Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D9/00—Crystallisation
  • B01D9/0018—Evaporation of components of the mixture to be separated
  • B01D9/0027—Evaporation of components of the mixture to be separated by means of conveying fluid, e.g. spray-crystallisation
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D9/00—Crystallisation
  • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present invention relates to a process for the preparation of aclidinium salts, particularly aclidinium bromide.
• the invention also concerns a pharmaceutical composition comprising aclidinium in the form of a dry powder, solution or suspension.
• the present invention relates to a novel process for the preparation of aclidinium salts.
• the chemical name of aclidinium is (3R)-3-[2-hydroxy(di-2-thienyl)acetoxy]-1 -(3-phenoxypropyl)-1 - azoniabicyclo[2.2.2]octane.
• the structure of the aclidinium salts is depicted below (I).
• X " is a pharmaceutically acceptable anion, such as bromide, chloride or iodide.
• the preferred salt is aclidinium bromide, a quaternary ammonium salt.
• Aclidinium bromide is a white to off-white crystalline powder.
• the active form is the R-isomer and the S-isomer has small affinity for muscarinic receptors in vitro and limited effect on acetylcholine induced bronchoconstriction.
• the drug is formulated as an inhalation powder, comprised of a mixture of micronized aclidinium bromide and a-lactose monohydrate.
• Aclidinium bromide is a muscarinic antagonist and is available commercially as Bretaris Genuair (EU Members States), Althoughza Pressair (US and Canada) and Eklira Genuair (UK).
• This process is able to reduce the reaction time to 8 hours, using a specific solvent (ketones or cyclic ethers having a boiling point between 50°C and 210°C) while using a reduced amount of the reagent 3-phenoxypropyl bromide.
• ketones or cyclic ethers having a boiling point between 50°C and 210°C ketones or cyclic ethers having a boiling point between 50°C and 210°C
• reaction temperature in some cases, must be extremely high, which brings extra operational challenges to the process.
• a process for preparing (3R)-3-[2- Hydroxy(di-2-thienyl)acetoxy]-1 -(3-phenoxypropyl)-1 -azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) by 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 that are selected from the group of amides and/or the group of solvents with a sulfoxide group.
• the present invention provides a crystalline aclidinium bromide characterized by a powder XRPD pattern having peaks at 7.7 ⁇ 0.2° 2 ⁇ , 10.4 ⁇ 0.2° 2 ⁇ , 13.2 ⁇ 0.2° 2 ⁇ , 13.8 ⁇ 0.2° 2 ⁇ , 19.9 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 20,20.8 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 25.7 ⁇ 0.2° 2 ⁇ , 26.1 ⁇ 0.2° 2 ⁇ , 29.2 ⁇ 0.2° 2 ⁇ , 30.8 ⁇ 0.2° 2 ⁇ .
• the present invention provides a mixture of crystalline and amorphous aclidinium bromide, optionally obtainable according to the process described herein, characterized by a powder XRPD pattern as depicted below:
• the present invention provides a process of preparing aclidinium bromide, which process comprises drying a solution of aclidinium bromide in a solvent or a mixture of solvents, preferably by spray drying.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable salt of aclidinium, preferably aclidinium bromide, as disclosed herein and a pharmaceutically acceptable excipient.
• aclidinium bromide is made according to the process described herein.
• the present invention provides aclidinium bromide as disclosed herein, or aclidinium bromide obtained according to the process as disclosed herein; or a pharmaceutical composition comprising aclidinium bromide as disclosed herein for use in medicine, preferably for use in treating chronic obstructive pulmonary disease (COPD).
• COPD chronic obstructive pulmonary disease
• aclidinium bromide involves a transesterification reaction between 3R - quinucidinol (II) and MDTG (III) to produce N-despropylaclidinium (IV) , followed by the reaction of N- despropylaclidinium with 3-phenoxypropyl bromide (V) (quaternization reaction) to synthetize aclidinium bromide (Scheme 1 ).
