WO2014174233A1

WO2014174233A1 - Preparation of drug particles by micronisation

Info

Publication number: WO2014174233A1
Application number: PCT/GB2014/000154
Authority: WO
Inventors: Marc Saunders
Original assignee: Kuecept Limited
Priority date: 2013-04-26
Filing date: 2014-04-25
Publication date: 2014-10-30
Also published as: GB201307659D0

Abstract

The present invention relates to a process for preparing a crystalline micronised particulate of tiotropium bromide. The process involves suspending the drug in a water immiscible anti-solvent in which the drug has little or no solubility and micronizing the suspension. The resulting drug particles are physically stable with regard to agglomeration and/or aggregation on storage.

Description

GB Application 26/03/2013; Application numberl307659.1

Title; Preparation of drug particles by micronisation

Description

Field of the Invention

The present invention relates to a process for preparing micronised particles of a water soluble anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Said particles are suitable for use in pharmaceutical applications such as treatment of respiratory diseases.

Background to the Invention It is known that water soluble, hydrophilic compounds tend to undergo a degree of physical form change post mechanical activation due to the absorption of moisture; this is a result of the generation of process induced structural disorder during mechanical attrition and subsequent absorption of atmospheric moisture post processing which results in recrystallisation of the surface amorphous content. This problem can seriously affect the physical and chemical stability of the drug and its subsequent performance in formulations for inhaled therapies.

Tiotropium is an anticholinergic bronchodilator drug commercially available as the bromide salt form, namely (1α,2β,4β,7β)- 7-[(hydroxidi-2-thienylacetyl)oxy]- 9,9-dimethyl- 3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide, hereinafter indicated as tiotropium bromide. Using conventional methods of micronisation, for instance air-jet milling or high-pressure homogenization, amorphous regions and / or lattice defects are introduced into the sample, which means that once micronized and isolated, the sample has a strong tendency to absorb environmental moisture and undergo a degree of physical form change. This rate of change is dependant on the storage conditions employed and hence special care is required to maintain steady conditions throughout the subsequent drug product manufacturing processes. This poses significant challenges, particularly for the preparation of dry powder formulations for administration by inhalation.

Various processes have been proposed to process drugs to alter certain physicochemical properties of the drug. However many of those processes involve the use of solvents that have low pharmacological tolerability and therefore their residual presence needs to be strictly monitored. In addition, many of these solvents are highly flammable, making larger scale commercial manufacture difficult. Other known solvent treatment processes, including those using polar solvents, water, or water vapour, tend to cause local solvation processes to occur that subsequently leads to particle growth or irreversible aggregation and agglomeration during drying or storage. In addition, it is well known that the current state-of-the-art high energy physical processing procedures, such as air jet milling, dry powder ball-milling or high pressure homogenisation, result in a partial loss of drug crystallinity. These micronised materials are often subjected to post micronisation conditioning; for example, storage under elevated temperature and/or relative humidity in order to condition out any process induced structural disorder and/or amorphous content.

For example, WO 2009/074662 discloses the use of conditioning the post micronised material of a water soluble drug, such as a glycopyrronium salt, under elevated temperatures (>40°C) and dry conditions for varying periods of time in order to condition/recrystallise the process induced structural disorder and amorphous content and prevent further irreversible agglomeration occurring on storage. However, exposing the aforementioned material to conditions of elevated relative humidity post micronisation results in the rapid formation of crystal bridges and irreversible particle agglomeration/crystal growth and therefore this post-micronisation elevated temperature conditioning is critical to maintaining a stable product.

Analogously, WO 2009/074666 discloses a method for making micronised active particles of water soluble drugs such as a glycopyrronium salt for use in a pharmaceutical composition for pulmonary inhalation that involves high pressure homogenisation of said particles in a polar anti-solvent, for instance acetone, ethanol or propan-l-ol, to achieve particle size reduction and subsequent conditioning of the micronised material under dry elevated temperatures to achieve a physically stable powder with respect to agglomeration / aggregation or particle growth. WO 2005/025536 discloses a method for making composite active particles for use in a pharmaceutical composition for pulmonary inhalation that involves jet milling active particles with certain additive materials to maintain stability and enhance fine particle fraction and fine particle dose. Glycopyrronium is cited among other active ingredients. It is anyway difficult and time consuming to eliminate said additives if not needed.

