HK1260031A1 - Preparation of micronized particles of an antimuscarinic compound by hydrodynamic cavitation - Google Patents

Description

Process for the preparation of micronized particles of an antimuscarinic compound by hydrodynamic cavitation

Technical Field

The present invention relates to a process for the preparation of crystalline particles of an antimuscarinic drug by hydrodynamic cavitation. The size of these crystalline particles can be controlled by process parameters and range between 0.5 and 15 microns.

The particles are suitable for the production of pharmaceutical preparations for the prophylaxis and/or treatment of respiratory diseases.

Background

Water-soluble quaternary ammonium compounds known to have antimuscarinic activity tend to agglomerate during storage; this is due to the formation of crystalline bridges between adjacent particles due to absorption of moisture after micronization and subsequent recrystallization of the surface amorphous content resulting from the high energy micronization process. This problem affects in particular the physical stability of the drug and its subsequent performance in the formulation.

Glycopyrronium (Glycopyrronium) is an antimuscarinic drug, commercially available for many years as the bromide salt.

Glycopyrronium bromide has two chiral centers, which correspond to four isomeric forms comprising 2 pairs of diastereomers, namely (3S,2'R) -, (3R,2' S) -, (3R,2'R) -and (3S,2' S) - [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1, 1-dimethylpyrrolidinium bromide. Commercially available glycopyrrolate consists of purified "threo" diastereomers (3R,2'S) and (3S,2' R), and is hereinafter denoted as rac-glycopyrrolate.

However, like other antimuscarinic drugs, glycopyrronium salts have significant stability problems, especially immediately after the conventional micronization process by milling.

In fact, once micronized glycopyrrolate has a strong tendency to aggregate and/or agglomerate, which severely hampers downstream pharmaceutical processing, in particular for the preparation of dry powder formulations capable of delivering a good respirable fraction by inhalation administration.

Various approaches have been proposed to alter certain physicochemical properties of drugs. However, many of these processes involve the use of solvents which tend to cause local solvation processes which in turn lead to particle growth and/or irreversible aggregation and agglomeration during drying or storage.

Furthermore, it is well known that current state-of-the-art high energy physical processing methods such as air jet milling, dry powder ball milling or high pressure homogenization can result in a partial loss of crystallinity of the drug substance. These micronized materials are typically conditioned at high temperatures for extended periods of time after micronization to adjust any process-induced structural disorder and/or amorphous content.

In view of these considerations, it would be highly advantageous to provide a process for preparing glycopyrronium salt crystalline particles that are physically stable, having a narrow particle size suitable for delivery by inhalation.

The method of the present invention solves this problem.

Summary of The Invention

In a first aspect, the present invention relates to a process for the preparation of micronized crystalline particles of a pharmaceutically acceptable salt of glycopyrronium, which process comprises the steps of:

(a) in a first chamber of a controlled flow hydrodynamic cavitation device, a solution stream F comprising a pharmaceutically acceptable salt of glycopyrronium and one or more surfactants dissolved in a solvent selected from the group consisting of 1-butanol, 2-propanol and mixtures thereof with ethanol₁With one or more antisolvents F selected from the group consisting of diethyl ether, n-heptane and methyl tert-butyl ether (MTBE), and mixtures thereof₂Mixing;

(b) treatment of the mixture flow F by means of a partially constricted flow₁And F₂To produce controlled hydrodynamic cavitation, thereby causing nucleation and direct production of nanocrystals of a glycopyrronium salt;

(c) diverting a flow of the mixture into a second chamber of the controlled flow cavitation device and further treating the flow of the mixture for a time equal to or less than 10 milliseconds;

(d) collecting the resulting stream in a receiver containing a mixture of n-heptane and MTBE in a ratio of 10:90v/v to 40:60v/v to allow the nanoparticles to pool;

(e) drying the granules to harden the pooled granules;

(f) removing the surfactant; and

(g) the resulting micronized particles were further dried.