• bases for the transesterification reaction a variety of bases can be used, among others: K 2 C0 3 , sodium methoxide, sodium ethoxide, sodium tert butoxide, triazabicyclodecene (TBD) and
• DBU 8-Diazabicyclo[5.4.0]undec-7-ene
• the process of the present invention is able to overcome the disadvantages of the prior art while carrying out the reaction at a temperature below 100 °C, namely at temperatures around room temperature, most preferably at temperatures from 20 to 30 °C, preferably at a temperature around 30 °C or 20 °C .
• the reaction time is maintained at less than 8 hours, preferably less than 6 hours, more preferably less than 4 hours, and the amount of genotoxic reagent used is preferably maintained in the range of 1 .2 to 2.0 mole equivalents.
• the solvent chosen can be a solvent with a sulfoxide group, preferably dimethylsulfoxide (DMSO), diethylsulfoxide, or any of the solvents of the amide group, preferably dimethylformamide (DMF), (dimethylacetamide) DMA, or mixtures thereof.
• a further advantage of the quaternization reaction described is that the solid material thus obtained can be micronized to achieve the desired particle size range, for example a particle size distribution suitable for inhalation.
• Figure 1 - depicts the powder XRPD pattern of an anhydrous crystalline form of aclidinium bromide.
• Figure 2 - depicts the Scanning Electron Microscopy (SEM) of the product with particles presenting plate like shape particles.
• Figure 3 - depicts the Scanning Electron Microscopy (SEM) of the product with particles presenting cube-shape particles.
• Figure 4 - depicts the Scanning Electron Microscopy (SEM) of the product with particles presenting very small parallel piped shape particles.
• Figure 5 depicts the Thermal Gravimetric Analysis of anhydrous aclidinium bromide
• Figure 6 - depicts a Differential Scanning Calorimetry (DSC) of anhydrous aclidinium bromide.
• Figure 7 - depicts a XRPD pattern of a mixture of crystalline form and amorphous aclidinium bromide obtained by spray drying process.
• FIG. 8 - depicts the Scanning Electron Microscopy (SEM) of the product after micronization DETAILED DESCRIPTION OF THE INVENTION
• 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 20 °C, suitably about 30°C, or about 20°C.
• 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.
• the reaction takes place at a pressure below the atmospheric pressure.
• Standard atmospheric pressure is 101325 Pa (equivalent to 760mmHg), and preferably the pressure is below this.
• the pressure may be below the ambient atmospheric pressure, based on the location where the reaction is taking place.
• any alcohol formed during the reaction is removed from the reaction mixture.
• 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.
• the purity achieved is above 99.5% without the need for any crystallization step.
• a crystallization step may be needed in order to achieve the desired purity.
• 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 to2.0, more preferably about 1 .8.
• the content of the genotoxic impurity 3-phenoxypropyl bromide in the final product is always below 500 ppm, more preferably below 200ppm.
• 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.
• 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.
• the aclidinium bromide obtained is crystalline.
• the aclidinium bromide obtained is a mixture of crystalline and amorphous material.
• 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 7.7 ⁇ 0.2° 2 ⁇ , 10.4 ⁇ 0.2° 2 ⁇ , 13.2 ⁇ 0.2° 2 ⁇ , 13.8 ⁇ 0.2° 2 ⁇ , 19.9 ⁇ 0.2° 2 ⁇ , 20.3 ⁇ 0.2° 20,20.8 ⁇ 0.2° 2 ⁇ , 24.2 ⁇ 0.2° 2 ⁇ , 25.7 ⁇ 0.2° 2 ⁇ , 26.1 ⁇ 0.2° 2 ⁇ , 29.2 ⁇ 0.2° 2 ⁇ , 30.8 ⁇ 0.2° 2 ⁇ .
• This anhydrous crystalline form can be obtained with different crystal habits and morphologies.
• 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.