In view of these considerations, it would be highly advantageous to provide a process for preparing micronised particles of a water soluble drug, in this case Tiotropium bromide, that is physically stable post processing and does not need further treatments for avoiding physical instability, in particular the formation of agglomerates / particle and crystal growth.

The problem is solved by the process of the present invention. Summary of the Invention

In a first aspect the present invention relates to a process for the preparation of micronised particles of the pharmaceutically acceptable bromide salt of Tiotropium, the process comprising the steps of:

i) feeding the micronsation chamber of a wet milling apparatus containing grinding media with a water immiscible anti-solvent having a dielectric constant equal to or lower than 15 and a density of 1.2 to 2 g/cm³; ii) suspending particles of the tiotopium bromide salt in said anti-solvent, iii) micronising said suspended particles at a pressure of 0-2 bar (0-200 kPa) by means of said grinding media;

iv) optionally, drying the obtained micronized particles; whereby at least 90% of said particles have a diameter of less than 10 micron.

The process of the invention is carried out in the absence of any additive acting as stabilising agent.

In a second aspect, the invention is directed to a process for preparing a formulation for inhalation comprising the step of mixing the above micronised particles with one or more propellants or carriers. In a third aspect, the invention relates to physically stable micronised crystalline particles of the pharmaceutically acceptable salt tiotropium bromide obtainable by the aforementioned process. In a fourth aspect, the invention relates a formulation for inhalation comprising the aforementioned micronised particles.

In a fifth aspect, the invention concerns an inhaler filled with the above formulation. Definitions

The term 'micronisation' as used herein refers to the process of reducing the average diameter of a solid material's particles. Usually, the term micronisation is used when the particles that are produced are only a few micrometres in diameter. Traditional micronisation techniques are based on the use of friction to reduce particle size. Such methods include milling and grinding. Reduction in particle size may also take place as a result of collision and impact.

The term "aggregate" as used herein means to assemble or combine together. Freshly micronised drugs tend to take the form of a fine powder that tends to spontaneously coalesce over time to form aggregates of the drug. These aggregates resemble a less fine or even coarse powder.

The term "agglomerate" as used herein means to form into a mass or cluster, particularly in the presence of moisture. Agglomerates of micronised drugs tend on storage, particularly in the presence of moisture, to form a coarse powder, clumps or even a substantially singular mass of drug.

The term "physically stable" as used herein means that, on storage, there is no evidence of particle growth or agglomeration of the drug particles. There should not be a significant increase in the particle size which 95% of the particles in the drug product have a diameter of less than, as measured by the cumulative distribution . If agglomeration is seen, then this value will change very quickly. The cumulative distribution of a particulate product gives an indication of the amount of different particle sizes within a sample. The cumulative distribution of a sample may be measured using any suitable apparatus. One particular apparatus that can be used is the Sympatec Dry Dispersion Size Analyser

The presence of agglomerates of the drug in the formulation may alternatively be detected by a Near Infrared Spectrophotometer provided with a microscope according to methods known to the skilled person.

The term "chemically stable" refers to a drug that, upon storage, meets the requirements of the EMEA Guideline CPMP/QWP/ 122/02 referring to "Stability Testing of Existing Active Substances and Related Finished Products".

The term "anti-solvent" as used herein means a liquid having little or no solvation capacity for the drug. The solubility of the drug in the anti-solvent should be less than about lmg/ml determined according to methods known to the skilled person. Preferably, the solubility of the drug should be less than about 100 μg/ml. More preferably, the solubility of the drug should be less than about 10 μg/ml.

The term "water immiscible" means that less than 100 ppm, and preferably less than 10 ppm of water can dissolve in the anti-solvent. The amount of residual water can be determined according to methods known to the skilled person, such as Karl-Fisher.

The term "conditioning" means an exposure of the powder placed in a suitable container to a combination of temperature and relative humidity conditions kept under control.

The term "stabilising agent" as used herein, refers to agents which are used to stabilise a drug in order to reduce or prevent the drug from agglomerating or aggregating. A stabilising agent generally reduces the cohesion between particles and prevents fine particles becoming attached to each other. Stabilising agents include metal stearates such as magnesium stearate and calcium stearate, ionic and non-ionic surfactants, and polyers such as cellulose ethers, PVP or PVA. The "particle size" is the Gaussian distribution of the diameter of particles.