Preferably, the surfactant is selected from lecithin, nonionic surfactants such asAndsugar-based surfactants such as sucrose stearate and sucrose palmitate and mixtures thereof in any proportion.

In a second aspect, the present invention relates to a process for the preparation of a formulation for inhalation comprising the step of mixing micronized particles as described above with one or more propellants or carriers.

In a third aspect, the present invention relates to a pressurized formulation for inhalation comprising micronized particles of a pharmaceutically acceptable salt of glycopyrronium obtained by the claimed process, suspended in a pressurized liquefied propellant.

In a fourth aspect, the present invention relates to a pressurised metered dose inhaler (pMDI) filled with the above formulation.

In a fifth aspect, the present invention relates to a dry powder formulation comprising micronized particles of a pharmaceutically acceptable salt of glycopyrronium obtained by the claimed process and particles of a physiologically acceptable pharmacologically inert solid carrier.

In a sixth aspect, the present invention relates to a dry powder inhaler filled with the formulation described above.

Definition of

The term "controlled flow hydrodynamic cavitation device" refers to any device suitable for producing particles of organic material. Such devices are known in the art. Cavitation is the formation of bubbles and cavities in a liquid stream, caused by localized pressure drops in the liquid stream. Find et al (Journal of Materials Research, vol. 16, No. 12, 12.2001) of a paper entitled "Hydrodynamic cavitation as a tool to control macro-, micro-and nano-Properties of organic Materials" relates to Hydrodynamic cavitation for the production of solid Materials.

The term "micronization" refers to a process of reducing the average diameter of particles of solid material. Generally, the term micronization is used when the particles produced are only a few microns in diameter. Traditional micronization techniques are based on the use of friction to reduce particle size. Such methods include milling and grinding. Particle size reduction may also occur due to collisions and impacts.

The verb "aggregate" means to aggregate or merge together. Freshly micronized drug tends to take the form of a fine powder, which tends to spontaneously agglomerate over time to form aggregates of the drug. These aggregates resemble fine or even coarse powders.

The verb "agglomerate" means the formation of a cluster or cluster of particles, particularly in the presence of moisture. Agglomerates of micronized drug tend to form coarse powders, lumps or even substantially single drug agglomerates upon storage, particularly in the presence of moisture.

The presence of drug agglomerates in the formulation can be detected according to known methods by means of a near infrared spectrophotometer equipped with a microscope.

The term "physically stable" means that there is no evidence of particle growth and/or agglomeration of the drug particles upon storage.

The size of the drug particles and their agglomeration can be determined according to known methods.

One specific apparatus that may be used is a neopataxy dry dispersion particle Size Analyzer (Sympatec dry dispersion Size Analyzer).

The term "chemically stable" refers to a drug which, on storage, meets the requirements of the EMEA guidelines CPMP/QWP/122/02 for the Stability test (Stability Testing of existing active substances and Related Finished Products) for existing active substances and Related Finished Products.

The term "anti-solvent" refers to a liquid that has little or no solvating power for a drug. The solubility of the drug in the anti-solvent, as determined by known methods, should be less than about 1 mg/ml. Preferably, the solubility of the drug should be less than about 100 μ g/ml. More preferably, the solubility of the drug should be less than about 10 μ g/ml.

The term "immiscible with water" means that less than 100ppm, and preferably less than 10ppm, of water can be dissolved in the anti-solvent. The amount of residual water can be determined according to known methods such as the Karl-Fischer (Karl-Fischer) method.

The term "conditioning" refers to exposing a powder to a combination of temperature and relative humidity controlled conditions.

"particle size" is a gaussian distribution of particle diameters.

The particle size can be quantified by measuring the volume diameter by laser diffraction using a suitable known instrument, such as a Malvern (Malvern) or neopatak apparatus.

The Volume Diameter (VD) is related to the Mass Diameter (MD) by the density of the particles (the size independent density of the particles is assumed).

The particle size is expressed in volume diameter and the particle size distribution is expressed in d (v0.5), which corresponds to a diameter of 50% by volume of the particles, and also in d (v0.9) and d (v0.1), which respectively represent values for 90% and 10% of the particles of the sample having a lower volume diameter.