• the crystalline form of aclidinium bromide provided may comprise a minor amount of amorphous aclidinium bromide.
• the amount is less than 20% 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).
• thermocycling process When a thermocycling process is used to crystallize the product, cube-shape particles are obtained, as shown in Fig.3.
• the product morphology consists of very small parallel piped shape particles, as shown in Fig.4.
• 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.
• Anhydrous crystalline aclidinium bromide is further characterized by a Differential Scanning Calorimetry (DSC) thermogram - Fig.6 - having 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.
• DSC Differential Scanning Calorimetry
• 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.
• the drying step is a spray drying step.
• said solvent or a mixture of solvents are selected from solvents with a sulfoxide group.
• the said mixture contains DMSO and most preferably the solvent is DMSO.
• 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.
• the XRPD pattern (Fig.7) depicts a mixture of a crystalline form and amorphous aclidinium bromide obtained by a spray drying process.
• the invention also concerns a pharmaceutical composition
• 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.
• the pharmaceutical acceptable salt form is aclidinium bromide.
• the pharmaceutical acceptable carrier is lactose or a-lactose monohydrate.
• 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.
• 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 a-lactose monohydrate.
• the invention can encompass a pharmaceutical composition as described herein wherein aclidinium bromide is replaced with an alternative pharmaceutically acceptable salt form of aclidinium.
• the salt form used is preferably aclidinium bromide.
• 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.
• a suitable chloride or iodide reagent should be used.
• 3-phenoxypropyl chloride may be used instead of 3- phenoxypropyl bromide.
• HPLC analysis of the products of the following examples was conducted on a Zorbaz SB-C3 column (150mm x 3.0mm x 3.5 ⁇ ).
• the mobile phase at a flow of 1 .2 ml/min was a binary system of water (containing sodium methanesulfonate and potassium dihydrogenphosphate at pH3.0 - Phase A) and a mixture of methanol:acetonitrile:phase A (10:40:50 v/v/v).
• the total run time was 50 minutes.
• 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%.
• the organic solution is concentrated under vacuum at a temperature equal to, or lower than, 50°C until a final volume of 50ml.
• the suspension was cooled to 20°/25°C and stirred at this temperature over, at least, 2 hours.
• the suspension was cooled to a temperature between 10°C and 15°C and stirred at this temperature over, at least, 4 hours.
• the product was filtered and washed with isopropyl ether previously cooled to a temperature between 10°C and 15°C.
• reaction mixture is washed with a 20% aqueous solution of NaCI four times, until the content of DTG by-product in organic phase was ⁇ . 1 .5%.
• 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.
• the suspension was stirred at about 30°C until the content of the starting material content is below 0.5% in area by HPLC.
• acetonitrile 43ml 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.
• the product was filtered and washed with acetonitrile, previously cooled to a temperature between 10°C and 15°C.
• the suspension was stirred at 30°C until the content of the starting material content is below 0.5% in area by HPLC.
• acetonitrile 43ml 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.
• the product was filtered and washed with acetonitrile, previously cooled to a temperature between 10°C and 15°C.
• acetonitrile 54ml 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.
• the product was filtered and washed with acetonitrile previously cooled to a temperature between 10°C and 15°C.
• the product crystallized and a slowly cooling was done until a temperature between 20°c and 25°C.
• the suspension was stirred over 2 hours while maintaining the temperature between 20°C and 25°C.
• 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 ⁇ ).
• a 1 .5" jet miller (Fluid Jet Mill J20/DS20) was used for the micronization fed with pure nitrogen.
• the powder was added at constant flow rate by a double-screw type feeder, with Venturi and nozzles pressure between 4 to 10 bar.
• 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.
• the SEM image of the micronized material revealed a homogeneous PSD (Fig 8). Batch Dv10; Dv50;Dv90 HPLC purity (area)
• the instrument used was TGA/SDRA 851 e (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 1 0°C/min
• the instrument used was a Phillips SEM 525 microscope equipped with an external SE detector.

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