Said particle size can be quantified by measuring the volume diameter by laser diffraction using suitable known instruments such as, for instance, the Sympatec pressure titration dry powder size analyse.

The volume diameter (VD) is related to the mass diameter (MD) by the density of the particles (assuming a size independent density for the particles).

In the present application, the particle size is expressed in terms of volume diameter and the particle size distribution is expressed in terms of the volume median diameter (VMD) which corresponds to the diameter of 50 percent by weight of the particles [dv(0.5)], and, also in terms of [dv(0.9)] and [dvO.l } which express the values under which 90% of particles and 10% of the particles of a sample have a lower volume diameter, respectively

The term "good flowability", us used herein, refers to a formulation that is easy handled during the manufacturing process and is able to ensure an accurate and reproducible delivering of the therapeutically effective dose.

Flow characteristics can be evaluated by different tests such as angle of repose, Carr's index, Hausner ratio or flow rate through an orifice. The term "good homogeneity" refers to a formulation wherein, upon mixing, the uniformity of distribution of the active ingredient, expressed as coefficient of variation (CV) also known as relative standard deviation (RSD), is less than 2.5%, preferably equal to or less than 1.5%. The term "respirable fraction" refers to an index of the percentage of active particles which would reach the deep lungs in a patient.

The respirable fraction, also termed fine particle fraction, is evaluated using a suitable in vitro apparata such as Multistage Cascade Impactor or Multi Stage Liquid Impinger (MLSI) according to procedures reported in common Pharmacopoeias.

It is calculated by the ratio between the respirable dose and the delivered dose. The delivered dose is calculated from the cumulative deposition in the apparatus, while the respirable dose (fine particle dose) is calculated from the deposition on Stages 3 (S3) to filter (AF) corresponding to particles < 4.7 microns.

Detailed description of the invention

The present invention is directed to a process for the preparation of micronised particles of a pharmaceutically acceptable salt of tiotropium.

It has been found that, by operating according to the conditions disclosed hereinafter, a physically stable powder is obtained that might avoid all the usual post micronisation physicochemical issues that make conventional formulation processing difficult, especially in the production of dry powder formulations for administration by inhalation.

In particular it has been found that the drug particles which result from the process of the invention are stable such that they are aggregation and/or agglomeration resistant. In other words, the tendency of the resulting dry micronised material to aggregate and/or agglomerate post processing is minimised or completely avoided.

Said drug particles also show good flow properties. Further, the drug particles are substantially free of amorphous content, which results in a physically stable product..

More surprisingly this is obtained without adding further stabilising agents and without resorting to tedious and time consuming post micronisation conditioning steps at elevated temperatures.

Even more surprisingly, it has been found that, by operating according to the conditions of the process of the invention, a uniform suspension is obtained without the use of any excipients such as the aforementioned stabilising agents. Therefore, micronisation of the drug is carried out in the absence of any further excipients.

This makes the process of the invention much simpler to carry out.

Advantageously any organic or inorganic pharmaceutically acceptable salt of tiotropium may be used. Organic salts may comprise, for instance, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, methanesulfonate, benzenesulfonate and benzoate, while inorganic salt in include, but are not limited to, fluoride chloride, bromide, iodide, phosphate, nitrate and sulphate. Preferably, an inorganic salt is used selected from the group consisting of fluoride, chloride, bromide, and iodide, preferably chloride or bromide, more preferably bromide.

Preferably, micronisation should take place in the absence of water. The anti-solvent should be hence water immiscible and should contain no dissolved water.

Said anti-solvent should have a dielectric constant lower than 15 and a density of 0.7 to 2 g/cm A person skilled in the art would readily be able to determine the dielectric constant and the density of the anti-solvent, according to known methods. Advantageously, the water immiscible anti-solvent may be a water immiscible hydrocarbon or derivative thereof which is liquid at room temperature and pressure (about 20 °C and about 1 atm). In fact it has been surprisingly found that processing in water miscible anti-solvents previously employed in particle size reduction by high pressure homogenization, for example acetone, ethanol or propan-l-ol, resulted in post micronisation particle agglomeration during drying at low temperatures.