In aerosolization, particle size is expressed as Mass Aerodynamic Diameter (MAD) and particle size distribution is expressed as Mass Median Aerodynamic Diameter (MMAD). MAD represents the ability of particles suspended in an air stream to be transported. MMAD corresponds to a mass aerodynamic diameter of 50 wt% of the particles.

The term "good flow" refers to a formulation that is easy to handle during manufacture and that ensures accurate and reproducible delivery of a therapeutically effective dose.

Flow characteristics can be evaluated by different tests, such as angle of repose, Carr's index, Hausner ratio (Hausner ratio) or flow rate through an orifice.

The term "good homogeneity" refers to a formulation wherein the homogeneity of the distribution of the active ingredient expressed as the Coefficient of Variation (CV), also referred to as the Relative Standard Deviation (RSD), is equal to or less than 5.0% when mixed.

The term "respirable fraction" refers to an index of the percentage of active ingredient particles that will reach the deep lungs of a patient.

The respirable fraction, also called Fine Particle Fraction (FPF), is assessed using a suitable in vitro device such as an anderson multistage Impactor (ACI), a multistage Liquid Impactor (MLSI) or a Next Generation Impactor (NGI), preferably by ACI, according to methods reported in the general pharmacopoeia, in particular the european pharmacopoeia (eur.ph.)7.3, 7 th edition. It is calculated as a percentage between the fine particle mass (previous fine particle dose) and the delivered dose.

The delivered dose is calculated from the cumulative deposition in the device, while the fine particle mass is calculated from the deposition of particles with a diameter <5.0 microns.

Drawings

Fig. 1a and 1 b-are a front view (left side) and a perspective view (right side), respectively, of a hydrodynamic cavitation device.

Fig. 2-a cross-sectional view of the hydrodynamic cavitation device taken in longitudinal section.

Figure 3-SEM photograph of rac-glycopyrrolate particles at different magnifications.

Detailed Description

The present invention relates to a process for preparing micronized crystalline particles of a pharmaceutically acceptable salt of glycopyrronium by controlling hydrodynamic cavitation to achieve nucleation in the crystallization step.

It has been found that by operating according to the conditions disclosed below, a physically stable crystalline powder of a pharmaceutically acceptable salt of glycopyrronium can be obtained, having particles of narrow size suitable for inhalation.

In particular, it has been found that the drug particles obtained by the process of the present invention are stable, and therefore they are resistant to aggregation and/or agglomeration. In other words, the tendency of the resulting dry micronized material to aggregate and/or agglomerate after processing is minimized or completely avoided.

The drug particles also exhibit better flowability than conventional jet milled micronized materials.

Advantageously, any organic or inorganic pharmaceutically acceptable salt of glycopyrronium can be used. Organic salts may include, for example, formates, acetates, trifluoroacetates, propionates, butyrates, lactates, citrates, tartrates, malates, maleates, succinates, methanesulfonates, benzenesulfonates and benzoates, while inorganic salts may include, but are not limited to, fluorides, chlorides, bromides, iodides, phosphates, nitrates and sulfates.

Preferably, an inorganic salt selected from fluoride, chloride, bromide and iodide is used, preferably chloride or bromide, even more preferably bromide.

Glycopyrronium can be used in the form of any pure enantiomer or diastereomer or any combination thereof.

Preference is given to using (3S,2'R), (3R,2' S) -3- [ (cyclopentylhydroxyphenylacetyl) oxy ] -1, 1-dimethylpyrrolidinium bromide racemic mixture, which is also known as rac-glycopyrrolate.

FIG. 1 illustrates a hydrodynamic cavitation device suitable for use in practicing the method of the present invention. Fig. 2 illustrates a cross section thereof.

The apparatus of FIG. 1 comprises a first chamber 1 and four chambers for introducing a fluid stream F₁An inlet leading into said chamber and a first outlet 7' for delivering fluid into the second chamber 6.

