the reaction is considered complete.

(56) The reaction mixture is washed with a 20% aqueous solution of NaCl four times, until the content of DTG by-product in organic phase was 1.5%.

(57) The organic phase was dried and concentrated under vacuum at a temperature equal to, or lower than 40 C. until a final volume of 25 ml.

(58) The suspension was cooled to 10/15 C. and stirred at this temperature, at least, 5 hours.

(59) The desired product (8.5 g) was obtained with a purity of, not less than 98.0% by HPLC

Example 3

Quaternization Reaction

Synthesis of aclidinium bromide-(3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (Compound I)

(60) In an inert atmosphere, to a suspension of (3R)-Azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (5 g; 14.26 mmol) in 30 ml of DMF, 3-phenoxypropyl bromide (3.42 ml, 21.68 mmol) was added slowly at a temperature between 2 C. and 25 C.

(61) The suspension was stirred at about 30 C. until the content of the starting material content is below 0.5% in area by HPLC.

(62) When the reaction was completed acetonitrile (43 ml) was added to the suspension. The suspension was cooled at a temperature between 20 C. and 25 C. and stirred over 2 hours while maintaining the temperature between 20 C. and 25 C.

(63) The product was filtered and washed with acetonitrile, previously cooled to a temperature between 10 C. and 15 C.

(64) Aclidinium bromide was obtained (7.48 g) with a purity of 99.4% in area by HPLC.

Examples 4 to 8

Quaternization Reaction

(65) In examples 4 to 8, the process followed was the process described in example 3 where different quantities of the reaction solvent and of the reagent 3-phenoxypropyl bromide were used.

(66) TABLE-US-00001 Equivalents Amount of 3- of Reaction phenoxypropyl solvent temperature Reaction Yield Ex: bromide Solvent ml/g ( C.) time (h) (%) 4 1.88 DMF 8.6 30 91 5 1.88 DMF 3.7 30 3.5 90.8 6 1.16 DMF 3.7 30 6.5 90.6 7 1.52 DMF 6.15 30 88.8 8 1.52 DMF 6.15 20 7 92.2

(67) Using DMF as solvent the selected parameters were: 1,88 eq of 3-phenoxypropyl bromide; amount of solvent 3.7 ml/g; temperature 30 C.

Example 9

Quaternization Reaction

Synthesis of aclidinium bromide-(3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (compound I)

(68) In an inert atmosphere, to a suspension of (3R)-Azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (5 g, 14.26 mmol) in 30 ml of DMA, 3-phenoxypropyl bromide (4.23 ml, 26.82 mmol) was added slowly at a temperature between 20 C. and 25 C.

(69) The suspension was stirred at 30 C. until the content of the starting material content is below 0.5% in area by HPLC.

(70) When the reaction was completed, acetonitrile (43 ml) was added to the suspension. The suspension was cooled at a temperature between 20 C. and 25 C. and stirred over 2 hours while maintaining the temperature between 20 C. and 25 C.

(71) The product was filtered and washed with acetonitrile, previously cooled to a temperature between 10 C. and 15 C.

(72) Aclidinium bromide is obtained (7.4 g) with a purity of 98.98% in area by HPLC.

Example 10

Quaternization Reaction

Synthesis of aclidinium bromide-(3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (compound I)

(73) In an inert atmosphere, to a suspension of (3R)-azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (4.50 g, 12.84 mmol) in 27.7 ml of DMSO, 3-phenoxypropyl bromide (3.80 ml, 24.14 mmol) was added at a temperature of about 30 C.

(74) The suspension was stirred at 30 C. until the content of the starting material content is below 0.5% in area by HPLC.

(75) When the reaction is completed, acetonitrile (54 ml) was added to the suspension; the suspension was cooled at a temperature between 20 C. and 25 C. and stirred over 2 hours while maintaining the temperature between 20 C. and 25 C.

(76) The product was filtered and washed with acetonitrile previously cooled to a temperature between 10 C. and 15 C.

(77) Aclidinium bromide was obtained (5.8 g) with a purity of 99.88% in area by HPLC.

Example 11

Purification of Compound (I)

Purification of aclidinium bromide-(3R)-3-[2-hydroxyl(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (Compound I)

(78) In an inert atmosphere, (3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (50 g) was added to 500 ml of dimethylsulfoxide at a temperature between 40 C. and 45 C. To the solution obtained, 11 of acetonitrile was added slowly.

(79) The product crystallized and a slowly cooling was done until a temperature between 20 C. and 25 C.

(80) The suspension was stirred over 2 hours while maintaining the temperature between 20 C. and 25 C.

(81) Aclidinium bromide purified was obtained (33 g) and with a purity of 99.91% in area by HPLC.

Example 12

Micronization

(82) Micronization was conducted by jet milling in order to conclude if the particle size distribution (PSD) of the aclidinium bromide could be easily adjusted to a range suitable for inhalation (1-5 m). A 1.5 jet miller (Fluid Jet Mill J20/DS20) was used for the micronization fed with pure nitrogen. In this example the powder was added at constant flow rate by a double-screw type feeder, with Venturi and nozzles pressure between 4 to 10 bar.

(83) The analytical results obtained are summarized in the table below. The product obtained had a PSD within the inhalable range with a purity higher than 99.5% and high yield (90% wt.). With only one passage the powder reached the desirable PSD, and no presence of amorphous material could be detected on the product. In addition the SEM image of the micronized material revealed a homogeneous PSD (FIG. 8).

(84) TABLE-US-00002 Batch Dv10; Dv50; Dv90 HPLC purity (area) Starting raw material 6.1; 15.5; 35.9 99.9% Product after 1 cycle 1.3; 2.4; 4.6 99.7% Batch 1 Product after 1 cycle 1.5; 2.6; 4.8 99.5% Batch 2
Measuring Conditions

(85) All XRPD were obtained using high throughput XRPD set-up. Data collection was carried out at room temperature using monochromatic CuK.sub. radiation in the 2 region between 1.5 and 41.5.

(86) TGA/DSC

(87) The instrument used was TGA/SDRA 851e (Mettler-Toledo) that was calibrated for temperature with In and Al. The seals were pin holed and the crucible heated in the TGA from 25 C. to 300 C., at a heating rate of 10 C./min

(88) SEM

(89) The instrument used was a Phillips SEM 525 microscope equipped with an external SE detector.