In some embodiments, the anti-solvent is an n-alkane or haloalkane which is liquid at room temperature and pressure. Suitable alkanes range from n-pentane (C5H ) to n- C17H36 which are all liquid at room temperature and pressure. Preferred alkanes include n-pentane, n-hexane, n-heptane, n-octane, n-nonane and n-decane. In some embodiments, the n-alkane may be n-pentane, n-hexane, n-heptane or n-octane. In a particular embodiment, the alkane is n-heptane.

In other embodiments, the anti-solvent is a fluoroalkane or a hydrofluoroalkane. Suitable fluoroalkanes and hydrofluoroalkanes include perfluoropentane, perfluorohexane, perfluoroheptane, perfluorooctane, perfluorononane, perfiuorodecane and any hydrogen substituted derivative thereof such as 2H,3H- decafluoropentane.

In a particularly preferred embodiment of the invention, the anti-solvent is perfiuorodecane or decafluoropentane. According to step (ii), the particles of the tiotropiumsalt are suspended in a water immiscible anti-solvent to give a suspension.

Said particles may be in a coarse particulate form or, alternatively it may have a pre- reduced particle size. Advantageously, said particles shall be nominally crystalline such that the atoms or molecules are arranged in a regular, periodic manner. However, the crystalline drug may contain some amorphous regions. Preferably, the drug should have a crystallinity equal to or higher than 90% or, more preferably, higher than 95%, more preferably higher than 98% as determined according to methods known to the skilled person.

The drug may be suspended in the chosen anti-solvent at a drug/solvent ratio of between about 1:200 w/v and about 200:1 w/v. Preferably, the drug/solvent ratio is between about 1:1 w/v and about 200:1 w/v, more preferably between about 50:1 w/v and about 150:1 w/v. In a preferred embodiment, the drug/solvent ratio may be 100:1 w/v.

This suspension is then treated to reduce the particle size of the drug. Stabilising agents or any other excipients are not added to the suspension as these are not required in order to obtain a stable product.

Therefore, In particular embodiments, a suspension consisting essentially of the tiotropium salt suspended in the water immiscible anti-solvent is micronised. This allows the production of a pure drug product which is free from other substances. Micronising equipment is well known in the art and includes a variety of grinding and milling machinery. For example, suitable milling machinery for use in wet milling using an anti-solvent includes impact mills such as ball mills and planetary mills. Advantageously, the micronising equipment is provided with a rotor or disc operating at a suitable speed.

In a preferred embodiment, the tiotropium salt is wet ball milled using a Fritsch Planetary Mill PULVERISETTE or Lena DM100 micro mill. Other suitablemicronizing apparatus includes horizontal bead mills, for instance DYNO^®- MILL; rotor-stator homogenisers, for instance Polytron, Silverson and Heidolf mixers; and annular gap bead mills, for instance FrymaKoruma Stirrer Bead CoBall^®-Mill, type MS.

In a preferred embodiment, the tiotropium salt is treated in the milling apparatus disclosed in WO 2007/020407 whose content is incorporated herein by reference.

In micronisation, some techniques involve the use of grinding or milling media to help to reduce the particle size of the drug. In the process of the present invention, such media of the same or different size are used and are present in the drug suspension whilst micronisation is taking place.

The grinding media may be selected from grinding or milling beads formed of a material selected from the group consisting of polystyrene, polymethyl methacrylate (PMMA), polyamid, polycarbonate, polyurethane, Soda Lime Glass, steatite, ZirTA- NOR (Zirconia Toughened Alumina), zirconia silicate, zirconia silica, high density zirconia silica, toughened zirconia silica, magnesium stabilized zirconia oxide, cerium stabilized zirconia oxide, Yttrium stabilized zirconia oxide, tungsten carbide, silicon nitride or silicon carbide. In some embodiments, the grinding media are zirconium oxide milling beads. For processing, the diameter of the grinding media particles should be less than 25 mm, more preferably less that 5 mm, ideally less than 2 mm. The micronization step should take place at a pressure of 0-2 corresponds to a pressure of between 0 and 200 kPa.