The second chamber 6 comprises two inner mixing zones 8, 9 (fig. 2) and a second outlet 7 for discharging fluid.

Further details of this device are disclosed in co-pending U.S. patent application serial No. 14/216,188, the teachings of which are incorporated herein by reference in their entirety.

Although it is preferred that the cross-section of the first chamber 1 is rectangular and the cross-section of the second chamber 6 is cylindrical, the two chambers may have any geometrical shape, for example square or hexagonal, without departing from the scope of the invention.

A cavitation generator, such as an orifice, is disposed within the first chamber 1 along or near the centerline.

The orifices are positioned so that all flows converge on a single point. Instead of discs with orifices, crossheads, rear propellers or any other fixing means producing minimal pressure losses may be used.

The orifice is configured to generate a hydrodynamic cavitation field downstream of the baffle by localized fluid flow constriction. In this embodiment, the orifice is a hole drilled in the disk.

Although the local constriction is an annular orifice, the skilled person will appreciate that the local constriction defined between the walls forming the flow-through channel and the baffle may not be annular if the cross-section of the flow-through channel has any other geometry than circular.

Also, if the cross-section of the hole is not circular, the local constriction may not be annular. Preferably, the cross-sectional geometry of the first chamber matches the cross-sectional geometry of the baffle (e.g., circular-circular, square-square, etc.).

To further facilitate the generation and control of cavitation fields downstream of the orifice, the orifice is configured to be removable and replaceable with any orifice having various shapes and configurations to generate different controlled flow dynamic cavitation fields. The shape and configuration of the orifice can significantly affect the characteristics of the cavitation flow and, correspondingly, the quality of the crystallization.

While there are an unlimited variety of shapes and configurations that may be used within the scope of the present invention, several acceptable baffle shapes and configurations are disclosed in U.S. patent 7,314,516, the teachings of which are incorporated herein by reference in their entirety.

It should be understood that the orifice may be removably secured to the stem in any acceptable manner.

In operation of the device shown in fig. 1, a first fluid stream F consisting of a solution comprising a pharmaceutically acceptable salt of glycopyrronium dissolved in a suitable solvent and one or more surfactants₁Enters the first chamber 1 via the inlet 2 and moves through the orifices in the disc in the direction of the convergence point. Second fluid stream F consisting of a suitable anti-solvent₂Enters the first chamber 1 via one or more inlets 3, 4 and 5 and is brought into contact with the first fluid stream F at a convergence point (crystallization zone, 10)₁And (4) mixing.

The above indications of the inlets to be used are merely exemplary as they are replaceable.

Advantageously, the total flow of anti-solvent is in any ratio through the three inlets 3, 4 and 5, respectively.

Preferably, the total flow of anti-solvent is through the three inlets 3, 4 and 5 in a ratio of 40%: 30%, respectively.

According to the knowledge of the skilled person, the pressure, temperature and flow rate should be varied along the four inlets.

Advantageously, the temperature of all inlets is maintained at room temperature. More advantageously, the pressure at inlet 1 is maintained at 400-.

In a preferred embodiment, the flow rate of the glycopyrronium solution is maintained at 10-15%, more preferably 12% of the total flow rate of the anti-solvent.

Mixed first and second streamsBody flow i.e. F₁And F₂Then contracted by local flow, wherein the first and second fluid streams (i.e., F)₁And F₂) Is increased to a minimum velocity (i.e., the velocity at which cavitation bubbles begin to appear) by the first and second fluid streams, i.e., F₁And F₂Is determined by the physical properties of (a). When the first and second fluid streams are F₁And F₂Upon local flow constriction, a hydrodynamic cavitation field (which produces cavitation bubbles) is formed downstream of the baffle.

The fluid containing the tiny crystals leaves the first chamber 1 through outlet 7' and enters the second chamber 6 with two additional mixing zones 8, 9 to allow for longer residence time and allow for additional mixing of the solvent and anti-solvent.

Advantageously, the fluid containing the tiny crystals is retained in the second mixing chamber for a time of 1 to 5 milliseconds, preferably 2-3 milliseconds.

The permanence of the flow in the first chamber and in the mixing zone of the second chamber should be adjusted by the person skilled in the art according to his knowledge and according to the desired particle size.

The two fluids used in the process have different solvent compositions, one being a solution of the compound to be processed in a suitable solvent or solvent combination ("feed solution") and the other being a suitable solvent or solvent combination ("antisolvent") capable of inducing precipitation of the compound from solution, which is selected by relatively low solvation properties with respect to the compound.

Advantageously, the solvent is selected from 1-butanol, 2-propanol and mixtures thereof with ethanol in any ratio. The preferred solvent is 2-propanol.

The solvent used in the process of the present invention also comprises a suitable surfactant that mitigates agglomeration that may occur during hydrodynamic cavitation crystallization and allows for spontaneous pooling of the surfactant of particles having a target particle size.

Advantageously, the amount of surfactant relative to the glycopyrronium salt is present in a weight ratio of from 70:30 to 30:70, preferably from 65:35 to 55:45w/w, more preferably 62:38 w/w.

The surfactant may be selected from lecithin from any source, such as soya, non-ionic surfactants such as tween (tween) and span (spans), sugar-based surfactants such as sucrose stearate and sucrose palmitate, and mixtures thereof in any proportion.

Preferably a mixture of lecithin and span 60 is used, preferably in a ratio of 50:50 w/w.

In another preferred embodiment, lecithin alone may be used.

In another preferred embodiment, a mixture of soy lecithin, sorbitan monostearate (span) 60 and sucrose stearate may be used, more preferably in a ratio of 47:47:6 w/w/w.

Advantageously, the anti-solvent is selected from diethyl ether, n-heptane and methyl tert-butyl ether (MTBE) and mixtures thereof in any proportion.

Advantageously, the anti-solvent is a mixture of n-heptane and MTBE in any ratio ranging from 20:80v/v to 30:70v/v, even more preferably in a ratio of 25:75 v/v.

In a specific embodiment, MTBE alone may be used.

Typically, the stream of the mixture leaving the second chamber 6 from the outlet 7 contains particles of a glycopyrronium salt, said particles having a particle size of equal to or less than 100nm, preferably between 50 and 70 nm.

The fluid stream is collected in a suitable receiver, such as a stirred stainless steel tank with temperature control, comprising a mixture of n-heptane and MTBE in a ratio of from 10:90v/v to 40:60v/v, preferably from 20:80v/v to 30:70v/v, more preferably in a ratio of 25:75 v/v.

The particles are mixed in the receptacle for a short period of time, typically less than 30 minutes, preferably less than 15 minutes.

Generally, one skilled in the art will adjust the mixing time to achieve the desired micron particle size.

The product is isolated and harvested using conventional recovery techniques.

For example, the preferred surfactants described above are soluble in n-heptane.

Thus, in a preferred embodiment of the invention, the fluid containing the glycopyrronium salt particles is first filtered; the collected particles are then dried and resuspended in n-heptane, mixed, for example for 1 hour, filtered again, washed a second time with n-heptane and finally dried in vacuo, for example at 50 ℃.

Advantageously, the total amount of surfactant in the final product is less than 5% w/w, more advantageously less than 1%, preferably equal to or less than 0.1%, even more preferably equal to or less than 0.01% w/w.

Advantageously, the collected glycopyrronium salt particles should 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 substance should have a crystallinity of equal to or higher than 90%, or more preferably higher than 95%, more preferably higher than 98%, as determined according to known methods.

All resulting glycopyrronium salt particles should have a volume diameter of between 0.5 and 15 microns.

Advantageously, at least 90% of the resulting particles d (v0.9) should have a diameter of less than 10 microns, preferably less than 8 microns, more preferably less than 7 microns. Advantageously, d (v0.5) is from 1 to 5 microns, more advantageously from 1.5 to 4 microns, preferably from 2 to 3 microns. More preferably, no more than 10% of all glycopyrronium particles have a diameter of less than 0.6 micrometer, even more preferably equal to or less than 0.8 micrometer.