Some micronisation techniques use high pressure in order to reduce the size of the drug particles. For example, pressures of between 500 bar and 2000 bar are commonly used in homogenisers. Surprisingly, it has been found that it is not necessary to use elevated pressure in the present invention. Preferably, the micronisation of the drug is carried out at a pressure of between 50 kPa and about 200 kPa. More preferably, a pressure of between 50 kPa and 150 kPa is used. Even more preferably, the micronisation of the drug is carried out at a pressure of 80 kPa and 120 kPa.

Suitable conditions for micronising the suspension will vary with the apparatus and the processing anti-solvent. In general, when an apparatus provided with a disc/rotor is used, the speed of the disc/rotor at which the suspension is micronized may be between about 50 and about 500 rpm, preferably between about 100 and about 400 rpm, more preferably between about 150 and about 300 rpm. When the anti-solvent is 2H,3H-decafluoropentane, the disc/rotor speed at which the suspension is treated could be between 100 and 300 rpm. Suitable temperatures for homogenising the suspension will vary with the drug and the anti-solvent concerned. In general, the temperature at which the suspension is homogenised is below the boiling point of the anti-solvent. Advantageously, the micronization step is performed at a temperature comprised between about 0 °C and 40 °C, more advantageously between 5 °C and about 35°C. Preferably, the suspended drug is micronised at a temperature comprised between 10 °C and 30 °C and, more preferably between 10°C and 25 °C.

In a particular embodiment , the micronisation step is carried out at ambient temperature (20 ± 2 °C).

Suitable times for micronizing the suspended drug particles will vary with the anti- solvent and the grinding media concerned. In general, the suspended drug particles are treated for 1 to 300 minutes, preferably 15 to 240 minutes, more preferably 15 to 90 minutes. When the anti-solvent is 2H,3H-decafluoropentane and the grinding media is zirconium oxide balls of a 1 mm diameter, the suspension is treated at a speed of 200 rpm preferably for 30 to 90 minutes, more preferably for 60 minutes.

In some embodiments, a first anti-solvent may be used in the micronisation process and a second anti-solvent may be optionally used to wash the micronised drug particles. In this regard, the process may further comprise a washing step in which a second anti-solvent is used to wash the micronised drug particles. Preferably, the second anti-solvent used in the washing step has a relatively high vapour pressure such that it can be removed during drying at a relatively low temperature (e.g. below 35 °C). In other words, the second anti-solvent should be relatively volatile such that it can be removed during drying at a relatively low temperature (e.g. below 35 °C). Advantageously, the vapour pressure of the second anti-solvent is higher than 5 kPa. More advantageously, the vapour pressure of the second anti-solvent is higher than 10 kPa. Preferably, the vapour pressure of the second anti-solvent is higher than 20 kPa. More preferably, the vapour pressure of the second anti-solvent is higher than 30 kPa. Even more preferably, the vapour pressure of the second anti-solvent is higher than 40 kPa. In certain embodiments, the vapour pressure of the second anti-solvent may be higher than 50 kPa. In other embodiments, the vapour pressure of the second anti- solvent may be higher than 60 kPa, preferably higher than 70 kPa. These vapour pressures are measured at 20 °C at 1 atm according to methods known to the skilled person.

In some embodiments, the second anti-solvent has a boiling point lower than 100 °C. Advantageously, the anti-solvent has a boiling point lower than 90 °C. More advantageously, the second anti-solvent has a boiling point lower than 80 °C. Preferably, the second anti-solvent has a boiling point lower than 70 °C. More preferably, the second anti-solvent has a boiling point lower than 60 °C. Even more preferably, the second anti-solvent has a boiling point lower 50 °C. In certain embodiments, the second anti-solvent has a boiling point lower than 40 °C, preferably lower than 35 °C, more preferably lower than 30 °C.

These boiling points are determined according to methods known to the skilled person Having a relatively high vapour pressure and/or low boiling point allows the drug particles to be dried at a relatively low temperature (e.g. below 35 °C). Particular anti- solvents which are preferred for the washing step are decafluoropentane and pentane. Instead of using a second anti-solvent to wash the micronised drug particles, the first anti-solvent in which the water soluble drug is micronised may have the properties described above for the second anti-solvent. Therefore, in some embodiments, the first anti-solvent may have a relatively high vapour pressure such that it can be removed during drying at a relatively low temperature (e.g. below 35 °C). Preferred vapour pressures are as above for the second anti-solvent. Further, the first anti- solvent may have a relatively low boiling point, for example, below 100 °C. Preferred boiling points are as above for the second anti-solvent.