In the present context, the particle size is determined as volume diameter according to known methods, for example based on laser diffraction using suitable devices such as Mastersizer devices (Malvern Instruments Ltd, Worcestershire, UK) or dry dispersion particle size analyzers (newpatau Ltd, claus tall-deller feld, germany).

Typically, drug particles of this size are suitable for administration by inhalation. In fact, particles having a particle size greater than about 10 microns may strike the walls of the throat and generally do not reach the lungs.

Advantageously, the micronized crystalline drug particles obtained with the process of the present invention may be physically and chemically stable for at least one month at ambient conditions (22 ± 2 ℃ and 60% relative humidity). Preferably, the micronized particles are stable for at least 3 months under the same environmental conditions.

Physical stability should be determined using a neopataxyl dry dispersion particle size analyzer, while chemical stability should be determined according to known methods such as HPLC.

Alternatively, the physical stability can be determined using the specific surface area of the drug particles analyzed by adsorption analysis, BET surface measurement according to methods known in the art.

Optionally, in order to further reduce the tendency of the glycopyrronium salt to aggregate and/or agglomerate during storage, the conditioning step may be carried out on the particles obtained with the process of the invention according to the conditions reported in EP2234595, the teachings of which are incorporated by reference in their entirety, but in a shorter time (less than one hour).

Alternatively, the particles may be conditioned by charging them into a rotating drum with a wet conditioning gas. The particles are then suspended in the moving conditioning chamber for a short period of time, for example 1-30 minutes. The rotating tube allows the particles to be kept a sufficient distance so that they do not agglomerate during the conditioning step. This method of regulation is significantly faster than typical environmental regulations, which may take days or weeks.

The glycopyrronium salt particles obtained according to the process of the invention can be mixed with propellant or carrier particles to provide formulations with good homogeneity.

The invention therefore also includes formulations suitable for administration by inhalation comprising glycopyrronium particles obtainable by the method of the invention in combination with one or more medicaments useful in the treatment of respiratory diseases, for example,

short and long acting β₂Agonists such as terbutaline, salmeterol, formoterol, miloterol, indacaterol, oloterol and fenoterol, corticosteroids such as rofleponide, flunisolide, budesonide, ciclesonide, mometasone and its esters, i.e. furoate, fluticasone and its esters, i.e. propionate and furoate.

In particular, in one embodiment, the invention comprises an inhalable pressurized formulation in the form of a suspension of the above-described micronized particles in a pressurized liquefied propellant, preferably a Hydrofluoroalkane (HFA) propellant selected from the group consisting of 1,1,1, 2-tetrafluoroethane (HFA134a), 1,1,1,2,3,3, 3-heptafluoropropane (HFA227), and any mixtures thereof.

In another embodiment, the present invention comprises an inhalable dry powder formulation comprising a mixture of micronized particles as described above with physiologically acceptable pharmacologically inert solid carrier particles, such as lactose, preferably α -lactose monohydrate and optionally other additives such as magnesium stearate.

The formulations may be administered by a suitable device, for example a pressurised metered dose inhaler (pMDI) or a Dry Powder Inhaler (DPI).

The micronized particles obtainable by the process of the present invention may be used for prophylactic purposes or for symptomatic relief of a variety of conditions including: respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and all types of asthma. Other respiratory diseases where the product of the invention may be beneficial are characterised by obstruction of the peripheral airways due to inflammation and the 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).

In addition, the particles are useful for treating smooth muscle disorders, such as urinary incontinence and irritable bowel syndrome; skin diseases such as psoriasis; hyperhidrosis and gastrointestinal ulcers.

The present invention is further illustrated in detail by the following examples.

Examples

EXAMPLE 1 preparation of micronized powder of rac-glycopyrrolate

The method is carried out using the apparatus of figure 1.