The process preferably involves a step of drying the micronised drug particles to remove any residual anti-solvent. Preferably, the drug particles are dried under a temperature of less than 40°C, preferably less than 35°C, more preferably less than 30°C, and even more preferably less than 25°C, to remove any residual anti-solvent. This can be achieved using any drying process known in the art such as vacuum drying, spray drying or supercritical fluid drying. Preferably the drug particles are spray-dried or vacuum dried.

The dried drug particles are preferably sieved, for example, through a 100 μιη mesh sieve, to separate any residual grinding media and the resulting fine powder drug material collected.

In particular embodiments, if the antisolvent is suitable for pharmaceutically purposes, the obtained suspension could be used or further processed without the need for drying.

After collection, the obtained particles the tiotropium salt are substantially crystalline. Preferably, said particles should have a crystallinity equal to or higher than 90% or, more preferably, equal to or higher than 95%, more preferably higher than 98% as determined on the whole powder according to methods known to the skilled person. The cohesive/adhesive balance of the resulting formulation produces particles in the range 0.5 to 1.5, with the majority of particles in the range 0.7 to 0.9.

At least 90% of the obtained particles the tiotropium salt should have a diameter of less than 10 micron, advantageously of less than 9 micron, preferably of less than 8 micron, more preferably of less than 7 micron. In a preferred embodiment, no more than 60 % of the obtained particles have a diameter equal to or greater than 6 microns. Preferably the D50 is comprised between 1 and 3.5 microns, more preferably between 1.2 and 3 microns.

In this context, the particle size is determined as volume diameter according to methods known to the skilled person such as laser diffraction based on the use of suitable apparatus such as Malvern or Sympatec apparatus.

In general, drug particles of this size are suitable for administration by inhalation.

In fact particles having a particle size greater than about 10 micron are likely to impact the walls of the throat and generally do not reach the lung.

Advantageously, the micronized drug particles obtainable with the process of the invention could be physically and chemically stable for at least a month at ambient conditions (22 ± 2°C and 60% relative humidity). Preferably, said micronized particles could be stable for at least 6 months at the same ambient conditions. More preferably, said particles could be stable for at least 1 month at 40°C and 75% relative humidity, even more preferably for 6 months.

The physical stability shall be measured by using a Sympatec Dry Dispersion Size Analyser, while the chemical stability shall be determined according to method known to the skilled person such as HPLC.

Alternatively, the physical stability may be measured using the specific surface area of the drug particles analysed by adsorption analysis, BET surface measurement, according to a method known to the skilled person.

In this case, there should not be a significant decrease in specific surface area of the drug particles after 1 month, preferably after 6 months, upon storage at ambient conditions (22± 2°C and 60% relative humidity). Preferably, there could be a decrease of less than 1 m²/g, more preferably less than 0.5 m²/g and even more preferably less than 0.2 m²/g in specific surface area of the drug particles after 1 month, preferably after 6 months upon storage at the same ambient conditions.

Particles of tiotropium bromide that have been obtained in accordance with the process of the present invention have a reduced tendency to agglomerate and thus provide a substantially stable solid bulk drug that facilitates further processing i.e. admixing with propellants or carrier particles, thus providing formulations having a good homogeneity.

Therefore, the present invention also encompasses inhalable pressurized formulation in form of suspension of the aforementioned micronised particles in a pressure- liquefied propellant, preferably a hydrofluoroalkane (HFA) propellant selected from the group of 1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,1,2,3,3,3- heptafluoro -propane (HFA227) and any mixtures thereof.

Furthermore, the present invention encompasses inhalable dry powder formulations comprising the aforementioned micronised particles in admixture with particles of a physiologically acceptable pharmacologically-inert solid carrier, such as lactose, preferably alpha-lactose monohydrate.

Said formulations can be administered by suitable devices such as pressurized metered dose inhalers (pMDIs) or dry powder inhalers (DPIs).