A mixture of 6 g of rac-glycopyrrolate and 9.75 g of soya lecithin span 60 sucrose stearate 47:47:6w/w/w was dissolved in 400ml of 2-propanol (solution A). The resulting solution a enters the first chamber 1 through inlet 2 and is maintained at a temperature of 50 c and a pressure of 500 psi.

The anti-solvent n-heptane enters the same chamber 1 from inlets 3, 4 and 5 and the total flow rate maintained at 25 c and 5000psi pressure is divided into about 40%: 30%: 30% passing through the three inlets.

The flow rate of solution a was maintained at about 12% of the total flow of anti-solvent.

The glycopyrronium solution and the anti-solvent are then passed through an orifice to cause hydrodynamic cavitation to effect nucleation. The pressure was maintained at 5000 psi.

The 4 streams were mixed at a convergence point where controlled flow hydrodynamic cavitation caused nucleation. The mixture stream then exits chamber 1 through outlet 7' and enters second chamber 6, maintained at 5000psi pressure, through 2 additional mixing zones for a2 millisecond period. The stream leaves the second chamber 6 through outlet 7 and is collected in a receiver containing heptane/MTBE in a 25%/75% v/v ratio. The receiver was maintained at a constant ratio of heptane MTBE with a metering pump. The mixture was allowed to mix in the receiver for about 5 minutes.

The resulting particles were filtered off using a Millipore pressure filter. They were then dried in vacuo, resuspended in n-heptane at 60 ℃, mixed for 1 hour, and filtered again. The washing procedure was repeated three times.

The amount of residual surfactant showed less than 4% w/w.

The resulting material was then tested as reported in example 2.

EXAMPLE 2 analysis of the rac-glycopyrrolate powder material of example 1

The morphology, drug content, crystallinity, density, hygroscopicity and particle size of the microparticles obtained in example 1 were characterized.

The morphology of the microparticles was measured by Scanning Electron Microscopy (SEM) using a JSM-6480LV instrument (JEOL Ltd, Tokyo, Japan). Examination revealed unusual morphology in the petal arrangement (see fig. 3).

Drug content was determined by UPLC-PDA assay. No degradation/impurity peaks above the detection limit of the analytical method were detected at the time of release and/or after 3 months.

Crystallinity was determined by Differential Scanning Calorimetry (DSC) using a Q2000 apparatus (TA Instruments, n.cassel, te. The temperature is 10 ℃ min^-1The temperature was raised to 250 ℃. The sample showed a clear sharp melting at 191.5 ℃ followed by the onset of degradation. No glass transition was observed due to the highly crystalline nature of the sample. This result was confirmed by powder XRD diffraction.

Water absorption was determined by Dynamic Vapor Sorption (DVS) using a Q5000SA apparatus (TA instruments, n.y., tlahua, USA). The adsorption cycle was determined by a direct (relatively modest) ramp from 10% r.h to 90% r.h., with an initial equilibration time of 60 minutes at 0% r.h.

This behavior is typical of crystalline materials, which have a low hygroscopicity of less than 2.5%.

The density of the powder was measured by helium gas assay (helium picometer) using an AccPyc II 1340 instrument (Micromeritics, milan, italy). The average value calculated from three replicate measurements was 1.3917g/cm³。

Particle size was determined by laser diffraction using a neopataku dry dispersion particle size analyzer (claustol-willerfield, germany).

The powder was dispersed for both assay conditions at 1 and 4 bar air pressure.

The average d [ v,10], d [ v,50], d [ v,90] values were calculated from three replicate measurements. The span (span) is calculated using the following equation:

span ═ d (v,0.9) -d (v,0.1) ]/d (v,0.5)

The values obtained for the particle sizes reported in table 1 are not significantly affected by the dispersion pressure, indicating a free-flowing powder without hard agglomerates.

TABLE 1

No significant increase in particle size was observed upon storage at ambient conditions (22 ± 2 ℃ and 60% relative humidity) for at least 3 months.

Example 3 preparation of a Dry powder formulation wherein the active ingredient is rac-glycopyrrolate

α -lactose monohydrate SpheroLac 100(Meggle) and magnesium stearate monohydrate were co-milled in a jet mill unit in a ratio of 98: 2% by weight (hereinafter referred to as premix), this premix was then mixed with α -lactose monohydrate Capsulac (212-.

The formulations were evaluated for satisfactory bulk powder content uniformity (RSD of 1.1%).

Loading a quantity of inhalation powder into a multi-dose dry powder inhaler(ChiesiFarmaceutici SpA, Italy).

Aerodynamic assessment of particle size distribution was obtained by using the Next Generation Impactor (NGI) according to the method detailed in the european pharmacopoeia (european pharmacopoeia 7 th edition: 278-82). The following parameters were calculated: i) a Delivered Dose (DD), which is the amount of drug delivered from the device recovered in all parts of the impactor; ii) a Fine Particle Mass (FPM), which is the amount of delivered dose having a particle size equal to or less than 5.0 microns; iii) Fine Particle Fraction (FPF), which is the ratio of fine particle mass to delivered dose; iv) MMAD ± GSD; and v) ultra-fine FPF, which is the percentage of fine particulate matter having a particle size equal to or less than 1.0 micron. The results (average, n ═ 6) are reported in table 2.

TABLE 2

Showing good delivered dose, indicating no significant retention in the DPI device. The fine particle fraction is also satisfactory.

Claims (11)

1. A process for the preparation of micronized particles of a pharmaceutically acceptable salt of glycopyrronium, the process comprising the steps of:

(a) in a first chamber of a controlled flow hydrodynamic cavitation device, a solution stream F comprising a pharmaceutically acceptable salt of glycopyrronium and one or more surfactants dissolved in a solvent selected from the group consisting of 1-butanol, 2-propanol and mixtures thereof with ethanol₁With one or more antisolvents F selected from the group consisting of diethyl ether, n-heptane and methyl tert-butyl ether (MTBE), and mixtures thereof₂Mixing;

(b) treatment of the mixture flow F by means of a partially constricted flow₁And F₂To produce controlled hydrodynamic cavitation, thereby causing nucleation and direct production of nanocrystals of a glycopyrronium salt;

(c) the mixture flow F₁And F₂Transferring to a second chamber of the controlled flow cavitation device and further processing the flow of the mixture for a time of less than 10 milliseconds;

(d) collecting the resulting stream in a receiver containing a mixture of n-heptane and MTBE in a ratio of 10:90v/v to 40:60v/v such that the nanoparticles are pooled;

(e) drying the granules to harden the pooled granules;

(f) removing the surfactant; and

(g) the resulting micronized particles were further dried.

2. The method of claim 1, wherein the pharmaceutically acceptable salt of glycopyrronium is a bromide salt.

3. The method according to claim 1 or 2, wherein the surfactant is selected from lecithin, non-ionic surfactants such as tween and span, and sugar-based surfactants such as sucrose stearate and sucrose palmitate, and mixtures thereof in any proportion.

4. The method of any one of claims 1-3, wherein the solvent is 2-propanol (propanool).

5. The process of any one of claims 1-4, wherein the anti-solvent is n-heptane.

6. The method of any one of claims 1-5, wherein the surfactant is a mixture of soy lecithin, sorbitan monostearate (span) 60, and sucrose stearate.

7. A process for the preparation of a formulation for inhalation comprising the step of mixing micronized particles according to claims 1 to 6 with one or more propellants or carriers.

8. A pressurized formulation for inhalation comprising micronized particles of a pharmaceutically acceptable salt of glycopyrronium suspended in a pressurized liquefied propellant obtained according to the process of any of claims 1 to 6.

9. A pressurized metered dose inhaler (pMDI) filled with the formulation of claim 8.

10. A dry powder formulation comprising a mixture of micronized particles of a pharmaceutically acceptable salt of glycopyrronium obtained according to the process of any of claims 1 to 6 and physiologically acceptable, pharmacologically inert solid carrier particles.

11. A dry powder inhaler filled with the formulation of claim 10.