The micronized particles obtainable with the process of the invention may be used for prophylactic purposes or for symptomatic relief for a wide range of conditions including: respiratory disorders such as chronic obstructive pulmonary disease (COPD) and asthma of all types. Other respiratory disorders for which the product of the invention may be beneficial are those characterized by obstruction of the peripheral airways as a result of inflammation and presence of mucus, such as chronic obstructive bronchiolitis, chronic bronchitis, emphysema, acute lung injury (ALI), cystic fibrosis, rhinitis, and adult or respiratory distress syndrome (ARDS).

Claims

1. A process for the preparation of a stable micronised form of tiotropium bromide, the process comprising:

micronising crystalline tiotropium bromide in a water immiscible anti-solvent in the absence of a stabilising agent at a pressure of between 0 and 2 bar to provide tiotropium bromide particles in which no more than 40 % are greater than 6 μηι, preferably no more than 30 % are above 6 microns, more preferably no more than 20 % are above 6 microns.

2. A process according to claim 1, wherein the D50 is between 1-3.5 microns, preferably 1.2-3 μπι.

3. A process according to claim 1 or claim 2, wherein the resulting micronised tiotropium bromide has a Specific Surface Area of 2-5 m² g, preferably 2.5 to 4.5 m^2/g, even more preferably 3-4 m^2/g.

4. A process according to any preceding claim, wherein the cohesive/adhesive balance of the resulting micronised tiotropium bromide is between 1.0 - 2, preferably between 1.0— 1.5, even more preferably between 1- 1.25.

5. A process according to any preceding claim, wherein a suspension consisting essentially of the crystalline water soluble tiotropium bromide, and optionally grinding or milling media, suspended in the water immiscible anti-solvent is micronised.

6. The process according to any preceding claim, wherein the anti-solvent has a dielectric constant of 15 or less.

7. The process according to any preceding claim, wherein the anti-solvent has a density of 1.2 to 2 g/cm³.

8. The process according to any preceding claim, wherein the anti-solvent is an alkane, a cycloalkane or alkane derivative which is liquid at room temperature and pressure.

9. The process according to any preceding claim, wherein the anti-solvent is an alkane, a fluoroalkane or a hydrofluoroalkane which is liquid at room temperature and pressure.

10. The process according to any preceding claim, wherein the anti-solvent is heptane, perfluorodecane or decafluoropentane.

11. The process according to any preceding claim, further comprising a washing step in which a second anti-solvent is used to wash the micronised tiotropium bromide particles.

12. The process according to claim 11, wherein the second anti-solvent has a boiling point below 40°C.

13. The process according to claim 11 or 12, wherein the vapour pressure of the second anti- solvent is more than about 40 kPa.

14. The process according to claim 12 or claim 13, wherein the second anti-solvent is decafluoropentane or pentane.

15. The process according to any preceding claim, further comprising a drying step of drying the micronised tiotropium bromide particles at a temperature of less than 40 °C to remove any residual anti-solvent.

16. The process according to claim 15, wherein the micronised tiotropium bromide particles are dried using vacuum drying.

17. The process according to any preceding claim, wherein the crystalline water soluble tiotropium bromide is micronised in a ball mill, and wherein the anti-solvent contains grinding media.

18. The process according to any preceding claim, wherein the tiotropium bromide is micronised between about 5 °C and about 30 °C.

19. The process according to any preceding claim, wherein the tiotropium bromide is micronised at a disc speed of 200 rpm and for 30 to 90 minutes.

20. The process according to any preceding claim, comprising suspending tiotropium bromide in a water immiscible anti-solvent containing multi-particulate grinding media; micronising the suspension at between about 5 °C and about 30 °C at between 0 and 2 bar using wet bead milling to give tiotropium bromide particles where 100 % are less than about 10 um; and drying the drug particles at less than 35°C under vacuum to remove any residual anti-solvent.

21. A stable micronised crystalline form of tiotropium bromide prepared using the process of any preceding claim.

22. An inhalable dry powder formulation that contains tiotropium bromide that has been prepared using the process according to any one of claims 1 to 20.

23. An inhalable formulation for use in a metered dose inhaler that contains tiotropium bromide suspended in a propellant, wherein the tiotropium bromide has been prepared using the process according to any one of claims 1 to 20.